WO2025210538A1 - Agents de dégradation bifonctionnels - Google Patents

Agents de dégradation bifonctionnels

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Publication number
WO2025210538A1
WO2025210538A1 PCT/IB2025/053467 IB2025053467W WO2025210538A1 WO 2025210538 A1 WO2025210538 A1 WO 2025210538A1 IB 2025053467 W IB2025053467 W IB 2025053467W WO 2025210538 A1 WO2025210538 A1 WO 2025210538A1
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WIPO (PCT)
Prior art keywords
insulin
antibody
binding
moiety
composition
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Pending
Application number
PCT/IB2025/053467
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English (en)
Inventor
Sampat Ingale
Christian M. VIDAL
Brian M. LINHARES
Charlotte Bredo SPLIID
Ana M. ESTRELLA
Silvina DEL CARMEN
Brett RASILE
Bruce D. CAR
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Biohaven Therapeutics Ltd
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Biohaven Therapeutics Ltd
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Publication of WO2025210538A1 publication Critical patent/WO2025210538A1/fr
Pending legal-status Critical Current
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Classifications

    • 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
    • A61K47/6891—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
    • 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
    • A61K47/6843—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 material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin

Definitions

  • an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant, and particularly to bifunctional molecules which contain a circulating protein binding moiety linked through a linker group to a cellular receptor- binding moiety to treat diabetes and other insulin disorders.
  • BACKGROUND OF THE INVENTION [002] Diabetes often has an autoimmune component. Neutralizing antibodies generated against insulin reduce the effectiveness of insulin in diabetic patients. Many ⁇ -cell proteins are the targets of autoimmune responses in Type 1 diabetes (T1D). A contribution comes from the protein products of the insulin gene: preproinsulin (PPI), proinsulin (PI), or insulin.
  • the invention provides a composition of matter (an agent, a TRAP) comprising: a target-binding moiety that can bind to anti-insulin antibodies, a cellular receptor-binding moiety that can bind to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on the surface degrading cells in a patient or subject, and a linker moiety connecting the binding moiety and the cellular receptor-binding moiety, wherein the linker moiety can be a single peptide bond or a larger linker moiety.
  • the composition of matter is a bifunctional anti-proinsulin and or anti-insulin autoantibody degrader.
  • the composition of matter (the agent, the TRAP) has the structure: R CN ⁇ (Xaa)y ⁇ R CC , , or a salt thereof.
  • the composition of matter (the agent, the TRAP) has the structure of formula AGN105: or a salt thereof, wherein the composition of matter may have additional elements described in this specification.
  • the composition of matter is selected from among group consisting of the constructs in the following TABLE. TABLE 1
  • the target-binding moiety is insulin, an insulin variant, or an insulin analogue.
  • the target-binding moiety is proinsulin, a proinsulin variant, or a proinsulin analogue.
  • the target-binding moiety is an insulin-IgG1 Fc fusion construct.
  • the target-binding moiety is a proinsulin-IgG1 Fc fusion protein.
  • the proinsulin-IgG1 Fc fusion protein can be expressed in and produced from a mammalian cell system because of the Fc domain, which also allows for purification of the expressed protein.
  • the proinsulin- IgG1 Fc fusion protein can then be conjugated to ASGPR-binder via MATE reagent, resulting in a bifunctional degrader molecule.
  • Persons having ordinary skill in the biomedical art can introduce LALA mutations into the Fc region to attenuate immune effector function via abrogation of FcgR.
  • Persons having ordinary skill in the biomedical art can also introduce PA mutations to attenuate immune effector function via abrogation of c1q binding. They can use a DNA sequence encoding a proinsulin-IgG1 Fc fusion protein for recombinant production of proinsulin-IgG1 Fc fusion protein in mammalian systems.
  • the target-binding moiety is a proinsulin-IgG1 Fc fusion construct.
  • the target-binding moiety is selected from among group consisting of the constructs in the following TABLE: TABLE 2 .
  • the cellular receptor-binding moiety comprises an ASGPR binding group according to the chemical structure: wherein the cellular receptor-binding moiety has additional elements described in this specification.
  • the cellular receptor-binding moiety is selected from among group consisting of the constructs listed in the following TABLE. TABLE 3
  • variable domain of an antibody of rodent origin can be fused to a constant domain of human origin, thus keeping the specificity of the rodent antibody.
  • the human origin domain need not originate directly from a human because it is first synthesized in a human. Instead, human domains can
  • the antibody can be partially or completely humanized.
  • steps used to humanize a monoclonal antibody are (1) determining the nucleotide and predicted amino acid sequence of the starting antibody light and heavy variable domains; (2) designing the humanized antibody, i.e., deciding which antibody framework region to use during the humanizing process; (3) the actual humanizing methodologies/techniques; and (4) the transfection and expression of the humanized antibody.
  • the term “IgG” antibody has the biomedical art-recognized meaning.
  • insulin efsitora alfa means the selective agonist of insulin receptor (IR) that is a fusion protein composed of human IR agonists fused with the crystallizable (Fc) domain of human immunoglobulin G2 (lgG2) fragment, with a molecular weight of 64.1 kDa.
  • IR insulin receptor
  • Fc crystallizable domain of human immunoglobulin G2
  • IGF insulin growth factor
  • insulin receptor has the biomedical art-recognized meaning.
  • the insulin receptor has two main subunits: ⁇ and ⁇ .
  • the ⁇ subunit contains five main domains, L1 (AA 28–174) CR (AA 182–339), and L2 (AA 340–497), and two fibronectin subunits: FnIII-1 (residue 624–726) and FnIII-2 (757–842).
  • the two ⁇ -subunits are linked by four disulfide bonds.
  • the insulin receptor ⁇ has different isoforms (IRA and IRB), depending on the gene splicing of exon 11.
  • Insulin receptor B differs from insulin receptor A by including exon 11.
  • the 12-amino acid sequence (residues 745–756) derived from exon 11 is present in the insulin receptor B isoform but absent in the insulin receptor A isoform.
  • the isoforms have functionally different internalization and recycling. Insulin receptor A exhibits a greater internalization and recycling rate than insulin receptor B. Insulin receptor A exhibits a higher affinity for IGFs than IRB. Both isoforms have similar affinity for insulin Binding to these isoforms very different to proinsulin. Because of these differences, insulin receptor B is preferentially associated with metabolic and differentiating signals. Insulin receptor A mainly favors cell growth, proliferation, and survival. See Beneit et al., Cardiovasc. Diabetol., 15, 161 (2016).
  • IGF-2 insulin-like growth factor 2
  • IGF-2 has growth- regulating, insulin-like and mitogenic activities.
  • IGF-2 has growth- regulating, insulin-like and mitogenic activities.
  • IGF-2 has growth- regulating, insulin-like and mitogenic activities.
  • IGF-2 has growth- regulating, insulin-like and mitogenic activities.
  • IGF-2 has growth- regulating, insulin-like and mitogenic activities.
  • the term “insulin” has the biomedical art-recognized meaning. Insulin can be produced by chemical synthesis.
  • IVIG has the biomedical art-recognized meaning of the administration of intravenous immunoglobulin.
  • linker moiety has the biomedical art-recognized meaning of a moiety of a chemical compound that links one moiety of the chemical compound to another moiety of the same compound.
  • MoDE has the proprietary meaning of molecular degraders. See International Patent Publications WO 2019/199634 (Yale University) and WO 2019/199621 (Yale University).
  • moiety has the biomedical meaning of a defined chemical group or entity with a particular structure or activity.
  • a moiety generally refers to a part of a molecule.
  • a binding moiety maintains one or more desired structural features, properties, functions, or properties, e.g., 3-dimension structure, antigen specificity, antigen-binding capacity, or immunological functions, etc. comparable to its corresponding binding protein, e.g., an antibody.
  • a moiety is monovalent.
  • a moiety is bivalent.
  • a moiety is polyvalent.
  • the term “monotherapy” has the biomedical art-recognized meaning of the administration of a single active or therapeutic compound to a subject. Monotherapy usually is the administration of a therapeutically effective amount of an active composition.
  • MATE or MATES Multimodal Antibody Therapy Enhancers
  • the term “nanobody” has the biomedical art-recognized meaning.
  • the term “antibody” refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that specifically binds an antigen.
  • the term "on” has the plain meaning. When an element is referred to as being on another element, it can be directly in contact with the other element or intervening elements may be present therebetween. When an element is referred to as being “directly on” another element, there are no intervening elements present. [00102]
  • the term “or” as used in this specification means “and/or.” The term “and/or” as used in this specification includes all combinations of one or more of the associated listed items.
  • the term “other degrading cells” has the biomedical art-recognized meaning. Asialoglycoprotein receptors (ASGPRs) are on the glandular cells of the gallbladder and the stomach, as well as on hepatocytes.
  • ASGPRs Asialoglycoprotein receptors
  • the term “partially humanized” has the biomedical art-recognized meaning a protein, e.g., an antibody, is genetically engineered so it more closely resembles the polypeptide structure of the human homologue.
  • a variable domain of an antibody of rodent origin can be fused to a constant domain of human origin, thus keeping the specificity of the rodent antibody.
  • the domain of human origin need not originate directly from a human because it is first synthesized in a human. Instead, human domains can be generated in rodents whose genome incorporates human immunoglobulin genes.
  • the antibody can be partially or completely humanized.
  • Proinsulin can also be produced by chemical synthesis.
  • the chemically synthesized proinsulin is comparable to commercial proinsulin for the surface plasmon resonance (SPR) assay.
  • Proinsulin does not bind to the insulin receptor.
  • protein binding moiety has the biomedical art-recognized meaning of a region of a chemical composition, e.g., a polypeptide region of a chemical composition, that specifically binds to a protein, e.g., a specific protein.
  • ROC has the biomedical art-recognized meaning of receiver operating characteristic curve.
  • the term “subject” and the term “patient” have the biomedical art-recognized meanings.
  • patient includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment.
