WO2026002995A1

WO2026002995A1 - Target-specific fap-activated topoisomerase inhibitor conjugates and uses thereof

Info

Publication number: WO2026002995A1
Application number: PCT/EP2025/067754
Authority: WO
Inventors: Francis Wilson; Ellen WATTS; Thomas CLOUGH; David Jones; Graham Robert Pye-Smith SPENCE; Victoria JUSKAITE; Manuel Pinto; Douglas SAMMON; Ruairidh EDWARDS; Hanna BUIST
Original assignee: Avacta Life Sciences Ltd
Current assignee: Avacta Life Sciences Ltd
Priority date: 2024-06-24
Filing date: 2025-06-24
Publication date: 2026-01-02
Anticipated expiration: 2026-12-24

Abstract

Provided herein are compounds, including compounds of Formula (I') and (I), and pharmaceutically acceptable salts thereof, and constructs, including constructs of Formula (II') and (II), and pharmaceutically acceptable salts thereof, which comprise a fibroblast activating protein (FAP)-cleavable moiety and are capable of delivering a camptothecin to FAP-expressing tissues (e.g., cancers). Also provided herein are pharmaceutical compositions and kits comprising the same, as well as methods of using the same.

Description

TARGET-SPECIFIC FAP-ACTIVATED TOPOISOMERASE INHIBITOR CONJUGATES AND USES THEREOF R^ELATED A^PPLICATION [1] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. provisional application number 63/663,365, filed June 24, 2024, U.S. provisional application number 63/663,428, filed June 24, 2024, U.S. provisional application number 63/703,540, filed October 4, 2024, U.S. provisional application number 63/703,553, filed October 4, 2024, U.S. provisional application number 63/711,307, filed October 24, 2024, U.S. provisional application number 63/794,203, filed April 25, 2025, U.S. provisional application number 63/824,653, filed June 16, 2025, each of which is incorporated by reference herein in its entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [2] The content of the electronic sequence listing (A122470043WO00-SEQ-HJD.xml; Size: 565,339 bytes; and Date of Creation: June 23, 2025) is herein incorporated by reference in its entirety. BACKGROUND [3] Prodrugs that can be specifically activated within the tumor microenvironment offer a powerful approach to cancer therapy by providing enhanced selectivity and reducing off-target effects. These prodrugs remain inert in the body until they encounter the unique physiological conditions of the tumor, such as acidic pH, high enzymatic activity, or specific reductive environments. This targeted activation ensures that the therapeutic agent is released directly at the tumor site, minimizing damage to healthy tissues and reducing systemic toxicity. Moreover, tumor-specific activation can improve drug efficacy, as the active form of the drug is concentrated where it is most needed, potentially allowing for higher doses to be used safely. This strategy enhances treatment precision and can overcome some of the challenges associated with traditional chemotherapy. SUMMARY [4] Provided herein are compounds and constructs comprising a fibroblast activating protein (FAP)- cleavable moiety that are capable of delivering a camptothecin to FAP-expressing tissues (e.g., cancers). Also provided herein are pharmaceutical compositions comprising the constructs provided herein, and kits comprising the same.

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[5] In one aspect, provided herein are compounds of Formula (I′): and pharmaceutically acceptable salts thereof, wherein R′, L¹, X, R^2A, R^3A, n, R², R³, R⁴, m, L², and CAM are as described herein. [6] In another aspect, provided herein are compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein R^A, L^A, L¹, X, R^2A, R^3A, n, R², R³, R⁴, m, L², and CAM are as described herein. [7] In certain embodiments, for example, a compound described herein (e.g., a compound of Formula (I′) or (I)) is selected from those recited in Table 4 (infra), and pharmaceutically acceptable salts thereof. [8] In one aspect, provided herein are constructs of Formula (II′): and pharmaceutically acceptable salts thereof, wherein R′′, L¹, X, R^2A, R^3A, n, R², R³, R⁴, m, L², and CAM are as described herein. [9] In another aspect, provided herein are constructs of Formula (II): , and pharmaceutically acceptable salts thereof, wherein Z, R^B, L^A, L¹, X, R^2A, R^3A, n, R², R³, R⁴, m, L², and CAM are as described herein. [10] In certain embodiments, for example, a construct described herein (e.g., a construct of Formula (II′) or (II)) is selected from those recited in Table 5A (infra), and pharmaceutically acceptable salts thereof. [11] In another aspect, provided herein are compounds selected from those recited in Table 5B (infra), and pharmaceutically acceptable salts thereof. [12] In another aspect, provided herein are pharmaceutical compositions comprising a construct described herein (e.g., a construct of Formula (II′) or (II)) or a pharmaceutically acceptable salt thereof,

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and a pharmaceutically acceptable carrier. In certain embodiments, a pharmaceutical composition provided herein comprises an effective amount (e.g., therapeutically effective amount) of a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof. [13] As described herein, constructs and pharmaceutical compositions provided herein can deliver a camptothecin to FAP-expressing tissues (e.g., cancers) and are therefore useful for treating diseases characterized by fibroblast activation protein upregulation in a subject. [14] In other aspects, provided herein are methods and uses of the constructs and pharmaceutical compositions provided herein, including, but not limited to, the following: (a) Methods of treating a disease characterized by fibroblast activation protein upregulation (e.g., cancer, fibrosis, or inflammation) in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct described herein (e.g., a construct of Formula(II′) or (II)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. (b) Methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. (c) Methods of administering to a subject a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. [15] In another aspect, provided herein are constructs (e.g., of Formula (II′) or (II)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in any of the methods provided herein. [16] In another aspect, provided herein are uses of constructs (e.g., of Formula (II′) or (II)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, as medicaments and/or in the preparation of medicaments. [17] The details of certain embodiments of the disclosure are set forth in the Detailed Description, as described below. Other embodiments of the disclosure will be apparent from the Drawings, Definitions, Examples, Abstract, and Claims. B^RIEF D^{ESCRIPTION OF THE} D^RAWINGS [18] Non-limiting embodiments of the present disclosure will be described by way of example with reference to the accompanying figures, which are schematic and are not intended to be drawn to scale. In the figures, each identical or nearly identical component illustrated is typically represented by a single numeral. For purposes of clarity, not every component is labeled in every figure, nor is every component of each embodiment of the disclosure shown where illustration is not necessary to allow those of ordinary skill in the art to understand the disclosure. In the figures:

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[19] FIG.1 shows size-exclusion chromatography (SEC) profiles of purified Affimer® conjugates containing either linker-payload 2 (LP2) or 1 (LP1) (see Table 13), as indicated. The SEC profiles of the unconjugated Affimer® precursor (bottom peak) are also shown for FAP-2-TEV-CTCys-LP2 and FAP- 2-FAP-1-H-CTCys-LP2. [20] FIG.2 shows liquid chromatograph-mass spectrometry (LC-MS) analysis for purified Affimer® conjugates. For the LP2 conjugates, the spectra of the unconjugated Affimer® precursor are also shown, with the corresponding shift in mass indicated. All Affimer® conjugates display the expected mass for DAR=1. [21] FIG.3 shows single-cycle kinetics SPR analysis of the binding of single-domain Affimer® conjugates to human FAPalpha. The KD affinities are shown in the embedded table, showing equivalent FAP-binding affinities to the parent Affimer® protein. [22] FIG.4 shows single-cycle kinetics SPR analysis of the binding of two-domain Affimer® conjugates to human FAPalpha. The KD affinities are shown in the embedded table, showing equivalent FAP-binding affinities to the parent Affimer® protein. [23] FIG.5 shows cellular cytotoxicity assays using HEK293T cells (FAP-negative) or cells overexpressing FAP (HEK-FAP). Cells were incubated with the different LP2 Affimer® conjugates or unconjugated linker-payload, either alone or in the presence of hFAP or FAPi, as indicated, for 4 days in the presence of FBS substitute Panexin (which contains low levels of FAP). The warhead was also included as a positive control. The antiproliferative/cytotoxic effect of the compounds was measured as % inhibition relative to vehicle control. [24] FIG.6 shows cellular cytotoxicity assays using HEK293T cells (FAP-negative) or cells overexpressing FAP (HEK-FAP). Cells were incubated with the different LP1 Affimer® conjugates or unconjugated linker-payload, either alone or in the presence of hFAP or FAPi, as indicated, for 4 days in the presence of FBS substitute Panexin (which contains low levels of FAP). The warhead was also included as a positive control. The antiproliferative/cytotoxic effect of the compounds was measured as % inhibition relative to vehicle control. [25] FIG.7 shows co-culture assays using LS174T-GFP colorectal adenocarcinoma cells (FAP- negative) in the presence (co-culture) or absence (mono-culture) of human colonic fibroblast (HCoF) cells. Cells were incubated with the different LP2 Affimer® conjugates, either alone or in the presence of hFAP or FAPi, as indicated, for 4 days in the presence of FBS substitute Panexin (which contains low levels of FAP). The warhead was also included as a positive control. The antiproliferative/cytotoxic effect of the compounds was measured as % GFP positive cells using Incucyte. [26] FIG.8 shows co-culture assay using MiaPaCa2-GFP pancreatic cancer cells (FAP-negative) in the presence (co-culture) or absence (mono-culture) of human pancreatic stellate (hPSC) stromal cells. Cells were incubated with 10nM Affimer® conjugates (FAP-2-FAP-1-H-L3Cys-LP2 or 2FAP-2-FAP-1- H-L3Cys-LP1) for 5 days in the presence of FBS substitute Panexin (which contains low levels of FAP). The warhead was also included as a positive control. The antiproliferative/cytotoxic effect of the compounds was measured as % GFP positive cells using Incucyte.

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[27] FIG.9 shows size-exclusion chromatography (SEC) profiles of Affimer® constructs conjugated to 5 kDa PEG within Loop3, Loop7, the N-terminus, and/or the C-terminus. The unconjugated parent proteins are also shown at the bottom of the figures. Single-domain FAP-2 (left figure) and two-domain FAP-2-FAP-1-H (right figure) exemplars are shown. A key to the right of each figure shows the location of the PEG conjugation sites: L3 – loop3, L7 – loop7, CT – C-terminus, NT – N-terminus.1x, 2x, and 3xPEG conjugated species are shown. [28] FIG.10 shows single-cycle kinetics SPR analysis of the binding of two-domain Affimer® PEG conjugates (1x, 2x, or 3x PEG conjugates) to human FAPalpha. The similar kinetic profiles demonstrate equivalent FAP-binding to the parent Affimer® protein. [29] FIG.11 shows single-cycle kinetics SPR analysis of the binding of single-domain Affimer® PEG conjugates (1x or 2x PEG conjugates) to human FAPalpha. The similar kinetic profiles demonstrate equivalent FAP-binding to the parent Affimer® protein. [30] FIG.12A shows the internalization of FAP-binding AFFIMER® proteins and monoclonal antibodies as measured by the percent downregulation of cell surface AFFIMER® protein. Internalizing monoclonal antibodies (three right-hand bars) were used as positive internalizing controls. [31] FIG.12B shows the internalization of FAP-binding AFFIMER® proteins in FAP-expressing cells as measured by area under the curve (AUC) over 24 hours. Dye-conjugated Sibrotuzumab antibody and human IgG1 were used as negative and positive controls, respectively. [32] FIG.12C shows the percent inhibition of FAP enzyme activity from a panel of 17 FAP-binding AFFIMER® proteins. FAP activity was measured by its ability to cleave 3144-AMC to produce fluorescent AMC. The FAP inhibitor SP-13786 (FAPi) was used as a control. [33] FIG.12D shows AFFIMER® protein stability under stress temperature conditions. FAP-2 single- domain (left) and FAP-2-FAP-1 two-domain (right) AFFIMER® proteins were incubated at 4°C, 37°C, or 45°C for 1 week. Protein aggregation in the samples was assessed by SEC. SEC profiles for the stressed samples are shown with the percent purity for the monomeric species indicated. [34] FIG.13 shows that FAP expression correlates with SLFN11 expression across multiple tumor types. Scatter plots show the relationship between FAP and SLFN11 mRNA expression (log2(TPM+1)) in small cell lung cancer, pancreatic cancer, cervical cancer and gastric cancer. Each dot represents a tumor sample. Light grey (far left) indicates FAP negative patients, dark gray (bottom) indicates FAP positive, low SLFN11 expressing patients, and medium gray (top right) indicates FAP positive high SLFN11 patients. Linear regression analysis with correlation coefficients (R) and p-values are overlaid. [35] FIG.14 shows size-exclusion chromatography (SEC) profiles of anti-CEACAM5 conjugates containing different linker payloads (LP2, LP3, LP4 and LP10) following incubation of antibody conjugates at 37, or 45°C for 1 week at 1mg/ml or at baseline (time 0). Table shows the percent aggregate increase at 37 and 45°C compared to time 0, and corresponds to the % of protein present in the SEC profile which is of a higher order than the monomeric peak.

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[36] FIG.15 shows binding of anti-EDB-F, anti-LRRC15 and anti-CEACAM5 antibody conjugates containing different linker payloads to target expressing cells, determined by flow cytometry. The respective naked antibodies are also shown. [37] FIG.16 shows cytotoxicity in FAP-negative (HEK293T) and FAP-overexpressing (HEK293T- FAP) cells after 4-day incubation with LP2 antibody conjugates or unconjugated linker-payload, with or without recombinant FAP or FAP inhibitor, in FBS substitute Panexin-containing medium (which contains low levels of FAP). Warhead was included as a positive control. Cytotoxicity was measured as % inhibition relative to vehicle control. [38] FIG.17 shows cytotoxicity in FAP-negative (HEK293T) and FAP-overexpressing (HEK293T- FAP) cells after 4-day incubation with LP3 antibody conjugates or unconjugated linker-payload, with or without recombinant FAP or FAP inhibitor, in FBS substitute Panexin-containing medium (which contains low levels of FAP). Warhead was included as a positive control. Cytotoxicity was measured as % inhibition relative to vehicle control. [39] FIG.18 shows cytotoxicity in FAP-negative (HEK293T) and FAP-overexpressing (HEK293T- FAP) cells after 4-day incubation with LP4 antibody conjugates or unconjugated linker-payload, with or without recombinant FAP or FAP inhibitor, in FBS substitute Panexin-containing medium (which contains low levels of FAP). Warhead was included as a positive control. Cytotoxicity was measured as % inhibition relative to vehicle control. [40] FIG.19 shows cytotoxicity in FAP-negative (HEK293T) and FAP-overexpressing (HEK293T- FAP) cells after 4-day incubation with LP5 antibody conjugates or unconjugated linker-payload, with or without recombinant FAP or FAP inhibitor, in FBS substitute Panexin-containing medium (which contains low levels of FAP). Warhead was included as a positive control. Cytotoxicity was measured as % inhibition relative to vehicle control. [41] FIGs.20A-20B show cytotoxicity of FAP-negative LS174T-GFP cells as mono-culture (FIG. 20A) or co-culture with FAP-expressing fibroblasts (FIG.20B) after 5-day incubation with anti- CEACAM5-LP2 antibody conjugate, with or without recombinant FAP or FAP inhibition, in complete MammoCult medium (chemically defined with no exogenous FAP). Warhead was included as a positive control. Tumour specific cytotoxicity was measured as % inhibition relative to vehicle control using GFP fluorescence. [42] FIGs.21A-21B show cytotoxicity of FAP-negative MDA-MB-231-GFP cells as 3D spheroid mono-culture (FIG.21A) or co-culture with FAP-expressing human mammary fibroblast (HMF) cells (FIG.21B) after 7-day incubation with anti-CEACAM5-LP2 antibody conjugate, with or without recombinant FAP or FAP inhibition, in complete Mammocult medium (chemically defined with no exogenous FAP). Warhead was included as positive control. Tumour spheroid specific cytotoxicity was measured as % inhibition relative to vehicle control using GFP fluorescence. [43] FIGs.22A-22B show change in tumour volume (FIG.22A) or body weight (FIG.22B) following treatment with vehicle, anti-CEACAM5 antibody or anti-CEACAM5 conjugates containing

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different linker-payloads in a cell-line derived xenograft (CDX) model of LS174T cells engineered to express FAP. Data are plotted as mean + standard error of mean (SEM). [44] FIG.23 shows levels of released exatecan warhead in tumor and plasma, measured by LC/MS, after treatment with anti-CEACAM5-LP2 in a cell-line derived xenograft (CDX) model of LS174T cells engineered to express FAP. Data are plotted as mean + standard error of mean (SEM). D^ETAILED D^ESCRIPTION [45] FAP is a post-prolyl cleaving serine protease that can cleave on the C-terminal side of an internal proline residue. Provided herein are compounds and constructs comprising a FAP-cleavable moiety that are capable of delivering a camptothecin to FAP-expressing tissues (e.g., cancers). Also provided herein are pharmaceutical compositions comprising the constructs provided herein, and kits comprising the same. General Definitions [46] The following definitions are general terms used throughout the present disclosure. [47] The term “camptothecin” refers to a compound (or a radical thereof) belonging to the class of compounds considered to be camptothecins, camptothecin analogs, camptothecin derivatives or camptothecin conjugates. In some embodiments, the term “camptothecin” refers to a compound (or a radical thereof) derived from the camptothecin five-ring backbone: , optionally with one or more modifications or substituents. Camptothecins may exist in the lactone or carboxylate forms, and the term “camptothecin” refers to either or both alternatives. Examples of camptothecins include, but are not limited to, irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]- carbonyloxycamptothecin), belotecan, Dxd (N-((1S,9S)-9-Ethyl-5-fluoro-9-hydroxy-4-methyl-10,13- dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)-2- hydroxyacetamide), SN-38 ((4S)-4,11-Diethyl-4,9-dihydroxy-1,4-dihydro-3H,14H- pyrano[3’,4’:6,7]indolizino[1,2-b]quinoline-3,14-dione), topotecan ((S)-9-N,N-dimethylaminoethyl-10- hydroxycamptothecin), 10-aminocamptothecin, 9-aminocamptothecin (9-amino-20(S)-camptothecin), 9- nitrocamptothecin (rubitecan), lurtotecan (7-(4-methylpiperazinomethylene)-10,11-ethylenedioxy-20(S)- camptothecin), exatecan, karenitecin, homocamptothecin, 10-hydroxycamptothecin, 9- hydroxycamptothecin, 9-hydroxy-10-dimethylaminomethyl camptothecin, 10,11- methylendioxycamptothecin, 9-chloro-10,11-methylenedioxy-camptothecin, 7-ethyl-10- hydroxycamptothecin, 7-ethylcamptothecin, silatecan, TAS103, 9-amino-10,11- methylenedioxycamptothecin, 7-(2-N-isopropylamino)ethyl)-(20S)-camptothecin, (7-(4-

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methylpiperadinomethylene)-10,11-ethylenedioxy-20(S)-camptothecin, 7-(4- methylpiperadinomethylene)-10,11-methylenedioxy-20-camptothecin, and stereoisomers thereof. [48] The term “self-immolative linker” or “self-eliminating linker” refers to a temporary extender, spacer, or placeholder unit attaching two or more molecules together by chemical bonds that are cleaved under defined conditions to release the two molecules. In general, a self-immolative or self-eliminating linker may be linear or branched, and may link two or more of the same molecules together, or may link two or more different molecules together. The self-immolative or self-eliminating linker may degrade, decompose, or fragment under, for example, physiological conditions, acidic conditions, basic conditions, or in the presence of specific chemical agents. Examples of self-eliminating linkers include, but are not limited to, p-aminobenzyloxycarbonyl (PABC) and 2,4-bis(hydroxymethyl)aniline. In certain embodiments, the self-immolative linker includes one or more moieties that are hydrolyzed under physiological conditions to reveal the desired molecule (e.g., a camptothecin). In other embodiments, the self-immolative linker is cleaved by an enzymatic activity of the host animal. [49] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N⁺(C1-4 alkyl)4- salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic

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ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. [50] Throughout the present disclosure, references to “the compound” and “a compound” provided herein are intended to encompass the compound or group of compounds, and also pharmaceutically acceptable salts, stereoisomers, tautomers, solvates (e.g., hydrates), and isotopically labeled derivatives thereof. [51] The term “amino acid” or “amino acid residue” encompasses all compounds, whether natural or synthetic, which include both an amino functionality and an acid functionality, including amino acid analogues and derivatives. In certain embodiments, the amino acids contemplated in the present invention are those naturally occurring amino acids found in proteins, or the naturally occurring anabolic or catabolic products of such amino acids, which contain amino and carboxyl groups. Naturally occurring amino acids are identified throughout by the conventional three- letter and/or one-letter abbreviations, corresponding to the trivial name of the amino acid, in accordance with the following list. The abbreviations are accepted in the peptide art and are recommended by the IUPAC-IUB commission in biochemical nomenclature. The term “amino acid residue” further includes analogues, derivatives, and congeners of any specific amino acid referred to herein, as well as C-terminal or N-terminal protected amino acid derivatives (e.g., modified with an N-terminal or C-terminal protecting group). [52] The terms “composition” and “formulation” are used interchangeably. [53] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such

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as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non- human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease or condition. [54] The term “administer,” “administering,” or “administration” refers to injecting, implanting, providing or otherwise introducing a compound described herein, or a composition thereof, in, to or on a subject. [55] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. [56] The terms “condition,” “disease,” and “disorder” are used interchangeably. [57] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. In certain embodiments, an effective amount is an amount sufficient for delivering a camptothecin to a FAP-expressing tissue. In certain embodiments, an effective amount is an amount sufficient for delivering a camptothecin to the site of a cancer. [58] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition, alone or in combination with other therapies. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease characterized by FAP upregulation. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating cancer, fibrosis, or inflammation. [59] The term “fibroblast activating protein” or “FAP” refers to fibroblast activation protein alpha (FAPa, or simply FAP; EC 3.4.21.-), also known as seprase or 170 kDa melanoma membrane-bound gelatinase. FAP is a homodimeric integral membrane protein belonging to the serine protease family and to the dipeptidyl peptidase (DPP-IV)-like subfamily.

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[60] The term “target tissue” refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is the object to which a compound, particle, and/or composition of the present disclosure is delivered. A target tissue may be an abnormal or unhealthy tissue, which may need to be treated. A target tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the target tissue is the liver. In certain embodiments, the target tissue is the lung. A “non-target tissue” is any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is not a target tissue. In certain embodiments, a target tissue is a tissue that expresses FAP. [61] An “binding moiety” includes a specific part or component of a molecule that is responsible for its ability to bind or interact with another molecule (e.g., a target molecule), often with high specificity. In some embodiments, a binding moiety specifically binds to a target molecule. “Specifically binds” refers to the ability of a binding moiety to bind to a target molecule binding partner with a degree of affinity or avidity that enables the molecule to be used to distinguish the target molecule from an appropriate control in a binding assay or other binding context. With respect to an antibody or AFFIMER®, for example, “specifically binds” refers to the ability of the antibody or AFFIMER® to bind to a specific target molecule with a degree of affinity or avidity, compared with an appropriate reference molecule or molecules, that enables the antibody or AFFIMER® to be used to distinguish the specific target molecule from others, as described herein. In some embodiments, an antibody or AFFIMER® specifically binds to a target molecule if the antibody or AFFIMER® has a K_D for binding the target molecule of at least about 10^-4 M, 10^-5 M, 10^-6 M, 10^-7 M, 10^-8 M, 10^-9 M, 10^-10 M, 10^-11 M, 10- ¹² M, 10^-13 M, or less. [62] An “antigen-binding moiety” includes a specific part or component of a molecule that binds to a target antigen (e.g., tumor, e.g., cancer antigen), and encompasses monoclonal antibodies, polyclonal antibodies, monospecific and multispecific antibodies (e.g., bispecific antibodies, trispecific antibodies etc.), and antibody fragments, provided they bind to the relevant target molecule(s). A “cell-binding moiety” is a type of antigen-binding moiety that binds to a target antigen on the surface of a cell, such as a cancer cell. [63] An “antibody” includes a polypeptide that comprises at least one immunoglobulin variable domain or at least one site, e.g., paratope, that specifically binds to an antigen. A typical antibody molecule comprises a heavy chain variable region (VH) and/or a light chain variable region (VL), which are usually involved in antigen binding. VH and VL regions can be further subdivided into regions of hypervariability, also known as “complementarity determining regions” (“CDR”), interspersed with regions that are more conserved, which are known as “framework regions” (“FR”). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The term “antibody” also includes antigen binding fragments thereof (e.g., Fab fragment, a F(ab')2 fragment, a Fv fragment or a scFv fragment).

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[64] An “AFFIMER^® polypeptide” refers to a polypeptide comprising a modified version of human Stefin A as well as one or two, preferably two, heterologous peptides. AFFIMER® polypeptides include small, engineered proteins designed to bind specifically to target molecules. They are derived from human Stefin A scaffold proteins and have distinct loop structures that confer their binding properties. The different loop structures of an AFFIMER® polypeptide, based on their design and origin, typically include two variable “loop” structures. A Variable Loop 2 (VL2) is one of the primary loops responsible for binding specificity. It is engineered to interact with the target molecule through various amino acid substitutions, providing a high degree of diversity and specificity. A Variable Loop 4 (VL4) also contributes significantly to the binding interaction. The combination of VL2 and VL4 provides the structural diversity often needed for high-affinity binding to a wide range of targets. While not loops per se, the framework regions (collectively the scaffold) support the variable loops structurally. These regions are typically more conserved and provide a stable scaffold to present the variable loops in the correct orientation for target binding. Chemical Definitions [65] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7^th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987. [66] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer, or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw- Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

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[67] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example, “C1-6 alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. [68] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive. [69] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl. [70] The term “halo” or “halogen” refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I). [71] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C_1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert- amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-12 alkyl (such as unsubstituted C1-6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec- Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-12 alkyl (such as substituted C1-6 alkyl, e.g., -CH2F, -CHF2, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, or benzyl (Bn)).

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[72] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C1-20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C1-10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1-9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C1-7 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C1-5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C_1-4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C_1-3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C_1-2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include -CHF₂, -CH₂F, -CF₃, -CH₂CF₃, -CF₂CF₃, -CF₂CF₂CF₃, -CCl₃, -CFCl₂, -CF₂Cl, and the like. [73] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkyl group is an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-20 heteroalkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-12 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-11 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-10 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-9 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-8 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-7 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“C1-6 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1-5

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heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1-4 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“C1-3 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“C1-2 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“C1 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C2-6 heteroalkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. [74] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C_2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C_2-12 alkenyl”). In some embodiments, an alkenyl group has 2 to 11 carbon atoms (“C_2-11 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C_2-10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C_2-9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C_2-8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C_2-7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C_2-6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C_2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C_2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C_2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atom (“C₂ alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C_2-4 alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and the like. Additional examples of alkenyl include heptenyl (C₇), octenyl (C₈), octatrienyl (C₈), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., -CH=CHCH3 or may be in the (E)- or (Z)- configuration. [75] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkenyl group is an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one

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or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-20 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-12 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-11 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-10 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“C2-9 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C_2-8 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C_2-7 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C_2-6 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C_2-5 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C_2-4 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C_2-3 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C₂ heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C_2-6 heteroalkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. [76] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2- butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl

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(C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. [77] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorous within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, the heteroalkynyl group is an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, and sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C_2-20 heteroalkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C_2-10 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C_2-9 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C_2-8 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C_2-7 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C_2-6 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C_2-5 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“C_2-4 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C2-3 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C₂ heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C1-6 heteroalkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. [78] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non- aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8

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carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include the aforementioned C_3-8 carbocyclyl groups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), spiro[4.5]decanyl (C₁₀), and the like. Exemplary C_3-8 carbocyclyl groups include the aforementioned C_3-10 carbocyclyl groups as well as cycloundecyl (C₁₁), spiro[5.5]undecanyl (C₁₁), cyclododecyl (C₁₂), cyclododecenyl (C₁₂), cyclotridecane (C₁₃), cyclotetradecane (C₁₄), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits. [79] “Cycloalkyl” refers to a saturated carbocyclyl group. In some embodiments, a cycloalkyl group has from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 7 ring carbon atoms (“C3-7 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is

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independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. [80] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorous (“3-14 membered heterocyclyl”). In certain embodiments, the heterocyclyl group is a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heterocyclyl group, as valency permits. For example, in heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 8-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits. [81] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. [82] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl,

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oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6- membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzo- thienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydro- pyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7- dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3- b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like. [83] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C_6-14 aryl”). In some embodiments, an aryl group has 6-10 ring carbon atoms (“C_6-10 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. [84] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, silicon, boron, and phosphorous (“5-14 membered heteroaryl”). In certain embodiments, the heteroaryl group is a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6,

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10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The point of attachment can be either to a ring carbon atom or a ring heteroatom of the heteroaryl group, as valency permits. For example, in heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. [85] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. [86] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups

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containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl. [87] The term “acyl” refers to a non-cyclic group comprising a C=O, C=N, or C=S moiety. Exemplary acyl groups include aldehydes (-CHO), carboxylic acids (-CO₂H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. [88] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In general, the term “substituted” when referring to a chemical group means that at least one hydrogen present on the group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The invention is not limited in any manner by the exemplary substituents described herein. [89] In certain embodiments, exemplary substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, P(R^cc)3⁺X-, -P(OR^cc)3⁺X-, -P(R^cc)4, -P(OR^cc)4, -OP(R^cc)2, -OP(R^cc)3⁺X-, -OP(OR^cc)2, -OP(OR^cc)3⁺X-, - OP(R^cc)4, -OP(OR^cc)4, -B(R^aa)2, -B(OR^cc)2, -BR^aa(OR^cc), C1-20 alkyl, C1-20 haloalkyl, C2-20 alkenyl, C2-20 alkynyl, C1-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3-14 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein X- is a counterion;

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or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R^bb)2, =NNR^bbC(=O)R^aa, =NNR^bbC(=O)OR^aa, =NNR^bbS(=O)2R^aa, =NR^bb, or =NOR^cc; each instance of R^aa is, independently, selected from C1-20 alkyl, C1-20 haloalkyl, C2-20 alkenyl, C2- 20 alkynyl, C1-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3-14 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R^aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; each instance of R^bb is, independently, selected from hydrogen, -OH, -OR^aa, -N(R^cc)2, -CN, - C(=O)R^aa, -C(=O)N(R^cc)2, -CO2R^aa, -SO2R^aa, -C(=NR^cc)OR^aa, -C(=NR^cc)N(R^cc)2, -SO2N(R^cc)2, -SO2R^cc, - SO2OR^cc, -SOR^aa, -P(=O)(R^aa)2, -P(=O)(OR^cc)2, -P(=O)(N(R^cc)2)2, C1-20 alkyl, C1-20 haloalkyl, C2-20 alkenyl, C2-20 alkynyl, C1-20 heteroalkyl, C2-20 heteroalkenyl, C2-20 heteroalkynyl, C3-14 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R^bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and each instance of R^cc is, independently, selected from hydrogen, C_1-20 alkyl, C_1-20 haloalkyl, C_2-20 alkenyl, C_2-20 alkynyl, C_1-20 heteroalkyl, C_2-20 heteroalkenyl, C_2-20 heteroalkynyl, C_3-14 carbocyclyl, 3-14 membered heterocyclyl, C_6-14 aryl, and 5-14 membered heteroaryl, or two R^cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring. [90] In certain embodiments, the molecular weight of a substituent (e.g., carbon atom substituent) is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms. [91] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -OR^aa, -SR^aa, -SCN, -N(R^bb)2, -CN, - NO2, -C(=O)R^aa, -CO2R^aa, -C(=O)N(R^bb)2, -OC(=O)R^aa, -OCO2R^aa, -OC(=O)N(R^bb)2, -NR^bbC(=O)R^aa, - NR^bbCO2R^aa, or -NR^bbC(=O)N(R^bb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-10 alkyl, (R^bb)2, -OC(=O)R^aa, -OCO2R^aa, - OC(= wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3- nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

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[92] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)R^aa, -CO2R^aa, -C(=O)N(R^bb)2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)R^aa, -CO2R^aa, - C(=O)N(R^bb)2, or a nitrogen protecting group, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or a nitrogen protecting group. [93] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated herein by reference. Non-limiting examples of nitrogen protecting groups include benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds). In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. [94] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, -C(=O)R^aa, -CO₂R^aa, -C(=O)N(R^bb)₂, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)R^aa, -CO2R^aa, - C(=O)N(R^bb)2, or an oxygen protecting group, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl or an oxygen protecting group. [95] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, an oxygen protecting group is a silyl group. Non-limiting examples of oxygen protecting groups include t-butyldiphenylsilyl (TBDPS), t- butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2- trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl

