WO2024178155A1 - Conjugués de trans-cyclooctène - Google Patents

Conjugués de trans-cyclooctène Download PDF

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WO2024178155A1
WO2024178155A1 PCT/US2024/016775 US2024016775W WO2024178155A1 WO 2024178155 A1 WO2024178155 A1 WO 2024178155A1 US 2024016775 W US2024016775 W US 2024016775W WO 2024178155 A1 WO2024178155 A1 WO 2024178155A1
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compound
mmol
conjugate
cancer
lcms
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José Manuel Mejía ONETO
Jesse M. McFARLAND
Jaime R. CABRERA-PARDO
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Tambo Inc
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Tambo Inc
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Priority to CN202480026270.1A priority Critical patent/CN121001752A/zh
Priority to JP2025547702A priority patent/JP2026508188A/ja
Priority to EP24714636.8A priority patent/EP4669357A1/fr
Publication of WO2024178155A1 publication Critical patent/WO2024178155A1/fr
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    • A—HUMAN NECESSITIES
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/70—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with ring systems containing two or more relevant rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present disclosure relates generally trans-cyclooctene conjugates for bioorthogonal delivery of a payload to a targeted location in a subject, which conjugates have applications, e.g., in the treatment of cancer, tumor growth, and immunotherapy.
  • Bioorthogonal conjugation or click reactions are selective and orthogonal (non-interacting with) functionalities found in biological systems, and have found use in various applications in the fields of chemistry, chemical biology, molecular diagnostics, and medicine, where they can be used to facilitate the selective manipulation of molecules, cells, particles and surfaces, and the tagging and tracking of biomolecules in vitro and in vivo.
  • These reactions include the Staudinger ligation, the azide-cyclooctyne cycloaddition, and the inverse-electron-demand Diels-Alder reaction.
  • conjugates for use in bioorthogonal reactions which conjugates comprise a payload covalently bonded to one or more optionally substituted trans-cyclooctene moieties via a linker.
  • the payload is a taxane, such as paclitaxel, a taxane, a topoisomerase inhibitor, or a MMAE payload, or a derivative, or analog thereof.
  • a method for delivering an effective amount of a payload i.e., a taxane, such as paclitaxel, a topoisomerase inhibitor, or a MMAE payload, or a derivative, or analog thereof
  • a payload i.e., a taxane, such as paclitaxel, a topoisomerase inhibitor, or a MMAE payload, or a derivative, or analog thereof
  • the method comprising administering to the subject at the target location a therapeutic support composition as described herein, and administering to the subject a conjugate, or the pharmaceutically acceptable salt or composition thereof, as described herein.
  • the conjugate comprises one or more solubilizing groups.
  • a method for treating cancer comprising administering to a subject in need thereof, a therapeutic support composition as described herein to a target location, and administering to the subject a conjugate, or the pharmaceutically acceptable salt or composition thereof, as described herein.
  • the cancer is metastatic.
  • the cancer is melanoma, renal cancer, prostate cancer, ovarian cancer, endometrial carcinoma, breast cancer, glioblastoma, lung cancer, soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, gastric carcinoma, squamous cell carcinoma of head/neck, anal/vulvar carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, cervical carcinoma, hepatocellular carcinoma, Kaposi's sarcoma, Non-Hodgkin’ s lymphoma, Hodgkin’s lymphoma, Wilm’s tumor/neuroblastoma, bladder cancer, thyroid adenocarcinoma, pancreatic neuroendocrine tumors, prostatic adenocarcinoma, nasopharyngeal carcinoma, malignant extrinsic or intrinsic airway compression, or cutaneous T-cell lymphoma.
  • the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer.
  • the cancer is a solid tumor.
  • the cancer is a lymphoma or leukemia.
  • the cancer is a hematological malignancy.
  • Figure 1 shows percent body weight changes after administering SQT01 combination with Compound 32 to CrTac:NCr-Foxnlnu mice bearing NCI-N87 Subcutaneous Xenografts. Error bars represent standard error of the mean (SEM).
  • Figure 2 shows tumor volume traces after administering SQT01 combination with Compound 32 to CrTac:NCr-Foxnlnu mice bearing NCI-N87 Subcutaneous Xenografts.
  • the modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity).
  • the modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints.
  • the expression “from about 2 to about 4” also discloses the range “from 2 to 4.”
  • the term “about” may refer to plus or minus 10% of the indicated number.
  • “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9- 1.1.
  • Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.
  • the conjunctive term “or” includes any and all combinations of one or more listed elements associated by the conjunctive term.
  • the phrase “an apparatus comprising A or B” may refer to an apparatus including A where B is not present, an apparatus including B where A is not present, or an apparatus where both A and B arc present.
  • the phrases “at least one of A, B, . . . and N” or “at least one of A, B, . . . N, or combinations thereof’ are defined in the broadest sense to mean one or more elements selected from the group comprising A, B, . . . and N, that is to say, any combination of one or more of the elements A, B, . . . or N including any one element alone or in combination with one or more of the other elements which may also include, in combination, additional elements not listed.
  • alkoxy refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy.
  • alkyl as used herein, means a straight or branched, saturated hydrocarbon chain containing from 1 to 30 carbon atoms.
  • lower alkyl or “C 1- C 6 -alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms.
  • C1-C3- alkyl means a straight or branched chain hydrocarbon containing from 1 to 3 carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n- heptyl, n-octyl, n-nonyl, and n-decyl.
  • alkenyl as used herein, means a hydrocarbon chain containing from 2 to 30 carbon atoms with at least one carbon-carbon double bond.
  • the alkenyl group may be substituted or unsubstituted.
  • the alkenyl group may be substituted with an aryl group, such as a phenyl.
  • alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 30 carbon atoms, such as 2 to 20, or 2 to 10 carbon atoms and having at least 1 site of triple bond unsaturation.
  • alkyne also includes non-aromatic cycloalkyl groups of from 5 to 20 carbon atoms, such as from 5 to 10 carbon atoms, having single or multiple rings and having at least one triple bond.
  • alkynyl groups include, but are not limited to acetylenyl (-C ⁇ CH), and propargyl (-CH 2 C ⁇ CH), and cycloalkynyl moieties, such as, but not limited to, substituted or unsubstituted cyclooctyne moieties.
  • alkoxyalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • alkylene refers to a divalent group derived from a straight or branched chain hydrocarbon of 1 to 30 carbon atoms, for example, of 2 to 10 carbon atoms.
  • alkylene include, but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH(CH 3 )CH 2 -, -C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, and –CH 2 CH 2 CH 2 CH 2 CH 2 -.
  • amino acid refers to both natural and unnatural amino acids, protected natural and unnatural amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally encoded amino acids include 20 common amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine) and pyrrolidine and selenocysteine.
  • Amino acid analogs refer to compounds having the same basic chemical structure as a naturally occurring amino acid, i.e., by way of example only, an ⁇ -carbon attached to a hydrogen, carboxyl group, amino group, and R group. Such analogs can have a modified R group (e.g., norleucine as an example) or retain a modified peptide backbone while retaining the same basic chemical structure as a natural amino acid.
  • a modified R group e.g., norleucine as an example
  • Non-limiting examples of amino acid analogs include citrulline, homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium, homophenylalanine, ornithine, formyl glycine, phenyl glycine, para-azidophenyl glycine, para- azidophenylalanine, para-acetophenylalanine, 4-(3-methyl-(1,2,4,5-tetrazine))-phenylglyine, and 4-(3- methyl-(1,2,4,5-tetrazine))-phenylalanine.
  • aryl refers to a phenyl group, or bicyclic aryl or tricyclic aryl fused ring systems.
  • Bicyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to a phenyl group.
  • Tricyclic fused ring systems are exemplified by a phenyl group appended to the parent molecular moiety and fused to two other phenyl groups.
  • Representative examples of bicyclic aryls include, but are not limited to, naphthyl.
  • tricyclic aryls include, but are not limited to, anthracenyl.
  • the monocyclic, bicyclic, and tricyclic aryls are connected to the parent molecular moiety through any carbon atom contained within the rings, and can be unsubstituted or substituted.
  • azide refers to the functional group -N3.
  • cycloalkyl refers to a carbocyclic ring system containing three to ten carbon atoms, zero heteroatoms and zero double bonds.
  • Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl.
  • Cycloalkyl also includes carbocyclic ring systems in which a cycloalkyl group is appended to the parent molecular moiety and is fused to an aryl group as defined herein, a heteroaryl group as defined herein, or a heterocycle as defined herein.
  • cycloalkenyl as used herein, means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
  • exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • cyclooctene refers to a substituted or unsubstituted non-aromatic cyclic alkyl group of 8 carbon atoms, having a single ring with a double bond.
  • cyclooctene groups include, but are not limited to, substituted or unsubstituted trans-cyclooctene (TCO).
  • fluoroalkyl as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine.
  • Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl such as 3,3,3-trifluoropropyl.
  • alkoxyfluoroalkyl refers to an alkoxy group, as defined herein, appended to the parent molecular moiety through a fluoroalkyl group, as defined herein.
  • fluoro alkoxy means at least one fluoroalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of fluoroalkoxy include, but are not limited to, difluoromethoxy, trifluoromethoxy and 2,2,2- trifluoroethoxy.
  • halogen or “halo” as used herein, means Cl, Br, I, or F.
  • haloalkyl as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a halogen.
  • haloalkoxy means at least one haloalkyl group, as defined herein, is appended to the parent molecular moiety through an oxygen atom.
  • heteroalkyl means an alkyl group, as defined herein, in which one or more of the carbon atoms has been replaced by a heteroatom selected from S, Si, O, P and N. The heteroatom may be oxidized.
  • Representative examples of heteroalkyls include, but are not limited to, alkyl ethers, secondary and tertiary alkyl amines, and alkyl sulfides.
  • Heteroalkylene refers to a divalent heteroalkyl group. “Heteroalkylene” groups must have at least one carbon and at least one heteroatomic group within the chain.
  • the term “heteroalkylene” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms may be independently replaced with the same or different heteroatomic group.
  • Heteroatomic groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O)2-, and the like, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein, such as with an oxo.
  • heteroalkylene groups include, e.g., polyethers, -CH 2 OCH 2 -, -CH(CH 3 )OCH 2 -, -CH 2 CH 2 OCH 2 -, -OCH 2 -, -CH(CH 3 )O-, -CH 2 CH 2 O-, -CH 2 CH 2 OC(O)-, -CH 2 CH 2 OCH 2 CH 2 OCH 2 -, -CH 2 CH 2 OCH 2 CH 2 O-, -CH 2 SCH 2 -, -CH(CH 3 )SCH 2 -, -CH 2 CH 2 SCH 2 -, -CH 2 CH 2 SCH 2 CH 2 SCH 2 -, -SCH 2 -, -CH(CH 3 )S-, -CH2CH2S-, -CH2CH2SCH2CH2S-, -CH2S(O)2CH2-, -CH(CH3)S(O)2CH2-, -CH2CH2S(O)2
  • heteroalkylene includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.