  • TBT has the meaning described in this specification of target binding moiety, a cellular receptor-binding moiety. In some embodiments of this specification, the TBT binds to ASGPR.
  • TBT has the meaning described in this specification of a targeted removal of aberrant protein.
  • a TRAP is a bifunctional degrader.
  • the term “treating” and the “treat” has the biomedical art-recognized meaning of the management and care of a patient for combating a disease, condition, or disorder and includes the administration of a composition described in this specification to alleviate the symptoms or complications of a disease, condition, or disorder, or to eliminate the disease, condition, or disorder.
  • the term “Type 1 diabetes mellitus” has the biomedical art-recognized meaning of a chronic autoimmune disease that occurs when the immune system attacks the pancreas' insulin-producing cells, resulting in the autoimmune eradication of ⁇ -cells in pancreatic islets. Insulin can no longer be synthesized or be secreted into the blood.
  • the invention provides a composition of matter (agent) comprising: a binding moiety that can bind to anti-insulin antibody, a cellular receptor-binding moiety that binds to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on the surface degrading cells in a patient or subject, and a linker moiety linking the antibody moiety and the cellular receptor-binding moiety.
  • the invention provides a composition of matter (an agent) having a structure selected from the Markush group of structures consisting of: R CN ⁇ (Xaa)y ⁇ R CC ,
  • each cellular receptor-binding moiety independently has the structure of ⁇ (R CN ⁇ (Xaa)y ⁇ R CC ) or salt form thereof.
  • one and no more than one cellular receptor-binding moiety is bonded to a linker moiety.
  • b is 1.
  • two or more cellular receptor-binding moiety is bonded to a single linker moiety.
  • b is 2 or more.
  • an agent comprises one and no more than one cellular receptor-binding moiety.
  • c is 1.
  • b is 1 and c is 1.
  • a is 1, b is 1 and c is 1.
  • an agent comprises two or more
  • each cellular receptor-binding moiety in an agent is the same.
  • each linker moiety connecting a cellular receptor-binding moiety to an antibody moiety is the same.
  • the TBT in agents is the same.
  • the ⁇ L ⁇ (TBT) b are the same.
  • the target binding moiety comprises a moiety selected from the Markush group consisting of one or more amino acid residues, a peptide moiety, a cyclic peptide moiety, a peptide comprising one or more natural amino acid residues, and a peptide comprising one or more unnatural natural amino acid residues.
  • each binding moiety in an agent may be of the same binding moiety or a pharmaceutically acceptable salt thereof.
  • the binding moiety comprises a moiety selected from the Markush group consisting of one or more amino acid residues, a peptide moiety, a cyclic peptide moiety, a peptide comprising one or more natural amino acid residues, and a peptide comprising one or more unnatural natural amino acid residues.
  • an antibody binding moiety comprises one or more amino acid residues, each independently natural or unnatural.
  • a binding moiety e.g., a protein binding moiety, e.g., an antibody binding moiety, e.g., a universal antibody binding moiety
  • a binding moiety has the structure of ABT101 or a salt form thereof, wherein: each of R 1 , R 3 and R 5 is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: R 1 and R 1
  • R 5 groups are optionally taken with their intervening atoms to form a C 1-10 optionally substituted bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with –S–, –SS–, –N(R)–, –O–, – C(O)–, –OC(O)–, –C(O)O–, –C(O)N(R)–, –N(R)C(O)–, –S(O)–, –S(O) 2 –, or –Cy 1 –, wherein each –Cy 1 – is independently a 5-6 membered heteroarylenyl with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of R 1’ , R 3’ and R 5’ is independently hydrogen or optionally substituted C 1-3 aliphatic; each of R 2 , R 4 and R 6 is independently hydrogen, or optionally substituted C 1-4 aliphatic
  • L 1 is an optionally substituted trivalent group selected from C 1 -C 20 aliphatic or C 1 -C 20 heteroaliphatic having 1-5 heteroatoms, wherein one or more methylene units of the group are optionally and independently replaced with ⁇ C(R’) 2 ⁇ , ⁇ Cy ⁇ , ⁇ O ⁇ , ⁇ S ⁇ , ⁇ S ⁇ S ⁇ , ⁇ N(R’) ⁇ , ⁇ C(O) ⁇ , ⁇ C(S) ⁇ , ⁇ C(NR’) ⁇ , ⁇ C(O)N(R’) ⁇ , ⁇ N(R’)C(O)N(R’) ⁇ , ⁇ N(R’)C(O)O ⁇ , ⁇ S(O) ⁇ , ⁇ S(O) 2 ⁇ , ⁇ S(O) 2 N(R’) ⁇ , ⁇ C(O)S ⁇ , or ⁇ C(O)O ⁇ .
  • L 1 is –(CH 2 CH 2 O) 2-4 – or –(CH 2 CH 2 O) 2 –.
  • Some antibody binding moieties and technologies for identifying or assessing antibody binding moieties are described in International Patent Publications WO 2019/023501 (Kleo Pharmaceuticals, Inc.) and WO 2019/136442 (Kleo Pharmaceuticals, Inc.), each of which is incorporated in this specification in its entirety by reference. Persons having ordinary skill in the biomedical art know that additional technologies in the biomedical art may be suitable for identifying or assessing antibody binding moieties in accordance with this specification. In
  • an antibody binding moiety comprises one or more amino acid residues, each independently natural or unnatural.
  • selected locations of antibody moieties are used for conjugation.
  • K246 or K248 of an antibody agent are conjugation locations.
  • a conjugation location is K246 of heavy chain (unless otherwise specified, locations in this specification include corresponding residues in, e.g., modified sequence, e.g., longer, shorter, rearranged, etc., sequences.
  • a location is K248 of heavy chain.
  • a location is K288 or K290 of heavy chain.
  • a location is K288 of heavy chain.
  • a location is K290 of heavy chain. In some embodiments, a location is K317.
  • an antibody moiety is a moiety of an IgG1 antibody or a fragment thereof. In some embodiments, an antibody moiety is a moiety of an IgG2 antibody or a fragment thereof. In some embodiments, an antibody moiety is a moiety of an antibody or a fragment thereof.
  • a composition comprises a plurality of MATE agents, wherein antibody moieties of the plurality of MATE agents are independently an antibody moiety of an IgG1, IgG2, or IgG4 antibody, or a fragment thereof. [00147] In some embodiments, antibody heavy chains are selectively conjugated/labeled over light chains.
  • moieties of interest e.g., target binding moieties
  • antibody moieties of a particular type of antibodies e.g., IgG1
  • particularly sites typically one or two particularly sites, e.g., K246 and K248 of an IgG1 heavy chain and amino acid residues corresponding thereto.
  • about 10%-100% of all, or substantially all, moieties of interest, e.g., target binding moieties, conjugated to antibody moieties of IgG2 antibodies or fragments thereof are at K251 and K253 of an IgG2 heavy chain and amino acid residues corresponding thereto. In some embodiments, about 10%-100% of all, or substantially all, moieties of interest, e.g., target binding moieties, conjugated to antibody moieties of IgG2 antibodies or fragments thereof are at K239 and K241 of a heavy chain and amino acid residues corresponding thereto.
  • about 10%-100% of all, or substantially all, moieties of interest are conjugated to antibody moieties of IgG1, IgG2, and/or IgG4 antibodies, or fragments thereof, e.g., for conjugation products with IgG1 antibodies or fragments thereof (antibody moieties being of IgG1 antibodies or fragments thereof), IgG2 antibodies or fragments thereof (antibody moieties being of IgG2 antibodies or fragments thereof), IgG4 antibodies or fragments thereof (antibody moieties being of IgG4 antibodies or
  • a first composition is a composition comprising a first agent as described in this specification.
  • second agents independently comprise second reactive groups.
  • a second composition is a composition comprising a plurality of agents as described in this specification, wherein each cellular receptor-binding moiety is independently a reactive group as described in this specification.
  • a second composition is an antibody composition, wherein antibodies in the composition are not chemically modified.
  • the invention provides agents each independently comprising an antibody binding moiety that binds to an antibody agent, a reactive group, a cellular receptor-binding moiety, and optionally one or more linker moieties linking such groups/moieties.
  • agents are useful as reaction partners, e.g., first agents) for conjugating moieties of interest, e.g., target binding moieties, reactive groups, e.g., second reactive groups) to agents comprising antibody moieties, e.g., second agents).
  • LG is a group comprising an antibody binding moiety; RG is a reactive group; LRM is a linker; and TBT is a cellular receptor-binding moiety.
  • L G is or comprises an antibody binding moiety as described in this specification, and a linker which links an antibody binding moiety and RG.
  • L G is or comprises R LG ⁇ L LG ⁇ , wherein R LG is or comprises an antibody binding moiety, and L LG is a linker moiety as described in this specification.
  • L G is ABT-L LG ⁇ .
  • L LG is ⁇ L LG1 ⁇ L LG2 ⁇ , wherein each of L LG1 and L LG2 is independently a linker moiety as described in this specification.
  • L LG is ⁇ L LG1 ⁇ L LG2 ⁇ L LG3 ⁇ , wherein each of L LG1 , L LG2 and L LG3 is independently as linker moiety described in this specification.
  • L LG is ⁇ L LG1 ⁇ L LG2 ⁇ L LG3 ⁇ L LG4 ⁇ , wherein each of L LG1 , L LG2 , L LG3 and L LG4 is independently a linker moiety as described in this specification.
  • L LG1 is bonded to R LG .
  • L LG1 is bonded to cellular receptor-binding moiety.
  • L LG is ⁇ L LG1 ⁇
  • a reactive group comprises L LG2 , L LG3 and L LG4 .
  • L LG is ⁇ L LG1 ⁇ L LG2 ⁇
  • a reactive group comprises L LG3 and L LG4 .
  • L LG is ⁇ L LG1 ⁇ L LG2 ⁇ L LG3 ⁇
  • a reactive group comprises L LG4 .