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(EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2- trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv). In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl. [96] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)R^aa, -CO2R^aa, -C(=O)N(R^bb)2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, -C(=O)R^aa, -CO2R^aa, - C(=O)N(R^bb)₂, or a sulfur protecting group, wherein R^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C_1-6 alkyl or a sulfur protecting group. [97] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl. [98] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F-, Cl-, Br-, I-), NO3-, ClO4-, OH-, H2PO4-, HCO3-, HSO4-, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10- camphor sulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4-, PF4-, PF6-, AsF6-, SbF6-, B[3,5-(CF3)2C6H3]4]-, B(C6F5)4-, BPh4-, Al(OC(CF3)3)4-, and carborane anions (e.g., CB11H12- or (HCB11Me5Br6)-). Exemplary counterions which may be multivalent include CO3^2-, HPO4^2-, PO4^3-, B4O7^2-, SO4^2-, S2O3^2-, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes. [99] The term “amino acid sidechain” refers to that portion of an amino acid other than -CH(NH2)COOH, as defined by K. D. Kopple, "Peptides and Amino Acids", W. A. Benjamin Inc., New York and Amsterdam, 1966, as defined on pages 2 and 33. For the most part, the amino acids used in the application of this disclosure are those naturally occurring amino acids found in proteins,

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or the naturally occurring anabolic or catabolic products of such amino acids which contain amino and carboxyl groups. Amino acid sidechains include side chains selected from those of the following amino acids: glycine, alanine, valine, cysteine, leucine, iso leucine, serine, threonine, methionine, glutamic acid, aspartic acid, glutamine, asparagine, lysine, arginine, proline, histidine, phenylalanine, tyrosine, and tryptophan, and those amino acids and amino acid analogs which have been identified as constituents of peptidylglycan bacterial cell walls. Amino acid residues having “basic sidechains” include Arg, Lys and His. Amino acid residues having “acidic sidechains” include Glu and Asp. Amino acid residues having “neutral polar sidechains” include Ser, Thr, Asn, Gln, Cys and Tyr. Amino acid residues having “neutral non-polar sidechains” include Gly, Ala, Val, Ile, Leu, Met, Pro, Trp and Phe. Amino acid residues having “non-polar aliphatic sidechains” include Gly, Ala, Val, Ile and Leu. Amino acid residues having “hydrophobic sidechains” include Ala, Val, Ile, Leu, Met, Phe, Tyr and Trp. Amino acid residues having “small hydrophobic sidechains” include Ala and Val. Amino acid residues having “aromatic sidechains” include Tyr, Trp and Phe. [100] These and other exemplary substituents are described in more detail in the Detailed Description, Drawings, Examples, and Claims. The embodiments provided herein are not limited in any manner by the above exemplary listing of substituents. Compounds and Constructs [101] As described herein, provided herein are compounds and constructs comprising a camptothecin conjugated to a FAP-cleavable moiety. [102] In one aspect, provided herein are compounds of Formula (I′): , and pharmaceutically acceptable salts thereof, wherein: CAM is a camptothecin; R′ is -L^A-R^A, hydrogen, halogen, -OR^O, -CO2R^O, -N(R^N)2, -C(=O)N(R^N)2, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted; R^A is a reactive handle; L^A is a bond, C1-30 alkylene, C1-30 haloalkylene, C2-30 alkenylene, C2-30 alkynylene, C1-30 heteroalkylene, C2-30 heteroalkenylene, C2-30 heteroalkynylene, C3-10 carbocyclylene, 3- to 10-membered heterocyclylene, C_6-10 arylene, 5- to 10-membered heteroarylene, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkylene, haloalkylene alkenylene,

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alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, carbocyclylene, heterocyclylene, arylene, heteroarylene, PEG, or PSar is independently optionally substituted; L¹ is a bond, C3-10 carbocyclylene, C6-10 arylene, 3- to 10-membered heterocyclylene, or 5- to 10- membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted; R² and each instance of R^2A are independently hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein L^A and R² are joined together, or L^A and R^2A are joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted; R³ is hydrogen or optionally substituted C1-6 alkyl; each instance of R^3A is hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain; each instance of R⁴ is independently halogen, C₁-₆ alkyl, C_1-6 haloalkyl, -OR^O, or -N(R^N)₂, wherein the alkyl or haloalkyl is optionally substituted; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2; X is a bond, -C(=O)-, -OC(=O)-, -N(R^N)C(=O)-, -S(=O)₂-, or -S(=O)-; L² is a bond, or -N(H)-L²- is a bond or a self-immolative linker, wherein the self-immolative linker is optionally substituted with -L^A-R^A; each instance of R^O is independently H, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 haloalkyl, optionally substituted C_3-7 carbocyclyl, or optionally substituted C_1-6 acyl; and each instance of R^N is independently H, optionally substituted C_1-6 alkyl, optionally substituted C_{3-7 -} carbocyclyl, or optionally substituted C_1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl; and wherein the compound comprises at least one instance of -L^A-R^A. [103] In certain embodiments, the compound of Formula (I′), is of Formula (I), or a pharmaceutically acceptable salt thereof. [104] In one aspect, provided herein are compounds of Formula (I): , and pharmaceutically acceptable salts thereof, wherein: CAM is a camptothecin; R^A is a reactive handle; L^A is a bond, C1-30 alkylene, C1-30 haloalkylene, C2-30 alkenylene, C2-30 alkynylene, C1-30 heteroalkylene, C2-30 heteroalkenylene, C2-30 heteroalkynylene, C3-10 carbocyclylene, 3- to 10-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, polyethylene glycol (PEG), or any combination thereof, wherein each alkylene, haloalkylene alkenylene, alkynylene, heteroalkylene,

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heteroalkenylene, heteroalkynylene, carbocyclylene, heterocyclylene, arylene, heteroarylene, and PEG is independently optionally substituted; L¹ is a bond, C3-10 carbocyclylene, C6-10 arylene, 3- to 10-membered heterocyclylene, or 5- to 10- membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted; R² and each instance of R^2A are independently hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein L^A and R² are joined together, or L^A and R^2A are joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted; R³ is hydrogen or optionally substituted C1-6 alkyl; each instance of R^3A is hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain; each instance of R⁴ is independently halogen, C₁-₆ alkyl, C_1-6 haloalkyl, -OR^O, or -N(R^N)₂, wherein the alkyl or haloalkyl is optionally substituted; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2; X is a bond, -C(=O)-, -OC(=O)-, -N(R^N)C(=O)-, -S(=O)₂-, or -S(=O)-; L² is a bond, or -N(H)-L²- is a bond or a self-immolative linker; each instance of R^O is independently H, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 haloalkyl, optionally substituted C_3-7 carbocyclyl, or optionally substituted C_1-6 acyl; and each instance of R^N is independently H, optionally substituted C_1-6 alkyl, optionally substituted C_3-7 carbocyclyl, or optionally substituted C_1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. [105] In certain embodiments, the compound is of Formula (I-A): or a pharmaceutically acceptable salt thereof. [106] In certain embodiments, the compound is of Formula (I-B):

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or a pharmaceutically acceptable salt thereof, wherein -N(H)-L²- is a bond or a self-immolative linker. [107] In certain embodiments, the compound is of Formula (I-C): or a pharmaceutically acceptable salt thereof, wherein -N(H)-L²- is a bond or a self-immolative linker. [108] In certain embodiments, the compound is of Formula (I-D): , or a pharmaceutically acceptable salt thereof. [109] In certain embodiments, the compound is of Formula (I-E): , or a pharmaceutically acceptable salt thereof.

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[110] In certain embodiments, the compound is of Formula (I-F): or a pharmaceutically acceptable salt thereof. [111] In certain embodiments, the compound is of Formula (I-G): , or a pharmaceutically acceptable salt thereof. [112] In certain embodiments, the compound is of Formula (I-H): , or a pharmaceutically acceptable salt thereof, wherein -N(H)-L²- is a bond or a self-immolative linker.

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[113] In certain embodiments, the compound is of Formula (I-I): , or a pharmaceutically acceptable salt thereof, wherein -N(H)-L²- is a bond or a self-immolative linker. [114] In one aspect, provided herein are constructs of Formula (II′): or a pharmaceutically acceptable salt thereof, wherein: R′′ is -L^A-R^B-Z, hydrogen, halogen, -OR^O, -CO₂R^O, -N(R^N)₂, -C(=O)N(R^N)₂, C₁-₃₀ alkyl, C_1-30 haloalkyl, C_1-30 heteroalkyl, C_2-30 alkenyl, C_2-30 heteroalkenyl, C_2-30 alkynyl, C_2-30 heteroalkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted; Z is a binding moiety; R^B is a diradical of a reactive handle; CAM is a camptothecin; L^A is a bond, C_1-30 alkylene, C_1-30 haloalkylene, C_2-30 alkenylene, C_2-30 alkynylene, C_1-30 heteroalkylene, C_2-30 heteroalkenylene, C_2-30 heteroalkynylene, C_3-10 carbocyclylene, 3- to 10-membered heterocyclylene, C_6-10 arylene, 5- to 10-membered heteroarylene, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkylene, haloalkylene alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, carbocyclylene, heterocyclylene, arylene, heteroarylene, PEG, or PSar is independently optionally substituted; L¹ is a bond, C3-10 carbocyclylene, C6-10 arylene, 3- to 10-membered heterocyclylene, or 5- to 10- membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted; R² and each instance of R^2A are independently hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein L^A and R² are joined together, or L^A and R^2A are joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted;

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R³ is hydrogen or optionally substituted C1-6 alkyl; each instance of R^3A is hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain; each instance of R⁴ is independently halogen, C1-6 alkyl, C1-6 haloalkyl, -OR^O, or -N(R^N)2, wherein the alkyl or haloalkyl is optionally substituted; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2; X is a bond, -C(=O)-, -OC(=O)-, -N(R^N)C(=O)-, -S(=O)2-, or -S(=O)-; L² is a bond, or -N(H)-L²- is a bond or a self-immolative linker, wherein the self-immolative linker is optionally substituted with -L^A-R^B-Z; each instance of R^O is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl; and each instance of R^N is independently H, optionally substituted C_1-6 alkyl, optionally substituted C_{3-7 -} carbocyclyl, or optionally substituted C_1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl; and wherein the compound comprises at least one instance of -L^A-R^B-Z. [115] In certain embodiments, the construct of Formula (II′), is of Formula (II), or a pharmaceutically acceptable salt thereof. [116] In one aspect, provided herein are constructs of Formula (II): , or a pharmaceutically acceptable salt thereof, wherein: Z is a binding moiety; R^B is a diradical of a reactive handle; CAM is a camptothecin; L^A is a bond, C1-30 alkylene, C1-30 haloalkylene, C2-30 alkenylene, C2-30 alkynylene, C1-30 heteroalkylene, C2-30 heteroalkenylene, C2-30 heteroalkynylene, C3-10 carbocyclylene, 3- to 10-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, polyethylene glycol (PEG), or any combination thereof, wherein each alkylene, haloalkylene alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, carbocyclylene, heterocyclylene, arylene, heteroarylene, and PEG is independently optionally substituted; L¹ is a bond, C3-10 carbocyclylene, C6-10 arylene, 3- to 10-membered heterocyclylene, or 5- to 10- membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted; R² and each instance of R^2A are independently hydrogen or optionally substituted C1-C6 alkyl; or

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optionally wherein L^A and R² are joined together, or L^A and R^2A are joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted; R³ is hydrogen or optionally substituted C1-6 alkyl; each instance of R^3A is hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain; each instance of R⁴ is independently halogen, C1-6 alkyl, C1-6 haloalkyl, -OR^O, or -N(R^N)2, wherein the alkyl or haloalkyl is optionally substituted; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2; X is a bond, -C(=O)-, -OC(=O)-, -N(R^N)C(=O)-, -S(=O)2-, or -S(=O)-; L² is a bond, or -N(H)-L²- is a bond or a self-immolative linker; each instance of R^O is independently H, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 haloalkyl, optionally substituted C_3-7 carbocyclyl, or optionally substituted C_1-6 acyl; and each instance of R^N is independently H, optionally substituted C_1-6 alkyl, optionally substituted C_3-7 carbocyclyl, or optionally substituted C_1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. [117] In certain embodiments, the construct is of Formula (II-A): , or a pharmaceutically acceptable salt thereof. [118] In certain embodiments, the construct is of Formula (II-B): or a pharmaceutically acceptable salt thereof, wherein -N(H)-L²- is a bond or a self-immolative linker.

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[119] In certain embodiments, the construct is of Formula (II-C): , or a pharmaceutically acceptable salt thereof, wherein -N(H)-L²- is a bond or a self-immolative linker. [120] In certain embodiments, the construct is of Formula (II-D): , or a pharmaceutically acceptable salt thereof. [121] In certain embodiments, the construct is of Formula (II-E): , or a pharmaceutically acceptable salt thereof.

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[122] In certain embodiments, the construct is of Formula (II-F): , or a pharmaceutically acceptable salt thereof. [123] In certain embodiments, the construct is of Formula (II-G): , or a pharmaceutically acceptable salt thereof. [124] In certain embodiments, the construct is of Formula (II-H): , or a pharmaceutically acceptable salt thereof, wherein -N(H)-L²- is a bond or a self-immolative linker.

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[125] In certain embodiments, the construct is of Formula (II-I): or a pharmaceutically acceptable salt thereof, wherein -N(H)-L²- is a bond or a self-immolative linker. Camptothecin (CAM) [126] As generally defined herein, CAM is a camptothecin. In certain embodiments, CAM is any camptothecin provided herein. In certain embodiments, CAM is exatecan, SN-38, Dxd, belotecan, or topotecan. In certain embodiments, CAM is exatecan, SN-38, Dxd, or belotecan. In certain embodiments,

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R′, R′′ [127] As generally defined herein, R′ is -L^A-R^A, hydrogen, halogen, -OR^O, -CO2R^O, -N(R^N)2, - C(=O)N(R^N)2, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-10 aryl, 5- to 10- membered heteroaryl, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted. _[128] In certain embodiments, R′ is hydrogen, halogen, -OR^O, -CO₂R^O, -N(R^N)₂, -C(=O)N(R^N)₂, C₁-₃₀ alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, PEG, PSar, or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted. In certain embodiments, R′ is hydrogen, C₁-₃₀ alkyl, C_1-30 haloalkyl, C_1-30 heteroalkyl, C_2-30 alkenyl, C_2-30 heteroalkenyl, C_2-30 alkynyl, C_2-30 heteroalkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, PEG, or PSar or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted. In certain embodiments, R′ is hydrogen, R^1A, C₁-₂₀ alkyl, C_1-20 haloalkyl, C_1-20 heteroalkyl, C_2-20 alkenyl, C_2-20 alkynyl, PEG, or PSar, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, PEG, or PSar, is optionally substituted. In certain embodiments, R′ is C₁-₂₀ alkyl, C_1-20 haloalkyl, C_1-20 heteroalkyl, C_2-20 alkenyl, C_2-20 alkynyl, PEG, or PSar, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl,

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or alkynyl, is optionally substituted. In certain embodiments, R′ is C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20 alkynyl, PEG, or PSar, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, or alkynyl, is optionally substituted. In some embodiments, R′ is C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted. In some embodiments, R′ is C1-10 alkyl or C1-10 haloalkyl. In some embodiments, R′ is -Me, -Et, -Pr, or -Bu. In some embodiments, R′ is - Me or -Et. In some embodiments, R′ is -Me or -CF3. In some embodiments, R′ is C1-10 heteroalkyl, C2-10 heteroalkenyl, or C2-10 heteroalkynyl, wherein the heteroalkyl, heteroalkenyl, or heteroalkynyl is optionally substituted. [129] In some embodiments, R′ is hydrogen or halogen. In some embodiments, R′ is halogen. In some embodiments, R′ is -F, -Cl, or -Br. In some embodiments, R′ is hydrogen or -F. [130] In some embodiments, R′ is -OR^O, -CO₂R^O, -N(R^N)₂, -C(=O)N(R^N)₂, C_1-30 heteroalkyl, C_2-30 heteroalkenyl, C_2-30 heteroalkynyl, PEG, PSar, or any combination thereof, wherein each heteroalkyl, heteroalkenyl, heteroalkynyl, PEG, or PSar is independently optionally substituted. In some embodiments, R′ is -OR^O, -CO₂R^O, -N(R^N)₂, or -C(=O)N(R^N)₂. In some embodiments, R′ is -OR^O or - CO₂R^O. In some embodiments, R′ is -N(R^N)₂ or -C(=O)N(R^N)₂. In some embodiments, R′ is -OR^O or - N(R^N)₂. In some embodiments, R′ is -CO₂R^O or -C(=O)N(R^N)₂. In some embodiments, R′ is -OH or - OMe. In some embodiments, R′ is -NH₂, -NHMe, or -NMe₂. In some embodiments, R′ is -CO₂H, or - CO₂Me. In some embodiments, R′ is -C(=O)NH₂, -C(=O)N(H)Me, or -C(=O)NMe₂. [131] In some embodiments, R′ is C_3-10 carbocyclyl or 3- to 10-membered heterocyclyl, wherein each carbocyclyl or heterocyclyl is independently optionally substituted. In some embodiments, R′ is C3-7 carbocyclyl, wherein each carbocyclyl is optionally substituted. In some embodiments, R′ is C_5-6 carbocyclyl, wherein each carbocyclyl is optionally substituted. In some embodiments, R′ is 3- to 7- membered heterocyclyl, wherein each heterocyclyl is optionally substituted. In some embodiments, R′ is 5- to 6-membered heterocyclyl, wherein each heterocyclyl is optionally substituted. [132] In some embodiments, R′ is C6-10 aryl or 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted. In some embodiments, R′ is optionally substituted phenyl. In some embodiments, R′ is optionally substituted napthyl. In some embodiments, R′ is 5- to 6-membered heteroaryl, wherein each heteroaryl is optionally substituted. In some embodiments, R′ is 9- to 10- membered heteroaryl, wherein each heteroaryl is optionally substituted. [133] In some embodiments, R′ is PEG or PSar, wherein the PEG or PSar is independently optionally substituted. In some embodiments, R′ is PEG or PSar. In some embodiments, R′ is PEG, wherein the PEG is optionally substituted. In some embodiments, R′ is PEG. In some embodiments, R′ is . In some embodiments, R′ is PSar, wherein the PSar is optionally substituted. In some embodiments, R′ is PSar. [134] In some embodiments, R′ is -L^A-R^A or hydrogen. In some embodiments, R′ is -L^A-R^A. In some embodiments, R′ is hydrogen.

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[135] In some embodiments, R′ is hydrogen, halogen, -OR^O, -CO2R^O, -N(R^N)2, -C(=O)N(R^N)2, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted; and L² is a self-immolative linker substituted with -L^A-R^A. In some embodiments, R′ is hydrogen; and L² is a self-immolative linker substituted with -L^A-R^A. _[136] As generally defined herein, R′′ is -L^A-R^B-Z, hydrogen, halogen, -OR^O, -CO₂R^O, -N(R^N)₂, - C(=O)N(R^N)₂, C₁-₃₀ alkyl, C_1-30 haloalkyl, C_1-30 heteroalkyl, C_2-30 alkenyl, C_2-30 heteroalkenyl, C_2-30 alkynyl, C_2-30 heteroalkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, 5- to 10- membered heteroaryl, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted. [137] In certain embodiments, R′′ is hydrogen, halogen, -OR^O, -CO₂R^O, -N(R^N)₂, -C(=O)N(R^N)₂, C₁-₃₀ alkyl, C_1-30 haloalkyl, C_1-30 heteroalkyl, C_2-30 alkenyl, C_2-30 heteroalkenyl, C_2-30 alkynyl, C_2-30 heteroalkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, PEG, PSar, or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted. In certain embodiments, R′′ is hydrogen, C1-30 alkyl, C1-30 haloalkyl, C_1-30 heteroalkyl, C_2-30 alkenyl, C_2-30 heteroalkenyl, C_2-30 alkynyl, C_2-30 heteroalkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, PEG, or PSar or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted. In certain embodiments, R′′ is hydrogen, R^1A, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20 alkynyl, PEG, or PSar, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, PEG, or PSar, is optionally substituted. In certain embodiments, R′′ is C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20 alkynyl, PEG, or PSar, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, or alkynyl, is optionally substituted. In certain embodiments, R′′ is C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C2-20 alkenyl, C2-20 alkynyl, PEG, or PSar, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, or alkynyl, is optionally substituted. In some embodiments, R′′ is C1-10 alkyl, C2-10 alkenyl, or C2-10 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted. In some embodiments, R′′ is C1-10 alkyl or C1-10 haloalkyl. In some embodiments, R′′ is -Me, -Et, -Pr, or -Bu. In some embodiments, R′′ is - Me or -Et. In some embodiments, R′′ is -Me or -CF3. In some embodiments, R′′ is C1-10 heteroalkyl, C2-10 heteroalkenyl, or C2-10 heteroalkynyl, wherein the heteroalkyl, heteroalkenyl, or heteroalkynyl is optionally substituted. [138] In some embodiments, R′′ is hydrogen or halogen. In some embodiments, R′′ is halogen. In some embodiments, R′′ is -F, -Cl, or -Br. In some embodiments, R′′ is hydrogen or -F.

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[139] In some embodiments, R′′ is -OR^O, -CO2R^O, -N(R^N)2, -C(=O)N(R^N)2, C1-30 heteroalkyl, C2-30 heteroalkenyl, C2-30 heteroalkynyl, PEG, PSar, or any combination thereof, wherein each heteroalkyl, heteroalkenyl, heteroalkynyl, PEG, or PSar is independently optionally substituted. In some embodiments, R′′ is -OR^O, -CO2R^O, -N(R^N)2, or -C(=O)N(R^N)2. In some embodiments, R′′ is -OR^O or - CO2R^O. In some embodiments, R′′ is -N(R^N)2 or -C(=O)N(R^N)2. In some embodiments, R′′ is -OR^O or - N(R^N)2. In some embodiments, R′′ is -CO2R^O or -C(=O)N(R^N)2. In some embodiments, R′′ is -OH or - OMe. In some embodiments, R′′ is -NH2, -NHMe, or -NMe2. In some embodiments, R′′ is -CO2H, or - CO2Me. In some embodiments, R′′ is -C(=O)NH2, -C(=O)N(H)Me, or -C(=O)NMe2. _[140] In some embodiments, R′′ is C_3-10 carbocyclyl or 3- to 10-membered heterocyclyl, wherein each carbocyclyl or heterocyclyl is independently optionally substituted. In some embodiments, R′′ is C_3-7 carbocyclyl, wherein each carbocyclyl is optionally substituted. In some embodiments, R′′ is C_5-6 carbocyclyl, wherein each carbocyclyl is optionally substituted. In some embodiments, R′′ is 3- to 7- membered heterocyclyl, wherein each heterocyclyl is optionally substituted. In some embodiments, R′′ is 5- to 6-membered heterocyclyl, wherein each heterocyclyl is optionally substituted. [141] In some embodiments, R′′ is C_6-10 aryl or 5- to 10-membered heteroaryl, wherein each aryl or heteroaryl is optionally substituted. In some embodiments, R′′ is optionally substituted phenyl. In some embodiments, R′′ is optionally substituted napthyl. In some embodiments, R′′ is 5- to 6-membered heteroaryl, wherein each heteroaryl is optionally substituted. In some embodiments, R′′ is 9- to 10- membered heteroaryl, wherein each heteroaryl is optionally substituted. [142] In some embodiments, R′′ is PEG or PSar, wherein the PEG or PSar is independently optionally substituted. In some embodiments, R′′ is PEG or PSar. In some embodiments, R′′ is PEG, wherein the PEG is optionally substituted. In some embodiments, R′′ is PEG. In some embodiments, R′′ is . In some embodiments, R′′ is PSar, wherein the PSar is optionally substituted. In some embodiments, R′′ is PSar. [143] In some embodiments, R′′ is -L^A-R^B-Z or hydrogen. In some embodiments, R′′ is -L^A-R^B-Z. In some embodiments, R′′ is hydrogen. [144] In some embodiments, R′′ is hydrogen, halogen, -OR^O, -CO2R^O, -N(R^N)2, -C(=O)N(R^N)2, C1-30 alkyl, C1-30 haloalkyl, C1-30 heteroalkyl, C2-30 alkenyl, C2-30 heteroalkenyl, C2-30 alkynyl, C2-30 heteroalkynyl, C3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C6-10 aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted; and L² is a self-immolative linker substituted with -L^A-R^B-Z. In some embodiments, R′′ is hydrogen; and L² is a self-immolative linker substituted with -L^A-R^B-Z.

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L² [145] As generally defined herein, L² is a bond, or -N(H)-L²- is a bond or a self-immolative linker. In some embodiments, L² is a bond, or -N(H)-L²- is a bond or a self-immolative linker, wherein the self- immolative linker is optionally substituted with -L^A-R^A. In some embodiments, L² is a bond, or -N(H)-L²- is a bond or a self-immolative linker, wherein the self-immolative linker is optionally substituted with - L^A-R^B-Z. In certain embodiments, L² is a bond, or -N(H)L²- is a bond. In certain embodiments, L² is a bond, or -N(H)-L²- is a self-immolative linker. In certain embodiments, L² is a bond, or -N(H)-L²- is a self-immolative linker, wherein the self-immolative linker is optionally substituted with -L^A-R^A. In certain embodiments, L² is a bond, or -N(H)-L²- is a self-immolative linker, wherein the self-immolative linker is optionally substituted with -L^A-R^B-Z. In certain embodiments, -N(H)-L²- is a bond or a self- immolative linker. In certain embodiments, -N(H)-L²- is a bond or a self-immolative linker optionally substituted with -L^A-R^A. In certain embodiments, -N(H)-L²- is a bond or a self-immolative linker optionally substituted with -L^A-R^B-Z. In certain embodiments, L² is a bond. In certain embodiments, - N(H)-L²- is a bond. In certain embodiments, -N(H)-L²- is a self-immolative linker. In certain embodiments, -N(H)-L²- is a self-immolative linker optionally substituted with -L^A-R^A. In certain embodiments, -N(H)-L²- is a self-immolative linker optionally substituted with -L^A-R^B-Z. In certain embodiments, the self-immolativel linker is not substituted with -L^A-R^A. In some embodiments, the self- immolative linker is substituted with -L^A-R^A. In certain embodiments, the self-immolative linker is not substituted with -L^A-R^B-Z. In certain embodiments, the self-immolative linker is substituted with -L^A-R^B- Z. In certain embodiments, the self-immolative linker is cleaved to release CAM. [146] In certain embodiments, -N(H)-L²- is of the formula: * denotes the point of attachment to CAM; r is 0, 1, 2, or 3; each instance of Ring A is independently 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or phenyl; each instance of Y is independently a bond, optionally substituted C1-8 alkylene, or optionally substituted C1-8 heteroalkylene; each instance of R⁵ is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, -OR^O, -CO2R^O, -N(R^N)2, -C(=O)N(R^N)2, PEG, PSar, -L⁵-R^5A, -C(=O)-L⁵-R^5A, or - L^A-R^A, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, PEG or PSar is optionally substituted, including optionally with one or more instances of R^5A; L⁵ is a bond, C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, PEG, or PSar, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted; each instance of R^5A is independently C1-6 alkyl, -OR^O, -CO2R^O, -N(R^N)2, -C(=O)N(R^N)2, PEG, or PSar; and

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p is 0, 1, 2, 3, or 4 as permitted by valency. _[147] In certain embodiments, -N(H)-L²- is of the formula: , wherein: * denotes the point of attachment to CAM; r is 0, 1, 2, or 3; each instance of Ring A is independently 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or phenyl; each instance of Y is independently a bond, optionally substituted C_1-8 alkylene, or optionally substituted C_1-8 heteroalkylene; each instance of R⁵ is independently halogen, C_1-20 alkyl, C_1-20 haloalkyl, C_1-20 heteroalkyl, C₁-₂₀ alkenyl, C₁-₂₀ alkynyl, -OR^O, -CO₂R^O, -N(R^N)₂, -C(=O)N(R^N)₂, PEG, PSar, -L⁵-R^5A, -C(=O)-L⁵-R^5A, or - L^A-R^B-Z, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, PEG or PSar is optionally substituted, including optionally with one or more instances of R^5A; L⁵ is a bond, C_1-20 alkylene, C_1-20 haloalkylene, C_1-20 heteroalkylene, PEG, or PSar, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted; each instance of R^5A is independently C₁-₆ alkyl, -OR^O, -CO₂R^O, -N(R^N)₂, -C(=O)N(R^N)₂, PEG, or PSar; and p is 0, 1, 2, 3, or 4 as permitted by valency. [148] In certain embodiments, -N(H)-L²- is of the formula: , wherein: * denotes the point of attachment to CAM; r is 0, 1, 2, or 3; each instance of Ring A is independently 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or phenyl; each instance of Y is independently a bond, optionally substituted C1-8 alkylene, or optionally substituted C1-8 heteroalkylene; each instance of R⁵ is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, -OR^O, -CO2R^O, -N(R^N)2, -C(=O)N(R^N)2, PEG, -L⁵-R^5A, or -C(=O)-L⁵-R^5A, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, or PEG is optionally substituted, including optionally with one or more instances of R^5A; L⁵ is a bond, C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, or PEG, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted; each instance of R^5A is independently C₁-₆ alkyl, -OR^O, -CO₂R^O, -N(R^N)₂, -C(=O)N(R^N)₂, or PEG; and

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p is 0, 1, 2, 3, or 4 as permitted by valency. [149] As generally defined herein, each instance of Ring A is independently 5- or 6-membered heterocyclyl, 5- or 6-membered heteroaryl, or phenyl. In certain embodiments, each instance of Ring A is independently 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl. In certain embodiments, each instance of Ring A is independently 5- or 6-membered heteroaryl or phenyl. In certain embodiments, at least one instance of Ring A is phenyl. In certain embodiments, at least one instance of Ring A is 5- or 6-membered heteroaryl. In certain embodiments, at least one instance of Ring A is 5- or 6- membered N-heteroaryl. In certain embodiments, at least one instance of Ring A is pyridyl, pyrrolyl, or thiazolyl. In certain embodiments, at least one instance of Ring A is 5- to 6-membered heterocyclyl. In certain embodiments, at least one instance of Ring A is 5- to 6-membered N-heterocyclyl. In certain embodiments, at least one instance of Ring A is pyrrolidinyl. [150] As generally defined herein, r is 0, 1, 2, or 3. In certain embodiments, r is 1 or 2. In certain embodiments, r is 1. In certain embodiments, r is 2. [151] As generally defined herein, each instance of Y is independently a bond, optionally substituted C_1-8 alkylene, or optionally substituted C_1-8 heteroalkylene. In certain embodiments, each instance of Y is optionally substituted C_1-8 alkylene or optionally substituted C_1-8 heteroalkylene. In certain embodiments, each instance of Y is optionally substituted C_1-4 alkylene or optionally substituted C_1-4 heteroalkylene. In certain embodiments, Y comprises one or more instances of -N(Me)-, -N(H)-, -CO₂-, -O-, -S(=O)₂-, - P(=O)(OH)O-, -P(=O)(OMe)O-, -P(=O)(OEt)O-, -C(Me)H-, or -CH₂-. In certain embodiments, Y comprises one or more instances of -N(H)-, -CO2-, -P(=O)(OEt)O-, -C(Me)H-, or -CH2-. In certain embodiments, at least one instance of Y is a bond. In certain embodiments, at least one instance of Y is - CH₂-. In certain embodiments, at least one instance of Y is -CO₂CH₂-. In certain embodiments, at least one instance of Y is -N(H)CO2CH2-. In certain embodiments, at least one instance of Y is -P(=O)(OEt)O- C(Me)H-. In certain embodiments, at least one instance of Y i H2-. [152] In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM.