  • heteroalkylene includes groups such as amides or other functional groups having an oxo present on one or more carbon atoms.
  • heteroaryl refers to an aromatic monocyclic ring or an aromatic bicyclic ring system or an aromatic tricyclic ring system.
  • the aromatic monocyclic rings are five or six membered rings containing at least one heteroatom independently selected from the group consisting of N, O and S (e.g.1, 2, 3, or 4 heteroatoms independently selected from O, S, and N).
  • the five membered aromatic monocyclic rings have two double bonds and the six membered six membered aromatic monocyclic rings have three double bonds.
  • the bicyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • the tricyclic heteroaryl groups are exemplified by a monocyclic heteroaryl ring appended to the parent molecular moiety and fused to two of a monocyclic cycloalkyl group, as defined herein, a monocyclic aryl group, as defined herein, a monocyclic heteroaryl group, as defined herein, or a monocyclic heterocycle, as defined herein.
  • monocyclic heteroaryl include, but are not limited to, pyridinyl (including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl, pyrazinyl, thienyl, furyl, thiazolyl, thiadiazolyl, isoxazolyl, pyrazolyl, and 2-oxo-l,2-dihydropyridinyl.
  • bicyclic heteroaryl include, but are not limited to, chromenyl, benzothienyl, benzodioxolyl, benzotriazolyl, quinolinyl, thienopyrrolyl, thienothienyl, imidazothiazolyl, benzothiazolyl, benzofuranyl, indolyl, quinolinyl, imidazopyridine, benzooxadiazolyl, and benzopyrazolyl.
  • tricyclic heteroaryl include, but are not limited to, dibenzofuranyl and dibenzothienyl.
  • the monocyclic, bicyclic, and tricyclic heteroaryls are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted.
  • heterocycle or “heterocyclic” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle.
  • the monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.
  • the three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S.
  • the five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S.
  • the six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • the seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S.
  • monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1 ,3-dioxanyl, 1,3-dioxolanyl, 1 ,3-dithiolanyl, 1 ,3-dithianyl, l,3-dimethylpyrimidine-2,4(lH,3H)-dione, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl,
  • the bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a spiro heterocycle group, or a bridged monocyclic heterocycle ring system in which two non-adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms.
  • bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3- dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2, 3 -dihydroisoquinoline, 2-azaspiro[3.3]heptan-2-yl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), 2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl.
  • Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non- adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms.
  • tricyclic heterocycles include, but are not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.1 3,7 ]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.1 3,7 ]decane).
  • hydroxyl as used herein, means an —OH group.
  • hydroxyalkyl as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by a hydroxyl group.
  • the number of carbon atoms in a hydrocarbyl substituent is indicated by the prefix “Cx-Cy-” or “Cx-y,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • Cx-Cy- or “Cx-y,” wherein x is the minimum and y is the maximum number of carbon atoms in the substituent.
  • C1-C3-alkyl” and “C1-3alkyl” refer to an alkyl substituent containing from 1 to 3 carbon atoms.
  • the two conventions “C x -C y -” and “C x-y ” are used interchangeably and have the same meaning.
  • substituted refers to a group that may be further substituted with one or more non- hydrogen substituent groups.
  • tetrazine refers to a substituted or unsubstituted aromatic cyclic group of 2 carbon atoms and 4 nitrogen atoms, having a single ring with three double bonds.
  • tetrazine groups include 1,2,3,4-tetrazine and 1,2,4,5-tetrazine.
  • 1,2,4,5-tetrazine is referred to as a “Tz” group.
  • selective delivering refers to delivering an agent (e.g., a payload) to an organ or tissue (or portion thereof) in need of treatment or diagnosis, without significant binding to other non- target organs or tissues (or portions thereof).
  • the term “payload” refers to an agent for delivery to a target site in a subject. Payloads include therapeutic agents.
  • therapeutic agent refers to an agent capable of treating and/or ameliorating a condition or disease, or one or more symptoms thereof, in a subject. Therapeutic agents of the present disclosure also include prodrug forms of therapeutic agents.
  • diagnostic agent refers to agents that assist in diagnosing conditions or diseases. Representative diagnostic agents include imaging agents such as paramagnetic agents, optical probes, radionuclides, and the like. Paramagnetic agents are imaging agents that are magnetic under an externally applied field.
  • paramagnetic agents include, but are not limited to, iron particles including iron nanoparticles and iron microparticles.
  • Optical probes are fluorescent compounds that can be detected by excitation at one wavelength of radiation and detection at a second, different, wavelength of radiation.
  • Optical probes of the present disclosure include, but are not limited to, Cy5.5, Alexa 680, Cy5, DiD (1,1’-dioctadecyl-3,3,3’,3’-tetramethylindodicarbocyanine perchlorate) and DiR (1,1’- dioctadecyl-3,3,3’,3’-tetramethylindotricarbocyanine iodide).
  • Other optical probes include quantum dots.
  • Radionuclides are elements that undergo detectable radioactive decay. Radionuclides useful in embodiments of the present disclosure include, but are not limited to, 3 H, 11 C, 13 N, 18 F, 19 F, 60 Co, 64 Cu, 67 Cu, 68 Ga, 82 Rb, 89 Zr, 90 Sr, 90 Y, 99 Tc, 99m Tc, 111 In, 123 I, 124 I, 125 I, 129 I, 131 I, 137 Cs, 177 Lu, 186 Re, 188 Re, 211 At, Rn, Ra, Th, U, Pu, and 241 Am.
  • targeting agent refers to a chemical or biological agent that specifically binds to a target (e.g., a targeted organ or tissue), thereby forming a stable association between the targeting agent and the specific target.
  • a target e.g., a targeted organ or tissue
  • stably associated or “stable association” is meant that a moiety is bound to or otherwise associated with another moiety or structure under standard physiological conditions. Bonds may include covalent bonds and non-covalent interactions, such as, but not limited to, ionic bonds, hydrophobic interactions, hydrogen bonds, van der Waals forces (e.g., London dispersion forces), dipole- dipole interactions, and the like.
  • a targeting agent may be a member of a specific binding pair, such as, but are not limited to: a member of a receptor/ligand pair; a ligand-binding portion of a receptor; a member of an antibody/antigen pair; an antigen-binding fragment of an antibody; a hapten; a member of a lectin/carbohydrate pair; a member of an enzyme/substrate pair; biotin/avidin; biotin/streptavidin; digoxin/antidigoxin; a member of a DNA or RNA aptamer binding pair; a member of a peptide aptamer binding pair; and the like.
  • Targeting agents include ligands that specifically bind (or substantially specifically bind) a particular clinically-relevant target receptor or cell surface target.
  • the ligand can be an antibody, peptide, nucleic acid, phage, bacteria, virus, or other molecule with a specific affinity for a target receptor or cell surface target.
  • receptors and cell surface targets include, but are not limited to, PD-1, CTLA-4, HER2/neu, HER1/EGFR, VEGFR, 4-1BB, GITR, LT4 - human mAb directed against the inhibitory immune checkpoint receptor immunoglobulin-like transcript 4 (ILT4; leukocyte immunoglobulin-like receptor subfamily B member 2, LILRB2, lymphocyte immunoglobulin-like receptor 2, LIR2, monocyte/macrophage immunoglobulin-like receptor 10, MIR-10, CD85d, or other cellular receptors or cell surface targets. Additional examples are included in various embodiments disclosed herein.
  • ILT4 inhibitory immune checkpoint receptor immunoglobulin-like transcript 4
  • targeted organ or tissue refers to an organ or tissue that is being targeted for delivery of the payload.
  • Representative organs and tissues for targeting include those that can be targeted by chemical or biological targeting agents, as well as those organs and tissues that cannot be targeted by chemical or biological targeting agents.
  • implanting refers to surgical implantation into a subject’s body.
  • contacting refers to the process of bringing into contact at least two distinct species such that they can interact with each other, such as in a non-covalent or covalent binding interaction or binding reaction. It should be appreciated, however, the resulting complex or reaction product can be produced directly from an interaction or a reaction between the added reagents or from an intermediate from one or more of the added reagents or moieties, which can be produced in the contacting mixture.
  • binding agent refers to an agent having a functional group capable of forming a covalent bond to a complementary functional group of another binding agent in a biological environment. Binding between binding agents in a biological environment may also be referred to as bioconjugation. Binding agents include bioorthogonal binding agents, which are binding agents having bioorthogonal functional groups. Bioorthogonal functional groups of bioorthogonal binding agents selectively react with a complementary bioorthogonal functional group of another bioorthogonal binding partner.
  • Bioorthogonal moieties or functional groups of bioorthogonal binding agents include, but are not limited to, an azide and alkyne for formation of a triazole via Click-chemistry reactions, trans-cyclooctene (TCO) and tetrazine (Tz) (e.g., 1, 2,4,5- tetrazine), and others.
  • TCO trans-cyclooctene
  • Tz tetrazine
  • the binding agents useful in the present disclosure may have a high reactivity with the corresponding binding agent so that the reaction is rapid.
  • the term “functionalized” refers to a moiety having a functional group attached to the moiety, such as for example a moiety having a binding agent functional group (e.g., a bioorthogonal functional group) attached thereto.
  • a binding agent functional group e.g., a bioorthogonal functional group
  • administering refers to any suitable route of administration to a subject, such as, but not limited to, oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject.
  • pharmaceutically effective amount and “therapeutically effective amount” refer to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and/or to prevent or reduce the risk of the occurrence or reoccurrence of the disease or disorder or symptom(s) thereof.
  • a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause the tumor to shrink or decrease the growth rate of the tumor.
  • the term “subject,” “patient,” or “organism” includes humans and mammals (e.g., mice, rats, pigs, cats, dogs, and horses). Typical subjects to which an agent(s) of the present disclosure may be administered may include mammals, particularly primates, especially humans.
  • suitable subjects may include, for example, livestock such as cattle, sheep, goats, cows, swine, and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and domesticated animals particularly pets such as dogs and cats.
  • suitable subjects may include mammals, such as rodents (e.g., mice, rats, hamsters), rabbits, primates, and swine such as inbred pigs and the like.
  • treating means the treating or treatment of a disease or medical condition or symptom(s) thereof in a patient, such as a mammal (particularly a human) that includes: (a) ameliorating the disease or medical condition or symptom(s) thereof, such as, eliminating or causing regression of the disease or medical condition or symptom(s) thereof in a patient; (b) suppressing the disease or medical condition or symptom(s) thereof, for example by, slowing or arresting the development of the disease or medical condition or symptom(s) thereof in a patient; or (c) alleviating a symptom of the disease or medical condition or symptom(s) thereof in a patient.
  • physiological conditions is meant to encompass those conditions compatible with living cells, e.g., predominantly aqueous conditions of a temperature, pH, salinity, etc. that are compatible with living cells.
  • groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.