  • each of L LG1 , L LG2 , L LG3 and L LG4 is independently L. [00171]
  • L LG4 is a covalent bond.
  • L LG4 is not a covalent bond. In some embodiments, L LG4 is ⁇ O ⁇ . In some embodiments, L LG4 is ⁇ N(R’) ⁇ . In some embodiments, L LG4 is ⁇ NH ⁇ . In some embodiments, L LG4 is ⁇ N(CH 3 ) ⁇ . In some embodiments, L LG4 is ⁇ N(R’) ⁇ , and L LG3 is ⁇ O ⁇ . In some embodiments, R’ is optionally substituted C 1-6 alkyl. In some embodiments, L LG4 is ⁇ S ⁇ . [00172] In some embodiments, R LG is or comprises an antibody binding moiety. In some embodiments, R LG is or comprises a protein binding moiety.
  • R LG is or comprises an antibody binding moiety. In some embodiments, R LG is an antibody binding moiety. In some embodiments, R LG is a protein binding moiety. In some embodiments, R LG is an antibody binding moiety. [00173] In some embodiments, R LG is ABT101, R c ⁇ (Xaa)z ⁇ , a nucleic acid moiety, or a small molecule moiety. In some embodiments, R LG is or comprises ABT101. In some embodiments, R LG is or comprises Rc ⁇ (Xaa)z ⁇ . In some embodiments, R LG is or comprises a small molecule moiety. In some embodiments, R LG is or comprises a peptide agent.
  • R LG is or comprises a nucleic acid agent. In some embodiments, R LG is or comprises an aptamer agent. In some embodiments, an antibody binding moiety is or comprises ABT101. In some embodiments, a protein binding moiety is or comprises ABT101. In some embodiments, an antibody binding moiety is or comprises ABT101. In some embodiments,
  • an antibody binding moiety is or comprises Rc ⁇ (Xaa)z ⁇ .
  • a protein binding moiety is or comprises Rc ⁇ (Xaa)z ⁇ .
  • an antibody binding moiety is or comprises Rc ⁇ (Xaa)z ⁇ .
  • target binding moieties may be conjugated to antibody moieties optionally through linker moieties using technologies described in published U.S. Patent Publication 2020/0190165.
  • PG protecting group
  • LG leaving group
  • transformation condition persons having ordinary skill in the biomedical art know that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated.
  • leaving groups include but are not limited to, halogens, e.g. fluoride, chloride, bromide, iodide, sulfonates, e.g. mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.
  • an oxygen protecting group includes carbonyl protecting groups, hydroxyl protecting groups, etc.
  • Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4-methoxy- crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9- fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl.
  • silyl ethers examples include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t- butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers.
  • Alkyl ethers include methyl, benzyl, p- methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives.
  • ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2-picolyl and 4-picolyl.
  • Amino protecting groups are well known in the biomedical art and include those described in Greene’s Protecting Groups in Organic Synthesis (John Wiley & Sons, 2014), the entirety of which is incorporated in this specification by reference.
  • Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like.
  • Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.
  • reaction partners are generally contacted with each other under conditions and for a time sufficient for production of the desired results, e.g., formation of product agents and compositions thereof to desired extents.
  • reaction conditions/reaction times may be assessed and used if they are suitable for desired purposes in accordance with this specification; certain such conditions, reaction times, assessment, etc. are described in the Examples.
  • an agent formed e.g., a product MATE agent
  • a cellular receptor-binding moiety in a product agent e.g., a MATE agent
  • a reaction partner e.g., a first agent comprising a cellular receptor-binding moiety
  • an antibody moiety in a product agent e.g., a MATE agent
  • a reaction partner e.g., a second agent comprising an antibody moiety
  • linker moieties or a part thereof connected to target binding moieties and/or antibody moieties may be transferred from reaction partners, e.g., L RM of formula AGN110 or a salt thereof.
  • L RG2 is ⁇ C(O) ⁇ , and is bonded to ⁇ NH ⁇ of a target agent moiety, e.g., ⁇ NH ⁇ in a side chain of a lysine residue of a protein moiety, which in some embodiments, is an antibody moiety.
  • a target agent moiety e.g., ⁇ NH ⁇ in a side chain of a lysine residue of a protein moiety, which in some embodiments, is an antibody moiety.
  • the invention provides products of provided processes, which have low levels of damage to antibody moieties compared to processes comprising steps performed for antibody binding moiety removal but not for substantial conjugation of moieties of interest, e.g. target binding moieties.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • compositions can be administered by intravenous infusion, orally, topically, intraperitoneally, intravesically, or intrathecally.
  • Parenteral administration, oral administration, and intravenous administration are the preferred methods of administration.
  • the formulations of compounds can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include these components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • Plurality of agents the invention provides a composition comprising a plurality of agents, wherein each agent independently comprises: an antibody moiety, a cellular receptor-binding moiety, and optionally a linker moiety linking an antibody binding moiety and a cellular receptor-binding moiety.
  • product agents are MATE agents.
  • an antibody agent moiety comprises IgG Fc region.
  • an antibody moiety is connected to a cellular receptor-binding moiety through an amino group optionally through a linker. In some embodiments, it is through a lysine residue wherein the amino group of the side chain is connected to a
  • the invention provides a composition comprising a plurality of agents each of which independently comprising: an antibody moiety, a cellular receptor-binding moiety, and optionally a linker moiety linking an antibody moiety and a cellular receptor-binding moiety; wherein agents of the plurality share the same or substantially the same antibody moiety, and a cellular receptor-binding moiety at least one common location; and wherein about 1%-100% of all agents that comprise the antibody moiety and the cellular receptor-binding moiety are agents of the plurality.
  • agents of the plurality share the same or substantially the same antibody moiety, and a cellular receptor-binding moiety at least one common location; and wherein about 1%-100% of all agents that comprise the antibody moiety and the cellular receptor-binding moiety are agents of the plurality.
  • HDX-MS is continuing to be performed.
  • the inventors are modeling the antibody Fc-and bifunctional degrader interaction to predict paratope regions in parallel with HDX-MS.
  • Protein sequencing In one method of protein sequencing, eight digestions are prepared using five enzymes (pepsin, Lys C, trypsin, chymotrypsin, Asp N). The digestions for the sample are processed with disulfide reduction, cysteine blocking, and then enzyme digestion. Digestions were analyzed by LC-MS/MS using a Thermo-Fisher Orbitrap fusionTM mass spectrometer. Peptides are characterized from LC -MS/MS data using de nova peptide sequencing and then assembled into antibody sequences.
  • Assays used to determine proof of concept [00197] The inventors used these assays to determine proof-of-concept for the anti- insulin/proinsulin autoantibody bifunctional agents of the invention.
  • Biophysical assay Surface plasmon resonance assay (insulin receptor). The inventors produced mutant insulin conjugated with GN3 and is being tested for binding to the insulin receptor by surface plasmon resonance assay. Additional mutant insulins conjugated with GN3 are produced synthetically.
  • Insulin receptors are also produced synthetically. qPCR method primer sequence IR-forward: GCAACATCACCCACTACCTGGT (SEQ ID NO: 39). qPCR method primer sequence IR-reverse: GAATGGTGGAGACCAGGTCCTC (SEQ ID NO: 40).
  • FIG. 1 Cellular Assay. iLite Insulin reporter assay (DT-40). Assay principle: Overexpression of insulin receptor and transfection of a non-canonical STAT5 recognition motif and a STAT5 expression vector. Thus, insulin signaling via the insulin receptor results in STAT5 phosphorylation, dimerization, and transcriptional activation of a promoter leading to luciferase production.
  • Insulin receptor-binding to human insulin via surface plasmon resonance Biophysical assessment of insulin/IGF1 binding to their respective receptors was demonstrated. Weak binding of proinsulin constructs to insulin receptor
  • NOD Nonobese diabetic
  • MSD MesoScale Discovery
  • an antibody binding moiety is a moiety, e.g., small molecule moiety, peptide moiety, nucleic acid moiety, etc., that can selectively bind to IgG, and when used in provided technologies can provide and/or stimulate ADCC and/or ADCP.
  • peptide display technologies e.g., phase display, non-cellular display, etc., can identify antibody binding moieties.
  • an antibody binding moiety is a moiety, e.g., small molecule moiety, peptide moiety, nucleic acid moiety, etc., that can bind to IgG and optionally can compete with known antibody binders, e.g., protein A, protein G, protein L, etc.
  • an antibody binding moiety e.g., an antibody binding moiety
  • a Meditope agent moiety See United States Patent Publication 2019/0111149 (Gardiner et al.).
  • an antibody binding moiety e.g., an antibody binding moiety
  • an antibody binding moiety e.g., an antibody binding moiety
  • an antibody binding moiety e.g., an antibody binding moiety, binds to IgG1, IgG2, and IgG4.
  • antibody binding moieties bind to targets, e.g., antibody agents for antibody binding moieties) with a K D that is about 1 mM -1 pM or less.
  • a K D is about 1 mM, 0.5 mM, 0.2 mM, 0.1 mM, 0.05 mM, 0.02 mM, 0.01 mM, 0.005 mM, 0.002 mM, 0.001 mM, 500 nM, 200 nM, 100 nM, 50 nM, 20 nM, 10 nM, 5 nM, 2 nM, 1 nM, 0.5 nM, 0.2 nM, 0.1 nM, or less.
  • K D is an affinity selected from the Markush group of affinities consisting of about 1 mM or less, about 0.5 mM or less, about 0.1 mM or less, about 0.05 mM or less, about 0.01 mM or less, about 0.005 mM or less, about 0.001 mM or less, about 500 nM or less, about 200 nM or less, about 100 nM or less, about 50 nM or less, about 20 nM or less, about 10 nM or less, about 5 nM or less, about 2 nM or less, and about 1 nM or less.
  • antibody binding moieties bind to IgG antibody agents with K D described in this specification.
  • antibodies of several properties and activities may be recruited by antibody binding moieties described in this specification.
  • such antibodies include antibodies administered to a subject, e.g., for therapeutic purposes.