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[153] In certain embodiments, -N(H)-L²- is of the formula: , p . In certain embodiments, -N(H)-L²- is of the formula: erein * denotes the point of attachment to CAM. In certain embodiments, mula: or , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. [154] In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula:

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, wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula:

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, wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point

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of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula:

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, wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. In certain embodiments, -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. [155] As generally defined herein, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 0, 1, 2, or 3. In certain embodiments, p is 0, 1, or 2. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. [156] As generally defined herein, each instance of R⁵ is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C_1-20 heteroalkyl, C₁-₂₀ alkenyl, C₁-₂₀ alkynyl, -OR^O, -CO₂R^O, -N(R^N)₂, -C(=O)N(R^N)₂, PEG, PSar, -L⁵-R^5A, -C(=O)-L⁵-R^5A, or -L^A-R^A, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, PEG or PSar is optionally substituted, including optionally with one or more instances of R^5A; or each instance of R⁵ is independently halogen, C_1-20 alkyl, C_1-20 haloalkyl, C_1-20 heteroalkyl, C₁-₂₀ alkenyl, C₁-₂₀ alkynyl, -OR^O, -CO2R^O, -N(R^N)2, -C(=O)N(R^N)2, PEG, PSar, -L⁵-R^5A, -C(=O)-L⁵-R^5A, or -L^A-R^B-Z, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, PEG or PSar is optionally substituted, including optionally with one or more instances of R^5A. In some embodiments, each instance of R⁵ is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, -OR^O, -CO2R^O, -N(R^N)2, - C(=O)N(R^N)2, PEG, PSar, -L⁵-R^5A, -C(=O)-L⁵-R^5A, or -L^A-R^A, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, PEG or PSar is optionally substituted, including optionally with one or more instances of R^5A. In some embodiments, each instance of R⁵ is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, -OR^O, -CO2R^O, -N(R^N)2, -C(=O)N(R^N)2, PEG, PSar, -L⁵- R^5A, -C(=O)-L⁵-R^5A, or -L^A-R^B-Z, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, PEG or PSar is optionally substituted, including optionally with one or more instances of R^5A. In some embodiments, each instance of R⁵ is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, -OR^O, -CO2R^O, -N(R^N)2, -C(=O)N(R^N)2, PEG, -L⁵-R^5A, or -C(=O)-L⁵-R^5A, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, or PEG is optionally substituted, including

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optionally with one or more instances of R^5A. [157] In some embodiments, at least one instance of R⁵ is -L^A-R^A. In some embodiments, at least one instance of R⁵ is -L^A-R^B-Z. _[158] In certain embodiments, at least one instance of R⁵ is halogen, C_1-6 alkyl, C_1-6 haloalkyl, C_1-6 heteroalkyl, C1-6 alkenyl, C1-6 alkynyl, -OR^O, -CO2R^O, -N(R^N)2, or -C(=O)N(R^N)2. In certain embodiments, at least one instance of R⁵ is halogen, C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, -OR^O, -CO₂R^O, -N(R^N)₂, or -C(=O)N(R^N)₂. In certain embodiments, at least one instance of R⁵ is -Br, -Cl, -F, unsubstituted C_1-4 alkyl, -CF₃, -CH₂OH, -CH₂OMe, -CH₂OEt, -OH, -OMe, -OEt, -CO₂H, -CO₂Me, - CO₂Et, -CH₂NH₂, -CH₂NHMe, -CH₂NMe₂, -NH₂, -NHMe, -NMe₂, -C(=O)NH₂, -C(=O)NHMe, -C(=O)NMe₂, or . In certain embodiments, at least one instance [159] In certain embodiments, at least one instance of R⁵ is C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, PEG, -L⁵-R^5A, or -C(=O)-L⁵-R^5A. In certain embodiments, at least one instance of R⁵ is C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, PEG, -L⁵-R^5A, or -C(=O)-L⁵-R^5A. In certain embodiments, at least one instance of R⁵ is PEG, -L⁵-R^5A, or -C(=O)-L⁵-R^5A. In certain embodiments, at least one instance of R⁵ is PEG. In certain embodiments, at least one instance of R⁵ is of the formula: , wherein q1 is an integer from 1-25, inclusive, and R^O is H, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 haloalkyl, optionally substituted C_3-7 carbocyclyl, or optionally substituted C_1-6 acyl. In certain embodiments, at least one instance of R⁵ is of the formula: , wherein q1 is an integer from 1-25, inclusive, and each instance of R^N is independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. [160] In certain embodiments, R⁵ is -L⁵-R^5A or -C(=O)-L⁵-R^5A. In certain embodiments, R⁵ is -L⁵-R^5A. In certain embodiments, R⁵ is -C(=O)-L⁵-R^5A. [161] As generally defined herein, L⁵ is a bond, C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, PEG, or PSar, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted. In some embodiments, L⁵ is a bond, C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, or PEG, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted. In some embodiments, L⁵ is a bond. In some embodiments, L⁵ is C1-10 alkylene, C1-10 haloalkylene, C1-10 heteroalkylene, or PEG. In some _{embodiments, L5 is of the formula: or , wherein q1 is an integer from 1-25,}

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inclusive. In some embodiments, L⁵ is C1-6 heteroalkylene. In some embodiments, L⁵ or -C(=O)-L⁵- is . [162] As generally defined herein, each instance of R^5A is independently C₁-₆ alkyl, -OR^O, -CO₂R^O, - N(R^N)₂, -C(=O)N(R^N)₂, PEG, or PSar. In some embodiments, each instance of R^5A is independently C₁-₆ alkyl, -OR^O, -CO₂R^O, -N(R^N)₂, -C(=O)N(R^N)₂, or PEG. In certain embodiments, at least one instance of R^5A is C₁-₆ alkyl, -OR^O, -CO₂R^O, -N(R^N)₂, or -C(=O)N(R^N)₂. In certain embodiments, at least one instance of R^5A is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, -OH, -OMe -OEt, -CO2H, -CO2Me, -CO2Et, -NH2, -NHMe, -NMe2, -C(=O)NH2, -C(=O)NHMe, or -C(=O)NMe2. In certain embodiments, at least one instance of R^5A is PEG. In certain embodiments, at least one instance of R^5A is of the formula: , wherein q1 is an integer from 1-25, inclusive, and R^O is H, optionally substituted C1- 6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl. In certain embodiments, at least one instance of R^5A is of the formula: , wherein q1 is an integer from 1-25, inclusive, and each instance of R^N is independently H, optionally substituted C_1-6 alkyl, optionally substituted C_3-7 carbocyclyl, or optionally substituted C_1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. [163] In certain embodiments, at least one instance of R⁵ is of the formula: or , wherein q1 is an integer from 1-25, inclusive. In certain embodiments, at least one instance of R⁵ is of the formula: or , wherein q1 is an integer from 1-15, inclusive. In certain embodiments, at least one instance of R⁵ is . In certain embodiments, at least one instance . [164] In certain embodiments, at least one instance of R⁵ is PSar. In certain embodiments, at least one

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instance of R⁵ is of the formula , wherein q3 is an integer from 1-25, inclusive, and each instance of R^N is H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted C1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In some embodiments, at least one instance of R⁵ is of the formula , wherein q3 is an integer from 1-25, inclusive, and each instance of R^N is H, optionally substituted C_1-6 alkyl, optionally substituted C_3-7 carbocyclyl, optionally substituted C_1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In some embodiments, at least one instance of R⁵ is of the formula t e o ua . R⁴, m [165] As generally defined herein, m is 0, 1, 2, 3, 4, 5, 6, or 7. In certain embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In certain embodiments, m is 0, 1, 2, 3, 4, or 5. In certain embodiments, m is 0, 1, 2, 3, or 4. In certain embodiments, m is 0, 1, 2, or 3. In certain embodiments, m is 0, 1, or 2. In certain embodiments, m is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6. In certain embodiments, m is 7. [166] As generally defined herein, each instance of R⁴ is independently halogen, C1-6 alkyl, C1-6 haloalkyl, -OR^O, or -N(R^N)2, wherein the alkyl or haloalkyl is optionally substituted. In certain embodiments, at least one instance of R⁴ is Br, Cl, F, Me, Et, -CF3, -OEt, -OMe, -OH, -NMe2, -NHMe, or -NH2. In certain embodiments, at least one instance of R⁴ is optionally substituted C1-4 alkyl. In certain embodiments, at least one instance of R⁴ is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, or t-Bu. In certain embodiments, at least one instance of R⁴ is Me or Et. In certain embodiments, at least one instance of R⁴ is optionally substituted C_1-4 haloalkyl. In certain embodiments, at least one instance of R⁴ is -CF₃. In certain embodiments, at least one instance of R⁴ is halogen. In certain embodiments, at least one instance of R⁴ is Br, Cl, or F. In certain embodiments, at least one instance of R⁴ is F. In certain embodiments,

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each instance of R⁴ is the same. In certain embodiments, at least one instance of R⁴ is different. In certain embodiments, each instance of R⁴ is different. X [167] As generally defined herein, X is a bond, -C(=O)-, -OC(=O)-, -N(R^N)C(=O)-, -S(=O)2-, or -S(=O)-. In certain embodiments, X is -C(=O)-, -OC(=O)-, -N(R^N)C(=O)-, -S(=O)2-, or -S(=O)-. In certain embodiments, X is -C(=O)- or -S(=O)2-. In certain embodiments, X is a bond. In certain embodiments, X is -C(=O)- or -OC(=O)-. In certain embodiments, X is -S(=O)2- or -S(=O)-. In certain embodiments, X is -C(=O)-. In certain embodiments, X is -OC(=O)-. In certain embodiments, X is -N(R^N)C(=O)-. In certain embodiments, X is -S(=O)2-. In certain embodiments, X is - S(=O)-. L¹, L^A, R^A, R^B [168] As generally defined herein, L¹ is a bond, C_3-10 carbocyclylene, C_6-10 arylene, 3- to 10-membered heterocyclylene, or 5- to 10-membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, L¹ is a bond. In certain embodiments, L¹ is C_3-10 carbocyclylene, C_6-10 arylene, 3- to 10-membered heterocyclylene, or 5- to 10-membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted. In certain embodiments, L¹ is C_3-10 carbocyclylene or C_6-10 arylene, wherein the carbocyclylene or arylene are optionally substituted. In certain embodiments, L¹ is C_3-10 carbocyclylene or 3- to 10-membered heterocyclylene, wherein the carbocyclylene or heterocyclylene are optionally substituted. In certain embodiments, L¹ is C_6-10 arylene or 5- to 10-membered heteroarylene, wherein the arylene or heteroarylene are optionally substituted. In certain embodiments, L¹ is 5- to 10-membered heteroarylene or 5- to 6-membered heterocyclylene, wherein the heteroarylene or heterocyclylene are optionally substituted. In certain embodiments, L¹ is phenylene, wherein the phenylene is optionally substituted. In certain embodiments, L¹ is naphthylene, wherein the phenylene is optionally substituted. In certain embodiments, L¹ is C3-C7 carbocyclylene, wherein the carbocyclylene is optionally substituted. In certain embodiments, L¹ is 5- to 10-membered heteroarylene, wherein the heteroarylene is optionally substituted. In certain embodiments, L¹ is 5- or 6-membered heteroarylene, wherein the heteroarylene is optionally substituted. In certain embodiments, L¹ is 3- to 7-membered heterocyclylene, wherein the heterocyclylene is optionally substituted. , each of which is independently optionally substituted, wherein * denotes the point of

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attachment to L^A. In certain embodiments, , , wherein * denotes the point of attachment to L^A. In certain embodiments, L¹ is of the formula: attachment to L^A. In certain embodiments, L¹ is of the formula: denotes the point of attachment to L^A. In certain embodiments, L¹ is of the formula: denotes the point of attachment to L^A. In certain embodiments, L¹ is of the , wherein * denotes the point of attachment to L^A. In certain embodiments, L¹ is of the formula: , wherein * denotes the point of attachment to L^A. In certain embodiments, L¹ is of the formula: , wherein * denotes the point of attachment to L^A. In certain embodiments, L¹ is of the formula: , wherein * denotes the point of attachment to L^A.

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In certain embodiments, L¹ is of the formula: , wherein * denotes the point of attachment _{to LA. In certain embodiments, L1 is of the formula:} _{, wherein * denotes the point of} attachment to L^A. In certain embodiments, L¹ is of the formula: , wherein * denotes the point of attachment to L^A. In certain embodiments, L¹ is of the formula: , wherein * denotes the point of attachment to L^A. In certain embodiments, L¹ is of the formula: , wherein * denotes the point of attachment to L^A. [170] As generally defined herein, L^A is a bond, C_1-30 alkylene, C_1-30 haloalkylene, C_2-30 alkenylene, C_2- ₃₀ alkynylene, C_1-30 heteroalkylene, C_2-30 heteroalkenylene, C_2-30 heteroalkynylene, C_3-10 carbocyclylene, 3- to 10-membered heterocyclylene, C_6-10 arylene, 5- to 10-membered heteroarylene, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkylene, haloalkylene alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, carbocyclylene, heterocyclylene, arylene, heteroarylene, PEG, or PSar is independently optionally substituted; optionally wherein L^A and R² are joined together, or L^A and R^2A are joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted. In some embodiments, L^A is a bond, C_1-30 alkylene, C_1-30 haloalkylene, C_2-30 alkenylene, C_2-30 alkynylene, C_1-30 heteroalkylene, C_2-30 heteroalkenylene, C_2-30 heteroalkynylene, C_3-10 carbocyclylene, 3- to 10- membered heterocyclylene, C_6-10 arylene, 5- to 10-membered heteroarylene, polyethylene glycol (PEG), or any combination thereof, wherein each alkylene, haloalkylene alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, carbocyclylene, heterocyclylene, arylene, heteroarylene, and PEG is independently optionally substituted; optionally wherein L^A and R² are joined together, or L^A and R^2A are joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted. In certain embodiments, L^A is a bond, C1-30 alkylene, C1-30 haloalkylene, C2-30 alkenylene, C2-30 alkynylene, C1-30 heteroalkylene, C2-30 heteroalkenylene, C2-30 heteroalkynylene, C3-10 carbocyclylene, 3- to 10-membered heterocyclylene, C6-10 arylene, 5- to 10-

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membered heteroarylene, polyethylene glycol (PEG), or any combination thereof, wherein each alkylene, haloalkylene alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, carbocyclylene, heterocyclylene, arylene, heteroarylene, and PEG is independently optionally substituted. In certain embodiments, L^A is a bond, C1-20 alkylene, C1-20 haloalkylene, C2-20 alkenylene, C2-20 alkynylene, C1-20 heteroalkylene, C2-20 heteroalkenylene, C2-20 heteroalkynylene, C3-10 carbocyclylene, 3- to 10-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, polyethylene glycol (PEG), or any combination thereof, wherein each alkylene, haloalkylene alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, carbocyclylene, heterocyclylene, arylene, heteroarylene, and PEG is independently optionally substituted. In certain embodiments, L^A is C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, C2-20 alkenylene, C2-20 alkynylene, polyethylene glycol (PEG), or any combination thereof, wherein the alkylene, haloalkylene, heteroalkylene, alkenylene, or alkynylene is optionally substituted. [171] In certain embodiments, L^A is a bond. [172] In certain embodiments, L^A comprises C_1-10 alkylene, C_2-10 alkenylene, or C_2-10 alkynylene, wherein the alkylene, alkenylene, or alkynylene is optionally substituted. In certain embodiments, L^A comprises C_1-4 alkylene. In certain embodiments, L^A comprises -CH₂-. In certain embodiments, L^A comprises C_1-6 haloalkylene. [173] In certain embodiments, L^A comprises C1-10 heteroalkylene, C2-10 heteroalkenylene, C2-10 heteroalkynylene. In certain embodiments, L^A comprises C_1-10 heteroalkylene, C_2-10 heteroalkenylene, C_2- 10 heteroalkynylene, wherein the heteroalkylene, heteroalkenylene, or heteroalkynylene comprises at least one oxygen atom. In certain embodiments, L^A comprises C_1-10 heteroalkylene, C_2-10 heteroalkenylene, C_2- ₁₀ heteroalkynylene, wherein the heteroalkylene, heteroalkenylene, or heteroalkynylene comprises at least one nitrogen atom. In certain embodiments, L^A comprises -O-. In certain embodiments, L^A comprises - CO2-. In certain embodiments, L^A comprises -N(R^N)-, wherein R^N is H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, L^A comprises -N(R^N)C(=O)-, wherein R^N is H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. [174] In certain embodiments, L^A comprises C3-10 carbocyclylene, 3- to 10-membered heterocyclylene, C6-10 arylene, or 5- to 10-membered heteroarylene. In certain embodiments, L^A comprises C3-7 carbocyclylene. In certain embodiments, L^A comprises cyclohexylene. In certain embodiments, L^A comprises . In certain embodiments, L^A comprises 3- to 7-membered heterocyclylene. In certain embodiments, L^A comprises 5- to 7-membered heterocyclylene. In certain embodiments, L^A comprises phenylene. In certain embodiments, L^A comprises . In certain embodiments, L^A comprises naphthylene. In certain embodiments, L^A comprises 5- to 6-membered heteroarylene. In

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certain embodiments, L^A comprises 10-membered heteroarylene. In certain embodiments, L^A comprises 5- to 10-membered heteroarylene comprising at least one nitrogen atom. In certain embodiments, L^A comprises pyrrolylene, pyrazolylene, imidazolylene, or triazolylene. In certain embodiments, L^A comprises . In certain embodiments, L^A comprises pyridinylene, pyrazinylene, or pyrimidinylene. In certain embodiments, L^A comprises quinolinylene. [175] In certain embodiments, L^A comprises PEG or PSar. In certain embodiments, L^A comprises PEG. In certain embodiments, L^A comprises the formula: , wherein q1 is an integer from 1-25. In certain embodiments, L^A comprises PEG. In certain embodiments, L^A comprises the formula: wherein q1 is an integer from 1-15. In certain embodiments, L^A comprises the formula: wherein q1 is an integer from 5-10. [176] In certain embodiments, L^A comprises PSar. In certain embodiments, L^A comprises the formula , wherein q3 is an integer from 1-25, inclusive, and each instance of R^N is H, optionally substituted C_1-6 alkyl, optionally substituted C_3-7 carbocyclyl, optionally substituted C_1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, L^A comprises the formula , wherein q3 is an integer from 1-25, inclusive. In certain embodiments, L^A comprises the formula , wherein q3 is an integer from 1-10, inclusive. In certain embodiments, L^A comprises the formula . certain embodiments, L^A comprises the formula .

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[177] In certain embodiments, L^A comprises the formula from 1-25, inclusive, and each instance of R^N is H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted C1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, L^A comprises the formula , wherein q3 is an integer from 1-25, inclusive, and each instance of R^N is H, optionally substituted C_1-6 alkyl, optionally substituted C_3-7 carbocyclyl, optionally substituted C_1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, L^A comprises the formula e o ua . _[178] In certain embodiments, L^A comprises the formula , wherein q3 is an integer from 1-25, inclusive, and each instance of R^N is H, optionally substituted C1-6 alkyl, optionally substituted C_3-7 carbocyclyl, optionally substituted C_1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain _{embodiments, LA comprises the formula} _{, wherein q3 is an integer from} 1-25, inclusive, and each instance of R^N is H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, optionally substituted C1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, L^A comprises the

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formula , wherein q3 is an integer from 1-10, inclusive. In certain embodiments, L^A comprises the formula . [179] In certain embodiments, L^A comprises: . certain embodiments, L^A is of the formula: , wherein q1 is an integer from 5-10. [180] As generally defined herein, q1 is an integer from 1-25, inclusive. In certain embodiments, q1 is an integer from 1-20, inclusive. In certain embodiments, q1 is an integer from 1-15, inclusive. In certain embodiments, q1 is an integer from 1-15, inclusive. In certain embodiments, q1 is an integer from 1-10, inclusive. In certain embodiments, q1 is an integer from 1-5, inclusive. In certain embodiments, q1 is an integer from 2-25, inclusive. In certain embodiments, q1 is an integer from 2-20, inclusive. In certain embodiments, q1 is an integer from 2-15, inclusive. In certain embodiments, q1 is an integer from 2-10, inclusive. In certain embodiments, q1 is an integer from 2-5, inclusive. In certain embodiments, q1 is an integer from 5-25, inclusive. In certain embodiments, q1 is an integer from 5-20, inclusive. In certain embodiments, q1 is an integer from 5-15, inclusive. In certain embodiments, q1 is an integer from 5-10, inclusive. In certain embodiments, q1 is 1. In certain embodiments, q1 is 2. In certain embodiments, q1 is 3. In certain embodiments, q1 is 4. In certain embodiments, q1 is 5. In certain embodiments, q1 is 6. In certain embodiments, q1 is 7. In certain embodiments, q1 is 8. In certain embodiments, q1 is 9. In certain embodiments, q1 is 10. [181] As generally defined herein, R^A is a reactive handle. As generally defined herein, R^B is a diradical of a reactive handle. The term “reactive handle” refers to any chemical moiety capable of reacting with another chemical moiety to form one or more covalent bonds. In certain embodiments, the reactive handle is any reactive handle capable of conjugating a compound provided herein (e.g., a compound of Formula (I′) or (I)), or a pharmaceutically acceptable salt thereof, to a binding moiety to form a construct as provided herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof.

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[182] In certain embodiments, the reactive handle undergoes bioconjugation, such as to a protein, e.g., an antibody. In certain embodiments, the reactive handle is capable of reacting with a cysteine residue (cysteine bioconjugation). In certain embodiments, the reactive handle is capable of reacting with a lysine residue (lysine bioconjugation). In certain embodiments, the reactive handle is capable of reacting with a tyrosine or tryptophan residue (tyrosine or tryptophan bioconjugation). In certain embodiments, the reactive handle is site specific. In certain embodiments, the reactive handle is a cysteine-selective reactive handle. In certain embodiments, the reactive handle is a lysine-selective reactive handle. In certain embodiments, the reactive handle is a tyrosine-selective or tryptophan-selective reactive handle. Reactive handles are disclosed, for example, in Rostovtsev, V. V. et al. Angew. Chem.2002, 114, 2708- 2711, Bernardin, B. et al. Nat. Protocol.2019, 14, 86-99, Szijj, P. A. et al. Org. Biomol. Chem.2020, 18, 9018-9028, and Yang, Q. et al. Research 2024, 7, 0410, each of which is incorporated herein by reference in its entirety. Non-limiting examples of reactive moieties include alkenes, alkynes, alcohols, amines, thiols, azides, esters, amides, halogens, and the like. In certain embodiments, the reactive handle comprises a maleimide, NHS-ester, amine, isocyanate, isothiocyanate, benzoyl fluoride, iodoacetamide, thiol, propionitrile, diazonium salt, aldehyde, aniline, ketone, iodoacetamide, alkyne, or azide moiety. In certain embodiments, the reactive handle comprises a maleimide. In certain embodiments, the reactive handle comprises an azide. In certain embodiments, the reactive handle comprises an alkyne. [183] In certain embodiments, the reactive handle undergoes click chemistry. “Click chemistry” is a describes chemistry tailored to generate substances quickly and reliably by joining small units together. See, e.g., Kolb, Finn and Sharpless Angewandte Chemie International Edition 2001, 40, 2004–2021; Evans, Australian Journal of Chemistry, 2007, 60, 384–395. Exemplary coupling reactions (some of which may be classified as “click chemistry”) include, but are not limited to, formation of esters, thioesters, amides (e.g., such as peptide coupling) from activated acids or acyl halides; nucleophilic displacement reactions (e.g., such as nucleophilic displacement of a halide or ring opening of strained ring systems); azide-alkyne Huisgen cycloaddition; thiol-yne addition; imine formation; Michael additions (e.g., maleimide addition); and Diels-Alder reactions (e.g., tetrazine [4 + 2] cycloaddition). As an example, in the case of reactions between an azide and alkyne reactive moieties to form triazolylene linkages, alkyne-azide 1,3-cycloadditions may be used (e.g., the Huisgen alkyne-azide cycloaddition). In certain embodiments, the alkyne-azide cycloaddition is copper-catalyzed. In certain embodiments, the alkyne-azide cycloaddition is strain-promoted. Examples of alkyne-azide reactions can be found in, e.g., Kolb, Finn and Sharpless Angewandte Chemie International Edition 2001, 40, 2004-2021; Kolb and Sharpless, Drug Discov Today 2003, 24, 1128-1137; and Evans, Australian Journal of Chemistry 2007, 60, 384–395.

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[184] In certain embodiments, the reactive handle comprises a halogen, alkene, alkyne, azide, tetrazine, or a moiety of one of the following formulae: [185] The table below shows examples of reactive handles and their associated selectivity, e.g., for different amino acid residues.

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[186] In certain embodiments, R^A comprises . certain embodiments, R^B comprises in * denotes the point of attachment to the binding moiety. iments, R^A comprises . some embodiments, R^A comprises . some embodiments, R^A comprises . some embodiments, R^A comprises wherein * denotes the point of attachment to the binding moiety. In some embodiments, R^A comprises , wherein * denotes the point of attachment to the binding moiety. In some embodiments, R^A comprises , wherein * denotes the point of attachment to the binding moiety. R², R^2A, R³, R^3A, n [188] As generally defined herein, R² is hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein L^A and R² are joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted. In certain embodiments, R² is hydrogen or optionally substituted C1-C6 alkyl. In certain embodiments, R² is H. In certain embodiments, R² is optionally substituted C1-4 alkyl. In certain embodiments, R² is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, or t- Bu. In certain embodiments, R² is -(CH₂)₂NMe₂.

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[189] In certain embodiments, L^A and R² are joined together with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted. In certain embodiments, L^A and R² are joined together with the intervening atoms to form an optionally 5- to 6- membered heterocyclyl ring. In certain embodiments, L^A and R² are joined together with the intervening atoms to form an optionally substituted 5- to 6-membered heterocyclic ring fused to an aryl ring. In certain embodiments, L^A and R² are joined together with the intervening atoms to form optionally substituted isoindolinyl. In certain embodiments, L^A and R² are joined together with the intervening atoms to form . [190] As generally defined herein, R³ is hydrogen or optionally substituted C1-6 alkyl. In certain embodiments, R³ is hydrogen or unsubstituted C1-6 alkyl. In certain embodiments, R³ is hydrogen or optionally substituted C1-4 alkyl. In certain embodiments, R³ is Me, Et, n-Pr, i- Pr, n-Bu, i-Bu, or t-Bu. In certain embodiments, R³ is H, Me, or Et. In certain embodiments, R³ is Et or Me. In certain embodiments, R³ is H or Me. In certain embodiments, R³ is H. In certain embodiments, R³ is Me. [191] As generally defined herein, n is 0, 1, or 2. In certain embodiments, n is 0 or 1. In certain embodiments, n is 1 or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. [192] As generally defined herein, each instance of R^2A is independently hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein L^A and R^2A are joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted. In certain embodiments, each instance of R^2A is independently hydrogen or optionally substituted C1-C6 alkyl. In certain embodiments, at least one instance of R^2A is H. In certain embodiments, at least one instance of R^2A is optionally substituted C1-4 alkyl. In certain embodiments, at least one instance of R^2A is Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, or t-Bu. In certain embodiments, at least one instance of R^2A is - (CH2)2NMe2. [193] In certain embodiments, L^A and R^2A are joined together with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted. In certain embodiments, L^A and R^2A are joined together with the intervening atoms to form an optionally 5- to 6- membered heterocyclyl ring. In certain embodiments, L^A and R^2A are joined together with the intervening atoms to form an optionally substituted 5- to 6-membered heterocyclic ring fused to an aryl ring. In certain embodiments, L^A and R^2A are joined together with the intervening atoms to form optionally substituted isoindolinyl. In certain embodiments, L^A and R^2A are joined together with the intervening atoms to form .

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[194] As generally defined herein, each instance of R^3A is hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain. In certain embodiments, each instance of R^3A is hydrogen or an amino acid side chain. In certain embodiments, each instance of R^3A is optionally substituted C1-6 alkyl or an amino acid side chain. In certain embodiments, at least one instance of R^3A is an amino acid side chain. In certain embodiments, at least one instance of R^3A is a basic amino acid sidechain. In certain embodiments, at least one instance of R^3A is an acidic amino acid sidechain. In certain embodiments, at least one instance of R^3A is a neutral amino acid sidechain. In certain embodiments, at least one instance of R^3A is a hydrophobic amino acid sidechain. In certain embodiments, each instance of R^3A is hydrogen or optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R^3A is hydrogen or optionally substituted C1-4 alkyl. In certain embodiments, at least one instance of R^3A is Me, Et, n-Pr, i- Pr, n-Bu, i-Bu, or t-Bu. In certain embodiments, at least one instance of R^3A is H, Me, or -CH₂OR^O. In certain embodiments, at least one instance of R^3A is H, Me, or -CH₂OH. In certain embodiments, at least one instance of R^3A is H, Me, or Et. In certain embodiments, at least one instance of R^3A is Et or Me. In certain embodiments, at least one instance of R^3A is H or Me. In certain embodiments, at least one instance of R^3A is -CH₂OR^O or Me. In certain embodiments, at least one instance of R^3A is -CH₂OH or Me. In certain embodiments, at least one instance of R^3A is H. In certain embodiments, at least one instance of R^3A is Me. In certain embodiments, at least one instance of R^3A is -CH₂OR^O. In certain embodiments, at least one instance of R^3A is -CH₂OH. R^O, R^N [195] As generally defined herein, each instance of R^O is independently H, optionally substituted C_1-6 alkyl, optionally substituted C_1-6 haloalkyl, optionally substituted C_3-7 carbocyclyl, or optionally substituted C_1-6 acyl. In certain embodiments, at least one instance of R^O is H. In certain embodiments, each instance of R^O is H. In certain embodiments, at least one instance of R^O is optionally substituted C_1-6 alkyl. In certain embodiments, at least one instance of R^O is optionally substituted C3-7 carbocyclyl. In certain embodiments, at least one instance of R^O is optionally substituted C1-6 acyl. [196] As generally defined herein, each instance of R^N is independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl. In certain embodiments, at least one instance of R^N is H. In certain embodiments, each instance of R^N is H. In certain embodiments, at least one instance of R^N is optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R^N is Me. In certain embodiments, each instance of R^N is Me. In certain embodiments, at least one instance of R^N is optionally substituted C3-7 carbocyclyl. In certain embodiments, at least one instance of R^N is optionally substituted C1-6 acyl. In certain embodiments, two R^N bonded to the same nitrogen are taken together to form optionally substituted 3-7 membered heterocyclyl.