  • the compounds may exist as stereoisomers wherein asymmetric or chiral centers are present.
  • the stereoisomers are “A” or “S” depending on the configuration of substituents around the chiral carbon atom.
  • the terms “A” and “5” used herein arc configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30.
  • Stereoisomers include enantiomers and diastereomers and mixtures of enantiomers or diastereomers.
  • Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel’s Textbook of Practical Organic Chemistry,” 5 th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or (3) fractional recrystallization methods.
  • the present disclosure also includes isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as, but not limited to, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 C1, respectively.
  • the compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors.
  • positron-emitting isotopes that can be incorporated are U C, 13 N, 15 O, and 18 F.
  • Isotopically-labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically- labeled reagent in place of non-isotopically-labeled reagent.
  • conjugates for use in bioorthogonal reactions.
  • the conjugates comprise a payload bonded to a trans-cyclooctene moiety.
  • the conjugates comprise a payload (i.e., a taxane, such as paclitaxel, a topoisomerase inhibitor, or a MMAE payload, or a derivative, or analog thereof) bonded to a trans-cyclooctene moiety comprising one or more solubilizing groups.
  • a conjugate of Formula A-I or Formula A-II, or a pharmaceutically acceptable salt thereof wherein: m is an integer from 1-10; r is 1 or 2; each D 1 is independently a taxane, a topoisomerase inhibitor, or a MMAE pay load, or a derivative, or analog thereof;
  • L 1 and L 2 are each independently a linker
  • G an optionally substituted trans-cyclooctene moiety; and each S 1 is independently a solubilizing group.
  • D 1 is a taxane, a topoisomerase inhibitor, or a MMAE payload, or a derivative, or analog thereof;
  • L 1 and L 2 are each independently a linker
  • G an optionally substituted trans-cyclooctene moiety; and each S 1 is independently a solubilizing group.
  • a conjugate of Formula A-II, or a pharmaceutically acceptable salt thereof wherein: m is an integer from 1-10; r is 1 or 2; each D 1 is independently a taxane, a topoisomerase inhibitor, or a MMAE payload, or a derivative, or analog thereof;
  • L 2 is a linker
  • G an optionally substituted trans-cyclooctene moiety; and each S 1 is independently a solubilizing group.
  • D 1 is a taxane payload, or a derivative, or analog thereof
  • L 1 and L 2 are each independently a linker
  • G an optionally substituted trans-cyclooctene moiety; and each S 1 is independently a solubilizing group.
  • the conjugate is not:
  • the moie ty is of Formula A-IIA: wherein: q is 0, 1, or 2; m is an integer from 1-10; R 1A , at each occurrence, is independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, and C1-4alkoxy; L 2 is a linker; and each S 1 is independently a solubilizing group.
  • the moiety is of Formula A-IIA: wherein: m is an integer from 1-10; R 1A is selected from the group consisting of C1-4alkyl, C1-4haloalkyl, and C1-4alkoxy; L 2 is a linker; and each S 1 is independently a solubilizing group. [0074] In some embodiments, each S 1 is independently selected from the group consisting of - NHC(NH)NH2, -P(O)(OH)2, -S(O)2OH, -(OCH2CH2)30-85-OCH3, -N(CH2CH2C(O)OH)2, or [0075] In some embodiments, one S 1 is -NHC(NH)NH 2 .
  • one S 1 is -P(O)(OH)2. [0077] In some embodiments, one S 1 is -S(O) 2 OH. [0078] In some embodiments, one S 1 is -(OCH2CH2)30-85-OCH3. [0079] In some embodiments, one S 1 is -N(CH 2 CH 2 C(O)OH) 2 .
  • one S 1 is [0081] In some embodiments, each S 1 is independently selected from -NHC(NH)NH 2 , -P(O)(OH) 2 , -S(O)2OH, -N(CH2CH2C(O)OH)2, or [0082] In some embodiments, L 1 is – OC(O)–, –C(O)O–, –NR 1f C(O)–, or –C(O)NR 1f –; and R 1f is hydrogen, C1-6alkyl, or C0-4alkylene–CO2H.
  • L 1 is –OC(O)–aa or –NHC(O)–aa, where bond aa is attached to D 1 .
  • L 2 is a heteroalkylene linker. In some embodiments, L 2 is a linear or branched heteroalkylene linker.
  • m is 2.
  • the moiet [0090] In some embodiments, the moiety . In some embodiments, the moiety In some embodiments, the . In some embodiments, the moiety n some embodiments, the moiety In some embodiments, the moiety embodiments, the moiety embodiments, the moiety, the moiety, the moiety, the moiety, the moiety, the moiety, the moiety, the moiety, the moiety, the moiety, the moiety, the moiety.
  • D 1 is a taxane, a topoisomerase inhibitor, or MMAE, or a derivative, or analog thereof.
  • D 1 is paclitaxel, or a derivative, or analog thereof.
  • D 1 is paclitaxel or isotaxel, or a derivative, or analog thereof.
  • D 1 is a topoisomerase inhibitor, or a derivative, or analog thereof.
  • D 1 is a campothecin, or a derivative, or analog thereof.
  • D 1 is MMAE, or a derivative, or analog thereof.
  • the terms “derivative” or “analog” or “derived from” as used in reference to a payload means that one or more atoms, including hydrogen or non-hydrogen atoms, of the original, unmodified payload is replaced by a covalent bond to one or more linker L 1 .
  • the D 1 pay loads are derived from the known payload and are modified to be covalently bonded to at least one optionally substituted trans-cyclooctene via a linker L 1 .
  • the D 1 payloads exhibit a binding activity or inhibition which is at least about 98%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, or about 50% of that observed in the original, unmodified payload.
  • a hydrogen atom bound to a heteroatom (e.g., N, O, or S) of the original, unmodified payload is replaced by a covalent bond to a linker L 1 .
  • a halogen atom on a payload is replaced for attachment to the remainder of the compound.
  • a hydrogen atom on a payload is replaced for attachment to the remainder of the compound.
  • the hydrogen atom is on a heteroatom.
  • the hydrogen atom is on a nitrogen.
  • the hydrogen atom is on an oxygen.
  • the hydrogen atom is on a carbon.
  • D 1 is:
  • D 1 is MMAE, or a derivative, or analog thereof.
  • D 1 is:
  • conjugates for use in bioorthogonal reactions wherein the conjugates comprise a payload bonded to a trans-cyclooctene moiety.
  • L 1 is a linker; m is 1 or 2; and each D 1 is independently a payload selected from the group consisting of:
  • G is selected from the group consisting of:
  • G is
  • G is
  • G is [0106] In some embodiments,
  • each D 1 is independently:
  • m is 1 and D 1 is:
  • m is 1.
  • L 1 is a linear linker.
  • m is 2.
  • L 1 is a branched linker.
  • L 1 is -C(O)O- or -O-.
  • composition comprising the conjugate, or a pharmaceutically acceptable salt thereof, as disclosed herein and a pharmaceutically acceptable carrier.
  • each linker L 1 or L 2 may independently have 1 to 100 linking atoms, and may include ethylene-oxy groups, amines, esters, amides, carbamates, carbonates, and ketone functional groups.
  • linkers may have from 1 to 50 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms, or from 1 to 40 linking atoms, or from 1 to 30 linking atoms, or from 1 to 20 linking atoms, or from 1 to 10 linking atoms, or from 1 to 5 linking atoms, or from 5 to 30 linking atoms, or from 10 to 30 linking atoms, or from 5 to 40 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms.
  • linker L 1 or L 2 may be a bond.
  • the linker of a Formula as disclosed herein may comprise one or more (e.g., 1-10 or 1-5) chain heteroatoms (e.g., O, N, S) and one or more (e.g., 1-10 or 1-5) alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene moieties; wherein each alkylene, alkenylene, alkynylene, arylene, heteroarylene, cycloalkylene or heterocycloalkylene moiety, may be independently optionally substituted with one to five substituents independently selected from oxo, halo, C1-4 alkyl, C1-4 alkoxy, and C1-4 haloalkyl.
  • the linker L 1 is not a bond. In some embodiments, L 1 is a cleavable linker. In some embodiments, L 1 is a non-cleavable linker. [0134] In certain embodiments, the linker L 2 is not a bond. In some embodiments, L 2 is a cleavable linker. In some embodiments, L 2 is a non-cleavable linker.
  • each R 110 is independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; and each R 120 is independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl.
  • L 1 is a heteroalkylene linker. In some embodiments, L 1 is a linear or branched heteroalkylene linker. In some embodiments, L 1 is a linear heteroalkylene linker. In some embodiments, L 1 is a branched heteroalkylene linker.
  • L 1 is –OC(O)–, –C(O)O–, –NR 1f C(O)–, or –C(O)NR 1f –; and R 1f is hydrogen, C 1-6 alkyl, or C 0-4 alkylene–CO 2 H.
  • L 1 is –OC(O)– aa or –NHC(O)– aa , where bond aa is attached to D 1 .
  • a pharmaceutical composition comprising the conjugate, or a pharmaceutically acceptable salt thereof, as disclosed herein and a pharmaceutically acceptable carrier.
  • linker L 1 may be a bond.
  • Representative linkers include, but are not limited to, those shown below:
  • Representative linkers include, but are not limited to, those shown below:
  • the linker of a Formula as disclosed herein may comprise one or more of polyethylene glycol (e.g., PEG having an average molecular weight of from 200 g/mol to 10,000 g/mol), ethylene-1, 2-diylbis(methylcarbamate, an arylene (e.e., phenylene), ethylene-oxy, amine, ester, amide, carbamate, ketone (i.e., formyl), or carbonate.
  • polyethylene glycol e.g., PEG having an average molecular weight of from 200 g/mol to 10,000 g/mol
  • ethylene-1 ethylene-1
  • 2-diylbis(methylcarbamate e.e., an arylene (e.e., phenylene), ethylene-oxy, amine, ester, amide, carbamate, ketone (i.e., formyl)
  • Formula A-I, A-II, B-I, etc. (e.g., L 1 or L 2 ) L 1 or L 2 ) may comprise .
  • the linker of a Formula as disclosed herein, e.g., in Formula A-I, A-II, B-I, etc. (e.g., L 1 or L 2 ) may comprise
  • the linker of a Formula as disclosed herein may comprise one or more natural or unnatural amino acids, which may be referred to as a peptide linker.
  • the linker may be bound thereto using a peptide linker made up of a carboxylic acyl unit, and one or more amino acids making up a protein or peptide sequence.
  • the linker may also contain a selfimmolating spacer which spaces the drug and the protein peptide sequence.
  • the linker of a Formula as disclosed herein may be a peptide linker represented by “A — Y — Z — X — W” in which “A” is the carboxylic acyl unit, “Y” and “Z” are each one or more natural or unnatural amino acids and together form a peptide sequence, and “X” and “W” are optional additional linkers having from 1 to 50 linking atoms, or from 5 to 10 linking atoms, or from 1 to 10 linking atoms which spaces the peptide and the drug, D 1 , or the bioorthogonal moiety.