  • antibodies recruited by antibody binding moieties comprise antibodies toward different antigens.
  • antibodies recruited by antibody binding moieties comprise antibodies whose antigens are not present on the surface or cell membrane of target cells.
  • antibodies recruited by antibody binding moieties comprise antibodies not targeting antigens present on surface or cell membrane of targets.
  • antigens on surface of target cells may interfere with the structure, conformation, and/or one or more properties and/or activities of recruited antibodies which bind such antigens.
  • recruited antibodies are those in IVIG.
  • IVIG may be administered before, concurrently with or subsequently to an agent or composition.
  • Antibodies of several types of immunoglobulin structures may be recruited.
  • one or more subclasses of IgG are recruited.
  • recruited antibodies are selected from the Markush group of antibody classes consisting
  • recruited antibodies can effectively interact with human Fc ⁇ receptor IIIA on macrophages.
  • macrophages are recruited to provide ADCC or ADCP activities toward a virus, e.g., a SARS-CoV-2 virus, and/or cells infected thereby.
  • NK cells are recruited to provide immune activities.
  • recruited antibodies can effectively interact with human Fc ⁇ receptor IIIA.
  • recruited antibodies can effectively interact with human Fc ⁇ receptor IIIA on dendritic cells.
  • antibody moieties in agents of this specification comprise one or more properties, structures and/or activities of recruited antibodies described in this specification.
  • Biophysical/biochemical potency assay to quantify target-engagement A biomolecule coupled to surface of sensor chip as ligand. As analyte is flowed in solution over immobilized ligand, binding to the sensor chip surface induces a change in refractive index proportional to bound mass.
  • An assay was done using a Biacore S200 instrument. This machine has a high sensitivity, low- medium throughput. A ligand variant fragment is dosed 1 nM to 1 ⁇ M and characterized by single cycle kinetics.
  • ASGPR-dependent uptake assay A HEK293 bioluminescent cell-based assay was used to assess ternary complex formation uptake by cells in vitro.
  • This on-mechanism endocytosis assay measures the accumulation of bifunctional degrader in HEK293 cells through the bifunctional degrader mechanism described in this specification.
  • a component of this assay is a determination of the receptor expression on the surfaces of the assay’s HEK293 cells.
  • Degradation assay is a direct, low-throughput Western blot measurement or a high-throughput assay using an activatable fluorescence-quencher probe.
  • Off-target assays include measurement of cytotoxicity through In vitro toxicity with HepG2 cells, e.g., in a CellTiter-Glo assay, measurement of hemagglutination by red blood cell interactions, measurement of PBMC, and measurement of off-target bindings in a house C-type lectin panel. Signal is boosted in the HEK293 versus HepG2 cells when measuring signal accumulation not degradation. Western assays can measure the degradation in HEK cells and other cell lines.
  • Next steps can include a competition assay with FC3 (qualitative). Manufacturing the agent. TABLE 14 P rifi ti n t H A 5 5
  • Agents of this specification may be prepared or isolated by synthetic and/or semi-synthetic methods or recombinant methods in accordance with this specification.
  • polypeptide agents e.g., cellular receptor-binding moiety peptide agents
  • provided agents are prepared synthetically.
  • provided agents are prepared using certain technologies described in International Patent Publication WO 2019/023501 (Kleo Pharmaceuticals, Inc.), which is incorporated in this specification in its entirety by reference.
  • the invention provides a method of synthesis, comprising the steps of: contacting a first agent comprising a cellular receptor-binding moiety linked to a first reactive group optionally through a first linker with a second agent comprising an antibody moiety linked to a second reactive group optionally through a second linker, wherein the first reactive group reacts with a second reactive group, and
  • AGN303 Native insulin with GN3
  • AGN302 Mutant insulin with GN3
  • ABT306 Alk-Native Insulin without GN3 (just peptide)
  • ABT304 Native Proinsulin
  • ABT305 Mutant Proinsulin
  • Non-GN3 peptide (ABT306) does not elicit internalization or ternary complex formation.
  • ABT410 is a proinsulin molecule with N-terminal H27R leading sequence and TEV recognition site. ABT410 was expressed as inclusion bodies in BL21(DE3) strain. After properly refolding and buffer exchange, target protein was cleaved by TEV protease, then purified by SP HP resins. The purified protein was formulated in 50 mM Tris/HCl, 150 mM sodium chloride, 10% glycerol, pH 7.5 by
  • UF/DF UF/DF.
  • the testing panel included protein concentration by Bradford, reducing and non-reducing SDS- PAGE, SEC-HPLC, endotoxin level and LC-MS.
  • Host cell E.coli BL21(DE3) competent cell
  • Coding vector name pET28a(+).
  • Protein Sequence [00433] ABT410 (before TEV digestion) MGMTMITNSPEISHHHHHHHHHHQLISEARENLYFQGGGGGFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAED LQVGQVELGGGPGAGSLQPLALEGSL QKRGIVEQCCTSICSLYQLENYCNG (SEQ ID NO: 19).
  • ABT410 (after TEV digestion) GGGGGFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAEDLQVGQVELGGGPGAGSLQPLALEGSLQKRGIVEQCCT SICSLYQLENYCNG.
  • Extinction coefficient 0.651 after digestion.
  • Molecular weight 9736.98 Da (-SH, after digestion).
  • pI 5.20 after digestion.
  • Refolding buffer 20 mM Tris/HCl,10 mM Glycine, 1 mM EDTA,1 mM GSH, 5 mM GSSG, pH 10.0.
  • Refolding buffer 20 mM Tris/HCl,10 mM Glycine, 1 mM EDTA,1 mM GSH, 5 mM GSSG, pH 10.0.
  • (2) Add DTT to solubilized inclusion bodies to a final concentration of 10 mM and mix completely.
  • Buffer exchange (UF/DF) and TEV digestion [00479] (1) Refolded sample was filtered by 0.45 ⁇ m filter firstly to remove visible precipitation before ultrafiltration. [00480] (2) Sample concentration was concentrated to ⁇ 3 mg/mL by UF device. [00481] (3) Concentrated sample was exchanged into TEV digestion buffer for six-fold volume by DF device. [00482] TEV digestion buffer: 25 mM Tris/HCl, 100 mM sodium chloride, pH 7.5, 10% glycerol. [00483] Buffer exchange by UF/DF: SP HP pool sample can be exchanged into final formulation buffer with six-fold volume by UF/DF device.
  • SP HP buffer C 50 mM NaAc, pH5.0, 10 mM sodium chloride, 10% glycerol, 0.1% Triton- X114.
  • Peak 1 fractions with good purity of SP HP purification were pooled and exchanged into final formulation buffer.
  • the purity of SEC-HPLC was 98.03%.
  • Formulation buffer 50 mM Tris/HCl, 150 mM sodium chloride, 10% glycerol, pH 7.5.
  • Product quality analysis The purified protein is subjected to quality control testing, including reducing and non-reducing SDS-PAGE, SEC-HPLC, Bradford assay, LC-MS, and endotoxin level.
  • Endotoxin level Purified proteins were subjected to endotoxin test in Limulus Amoebocyte Lysate (LAL) based kinetic turbidimetric test. Purified proteins were diluted based on maximum valid dilution (MVD) in LAL reagent water (Charles River/W110), then sample was loaded in Charles River Laboratories EndoSafe LAL Cartridges (Charles River/ PTS55F) and detected by Charles River Laboratories Endosafe NexGen-MCSTM instrument.
  • LAL Limulus Amoebocyte Lysate
  • Quality Control Stock Solutions The exact pipetting volume for stock solution should be calculated based on the actual antibody concentration of Reference Standard solutions.
  • Quality Control (QC) Stock 1 Freshly pipet 49 ⁇ L (8.16 mg/mL) of AGN6567 to 351 ⁇ L rat K 2 EDTA Plasma to give a final concentration of 1 mg/mL for total antibody in rat K 2 EDTA Plasma.
  • Quality Control (QC) Stock 2 Pipet 100 ⁇ L STD stock 1 to 900 ⁇ L rat K2EDTA Plasma to give a final concentration of 100 ⁇ g/mL for total antibody in rat K 2 EDTA Plasma.
  • Quality control (QC) samples are prepared by spiking individual QC stock solutions into blank rat K 2 EDTA Plasma described in the TABLE below: TABLE 28 Volume of source solution used ( ⁇ L) e
  • SIL ELVA Stock Dissolve 1 mg of SIL ELVA into 1 mL of diluent to give a concentration of 1 mg/mL for SIL ELVA and store at -70°C.
  • IS Stock 1 Pipet 20 ⁇ L of SIL ELVA stock to 1980 ⁇ L diluent to give a final concentration of 10 ⁇ g/mL SIL ELVA. Store at -70 o C.
  • AF647 78.0 ⁇ M.
  • AF647 31.0 ⁇ M.
  • AF647 30.9 ⁇ M.
  • AF647 27.4 ⁇ M.
  • AF647 48.6 ⁇ M.
  • Insulin receptor A exhibits a higher affinity for IGFs and a greater internalization and recycling rate than Insulin receptor B. Because of these differences, Insulin receptor B is preferentially associated with metabolic and differentiating signals. Insulin receptor A mainly favors cell growth, proliferation, and survival. TABLE 31 Surface plasmon resonance
  • mAb49 Human anti-Insulin antibody.
  • 6E9F1 Mouse anti-Insulin antibody. TABLE 32 Biochemistry selectivity (anti-insulin autoantibodies) ependent of insulin receptors. [00713] This finding provides flexibility with anti-human Insulin antibodies from different species in designing assays.
  • AGN303 Native insulin with GN3 Reference anti-insulin degrader control). Continued good positive control for internalization with HEK293-ASGPR (clone 3F7) cells + mouse anti-human insulin an. [00717] AGN411 (mutant construct) > AGN408 (native construct) for internalization, although minimal signal with either. Neither AGN411 (mutant construct) or AGN408 (native construct) induced internalization. [00718] AGN304: Proinsulin construct with C-terminal GN3 (Native) [00719] AGN305: Proinsulin construct with C-terminal GN3 (Mutant)
  • ABT306 Alk-native insulin without GN3 (peptide only).