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Z (Binding Moieties) [197] As generally defined herein, Z is a binding moiety. In some embodiments a binding moiety is polypeptide, for example one or more proteins (e.g., full length and/or peptide). In some embodiments, a binding moiety specifically binds to a target molecule, such as an antigen. Thus, in certain embodiments, a binding moiety is an antigen-binding moiety, for example, a cell-binding moiety. [198] In certain embodiments, a binding moiety is an antibody. In some embodiments, an antibody is a full-length antibody. In some embodiments, an antibody is a chimeric antibody. In some embodiments, an antibody is a human antibody. In some embodiments, an antibody is a humanized antibody. In some embodiments, an antibody is a Fab fragment, a F(ab')2 fragment, a Fv fragment or a scFv fragment. In some embodiments, an antibody is a single domain antibody (e.g., NANOBODY®) derived from a camelid antibody or a single domain antibody (e.g., NANOBODY®) derived from shark antibody. In some embodiments, an antibody is a diabody. In some embodiments, an antibody comprises a framework having a human germline sequence. In some embodiments, an antibody comprises a heavy chain constant domain selected from the group consisting of IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE constant domains. [199] In some embodiments, an antibody comprises a heavy (H) chain variable region (abbreviated herein as VH) and/or a light (L) chain variable region (abbreviated herein as VL). In some embodiments, an antibody comprises an immunoglobulin constant domain, e.g., an Fc domain. An immunoglobulin constant domain includes a heavy or light chain constant domain. Amino acid sequences of human heavy chain and light chain constant domains and their functional variations are known. [200] In some embodiments, the heavy chain of an antibody described herein is an alpha (α), delta (∆), epsilon (ε), gamma (γ) or mu (µ) heavy chain. In some embodiments, the heavy chain of an antibody described herein comprises a human alpha (α), delta (∆), epsilon (ε), gamma (γ) or mu (µ) heavy chain. In some embodiments, an antibody described herein comprises a human gamma 1 CH1, CH2, and/or CH3 domain. In some embodiments, the amino acid sequence of the VH domain comprises the amino acid sequence of a human gamma (γ) heavy chain constant domain. Non-limiting examples of human constant domain sequences have been described, e.g., see U.S. Pat. No.5,693,780 and Kabat E A et al., (1991) supra. In some embodiments, a VH domain comprises an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identical to any variable chain constant domains provided herein. [201] In some embodiments, an antibody is modified, e.g., modified via glycosylation, phosphorylation, sumoylation, and/or methylation. In some embodiments, an antibody is a glycosylated antibody, which is conjugated to at least one sugar or carbohydrate molecule. In some embodiments, at least one sugar or carbohydrate molecule is conjugated to an antibody via N-glycosylation, O- glycosylation, C-glycosylation, glypiation (GPI anchor attachment), and/or phosphoglycosylation. In some embodiments, at least one sugar or carbohydrate molecule is a monosaccharide, disaccharide, oligosaccharide, or glycan. In some embodiments, at least one sugar or carbohydrate molecule is a

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branched oligosaccharide or a branched glycan. In some embodiments, at least one sugar or carbohydrate molecule includes a mannose unit, a glucose unit, an N-acetylglucosamine unit, or a phospholipid unit. [202] In some embodiments, an antibody comprises a linker polypeptide. A linker polypeptide comprises at least two amino acid residues joined by at least one peptide bond and is used to link two molecules (e.g., two peptides or polypeptides) to each other. Examples of linker polypeptides have been reported (see e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R. J., et al. (1994) Structure 2:1121-1123). [203] In some embodiments, an antibody can be part of a larger immunoadhesion molecule, formed by covalent or noncovalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such immunoadhesion molecules include use of the streptavidin core region to make a tetrameric scFv molecule (Kipriyanov, S. M., et al. (1995) Human Antibodies and Hybridomas 6:93-101) and use of a cysteine residue, a marker peptide and a C-terminal polyhistidine tag to make bivalent and biotinylated scFv molecules (Kipriyanov, S. M., et al. (1994) Mol. Immunol.31:1047-1058). [204] In some embodiments an antibody is a bispecific antibody. A bispecific antibody includes a polypeptide or a complex (e.g., two covalently linked polypeptides or monospecific antibodies) that includes two different antigen binding sites, e.g., paratopes, that have different antigen binding specificities. For example, in one embodiment, a bispecific antibody is a polypeptide that includes two different antigen binding sites in which each antigen binding site binds to a different epitope of the same antigen. In other embodiments, a bispecific antibody is a polypeptide that includes two different antigen binding sites in which each site binds to a different antigen. In some embodiments, a bispecific antibody comprises two different sets of immunoglobulin variable domains, each set binding to a different epitope or group of epitopes. Examples of bispecific antibody formats are described, for example, in Shan et al., “In vivo pharmacokinetic enhancement of monomeric Fc and monovalent bispecific designs through structural guidance,” Communications Biology, Vol.4, Article No.1048 (2021).In some embodiments an antibody is a multispecific antibody. A multispecific antibody includes a polypeptide or a complex (e.g., two or more covalently linked polypeptides) that includes at least two different immunoglobulin variable domains or at least two different sites, e.g., paratopes, that specifically bind to one or more antigens. In some embodiments, a multispecific antibody includes a polypeptide that comprise at least two different sites in which each site binds to a different epitope of the same antigen. In other embodiments, a multispecific antibody includes a polypeptide that comprises at least two different sites in which each site binds to a different antigen. [205] In some embodiments, an antibody is a chimeric antibody, which includes antibodies that comprise a sequence from two or more species; for example, antibodies that comprise heavy and light chain variable region sequences and/or constant domain sequences from two or more species, such as antibodies having murine heavy and light chain variable regions linked to human constant domains. [206] In certain embodiments, an antibody is a human antibody. A human antibody includes antibodies that comprise variable and constant domains derived from human germline immunoglobulin sequences. The human antibodies of the disclosure can include amino acid residues not encoded by human germline

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immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and, in particular, CDR3. “Human antibody” is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. [207] In certain embodiments, an antibody is a humanized antibody. A humanized antibody includes antibodies that comprise heavy and/or light chain variable region sequences from a non-human species (e.g., a mouse) but in which at least a portion of the VH and/or VL sequence has been altered to be more “human-like,” i.e., more like human germline variable sequences. One type of humanized antibody is a CDR-grafted antibody, in which human CDR sequences are introduced into non-human VH and/or VL sequences to replace the corresponding nonhuman CDR sequences. In some embodiments, humanized anti-VH4-34 antibodies and antigen binding portions are provided. Such antibodies can be generated by obtaining murine anti-VH4-34 monoclonal antibodies using traditional hybridoma technology followed by humanization using in vitro genetic engineering, such as those disclosed in Kasaian et al PCT publication No. WO 2005/123126 A2. [208] In certain embodiments, an antibody is an antibody fragment. Non-limiting examples of antibody fragments include Fab, Fab’, scFv (single-chain variable fragments), Fc (fragment crystallizable regions), VHHs (e.g., camelid heavy-chain antibody), and other sdAbs (single-domain antibodies, e.g., NANOBODIES®). [209] In certain embodiments, a binding moiety is an AFFIMER® polypeptide. In some embodiments, the AFFIMER® polypeptides provided herein are based on a human Stefin A scaffold that has been modified to prevent amino terminal acetylation/oxidation and increase thermal stability. A protein scaffold includes a framework or structure that provides a stable platform for displaying functional protein domains or peptides, for example. These scaffolds are typically engineered proteins that have a robust and stable tertiary structure, allowing them to tolerate insertions, deletions, or substitutions without losing their overall fold and stability. In some embodiments, a scaffold comprises a sequence having at least 90% (e.g., at least 95%, at least 96%, at least 97%, or at least 98%) identity to the amino acid sequence of SEQ ID NO: 1 (human Stefin A): MIPGGLSEAK PATPEIQEIV DKVKPQLEEK TNETYGKLEA VQYKTQVVAG TNYYIKVRAG DNKYMHLKVF KSLPGQNEDL VLTGYQVDKN KDDELTGF (SEQ ID NO: 1) [210] Thus, various aspects herein relate to polypeptides comprising a scaffold that comprises a sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 1, wherein the scaffold sequence includes (a) an insertion of an amino acid between amino acid positions corresponding to M1 and I2 of the amino acid sequence of SEQ ID NO: 1 and (b) a mutation at an amino acid position corresponding to N32 of the amino acid sequence of SEQ ID NO: 1 and a heterologous peptide. In some embodiments, the insertion of an amino acid between amino acid positions corresponding to M1 and I2 of the amino acid sequence of SEQ ID NO: 1 assists in N-terminal methionine cleavage, reducing N- terminal heterogeneity (e.g., presence or absence of methionine and/or acetylation of methionine).

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[211] In some embodiments, a scaffold provided herein includes a modification that prevents amino terminal acetylation/oxidation relative to the naturally occurring human Stefin A protein. In some embodiments, a scaffold includes a modification that increases thermal stability (e.g., by at least 20%, at least 30%, at least 40%, or at least 50%) of the scaffold (or of a polypeptide containing the scaffold), relative to the naturally occurring human Stefin A protein. [212] In some embodiments, a scaffold (or scaffold sequence, i.e., an amino acid sequence within a scaffold) includes (a) an insertion of an amino acid between amino acid positions corresponding to M1 and I2 of the amino acid sequence of SEQ ID NO: 1 and (b) a mutation at an amino acid position corresponding to N32 of the amino acid sequence of SEQ ID NO: 1, as shown in the amino acid sequence of SEQ ID NO: 2: MGIPGGLSEA KPATPEIQEI VDKVKPQLEE KTGETYGKLE AVQYKTQV-X1-TN YYIKVRAGDN KYMHLKVFKS L-X2-EDLVLTGYQ VDKNKDDELT GF (SEQ ID NO: 2), wherein X1 is any heterologous peptide (e.g., having a length of about 4 to 16 amino acids) and X2 is any heterologous peptide (e.g., having a length of about 4 to 16 amino acids). [213] In some embodiments, a polypeptide comprises a scaffold comprising (a) a sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 1, wherein the scaffold sequence includes (i) an insertion of an amino acid (e.g., glycine) between amino acid positions corresponding to M1 and I2 of the amino acid sequence of SEQ ID NO: 1 and (ii) a mutation at an amino acid position corresponding to N32 (e.g., N32G) of the amino acid sequence of SEQ ID NO: 1, and (b) a heterologous peptide (e.g., two heterologous peptides). [214] In some embodiments, a polypeptide comprises a scaffold comprising (a) a sequence having at least 95% identity to the amino acid sequence of SEQ ID NO: 1, wherein the scaffold sequence includes (i) an insertion of an amino acid (e.g., glycine) between amino acid positions corresponding to M1 and I2 of the amino acid sequence of SEQ ID NO: 1 and (ii) a mutation at an amino acid position corresponding to N32 (e.g., N32G) of the amino acid sequence of SEQ ID NO: 1, and (b) a heterologous peptide (e.g., two heterologous peptides). [215] In some embodiments, a polypeptide comprises a scaffold comprising (a) a sequence having at least 98% identity to the amino acid sequence of SEQ ID NO: 1, wherein the scaffold sequence includes (i) an insertion of an amino acid (e.g., glycine) between amino acid positions corresponding to M1 and I2 of the amino acid sequence of SEQ ID NO: 1 and (ii) a mutation at an amino acid position corresponding to N32 (e.g., N32G) of the amino acid sequence of SEQ ID NO: 1, and (b) a heterologous peptide (e.g., two heterologous peptides). [216] In some embodiments, the insertion of an amino acid between amino acid positions corresponding to M1 and I2 of the amino acid sequence of SEQ ID NO: 1 is a glycine (G). In some embodiments, the insertion of an amino acid between amino acid positions corresponding to M1 and I2 of the amino acid sequence of SEQ ID NO: 1 is an alanine (A). In some embodiments, the insertion of an amino acid between amino acid positions corresponding to M1 and I2 of the amino acid sequence of SEQ

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ID NO: 1 is a serine (S). In some embodiments, the insertion of an amino acid between amino acid positions corresponding to M1 and I2 of the amino acid sequence of SEQ ID NO: 1 is a proline (P). In some embodiments, the insertion of an amino acid between amino acid positions corresponding to M1 and I2 of the amino acid sequence of SEQ ID NO: 1 is a threonine (T). In some embodiments, the mutation at an amino acid position corresponding to N32 of the amino acid sequence of SEQ ID NO: 1 is an N32G mutation (i.e., asparagine to glycine). [217] In some embodiments, the sequence of a scaffold has at least 95% identity to the amino acid sequence of SEQ ID NO: 2. In some embodiments, a sequence of a scaffold has 95% identity to about 98% identity to the amino acid sequence of SEQ ID NO: 2. In some embodiments, a sequence of a scaffold has about 98% identity to the amino acid sequence of SEQ ID NO: 2. In some embodiments, a scaffold comprises the amino acid sequence of SEQ ID NO: 2. In some embodiments, a scaffold consists of the amino acid sequence of SEQ ID NO: 2. [218] Percent identity in the context of DNA, RNA, or protein sequences refers to the percentage of positions (nucleotides in DNA/RNA or amino acids in proteins) that are identical in two aligned sequences when compared. Global and local alignment are two methods used in bioinformatics to align sequences, such as DNA, RNA, or proteins, to identify regions of similarity that may indicate functional, structural, or evolutionary relationships among the sequences. A global alignment aligns two sequences from beginning to end, attempting to align every residue in each sequence. This method typically uses the Needleman-Wunsch algorithm and is ideal for sequences of roughly equal size and when you expect that the sequences are similar over their entire length. A global alignment can introduce gaps as necessary to align as much of the sequences as possible. A local alignment finds the most similar subsequence(s) between two sequences. It does not require that the entirety of either sequence align. This method is typically implemented using the Smith-Waterman algorithm and is ideal for sequences that may have highly similar regions or motifs within otherwise dissimilar sequences. Unless stated otherwise, “identity” between two sequences is calculated using a global (end-to-end) alignment. Cysteine Modifications [219] Any one or more of the polypeptides (e.g., AFFIMER^® polypeptides) described herein can be modified to include one or more cysteine (C). Due to the unique reactivity of cysteine's thiol (-SH) group, these amino acids can be used to enable, for example, conjugation (e.g., via maleimide chemistry) of moieties of interest (e.g., drugs, fluorophores, PEG). [220] In some embodiments, one or more C is in an N-terminal region of the polypeptide, for example, within 10 amino acids (e.g., within 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acids) of the N terminus of the polypeptide. In some embodiments, a C-terminal region of the polypeptide, for example, within 10 amino acids (e.g., within 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acids) of the C terminus of the polypeptide. In some embodiments, one or more C is in a Loop 3 region of the polypeptide between a first heterologous peptide (Loop 2) and a second heterologous peptide (Loop 4), for example, a first peptide and a second peptide that specifically binds to FAP or HSA.

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[221] Fusion proteins can contain combinations of any polypeptide (e.g., AFFIMER^® polypeptide), for example, combinations of FAP binders, combinations of HSA binders, or FAP-HSA binder combinations). In some embodiments, a fusion protein comprises two polypeptides (e.g., AFFIMER^® polypeptides). In some embodiments, a fusion protein comprises three polypeptides (e.g., AFFIMER^® polypeptides). In some embodiments, a fusion protein comprises four polypeptides (e.g., AFFIMER^® polypeptides). In some embodiments, a fusion protein comprises five polypeptides (e.g., AFFIMER^® polypeptides). Any one or more of the polypeptides can include one or more cysteine. _[222] Each polypeptide (e.g., AFFIMER^® polypeptide) can contain any number of cysteines at any available position (e.g., N terminus, C terminus, Loop 3 region and/or linker region), enabling production of conjugates with multiple moieties of interest. [223] In some embodiments, a polypeptide binds specifically to FAP and comprises the amino acid sequence of any one of SEQ ID NOs: 213-316 or 335-351. [224] In some embodiments, a fusion protein comprises a polypeptide that binds specifically to FAP, wherein the polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 317-334 or 353- 388. [225] In some embodiments, a polypeptide binds specifically to HSA and comprises the amino acid sequence of SEQ ID NO: 389-442, 453 or 454. [226] In some embodiments, a fusion protein comprises a polypeptide that binds specifically to HSA, wherein the polypeptide comprises the amino acid sequence of any one of SEQ ID NOs: 443-452 or 455- 461. [227] In some embodiments, a fusion protein comprises (i) a polypeptide that binds specifically to FAP and a polypeptide that binds to HSA, wherein the fusion protein comprises the amino acid sequence of any one of SEQ ID NOs: 462-501 or 553-567. [228] In some embodiments, the scaffold further comprises a cysteine. In some embodiments, the cysteine is introduced at the C-terminus of the scaffold. In some embodiments, the cysteine is introduced at the N-terminus of the scaffold. In some embodiments, the cysteine is introduced between two heterologous proteins peptides (e.g., between a variable Loop 1 peptide and a variable Loop 2 peptide, e.g., between positions T51 and L73 of the amino acid sequence of SEQ ID NO: 1, or between positions T49 and L71 of the amino acid sequence of SEQ ID NO: 4). In some embodiments, the cysteine is introduced at a position in the scaffold corresponding to position D61 of the amino acid sequence of SEQ ID NO: 1. In some embodiments, two cysteines are introduced: a first cysteine at the C-terminus of the scaffold and a second cysteine at a position corresponding to the region between positions T51 and L73 of the amino acid sequence of SEQ ID NO: 1 (e.g., a position corresponding to position D61 of the amino acid sequence of SEQ ID NO: 1). The cysteine, in some embodiments, is used for conjugation (e.g., in the context of protein conjugates, described below). The use of cysteine for conjugation in AFFIMER® molecules also sets them apart from antibodies. In antibodies, cysteines are often part of the framework and/or variable regions of the antibodies, required to create and maintain the structure of the antibody (e.g., through disulfide bonds). Therefore, the use of cysteine conjugation in antibodies may cause

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structural, solubility, and/or other issues because key structural cysteine residues may be reduced. In contrast, AFFIMER® polypeptides are not limited in this manner and have significantly more flexibility with respect to conjugation. Heterologous Peptides [229] The AFFIMER® polypeptides provided herein include one or more heterologous peptide (heterologous to the modified human Stefin A scaffold) that enables the polypeptides to bind to a target with high affinity and exquisite selectivity. A heterologous peptide may be referred to herein as a variable Loop 2 peptide (comprising a variable Loop 2 sequence) or a variable Loop 4 peptide (comprising a variable Loop 4 sequence). A heterologous peptide is considered an “insertion” in a scaffold sequence, for example, of an AFFIMER® polypeptide, such that when the percent identity of the amino acid sequence of a scaffold is calculated relative to human Stefin A (wild-type human Stefin A), the heterologous peptide (or heterologous peptides) is excluded from the calculation. Thus, a polypeptide comprising a scaffold comprising a sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 1 does not factor a heterologous peptide into the percent identity calculation. For example, consider an AFFIMER® polypeptide having the following full-length sequence: MGIPGGLSEA KPATPEIQEI VDKVKPQLEE KTGETYGKLE AVQYKTQVXX XXXXXXXTNY YIKVRAGDNK YMHLKVFKSL XXXXXXXXXE DLVLTGYQVD KNKDDELTGF(SEQ ID NO: 3) [230] This sequence includes a scaffold sequence (SEQ ID NO: 4) as well as two heterologous peptide sequences (each designated “XXXXXXXXX”), each inserted into the scaffold sequence. MGIPGGLSEA KPATPEIQEI VDKVKPQLEE KTGETYGKLE AVQYKTQVTN YYIKVRAGDN KYMHLKVFKS LEDLVLTGYQ VDKNKDDELTGF(SEQ ID NO: 4) [231] The scaffold sequence (SEQ ID NO: 4) of the AFFIMER® polypeptide (SEQ ID NO: 3) has 90% identity to the scaffold sequence of human Stefin A (SEQ ID NO: 1): M-IPGGLSEAKPATPEIQEIVDKVKPQLEEKTNETYGKLEAVQYKTQVVAGTNYYIKVRA MGIPGGLSEAKPATPEIQEIVDKVKPQLEEKTGETYGKLEAVQYKTQV---TNYYIKVRA * ******************************.*************** ********* GDNKYMHLKVFKSLPGQNEDLVLTGYQVDKNKDDELTGF (SEQ ID NO: 1) GDNKYMHLKVFKSL----EDLVLTGYQVDKNKDDELTGF (SEQ ID NO: 4) ************** ********************* [232] In some embodiments, a heterologous peptide (e.g., an AFFIMER® variable Loop 2 peptide and/or an AFFIMER® variable Loop 4 peptide) comprises an amino acid sequence having a length of about 4 to about 20 amino acids. For example, a heterologous peptide can comprise an amino acid sequence having a length of about 8 to about 16 amino acids. In some embodiments, a heterologous peptide comprises an amino acid sequence having a length of 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids. In some embodiments, a heterologous peptide comprises an amino acid sequence having a length of 9 amino acids. In some embodiments, a heterologous peptide comprises an amino acid sequence having a length of 12 amino acids. In some embodiments, a heterologous peptide

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comprises an amino acid sequence having a length of 15 amino acids. In some embodiments, a heterologous peptide comprises an amino acid sequence having a length of 4 to 12, 5 to 12, 6 to 12, 4 to 10, 6 to 10, 8 to 10, 5 to 15, 6 to 15, 7 to 15, 5 to 13, 7 to 13, 9 to 13, 11 to 13, 8 to 18, 9 to 18, 10 to 18, 10 to 16, 12 to 16, or 14 to 16 amino acids. [233] In some embodiments, an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 4 to 12, 5 to 12, 6 to 12, 4 to 10, 6 to 10, or 8 to 10 amino acids and an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 4 to 12, 5 to 12, 6 to 12, 4 to 10, 6 to 10, or 8 to 10 amino acids. In some embodiments, an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 9 amino acids and an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 9 amino acids. In some embodiments, an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 9 amino acids and the polypeptide does not comprise an AFFIMER® variable Loop 2 peptide. [234] In some embodiments, an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 5 to 15, 6 to 15, 7 to 15, 5 to 13, 7 to 13, 9 to 13, or 11 to 13 amino acids and an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 5 to 15, 6 to 15, 7 to 15, 5 to 13, 7 to 13, 9 to 13, or 11 to 13 amino acids. [235] In some embodiments, an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 12 amino acids and an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 12 amino acids. [236] In some embodiments, an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 8 to 18, 9 to 18, 10 to 18, 10 to 16, 12 to 16, or 14 to 16 amino acids and an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 8 to 18, 9 to 18, 10 to 18, 10 to 16, 12 to 16, or 14 to 16 amino acids. In some embodiments, an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 15 amino acids and an AFFIMER® variable Loop 2 peptide comprises an amino acid sequence having a length of 15 amino acids. [237] In some embodiments, a heterologous peptide (e.g., an AFFIMER® variable Loop 2 peptide) is located in a sequence of a scaffold between amino acid positions corresponding to positions V47 and T51 of the amino acid sequence of SEQ ID NO: 1. As shown in the above alignment, positions V47 and T51 of the amino acid sequence of SEQ ID NO: 1 correspond respectively to positions V48 and T49 of the amino acid sequence of SEQ ID NO: 4, which is the scaffold sequence (minus any heterologous peptide) of, for example, an AFFIMER polypeptide comprising the amino acid sequence of SEQ ID NO: 2, wherein each of X1 and X2 is an independent heterologous peptide. Thus, in some embodiments, a heterologous peptide (e.g., an AFFIMER® variable Loop 2 peptide) is in a sequence of a scaffold between amino acid positions corresponding to positions V48 and T49 of the amino acid sequence of SEQ ID NO: 4. [238] In some embodiments, a heterologous peptide (e.g., an AFFIMER® variable Loop 4 peptide) is located in a sequence of a scaffold between amino acid positions corresponding to positions L73 and E78 of the amino acid sequence of SEQ ID NO: 1. As shown in the above alignment, positions L73 and E78

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of the amino acid sequence of SEQ ID NO: 1 correspond respectively to positions L71 and E72 of the amino acid sequence of SEQ ID NO: 4, which is the scaffold sequence (minus any heterologous peptide) of, for example, an AFFIMER polypeptide comprising the amino acid sequence of SEQ ID NO: 2, wherein each of X1 and X2 is an independent heterologous peptide. Thus, in some embodiments, a heterologous peptide (e.g., an AFFIMER® variable Loop 4 peptide) is located in a sequence of a scaffold between amino acid positions corresponding to positions L71 and E72 of the amino acid sequence of SEQ ID NO: 4. [239] In some embodiments, a polypeptide comprises a scaffold comprising the amino acid sequence of SEQ ID NO: 2, wherein X1 is a heterologous peptide having a length of 8 amino acids, and X2 is a heterologous peptide having a length of 8 amino acids. In some embodiments, a polypeptide comprises a scaffold comprising the amino acid sequence of SEQ ID NO: 2, wherein X1 is a heterologous peptide having a length of 9 amino acids, and X2 is a heterologous peptide having a length of 9 amino acids. In some embodiments, a polypeptide comprises a scaffold comprising the amino acid sequence of SEQ ID NO: 2, wherein X1 is a heterologous peptide having a length of 9 amino acids, and X2 is a heterologous peptide having a length of 0 amino acids (i.e., there is no second heterologous peptide). In some embodiments, a polypeptide comprises a scaffold comprising the amino acid sequence of SEQ ID NO: 2, wherein X1 is a heterologous peptide having a length of 10 amino acids, and X2 is a heterologous peptide having a length of 10 amino acids. In some embodiments, a polypeptide comprises a scaffold comprising the amino acid sequence of SEQ ID NO: 2, wherein X1 is a heterologous peptide having a length of 12 amino acids, and X2 is a heterologous peptide having a length of 12 amino acids. In some embodiments, a polypeptide comprises a scaffold comprising the amino acid sequence of SEQ ID NO: 2, wherein X1 is a heterologous peptide having a length of 15 amino acids, and X2 is a heterologous peptide having a length of 15 amino acids. [240] Exemplary variable Loop 2 sequences and variable Loop 4 sequences are provided in Table 1 below. Table 1. AFFIMER® Loop 2 and Loop 4 Sequences

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[241] In some embodiments, a heterologous peptide comprises a sequence selected from the amino acid sequence of any one of SEQ ID NOs: 5-108. [242] In some embodiments, a heterologous peptide comprises a sequence selected from the amino acid sequence of any one of SEQ ID NOs: 109-212. [243] In some embodiments, a polypeptide (e.g., an AFFIMER® polypeptide) comprises a variable Loop 2 peptide comprising the amino acid sequence of SEQ ID NO: 5 and a variable Loop 4 peptide comprising the amino acid sequence of SEQ ID NO: 109. In some embodiments, a polypeptide (e.g., an AFFIMER® polypeptide) comprises a variable Loop 2 peptide comprising the amino acid sequence of SEQ ID NO: 6 and a variable Loop 4 peptide comprising the amino acid sequence of SEQ ID NO: 110. [244] Exemplary polypeptide sequences described herein are provided in Table 2. Table 2. Polypeptide Sequences

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Rigid (R) Linker=AEAAAKEAAAKEAAAKEAAAKEAAAKEAAAK (SEQ ID NO: 502) Flexible (F) Linker=GGGGSGGGGSGGGGSGGGGSGGGGSGGGGSG (SEQ ID NO: 503) L3Cys=Loop 3 Cysteine (for conjugation to an agent, for example) L7Cys=Loop 3 Cysteine in second Affimer® polypeptide of an in-line fusion polypeptide (i.e., Loop 7 of the in-line fusion). CTCys=C-terminal Cysteine (for conjugation to and agent, for example) NTCys=N-terminal Cysteine (for conjugation to and agent, for example) [245] In some embodiments, a polypeptide comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to any one of SEQ ID NOs: 213-567 (Table 2). [246] In some embodiments, the polypeptide comprises an amino acid sequence having at least 80% identity to SEQ ID NO: 213. In some embodiments, the polypeptide comprises an amino acid sequence having at least 85% identity to SEQ ID NO: 213. In some embodiments, the polypeptide comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 213. In some embodiments, the polypeptide comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 213. In some embodiments, the polypeptide comprises an amino acid sequence having at least 98% identity to SEQ ID NO: 213. In some embodiments, the polypeptide comprises SEQ ID NO: 213. In some embodiments, the polypeptide consists of SEQ ID NO: 213. [247] In some embodiments, the polypeptide comprises an amino acid sequence having at least 80% identity to SEQ ID NO: 214. In some embodiments, the polypeptide comprises an amino acid sequence having at least 85% identity to SEQ ID NO: 214. In some embodiments, the polypeptide comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 214. In some embodiments, the polypeptide comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 214. In some embodiments, the polypeptide comprises an amino acid sequence having at least 98% identity to SEQ ID NO: 214. In some embodiments, the polypeptide comprises SEQ ID NO: 214. In some embodiments, the polypeptide consists of SEQ ID NO: 214. [248] In some embodiments, the polypeptide comprises an amino acid sequence having at least 80% identity to SEQ ID NO: 389. In some embodiments, the polypeptide comprises an amino acid sequence having at least 85% identity to SEQ ID NO: 389. In some embodiments, the polypeptide comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 389. In some

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embodiments, the polypeptide comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 389. In some embodiments, the polypeptide comprises an amino acid sequence having at least 98% identity to SEQ ID NO: 389. In some embodiments, the polypeptide comprises SEQ ID NO: 389. In some embodiments, the polypeptide consists of SEQ ID NO: 389. [249] In some embodiments, the polypeptide comprises an amino acid sequence having at least 80% identity to SEQ ID NO: 390. In some embodiments, the polypeptide comprises an amino acid sequence having at least 85% identity to SEQ ID NO: 390. In some embodiments, the polypeptide comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 390. In some embodiments, the polypeptide comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 390. In some embodiments, the polypeptide comprises an amino acid sequence having at least 98% identity to SEQ ID NO: 390. In some embodiments, the polypeptide comprises SEQ ID NO: 390. In some embodiments, the polypeptide consists of SEQ ID NO: 390. [250] In some embodiments, the polypeptide comprises an amino acid sequence having at least 80% identity to SEQ ID NO: 391. In some embodiments, the polypeptide comprises an amino acid sequence having at least 85% identity to SEQ ID NO: 391. In some embodiments, the polypeptide comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 391. In some embodiments, the polypeptide comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 391. In some embodiments, the polypeptide comprises an amino acid sequence having at least 98% identity to SEQ ID NO: 391. In some embodiments, the polypeptide comprises SEQ ID NO: 391. In some embodiments, the polypeptide consists of SEQ ID NO: 391. [251] In some embodiments, the polypeptide comprises an amino acid sequence having at least 80% identity to SEQ ID NO: 441. In some embodiments, the polypeptide comprises an amino acid sequence having at least 85% identity to SEQ ID NO: 441. In some embodiments, the polypeptide comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 441. In some embodiments, the polypeptide comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 441. In some embodiments, the polypeptide comprises an amino acid sequence having at least 98% identity to SEQ ID NO: 441. In some embodiments, the polypeptide comprises SEQ ID NO: 441. In some embodiments, the polypeptide consists of SEQ ID NO: 441. [252] In some embodiments, the polypeptide comprises an amino acid sequence having at least 80% identity to SEQ ID NO: 442. In some embodiments, the polypeptide comprises an amino acid sequence having at least 85% identity to SEQ ID NO: 442. In some embodiments, the polypeptide comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 442. In some embodiments, the polypeptide comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 442. In some embodiments, the polypeptide comprises an amino acid sequence having at least 98% identity to SEQ ID NO: 442. In some embodiments, the polypeptide comprises SEQ ID NO: 442. In some embodiments, the polypeptide consists of SEQ ID NO: 442. [253] In some embodiments, the polypeptide comprises an amino acid sequence having at least 80% identity to SEQ ID NO: 452. In some embodiments, the polypeptide comprises an amino acid sequence

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having at least 85% identity to SEQ ID NO: 452. In some embodiments, the polypeptide comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 452. In some embodiments, the polypeptide comprises an amino acid sequence having at least 95% identity to SEQ ID NO: 452. In some embodiments, the polypeptide comprises an amino acid sequence having at least 98% identity to SEQ ID NO: 452. In some embodiments, the polypeptide comprises SEQ ID NO: 452. In some embodiments, the polypeptide consists of SEQ ID NO: 452. [254] Non-limiting examples of other AFFIMER^® polypeptides that can be used in accordance with the disclosure include those described in International Publication Nos. WO2019/197583, WO2022/023540, WO2021/075930, WO2021/074683, WO2021/074695, WO2022/023538, WO2022/094262, WO2022/094237, WO2022/234003, WO2023/057567, and WO2023/057946, and WO2023/218243, each of which is incorporated by reference with respect the AFFIMER^® polypeptides described therein. [255] Other non-limiting examples of binding moieties include aptamers, ligands, receptor-binding domains, receptors, and small molecules. In some embodiments, a binding moiety is an aptamer. In some embodiments, a binding moiety is ligand. In some embodiments, a binding moiety is a receptor-binding domain. In some embodiments, a binding moiety is a receptor. In some embodiments, a binding moiety is a small molecule (e.g., a low molecular weight organic compound, typically less than 1,000 Daltons). [256] A binding moiety (e.g., antibody or AFFIMER^® polypeptide) of the disclosure can target (specifically bind to) any cancer target described herein. For example, a binding moiety can target disease antigens, such as cancer antigens (e.g., expressed on a solid tumor). In some embodiments, a cancer antigen is expressed by head and neck cancer cells (e.g., salivary gland cancer, squamous cell carcinoma of the head and neck (SCCHN), and/or adenoid cystic carcinoma), soft tissue sarcoma cells (e.g., undifferentiated pleomorphic sarcoma and/or dedifferentiated liposarcoma), breast cancer cells (e.g., triple-negative breast cancer), lung cancer cells (e.g., non-small cell lung cancer (NSCLC)), gastric cancer cells, colorectal cancer cells, and pancreatic ductal adenocarcinoma cells. In some embodiments, a cancer antigen is expressed by a cancer selected from pancreatic cancer, esophageal cancer, sarcoma, colorectal cancer, breast cancer (e.g., HR+ breast cancer or TNBC), NSCLC, SCLC, gastric cancer, ovarian cancer, and cholangiocarcinoma. [257] Non-limiting examples of cancer antigens expressed by head and neck cancer cells include [interlukin-8 (IL-8), melanoma associated antigens (MAGE), cytokeratin, E48 antigen, cathepsin D, pS2, P-glycoprotein, proliferating cell nuclear antigen (PCNA), TGF-a, TGG-b, E-cadherin, membrane type 1 matrix metalloprotease (MT1-MMP), CK19, CK8,Beta 2-microglobulin,CD 44,CD 80,1- ACT,CA125,Cyfra21-1, Cyclin D1, Ki6758, CKD2,MIB, C-erb2, and TGF-α. In some embodiments, a binding moiety is an antibody that binds to a head and neck cancer antigen selected from etuximab, nivolumab, pembrolizumab, ramucirumab, durvalumab, avelumab, trastuzumab, panitumumab, ipilimumab, necitumumab, zalutumumab, ofatumumab, blinatumomab, dostarlimab, elotuzumab, tisotumab vedotin, margetuximab, glembatumumab vedotin, enfortumab vedotin, cemiplimab, loncastuximab tesirine, trastuzumab deruxtecan, ipilimumab-nivolumab combination therapy,