  • one or more of the amino acids in the peptide linker is N-methylated.
  • Y may be at least one amino acid selected from the group consisting of alanine, valine, leucine, isolcucinc, methionine, phenylalanine, tryptophan and proline. In some embodiments, Y may be at least one amino acid selected from the group consisting of phenylalanine, alanine, and valine.
  • Z may be at least one amino acid selected from the group consisting of alanine, lysine, lysine protected with acetyl or formyl, arginine, arginine protected with tosyl or nitro groups, histidine, ornithine, ornithine protected with acetyl or formyl, and citrulline. In some embodiments, Z may be at least one amino acid selected from the group consisting of alanine, lysine and citrulline.
  • Y-Z combinations include Valine-Citrulline; Valine- Alanine; and Alanine- Alanine .
  • A is -OC(O)-.
  • X is -OC(O)-.
  • W is -OC(O)-.
  • X is absent and W is -OC(O)-.
  • the peptide linker is specifically tailored so that it will be selectively cleaved (e.g., enzymatically cleaved) releasing the drug, such as by one or more of the tumor-associated proteases.
  • the peptide linker has a chain length of two to four amino acid residues (i.e., a di-, tri-, or tetra-peptide). It will be understood, however, that peptide linkers up to five, six, seven, or eight amino acid residues may also suitably be employed.
  • the peptide linker is Phe-Lys, Val-Lys, Vai- Ala, Ala- Ala, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys, Ala-Lys, Val-Cit, Phe-Cit, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Ala, Gly-Phe- Leu-Gly [SEQ ID NO: 1], Ala-Leu-Ala-Leu [SEQ ID NO:2], Phe-N 9 -tosyl-Arg, or Phe-N 9 -Nitro-Arg.
  • the peptide linker is Phe-Lys, Val-Lys, Vai- Ala, Ala- Ala, Vai- Vai, Val-Cit, or D- Phe-L-Phe-Lys. In certain embodiments, the peptide linker is Val-Cit, Vai-Ala, or Ala-Ala.
  • the foregoing linkers may attach on the right-hand side to amino acid side chains of D 1 such
  • L 1 is –OC(O)L 4 – or –OC1-6alkyleneC(O)L 4 –;
  • L 4 is a bond, –N(R 12 )–C 2-3 alkylene–N(R 13 )C(O)–, –CH(NHC(O)R 14 )C 1-4 alkylene–S–S–C 1-4 alkylene– OC(O)–, —NHNHC(O)CH(NHC(O)R 15 )CH2C(O)–, –C1-6alkylene–CH(G x )OC(O)–, O R19 ;
  • R 12 , R 13 , R 14 , R 15 , and R 19 are each independently hydrogen or C
  • R 1B is selected from the group consisting of –NR 1c –CH 2 CH 2 –N(CH 3 ) 3 + , –N(R 1c )–CH 2 CH 2 –SO 3 H, –N(R 1c )–(CH 2 CH 2 O) 3 –CH 2 CH 2 N((CH 2 CH 2 O) 3 –CH 2 CH 2 –CO 2 H) 2 , and –N(R 1c )–CH(CH 2 O–CH 2 CH 2 –CO 2 H) 2 .
  • R 1A is C 1-4 alkyl.
  • R 1A is CH3.
  • R 1c is hydrogen.
  • R 1A is C1-4alkyl
  • R 1B is selected from the group consisting of G 1 , OH, -NR 1c -C 1-4 alkylene-G 1 , –NR 1c –C 1-4 alkylene–N(R 1d ) 2 , -N(R 1c )CHR 1e CO2H, -N(R 1c )CH2CO2H, and -N(R 1f )–CH2CH2-(N(CH2CO2H)CH2CH2)n- N(CH2CO2H)2;
  • R 1e is –C1-4alkylene–CO2H;
  • R 1f is hydrogen or C1-4alkylene–CO2H;
  • G 1 is a 4- to 8-membered monocyclic heterocyclyl containing a first nitrogen and optionally one additional heteroatom selected from nitrogen, oxygen, and sulfur, G 1 being attached at the first nitrogen and optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 al
  • R 1A is CH3; R 1e is –CH2CO2H; R 1f is hydrogen or CH 2 CO 2 H; and G 1 is a piperazinyl, morpholinyl, piperidinyl, azepanyl, or pyrrolidinyl, attached through a ring nitrogen atom and optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-4haloalkyl, halo, cyano, OH, –OC1-4alkyl, and oxo.
  • R 1B is selected from the group consisting of OH, N(H)CH2CO2H, –N(H)CHR 1e CO2H, –N(H)–CH2CH2–(N(CH2CO2H)CH2CH2)n–N(CH2CO2H)2, and –N(CH2CO2H)–CH2CH2–N(CH2CO2H)2; and R 1e is –CH2CO2H.
  • the moiety is selected from the group consisting of: O
  • provided is a conjugate, or a pharmaceutically acceptable salt thereof, where the conjugate is selected from Table A-1.
  • conjugate or a pharmaceutically acceptable salt thereof, where the conjugate is selected from Table B-l.
  • a method for delivering an effective amount of a payload i.e., a taxane, such as paclitaxel, or a camptothecin, such as exatecan, or a derivative, or analog thereof
  • a payload i.e., a taxane, such as paclitaxel, or a camptothecin, such as exatecan, or a derivative, or analog thereof
  • the method comprising administering to the subject at the target location a therapeutic support composition as described herein, and administering to the subject a conjugate, or the pharmaceutically acceptable salt or composition thereof, as described herein.
  • the therapeutic support composition comprises a support.
  • Supports may be biocompatible supports compositions, i.e., compatible with the subject’s body.
  • a support is non-toxic to the subject and does not substantially react with tissue or biological compounds in the subject.
  • the support can be a hydrogel, among others.
  • a support is capable of implantation into a subject’s body and supporting binding agents (e.g., tetrazine-containing group), as well as payloads after the binding agents conjugate.
  • Representative supports include, but are not limited to polymers, viscous or non-viscous liquid materials, gels, hydrogels, polysaccharide hydrogels, a cross-linked polymer matrix, a metal, a ceramic, a plastic, a bone graft material, alginate, cellulose, chitosan, hyaluronic acid, chondroitin sulfate, heparin, and the like. Supports also include particles, such as nanoparticles, microparticles, and the like.
  • Hydrogels may be polysaccharide hydrogels, alginate, cellulose, hyaluronic acid, chitosan, chitosin, chitin, hyaluronic acid, chondroitin sulfate, heparin, and the like.
  • Other suitable sugar-based biomaterials include those described in Polymer Advanced Technology, 2014, 25, 448-460.
  • Polymers that may be used as the support can include, but are not limited to, polyphosphazenes, polyanhydrides, polyacetals, poly(ortho esters), polyphosphoesters, polycaprolactones, polyurethanes, polylactides, polycarbonates, polyamides, and polyethers, and blends/composites/co-polymers thereof.
  • polyethers include, but are not limited to, poly(ethylene glycol) (PEG), polypropylene glycol) (PPG), triblock Pluronic ([PEG] n -[PPG] m -[PEG] n ), PEG diacrylate (PEGDA), and PEG dimethacrylate (PEGDMA), where n and m are each independently an integer from 1-100.
  • the support can also include proteins and other poly(amino acids), such as collagen, gelatin, elastin and elastin-like polypeptides, albumin, fibrin, poly(gamma-glutamic acid), poly(L-lysinc), poly(L-glutamic acid), poly(aspartic acid), and the like.
  • the support is a hydrogel. In some embodiments, the support is an alginate. In some embodiments, the support is chitin. In some embodiments, the support is a hyaluronic acid (e.g., a non-hydrogel hyaluronic acid substantially without crosslinks). In some embodiments, the support is chitosin. In some embodiments, the support is chitosan.
  • the support is a particle.
  • Particles of the present disclosure can have a diameter that is 2 cm or less, such as 1.5 cm or less, or 1 cm or less, or 0.5 cm or less.
  • the particles can be nanoparticles or microparticles.
  • Nanoparticles include particles having average dimensions in the nanometer scale (e.g., 1000 nm or less).
  • Microparticles are particles having average dimensions in the micrometer scale (e.g., 1000 pm or less). By “average” is meant the arithmetic mean.
  • the nanoparticlcs have a diameter ranging from 1 nm to 1 pm, such as from 10 nm to 1 pm, or 25 nm to 1 pm, or 50 nm to 1 pm, or 75 nm to 1 pm, or 100 nm to 1 pm, or 150 nm to 1 pm, or 200 nm to 1 m, or 250 nm to 1 pm, or 300 nm to 1 pm, or 350 nm to 1 pm, or 400 nm to 1 pm, or 450 nm to 1 pm, or 500 nm to 1 pm.
  • 1 nm to 1 pm such as from 10 nm to 1 pm, or 25 nm to 1 pm, or 50 nm to 1 pm, or 75 nm to 1 pm, or 100 nm to 1 pm, or 150 nm to 1 pm, or 200 nm to 1 m, or 250 nm to 1 pm, or 300 nm to 1 pm, or 350 nm to 1 pm, or 400 nm to 1 pm,
  • the microparticles have a diameter ranging from 1 pm to 1 mm, such as from 10 pm to 1 mm, or 25 pm to 1 mm, or 50 pm to 1 mm, or 75 pm to 1 mm, or 100 pm to 1 mm, or 150 pm to 1 mm, or 200 pm to 1 mm, or 250 pm to 1 mm, or 300 pm to 1 mm, or 350 pm to 1 mm, or 400 pm to 1 mm, or 450 pm to 1 mm, or 500 pm to 1 mm.
  • small particles on the order of 10-100 nm in diameter may be assembled to form larger complexes, such as clusters or assemblies on the order of 1-10 pm.
  • Particles of the present disclosure may be substantially spherical, such that the particles have a substantially circular cross-section.
  • Other particle shapes may also be used, such as, but not limited to, ellipsoid, cubic, cylindrical, conical, needle, or other irregular shapes.
  • a “particle” may take the form of any fabricated material, a molecule, cryptophan, a virus, a phage, etc.
  • the particle may be composed of a material, such as, but not limited to, a metal, a ceramic, a plastic, a glass, a composite, a polymer, a hydrogel, and the like.
  • the particles may be made of an inert material, such as alginate or iron oxide.
  • the particles may be magnetic and can be formed from a paramagnetic, super-paramagnetic or ferromagnetic material, or other material that responds to a magnetic field.
  • a particle may be of any shape, for example, spheres, rods, non- symmetrical shapes, etc.
  • the particles, or a group of several particles in a complex may be functionalized with a receptor that has a specific affinity to bind to or interact with a clinically relevant substrate.
  • the receptor may be inherent to the particle itself.
  • the particle itself may be a virus or a phage with an inherent affinity for certain substrates.