  • ABT307 Proinsulin-IgG1 Fc fusion, G4S linker, hIgG1 hinge (C > A), LALA-PA.
  • ABT308 Proinsulin-IgG1 Fc fusion, 5x G4S linker, hIgG1 hinge (C > A), LALA-PA.
  • AGN411 Proinsulin construct with N-terminal ⁇ GN3 (mutant)
  • AGN412 Synthetic Mutant insulin with ⁇ GN3. By comparison, AGN310 has ⁇ GN3.
  • AGN414 Proinsulin-Fc conjugate (ABT307-TBT4438)
  • AGN415 Proinsulin-Fc conjugate (ABT308-TBT4438)
  • AGN416 Synthetic Mutant insulin with ⁇ GN3 on insulin A chain. By comparison, other synthetic insulin-GN3 compounds synthesized have GN3 attached to insulin B chain.
  • AGN417 Native proinsulin with ⁇ GN3 on N-terminal.
  • AGN301 + labeled rabbit Ab should internalize (therefore positive signal) If add Proinsulin Fc protein, will compete with AGN301, and therefore have less signal
  • AGN301 + labeled mouse 6E9F1 Ab should internalize (therefore no signal).
  • AGN303 native proinsulin
  • Synthetic insulin MoDE has similar affinity to mAb49.
  • AGN310 mutant proinsulin
  • Synthetic insulin MoDE has similar affinity to mAb49.
  • Insulin agents can be captured with GalNAc-binding lectin VVL and detected with an anti- insulin antibody.
  • Proinsulin agents can be captured with an anti-insulin antibody and detected with anti- C-peptide antibody (provides higher sensitivity than VVL).
  • CD1 female mouse CD1 Strain CRL#: Crl:CD1(ICR).
  • Age and weight range at start of study Animals aged six-eight weeks with body weight of approximately 25-30 g.
  • the mouse is a well characterized system for drug efficacy evaluation.
  • Administration of agents [00861] Dose: 1 mg/kg or 8.8 mg/mL.
  • mice On day 0, animals is weighed and randomly assigned to groups. All groups of animals receive their treatment of 1 mg/kg AGN417, as described in the TABLE below, either intravenously or subcutaneously. After a defined period, three animals from each group will undergo blood collection at two time points: the first time point involves collecting around 100 ⁇ l of blood from the submandibular vein, and the second will involve cardiac exsanguination following carbon dioxide asphyxiation. Blood samples from individual animals is collected in K3EDTA tubes, and plasma is separated. All samples are stored at -80°C until further analysis. [00870] Non-fasting blood glucose levels is monitored by collecting a small blood drop from a tail nick at the tip of the tail.
  • the blood is applied to a One-Touch test strip and measured using a One-Touch Ultra 2 Glucometer in three mice per group at the following time points: pre-dose, five minutes, ten minutes, fifteen minutes, thirty minutes, one hour, and two hours post-dose. TABLE 46 . After dosing, weights is recorded daily.
  • Plasma levels of AGN417 are determined by in-house developed MSD. Data are presented in tabular form. A standard pharmacokinetic analysis is to be performed for each dose group. EXAMPLE 25 Pharmacodynamics. [00875] Study design: 13.3 nmol/kg anti-insulin autoantibodies – 6E9F1 intravenously (2 mg/kg).133 nmol/kg AGN310 intravenously – 1:10 ratio. [00876] An assay in mice showed a 39% depletion by AGN310, based on area under the curve. [00877] The inventors performed a pharmacodynamics evaluation of AGN310 in nude mice. Nude mouse plasma causes no interference in antibody detection. [00878] Degrader interference could be prevented by diluting samples to below 10 ng/mL antibody. EXAMPLE 26 Pharmacodynamics. NOD mouse insulin inhibition. TABLE 47 l f i
  • TRAP agents were administered to NOD mice to assay NOD mouse insulin inhibition in vivo.
  • AGN310 and AGN417 were administered, each both intravenously and subcutaneously.
  • NOD mice were assayed for body weight and glucose levels (PharmaLegacy).
  • Body weight taken at each dosing, every five days.
  • Non-fasting blood glucose taken every two weeks via tail vein bleed (9-10 AM).
  • AGN303 (native proinsulin) and AGN310 (mutant proinsulin) Insulin agents were well- tolerated when administered at 3 mg/kg intravenously in pre-diabetic NOD mice, with no observed adverse events and no changes in glycemia when measured at twelve hours-post dose.
  • EXAMPLE 29 AGN310 extended tolerability in NOD female mice.
  • the objective of this EXAMPLE was to investigate the longer-term effects of multi-dosing IV AGN310 on NOD female mice.
  • mice given AGN417 intravenous and subcutaneous doses up to 3 mg/kg were well-tolerated, but exposure correlated with transient reduction in blood glucose levels of approximately 50 mg/dL. At no point during pharmacokinetic studies did blood glucose fall below reference range intervals. Blood glucose levels returned to vehicle control animal levels when food was provided. The current study will evaluate the dose-response relationship of AGN417 in rats. The low dose of 15 mg/kg is a low multiple of previous doses in mice, and the mid and high doses of 50 and 150 mg/kg study will explore tolerability and attempt to build a dose-response relationship.
  • the subcutaneous dose of 50 mg/kg is intended to understand the subcutaneous bioavailability and pharmacokinetic profile relative to intravenous administration.
  • the Wistar Han IGS rat was chosen as the animal model for this assay because it is an accepted rodent species for nonclinical toxicity testing by regulatory agencies.
  • Assays in laboratory animals provide a basis for extrapolation to humans and are required to support regulatory submissions. Acceptable models that do not use live animals currently do not exist.
  • the housing set-up is as specified in the United States Department of Agriculture Animal Welfare Act (9 C.F.R., Parts 1, 2 and 3) and as described in the Guide for the Care and Use of Laboratory Animals (National Research Council, Current edition; Office of Laboratory Animal Welfare, Current edition). Animals are separated during designated procedures/activities or separated as required for monitoring and/or health purposes, as deemed appropriate by Study Director and/or staff veterinarian.
  • Bone marrow smear evaluation Bone marrow smears are collected and prepared. Evaluation of stained smears may be performed. TABLE 61 Bioanalytical Sample Collection, Target Time Post-dose on Days 1 and 7 r ical analyses including regression analysis and descriptive statistics including arithmetic means and standard deviations, accuracy, and precision are performed. [00909] Toxicokinetic evaluation. TK parameters are generated using the concentration units provided by the bioanalytical lab. Concentration values below the limit of quantitation are treated as zero for the purposes of TK data analysis. TABLE 62 P b i d
  • composition of matter of Embodiment 1, wherein the cellular receptor binding moiety is a low-density lipoprotein receptor-related protein 1 (LRP1), a low-density lipoprotein receptor (LDLR), a Fc ⁇ receptor I-binding group, a FcRn binding group, a transferrin receptor binding group, or a macrophage scavenger receptor binding group.
  • LRP1 low-density lipoprotein receptor-related protein 1
  • LDLR low-density lipoprotein receptor
  • Fc ⁇ receptor I-binding group a FcRn binding group
  • transferrin receptor binding group a transferrin receptor binding group
  • macrophage scavenger receptor binding group a macrophage scavenger receptor binding group.
  • composition of matter of Embodiment 25, wherein binding moiety comprises a peptide moiety that binds to a specific amino acid residue of the glycan-specific IgG antibody comprises a peptide moiety that binds to a specific amino acid residue of the glycan-specific IgG antibody.
  • a composition comprising: a first composition of matter comprising: an antibody moiety, a cellular receptor binding moiety which binds to hepatocytes or other degrading cells through asialoglycoprotein receptors (ASGPR) of hepatocytes or other cell receptors on the surface degrading cells in a patient or subject, and a linker moiety linking the antibody moiety and the cellular receptor binding moiety, and at least one additional composition of matter comprising a moiety capable of binding to the antibody that forms the antibody moiety of the first composition of matter.
  • ASGPR asialoglycoprotein receptors
  • Non-patent literature [00983] Abhinandan & Martin, Analysis and improvements to Kabat and structurally correct numbering of antibody variable domains. Molecular Immunology, 45(14), 3832–3839 (2008)., providing the Martin (enhanced Chothia) CDR definitions and numbering used for biologics. [00984] Acqua et al., Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences. The Journal of Immunology, 169(9), 5171-5180 (2002). [00985] Aguirre, et.al., Insulin-like growth factor 1 in the cardiovascular system. Rev. Physiol. Biochem. Pharmacol., Vol.175, pages 1-45 (2016).
  • This publication shows the schematic structure of insulin, IGFs, and their receptors. Resemblances between insulin and IGFs allow them to cross-interact with each other’s receptors. IGF2 can also interact with IGF1R, hybrid receptors, and the insulin receptor, with a lower affinity. IGF1 can also bind to IGF2R, albeit with less affinity to that of its putative receptor. [00986] Akashi et al., Inter. Immu. (1997). In NOD mouse model, insulin autoreactive B cells induce diabetes, while B cell deficiency or depletion protects from Type 1 diabetes and allows for normoglycemia. [00987] Al-Lazikani, Lesk, & Chothia, C. (1997).
  • Burrack, Martinov, & Fife, T cell-mediated beta cell destruction Autoimmunity and alloimmunity in the context of Type 1 diabetes. Front Endocrinol (Lausanne), 8, 343 (December 5, 2017). Type 1 diabetes results from destruction of pancreatic ⁇ cells by T cells of the immune system. Despite improvements in insulin analogs and continuous blood glucose level monitoring, there is no cure for
  • INSR and IGF1R are composed of two ⁇ dimers which associate to form heterotetrameric complexes.
  • the ⁇ dimers are linked together by disulfide bonds and two dimers are also linked by disulfide bonds to form the tetramer.