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spartalizumab, rilotumumab, and onartuzumab. In some embodiments, a binding moiety is an AFFIMER^® polypeptide that binds to a head and neck cancer antigen. [258] Non-limiting examples of cancer antigens expressed by soft tissue sarcoma cells include MYF4, MYF3, FLI1, erythroblast transformation-specific transcription factor (ERG), Brachyury, SOX10, SATB2, β-catenin, MDM2, CDK4, SMARCB1, SDHB, TFE3, ALK, STAT6, DOG1, TLE1, MUC4, GRIA2, CD34, desmin, epithelial membrane antigen (EMA), keratin cocktail AE1/AE3, S100 protein, and alpha smooth muscle actin (α-SMA), CD31, KIT, Ano-1, α-fetoprotein, OCT3/4, SALL4m, CD30, placental alkaline phosphatase (PLAP), cytokeratin, actin, caldesmon, myoglobin, myogenin, CD45, CD20, CD79a, CD15, CD1a, CD68, CD3, myeloperoxidase, TdT, CD21, CD23, CD36, Von Willebrand factor, neuron -specific endolase, CD56, CD57, PGP5.5, synaptophysin, chromogranin, neuro N, neurofilaments, HMB-45, micropthalmia transcription factor (MITF), Melan-A, FLI1, AP1β, TLE1, ROS1, NR4A3, BCL2, WT1, MYC, NUT, BCL6, ZAP70, SDHB/A, and NY-ESO-1. In some embodiments, a binding moiety is an antibody that binds to a soft tissue sarcoma antigen selected from olaratumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, trastuzumab, cetuximab, panitumumab, ramucirumab, ipilimumab, necitumumab, blinatumomab, dostarlimab, enfortumab vedotin, tisotumab vedotin, margetuximab, glembatumumab vedotin, elotuzumab, onartuzumab, trastuzumab deruxtecan, anetumab ravtansine, nivolumab-ipilimumab combination therapy, spartalizumab, rilotumumab, larotrectinib, gemtuzumab ozogamicin, figitumumab, emtansine, zalutumumab, and ofatumumab. In some embodiments, a binding moiety is an AFFIMER^® polypeptide that binds to a soft tissue sarcoma antigen. [259] Non-limiting examples of cancer antigens expressed by breast cancer cells include HER2, estrogen receptor (ER), progesterone receptor (PR), MUC1, EGFR, NY-ESO-1, Mammaglobin-A, BRCA1, BRCA2, p53, CD24, CD44, GD2, B7-H4, CEA, TROP2, CXCR4, ERBB3, mesothelin, and cyclin D1. In some embodiments, a binding moiety is an antibody that binds to a breast cancer antigen selected from trastuzumab, pertuzumab, ado-trastuzumab emtansine, trastuzumab deruxtecan, bevacizumab, sacituzumab govitecan, margetuximab, pembrolizumab, nivolumab, ipilimumab, atezolizumab, durvalumab, cetuximab, catumaxomab, bevacizumab-awwb, trastuzumab-dttb, trastuzumab-qyyp, rituximab, tisotumab vedotin, elotuzumab, ibritumomab tiuxetan, panitumumab, brentuximab vedotin, polatuzumab vedotin, ramucirumab, glembatumumab vedotin, gemtuzumab ozogamicin, trastuzumab-pkrb, zanolimumab, amatuximab, figitumumab, necitumumab, vopratelimab, tremelimumab, blinatumomab, inotuzumab ozogamicin, daratumumab, ofatumumab, obinutuzumab, etigilimab, zimberelimab, spartalizumab, nivolumab-relatlimab, cemiplimab, amivantamab, anetumab ravtansine, enfortumab vedotin, larotrectinib, and ipilimumab-relatlimab. In some embodiments, a binding moiety is an AFFIMER^® polypeptide that binds to a breast cancer antigen. [260] Non-limiting examples of cancer antigens expressed by lung cancer cells include GFR, ALK, KRAS, PD-L1, ROS1, MET, HER2, BRAF, RET, TP53, CEA, MUC1, NY-ESO-1, WT1, Mesothelin, Survivin, CA-125, TROP2, CD56, and GD2. In some embodiments, a binding moiety is an antibody that binds to a lung cancer antigen selected from pembrolizumab, nivolumab, atezolizumab, durvalumab,

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avelumab, cetuximab, necitumumab, ramucirumab, trastuzumab, ipilimumab, panitumumab, elotuzumab, trastuzumab deruxtecan, dostarlimab, onartuzumab, blinatumomab, figitumumab, zalutumumab, margetuximab, glembatumumab vedotin, enfortumab vedotin, amivantamab, anetumab ravtansine, cemiplimab, spartalizumab, larotrectinib, ibritumomab tiuxetan, ofatumumab, rilotumumab, loncastuximab tesirine, and tebentafusp. In some embodiments, a binding moiety is an AFFIMER^® polypeptide that binds to a lung cancer antigen. [261] Non-limiting examples of cancer antigens expressed by gastric cancer cells include HER2, EGFR, CEA, MUC1, PD-L1, VEGFR2, Claudin 18.2, MAGE-A3, NY-ESO-1, FGFR2, Mesothelin, Survivin, CD133, CD44, CA-72-4, p53, CEACAM5, Cyclin D1, AFP, and ALDH1. In some embodiments, a binding moiety is an antibody that binds to a gastric cancer antigen selected from trastuzumab, ramucirumab, pembrolizumab, nivolumab, ipilimumab, cetuximab, bevacizumab, trastuzumab deruxtecan, zolbetuximab, avelumab, durvalumab, atezolizumab, necitumumab, margetuximab, tremelimumab, panitumumab, rituximab, tisotumab vedotin, elotuzumab, blinatumomab, inotuzumab ozogamicin, gemtuzumab ozogamicin, glembatumumab vedotin, trastuzumab-qyyp, trastuzumab-dttb, bevacizumab-awwb, nivolumab-relatlimab, spartalizumab, cemiplimab, amivantamab, anetumab ravtansine, enfortumab vedotin, daratumumab, ofatumumab, obinutuzumab, epcoritamab, vopratelimab, zanolimumab, amatuximab, figitumumab, necitumumab, zimberelimab, larotrectinib, pertuzumab, pralatrexate, onartuzumab, nivolumab-ipilimumab combination, and ipilimumab-relatlimab. In some embodiments, a binding moiety is an AFFIMER^® polypeptide that binds to a gastric cancer antigen. [262] Non-limiting examples of cancer antigens expressed by colorectal cancer cells include CEA, EGFR, HER2, MUC1, KRAS, BRAF, TP53, PD-L1, VEGF, CD133, CD44, CA-19-9, TROP2, NY-ESO- 1, MAGE-A3, Mesothelin, CEACAM5, ALDH1, Claudin 18.2, and Survivin. In some embodiments, a binding moiety is an antibody that binds to a colorectal cancer antigen selected from cetuximab, panitumumab, bevacizumab, ramucirumab, trastuzumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, avelumab, necitumumab, zalutumumab, ipilimumab, dostarlimab, enfortumab vedotin, elotuzumab, margetuximab, glembatumumab vedotin, trastuzumab deruxtecan, onartuzumab, rilotumumab, figitumumab, blinatumomab, loncastuximab tesirine, spartalizumab, cemiplimab, ibritumomab tiuxetan, ofatumumab, talimogene laherparepvec, anetumab ravtansine, and tebentafusp. In some embodiments, a binding moiety is an AFFIMER^® polypeptide that binds to a colorectal cancer antigen. [263] Non-limiting examples of cancer antigens expressed by pancreatic ductal adenocarcinoma cells include CA19-9, CEA, MUC1, MUC4, KRAS, p53, EGFR, PD-L1, Mesothelin, CEACAM6, Claudin 18.2, VEGF, TROP2, CD44, CD133, ALDH1, WT1, NY-ESO-1, Survivin, and Glypican-1. In some embodiments, a binding moiety is an antibody that binds to a pancreatic ductal adenocarcinoma antigen selected from rastuzumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, cetuximab, ramucirumab, necitumumab, ipilimumab, panitumumab, elotuzumab, dostarlimab, avelumab, margetuximab, glembatumumab vedotin, onartuzumab, figitumumab, blinatumomab, enfortumab

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vedotin, talimogene laherparepvec, rilotumumab, trastuzumab deruxtecan, loncastuximab tesirine, spartalizumab, cemiplimab, zalutumumab, ibritumomab tiuxetan, ofatumumab, anetumab ravtansine, tebentafusp, and olaratumab. In some embodiments, a binding moiety is an AFFIMER^® polypeptide that binds to a pancreatic ductal adenocarcinoma antigen. [264] A binding moiety, such as an AFFIMER® polypeptide or antibody, in some embodiments, binds to an antigen selected from the following antigens: 5T4, ADAM17, ADAM9, ALK, angiopoietin2, Axl, AXL, B7H3, B7H4, BAFF, BCMA, BSG, c-kit, CA-IX, CA125, CA6, CAIX, CCR5, CCR7, CD123, CD134, CD137, CD138, CD152, CD184, CD19, CD20, CD200, CD205, CD22, CD221, CD228, CD23, CD24, CD25, CD27, CD276, CD279, CD28, CD30, CD319, CD33, CD37, CD38, CD40, CD44, CD45, CD46, CD47, CD51, CD52, CD56, CD7, CD70, CD73, CD74, CD79B, CD79b, CD80, CD99, CDH3, CDH6, CEACAM5, CEACAM6, CLAUDIN18.2, CLDN6, CLDN9, CLL-1, cMET, CSF-R1, CSF2, CTGF, CTLA4, CXCR4, DCLK1, DDR1, DLK1, DLL3, DLL4, DPEP3, DR5, DSG2, EDB-Fn, EFNA4, EGFL7, EGFR, ENB-FN, ENO1, ENPP3, EpCAM, EphA2, EphA3, ETB, FAP, FCRL5, FGFR2, FGFR3, Flt3, FOLR, FR1, FRα, FUT3, GC-C, GD3, gelatinase B, Globo H, GLUT1, glypican3, GPNMB, GPR20, GPRC5D, GUCY2C, HER1, HER2, HER3, HGFR, HLA-DR, ICOSL, IGF-1R, IGF1, IGF2, IL17A, IL17F, IL1RAP, IL2, IL6, ITGB6, KAAG1, KIR2D, LAG3, LAMP-1, Lewis-Y antigen, LIV-1, LIV1, LRRC15, LTα, Ly6E, LYPD3, MIF, MSLN, Muc1, MUC1, Muc16, MUC5AC, Nectin-4, Notch-3, Notch1, OAcGD2, PCDP1, PDL1, PDL2, p53, PRL receptor, PSMA, PTK7, RON, ROR1, ROR2, RNF43, SDC1, SEZ6, SLAMF2, SLAMF6, SLAMF7, SSEA-4, sTn, STEAP1, TAG72, TAA, TDGF1, TEM1, Tenascin C, TF (Tissue Factor), TGFb, TIGIT, TIM1, TNF-α, TNFR, TRAIL, TRAIL- R2, TROP2, TWEAKR, TYRP1, VEGF2, VEGFR2, Vimentin, and VISTA. [265] A binding moiety, such as an AFFIMER® polypeptide or antibody, in some embodiments, binds to an antigen selected from the following antigens: CEACAM5, CLAUDIN18.2, CLAUDIN4, CMET, DLL3, EDB-FN, FAP, FRα, HER2, HER3, LLRC15, Nectin-4, TF (Tissue Factor), and TROP2. [266] In some embodiments, a binding moiety specifically binds to 5T4. In some embodiments, a binding moiety specifically binds to ADAM17. In some embodiments, a binding moiety specifically binds to ADAM9. In some embodiments, a binding moiety specifically binds to ALK. In some embodiments, a binding moiety specifically binds to angiopoietin2. In some embodiments, a binding moiety specifically binds to Axl. In some embodiments, a binding moiety specifically binds to AXL. In some embodiments, a binding moiety specifically binds to B7H3. In some embodiments, a binding moiety specifically binds to B7H4. In some embodiments, a binding moiety specifically binds to BAFF. In some embodiments, a binding moiety specifically binds to BCMA. In some embodiments, a binding moiety specifically binds to BSG. In some embodiments, a binding moiety specifically binds to c-kit. In some embodiments, a binding moiety specifically binds to CA-IX. In some embodiments, a binding moiety specifically binds to CA125. In some embodiments, a binding moiety specifically binds to CA6. In some embodiments, a binding moiety specifically binds to CAIX. In some embodiments, a binding moiety specifically binds to CCR5. In some embodiments, a binding moiety specifically binds to CCR7. In some embodiments, a binding moiety specifically binds to CD123. In some embodiments, a binding

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moiety specifically binds to CD134. In some embodiments, a binding moiety specifically binds to CD137. In some embodiments, a binding moiety specifically binds to CD138. In some embodiments, a binding moiety specifically binds to CD152. In some embodiments, a binding moiety specifically binds to CD184. In some embodiments, a binding moiety specifically binds to CD19. In some embodiments, a binding moiety specifically binds to CD20. In some embodiments, a binding moiety specifically binds to CD200. In some embodiments, a binding moiety specifically binds to CD205. In some embodiments, a binding moiety specifically binds to CD22. In some embodiments, a binding moiety specifically binds to CD221. In some embodiments, a binding moiety specifically binds to CD228. In some embodiments, a binding moiety specifically binds to CD23. In some embodiments, a binding moiety specifically binds to CD24. In some embodiments, a binding moiety specifically binds to CD25. In some embodiments, a binding moiety specifically binds to CD27. In some embodiments, a binding moiety specifically binds to CD276. In some embodiments, a binding moiety specifically binds to CD279. In some embodiments, a binding moiety specifically binds to CD28. In some embodiments, a binding moiety specifically binds to CD30. In some embodiments, a binding moiety specifically binds to CD319. In some embodiments, a binding moiety specifically binds to CD33. In some embodiments, a binding moiety specifically binds to CD37. In some embodiments, a binding moiety specifically binds to CD38. In some embodiments, a binding moiety specifically binds to CD40. In some embodiments, a binding moiety specifically binds to CD44. In some embodiments, a binding moiety specifically binds to CD45. In some embodiments, a binding moiety specifically binds to CD46. In some embodiments, a binding moiety specifically binds to CD47. In some embodiments, a binding moiety specifically binds to CD51. In some embodiments, a binding moiety specifically binds to CD52. In some embodiments, a binding moiety specifically binds to CD56. In some embodiments, a binding moiety specifically binds to CD7. In some embodiments, a binding moiety specifically binds to CD70. In some embodiments, a binding moiety specifically binds to CD73. In some embodiments, a binding moiety specifically binds to CD74. In some embodiments, a binding moiety specifically binds to CD79b. In some embodiments, a binding moiety specifically binds to CD79B. In some embodiments, a binding moiety specifically binds to CD80. In some embodiments, a binding moiety specifically binds to CD99. In some embodiments, a binding moiety specifically binds to CDH3. In some embodiments, a binding moiety specifically binds to CDH6. In some embodiments, a binding moiety specifically binds to CEACAM5. In some embodiments, a binding moiety specifically binds to CEACAM6. In some embodiments, a binding moiety specifically binds to CLAUDIN18.2. In some embodiments, a binding moiety specifically binds to CLDN6. In some embodiments, a binding moiety specifically binds to CLDN9. In some embodiments, a binding moiety specifically binds to CLL- 1. In some embodiments, a binding moiety specifically binds to cMET. In some embodiments, a binding moiety specifically binds to CSF-R1. In some embodiments, a binding moiety specifically binds to CSF2. In some embodiments, a binding moiety specifically binds to CTGF. In some embodiments, a binding moiety specifically binds to CTLA4. In some embodiments, a binding moiety specifically binds to CXCR4. In some embodiments, a binding moiety specifically binds to DCLK1. In some embodiments, a binding moiety specifically binds to DDR1. In some embodiments, a binding moiety specifically binds to

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DLK1. In some embodiments, a binding moiety specifically binds to DLL3. In some embodiments, a binding moiety specifically binds to DLL4. In some embodiments, a binding moiety specifically binds to DPEP3. In some embodiments, a binding moiety specifically binds to DR5. In some embodiments, a binding moiety specifically binds to DSG2. In some embodiments, a binding moiety specifically binds to EDB-Fn. In some embodiments, a binding moiety specifically binds to EFNA4. In some embodiments, a binding moiety specifically binds to EGFL7. In some embodiments, a binding moiety specifically binds to EGFR. In some embodiments, a binding moiety specifically binds to ENB-FN. In some embodiments, a binding moiety specifically binds to ENO1. In some embodiments, a binding moiety specifically binds to ENPP3. In some embodiments, a binding moiety specifically binds to EpCAM. In some embodiments, a binding moiety specifically binds to EphA2. In some embodiments, a binding moiety specifically binds to EphA3. In some embodiments, a binding moiety specifically binds to ETB. In some embodiments, a binding moiety specifically binds to FAP. In some embodiments, a binding moiety specifically binds to FCRL5. In some embodiments, a binding moiety specifically binds to FGFR2. In some embodiments, a binding moiety specifically binds to FGFR3. In some embodiments, a binding moiety specifically binds to Flt3. In some embodiments, a binding moiety specifically binds to FOLR. In some embodiments, a binding moiety specifically binds to FR1. In some embodiments, a binding moiety specifically binds to FRα. In some embodiments, a binding moiety specifically binds to FUT3. In some embodiments, a binding moiety specifically binds to GC-C. In some embodiments, a binding moiety specifically binds to GD3. In some embodiments, a binding moiety specifically binds to gelatinase B. In some embodiments, a binding moiety specifically binds to Globo H. In some embodiments, a binding moiety specifically binds to GLUT1. In some embodiments, a binding moiety specifically binds to glypican3. In some embodiments, a binding moiety specifically binds to GPNMB. In some embodiments, a binding moiety specifically binds to GPR20. In some embodiments, a binding moiety specifically binds to GPRC5D. In some embodiments, a binding moiety specifically binds to GUCY2C. In some embodiments, a binding moiety specifically binds to HER1. In some embodiments, a binding moiety specifically binds to HER2. In some embodiments, a binding moiety specifically binds to HER3. In some embodiments, a binding moiety specifically binds to HGFR. In some embodiments, a binding moiety specifically binds to HLA- DR. In some embodiments, a binding moiety specifically binds to ICOSL. In some embodiments, a binding moiety specifically binds to IGF-1R. In some embodiments, a binding moiety specifically binds to IGF1. In some embodiments, a binding moiety specifically binds to IGF2. In some embodiments, a binding moiety specifically binds to IL17A. In some embodiments, a binding moiety specifically binds to IL17F. In some embodiments, a binding moiety specifically binds to IL1RAP. In some embodiments, a binding moiety specifically binds to IL2. In some embodiments, a binding moiety specifically binds to IL6. In some embodiments, a binding moiety specifically binds to ITGB6. In some embodiments, a binding moiety specifically binds to KAAG1. In some embodiments, a binding moiety specifically binds to KIR2D. In some embodiments, a binding moiety specifically binds to LAG3. In some embodiments, a binding moiety specifically binds to LAMP-1. In some embodiments, a binding moiety specifically binds to Lewis-Y antigen. In some embodiments, a binding moiety specifically binds to LIV-1. In some

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embodiments, a binding moiety specifically binds to LIV1. In some embodiments, a binding moiety specifically binds to LRRC15. In some embodiments, a binding moiety specifically binds to LTα. In some embodiments, a binding moiety specifically binds to Ly6E. In some embodiments, a binding moiety specifically binds to LYPD3. In some embodiments, a binding moiety specifically binds to MIF. In some embodiments, a binding moiety specifically binds to MSLN. In some embodiments, a binding moiety specifically binds to Muc1. In some embodiments, a binding moiety specifically binds to MUC1. In some embodiments, a binding moiety specifically binds to Muc16. In some embodiments, a binding moiety specifically binds to MUC5AC. In some embodiments, a binding moiety specifically binds to Nectin-4. In some embodiments, a binding moiety specifically binds to Notch-3. In some embodiments, a binding moiety specifically binds to Notch1. In some embodiments, a binding moiety specifically binds to OAcGD2. In some embodiments, a binding moiety specifically binds to p53. In some embodiments, a binding moiety specifically binds to PCDP1. In some embodiments, a binding moiety specifically binds to PDL1. In some embodiments, a binding moiety specifically binds to PDL2. In some embodiments, a binding moiety specifically binds to PRL receptor. In some embodiments, a binding moiety specifically binds to PSMA. In some embodiments, a binding moiety specifically binds to PTK7. In some embodiments, a binding moiety specifically binds to RNF43. In some embodiments, a binding moiety specifically binds to RON. In some embodiments, a binding moiety specifically binds to ROR1. In some embodiments, a binding moiety specifically binds to ROR2. In some embodiments, a binding moiety specifically binds to SDC1. In some embodiments, a binding moiety specifically binds to SEZ6. In some embodiments, a binding moiety specifically binds to SLAMF2. In some embodiments, a binding moiety specifically binds to SLAMF6. In some embodiments, a binding moiety specifically binds to SLAMF7. In some embodiments, a binding moiety specifically binds to SLITRK6. In some embodiments, a binding moiety specifically binds to SSEA-4. In some embodiments, a binding moiety specifically binds to STEAP1. In some embodiments, a binding moiety specifically binds to sTn. In some embodiments, a binding moiety specifically binds to TAA. In some embodiments, a binding moiety specifically binds to TAG72. In some embodiments, a binding moiety specifically binds to TDGF1. In some embodiments, a binding moiety specifically binds to TEM1. In some embodiments, a binding moiety specifically binds to Tenascin C. In some embodiments, a binding moiety specifically binds to TF (Tissue Factor). In some embodiments, a binding moiety specifically binds to TGFb. In some embodiments, a binding moiety specifically binds to TIGIT. In some embodiments, a binding moiety specifically binds to TIM1. In some embodiments, a binding moiety specifically binds to TNF-α. In some embodiments, a binding moiety specifically binds to TNFR. In some embodiments, a binding moiety specifically binds to TRAIL. In some embodiments, a binding moiety specifically binds to TRAIL-R2. In some embodiments, a binding moiety specifically binds to TROP2. In some embodiments, a binding moiety specifically binds to TWEAKR. In some embodiments, a binding moiety specifically binds to TYRP1. In some embodiments, a binding moiety specifically binds to VEGF2. In some embodiments, a binding moiety specifically binds to VEGFR2. In some embodiments, a binding moiety specifically binds to vimentin. In some embodiments, a binding moiety specifically binds to VISTA.

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[267] Some aspects of the disclosure related a method of treating cancer, such as a solid tumor, comprising administering to the subject a therapeutically effective amount of a construct (e.g., an antibody-drug conjugate or AFFIMER®-drug conjugate) provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to an antigen selected from CEACAM5, CLAUDIN18.2, CLAUDIN4, CMET, DLL3, EDB-FN, FAP, FRα, HER2, HER3, LLRC15, Nectin-4, TF (Tissue Factor), TROP2. [268] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to CEACAM5. In some embodiments, a binding moiety comprises labetuzumab, M9140, cibisatamab, LM-24C5, NEO-201, precemtabart tocentecan, actinium 225 labeled anti-CEA antibody, BA-1202, BGC-477, BGC-477, EBC-129, IBI-3020, NILK-2301, NILK-2401, PF-08046050, ABC-101, ATOR-4066, CEA ISAC, LM-004, NI-3301, PM-4008, TBADC-02, or GB-7012. In some embodiments, a binding moiety comprises tusamitamab (see, e.g., US Patent No.11,332,542). [269] Tusamitamab [270] Heavy Chain: EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGITYAPSTVK GRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQGTLVTVSSASTKGPSVF PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 504) [271] Light Chain: DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVPSRFSGSG SGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC (SEQ ID NO: 505) [272] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to CLAUDIN18.2. In some embodiments, a binding moiety comprises zolbetuximab (see, e.g., Davies M, Nucleic Acids Res.2015; 43(W1):W612-20). In some embodiments, a binding moiety comprises LM-302. In some embodiments, a binding moiety comprises IBI343. [273] Zolbetuximab [274] Heavy Chain:

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QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDSYTNYNQK FKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSWRGNSFDYWGQGTTLTVSSASTKGPSVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 506) [275] Light Chain: DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGV PDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKH KVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 507) [276] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to CLAUDIN4. In some embodiments, a binding moiety comprises ASP1002. In some embodiments, a binding moiety comprises KM3900 (see, e.g., US Patent No.8,076,458). [277] KM3900 [278] Heavy Chain: MGYSYIFLLSGTAGGLSEVQLQQSGPELVKPGASVKISCKASGYTFTDYYMNWVKQSHGKSLEY IGAVVPNNGVPTYNQKFKGKATLTVDKSSSTAYMELRSLTSEDSAVYYCARPHYYYAGRSGAMD YWGQGTSVTVSS (SEQ ID NO: 508) [279] Light Chain: MDFQVQIFSFLLISASVIMSRGQIVLTQSPAIMSASLGERVTMTCTASSTVSSTYLHWYQQKPGSSP KLYIYSTSNLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCHQYHRSPPTFGGGTKLEIK (SEQ ID NO: 509) [280] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to CMET (C-MET). In some embodiments, a binding moiety comprises telisotuzumab. In some embodiments, a binding moiety comprises REGN5093. In some embodiments, a binding moiety comprises MYTX-011. In some embodiments, a binding moiety comprises rilotumumab (see, e.g., Kanehusa, M et al. Nucleic Acids Research.2016, 44(D1), D457–D462). In some embodiments, a binding moiety comprises farletuzumab (see, e.g., Davies M, Nucleic Acids Res.2015; 43(W1):W612- 20). In some embodiments, a binding moiety comprises rovalpituzumab (see, e.g., Kanehusa, M et al. Nucleic Acids Research.2016, 44(D1), D457–D462). In some embodiments, a binding moiety comprises tisotumab (see, e.g., Kanehusa, M et al. Nucleic Acids Research.2016, 44(D1), D457–D462).

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[281] Rilotumumab [282] Heavy Chain: QVQLQESGPGLVKPSETLSLTCTVSGGSISIYYWSWIRQPPGKGLEWIGYVYYSGSTNYNPSLKSR VTISVDTSKNQFSLKLNSVTAADTAVYYCARGGYDFWSGYFDYWGQGTLVTVSSASTKGPSVFP LAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNF GTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHDWLNGKEYKCKVSN KGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 510) [283] Light Chain: EIVMTQSPATLSVSPGERATLSCRASQSVDSNLAWYRQKPGQAPRLLIYGASTRATGIPARFSGSG SGTEFTLTISSLQSEDFAVYYCQQYINWPPITFGQGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVV CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC (SEQ ID NO: 511) [284] Farletuzumab [285] Heavy Chain: EVQLVESGGGVVQPGRSLRLSCSASGFTFSGYGLSWVRQAPGKGLEWVAMISSGGSYTYYADSV KGRFAISRDNAKNTLFLQMDSLRPEDTGVYFCARHGDDPAWFAYWGQGTPVTVSSASTKGPSVF PLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSS LGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 512) [286] Light Chain: DIQLTQSPSSLSASVGDRVTITCSVSSSISSNNLHWYQQKPGKAPKPWIYGTSNLASGVPSRFSGS GSGTDYTFTISSLQPEDIATYYCQQWSSYPYMYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGT ASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVY ACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 513) [287] Rovalpituzumab [288] Heavy Chain: QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYA DDFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARIGDSSPSDYWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESN

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GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 514) [289] Light Chain: EIVMTQSPATLSVSPGERATLSCKASQSVSNDVVWYQQKPGQAPRLLIYYASNRYTGIPARFSGSG SGTEFTLTISSLQSEDFAVYYCQQDYTSPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVV CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC (SEQ ID NO: 515) [290] Tisotumab [291] Heavy Chain: EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSSISGSGDYTYYTDSV KGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSPWGYYLDSWGQGTLVTVSSASTKGPSVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 516) [292] Light Chain: DIQMTQSPPSLSASAGDRVTITCRASQGISSRLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGS GTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC (SEQ ID NO: 517) [293] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to DLL3. In some embodiments, a binding moiety comprises tisotumab. [294] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to EDB-FN. In some embodiments, a binding moiety comprises radretumab, for example, formatted on hIgG1 (“L19”: see, e.g., Pini A, et al. J Biol Chem.1998 Aug 21;273(34):21769- 76). [295] Radretumab reformatted on hIgG1 [296] Heavy Chain: EVQLLESGGGLVQPGGSLRLSCAASGFTFSSFSMSWVRQAPGKGLEWVSSISGSSGTTYYADSVK GRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPFPYFDYWGQGTLVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQT YICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVV

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VDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENN YKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 518) [297] Light Chain: EIVLTQSPGTLSLSPGERATLSCRASQSVSSSFLAWYQQKPGQAPRLLIYYASSRATGIPDRFSGSG SGTDFTLTISRLEPEDFAVYYCQQTGRIPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC (SEQ ID NO: 519) [298] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to FAP. In some embodiments, a binding moiety comprises OMTX-705. In some embodiments, a binding moiety comprises BI-765179. In some embodiments, a binding moiety comprises GEN-1057. In some embodiments, a binding moiety comprises sibrotuzumab (see, e.g., US Patent No.20,090,304,718). [299] Sibrotuzumab [300] Heavy Chain: MGWSGVFIFILSGTAGVQSQVQLQQSGAELARPGASVNLSCKASGYTFTNNGINWLKQRTGQGL EWIGEIYPRSTNTLYNEKFKGKATLTADRSSNTAYMGLRSKTSGDSAVYFLVTVSAAKTTAPSVYP LAP (SEQ ID NO: 520) [301] Light Chain: MDFQVQIFSFLLISASVIISRGQIVLTQSPAIMSASPGEKVTMTCSASSGVNFMHWYQQKSGTSPK RWIFDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWSFNPPTFGGGTKLEIKRAD AAPTVS (SEQ ID NO: 521) [302] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to FRα. In some embodiments, a binding moiety comprises mirvetuximab. In some embodiments, a binding moiety comprises farletuzumab. [303] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to HER2. In some embodiments, a binding moiety comprises an antibody of Kadcyla, Enhertu, or RC48. In some embodiments, a binding moiety comprises trastuzumab (see, e.g., Ménard S., et al. Oncogene.2003 Sep 29;22(42):6570-8). In some embodiments, a binding moiety comprises pertuzumab (see, e.g., Adams C, Cancer Immunol Immunother.2006 Jun;55(6):717-27).