  • the particles can be functionalized by covalently or otherwise attaching or associating a receptor that specifically binds or otherwise recognizes a particular clinically relevant substrate.
  • the functionalized receptor can be an antibody, peptide, nucleic acid, phage, bacteria, virus, or any other molecule with a defined affinity for a target substrate.
  • Examples of material that may be used for the “particles” and/or “carrier” include polylactic acid, polyglycolic acid, PLGA polymers, alginates and alginate derivatives, gelatin, collagen, fibrin, hyaluronic acid, laminin rich gels, agarose, natural and synthetic polysaccharides, polyamino acids, polypeptides, polyesters, poly anhydrides, polyphosphazines, poly(vinyl alcohols), poly(alkylene oxides), poly(allylamines)(PAM), poly(acrylates), modified styrene polymers, pluronic polyols, polyoxamers, poly(uronic acids), poly(vinylpyrrolidone) and copolymers or graft copolymers of any of the above. These examples do not limit their concentration, their cross-linking with different agents, their method of administration, their tailored degradation profiles and other characteristics known to those skilled in the art.
  • the particles, or a group of several particles in a complex may be functionalized with a targeting agent (e.g., a ligand or antibody) that specifically binds (or substantially specifically binds) to a target (e.g., a target receptor or a cell surface target, such as a clinically relevant receptor or cell surface target (e.g., antigen)).
  • a targeting agent e.g., a ligand or antibody
  • a target receptor or a cell surface target e.g., a cell surface target, such as a clinically relevant receptor or cell surface target (e.g., antigen)
  • the targeting agent may be attached directly to the particle itself.
  • the biocompatable support is a targeting agent.
  • the targeting agent can be an antibody, peptide, nucleic acid, phage, bacteria, virus, or any other molecule with a specific affinity for a target receptor or cell surface target.
  • the receptor or cell surface target is PD-1, CTLA-4, HER2/neu, HER1/EGFR, VEGFR, 4-1BB, GITR, or other cellular receptors or cell surface targets.
  • the targeting agent is a monoclonal antibody.
  • a monoclonal antibody can be an entire monoclonal antibody, or a fragment thereof (e.g., antigen-binding fragment (Fab)).
  • the targeting agent is an antibody, or antibody fragment, that targets one or more of CD25 (NCBI Gene ID 3559), CEA (NCBI Gene ID 634), CEACAM5 (NCBI Gene ID 1048), ASPH (NCBI Gene ID 444), EGFR (NCBI Gene ID 1956), EPCAM (NCBI Gene ID 4072), VEGFR (NCBI Gene ID 3791), PDGFR (NCBI Gene ID 5159), TROP2 (NCBI Gene ID 4070), Nectin4 (NCBI Gene ID 81607), PSMA (NCBI Gene ID 2346), BCMA (NCBI Gene ID 608), CD22 (NCBI Gene ID 933), CD20 (NCBI Gene ID 920), CD19 (NCBI Gene ID 930), CD79b (NCBI Gene ID 974), CD38 (
  • the targeting agent is an antibody, or antibody fragment, that targets CD25, such as Daclizumab, RG6292, basiliximab, or HuMax-TAC, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CEA, such as Labetuzumab, 15-1-32, PR1A3, or cT84.66, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CEACAM5, such as tusamitamab or CC4, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets ASPH, such as PAN-622, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets EGFR, such as Cetuximab, necitumumab, nimotuzumab, matuzumab, AMG595, depatuxizumab, dapatuxizumab, duligotuzumab, futuximab, GC1118, imgatuzumab, panitumumab, alutumumab, tomuzotuximab, or laprituximab, or an antibody fragment derived therefrom.
  • EGFR such as Cetuximab, necitumumab, nimotuzumab, matuzumab, AMG595, depatuxizumab, dapatuxizumab, duligotuzumab, futuximab, GC1118, imgatuzumab, panit
  • the targeting agent is an antibody, or antibody fragment, that targets EPCAM, such as oportuzumab, citatuzumab, tucotuzumab, catumaxomab, edrecolomab, or adccatumumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets VEGFR, such as ramucizumab, ramucirumab, or vulinacimab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets PDGFR, such as olaratumab or ramucirumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets TROP2, such as sacituzumab or PrlEl 1, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets Nectin4, such as enfortumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets PSMA, such as J591 or MLN591, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets BCMA, such as belantamab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD22, such as moxetumomab, inotuzumab, epratuzumab, or pinatuzumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD20, such as ublituximab, ofatumumab, rituximab, obinutuzumab, tositumomab, or ibritumomab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD19, such as loncastuximab, XMAB-5574, MOR2Q8, coltuximab, denintuzumab, taplitumomab, or MDX-1 42, or an antibody fragment derived therefrom.
  • CD19 such as loncastuximab, XMAB-5574, MOR2Q8, coltuximab, denintuzumab, taplitumomab, or MDX-1 42, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD79b, such as polatuzumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD38, such as isatuximab, daratumumab, MOR202, or TAK-079, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD45, such as I-131-BC8, or lomab-B, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets endoglin, such as carotuximab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets FGFR2, such as bemarituzumab or aprutumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets C4.4A, such as lupartumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets Claudin-18.2, such as zolbetuximab, or claudiximab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets MMP9, such as andecaliximab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets folate receptor, such as mirvetuximab, farletuzumab, MORAb-202, MORAb-003, or SP8166, or an antibody fragment derived therefrom.
  • folate receptor such as mirvetuximab, farletuzumab, MORAb-202, MORAb-003, or SP8166, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets DLL3, such as rovalpituzumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD138, such as indatuximab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD56, such as lorvotuzumab, promiximab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD37, such as BI 836826, otlertuzumab, or naratuximab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD74, such as milatuzumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets mesothelin, such as anetumab, amatuximab, or MMOT-0530A, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets IL- 6R, such as tocilizumab or sarilumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets SLAMF7, such as elotuzumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets BAFF, such as belimumab, or an antibody fragment therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets MUC1, such as KL-6, MY.1E12, hMUCl-lH7, TAB004, huC242, clivatuzumab, 8HuDS6, gatipotuzumab, AR20.5, or cantuzumab, or an antibody fragment derived therefrom.
  • MUC1 such as KL-6, MY.1E12, hMUCl-lH7, TAB004, huC242, clivatuzumab, 8HuDS6, gatipotuzumab, AR20.5, or cantuzumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets GPC3, such as codrituzumab, ECT204, or MDX-1414, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets HER2, such as pertuzumab, trastuzumab, or margetuximab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets HER3, such as patritumab, seribantumab, lumretuzumab, elgemtumab, AV-203, CDX-3379, or GSK284933, or an antibody fragment derived therefrom.
  • HER3 such as patritumab, seribantumab, lumretuzumab, elgemtumab, AV-203, CDX-3379, or GSK284933, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD30, such as brentuximab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD33, such as gemtuzumab, BI 835858, vadastuximab, or lintuzumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD123, such as KHK2823, taclotuzumab, or G4723A, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets GPNMB, such as glembatumumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets cMET, such as telisotuzumab, onartuzumab, or SAIT301, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD 142, such as tisotumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets NaPi2B, such as lifastuzumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets GCC, such as indusatumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets STEAP1, such as vandortuzumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets MUC16, such as sofituzumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD70, such as vorsetuzumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CD44, such as bivatuzumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets vWF, such as caplacizumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets TNF, such as ozoralizumab, V565, or PF-05230905, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets IL- 6R, such as vobarilizumab, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets BCMA, such as LCAR-B38M, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets ADAMTS5, such as M6495, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CX3CR1, such as BI 655088, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets CXCR4, such as AD-214 or ALX-0651, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets TfRl, such as TXB4, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets VEGFR, such as CDP791, or an antibody fragment derived therefrom.
  • the targeting agent is an antibody, or antibody fragment, that targets PSMA, such as GY1, or an antibody fragment derived therefrom.
  • Other compounds or molecules such as fluorophores or autofluorescent or luminescent markers, which may assist in detecting the particles (e.g., in vivo detection), may also be attached to the particles.
  • the ligands and/or detectable labels may be attached directly to the particle or attached to the particle through bioorthogonal functional groups as described herein.
  • the support is a bone graft material, such as a bone graft substitute material.
  • a bone graft substitute material is a material structurally similar to bone.
  • a bone graft substitute material is bioresorbable such that the bone graft substitute material can dissolve or be absorbed in the body over time.
  • a bone graft substitute material can be osteoconductive, such that it facilitates blood vessel and new bone formation into the bone graft substitute material.
  • the bone graft substitute material is osteoinductive, such that it facilitates the formation of new bone through active recruitment of mesenchymal stem cells from the surrounding tissue.
  • growth factors such as bone morphogenetic proteins, may be included in the bone graft substitute material.
  • Bone graft substitute materials include, but are not limited to, hydroxyapatite, tricalcium phosphate, demineralized bone matrix, bovine collagen, calcium sulfate, calcium phosphate, cancellous bone chips, and the like, and combinations thereof.
  • Therapeutic support compositions of the present disclosure include a support and a first binding agent covalently linked to the support.
  • the binding agent may be attached to the support on a surface of the support, such as a solvent-accessible surface of the support (e.g., a surface of the support that is in contact with the surrounding solvent).
  • the binding agent is attached directly to the support.
  • the binding agent may be covalently attached to the surface of the support, e.g., through a covalent bond, such as an amide, amine, ester, carbamate, urea, thioether, thiocarbamate, thiocarbonate, thiourea, etc.
  • the binding agent is covalently attached to the support through an amide bond.
  • the binding agent may be linked to the support via a linker.
  • Any suitable linker can be used to link the binding agent to the support.
  • Representative linkers can have from 1 to 100 linking atoms, and can include ethylene-oxy groups, amines, esters, amides, carbamates, carbonates, and ketone functional groups.
  • linkers may have from 1 to 50 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms.
  • Representative linkers include, but are not limited to, those shown below:
  • the therapeutic support compositions comprise a support and a tetrazinecontaining group of formula:
  • linkers may have from 1 to 50 linking atoms, or from 5 to 50 linking atoms, or from 10 to 50 linking atoms.
  • the therapeutic support composition comprises units of formula: [0248] In some embodiments, the therapeutic support compositions comprise units of formula: . [0249] In some embodiments, the therapeutic support compositions comprise units of formula: [0 250] In some embodiments, the therapeutic support compositions comprise substituted hyaluronic acid having units of formula: wherein G inker of 1 to 100 linking atoms; and R 20 is as defined herein. [0251] In further embodiments, G [0252] In still further embodiments, G ydrogen or C1-4alkyl.
  • R 20 is hydrogen or C 1-4 alkyl.
  • the therapeutic support compositions comprise units of formula: ; [0 255] Additional therapeutic support compositions are exemplified in WO2017/044983, WO/2015/139025A1, and WO/2014/205126A1, the entire contents of each of which is incorporated herein by reference in their entirety.