  • the ⁇ subunit is the extracellular portion of the receptor while the ⁇ subunit spans the membrane and its cytoplasmic portion interacts with IRS proteins which are key intracellular mediators of insulin/IGF signaling.
  • Single ⁇ dimers are derived from separate genes and the INSR has two splice variants, INSR-B and INSR-A. Each variant shares the same membrane-spanning ⁇ subunit (dark blue) but differs in the extracellular ⁇ subunit (light pink or dark pink, respectively).
  • the IGF1R has different ⁇ and ⁇ subunits compared to the INSR (dark green). These combinations of ⁇ dimers allow for hybrid receptors, which bind insulin, IGF1, and IGF2 with differing affinities.
  • ⁇ dimers allow for hybrid receptors, which bind insulin, IGF1, and IGF2 with differing affinities.
  • ECL electrochemiluminescence
  • Immune cell infiltration into pancreatic islets involves mostly CD4+ & cytotoxic CD8+ T cells (leading to antigen spreading), but growing evidence of B cell infiltration & role in Type 1 diabetes pathogenesis.
  • Hu et al. Tissue-type plasminogen activator promotes murine myofibroblast activation through LDL receptor–related protein 1–mediated integrin signaling. The Journal of Clinical
  • Insulin and insulin precursors play role in pathogenesis of Type 1 diabetes, as mediated by CD4+ and CD8+ T cell responses to autoantigens.
  • PPI insulin precursors
  • PI insulin precursors
  • Michel, Boitard, & Bach Insulin autoantibodies in non-obese diabetic (NOD) mice.
  • NOD non-obese diabetic mice.
  • Clinical and Experimental Immunology 75(3), 457 (1989).
  • Moyers et al. Preclinical characterization of LY3209590, a novel weekly basal insulin Fc- fusion protein. J. Pharmacol. Exp. Ther., 382, 346-355 (September 2022) (Eli Lilly).
  • LY320959 is produced by Eli Lilly and Company, Indianapolis, Indiana and San Diego, California. [001039] Muguruma et al., Kinetics-based structural requirements of human immunoglobulin G binding peptides. ACS Omega, 4, 14390 ⁇ 14397 (2019). [001040] Mustafaoglu et al., Antibody purification via affinity membrane chromatography method utilizing nucleotide binding site targeting with a small molecule, Analyst, 141(24), 6571–6582 (November 28, 2016). [001041] Narendran, Mannering, & Harrison, Proinsulin—a pathogenic autoantigen in type 1 diabetes. Autoimmune Reviews, 2(4), 204-10 (June 1, 2003).
  • PA modification Residues METDTLLLWV LLLWVPGSTG DFVNQHLCGS HLVEALYLVC GERGFFYTPK TRREAEDLQV 60 GQVELGGGPG AGSLQPLALE GSLQKRGIVE QCCTSICSLY QLENYCNGGG GSEPKSADKT 120 HTCPPCPAPE AAGGPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE 180 VHNAKTKPRE EQYNSTYRVV SVLTVLHQDW LNGKEYKCKV SNKALAAPIE KTISKAKGQP 240 REPQVYTLPP SRDELTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT TPPVLDSDGS 300 FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPGK 344 Sequence Number (ID): 31 Leng
  • Molecule Type AA Features Location/Qualifiers: - source, 1..19 > mol_type, protein > organism, synthetic construct Residues: ELVAVITTDG STNYADSVK 19
  • composition of matter (the agent, the TRAP) has one of the structures:
  • Extracellular Protein Targeting Ligand refers to a target-binding moiety that can bind to an anti-proinsulin or anti-insulin antibody.
  • X 1 is 1 to 5 groups independently selected from O, S. N(R 6 ), arid C(R 4 XR 4 ), wherein if X ! group then X 1 is O, S, N(R”), or C(R 4 )(R 4 ), if X 1 is 2 groups then no more than 1 group of X 1 , S. or N(R 6 ), if X 1 is 3, 4, or 5 groups then no more than 2 groups of X 1 are O, S, orN(R & );
  • R* is selected from
  • heteroatoms independently selected from N. O, and S, each of which aryl, heterocycle., and heteroaryl is optionally substituted with 1, 2, 3, or 4 substituents;
  • Civ hydrogen, R u *, alkyl-CXP)- ⁇ . -C(O)-R ⁇ alkyl, haioalkyl, “()C(O)R ⁇ and ⁇ NRS-CCOJR’ 0 ;
  • R 10 is selected from aryl, alkyl-NR s -C(O)-R alkyl-aryl, alkyl -heteroaryl with 1 , 2, or 4 heteroatoms, alkyl -cyano, alkyLOR 6 , alkyl-NRV, NlV-hiR 6 -C(O)R ⁇ NRM(O>R 3 , alkenyl, ally 1, alkynyl, -N'R ( '-a1kenyi, -O-alkenyl, -NR ⁇ -alkynyL -NRMieteroatyl, ⁇ NR/’-aryl, -O-heteroaryL -O-ary! , and -O-alkynyl. each of which R’" is optionally substituted with 1 , 2, 3, or 4 substituents;
  • R ' at each occurrence is independently selected from hydrogen, alkyl, heteroalkyl, haioalkyl (including - €Fg -CHF ; , -CH>F, -ClfaCF?, -CH2CH2F, and -CF?CF-)> arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, hetcroaryl. heterocycle, -PR* 8 , and -NR S R 9 ;
  • R'' is independently selected at each occurrence from hydrogen, heteroalkyi, alkyl, haioalkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycle, -OR 6 , -NIV’R', C(0)R 3 , S(O)R 3 , C(S)R 3 , and S(O)’R 3 ,
  • R* andR' are independently selected at each occurrence from hydrogen, heteroalkyl, alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, haioalkyl, heteroatyl, heterocycle, -alkyl-OR 8 , - alkyl-MVR 9 , C(0)R 3 , S(O)R 3 , C(S)R 3 , and S(O) -RA
  • R* and K;‘ are independently selected at each occurrence from hydrogen, beteroalkyl. alkyl, arylalkyl, heteroarylalkyl, alkenyl, alkynyl, aryl, heteroatyl, and heterocycle;
  • each Linker' is a bond or a moiety that covalently links the ASGPR ligand to Linker’ 3 ;
  • Linker 0 is a bond or a moiety that covalentfy links Linker* to an Exlracellular Protein Targeting Ligand

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Abstract

L'invention concerne une composition de matière comprenant une fraction de liaison, une fraction de liaison aux récepteurs cellulaires qui se lie aux hépatocytes ou à d'autres cellules dégradantes par l'intermédiaire des récepteurs de l'asialoglycoprotéine (ASGPR) à la surface des hépatocytes ou d'autres cellules dégradantes chez un patient ou un sujet, et éventuellement une fraction de liaison reliant la fraction de liaison et la fraction de liaison aux récepteurs cellulaires, la composition de matière étant utile pour l'élimination chez un patient ou un sujet.
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Citations (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002060919A2 (fr) 2000-12-12 2002-08-08 Medimmune, Inc. Molecules a demi-vies longues, compositions et utilisations de celles-ci
US7658921B2 (en) 2000-12-12 2010-02-09 Medimmune, Llc Molecules with extended half-lives, compositions and uses thereof
US8088376B2 (en) 2004-11-12 2012-01-03 Xencor, Inc. Fc variants with altered binding to FcRn
WO2012017021A2 (fr) 2010-08-03 2012-02-09 Graffinity Pharmaceuticals Gmbh Ligands pour la purification d'anticorps et de protéine de fusion à fc par chromatographie d'affinité
US8969526B2 (en) 2011-03-29 2015-03-03 Roche Glycart Ag Antibody Fc variants
US20160243248A1 (en) * 2014-02-21 2016-08-25 Ecole Polytechnique Federale De Lausanne (Epfl) Glycotargeting therapeutics
WO2017046652A1 (fr) * 2015-09-19 2017-03-23 Ecole Polytechnique Federale De Lausanne Agents thérapeutiques de glycociblage
WO2017125885A1 (fr) 2016-01-23 2017-07-27 Biocon Limited Procédé bioanalytique pour analogues d'insuline
US20190023794A1 (en) * 2015-09-04 2019-01-24 The California Institute For Biomedical Research Insulin immunoglobulin fusion proteins
WO2019019962A1 (fr) 2017-07-25 2019-01-31 广州玻思韬控释药业有限公司 Préparation à libération contrôlée par pompe osmotique
WO2019023501A1 (fr) 2017-07-26 2019-01-31 Kleo Pharmaceuticals, Inc. Composés abt universels et leurs utilisations
US20190111149A1 (en) 2016-02-02 2019-04-18 Meditope Biosciences, Inc. Anti-egfr antibody drug conjugate
WO2019136442A1 (fr) 2018-01-08 2019-07-11 Kleo Pharmaceuticals, Inc. Agents de liaison à cd16a et leurs utilisations
WO2019199634A1 (fr) 2018-04-09 2019-10-17 Yale University Petites molécules bifonctionnelles pour cibler la dégradation sélective de protéines circulantes
WO2019199621A1 (fr) 2018-04-09 2019-10-17 Yale University Molécules bi-fonctionnelles pour dégrader des protéines circulantes
US20200190165A1 (en) 2017-04-28 2020-06-18 Ajinomoto Co., Inc. Compound having affinity substance to soluble protein, cleavable portion and reactive group, or salt thereof
US10821157B2 (en) * 2014-02-21 2020-11-03 Anokion Sa Glycotargeting therapeutics