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[304] Trastuzumab [305] Heavy Chain: EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSV KGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 522) [306] Light Chain: DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSR SGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVV CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC (SEQ ID NO: 523) [307] Pertuzumab [308] Heavy Chain: EVQLVESGGGLVQPGGSLRLSCAASGFTFTDYTMDWVRQAPGKGLEWVADVNPNSGGSIYNQR FKGRFTLSVDRSKNTLYLQMNSLRAEDTAVYYCARNLGPSFYFDYWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEY KCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESN GQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 524) [309] Light Chain: DIQMTQSPSSLSASVGDRVTITCKASQDVSIGVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSG SGTDFTLTISSLQPEDFATYYCQQYYIYPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVV CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC (SEQ ID NO: 525) [310] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to HER3. In some embodiments, a binding moiety comprises zenocutuzumab. In some embodiments, a binding moiety comprises patritumab (see, e.g., Davies M, Nucleic Acids Res.2015; 43(W1):W612-20). In some embodiments, a binding moiety comprises seribantumab. In some embodiments, a binding moiety comprises lumretuzumab.

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[311] Patritumab [312] Heavy Chain: QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLK SRVTISVETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFDLWGRGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG TQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKC KVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 526) [313] Light Chain: DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNPGQPPKLLIYWASTRESGVPD RFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKS GTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHK VYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 527) [314] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to LRRC15. In some embodiments, a binding moiety comprises LNTH-2403. In some embodiments, a binding moiety comprises SOT-106. In some embodiments, a binding moiety comprises ZL-6201. In some embodiments, a binding moiety comprises LRRC15-CD3. In some embodiments, a binding moiety comprises mAb211. In some embodiments, a binding moiety comprises samrotamab (see, e.g., US Patent No.11,045,480). In some embodiments, a binding moiety comprises ABBV-085 (see, e.g., International Publication No. WO2017/095805). [315] Samrotamab [316] Heavy Chain: EVQLVQSGAEVKKPGASVKVSCKASGYKFSSYWIEWVKQAPGQGLEWIGEILPGSDTTNYNEK FKDRATFTSDTSINTAYMELSRLRSDDTAVYYCARDRGNYRAWFGYWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWES NGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 528) [317] Light Chain: DIQMTQSPSSLSASVGDRVTITCRASQDISNYLNWYQQKPGGAVKFLIYYTSRLHSGVPSRFSGSG SGTDYTLTISSLQPEDFATYFCQQGEALPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVV

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CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC (SEQ ID NO: 529) [318] ABBV-085 [319] Heavy Chain: EVQLVQSGAEVKKPGASVKVSCKASGYKFSSYWIEWVKQAPGQGLEWIGSILPGSDTTNYNEKF KDRATFTSDTSINTAYMELSRLRSDDTAVYYCARDRGNYRAWFGYWGQGTLVTVSSASTKGPSV FPLAPSSKSTSGGTAllLGCLVKDYFPEPVTVSFVNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTP EVTCVLVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDfvLNGKEY KCKVSNKALPAPIEKTISKllKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP (SEQ ID NO: 530) [320] Light Chain: DIQMRQSPSSLSASVGDRVRIICRASODISNYLNWYQQKPGGAVKFLIYYISRLHSGVPSRFSGSG SGRDYLLIISSLQPEDFATYFCQQGEALPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVV CLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEV THQGLSSPVTKSFNRGEC (SEQ ID NO: 531) [321] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to Nectin-4. In some embodiments, a binding moiety comprises enfortumab (see, e.g., US Patent No.9,314, 538). In some embodiments, a binding moiety comprises ADRX‑0706. In some embodiments, a binding moiety comprises LY4052031. [322] Enfortumab [323] Heavy Chain: EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYNMNWVRQAPGKGLEWVSYISSSSSTIYYADSV KGRFTISRDNAKNSLSLQMNSLRDEDTAVYYCARAYYYGMDVWGQGTTVTVSSASTKGPSVFP LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL GTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYK CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNG QPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 532) [324] Light Chain: DIQMTQSPSSVSASVGDRVTITCRASQGISGWLAWYQQKPGKAPKFLIYAASTLQSGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQANSFPPTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACE VTHQGLSSPVTKSFNRGEC (SEQ ID NO: 533)

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[325] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to TF (Tissue Factor). In some embodiments, a binding moiety comprises tisotumab. [326] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to TROP2. In some embodiments, a binding moiety comprises sacituzumab (see, e.g., Zangard M, et al. Expert Opin Investig Drugs.2019 Feb;28(2):107-112). In some embodiments, a binding moiety comprises datopotamab. In some embodiments, a binding moiety comprises BNT325/DB-1305. [327] Sacituzumab [328] Heavy Chain: QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTYT DDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVSSASTK GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVT VPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMI SRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGK (SEQ ID NO: 534) [329] Light Chain: DIQLTQSPSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGSG SGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT HQGLSSPVTKSFNRGEC3 (SEQ ID NO: 535) [330] Some aspects relate to a method of treating a tumor in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct provided herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof wherein the binding moiety (Z) binds to BCMA, BCL2, BCL6, CD10, CD117 (c-Kit), CD123, CD13, CD138, CD184, CD19, CD20, CD21, CD22, CD23, CD274 (PD-L1), CD276 (B7-H3), CD30, CD303 (BDCA-2), CD304 (Neuropilin-1), CD317 (BST2), CD33, CD34, CD38, CD370 (CLEC9A), CD40, CD45, CD5, CD52, CD56, CD66, CD7, CD79A, CD79B, CD8, CD80, FCRL5, MUC1, PRAME, ROR1, SLAMF7 (CS1), TCL1, WT1, or c-MYC. In some embodiments, the tumor is a hematological tumor.

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Table 3. Antigens

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_[331] A binding moiety can be any one of the foregoing antibodies, AFFIMER^® polypeptides or any antibody or AFFIMER^® polypeptide that binds to any one or more of the foregoing cancer antigens.

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Species [332] In certain embodiments, the compound is selected from those in Table 4:

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0

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S } ;

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Y 0 Y Y T

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y y y

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and pharmaceutically acceptable salts thereof. [333] In certain embodiments, the construct is selected from those in Table 5A, and pharmaceutically acceptable salts thereof:

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*The binding moiety comprises FAP-1 or FAP-2 (SEQ ID NO: 213 or 214, respectively) comprising one or more cysteine modifications (e.g., cysteine substitutions) for conjugation to the maleimide reactive handle of LP1 or LP2.

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[334] In certain embodiments, the compound is selected from those in Table 5B:

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and pharmaceutically acceptable salts thereof.

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Pharmaceutical Compositions, Kits, and Administration [335] The present disclosure provides pharmaceutical compositions comprising a construct described herein (e.g., a construct of Formula (II′) or (II)) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers and/or excipients. In one aspect, provided herein is a pharmaceutical composition comprising a construct described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In certain embodiments, a construct described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. [336] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the construct described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit. [337] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage. [338] Relative amounts of the active ingredient, the pharmaceutically acceptable carrier or excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. [339] Pharmaceutically acceptable carriers/excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, solvents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, oils, butters, and/or waxes. Excipients such as coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition. [340] The constructs and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes of administration include intravenous administration (e.g., systemic intravenous injection) and direct intra-tumoral administration. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

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[341] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. [342] Constructs provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. [343] The exact amount of a construct required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular construct, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a construct described herein. [344] A construct or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The constructs or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, the additional agent is a chemotherapeutic agent. [345] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or construct described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or construct described herein.

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[346] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits provide instructions for treating a disease (e.g., cancer) in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition. Methods of Treatment and Uses [347] As described herein, constructs provided herein can deliver a camptothecin to FAP-expressing tissues (e.g., cancers). [348] In one aspect, provided herein are methods of treating a disease characterized by fibroblast activation protein (FAP) upregulation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided are constructs described herein (e.g., constructs of Formula (II′) or (II)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating a disease characterized by fibroblast activation protein (FAP) upregulation in a subject in need thereof. Also provided herein uses of constructs described herein (e.g., constructs of Formula (II′) or (II)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, as medicaments and/or in the preparation of medicaments (e.g., for treating a disease characterized by fibroblast activation protein (FAP) upregulation in a subject in need thereof). [349] In another aspect, provided herein are methods of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Also provided are constructs described herein (e.g., constructs of Formula (II′) or (II)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use in treating cancer in a subject in need thereof. Also provided herein uses of constructs described herein (e.g., constructs of Formula (II′) or (II)), and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, as medicaments and/or in the preparation of medicaments (e.g., for treating cancer). [350] In another aspect, provided herein are methods comprising administering to a subject a construct described herein (e.g., constructs of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject has a disease characterized by FAP upregulation. In some embodiments, the subject has cancer. [351] In some embodiments, the construct, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered by intravenous injection. [352] In some embodiments, the disorder characterized by FAP upregulation is cancer, fibrosis, or inflammation. In some embodiments, the disorder characterized by FAP upregulation is cancer. In some embodiments, the cancer is selected from head and neck cancer, soft tissue sarcoma, breast cancer, lung

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cancer, gastric cancer, colorectal cancer, pancreatic cancer, uterine cancer, ovarian cancer, cervical cancer, sarcoma, and melanoma. In some embodiments, the cancer is selected from head and neck cancer, soft tissue sarcoma, breast cancer, lung cancer, gastric cancer, colorectal cancer, pancreatic cancer, uterine cancer, ovarian cancer, and cervical cancer. In some embodiments, the cancer is selected from breast cancer, lung cancer, gastric cancer, pancreatic cancer, uterine cancer, ovarian cancer, and cervical cancer. In some embodiments, the cancer is triple-negative breast cancer (TNBC), gastric cancer, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), uterine cancer, ovarian cancer, pancreatic cancer, or cervical cancer. In some embodiments, the cancer is selected from head and neck cancer, soft tissue sarcoma, breast cancer, lung cancer, gastric cancer, colorectal cancer, and pancreatic ductal adenocarcinoma. In some embodiments, the cancer is head and neck cancer. In some embodiments, the head and neck cancer is salivary gland cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is soft tissue sarcoma. In some embodiments, the soft tissue sarcoma is undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is triple-negative breast cancer (TNBC). In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is pancreatic ductal adenocarcinoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is gastric cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is melanoma. [353] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. In certain embodiments, the cancer is a solid cancer. In certain embodiments, the cancer is a hematopoietic cancer (i.e., hematological cancer). [354] In certain embodiments, the cancer is a hematopoietic cancer (e.g., leukemia (e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B- cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma (e.g., Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL)), non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma)), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma, T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome)), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma,

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enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); a myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); multiple myeloma (MM); plasma cell neoplasia; familiar hypereosinophilia; inflammatory myofibroblastic tumors; immunocytic amyloidosis). In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is acute lymphoblastic leukemia (ALL). In certain embodiments, the cancer is early T-cell precursor (ETP)-acute lymphoblastic leukemia (ALL). [355] In certain embodiments, the cancer is musculoskeletal cancer (e.g., bone cancer (e.g., osteosarcoma, osteoid osteoma, malignant fibrous histiocytoma, Ewing’s sarcoma, chordoma, malignant giant cell tumor chordoma, chondrosarcoma osteochondroma, benign chondroma, chondroblastoma chondromyxofibroma, myelodysplastic syndrome (MDS)), muscle cancer (e.g., rhabdomyosarcoma, rhabdomyoma), connective tissue cancer, synovioma). [356] In certain embodiments, the cancer is a nervous system cancer (e.g., brain cancer (e.g., astrocytoma, medulloblastoma, glioma (e.g., astrocytoma, oligodendroglioma), glioblastomas, glioblastoma multiform, medulloblastoma, ependymoma, germinoma (i.e., pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, craniopharyngioma), spinal cord cancer, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroblastoma, primitive neuroectodermal tumors (PNT), meningeal cancer (e.g., meningioma, meningiosarcoma, gliomatosis), skull cancer, acoustic neuroma, ependymoma, hemangioblastoma, ocular cancer (e.g., intraocular melanoma, retinoblastoma)). [357] In certain embodiments, the cancer is selected from endocrine/exocrine cancers (e.g., thyroid cancer (e.g., papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma), pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors, ductal adenocarcinoma, insulinoma, glucagonoma, vipoma), adrenal gland cancer, neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), sebaceous gland carcinoma, sweat gland carcinoma). In certain embodiments, the cancer is sweat gland cancer (e.g., sweat gland carcinoma). [358] In certain embodiments, the cancer is liver cancer (e.g., hepatocellular cancer (HCC) (e.g., hepatocellular carcinoma, hepatoblastoma, hepatocellular adenoma), malignant hepatoma, hemangiomas, biliary cancer (e.g., cholangiocarcinoma)). [359] In certain embodiments, the cancer is head and neck cancer (e.g., squamous cell carcinoma of the head and neck (SCCHN), adenoid cystic carcinoma). In certain embodiments, the cancer is oral cancer (e.g., buccal cavity cancer, lip cancer, tongue cancer, mouth cancer, pharynx cancer, hypopharynx cancer (e.g., hypopharyngeal carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), salivary gland cancer). In certain embodiments, the

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cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma, esophageal adenocarcinoma, Barrett’s adenocarcinoma, esophageal leiomyosarcoma). [360] In certain embodiments, the cancer is gastrointestinal cancer (e.g., anal cancer, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), gall bladder cancer, gastric cancer (e.g., stomach cancer (e.g., stomach adenocarcinoma)), gastrointestinal stromal tumor (GIST), small bowel cancer (e.g., appendix cancer, small bowel carcinoma, e.g., small bowel adenocarcinoma), small intestine cancer, large bowel cancer, large intestine cancer). [361] In certain embodiments, the cancer is cardiovascular cancer (e.g., primary cardiac tumors, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma), cardiac myxoma, cardiac rhabdomyoma). [362] In certain embodiments, the cancer is lung cancer (e.g., bronchus cancer (e.g., bronchogenic carcinoma, bronchial adenoma), alveolar carcinoma, mesothelioma, small cell lung cancer (SCLC), non- small cell lung cancer (NSCLC), lung adenocarcinoma, chondromatous hamartoma, papillary adenocarcinoma). [363] In certain embodiments, the cancer is a genitourinary cancer (e.g., bladder cancer (e.g., urothelial carcinoma), urethral cancer, kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma), clear cell renal cell carcinoma, chromophobe renal cell carcinoma, papillary renal cell carcinoma, renal medullary cancer, nephroblastom),testicular cancer (e.g., seminoma, testicular embryonal carcinoma), germ cell cancer, prostate cancer (e.g., prostate adenocarcinoma), penile cancer (e.g., Paget’s disease of the penis and scrotum)). [364] In certain embodiments, the cancer is a gynecological cancer (e.g., endometrial cancer (e.g., uterine cancer (e.g., uterine sarcoma, choriocarcinoma), endometrial carcinoma), cervical cancer (e.g., cervical adenocarcinoma), ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), germ cell cancer, vulvar cancer (e.g., Paget’s disease of the vulva) vaginal cancer, fallopian tube cancer). [365] In certain embodiments, the cancer is breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, triple negative breast cancer, HER-2 positive breast cancer, HER2-negative breast cancer). [366] In certain embodiments, the cancer is skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC), dermatofribroma). [367] In certain embodiments, the cancer is a soft tissue cancer (e.g., intraepithelial neoplasms, epithelial carcinomas, epithelial sarcomas, adenocarcinomas, adenomas, fibrosarcomas, fibromas, liposarcomas, lipomas, myxomas, teratomas). [368] The terms “tumor” and “neoplasm” are used interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A tumor or neoplasm may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion,

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and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasia. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. [369] In certain embodiments, "treating a cancer" includes preventing the development of a cancer, reducing the symptoms of cancer, and/or inhibiting the growth of an established cancer or tumor. As used herein the term “inhibit” or “inhibition” in the context of cancer or tumor growth, for example, refers to a reduction in the rate of growth (i.e., reduction in the rate of proliferation of the cancer or tumor’s cells). In some embodiments, the term refers to a reduction in the rate of cancer or tumor growth to a level that is statistically significantly lower than an initial rate (e.g., the rate of tumor growth before administration or application of a construct provided herein). In some embodiments, the term refers to a reduction in the rate of cancer or tumor growth to a rate that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial rate (e.g., the rate of cancer or tumor growth before administration or application of a construct provided herein). [370] In certain embodiments, treating cancer can result in a reduction in size or volume of a tumor. For example, after treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor or by any reproducible means of measurement. In certain embodiments, the tumor size is reduced by at least 25% relative to its size prior to treatment. [371] In certain embodiments, treating cancer may further result in a decrease in number of tumors. For example, after treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement. The number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x).

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[372] In certain embodiments, treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. The number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x). [373] The term “inflammation” refers to inflammation caused by or resulting from an inflammatory disease or inflammatory condition. Inflammatory diseases and conditions include those diseases, disorders or conditions that are characterized by signs of pain (dolor, from the generation of noxious substances and the stimulation of nerves), heat (calor, from vasodilatation), redness (rubor, from vasodilatation and increased blood flow), swelling (tumor, from excessive inflow or restricted outflow of fluid), and/or loss of function (functio laesa, which can be partial or complete, temporary or permanent. Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and/or ulcerative inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and/or T-lymphocytes leading to abnormal tissue damage and/or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis,

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cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation. [374] Additional exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, hemolytic autoimmune anemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu’s arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter’s arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus, Type II diabetes mellitus), a skin condition (e.g., psoriasis, eczema, burns, dermatitis, pruritus (itch)), endometriosis, Guillain-Barre syndrome, infection, ischemic heart disease, Kawasaki disease, glomerulonephritis, gingivitis, hypersensitivity, headaches (e.g., migraine headaches, tension headaches), ileus (e.g., postoperative ileus and ileus during sepsis), idiopathic thrombocytopenic purpura, interstitial cystitis (painful bladder syndrome), gastrointestinal disorder (e.g., selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders (e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis), gastritis, diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD), inflammatory bowel disease (IBD) (e.g., Crohn’s disease, ulcerative colitis, collagenous colitis, lymphocytic colitis, ischemic colitis, diversion colitis, Behcet’s syndrome, indeterminate colitis) and inflammatory bowel syndrome (IBS)), lupus, multiple sclerosis, morphea, myasthenia gravis, myocardial ischemia, nephrotic syndrome, pemphigus vulgaris, pernicious anemia, peptic ulcers, polymyositis, primary biliary cirrhosis, neuroinflammation associated with brain disorders (e.g., Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease), prostatitis, chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, scleroderma, sarcoidosis, spondyloarthopathies, Sjogren’s syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g., frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo and Wegener’s granulomatosis. In certain embodiments, the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatitis. In certain embodiments, the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection). In certain embodiments, the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma,

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arthritis and inflammatory bowel disease). The constructs may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia. The constructs disclosed herein may also be useful in treating inflammation associated with cancer. [375] The term “fibrosis” refers to the development of fibrous connective tissue as a reparative response to injury or damage, including the pathological state of excessive production or excessive deposition of fibrous tissue, contraction of the extracellular matrix, and/or abnormalities of cells, fibronectin, and /or collagen. The term “fibrosis” refers to fibrosis of organs or tissues of the body, for example, of the heart, kidney, liver, joint, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal, or gastrointestinal tract. Fibrosis may occur as a result of various etiologies, including, for example, idiopathic pulmonary fibrosis (IPF), cystic fibrosis, iatrogenic drug-induced fibrosis, occupation-induced fibrosis, environment-induced fibrosis, diffuse parenchymal lung disease, granulomatous disease (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, hereditary disease (Hermansky Pudlac) Syndrome, tuberous sclerosis, neurofibromatosis, metabolic accumulation disease, familial interstitial lung disease), radiation-induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin-induced lung fiber Disease, chronic asthma, silicosis, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), renal fibrosis, tubulointerstitial fibrosis, glomerulonephritis, focal segmental glomerulosclerosis, IgA nephropathy Hypertension, alport, intestinal fibrosis, liver fibrosis, cirrhosis, alcohol-induced liver fibrosis, drug-induced liver fibrosis, hemochromatosis, non-alcoholic steatohepatitis (NASH), bile duct injury, primary biliary cirrhosis, infection-induced liver fibrosis, virus-induced liver fibrosis, autoimmune hepatitis, corneal scarring, hypertrophic scarring, Dupuytren’s disease, keloid, dermal fibrosis, cutaneous scleroderma, systemic sclerosis, spinal cord injury or fibrosis, myelofibrosis, vascular restenosis, atherosclerosis Arteriosclerosis, Wegener's granulomatosis, or Peyronie’s disease. [376] In certain embodiments, treating a disease characterized by fibroblast activation protein (FAP) upregulation (e.g., cancer, fibrosis, or inflammation) can result in an increase in average survival time of a population of subjects treated according to the present disclosure in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the construct of the present disclosure. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with the construct of the present disclosure. [377] In certain embodiments, treating a disease characterized by fibroblast activation protein (FAP) upregulation (e.g., cancer, fibrosis, or inflammation) can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a

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population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with the construct of the present disclosure. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease- related deaths per unit time following completion of a first round of treatment with the construct of the present disclosure. [378] In certain embodiments, treating a disease characterized by fibroblast activation protein (FAP) upregulation (e.g., cancer, fibrosis, or inflammation) can also result in an increased average progression- free survival time of a population of treated subjects in comparison to an untreated population. For example, the average progression-free survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average progression-free survival time of a population may be measured by any reproducible means. An increase in average progression-free survival time of a population may be measured, for example, by calculating for a population the average length of progression-free survival following initiation of treatment with the construct of the present disclosure. An increase in average progression-free survival time of a population may also be measured, for example, by calculating for a population the average length of progression-free survival following completion of a first round of treatment with the construct of the present disclosure. “Progression-free survival” as used herein refers to the length of time during and after medication or treatment during which the disease being treated (e.g., a disease characterized by fibroblast activation protein (FAP) upregulation (e.g., cancer, fibrosis, or inflammation)) does not get worse. [379] In certain embodiments, upon cleavage of the FAP-cleavable moiety, the camptothecin is released in its active for or in a form that is readily metabolized to its active form. In certain embodiments, a construct described here (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, has less than 50%, less than 60%, less than 70%, less than 80%, less than 90%, less than 95%, or less than 98% of the therapeutic activity of the active form of the camptothecin. [380] In certain embodiments, the FAP-cleavable moiety has a kca/Km for cleavage by FAP at least 10- fold greater than for cleavage by prolyl endopeptidase (EC 3.4.21.26; PREP). In certain embodiments, the FAP-cleavable moiety has a kca/Km for cleavage by FAP at least 100-fold, 1000-fold, 5000-fold, or 10,000-fold greater kca/Km. [381] In certain embodiments, a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, the construct, or a pharmaceutically acceptable salt thereof, has a therapeutic index that is at least 2 times greater than the therapeutic index of the camptothecin alone. In certain embodiments, a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, the construct, or a pharmaceutically acceptable salt thereof, has a therapeutic index that is at least at least 5, 10, 50, 100, 250, 500, 1000, 5000, or even 10,000 times greater of the camptothecin alone. [382] In certain embodiments, a larger percentage of the camptothecin is localized in a target tissue (e.g., tissue expressing FAP), relative to the administration of the camptothecin alone, when compared on

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an equivalent dose basis. In certain embodiments, the ratio of camptothecin localized to the target tissue relative to other tissue (e.g., blood, liver or heart) is at least 2 times greater for an equivalent dose of the construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, relative to the camptothecin alone. In certain embodiments, the ratio of camptothecin localized to the target tissue relative to other tissue (e.g., blood, liver or heart) is at least 5, 10, 100, or 1,000 times greater for an equivalent dose of the construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, relative to the camptothecin alone. [383] In certain embodiments, the maximum tolerated dose of a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, is at least 2 times greater than the maximum tolerated dose of the camptothecin alone. In certain embodiments, the maximum tolerated dose of a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, is at least 5, 10, 100, or 1000 times greater than the maximum tolerated dose of the camptothecin alone. [384] In certain embodiments, a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, has less than 10% activity relative to the free or active camptothecin derived or released therefrom. In an embodiment, a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, has less than 5% activity relative to the free or active camptothecin derived or released therefrom. In an embodiment, a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, has less than 1% activity relative to the free or active camptothecin derived or released therefrom. [385] In certain embodiments, the cell permeability of a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, is at least 50% less than the cell permeability of the camptothecin. In certain embodiments, the cell permeability of a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, is at least 60% less, 70% less, 80% less, 90% less, 95% less, 98% less, 99% less, or 99.9% less than the cell permeability of the camptothecin. [386] In certain embodiments, the circulating half-life of a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, is at least 25% longer than the circulating half-life of the camptothecin alone. In certain embodiments, the circulating half-life of a construct described herein (e.g., a construct of Formula (II′) or (II)), or a pharmaceutically acceptable salt thereof, is at least 50%, 75%, 100%, 150%, 200%, 500%, 750%, or even 1000% longer than the circulating half-life of the camptothecin alone. [387] Provided herein, in some aspects, are methods of selecting a patient in need of treatment using the polypeptides described herein. It should be understood that the terms “subject” and “patient” are used interchangeably herein. [388] Some aspects of the technology relate to methods of selecting a patient in need of treatment (e.g., cancer therapy), the methods comprising assaying a sample (e.g., a tumor tissue sample) from the subject for expression of FAP, and selecting the patient for treatment using a polypeptide

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described herein if FAP is expressed, for example, above a certain threshold level. In some embodiments, a method further comprises assaying the sample for expression of SLFN11. In some embodiments, a method further comprises selecting the patient for treatment using a polypeptide described herein if each of FAP and SLFN11 is expressed, for example, above respective threshold levels. _{[389] In some embodiments, a patient in need of treatment has a cancer selected from pancreatic} cancer, esophageal cancer, sarcoma, colorectal cancer, breast cancer (e.g., HR+ breast cancer or TNBC), NSCLC, SCLC, gastric cancer, ovarian cancer, and cholangiocarcinoma. In some embodiments, a patient in need of treatment has a solid tumor. In some embodiments, a patient in need of treatment has a sarcoma. In some embodiments, a patient in need of treatment has breast cancer. In some embodiments, a patient has HR+ breast cancer. In some embodiments, a patient in need of treatment has TNBC. _{[390] In some embodiments, a patient in need of treatment has previously been treated with a cancer} therapeutic, such as a cytotoxic agent. Non-limiting examples of such prior treatments include doxorubicin, daunorubicin, epirubicin, idarubicin, cyclophosphamide, ifosfamide, melphalan, busulfan, chlorambucil, carmustine, lomustine, temozolomide, cisplatin, carboplatin, oxaliplatin, methotrexate, 5- fluorouracil, capecitabine, cytarabine, gemcitabine, pemetrexed, mercaptopurine, thioguanine, vincristine, vinblastine, vinorelbine, paclitaxel, docetaxel, cabazitaxel, irinotecan, topotecan, etoposide, and teniposide. EXAMPLES _{[391] In order that the present disclosure may be more fully understood, the following examples are set} forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope. _{[392] The examples provided below include procedures, intermediates, and characterization data} useful, e.g., for the preparation of compounds provided herein. All synthetic steps, procedures, compounds (e.g., synthetic intermediates), reaction conditions, reaction mixtures, reagents, etc. are included herein as aspects of the present disclosure. Synthesis of Compounds and Conjugates _{[393] Exemplary methods and general procedures that may be used to provide the compounds of the} present disclosure are shown below. Abbreviations _{Ac Acyl} Aq. Aqueous Boc Tert-butoxycarbonyl DCM Dichloromethane DIEA Diisopropylethylamine 174/240 A1224.70043WO00

DMAP 4-Dimethylaminopyridine DMF Dimethylformamide DMSO Dimethylsulfoxide Et Ethyl h Hour(s) HATU Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium HOBt Hydroxybenzotriazole HPLC High performance liquid chromatography IPA Isopropyl alcohol LCMS Liquid chromatography-mass spectrometry NMI N-methylimidazole NMR Nuclear Magnetic Resonance Me Methyl rt Room temperature sat. Saturated T3P Propylphosphonic anhydride TCFH Tetramethylchloroformamidinium hexafluorophosphate TEA Triethylamine TFA Trifluroacetic acid THF Tetrahydrofuran _{TLC Thin layer chromatography} Ts Tosyl Examples and Intermediate Compounds Experimental Methods _{[394] All reagents were commercial grade and were used as received without further purification,} unless otherwise specified. Reagent grade solvents were used, unless otherwise specified. Reactions were conducted at room temperature unless otherwise specified. Manual normal phase column chromatography was carried out using glass columns over silica gel (200-300 mesh, SANPONT, Yucheng Chemical (Shanghai) Co., Ltd.). Automated normal phase flash chromatography was carried out using a Biotage Isolera equipped with WelFlash, SiO2 LS Irregular, 40-63 μm, 60 Å, (40 g, 120 g, 220 g, 330 g) cartridges. Preparative TLC was carried out using 20 cm x 20 cm silica gel F254 pre-coated plates, supplied by SANPONT, Yucheng Chemical (Shanghai) Co., Ltd. Preparative reverse phase HPLC was performed on Shimadzu LC-20AP (quaternary solvent pump, diode array detector, Agilent 10 Prep- C18, 250 x 21.2 mm, 10 µm or Boston Prep-C18, 250 x 21.2mm, 10 µm columns, 80% water + 0.1% formic acid/20% MeCN to 15% water +0.1% formic acid/85% MeCN, UV at 214 nm and 254 nm unless otherwise indicated). Compound analysis was performed by LCMS and NMR. LCMS data was collected using an Agilent Technologies 1290 series, Binary Pump, Diode Array Detector equipped with Agilent 175/240 A1224.70043WO00

EclipsePlus RRHD C18, 1.8μm, 3.0×50 mm columns, MS by electrospray ionisation, 98% water + 0.1% ammonia/2% MeCN to 100% MeCN method. NMR data was collected using Q.One Instruments, Quantum-I Plus 400 MHz spectrometer. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million. Data were acquired using Bruker TopSpin software and processed using MestreNova software. Compounds were typically dried using a lyophiliser. Compounds prepared were named using IUPAC nomenclature. Experimental Procedures [395] INTERMEDIATE A [396] Benzyl N-(N-(tert-butoxycarbonyl)-N-methylglycyl)-N-methylglycinate [397] To a mixture of N-(N-(tert-butoxycarbonyl)-N-methylglycyl)-N-methylglycine (2.0 g, 7.68 mmol, 1.0 eq) and K2CO3 (2.12 g, 15.37 mmol) in MeCN (20 mL) was added (bromomethyl)benzene (1.57 g, 9.22 mmol). The reaction mixture was stirred at rt overnight. The mixture was concentrated under vacuum and purified by column chromatography on silica gel to afford the title compound (2.5 g, yield: 92.9%) as a colourless oil. LCMS m/z = 251.2 [M-Boc+H]⁺.¹H NMR (400 MHz, DMSO-d6) δ 7.49 – 7.30 (m, 5H), 5.21 – 5.10 (m, 2H), 4.34 – 3.91 (m, 4H), 3.03 – 2.82 (m, 3H), 2.79 – 2.65 (m, 3H), 1.44 – 1.27 (m, 9H). [398] INTERMEDIATE B [399] Benzyl N-methyl-N-(methylglycyl)glycinate [400] To a solution of intermediate A (2.46 g, 7.02 mmol) in MeCN (18 mL) was added HCl (4 M in dioxane, 6 mL). The reaction mixture was stirred at rt for 1 h. The mixture was concentrated under vacuum, and used directly in the next step. LCMS m/z = 251.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 7.44 – 7.29 (m, 5H), 5.21 – 5.14 (m, 2H), 4.36 – 4.23 (m, 2H), 4.15 – 3.91 (m, 2H), 3.05 – 2.52 (m, 6H). [401] INTERMEDIATE C [402] Benzyl 2,2,5,8,11,14-hexamethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16- oate [403] To a solution of intermediate B (1.75 g, 7.02 mmol), N-(2-((tert-butoxycarbonyl)amino)ethyl)-N- methylglycine (1.63 g, 7.02 mmol) and NMI (3.46 g, 42.12 mmol) in MeCN (20 mL) was added TCFH