  • the hyaluronic acid derivative includes a hyaluronic acid having a plurality of glucuronic acid units and a tetrazine-containing group linked or directly bonded to a glucuronic acid unit of the hyaluronic acid.
  • the hyaluronic acid may also have a plurality of N-acetylglucosamine units.
  • the N-acetylglucosamine units of the hyaluronic acid are not linked or conjugated to the tetrazine-containing group.
  • the tetrazine-containing group can be linked or directly bonded through a carboxylic acid of a glucuronic acid unit.
  • the tetrazine-containing group can be incorporated into the hyaluronic acid from about 0.1% to about 80% as measured by the % of carboxylic acids being linked or conjugated to the tetrazine-containing group, such as about 1% to about 75%, about 5% to about 75%, about 10% to about 50%, or about 40% to about 75% as measured by the % of carboxylic acids being linked or conjugated to the tetrazine-containing group.
  • aspects of the present disclosure include methods for delivering a payload to a target location in a subject.
  • the method includes selectively delivering a payload to the target location in a subject.
  • Selective delivery of the payload includes delivering the payload to the target location (e.g., an organ or tissue, or portion thereof), without targeting other locations in the subject (e.g., other organs or tissues, or portions thereof) that do not need administration of the payload.
  • Selective delivery of the payload may he achieved through use of the support compositions and the functionalized payloads described herein.
  • a support composition of the present disclosure may be localized to a desired target location in a subject.
  • methods of the present disclosure may include administering to a subject a support composition as described herein.
  • the support composition may be administered to the subject at a desired target location in the subject.
  • the support composition may be implanted into the subject at the desired target location in the subject.
  • the support composition may be attached to a targeting agent as described herein, and the method may include administering the support composition to the subject (e.g., administered systemically).
  • the support composition that is attached to a targeting agent may localize at a desired target location in the subject through specific binding of the targeting agent to its target (e.g., antibodyantigen interaction, and the like), or may localize on the surface of a desired target (e.g., a cell surface) through specific binding of the targeting agent to its target (e.g., antibody-antigen interaction, and the like).
  • the method includes administering to the subject a functionalized payload such that the functionalized payload binds to the support composition to form a support complex.
  • the functionalized payload may be administered systemically to the subject.
  • contact between the binding agent of the support composition and the complementary binding agent of the functionalized payload may occur, such that the binding agent and its complementary binding agent bind to one another to form a support complex, thereby selectively delivering the payload to the target location in the subject.
  • selective delivery of the functionalized payload results in a concentration of the payload at the target location that is greater than the concentration of the payload elsewhere in the subject (e.g., at non-targeted areas in the subject).
  • a method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of a conjugate as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutic support composition.
  • the cancer is metastatic.
  • the cancer is melanoma, renal cancer, prostate cancer, ovarian cancer, endometrial carcinoma, breast cancer, glioblastoma, lung cancer, soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, gastric carcinoma, squamous cell carcinoma of head/neck, anal/vulvar carcinoma, esophageal carcinoma, pancreatic adenocarcinoma, cervical carcinoma, hepatocellular carcinoma, Kaposi’s sarcoma, Non-Hodgkin lymphoma, Hodgkin’s lymphoma Wilm’s tumor/neuroblastoma, bladder cancer, thyroid adenocarcinoma, pancreatic neuroendocrine tumors, prostatic adenocarcinoma, nasopharyngeal carcinoma, malignant extrinsic or intrinsic airway compression, or cutaneous T-cell lymphoma.
  • the approach can be used for the treatment and/or diagnosis of hematological malignancies such as myelodysplastic syndromes, acute myeloid leukemia, mycldysplastic syndromes, chronic myelogenous leukemia, chronic myelomonocytic leukemia, primary myelofibrosis, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, monoclonal gammopathy, plasma cell myeloma, follicular lymphoma, marginal zone lymphoma, classical Hodgkin lymphoma, monoclonal B- cell lymphocytosis, lymphoproliferative disorder NOS, T-cell lymphoma, precursor B-lymphoblastic leukemia, mantle cell lymphoma, plasmacytoma, Burkitt lymphoma, T-cell leukemia, hairy-cell leukemia, precursor T-lymphoblastic leukemia, nodular lymphocyte predominant Hod
  • the cancer is a melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer.
  • the cancer is a solid tumor.
  • the cancer is a lung carcinoma.
  • the cancer is a soft tissue sarcoma.
  • the soft tissue sarcoma is a fibrosarcoma, rhabdomyosarcoma, or Ewing’s sarcoma.
  • the method also comprises enhancing or eliciting an immune response.
  • the immune response is an increase in one or more of leukocytes, lymphocytes, monocytes, and eosinophils.
  • the method further comprising administering a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof.
  • an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof.
  • Anticancer agents, immunomodulatory agents, and their trans-cyclooctene prodrugs are known in the art.
  • Indications for this approach include cancer, both hematological and solid cancers.
  • the approach can be used for the treatment and/or diagnosis of soft tissue sarcomas: rhabdomyosarcoma, fibrosarcoma, Ewing’s sarcoma, and all the different subtypes of soft tissue sarcoma as well as osteosarcoma.
  • the compositions can be for the treatment and/or diagnosis of pigmented vilonodular synovitis.
  • compositions of the present disclosure find use in treatment and/or diagnosis of a condition or disease in a subject that is amenable to treatment or diagnosis by administration of the payload (e.g., the parent drug (i.e., the drug prior to conjugation to the composition)).
  • treatment is meant that at least an amelioration of the symptoms associated with the condition afflicting the subject is achieved, where amelioration is used in a broad sense to refer to at least a reduction in the magnitude of a parameter, e.g., symptom, associated with the condition being treated.
  • treatment also includes situations where the pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g., terminated, such that the subject no longer suffers from the condition, or at least the symptoms that characterize the condition.
  • Treatment may include inhibition, that is, arresting the development or further development of clinical symptoms, e.g., mitigating or completely inhibiting an active disease.
  • Treatment may include relief, that is, causing the regression of clinical symptoms.
  • the term “treating” includes any or all of: reducing growth of a solid tumor, inhibiting replication of cancer cells, reducing overall tumor burden, prolonged survival and ameliorating one or more symptoms associated with a cancer.
  • the subject to be treated can be one that is in need of therapy, where the subject to be treated is one amenable to treatment using the parent drug. Accordingly, a variety of subjects may be amenable to treatment using the compositions disclosed herein. Generally, such subjects arc “mammals,” with humans being of interest. Other subjects can include domestic pets (e.g., dogs and cats), livestock (e.g., cows, pigs, goats, horses, and the like), rodents (e.g., mice, guinea pigs, and rats, e.g., as in animal models of disease), as well as non-human primates (e.g., chimpanzees, and monkeys).
  • domestic pets e.g., dogs and cats
  • livestock e.g., cows, pigs, goats, horses, and the like
  • rodents e.g., mice, guinea pigs, and rats, e.g., as in animal models of disease
  • non-human primates
  • the functionalized payloads, therapeutic support compositions, additional therapeutic agents, and methods can be used for the treatment, prevention, and/or diagnosis of solid tumors, including but not limited to, melanoma (e.g., unresectable, metastatic melanoma), renal cancer (e.g., renal cell carcinoma), prostate cancer (e.g., metastatic castration resistant prostate cancer), ovarian cancer (e.g., epithelial ovarian cancer, such as metastatic epithelial ovarian cancer), endometrial carcinoma, breast cancer (e.g., triple negative breast cancer), glioblastoma (e.g., glioblastoma multiforme), and lung cancer (e.g., non-small cell lung cancer), soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, gastric carcinoma, squamous cell carcinoma of head/neck, anal/vulvar carcinoma, esophageal carcinoma, pancreatic cancer
  • melanoma
  • the disclosed approach lends itself well as an adjuvant / neoadjuvant system.
  • particles as disclosed herein could be placed during the biopsy, once the results from the study come back, the practitioner could deliver the appropriate cocktail to the desired site in the body. This would minimize the size of the tumor particularly in the context of a surgically resectable tumor. Then at the end of the surgery, the surgeon could place more particles around the surgical cavity and treat the patient with further doses of treatment (e.g. chemotherapy through the disclosed approach) to minimize the risk of any cancer cells that may have been missed in the surgical margins.
  • doses of treatment e.g. chemotherapy through the disclosed approach
  • the disclosed methods provide the ability to place particles as disclosed herein at the time of the biopsy.
  • the practitioner can deliver through to the biopsy site immunomodulatory agents such as TLR agonists, STING agonists, chemokines (agents that attract cancerous cells and/or immune cells) and adjuvants to enhance the immune system with fewer side effects as well as the chemotherapeutics agents combined with immunotherapy agents.
  • immunomodulatory agents such as TLR agonists, STING agonists, chemokines (agents that attract cancerous cells and/or immune cells) and adjuvants to enhance the immune system with fewer side effects as well as the chemotherapeutics agents combined with immunotherapy agents.
  • This combination approach would be beneficial to patients.
  • the chemotherapy agent would treat the solid tumor or specific location, while the enhanced response of the immunotherapy would help with distant metastatic sites.
  • compositions and methods could employ or be used with anthracyclines, taxanes, gemcitabine and other agents to enhance the efficacy of one or more immunomodulatory agents such as ipilimumab, nivolumab, pembrolizumab, avelumab (also known as MSB0010718C; Pfizer).
  • anthracyclines such as ipilimumab, nivolumab, pembrolizumab, avelumab (also known as MSB0010718C; Pfizer).
  • the disclosed methods may be used to treat or prevent cancer, including metastatic cancer.
  • Cancer is a group of related diseases that may include sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, enablement of replicative immortality, induction of angiogenesis, and the activation of invasion and metastasis.
  • the disclosed methods may enhance or elicits an immune response against a cancer in the subject.
  • the immune response may lead to an increase in one or more of leukocytes, lymphocytes, monocytes, and eosinophils.
  • Cancer that may be treated by the disclosed methods, includes, but is not limited to, astrocytoma, adrenocortical carcinoma, appendix cancer, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain cancer, brain stem cancer, brain stem glioma, breast cancer, cervical cancer, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, diffuse intrinsic pontine glioma, ductal cancer, endometrial cancer, ependymoma, Ewing’s sarcoma, esophageal cancer, eye cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal cancer, germ cell tumor, glioma, hepatocellular cancer, histiocytosis, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, Kaposi sarcoma, kidney cancer, laryngeal cancer, leukemia, liver cancer, lung cancer, lymph
  • the cancer that may be treated by the disclosed methods is melanoma, renal cancer, prostate cancer, ovarian cancer, breast cancer, glioma, lung cancer, soft tissue carcinoma, soft tissue sarcoma, osteosarcoma, or pancreatic cancer.
  • the cancer is a solid tumor.
  • the cancer is a soft tissue carcinoma.
  • the cancer is afibrosarcoma.
  • the cancer is diffuse intrinsic pontine glioma.
  • the cancer is a metastatic cancer.