WO2021072246A1 (fr) 2019-10-10 2021-04-15 Yale University Anticorps conçus comme agents de dégradation moléculaire par l'intermédiaire de récepteurs cellulaires
WO2021102052A1 (fr) 2019-11-18 2021-05-27 Kleo Pharmaceuticals, Inc. Technologies de conjugaison dirigée
WO2021155317A1 (fr) 2020-01-31 2021-08-05 Avilar Therapeutics, Inc. Composés se liant à l'asgpr pour la dégradation de protéines extracellulaires
WO2022235699A2 (fr) 2021-05-03 2022-11-10 Avilar Therapeutics, Inc. Composés puissants de liaison à l'asgpr permettant la dégradation d'immunoglobulines et d'autres protéines
WO2025035052A1 (fr) 2023-08-09 2025-02-13 Biohaven Therapeutics Ltd. Agents de dégradation moléculaires pour le traitement d'une néphropathie à iga

Patent Citations (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9562100B2 (en) 2000-12-12 2017-02-07 Medimmune Llc Molecules with extended half-lives, compositions and uses thereof
EP1355919A2 (fr) 2000-12-12 2003-10-29 Medimmune, Inc. Molecules a demi-vies longues, compositions et utilisations de celles-ci
US7083784B2 (en) 2000-12-12 2006-08-01 Medimmune, Inc. Molecules with extended half-lives, compositions and uses thereof
US7658921B2 (en) 2000-12-12 2010-02-09 Medimmune, Llc Molecules with extended half-lives, compositions and uses thereof
WO2002060919A2 (fr) 2000-12-12 2002-08-08 Medimmune, Inc. Molecules a demi-vies longues, compositions et utilisations de celles-ci
US8088376B2 (en) 2004-11-12 2012-01-03 Xencor, Inc. Fc variants with altered binding to FcRn
WO2012017021A2 (fr) 2010-08-03 2012-02-09 Graffinity Pharmaceuticals Gmbh Ligands pour la purification d'anticorps et de protéine de fusion à fc par chromatographie d'affinité
US8969526B2 (en) 2011-03-29 2015-03-03 Roche Glycart Ag Antibody Fc variants
US20160243248A1 (en) * 2014-02-21 2016-08-25 Ecole Polytechnique Federale De Lausanne (Epfl) Glycotargeting therapeutics
US10821157B2 (en) * 2014-02-21 2020-11-03 Anokion Sa Glycotargeting therapeutics
US20190023794A1 (en) * 2015-09-04 2019-01-24 The California Institute For Biomedical Research Insulin immunoglobulin fusion proteins
WO2017046652A1 (fr) * 2015-09-19 2017-03-23 Ecole Polytechnique Federale De Lausanne Agents thérapeutiques de glycociblage
WO2017125885A1 (fr) 2016-01-23 2017-07-27 Biocon Limited Procédé bioanalytique pour analogues d'insuline
US20190111149A1 (en) 2016-02-02 2019-04-18 Meditope Biosciences, Inc. Anti-egfr antibody drug conjugate
US20200190165A1 (en) 2017-04-28 2020-06-18 Ajinomoto Co., Inc. Compound having affinity substance to soluble protein, cleavable portion and reactive group, or salt thereof
WO2019019962A1 (fr) 2017-07-25 2019-01-31 广州玻思韬控释药业有限公司 Préparation à libération contrôlée par pompe osmotique
WO2019023501A1 (fr) 2017-07-26 2019-01-31 Kleo Pharmaceuticals, Inc. Composés abt universels et leurs utilisations
WO2019136442A1 (fr) 2018-01-08 2019-07-11 Kleo Pharmaceuticals, Inc. Agents de liaison à cd16a et leurs utilisations
WO2019199634A1 (fr) 2018-04-09 2019-10-17 Yale University Petites molécules bifonctionnelles pour cibler la dégradation sélective de protéines circulantes
WO2019199621A1 (fr) 2018-04-09 2019-10-17 Yale University Molécules bi-fonctionnelles pour dégrader des protéines circulantes
US20210145974A1 (en) * 2018-04-09 2021-05-20 Yale University Bifunctional Small Molecules to Target the Selective Degradation of Circulating Proteins
WO2021072246A1 (fr) 2019-10-10 2021-04-15 Yale University Anticorps conçus comme agents de dégradation moléculaire par l'intermédiaire de récepteurs cellulaires
WO2021102052A1 (fr) 2019-11-18 2021-05-27 Kleo Pharmaceuticals, Inc. Technologies de conjugaison dirigée
WO2021155317A1 (fr) 2020-01-31 2021-08-05 Avilar Therapeutics, Inc. Composés se liant à l'asgpr pour la dégradation de protéines extracellulaires
WO2022235699A2 (fr) 2021-05-03 2022-11-10 Avilar Therapeutics, Inc. Composés puissants de liaison à l'asgpr permettant la dégradation d'immunoglobulines et d'autres protéines
WO2025035052A1 (fr) 2023-08-09 2025-02-13 Biohaven Therapeutics Ltd. Agents de dégradation moléculaires pour le traitement d'une néphropathie à iga

Non-Patent Citations (101)

* Cited by examiner, † Cited by third party
Title
"AVMA Guidelines for the Euthanasia of Animals", article "American Veterinary Medical Association"
"Greene's Protective Groups in Organic Synthesis", 11 August 2014, JOHN WILEY & SONS
"Janeway's Immunobiology", 2014, TAYLOR & FRANCIS LIMITED
"Laboratory Methods in Enzymology: DNA", 2013, ELSEVIER
"National Research Council. Guide for the Care and Use of Laboratory Animals", NATIONAL INSTITUTES OF HEALTH
"the free encyclopedia, Dipeptidyl peptidase-4 inhibitor", WIKIPEDIA, 3 July 2024 (2024-07-03)
"The Merck Manual of Diagnosis and Therapy", 2018, MERCK SHARP & DOHME CORP.
ABHINANDANMARTIN: "Analysis and improvements to Kabat and structurally correct numbering of antibody variable domains", MOLECULAR IMMUNOLOGY, vol. 45, no. 14, 2008, pages 3832 - 3839, XP023437109, DOI: 10.1016/j.molimm.2008.05.022
ACQUA ET AL., JOURNAL OF IMMUNOLOGY, vol. 169, no. 9, 2002, pages 5171 - 5180
ACQUA ET AL.: "Increasing the affinity of a human IgG1 for the neonatal Fc receptor: biological consequences", THE JOURNAL OF IMMUNOLOGY, vol. 169, no. 9, 2002, pages 5171 - 5180, XP055283699, DOI: 10.4049/jimmunol.169.9.5171
AGUIRRE: "Insulin-like growth factor 1 in the cardiovascular system", REV. PHYSIOL. BIOCHEM. PHARMACOL., vol. 175, 2018, pages 1 - 45
AKASHI ET AL., INTER. IMMU., 1997
AL-LAZIKANI, LESKCHOTHIA, C.: "Standard conformations for the canonical structures of immunoglobulins", JOURNAL OF MOLECULAR BIOLOGY, vol. 273, no. 4, 1997, pages 927 - 948, XP004461383, DOI: 10.1006/jmbi.1997.1354
ALLEVA ET AL.: "An antigen-specific immunotherapeutic, AKS-107, deletes insulin-specific B cells and prevents murine autoimmune diabetes", FRONTIERS IN IMMUNOLOGY, vol. 15, 2024, pages 1367514
ALVESKIZILTEPEBILGICER: "Oriented surface immobilization of antibodies at the conserved nucleotide binding site for enhanced antigen detection", LANGMUIR, vol. 28, 2012, pages 9640 - 9648, XP055280632, DOI: 10.1021/la301887s
ANNALS OF INTERNAL MEDICINE., vol. 176, no. 3, March 2023 (2023-03-01), pages 427 - 9
ASADIBRUINKIEFFER: "Characterization of antibodies to products of proinsulin processing using immunofluorescence staining of pancreas in multiple species", JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY, vol. 63, no. 8, 2015, pages 646 - 662
BELFIORE ET AL., INSULIN RECEPTOR ISOFORMS IN PHYSIOLOGY AND DISEASE: AN UPDATED VIEW. ENDOCRINE REVIEWS, vol. 38, no. 1, October 2017 (2017-10-01), pages 379 - 431
BENEIT ET AL.: "Expression of insulin receptor (IR) A and B isoforms, IGF-IR, and IR/IGF-IR hybrid receptors in vascular smooth muscle cells and their role in cell migration in atherosclerosis", CARDIOVASC. DIABETOL., vol. 15, 2016, pages 161
BERMAN ET AL.: "Content and organization of the human Ig VH locus: definition of three new VH families and linkage to the Ig CH locus", EMBO J., vol. 7, 1988, pages 727
BERRY ET AL., J. VISU. EXP., 2013
BOHMER ET AL.: "Proinsulin autoantibodies are more closely associated with type 1 (insulin-dependent) diabetes mellitus than insulin autoantibodies", DIABETOLOGIA, vol. 34, November 1991 (1991-11-01), pages 830 - 4
BRANDT ET AL.: "Controlled intramolecular antagonism as a regulator of insulin receptor maximal activity", PEPTIDES, vol. 100, 2018, pages 18 - 23
BRIGHT ET AL.: "Stability of proinsulin in whole blood", CLINICAL BIOCHEMISTRY, vol. 52, 1 February 2018 (2018-02-01), pages 153 - 5
BURRACKMARTINOVFIFE: "T cell-mediated beta cell destruction: Autoimmunity and alloimmunity in the context of Type 1 diabetes", FRONT ENDOCRINOL (LAUSANNE, vol. 8, 5 December 2017 (2017-12-05), pages 343
CASALI ET AL.: "Frequency of B cells committed to the production of antibodies to insulin in newly diagnosed patients with insulin-dependent diabetes mellitus and generation of high affinity human monoclonal IgG to insulin", JOURNAL OF IMMUNOLOGY, vol. 144, no. 10, 15 May 1990 (1990-05-15), pages 3741 - 7
CHEN: "Effects of TCM on polycystic ovary syndrome and its cellular endocrine mechanism", FRONTIERS IN ENDOCRINOLOGY, vol. 14, 16 May 2023 (2023-05-16), pages 956772