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(5.91 g, 21.06 mmol) at 0 ^oC. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with water (120 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel to afford the title compound (800 mg, yield: 23.2 %) as colourless oil. LCMS m/z = 493.3 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d6) δ 7.39 – 7.37 (m, 2H), 7.32 – 7.31 (m, 2H), 7.25 – 7.19 (m, 1H), 5.17 – 5.14 (m, 2H), 4.49 (d, J = 5.8 Hz, 2H), 4.26 – 3.96 (m, 6H), 3.08 – 2.68 (m, 12H). [404] INTERMEDIATE D [405] 2,2,5,8,11,14-Hexamethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14-tetraazahexadecan-16-oic acid [406] To a solution of intermediate C (800 mg, 1.63 mmol) in EtOH (20 mL) was added 10% Pd/C (400 mg). The mixture was purged with H₂, and stirred at rt under H₂ for 2 h. The mixture was filtered and concentrated under vacuum to afford the title compound (400 mg, yield: 61 %) as a white solid. LCMS m/z = 403.3 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d₆) δ 4.33 – 3.96 (m, 8H), 2.97 – 2.74 (m, 12H), 1.43 – 1.31 (m, 9H). [407] INTERMEDIATE E [408] Methyl 3-(2-(2-((tert-butoxycarbonyl)(methyl)amino)-N- methylacetamido)acetamido)isonicotinate [409] To a solution of N-(N-(tert-butoxycarbonyl)-N-methylglycyl)-N-methylglycine (2.0 g, 7.68 mmol) and methyl 3-aminoisonicotinate (1.28 g, 8.45 mmol) in MeCN (20 mL) was added NMI (3.78 g, 46.10 mmol) and TCFH (6.46 g, 23.05 mmol) at 0 ^oC. The reaction mixture was stirred at room temperature for 4 h. The mixture was purified directly by reverse phase column to afford the title compound (800 mg, yield: 26.7 %) as a yellow solid. LCMS m/z = 395.2 [M+H]⁺, ¹H NMR (400 MHz, DMSO-d6) δ 10.55 – 10.45 (m, 1H), 9.30 – 9.02 (m, 1H), 8.52 – 8.44 (m, 1H), 7.77 – 7.65 (m, 1H), 4.26 – 4.00 (m, 4H), 3.88 – 3.83 (m, 3H), 3.11 – 2.74 (m, 6H), 1.43 – 1.30 (m, 9H). [410] INTERMEDIATE F [411] Methyl 3-(2-(2-((tert-butoxycarbonyl)(methyl)amino)-N-methylacetamido)-N- methylacetamido)isonicotinate

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[412] To a solution of intermediate E (800 mg, 2.02 mmol) and Cs2CO3 (1.32 g, 4.06 mmol) in DMF (10 mL) was added MeI (572 mg, 4.06 mmol). The reaction mixture was stirred at 40 ^oC overnight. The mixture was diluted with water (100 mL) and extracted with EtOAc (80 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel to give the title compound (300 mg, yield: 36.2 %) as a yellow solid. LCMS m/z = 409.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6) δ 8.83 – 8.79 (m, 1H), 8.69 – 8.61 (m, 1H), 7.94 – 7.84 (m, 1H), 4.09 – 3.77 (m, 7H), 3.09 (s, 3H), 2.94 – 2.71 (m, 6H), 1.41 – 1.32 (m, 9H). [413] INTERMEDIATE G [414] Methyl 3-(N-methyl-2-(N-methyl-2-(methylamino)acetamido)acetamido)isonicotinate [415] To a solution of intermediate F (300 mg, 0.734 mmol) in DCM (3 mL) was added TFA (1 mL) at 0 ^oC. The reaction mixture was stirred at rt for 1 h. The mixture was concentrated under vacuum and used directly in the next step. LCMS m/z = 309.2 [M+H]⁺. [416] INTERMEDIATE H [417] Methyl 3-(N,2,2,5,8,11,14-heptamethyl-4,7,10,13-tetraoxo-3-oxa-5,8,11,14- tetraazahexadecan-16-amido)isonicotinate [418] A solution of N-(N-(tert-butoxycarbonyl)-N-methylglycyl)-N-methylglycine (191 mg, 0.734 mmol), DIEA (0.5 mL, 2.936 mmol) and HATU (279 mg, 0.734 mmol) in DMF (3 mL) was stirred at 0 ^oC for 0.5 h, intermediate G (226 mg, 0.734 mmol) was added at 0 ^oC. The reaction mixture was stirred at room temperature for 2 h. The mixture was purified directly by reverse phase column chromatography to afford the title compound (220 mg, yield: 54.5%) as a yellow solid. LCMS m/z = 551.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6) δ 8.82 – 8.78 (m, 1H), 8.72 – 8.61 (m, 1H), 7.96 – 7.81 (m, 1H), 4.33 – 3.76 (m, 11H), 3.11 – 3.08 (m, 3H), 2.95 – 2.66 (m, 12H), 1.42 – 1.32 (m, 9H). [419] INTERMEDIATE I [420] Methyl 3-(N,5,8,11-tetramethyl-4,7,10-trioxo-2,5,8,11-tetraazatridecan-13- amido)isonicotinate

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[421] To a solution of intermediate H (220 mg, 0.399 mmol) in DCM (6 mL) was added TFA (2 mL) at 0 ^oC. The reaction mixture was stirred at rt for 1 h. The mixture was concentrated under vacuum and used directly in the next step. LCMS m/z = 451.3 [M+H]⁺. [422] INTERMEDIATE J [423] Methyl 3-(N,2,2,5,8,11,14,17,20,23,26-undecamethyl-4,7,10,13,16,19,22,25-octaoxo-3-oxa- 5,8,11,14,17,20,23,26-octaazaoctacosan-28-amido)isonicotinate [424] To a solution of intermediate I (163.5 mg, 0.363 mmol), intermediate D (146.1 mg, 0.363 mmol) and NMI (178.8 mg, 2.18 mmol) in MeCN (3 mL) was added TCFH (305.6 mg, 1.09 mmol) at 0 ^oC. The reaction mixture was stirred at rt for 1 h. The mixture was purified directly by reverse phase column chromatography to afford the title compound (160 mg, yield: 52.8%) as a yellow solid. LCMS m/z = 835.4 [M+H]⁺. [425] INTERMEDIATE K [426] 23-Azido-3,6,9,12,15,18,21-heptaoxatricosyl 4-methylbenzenesulfonate [427] To a solution of 23-azido-3,6,9,12,15,18,21-heptaoxatricosan-1-ol (400 mg, 1.01 mmol), TEA (0.21 mL, 1.52 mmol) and DMAP (25.0 mg, 0.20 mmol) in DCM (5.0 mL) was added TsCl (290 mg, 1.52 mmol). The reaction mixture was stirred at rt under N₂ for 4h. The mixture was poured into water (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to give the title compound (780 mg, crude) as oil. LCMS m/z = 567.2 [M+H₂O]⁺ [428] INTERMEDIATE L [429] Methyl 6-((23-azido-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)quinoline-4-carboxylate [430] To a solution of methyl 6-hydroxyquinoline-4-carboxylate (400 mg, 1.97 mmol) in MeCN (20 mL) was added intermediate K (1.00 g, 1.39 mmol) and Cs₂CO₃ (1.28 g, 3.94 mmol). The reaction mixture was stirred at 40 ^oC for 3h. The reaction mixture was quenched with MeOH (100 mL) and concentrated under vacuum. The residue was purified by silica column chromatography to afford the title compound (350 mg, 43%) as an orange oil. LCMS m/z = 581.3 [M+H]⁺ [431] Intermediate M was prepared similarly to intermediate L by nucleophilic substitution; see Table 6 below.

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Table 6: Nucleophilic substitution with intermediate K [432] INTERMEDIATE N [433] 6-((23-Azido-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)quinoline-4-carboxylic acid [434] A solution of intermediate L (70.0 mg, 0.12 mmol) in 1:1:1 THF/MeOH/water (6 mL) was added LiOH^.H₂O (10 mg, 0.24 mmol). The reaction mixture was stirred at rt for 3 h, and then concentrated under vacuum to afford the title compound. The crude product was used in the next step directly. LCMS m/z = 567.3 [M+H]⁺ [435] Intermediate O and P were prepared similarly to intermediate N by saponification; see Table 7 below. Table 7: Methyl ester saponification [436] INTERMEDIATE Q [437] Methyl (3-((23-azido-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)isonicotinoyl)-D-alanyl-L- prolinate [438] To a solution of intermediate O (100 mg, 0.19 mmol) in DMF (2 mL) was added methyl D- alanyl-L-prolinate (136 mg, 0.57 mmol), T3P (242 mg, 0.38 mmol) and DIEA (167 µL, 0.95 mmol). The mixture was stirred at rt overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound (75 mg, 56% yield) as an oil. LCMS: m/z = 699.3 [M+H]⁺; ¹H NMR (400 MHz, Chloroform-

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d) δ 8.71 (d, J = 7.3 Hz, 1H), 8.49 – 8.47 (m, 1H), 8.40 (d, J = 4.9 Hz, 1H), 7.97 (d, J = 4.9 Hz, 1H), 5.03 – 4.97 (m, 1H), 4.50 – 4.42 (m, 3H), 4.08 – 3.99 (m, 2H), 3.84 – 3.80 (m, 2H), 3.71 (s, 3H), 3.69 – 3.59 (m, 26H), 3.42 – 3.39 (m, 2H), 2.30 – 2.23 (m, 1H), 2.09 – 1.99 (m, 3H), 1.44 (d, J = 6.7 Hz, 3H). [439] Intermediates R and S were prepared in a similar manner to intermediate Q by amide coupling, see Table 8 below. Table 8: Amide coupling with D-alanyl-L-prolinate derivatives [440] INTERMEDIATE T [441] (3-((23-azido-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)isonicotinoyl)-D-alanyl-L-proline [442] To a solution of intermediate Q (608 mg, 775 μmol) in THF/MeOH/water (5 mL/5 mL/5 mL) was added LiOH^.H₂O (65 mg, 1.55 mmol). The mixture was stirred at rt for 1h. The mixture was concentrated under vacuum and carried forward without further purification. LCMS m/z = 707.4 [M+Na]⁺. [443] Intermediates U and V were prepared in a similar manner to intermediate T by ester hydrolysis, see Table 9 below. Table 9: Methyl ester hydrolysis.

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[444] INTERMEDIATE W [445] 6-((23-Azido-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)-N-((R)-1-((S)-2-(((2S,3S,4S,6R)-3- hydroxy-2-methyl-6-(((1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo- 1,2,3,4,6,11-hexahydrotetracen-1-yl)oxy)tetrahydro-2H-pyran-4-yl)carbamoyl)pyrrolidin-1-yl)-1- oxopropan-2-yl)quinoline-4-carboxamide [446] To a solution of intermediate U (80.0 mg, 0.11 mmol) and (8S,10S)-10-(((2R,4S,5S,6S)-4-amino- 5-hydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-6,8,11-trihydroxy-8-(2-hydroxyacetyl)-1-methoxy- 7,8,9,10-tetrahydrotetracene-5,12-dione hydrochloride (68.0 mg, 0.12 mmol) in DMF (6.0 mL) was added T₃P (50% in EtOAc, 126 µL, 0.21 mmol)) and DIEA (74.1 µL, 0.43 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was diluted with water (80 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by silica column chromatography to afford the title compound (70.0 mg, 52%) as a red solid. LCMS m/z = 1260.4 [M+H]⁺ ; ¹H NMR (400 MHz, DMSO-d₆) δ 14.11 – 13.91 (m, 1H), 13.26 (s, 1H), 9.16 – 8.94 (m, 1H), 8.78 – 8.68 (m, 1H), 7.96 – 7.33 (m, 8H), 5.28 – 5.15 (m, 1H), 4.96 – 4.80 (m, 2H), 4.62 – 4.41 (m, 3H), 4.34 – 3.73 (m, 13H), 3.60 – 3.47 (m, 28H), 3.01 – 2.91 (m, 2H), 2.21 – 1.41 (m, 9H), 1.31 – 1.24 (m, 2H), 1.14 (t, J = 7.0 Hz, 3H), 0.98 – 0.92 (m, 2H). [447] Intermediates X and Y were prepared similarly to intermediate W by amide formation between doxorubicin and the appropriate acid; see Table 10 below. Table 10: Amide coupling with doxorubicin

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[448] INTERMEDIATE Z [449] tert-Butyl (2-(5-amino-2-(hydroxymethyl)benzamido)ethyl)carbamate [450] To a stirred solution of 6-aminoisobenzofuran-1(3H)-one (500 mg, 3.35 mmol) in MeOH (10 mL) was added tert-butyl (2-aminoethyl)carbamate (1.08 g, 6.71 mmol). The reaction mixture was stirred at 100 ^oC overnight. The mixture was concentrated under vacuum, diluted with water (80 mL) and extracted with DCM (40 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel to the title compound (900 mg, yield: 87%) as a yellow oil. LCMS m/z = 310.2 [M+H]⁺.¹H NMR (400 MHz, DMSO-d6) δ 8.30 (t, J = 5.5 Hz, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.87 – 678 (m, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.58 (dd, J = 8.1, 2.4 Hz, 1H), 5.14 (s, 2H), 4.99 (t, J = 5.7 Hz, 1H), 4.34 (d, J = 5.6 Hz, 2H), 3.26 – 3.21 (m, 2H), 3.09 – 3.03 (m, 2H), 1.38 (s, 9H). [451] INTERMEDIATE AA

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[452] tert-Butyl (R)-(1-((4-(hydroxymethyl)phenyl)amino)-1-oxopropan-2-yl)carbamate [453] To a solution of (4-aminophenyl)methanol (100 mg, 0.81mmol) in DMF (3 mL) was added (tert- butoxycarbonyl)-D-alanine (154 mg, 0.81 mmol), HATU (617 mg, 1.62 mmol) and DIEA (0.71 mL, 4.06 mmol). The mixture was stirred at rt overnight. The mixture was poured into water (40 mL) and extracted with EtOAc (20 mL x 3). The organic layers were washed with brine, dried over Na₂SO₄ and concentrated under vacuum. The crude was purified by silica gel column to give the title compound (79 mg, 33% yield) as an oil. [454] INTERMEDIATE AB [455] tert-Butyl ((R)-1-((S)-2-((4-(hydroxymethyl)phenyl)carbamoyl)pyrrolidin-1-yl)-1- oxopropan-2-yl)carbamate [456] To a solution of (tert-butoxycarbonyl)-D-alanyl-L-proline (2.00 g, 6.99 mmol), (4- aminophenyl)methanol (860 mg, 6.99 mmol) and DIEA (4.9 mL, 28.0 mmol) in DMF (40 mL) was added HATU (2.66 g, 6.99 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was diluted with water (500 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, concentrated under vacuum to give the title compound (1.70 g, 62%) as a yellow solid. LCMS m/z = 392.15 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.22 – 9.51 (m, 1H), 7.57 – 7.50 (m, 2H), 7.27 – 7.20 (m, 2H), 7.12 – 6.97 (m, 1H), 5.13 – 5.05 (m, 1H), 4.45 – 4.09 (m, 4H), 3.73 – 3.41 (m, 2H), 2.30 – 1.76 (m, 4H), 1.36 (s, 9H), 1.20 – 0.99 (m, 3H). [457] Intermediates AC - AI were prepared in a similar manner to intermediate AB via amide coupling with D-alanyl-L-proline derivatives, see Table 11 below. Table 11: Amide coupling with D-alanyl-L-proline derivatives

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[458] INTERMEDIATE AJ

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[459] tert-Butyl ((R)-1-((S)-2-((4-((((4- nitrophenoxy)carbonyl)oxy)methyl)phenyl)carbamoyl)pyrrolidin-1-yl)-1-oxopropan-2- yl)carbamate [460] A solution of intermediate AB (700 mg, 1.79 mmol) and DIEA (0.47 mL, 2.69 mmol) in DMF (8.0 mL) was stirred at 0 °C for 20 min. Then bis(4-nitrophenyl) carbonate (817 mg, 2.69 mmol) in DMF (2 mL) was added at 0 °C and the reaction mixture was stirred at rt for 2 h. The mixture was diluted with water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica column chromatography to afford the title compound (900 mg, 48%) as a yellow solid. LCMS m/z = 557.10 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.40 – 9.67 (m, 1H), 8.33 – 8.28 (m, 2H), 7.67 – 7.63 (m, 2H), 7.59 – 7.55 (m, 2H), 7.45 – 7.38 (m, 2H), 7.16 – 6.92 (m, 1H), 5.27 – 5.22 (m, 2H), 4.47 – 4.39 (m, 1H), 4.35 – 4.05 (m, 1H), 3.72 – 3.44 (m, 2H), 2.11 – 1.87 (m, 4H), 1.36 (s, 9H), 1.19 – 1.02 (m, 3H). [461] Intermediates AK - AR were prepared in a similar manner to intermediate AJ via carbonate formation, see Table 12 below. Table 12: Carbonate formation with bis(4-nitrophenyl) carbonate or 4-nitrophenyl carbonochloridate

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[462] INTERMEDIATE AS [463] 4-((S)-1-((tert-Butoxycarbonyl)-D-alanyl)pyrrolidine-2-carboxamido)benzyl ((1S,9S)-9- ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H- benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)carbamate [464] To a solution of intermediate AJ (100 mg, 0.14 mmol) in DMF (2.0 mL) and pyridine (0.5 mL) was added HOBt (38.8 mg, 0.29 mmol), exatecan (81.6 mg, 0.14 mmol) and DIEA (0.1 mL, 0.57 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by silica column chromatography to afford the title compound (130 mg, 85%) as a yellow solid. LCMS m/z = 853.25 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 10.35 – 9.63 (m, 1H), 8.11 – 8.01 (m, 1H), 7.79 – 7.55 (m, 3H), 7.45 – 7.25 (m, 3H), 7.15 – 6.90 (m, 1H), 6.53 – 6.48 (m, 1H), 5.44 (s, 2H), 5.36 – 5.19 (m, 3H), 5.08 (s, 2H), 4.43 – 4.28 (m, 1H), 3.71 – 3.43 (m, 2H), 3.31 – 3.05 (m, 2H), 2.36 (d, J = 1.8 Hz, 3H), 2.25 – 2.02 (m, 3H), 2.02 – 1.76 (m, 5H), 1.39 – 1.32 (m, 9H), 1.21 – 1.00 (m, 3H), 0.88 (t, J = 7.3 Hz, 3H). [465] Intermediates AT – BA were prepared in a similar manner to intermediate AS via carbamate formation with exatecan, see Table 13 below.

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Table 13: Carbamate formation with exatecan

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[466] INTERMEDIATE BB

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[467] 4-((S)-1-(D-Alanyl)pyrrolidine-2-carboxamido)benzyl ((1S,9S)-9-ethyl-5-fluoro-9-hydroxy- 4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[d]pyrano[3',4':6,7]indolizino[1,2- b]quinolin-1-yl)carbamate [468] To a solution of intermediate AS (50.0 mg, 0.06 mmol) in DCM (0.9 mL) was added TFA (0.3 mL) at 0 ^oC. The reaction mixture was stirred at 0^oC for 1 h. The mixture was basified with sat. NaHCO3 (aq.) to pH ~9 and extracted with 3:1 DCM/IPA (20 mL x 3). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum to give the title compound (43.0 mg, 98%) as a yellow solid. LCMS m/z = 753.15 [M+H]⁺. [469] Intermediates BC - BI were prepared in a similar manner to intermediate BB via Boc deprotection, see Table 14 below. Table 14: Boc deprotection

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[470] INTERMEDIATE BJ

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[471] 4-((S)-1-((6-((23-Azido-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)quinoline-4-carbonyl)-D- alanyl)pyrrolidine-2-carboxamido)benzyl ((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13- dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7] indolizino[1,2-b]quinolin-1- yl)carbamate [472] To a solution of intermediate BB (50.0 mg, 0.09 mmol), intermediate N (73 mg, 0.10 mmol) and DIEA (46 µL, 0.26 mmol) in DMF (5.0 mL) was added T3P (50% in EtOAc, 104 µL, 0.18 mmol). The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with water (60 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography to afford the title compound (70.0 mg, 61%) as a yellow solid. LCMS: m/z = 1301.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d6) δ 14.11 – 13.91 (m, 1H), 13.26 (s, 1H), 9.16 – 8.94 (m, 1H), 8.78 – 8.68 (m, 1H), 7.96 – 7.33 (m, 8H), 5.28 – 5.15 (m, 1H), 4.96 – 4.80 (m, 2H), 4.62 – 4.41 (m, 3H), 4.34 – 3.73 (m, 13H), 3.60 – 3.47 (m, 28H), 3.01 – 2.91 (m, 2H), 2.21 – 1.41 (m, 9H), 1.31 – 1.24 (m, 2H), 1.14 (t, J = 7.0 Hz, 3H), 0.98 – 0.92 (m, 2H). [473] Intermediates BK - BT were prepared similarly to intermediate BJ by amide formation with the appropriate acid; see Table 15 below. Table 15: Amide coupling

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[474] INTERMEDIATE BU

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[475] 4-((S)-1-((3-(N,5,8,11,14,17,20,23-octamethyl-4,7,10,13,16,19,22-heptaoxo- 2,5,8,11,14,17,20,23-octaazapentacosan-25-amido)isonicotinoyl)-D-alanyl)pyrrolidine-2- carboxamido)benzyl ((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15- hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)carbamate [476] To a solution of intermediate BS (25 mg, 0.016 mmol) in DCM (1.8 mL) was added TFA (0.6 mL) at 0 ^oC. The reaction mixture was stirred at 0 ^oC for 1 h. The mixture was concentrated under vacuum, and used directly in the next step. LCMS m/z = 1455.5 [M+H]⁺. [477] INTERMEDIATE BV [478] 4-((S)-1-((3-(27-azido-N,3,6,9,12,15,18,21,24-nonamethyl-4,7,10,13,16,19,22,25-octaoxo- 3,6,9,12,15,18,21,24-octaazaheptacosanamido)isonicotinoyl)-D-alanyl)pyrrolidine-2- carboxamido)benzyl ((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15- hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)carbamate [479] To a solution of intermediate BU (23.2 mg, 0.016 mmol) and 3-azidopropanoic acid (11 mg, 0.096 mmol) in DMF (5 mL) was added DIEA (20.6 mg, 0.16 mmol) and HATU (18.2 mg, 0.048 mmol) at 0 ^oC. The reaction mixture was stirred at room temperature for 1 h. The mixture was diluted with water (50 mL) and extracted with CHCl₃/IPA (v/v 3:1) (20 mL × 3). The combined organic layers were concentrated under vacuum to afford the title compound (23 mg, yield: 65.1%) as a yellow solid. LCMS m/z = 1552.5 [M+H]⁺. [480] INTERMEDIATE BW (LP4)

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[481] 4-((S)-1-((6-((23-(4-((4-((2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexane-1- carboxamido)methyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12,15,18,21-heptaoxatricosyl)oxy) quinoline-4- carbonyl)-D-alanyl)pyrrolidine-2-carboxamido)benzyl ((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4- methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[d]pyrano[3',4':6,7]indolizino[1,2- b]quinolin-1-yl)carbamate [482] To a solution of intermediate BJ (60.0 mg, 0.05 mmol) in DCM (4.0 mL) was added 4-((2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-N-(prop-2-yn-1-yl)cyclohexane-1-carboxamide (25.0 mg, 0.09 mmol), CuBr (2.60 mg, 0.02 mmol) and PPh₃ (2.40 mg, 0.01 mmol). The reaction mixture was stirred at rt for 4 h. The mixture was concentrated under vacuum and purified by prep-HPLC to afford the title compound (21.7 mg, 30%) as a pink solid. LCMS: m/z = 788.5 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 – 9.51 (m, 1H), 9.19 – 9.09 (m, 1H), 8.82 – 8.71 (m, 1H), 8.24 – 8.14 (m, 1H), 8.06 – 7.73 (m, 4H), 7.67 – 7.59 (m, 2H), 7.57 – 7.52 (m, 1H), 7.47 – 7.24 (m, 5H), 7.04 – 6.94 (m, 2H), 6.50 (s, 1H), 5.50 – 5.35 (m, 2H), 5.29 – 4.83 (m, 6H), 4.59 – 4.12 (m, 7H), 3.94 – 3.46 (m, 26H), 3.24 – 3.06 (m, 4H), 2.40 – 1.46 (m, 20H), 1.38 – 1.21 (m, 6H), 0.92 – 0.83 (m, 5H). [483] Intermediates BX – CM were prepared similarly to intermediate BW by azide-alkyne cycloaddition with 4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)-N-(prop-2-yn-1-yl)cyclohexane-1- carboxamide; see Table 16 below. Table 16: Azide-alkyne cycloaddition

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[484] INTERMEDIATE CM [485] 4-((S)-1-((3-((23-(4-((4-((2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)methyl)cyclohexane-1- carboxamido)methyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12,15,18,21-heptaoxatricosyl)oxy)isonicotinoyl)- D-alanyl)pyrrolidine-2-carboxamido)-2-((methylamino)methyl)benzyl ((1S,9S)-9-ethyl-5-fluoro-9- hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H- benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1-yl)carbamate [486] To a solution of intermediate CE (50 mg, 0.029 mmol) in DCM (3 mL) was added TFA (1 mL) at 0^oC. The reaction mixture was stirred at 0^oC for 0.5 h. The mixture was concentrated under vacuum and used directly in the next step without further purification. LCMS m/z = 1569.5 [M+H]⁺. [487] Intermediate CN was prepared similarly to intermediate CM via Boc deprotection, see Table 17 below:

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Table 17: Boc Deprotection [488] INTERMEDIATE CO (LP10) [489] (10S,23S)-10-Ethyl-18-fluoro-10-hydroxy-19-methyl-5,9-dioxo-8-oxa-4,15- diazahexacyclo[14.7.1.0²,¹⁴.0⁴,¹³.0⁶,¹¹.0²⁰,²⁴]tetracosa-1(24),2(14),6(11),12,15,17,19-heptaen-23-yl {4- [(S)-1-[(R)-2-[3-(2-{2-[2-(2-{2-[2-(2-{2-[4-({4-[(2,5-dioxo-3-pyrrolin-1- yl)methyl]cyclohexylcarbonylamino}methyl)-1H-1,2,3-triazol-1- yl]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)isonicotinoylamino]propionyl]-2- pyrrolidinylcarbonylamino]-2-({N-methyl[(N-methyl{[N-methyl({N-methyl[(N-methyl{[N- methyl({N-methyl[(N-methyl{[N-methyl({N-methyl[(N- methylacetylamino)methyl]carbonylamino}methyl)carbonylamino]methyl}carbonylamino)methyl] carbonylamino}methyl)carbonylamino]methyl}carbonylamino)methyl]carbonylamino}methyl)car bonylamino]methyl}carbonylamino)methyl]carbonylamino}methyl)phenyl}methanecarbamate [490] To a solution of intermediate CM (47 mg, 0.029 mmol) and 3,6,9,12,15,18,21,24,27,30- decamethyl-4,7,10,13,16,19,22,25,28,31-decaoxo-3,6,9,12,15,18,21,24,27,30-decaazadotriacontanoic acid (22.3 mg, 0.029 mmol) in DMF (1 mL) was added DIEA (25 µL, 0.145 mmol) and HATU (17.0 mg, 0.029 mmol) at 0^oC. The reaction mixture was stirred at room temperature for 1 h. The mixture was purified by prep-HPLC to afford the title compound (12 mg, yield: 17.2%) as a yellow solid. LCMS m/z = 1161.3 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 10.52 – 9.82 (m, 1H), 8.76 – 8.55 (m, 2H), 8.33 (d, J = 4.8 Hz, 1H), 8.17 (t, J = 5.7 Hz, 1H), 8.12 – 7.97 (m, 1H), 7.80 – 7.65 (m, 3H), 7.64 – 7.26 (m, 4H), 6.99 (s, 2H), 6.50 (s, 1H), 5.42 – 4.72 (m, 8H), 4.56 – 3.77 (m, 35H), 3.60 – 3.41 (m, 26H), 3.25 – 3.01 (m, 5H), 2.93 – 2.71 (m, 32H), 2.37 (s, 3H), 2.18 – 1.97 (m, 6H), 1.85 – 1.53 (m, 8H), 1.43 – 1.07 (m, 8H), 0.87 (t, J = 7.5 Hz, 3H).

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[491] Intermediate CP was prepared similarly to intermediate CO via amide coupling, see Table 18 below: Table 18: Amide Coupling [492] INTERMEDIATE CQ [493] N-(tert-butoxycarbonyl)-S-(1-((4-(((1-(23-((4-(((R)-1-((S)-2-((4-(((((1S,9S)-9-ethyl-5-fluoro-9- hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H- benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1- yl)carbamoyl)oxy)methyl)phenyl)carbamoyl)pyrrolidin-1-yl)-1-oxopropan-2- yl)carbamoyl)quinolin-6-yl)oxy)-3,6,9,12,15,18,21-heptaoxatricosyl)-1H-1,2,3-triazol-4- yl)methyl)carbamoyl)cyclohexyl)methyl)-2,5-dioxopyrrolidin-3-yl)-L-cysteine [494] To a solution of intermediate BW (200 mg, 0.127 mmol) in DCM (10 mL) was added (tert- butoxycarbonyl)-L-cysteine (168 mg, 0.761 mmol) and TEA (90 mg, 0.888 mmol). The mixture was stirred at 20 °C for 3h. The mixture was concentrated under vacuum to give the title compound (240 mg, crude) as orange oil, which was used to the next step directly. LCMS: m/z = 1796.5 [M+H]⁺ [495] Intermediates CR – CT were synthesised in a similar manner to intermediate CQ via N-Boc- cysteine conjugation. See Table 19 below.