  • ICD immunogenic cell death
  • Calreticulin one of the DAMP molecules, which is normally in the lumen of endoplasmic reticulum (ER), is translocated after the induction of immunogenic apoptosis to the surface of dying cell where it functions as an "eat me” signal for professional phagocytes.
  • Other important surface exposed DAMPs are heat-shock proteins (HSPs), namely HSP70 and HSP90, which are under stress condition also translocated to the plasma membrane.
  • HMGB1 antigen-presenting cell
  • TLR Toll-like receptor
  • the functionalized payloads, therapeutic support compositions, and methods can be used for the treatment, prevention, and/or diagnosis of solid tumors, including but not limited to, melanoma (e.g. , unresectable, metastatic melanoma), renal cancer (e.g., renal cell carcinoma), prostate cancer (e.g., metastatic castration resistant prostate cancer), ovarian cancer (e.g., epithelial ovarian cancer, such as metastatic epithelial ovarian cancer), breast cancer (e.g., triple negative breast cancer), glioblastoma (e.g., glioblastoma multiforme), and lung cancer (e.g., non-small cell lung cancer), soft tissue sarcoma, fibrosarcoma, osteosarcoma, pancreatic cancer, among others.
  • melanoma e.g. , unresectable, metastatic melanoma
  • renal cancer e.g., renal cell carcinoma
  • prostate cancer e.g.,
  • therapeutic support compositions as disclosed herein could be placed during the biopsy, once the results from the study come back, the practitioner could administer the appropriate cocktail to deliver treatment to the desired site in the body (compound of Formula A-I, A-2, or a subformula disclosed herein, and optional additional therapeutic agent(s)).
  • the results of the biopsy may indicate the amount and type of treatment to deliver to the site of a tumor.
  • chcmokines agents that attract cancerous cells and/or immune cells
  • adjuvants to enhance the immune system with fewer side effects as well as the chemotherapeutics agents could be delivered and combined with immunotherapy agents.
  • the disclosed compounds and compositions may be administered prior to surgical resection.
  • the disclosed methods may minimize the size of the tumor prior to surgical resection. This would minimize the size of the tumor particularly in the context of a surgically resectable tumor.
  • the disclosed conjugates, compounds and compositions may be administered during surgical resection.
  • the disclosed conjugates, compounds and compositions may be administered after surgical resection.
  • Therapeutic support composition may be placed around the surgical cavity at the end of surgical resection and the subject may then be treated with further doses of a treatment to minimize the risk of any cancer cells that may have been missed in the surgical margins.
  • the disclosed methods may include multiple systemic doses of functionalized payload that focus at one location.
  • the disclosed methods may be used to deliver a second payload.
  • the disclosed methods may be used to administer a second functionalized payload if the tumor is resistant to the first payload.
  • a second payload may be a TCO-labeled payload of gemcitabine or docetaxel.
  • the TCO-labeled payload of gemcitabine or docetaxel may be administered in combination with doxorubicin.
  • the second functionalized payload may be activated by the therapeutic support composition used for the first prodrug.
  • the functionalized payloads disclosed herein may function as adjuvants. This combination approach would be beneficial to patients.
  • the chemotherapy agent would treat the solid tumor or specific location and may enhance or elicit an immune response, while the enhanced response of the immunotherapy of the functionalized payload and/or separate agent may help with distant metastatic sites.
  • the disclosed compositions and methods could employ or be used with anthracyclines, auristatins, vinca alkaloids, taxanes, gemcitabine, campothecin analogues and other agents to enhance the efficacy of ipilimumab, nivolumab, pembrolizumab, avelumab (also known as MSB0010718C; Pfizer).
  • the disclosed methods may be used to treat diffuse intrinsic pontine gliomas.
  • Diffuse intrinsic pontine gliomas are pediatric brainstem tumors that may be highly malignant and may be difficult to treat.
  • There is no known curative treatment for DIPG and survival odds have remained dismal over the past four decades.
  • DIPG patients have a median overall survival of just 11 months, with a two-year survival rate below 10%.
  • DIPG account for 75-80% of brainstem tumors in children, affecting an estimated 200-300 children in the U.S. each year. The rarity of this devastating disease and previous lack of experimental model systems has impeded research, and over the past four decades survival odds have remained the same.
  • Diagnosis of DIPG may begin with clinical symptoms and may be confirmed by MRI.
  • the disease may begin with several months of generalized symptoms, including behavioral changes and difficulties in school, double vision, abnormal or limited eye movements, an asymmetric smile, loss of balance, and weakness. Alternately, severe neurologic deterioration may happen more quickly, with symptoms present for less than a month prior to diagnosis.
  • Clinical examination may reveal the triad of multiple cranial neuropathies, long tract signs such as hyperreflexia and clonus, as well as ataxia. Expansion of the pons section of the brainstem may cause obstructive hydrocephalus and increased intracranial pressure.
  • the disclosed methods may be used to deliver molecular payloads to the site of a DIPG .
  • the disclosed methods may include delivering drugs systemically that are only activated at the tumor site.
  • the disclosed methods may be used as a neoadjuvant or adjuvant therapy.
  • the biomaterial may be placed during a biopsy.
  • the results of the biopsy may indicate the amount and type of treatment to deliver to the site of a tumor.
  • the disclosed compounds and compositions may be administered prior to surgical resection.
  • the disclosed methods may minimize the size of the tumor prior to surgical resection.
  • the disclosed compounds and compositions may be administered during surgical resection.
  • the disclosed compounds and compositions may be administered after surgical resection.
  • Biomaterial may be placed around the surgical cavity at the end of surgical resection and the subject may then be treated with further doses of a treatment.
  • the disclosed biodegradable gel may be implanted at the time of biopsy or surgery.
  • the disclosed methods may not require an additional invasive procedure to deliver additional doses of the disclosed compounds and compositions.
  • the disclosed methods may include multiple systemic doses of functionalized payload that focus at one location.
  • the disclosed methods may be used to deliver a second payload.
  • the disclosed methods may be used to administer a second functionalized payload if the tumor is resistant to the first payload.
  • a second payload may be a TCO-labeled payload of paclitaxel, docetaxel, anthracyclines, auristatins, vinca alkaloids, taxanes, gemcitabine, campothecin analogues, or other agents.
  • the TCO-labeled payload of gemcitabine, paclitaxel, or docetaxel may be administered in combination with doxorubicin.
  • the second functionalized payload may be activated by the therapeutic support composition used for the first prodrug.
  • Methods of treatment may include any number of modes of administering a disclosed conjugate, compound or composition.
  • Modes of administration may include tablets, pills, dragees, hard and soft gel capsules, granules, pellets, skin patches, skin creams, skin gels, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders.
  • the conjugate, compound or compositions disclosed herein may also be dispersed in a microparticle, e.g. a nanoparticulate composition.
  • the conjugates, compounds or compositions disclosed herein may be dissolved or suspended in a physiologically acceptable diluent, such as water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • a physiologically acceptable diluent such as water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers.
  • Suitable oils may include, for example, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
  • the conjugates, compounds or compositions disclosed herein may be administered in the form of an aqueous, lipid, oily, or other kind of solution or suspension, or even administered in the form of liposomes or nano-suspensions.
  • parenterally refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
  • Therapeutic support compositions are preferably administered locally at the site of a tumor, such as by injection or implantation.
  • Functionalized payloads such as conjugates of a Formula as disclosed herein, e.g., Formula A-I or A-II, may be administered by any convenient route, in view of a subject’s condition and judgment of medical professionals.
  • Parenteral administration is a suitable means of administering conjugates of a Formula as disclosed herein, e.g., Formula A-T or A-II.
  • the amount of composition administered to a subject can be initially determined based on guidance of a dose and/or dosage regimen of the parent drug.
  • compositions can provide for targeted delivery and/or enhanced serum half-life of the bound drug, thus providing for at least one of reduced dose or reduced administrations in a dosage regimen.
  • compositions can provide for reduced dose and/or reduced administration in a dosage regimen relative to the parent drug prior to being conjugated in a composition of the present disclosure.
  • the pharmaceutical formulation may be provided in unit dosage form.
  • the pharmaceutical formulation may be subdivided into unit doses containing appropriate quantities of the compositions of the present disclosure.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation, such as packeted tablets, capsules, and powders in pouches, vials, or ampoules.
  • kits comprising a conjugate, or a pharmaceutically acceptable salt thereof, as described herein, or the pharmaceutical composition comprising the same, and instructions for use thereof.
  • the kit further comprising the therapeutic support composition.
  • compositions of the present disclosure can be present in any suitable amount, and can depend on various factors including, but not limited to, weight and age of the subject, state of the disease, etc. Suitable dosage ranges for the composition of the present disclosure include from 0.1 mg to 10,000 mg, or 1 mg to 1000 mg, or 10 mg to 750 mg, or 25 mg to 500 mg, or 50 mg to 250 mg.
  • suitable dosages for the composition of the present disclosure include 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg.
  • multiple doses of a composition are administered.
  • the frequency of administration of a composition can vary depending on any of a variety of factors, e.g., severity of the symptoms, condition of the subject, etc.
  • a composition is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid).
  • compositions of the present disclosure can be administered at any suitable frequency, interval and duration.
  • the composition of the present disclosure can be administered once an hour, or two, three or more times an hour, once a day, or two, three, or more times per day, or once every 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days, so as to provide the desired dosage level to the subject.
  • representative intervals include 5 min, 10 min, 15 min, 20 min, 30 min, 45 min and 60 minutes, as well as 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 20 hr, and 24 hours.
  • composition of the present disclosure can be administered once, twice, or three or more times, for an hour, for 1 to 6 hours, for 1 to 12 hours, for 1 to 24 hours, for 6 to 12 hours, for 12 to 24 hours, for a single day, for 1 to 7 days, for a single week, for 1 to 4 weeks, for a month, for 1 to 12 months, for a year or more, or even indefinitely.
  • compositions of the present disclosure can be co-administered with another active agent.
  • Co-administration includes administering the composition of the present disclosure and active agent within 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 10 hr, 12 hr, 16 hr, 20 hr, or 24 hours of each other.
  • Coadministration also includes administering the composition of the present disclosure and active agent simultaneously or approximately simultaneously (e.g., within about 1 min, 5 min, 10 min, 15 min, 20 min, or 30 minutes of each other), or sequentially in any order.
  • the composition of the present disclosure and the active agent can each be administered once a day, or two, three, or more times per day so as to provide the desired dosage level per day.
  • Co-administration can be accomplished by coimplantation or coinjection.
  • co-administration can be accomplished by co-formulation, e.g., preparing a single pharmaceutical formulation including both the composition of the present disclosure and the active agent.
  • the composition of the present disclosure and the active agent can be formulated separately and co-administered to the subject.
  • composition of the present disclosure and the active agent can be present in a formulation in any suitable weight ratio, such as from 1: 100 to 100: 1 (w/w), or 1 :50 to 50: 1, or 1:25 to 25: 1, or 1 : 10 to 10:1, or 1 :5 to 5: 1 (w/w).
  • the composition of the present disclosure and the other active agent can be present in any suitable weight ratio, such as 1 :100 (w/w), 1 :75, 1 :50, 1 :25, 1 : 10, 1 :5, 1 :4, 1 :3, 1 :2, 1 : 1 , 2: 1, 3: 1, 4: 1, 5: 1, 10: 1, 25: 1, 50: 1, 75: 1, or 100: 1 (w/w).
  • Other dosages and dosage ratios of the composition of the present disclosure and the active agent are suitable in the formulations and methods described herein.
  • the invention provides a method of treating cancer or enhancing or eliciting an immune response comprising administering to a subject in need thereof: a therapeutically effective amount of a conjugate as disclosed herein (e.g., Formula A-I, A-II, etc.), or a pharmaceutically acceptable salt or composition thereof; a therapeutic support composition, as described herein; and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof.
  • a conjugate as disclosed herein e.g., Formula A-I, A-II, etc.
  • an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof.
  • the invention also provides a pharmaceutical combination comprising a conjugate described herein, or a pharmaceutically acceptable salt, or composition thereof; a therapeutic support composition, as described herein; and an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof, for use in the treatment or prevention of a cancer or for use in enhancing or eliciting an immune response.
  • the invention also provides the use of a pharmaceutical combination comprising a conjugate described herein, or a pharmaceutically acceptable salt, or composition thereof; a therapeutic support composition; and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof for the treatment or prevention of a cancer or for use in enhancing or eliciting an immune response.
  • a pharmaceutical combination comprising a conjugate described herein, or a pharmaceutically acceptable salt, or composition thereof; a therapeutic support composition; and a therapeutically effective amount of an additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans-cyclooctene prodrug thereof for the treatment or prevention of a cancer or for use in enhancing or eliciting an immune response.
  • the components of the pharmaceutical combinations may be administered/used simultaneously, separately, or sequentially, and in any order, and the components may be administered separately or as a fixed combination.
  • the delay of progression or treatment of diseases according to the invention may comprise administration of the first active ingredient in free or pharmaceutically acceptable salt form and administration of the second active ingredient in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in jointly therapeutically effective amounts or effective amounts, e.g. in daily dosages corresponding to the amounts described herein.
  • the individual active ingredients of the combination can be administered separately at different times during the course of therapy or concurrently in divided or single dosage forms. The present disclosure is therefore to be understood as embracing all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • a pharmaceutical combination defines either a fixed combination in one dosage unit form or separate dosages forms for the combined administration where the combined administration may be independently at the same time or at different times.
  • the therapeutic support composition and conjugate may be administered/used simultaneously (e.g., through coinjection or coimplantation), separately, or sequentially, followed by administration of the additional therapeutic agent selected from the group consisting of an anticancer agent, an immunomodulatory agent, or a trans- cyclooctene prodrug thereof.
  • the methods and uses in treating cancer include administering/localizing the therapeutic support composition at a tumor.
  • the administration of the conjugate, or a pharmaceutically acceptable salt, or composition thereof; the therapeutic support composition; and the additional therapeutic agent may inhibit the growth of the tumor.
  • Additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed conjugates and compositions. Sequential administration includes administration before or after the disclosed conjugates and compositions. An additional therapeutic agent may be administered before the disclosed conjugates and compositions. An additional therapeutic agent may be administered after the disclosed conjugates and compositions. An additional therapeutic agent may be administered at the same time as the disclosed conjugates and compositions. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed conjugates. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the disclosed conjugates or compositions. In some embodiments, administration of an additional therapeutic agent with a disclosed conjugate or composition may allow lower doses of the other therapeutic agents and/or administration at less frequent intervals.
  • the conjugates or compositions of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a conjugates of the present disclosure.
  • Exemplary anti-cancer agents include, but are not limited to, Abiraterone Acetate, Abitrexate (Methotrexate), Abraxane (Paclitaxel Albumin- stabilized Nanoparticle Formulation), ABVD, ABVE, ABVE-PC, AC, AC-T, Adcetris (Brentuximab Vedotin), ADE, Ado-Trastuzumab Emtansine, Adriamycin (Doxorubicin Hydrochloride), Adrucil (Fluorouracil), Afatinib Dimaleate, Afinitor (Everolimus), Aldara (Imiquimod), Aldesleukin, Alemtuzumab, Alimta (Pemetrexed Disodium), Aloxi (Palonosetron Hydrochloride), Ambochlorin (Chlorambucil), Aminolevulinic Acid, Anastrozole, Aprepitant, Aredia (Pamidronate Disodium
  • the anticancer agent may be a PBD dimer, calicheamicin, speromycin, tubulysin B, rhizoxin, dolastatin, didemnin B, camptothecin, CBI, temsirolimus, actinomycin D, epothilone B, taxol, cryptophycin, SN38, velcade, bruceantin, DAVLBH, DM1, Phyllanthoside, Alimta, T2 Toxin, MMC, vantalanib, vinorelbine, brefeldin, sunitinib, daunomycin, semaxanib, tarceva, iressa, irinotecan, LY- 541503, geldanomycin, gemcitabine, methotrexate, gleevec, topotecan, bleomycin, doxorubicin, cisplatin, N-mustards, etoposide, or 5-FU
  • an anticancer agent is an anthracycline. In certain embodiments, anticancer agent is a taxane. In certain embodiments, anticancer agent is gemcitabine. In certain embodiments, anticancer agent is doxorubicin. In certain embodiments, anticancer agent is docetaxel. In certain embodiments, anticancer agent is paclitaxel. In certain embodiments, anticancer agent is SN38. In certain embodiments, anticancer agent is monomethyl auristatin E. In certain embodiments, an anticancer agent is an alkylating agent, antimetabolite (folate antagonist, purine antagonist, pyrimidine antagonist), antibiotic, taxane, vinca alkaloid, or campothecin analogue.
  • anticancer agent is an alkylating agent, antimetabolite (folate antagonist, purine antagonist, pyrimidine antagonist), antibiotic, taxane, vinca alkaloid, or campothecin analogue.
  • the conjugates may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents and starting materials may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in Wuts, P. G. M., Greene, T. W., & Greene, T. W. (2006). Greene's protective groups in organic synthesis. Hoboken, NJ., Wiley- Interscience, and references cited therein.
  • the conjugates of this disclosure may contain one or more chiral centers. Accordingly, if desired, such conjugates can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such conjugates can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA).
  • intermediate i-7 (285 g, crude) which was carried forward as is.
  • General procedure for preparation of intermediate i-8 [0325] To a solution of intermediate i-7 (285 g, crude) in MeOH (2000 mL) was added KOH (42.5 g, 758 mmol) in H2O (1000 mL). The mixture was stirred at 25 °C for 1 hrs. LC-MS showed intermediate i-7 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was extracted with MTBE (5 L). The aqueous phase layers were diluted with sat. KHSO 4 (1L) aq.
  • Crude 6 was precipitated by addition of 4 M hydrochloric acid (100 mL), the suspension was cooled to 10 °C, and the precipitate was filtered off, washed with cold water, collected, and dried. Crude 6 was crystallized from toluene to give off-white crystals. Crystals were filtered, washed with toluene, and dried to give 6 (30.2 g, 95%). ESI m/z: 293.1 (M+1) + .
  • the combined organic layers were washed with water (100 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the undesired ester (0.87 g, 53% yield) as a colorless / slightly pale-yellow colored oil.
  • the aqueous layer was extracted with TBME (3 x 100 mL).
  • the combined TBME layers were washed with water (100 mL) and brine (100 mL).
  • Example 5 Synthesis of Compound 33 General procedure for preparation of compound 2 [0496] To a solution of triphosgene (25.8 g, 87.2 mmol, 1.45 eq.) in THF (150 mL) was added pyridine (6.47 g, 81.7 mmol, 6.60 mL, 1.36 eq.) at 0 °C under N2 atmosphere. After addition, compound 1 (10.0 g, 60.1 mmol, 8.54 mL, 1.00 eq.) in THF (150 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 hrs.
  • Example 12 Synthesis of Compound 113 General procedure for preparation of compound 11A [0570] To a solution of Target 183 (120 mg, 256 ⁇ mol, 1.0 eq., AcOH salt) and 11 (119 mg, 282 ⁇ mol, 1.1 eq.) in DMF (1.0 mL) was added DMAP (31.3 mg, 256 ⁇ mol, 1.0 eq.) and DIEA (66.2 mg, 512 ⁇ mol, 89.2 ⁇ L, 2.0 eq.), the mixture was stirred at 25 °C for 1.0 hr. LC-MS showed Target 183 was consumed completely, several new peaks were shown on LC-MS and ⁇ 97.3% of desired compound was detected.
  • DMAP 31.3 mg, 256 ⁇ mol, 1.0 eq.
  • DIEA 66.2 mg, 512 ⁇ mol, 89.2 ⁇ L, 2.0 eq.
  • Example 23 Efficacy Evaluation of Compound 32 as a Single Agent and in Combination with SQT01 in the NCI-N87 Human Gastric Tumor Xenograft Model
  • Study Objective The purpose of this study was to evaluate the anti-tumor activity of Compound 32 as a single agent and in combination with SQT01 in the NCI-N87 human gastric tumor xenograft model.
  • Example 24 In-Vitro Cell Viability Assessment Study Objective [0736] The objective of this study was to evaluate the anti-proliferation effect of test compounds, Compound 32 and Compound 33, in 5 cancer cell lines (Calu-3, HCC827, MDA-MB-468, NCI-N87, and T47D) with or without a tetrazine reagent. Deruxtecan, Exatecan, and Staurosporine were included as positive controls. This study was performed based on internal standards. Study Design [0737] The plating of cells and compound treatments are shown below in the plate map.
  • IC50 values of Compound 32 pre-treated with tetrazine reagent ranged from 0.005 to 0.115 ⁇ M and IC50 values of Compound 32 without tetrazine reagent pre-treatment ranged from 0.023 to 0.429 ⁇ M in all 5 cell lines; IC50 values of Compound 33 pre-treated with tetrazine reagent ranged from 0.004 to 0.072 ⁇ M in all 5 cell lines, and IC50 values of Compound 33 without tetrazine reagent pre-treatment were 9.154, 4.388 and 1.545 ⁇ M respectively in MDA-MB-468, NCI-N87 and T47D cells and more than 10 ⁇ M both in Calu-3 and HCC827 cells.

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Abstract

La présente divulgation concerne de manière générale des conjugués de trans-cyclooctène pour l'administration bioorthogonale d'une charge utile à un emplacement ciblé chez un sujet. Les compositions et les méthodes ont des applications dans le traitement de cancers, de croissances tumorales et d'immunothérapie.
PCT/US2024/016775 2023-02-21 2024-02-21 Conjugués de trans-cyclooctène Ceased WO2024178155A1 (fr)

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