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Table 19: N-Boc-cysteine conjugation [496] CYSTEINE CONJUGATE 1 A1224.70043WO00

[497] S-(1-((4-(((1-(23-((4-(((R)-1-((S)-2-((4-(((((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13- dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-1- yl)carbamoyl)oxy)methyl)phenyl)carbamoyl)pyrrolidin-1-yl)-1-oxopropan-2- yl)carbamoyl)quinolin-6-yl)oxy)-3,6,9,12,15,18,21-heptaoxatricosyl)-1H-1,2,3-triazol-4- yl)methyl)carbamoyl)cyclohexyl)methyl)-2,5-dioxopyrrolidin-3-yl)-L-cysteine [498] To a solution of intermediate CQ (240 mg, crude) in DCM (12 mL) was added TFA (4 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1h. The mixture was concentrated under vacuum and purified by Prep-HPLC to afford the title compound (72 mg, 33.4% yield) as a light yellow solid. LCMS: m/z = 1696.6 [M+H]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.62 – 9.59 (m, 1H), 9.25 – 9.06 (m, 1H), 8.80 – 8.70 (m, 1H), 8.25 – 8.15 (m, 1H), 8.08 – 7.75 (m, 4H), 7.69 – 7.60 (m, 2H), 7.58 – 7.51 (m, 1H), 7.49 – 7.22 (m, 5H), 5.47 – 5.37 (m, 2H), 5.33 – 5.17 (m, 3H), 5.13 – 4.83 (m, 3H), 4.52 – 4.43 (m, 3H), 4.28 – 4.04 (m, 5H), 3.95 – 3.45 (m, 40H), 2.60 – 2.52 (m, 1H), 2.40 – 2.32 (m, 3H), 2.25 – 1.50 (m, 14H), 1.39 – 1.16 (m, 7H), 0.94 – 0.81 (m, 5H). [499] Cysteine conjugates 2 - 4 were synthesised in a similar manner to cysteine conjugate 1 via Boc deprotection. See Table 20 below. [500] Table 20: Boc deprotection

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79 – – s, , ). Production, analysis and in vitro testing of Affimer® conjugates [501] Affimer® proteins, single-domain or two-domain in-line fusions containing engineered cysteine residues, were produced in E. coli. Different linker-payloads (e.g., LP1 or LP2) were conjugated to the thiol groups of the cysteine residues using maleimide chemistry. The conjugates were purified from the reaction mixtures using HIC and SEC purification. The integrity and DAR of the Affimer® conjugation products was monitored by LC-MS. The FAP-binding affinities of the Affimer® conjugates were assessed by SPR. Cellular cytotoxicity assays were performed using HEK293T cells overexpressing FAP and compared to parent cells (FAP-negative). Cells were incubated with the conjugates for 4 days in the presence of FBS substitute Panexin (which contains low levels of FAP). The antiproliferative/cytotoxic effect of the compounds was measured as % inhibition relative to vehicle control. Bystander effect was assessed using co-culture models, using GFP-expressing tumor cells (e.g., pancreatic MiaPaCa2-GFP cells and colorectal LS174T-GFP cells) and matched fibroblast cells (which express FAP to levels typically observed in tumors). Results of these studies are shown in Figures 1-8. [502] The conjugates used in Figures 1-8 are provided in Table 21 below: Table 21. Exemplary FAP-Cleavable Conjugates ID : 6 7 8 9

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Linker=AEAAAKEAAAKEAAAKEAAAKEAAAKEAAAK (SEQ ID NO: 502) L3Cys=Loop 3 Cysteine for conjugation to LP1 or LP2 CTCys=C-terminal Cysteine for conjugation to LP1 or LP2 For the constructs in Table 21, anti-FAP AFFIMER polypeptides include a cysteine (C) (underlined either in Loop 3 or at the C terminus) to which the LP1 or LP2 was conjugated: ) Production, analysis and in vitro testing of AFFIMER® conjugates with multiple cysteines for multi-drug conjugation [503] PEG-Malemide (5kDa) was conjugated to AFFIMER® constructs on available thiol groups. Thiols were introduced at specific locations within the AFFIMER® scaffold by the incorporation of Cys residues into the constructs. AFFIMER® constructs contained Cys residues at the Cterminus, within Loop3, and/or within Loop7 (Loop7 is only present in two-domain fusion proteins). These Cys enabled Malemide conjugation at each of the sites individually, or in combination. Figure 9 shows the analytical SEC-HPLC profiles of unmodified protein, and 1x, 2x, or 3x PEG conjugated constructs. Single domain (FAP-2) and two-domain (FAP-2-FAP-1-H) AFFIMER® exemplars are shown. These data demonstrate that FAP binding AFFIMERS® can be conjugated to Malemide at multiple sites within the protein scaffold. [504] Following conjugation to PEG, the two-domain and single-domain AFFIMER® conjugates were analysed for their ability to bind to human FAPalpha by SPR and compared with the unconjugated parent proteins (Figure 10 and 11, respectively). The 1x, 2x, and 3xPEG conjugated proteins showed equivalent kinetic profiles and affinities (Table 22) to their unconjugated parent proteins. This demonstrates that the

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conjugation of bulky constituents (PEG) to Affimer® constructs at multiple locations does not perturb FAPalpha binding. Table 22. Single cycle SPR kinetic analysis of AFFIMER® and AFFIMER® PEG conjugates to human FAPalpha. AFFIMER® conjugates (1, 2, or 3 PEG chains) were compared with their unconjugated parent proteins. Derived KD values are displayed and show equivalent FAP-binding affinities to the parent AFFIMER® protein. Internalization, FAP Enzyme Activity and Temperature Stability of FAP-binding AFFIMER® proteins and Monoclonal Antibodies [505] Multiple biologic, biophysical, and in silico tools were used to identify AFFIMER® proteins binding to FAP (examples in FIGs.12A-12D). Non-internalizing proteins, as well as the inability to inhibit FAP, are preferred characteristics to facilitate warhead cleavage by FAP in the extracellular matrix (ECM). Binding specificity for FAP was also confirmed, with lead AFFIMER® proteins unable to bind the related enzyme dipeptidyl peptidase IV (DPP-IV) or other cell surface proteins (data not shown). [506] AFFIMER® protein internalization was measured using two techniques (FIGs.12A-2B). As shown in FIG.12A, AFFIMER® proteins were evaluated for internalization based on down-regulation of AFFIMER® protein at the cell surface of FAP-expressing cells at 37°C vs.4°C by flow cytometry. Antibodies (right-hand three columns, FIG.12A) were used as positive internalizing controls. [507] To confirm non-internalization, as shown in FIG.12B, lead AFFIMER® proteins containing an engineered C-terminal cysteine residue were conjugated to the pH-sensitive pHrodo™ red dye and incubated with HEK-FAP cells. Cell internalization of the dye conjugates was monitored for 24 hours using INCUCYTE®. Dye-conjugated Sibrotuzumab and human IgG1 were used as negative and positive controls, respectively. FAP-binding candidate AFFIMER® proteins that do not internalize in FAP- expressing cells were selected for further screening. [508] To determine whether FAP-binding AFFIMER® proteins inhibited FAP enzyme activity, a panel of 17 FAP-binding AFFIMER® proteins were incubated with HEK-FAP cells. The FAP inhibitor SP- 13786 (FAPi) was used as a control. FAP activity was measured by its ability to cleave 3144-AMC to produce fluorescent AMC. As shown in FIG.12C, AFFIMER® proteins showed no inhibition of FAP enzyme activity.

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[509] To evaluate the stability of AFFIMER® proteins under stress temperature conditions, FAP-2 single-domain (FIG.12D, left) and FAP-2-FAP-1 two-domain (FIG.12D, right) AFFIMER® proteins were incubated at 4°C, 37°C, or 45°C for 1 week. Protein aggregation in the samples was assessed by size exclusion chromatography (SEC). SEC profiles for the temperature-stressed samples are shown in FIG.12D with the percent purity for the monomeric species indicated. Results show tested AFFIMER® proteins are stable under stress temperature conditions. Correlation of FAP and SLFN11 expression as a predictive biomarker for pre|CISION®-enabled therapeutics Introduction [510] Fibroblast activation protein is a post-proline protease highly expressed on cancer-associated fibroblasts (CAFs) in the tumor stroma of many solid tumors. The pre|CISION® platform leverages FAP enzymatic activity to release cytotoxic agents specifically within the tumor, minimizing systemic toxicity and enhancing intratumoral drug concentrations. [511] Schlafen 11 (SLFN11), is a DNA/RNA helicase-like protein and has emerged as a potential predictive biomarker of tumor sensitivity to DNA-damaging therapies, including topoisomerase I inhibitors, platinum agents and PARP inhibitors. SLFN11 expression leads to replication fork destabilization and impaired DNA repair, making SLFN11-positive tumors more susceptible to insult from DNA-damaging agents. The clinical utility of SLFN11 has been demonstrated in several studies [512] A potential synergy emerges when FAP and SLFN11 expression profiles are considered together as tumors co-expressing high levels of FAP and SLFN11 are most likely to respond to pre|CISION®- enabled DNA-damaging agents. In these tumors, high FAP expression enables efficient localisation and cleavage of pre|CISION® compounds, while SLFN11 expression enhances tumor cell susceptibility to the DNA damaging inducing payload. Identifying tumor types where this co-expression exists could allow for rational patient stratification and biomarker-driven clinical development. Methodology [513] To explore the potential utility of FAP and SLFN11 as complementary predictive biomarkers, mRNA expression data were analyzed from Tempus AI’s LENS platform, a large-scale multi-omics database encompassing over 160,000 solid tumor samples profiled by RNA sequencing. The analysis focused on 30 tumor indications and select subtypes, including pancreatic, breast, lung and colorectal cancer. Expression values were normalized and presented as log2(TPM+1). [514] To assess co-expression, FAP and SLFN11 expression levels were extracted for each tumor samples and visualized using scatter plots. To enhance interpretation, vertical and horizontal dashed lines were used to define biologically relevant expression cutoffs for both FAP and SLFN11. These thresholds delineated samples into quadrants representing combinations of negative, weak or strong FAP expression and low or high SLFN11 expression. [515] The proportion of samples in each quadrant was calculated and displayed directly on the plot, enabling quantification of prevalence of potentially targetable subgroups (strong FAP – high SLFN11 expression). A linear regression trendline was applied to assess the overall relationship between FAP and

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SLFN11 expression. Pearson’s R and the corresponding p-value were calculated and overlaid on each plot to evaluate the strength and statistical significance of the correlation. Results [516] FAP mRNA expression was found to significantly correlate with SLFN11 expression across select solid tumor indications. In small-cell lung cancer (SCLC) 30.5% of samples had strong FAP – high SLFN11 expression while 67.8% of pancreatic cancer samples had strong FAP – high SLFN11 expression.58.3% of cervical cancer samples demonstrated strong FAP – high SLFN11 expression and 47.2% of gastric samples (FIG.9). Collectively, these findings support the hypothesis that co-expression of FAP and SLFN11 can be leveraged for patient selection strategies, particularly in indications like pancreatic cancer. Compounds disclosed herein possess DNA damage-inducing payloads. The FAP- SLFN11 correlation could act as a predictive biomarker for the stratification of patients receiving compounds disclosed herein. Table 23. FAP-SLFN11 Correlation Summary

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Table 24. FAP-SLFN11 Correlation Summary

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Production, analysis and characterization of antibody conjugates Production and biophysical characterization [517] Antibodies against CEACAM5, EDB-fibronectin (EDB-F), LRRC15, and HER2 were commercially sourced, along with an antibody against Respiratory Syncytial Virus (RSV), which was used as an isotype control. Different linker-payloads (e.g., LP2, LP3 and LP4), designed with varying sensitivity to FAP cleavage, were conjugated to the thiol groups of cysteine residues within the antibody using maleimide chemistry with a target drug-to-antibody ratio (DAR) of 8. The conjugates were purified from the reaction mixtures using HIC and SEC purification. The integrity and DAR of the antibody conjugation products was monitored by LC-MS and HIC. Antibodies against different targets were successfully conjugated to multiple linker-payloads with excellent monomeric purity (>95%) and a target average DAR of 8 was achieved with LP2, LP3, LP5, and LP10 (Table 25). Table 25: Monomeric purity (SEC) and average DAR (HIC-UV, LC-MS) of antibody conjugates containing LP2, LP3, LP4, LP5, and LP10.

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[518] To determine the thermal stability of the ADCs, an accelerated stability study was conducted wherein the antibody conjugates were incubated at 4, 37, or 45°C for 1 week at 1 mg/mL. The samples were then analysed by SEC-HPLC. Antibody conjugates showed good thermal stability with less than 5% increase in aggregation after incubation at 37 or 45°C compared to incubation at 4°C or baseline (FIG. 14). Biological Data [519] FAP-enablement and solubility are provided in Table 26. Table 26

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Target binding [520] The target-binding ability of the antibody conjugates was assessed by flow cytometry to target positive cells. U87MG cells (EDB-F +ve, LRRC15+ve) were used to test for binding of anti-EDB-F and anti-LRRC15 conjugates. LS174T cells (CEACAM5+ve) were used for anti-CEACAM5 conjugates. Antibody conjugates retained ability to bind their respective targets to equivalent levels as non- conjugated naked antibodies (FIG.15). Anti-RSV conjugates were used as isotype controls and did not show binding as expected (data not shown). Cytotoxicity assays [521] Cytotoxicity assays were performed using HEK293T cells overexpressing FAP and compared to parent cells (FAP-negative). Cells were incubated with the antibody conjugates or linker-payloads for 4 days in the presence of FBS substitute Panexin (which contains low levels of FAP). Cytotoxicity was measured as % inhibition relative to vehicle control by CellTiterGlo (FIGs.16-19). [522] Linker-payloads exhibiting differential sensitivity to FAP-mediated cleavage demonstrated cytotoxicity profiles consistent with their enzymatic cleavage efficiency (kcat/Km). In the presence of a FAP inhibitor, minimal cytotoxicity was observed, confirming FAP-dependent activation. Under low FAP assay conditions (compound alone), LP2, LP3, and LP4 were cleaved to varying extents, resulting in cytotoxicity levels proportional to their FAP sensitivity, with LP3 exhibiting the lowest, LP2 intermediate, and LP4 the highest activity. Upon exposure to exogenous FAP or in cells expressing

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membrane-bound FAP, the cytotoxicity of the linker-payloads approached that of the unconjugated cytotoxic warhead. [523] Antibodies containing LP2 or LP3 retained FAP-dependent cytotoxicity, demonstrating enhanced activity in FAP-positive cells relative to FAP-negative controls (FIGs.16 and 17). Antibodies containing LP4 also retained FAP-dependent activity, as evidenced by reduced cytotoxicity in the presence of a FAP inhibitor; however, due to the high FAP sensitivity of LP4 and the presence of low FAP in the assay conditions, elevated cytotoxicity was observed in both FAP-positive and FAP-negative cells (FIG.18). As a negative control for FAP-enablement, antibodies were also conjugated to the non-cleavable FAP linker LP5. LP5 conjugates showed minimal cytotoxicity, which was independent of FAP, as expected (Fig.19). Bystander cytotoxicity via FAP-dependent activation in tumor-fibroblast co-culture models [524] Bystander effect was assessed using 2D or 3D co-culture models, using GFP-expressing tumor cells (e.g., colorectal LS174T-GFP or triple negative breast cancer MDA-MB-231-GFP cells) and matched fibroblast cells (which express FAP to levels typically observed in tumors). [525] In the 2D coculture model, bystander cytotoxicity assays were performed using LS174T- GFP tumor cells (CEACAM5 positive and FAP negative) as mono-culture or co-culture with human colonic fibroblasts (FAP positive). Cells were incubated with anti-CEACAM5-LP2 conjugates for 5 days in complete MammoCult medium (chemically defined with no exogenous FAP). Tumour specific cytotoxicity was measured as % inhibition relative to vehicle control by GFP fluorescence using the IncuCyte (FIG. 20). Anti-CEACAM5-LP2 exhibited FAP dependent cytotoxicity, where it shows minimal cytotoxicity as a single agent and is only fully active in the presence of recombinant FAP in mono-culture when compared to FAP inhibited and warhead alone conditions. In co-culture, fibroblast-derived endogenous FAP partially activated anti-CEACAM5-LP2 conjugate, resulting in measurable tumor cell killing consistent with a bystander effect. This partial activation achieved cytotoxicity levels within approximately 5-fold of those observed with the free warhead. Full activation, matching the potency of the warhead alone, was observed in the presence of exogenous recombinant FAP. [526] 3D spheroid cytotoxicity assays were performed using MDA-MB-231-GFP tumour cells (FAP negative) as mono-culture or co-culture with human mammary fibroblasts (FAP positive) grown in ultra-low attachment plates. Spheroids were incubated with anti-CEACAM5-LP2 conjugates for 7 days in complete MammoCult medium (chemically defined with no exogenous FAP). Tumour specific cytotoxicity was measured as % inhibition relative to vehicle control by GFP fluorescence using the IncuCyte (FIG. 21). Anti-CEACAM5-LP2 exhibited FAP dependent cytotoxicity, where it is inert as a single agent and only fully active in the presence of recombinant FAP in mono-culture when compared to FAP inhibited and warhead alone conditions. In the coculture, the presence of FAP-expressing fibroblasts was sufficient to fully activate the conjugate, resulting in tumor cell killing equivalent to that observed with the free cytotoxic payload. This

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demonstrates a robust bystander cytotoxicity effect mediated by stromal FAP activity in a 3D tumor microenvironment. In vivo efficacy [527] In vivo efficacy of anti-CEACAM5 conjugates was tested in a LS174T-hFAP (LS174T engineered to express FAP) cell-line derived xenograft (CDX) model. Cells from growing cultures were implanted subcutaneously into female NMRI nu/nu mice. At palpable tumor sizes of ~100-150mm3 the test compounds were injected intravenously once at 10mg/kg on day 8. Tumour growth and body weight were monitored twice weekly and at humane endpoints, the studies were terminated. The anti- CEACAM5 antibody alone did not show significant tumour growth inhibition compared to the vehicle control group. The anti-CEACAM5 conjugates showed various degree of efficacy: anti-CEACAM5-LP3 showed low tumour growth inhibition, anti-CEACAM5-LP4 showed higher efficacy and anti- CEACAM5-LP2 showed the best response with tumours starting to grow above ~250mm3 from day 39 only (FIG.22A). No signs of toxicity were observed with anti-CEACAM5-LP2. Very minor (less than 5%) and minor (less than 10%) body weight loss was seen with anti-CEACAM5-LP3 and anti- CEACAM5-LP4 respectively (FIG.22B). Tumor Uptake Data [528] To quantify the levels of released exatecan warhead in the tumor and plasma following dosing, we used a cell-line derived xenograft (CDX) model of LS174T cells engineered to express FAP. Cells from growing cultures were implanted subcutaneously into female NMRI nu/nu mice, and were allowed to develop to a size of 250mm³ -350mm³ before commencing with dosing. Animals were intravenously dosed with anti-CEACAM5-LP2 once at 13mg/kg, and sampled at either 4hr, 24hr, 72hr or 120hr post- dosing (n=3 per timepoint). LC/MS was used to quantify the concentration of released exatecan warhead in plasma and tumor samples (FIG.23). [529] Anti-CEACAM5-LP2 showed sustained exatecan uptake in tumors even at 120h, with no detectable levels in plasma at any timepoint. EQUIVALENTS AND SCOPE [530] In the claims, articles such as “a,” “an,” and “the” may mean one or more than one (i.e., at least one) unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all the group members are present in, employed in, or otherwise relevant to a given product or process. [531] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can

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be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising,” “containing,” “including,” “having,” and “composed of” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [532] The terms “about” and “substantially” preceding a numerical value mean ±10% of the recited numerical value. [533] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited. [534] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. [535] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

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Claims

CLAIMS What is claimed is: 1. A compound of Formula (I′): , or a pharmaceutically acceptable salt thereof, wherein: CAM is a camptothecin; R′ is -L^A-R^A, hydrogen, halogen, -OR^O, -CO₂R^O, -N(R^N)₂, -C(=O)N(R^N)₂, C₁-₃₀ alkyl, C_1-30 haloalkyl, C_1-30 heteroalkyl, C_2-30 alkenyl, C_2-30 heteroalkenyl, C_2-30 alkynyl, C_2-30 heteroalkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted; R^A is a reactive handle; L^A is a bond, C1-30 alkylene, C1-30 haloalkylene, C2-30 alkenylene, C2-30 alkynylene, C1-30 heteroalkylene, C2-30 heteroalkenylene, C2-30 heteroalkynylene, C3-10 carbocyclylene, 3- to 10-membered heterocyclylene, C6-10 arylene, 5- to 10-membered heteroarylene, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkylene, haloalkylene alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, carbocyclylene, heterocyclylene, arylene, heteroarylene, PEG, or PSar is independently optionally substituted; L¹ is a bond, C3-10 carbocyclylene, C6-10 arylene, 3- to 10-membered heterocyclylene, or 5- to 10- membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted; R² and each instance of R^2A are independently hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein L^A and R² are joined together, or L^A and R^2A are joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted; R³ is hydrogen or optionally substituted C1-6 alkyl; each instance of R^3A is hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain; each instance of R⁴ is independently halogen, C1-6 alkyl, C1-6 haloalkyl, -OR^O, or -N(R^N)2, wherein the alkyl or haloalkyl is optionally substituted; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2; X is a bond, -C(=O)-, -OC(=O)-, -N(R^N)C(=O)-, -S(=O)₂-, or -S(=O)-; L² is a bond, or -N(H)-L²- is a bond or a self-immolative linker, wherein the self-immolative linker is optionally substituted with -L^A-R^A;

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each instance of R^O is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl; and each instance of R^N is independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl; and wherein the compound comprises at least one instance of -L^A-R^A. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-A): 3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-B): wherein -N(H)-L²- is a bond or a self-immolative linker. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-C): wherein -N(H)-L²- is a bond or a self-immolative linker.

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5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-D): 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-E): 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-F):

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8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-G): 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-H): , wherein -N(H)-L²- is a bond or a self-immolative linker. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (I-I): , wherein -N(H)-L²- is a bond or a self-immolative linker.

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11. A construct of Formula (II′): or a pharmaceutically acceptable salt thereof, wherein: R′′ is -L^A-R^B-Z, hydrogen, halogen, -OR^O, -CO₂R^O, -N(R^N)₂, -C(=O)N(R^N)₂, C₁-₃₀ alkyl, C_1-30 haloalkyl, C_1-30 heteroalkyl, C_2-30 alkenyl, C_2-30 heteroalkenyl, C_2-30 alkynyl, C_2-30 heteroalkynyl, C_3-10 carbocyclyl, 3- to 10-membered heterocyclyl, C_6-10 aryl, 5- to 10-membered heteroaryl, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, PEG, or PSar is independently optionally substituted; Z is a binding moiety; R^B is a diradical of a reactive handle; CAM is a camptothecin; L^A is a bond, C_1-30 alkylene, C_1-30 haloalkylene, C_2-30 alkenylene, C_2-30 alkynylene, C_1-30 heteroalkylene, C_2-30 heteroalkenylene, C_2-30 heteroalkynylene, C_3-10 carbocyclylene, 3- to 10-membered heterocyclylene, C_6-10 arylene, 5- to 10-membered heteroarylene, polyethylene glycol (PEG), polysarcosine (PSar), or any combination thereof, wherein each alkylene, haloalkylene alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene, carbocyclylene, heterocyclylene, arylene, heteroarylene, PEG, or PSar is independently optionally substituted; L¹ is a bond, C_3-10 carbocyclylene, C_6-10 arylene, 3- to 10-membered heterocyclylene, or 5- to 10- membered heteroarylene, wherein the carbocyclylene, arylene, heterocyclylene, or heteroarylene is optionally substituted; R² and each instance of R^2A are independently hydrogen or optionally substituted C1-C6 alkyl; or optionally wherein L^A and R² are joined together, or L^A and R^2A are joined together, with the intervening atoms to form a 5- to 10-membered heterocyclic ring, wherein the heterocyclic ring is optionally substituted; R³ is hydrogen or optionally substituted C1-6 alkyl; each instance of R^3A is hydrogen, optionally substituted C1-6 alkyl, or an amino acid sidechain; each instance of R⁴ is independently halogen, C1-6 alkyl, C1-6 haloalkyl, -OR^O, or -N(R^N)2, wherein the alkyl or haloalkyl is optionally substituted; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, or 2; X is a bond, -C(=O)-, -OC(=O)-, -N(R^N)C(=O)-, -S(=O)2-, or -S(=O)-; L² is a bond, or -N(H)-L²- is a bond or a self-immolative linker, wherein the self-immolative linker is optionally substituted with -L^A-R^B-Z;

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each instance of R^O is independently H, optionally substituted C1-6 alkyl, optionally substituted C1-6 haloalkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl; and each instance of R^N is independently H, optionally substituted C1-6 alkyl, optionally substituted C3-7 carbocyclyl, or optionally substituted C1-6 acyl, or two R^N bonded to the same nitrogen are joined together to form optionally substituted 3-7 membered heterocyclyl; and wherein the construct comprises at least one instance of -L^A-R^B-Z. _{12. The construct of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of} Formula (II-A): _{13. The construct of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of} Formula (II-B): , wherein -N(H)-L²- is a bond or a self-immolative linker. _{14. The construct of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of} Formula (II-C): wherein -N(H)-L²- is a bond or a self-immolative linker. 228/240 A1224.70043WO00

15. The construct of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-D): 16. The construct of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-E): 17. The construct of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-F):

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18. The construct of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-G): 19. The construct of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-H): , wherein -N(H)-L²- is a bond or a self-immolative linker. 20. The construct of claim 11, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula (II-I): 21. The construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody.

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22. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the reactive handle comprises a maleimide. 23. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R^A comprises . 24. The construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R^B comprises , wherein * denotes the point of attachment to the binding moiety. 25. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein CAM is exatecan, SN-38, Dxd, belotecan, or topotecan. 26. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein CAM is exatecan. 27. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 1. 28. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 0. 29. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L² is a bond or -N(H)-L²- is a bond. 30. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein -N(H)-L²- is a self-immolative linker. 31. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein -N(H)-L²- is of the formula:

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* denotes the point of attachment to CAM; each instance of R⁵ is independently halogen, C1-20 alkyl, C1-20 haloalkyl, C1-20 heteroalkyl, C1-20 alkenyl, C1-20 alkynyl, -OR^O, -CO2R^O, -N(R^N)2, -C(=O)N(R^N)2, PEG, PSar, -L⁵-R^5A, or -C(=O)-L⁵-R^5A, wherein the alkyl, haloalkyl, heteroalkyl, alkenyl, alkynyl, or PEG is optionally substituted, including optionally with one or more instances of R^5A; L⁵ is a bond, C1-20 alkylene, C1-20 haloalkylene, C1-20 heteroalkylene, PEG, or PSar, wherein the alkylene, haloalkylene, or heteroalkylene is optionally substituted; each instance of R^5A is independently C1-6 alkyl, -OR^O, -CO2R^O, -N(R^N)2, -C(=O)N(R^N)2, or PEG; p is 0, 1, 2, 3, or 4. 32. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the -N(H)-L²- is of the formula: , wherein * denotes the point of attachment to CAM. 33. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein p is 0. 34. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L¹ is 5- to 10-membered heteroarylene, wherein the heteroarylene is optionally substituted. 35. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L¹ is of the formula: , wherein * denotes the point of attachment to L^A.

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36. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L¹ is of the formula: , wherein * denotes the point of attachment to L^A. 37. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L^A comprises the formula: integer from 1-25, inclusive. 38. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L^A comprises the formula: L^A comprises the formula an integer from 1-25, inclusive. 39. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L^A comprises: . 40. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L^A is of the formula: integer from 5-10. 41. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X is -C(=O)-.

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42. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R^2A is H. 43. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R^3A is Me. 44. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R² is H. 45. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R³ is H or Me. 46. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2. 47. The compound or construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R⁴ is halogen. 48. The compound of claim 1, wherein the compound is selected from those in Table 4, and pharmaceutically acceptable salts thereof. 49. A compound, wherein the compound is selected from those in Table 5B, and pharmaceutically acceptable salts thereof. 50. A construct, or a pharmaceutically acceptable salt thereof, comprising a compound selected from those in Table 5B, or a pharmaceutically acceptable salt thereof, conjugated to a binding moiety. 51. The construct of any one of claims 11-47 and 50, or a pharmaceutically acceptable salt thereof, wherein the binding moiety is selected from antibodies and AFFIMER® polypeptides (human Stefin A variants comprising two heterologous peptides). 52. The construct of any one of claims 11-47, 50, and 51, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to an antigen selected from 5T4, ADAM17, ADAM9, ALK, angiopoietin2, Axl, AXL, B7H3, B7H4, BAFF, BCMA, BSG, c-kit, CA- IX, CA125, CA6, CAIX, CCR5, CCR7, CD123, CD134, CD137, CD138, CD152, CD184, CD19, CD20, CD200, CD205, CD22, CD221, CD228, CD23, CD24, CD25, CD27, CD276, CD279, CD28, CD30, CD319, CD33, CD37, CD38, CD40, CD44, CD45, CD46, CD47, CD51, CD52, CD56, CD7, CD70, CD73, CD74, CD79B, CD79b, CD80, CD99, CDH3, CDH6, CEACAM5, CEACAM6,

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CLAUDIN18.2, CLDN6, CLDN9, CLL-1, cMET, CSF-R1, CSF2, CTGF, CTLA4, CXCR4, DCLK1, DDR1, DLK1, DLL3, DLL4, DPEP3, DR5, DSG2, EDB-Fn, EFNA4, EGFL7, EGFR, ENB-FN, ENO1, ENPP3, EpCAM, EphA2, EphA3, ETB, FAP, FCRL5, FGFR2, FGFR3, Flt3, FOLR, FR1, FRα, FUT3, GC-C, GD3, gelatinase B, Globo H, GLUT1, glypican3, GPNMB, GPR20, GPRC5D, GUCY2C, HER1, HER2, HER3, HGFR, HLA-DR, ICOSL, IGF-1R, IGF1, IGF2, IL17A, IL17F, IL1RAP, IL2, IL6, ITGB6, KAAG1, KIR2D, LAG3, LAMP-1, Lewis-Y antigen, LIV-1, LIV1, LRRC15, LTα, Ly6E, LYPD3, MIF, MSLN, Muc1, MUC1, Muc16, MUC5AC, Nectin-4, Notch-3, Notch1, OAcGD2, PCDP1, PDL1, PDL2, p53, PRL receptor, PSMA, PTK7, RON, ROR1, ROR2, RNF43, SDC1, SEZ6, SLAMF2, SLAMF6, SLAMF7, SSEA-4, sTn, STEAP1, TAG72, TAA, TDGF1, TEM1, Tenascin C, TF (Tissue Factor), TGFb, TIGIT, TIM1, TNF-α, TNFR, TRAIL, TRAIL-R2, TROP2, TWEAKR, TYRP1, VEGF2, VEGFR2, Vimentin, and VISTA. 53. The construct of claim 52, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to CEACAM5, CLAUDIN18.2, CLAUDIN4, CMET, DLL3, EDB-FN, FAP, FRα, HER2, HER3, LLRC15, Nectin-4, TF (Tissue Factor), or TROP2. 54. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to CEACAM5. 55. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to CLAUDIN18.2. 56. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to CLAUDIN4. 57. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to CMET. 58. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to DLL3. 59. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to EDB-FN. 60. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to FAP, optionally wherein Z is an AFFIMER® (a) comprising

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a Loop 2 and/or Loop 4 sequence of Table 1 (respectively SEQ ID NO: 5-108 and/or SEQ ID NO: 109-212) or (b) comprises a polypeptide sequence of Table 2 (SEQ ID NO: 213-501 or 553-567) 61. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to FRα 62. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to HER2. 63. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to HER3. 64. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to LLRC15. 65. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to Nectin-4. 66. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to TF (Tissue Factor). 67. The construct of claim 53, or a pharmaceutically acceptable salt thereof, wherein Z is an AFFIMER® or an antibody that specifically binds to TROP2. 68. The construct of any one of claims 11-47 and 50-67, or a pharmaceutically acceptable salt thereof, wherein Z comprises an antibody. 69. The construct of claim 68, or a pharmaceutically acceptable salt thereof, wherein the antibody is selected from trastuzumab, sacituzumab, datopotamab, enfortumab, telisotuzumab, mirvetuximab, tarlatamab, tisotumab, OMTX-705 (ADC), zenocutuzumab, patritumab, zolbetuximab, tusamitamab, M9140, samrotamab, L19, and ASP1002. 70. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is trastuzumab.

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71. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is sacituzumab. 72. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is datopotamab. 73. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is enfortumab. 74. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is telisotuzumab. 75. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is mirvetuximab. 76. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is tarlatamab. 77. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is tisotumab. 78. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is OMTX-705. 79. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is zenocutuzumab. 80. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is patritumab. 81. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is zolbetuximab. 82. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is tusamitamab.

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83. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is M9140. 84. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is samrotamab. 85. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is L19. 86. The construct of claim 69, or a pharmaceutically acceptable salt thereof, wherein the antibody is ASP1002. 87. The construct of claim 11, wherein the construct is selected from those in Table 5A. 88. A pharmaceutical composition comprising a construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 89. A method of treating a disease characterized by fibroblast activation protein (FAP) upregulation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 90. The method of claim 89, wherein the disorder characterized by FAP upregulation is cancer, fibrosis, or inflammation. 91. A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 92. A method comprising administering to a subject a construct of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 93. The method of claim 92, wherein the subject has a disease characterized by FAP upregulation. 94. The method of claim 92, wherein the subject has cancer. 95. The method of any one of claims 90, 91, or 94, wherein the cancer is selected from head and neck cancer, soft tissue sarcoma, breast cancer, lung cancer, gastric cancer, colorectal cancer, and pancreatic ductal adenocarcinoma.

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96. The method of claim 95, wherein the head and neck cancer is salivary gland cancer. 97. The method of claim 95, wherein the soft tissue sarcoma is undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma. 98. The method of claim 95, wherein the breast cancer is triple-negative breast cancer. 99. The method of any one of claims 89-98, wherein the construct, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered by intravenous injection. 100. The method of any one of claims 89-98, wherein the construct, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered by direct intra-tumoral administration. 101. A construct of any of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a disorder characterized by FAP upregulation in a subject. 102. Use of a construct of any of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as a medicament. 103. A method comprising selecting a subject for treatment with the polypeptide, the fusion protein, the protein conjugate, or the polynucleotide of any preceding claim based on expression of FAPα and SLFN11 in a tumor tissue sample from the subject, wherein expression of each of FAPα and SLFN11 is higher than a respective threshold level. 104. A method comprising assaying a tumor tissue sample from a subject for expression of FAPα and SLFN11 and selecting the subject for treatment with the polypeptide, the fusion protein, the protein conjugate, or the polynucleotide of any preceding claim when expression of each of FAPα and SLFN11 is higher than a respective threshold level. 105. The method of claim 103 or 104, wherein the tumor tissue is from a cancer listed in Table 23 or 24.

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