CHOEDURGANNAVARCHUNG: "Fc-binding ligands of immunoglobulin G: An overview of high affinity proteins and peptides", MATERIALS, vol. 9, no. 12, 2016, XP055490322, DOI: 10.3390/ma9120994
CHRISTIANSONSHULTZLEITER: "Adoptive transfer of diabetes into immunodeficient NODscid/scid mice: relative contributions of CD4+ and CD8+ T-cells from diabetic versus prediabetic NOD. NON-Thy-1a donors", DIABETES, vol. 42, no. 1, 1993, pages 44 - 55
CLARK ET AL., ASSAYS FOR INSULIN, PROINSULIN(S) AND C-PEPTIDE, 1999
COBB ET AL.: "A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in rhesus macaques", BIORXIV, vol. 2021-09, 2021, pages 2021 - 09
CONG ET AL.: "MicroRNA-218 promotes prostaglandin E2 to inhibit osteogenic differentiation in synovial mesenchymal stem cells by targeting 15-hydroxyprostaglandin dehydrogenase [NAD(+", MOL. MED. REP., vol. 16, 2017, pages 9347 - 9354
DAWSON ET AL., SCIENCE, vol. 266, 1994, pages 776 - 779
DELANO ET AL.: "Convergent solutions to binding at a protein-protein interface", SCIENCE, vol. 287, 2000, pages 1279 - 1283, XP000985914, DOI: 10.1126/science.287.5456.1279
DIMEGLIO ET AL.: "Type 1 diabetes", LANCET, vol. 391, no. 10138, 16 June 2018 (2018-06-16), pages 2449 - 2462
DLUDLA ET AL.: "Pancreatic β-cell dysfunction in type 2 diabetes: Implications of inflammation and oxidative stress", WORLD J DIABETES, vol. 14, no. 3, 15 March 2023 (2023-03-15), pages 130 - 146
ELSO ET AL.: "Replacing murine insulin 1 with human insulin protects NOD mice from diabetes", PLOS ONE, vol. 14, no. 12, 10 December 2019 (2019-12-10), pages 0225021
FANG ET AL., ANN. INTERN. MED., 2023
FATHALLAH ET AL.: "Effects of hypertonic buffer composition on lymph node uptake and bioavailability of rituximab, after subcutaneous administration", BIOPHARM. DRUG DISPOS., vol. 36, no. 2, March 2015 (2015-03-01), pages 115 - 25, XP055791149, DOI: 10.1002/bdd.1925
FOREMAN ET AL.: "LC-MS/MS based detection of circulating proinsulin derived peptides in patients with altered pancreatic beta cell function", MS BASED ANALYSIS OF CIRCULATING PROINSULIN DERIVED PEPTIDES: NEW OPPORTUNITIES FOR PRECISION DIAGNOSIS AND MANAGEMENT OF DIABETES, 2022
FROMMERKAHALY: "Type 1 diabetes and associated autoimmune diseases", WORLD JOURNAL OF DIABETES, vol. 11, no. 11, 15 November 2020 (2020-11-15), pages 527 - 539
GALAL ET AL.: "Insulin Receptor isoforms and insulin growth factor-like receptors: Implications in cell signaling, carcinogenesis, and chemoresistance", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 24, no. 19, 9 October 2023 (2023-10-09), pages 15006
GOY ET AL., DEVELOPMENT AND VALIDATION OF AN LC-MS/MS BASED QUANTITATIVE ASSAY FOR MARMOSET INSULIN IN SERUM, 2022
GRIFFETHBIANDANEF: "The emerging role of insulin-like growth factors in testis development and function", BASIC & CLINICAL ANDROLOGY, vol. 24, December 2014 (2014-12-01), pages 1 - 10
GU: "Islet autoantibody detection by electrochemiluminescence (ECL) assay", J. CLIN. CELLULAR IMMUNOLOGY, vol. 8, no. 6, 2017, pages 1000531
GUPTA ET AL.: "Computationally designed antibody-drug conjugates self-assembled via affinity ligands", NATURE BIOMEDICAL ENGINEERING, vol. 3, 2019, pages 917 - 929, XP036979549, DOI: 10.1038/s41551-019-0470-8
HASKINSMCDUFFIE: "Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone", SCIENCE, vol. 249, no. 4975, 1990, pages 1433 - 1436
HILGERT ET AL.: "A monoclonal antibody applicable for determination of C-peptide of human proinsulin by RIA", HYBRIDOMA, vol. 10, no. 3, 1991, pages 379 - 386, XP055925825, DOI: 10.1089/hyb.1991.10.379
HINMAN ET AL., CURR. DIAB. REP., 2014
HU ET AL.: "Tissue-type plasminogen activator promotes murine myofibroblast activation through LDL receptor-related protein 1-mediated integrin signaling", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 117, no. 12, 2007, pages 3821 - 3832
IKEMATSU ET AL.: "VH and V segment structure of anti-insulin IgG autoantibodies in patients with insulin-dependent diabetes mellitus: Evidence for somatic selection", JOURNAL OF IMMUNOLOGY, vol. 152, no. 3, 1 February 1994 (1994-02-01), pages 1430 - 1441, XP009088527
JORNS ET AL.: "Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes", DIABETOLOGIA, vol. 57, 6 December 2014 (2014-12-06), pages 512 - 521
KRULJEC ET AL.: "Alternative affinity ligands for immunoglobulins", BIOCONJUGATE CHEM., vol. 28, no. 8, 2017, pages 2009 - 2030, XP055514125, DOI: 10.1021/acs.bioconjchem.7b00335
KRULJEC ET AL.: "Development and characterization of peptide ligands of immunoglobulin G Fc region", BIOCONJUGATE CHEM., vol. 29, no. 8, 2018, pages 2763 - 2775
KUGLIN ET AL.: "Proinsulin autoantibodies: association with type I diabetes but not with islet cell antibodies, insulin autoantibodies or HLA-DR type", J. AUTOIMMUN., vol. 3, no. 5, 1 October 1990 (1990-10-01), pages 573 - 7
KUGLINGRIESKOLB: "Evidence of IgG autoantibodies against human proinsulin in patients with IDDM before insulin treatment", DIABETES, vol. 37, no. 1, 1988, pages 130 - 2
LANDRY ET AL., ASSAY DRUG DEV. TECHNOL., vol. 11, no. 5, June 2013 (2013-06-01), pages 326 - 32
LARSSON ET AL.: "TEDDY Study Group. Children followed in the TEDDY study are diagnosed with type 1 diabetes at an early stage of disease", PEDIATR. DIABETES, vol. 15, no. 2, March 2013 (2013-03-01), pages 118 - 26
LEETE ET AL., FRONTIERS IN IMMUNOLOGY, 2021
LEFRANCET: "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains", DEVELOPMENTAL & COMPARATIVE IMMUNOLOGY, vol. 27, no. 1, 2003, pages 55 - 77
LING ET AL.: "Increased plasmablasts enhance T cell-mediated beta cell destruction and promote the development of type 1 diabetes", MOLECULAR MEDICINE, vol. 28, no. 1, 2022, pages 18
LIU ET AL.: "Immune and metabolic effects of antigen-specific immunotherapy using multiple β-cell peptides in Type 1 diabetes", DIABETES, vol. 71, no. 4, 1 April 2022 (2022-04-01), pages 722 - 732, XP093109975, DOI: 10.2337/db21-0728
LUONG ET AL.: "Analytical and biosensing platforms for insulin: A review", SENSORS AND ACTUATORS REPORTS, vol. 3, 2021, pages 100028, XP093075339, DOI: 10.1016/j.snr.2021.100028
MANNERINGBHATTACHARJEE: "Insulin's other life: An autoantigen in type 1 diabetes", IMMUNOLOGY & CELL BIOLOGY, vol. 99, no. 5, May 2021 (2021-05-01), pages 448 - 460
MICHELBOITARDBACH: "Insulin autoantibodies in non-obese diabetic (NOD) mice", CLINICAL AND EXPERIMENTAL IMMUNOLOGY, vol. 75, no. 3, 1989, pages 457
MOYERS ET AL.: "Preclinical characterization of LY3209590, a novel weekly basal insulin Fc-fusion protein", J. PHARMACOL. EXP. THER., vol. 382, September 2022 (2022-09-01), pages 346 - 355, XP093145926, DOI: 10.1124/jpet.122.001105
MUGURUMA ET AL.: "Kinetics-based structural requirements of human immunoglobulin G binding peptides", ACS OMEGA, vol. 4, 2019, pages 14390 - 14397, XP055820637, DOI: 10.1021/acsomega.9b01104
MUSTAFAOGLU ET AL.: "Antibody purification via affinity membrane chromatography method utilizing nucleotide binding site targeting with a small molecule", ANALYST, vol. 141, no. 24, 28 November 2016 (2016-11-28), pages 6571 - 6582, XP055719153, DOI: 10.1039/C6AN02145J
NARENDRANMANNERINGHARRISON: "Proinsulin-a pathogenic autoantigen in type 1 diabetes", AUTOIMMUNE REVIEWS, vol. 2, no. 4, 1 June 2003 (2003-06-01), pages 204 - 10
NATHGODATFLEMMINGURH: "Deciphering the interaction between neonatal fc receptor and antibodies using a homogeneous bioluminescent immunoassay", THE JOURNAL OF IMMUNOLOGY, vol. 207, no. 4, 2021, pages 1211 - 1221, XP093257630, DOI: 10.4049/jimmunol.2100181
NEYRINCK: "Oxidative stress in the pathogenesis and evolution of chronic kidney disease: untangling Ariadne's thread", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 20, no. 15, 29 July 2019 (2019-07-29), pages 3711
NISHINANJO: "Insulin gene mutations and diabetes", J. DIABETES INVESTIG., vol. 2, no. 2, 7 April 2011 (2011-04-07), pages 92 - 100
O'KELL ET AL.: "Exploration of autoantibody responses in canine diabetes using protein arrays", SCIENTIFIC REPORTS, vol. 12, no. 1, 2022, pages 2490
PETERSEN ET AL., DIABETES, 1994
PETERSEN ET AL.: "Detection of GAD antibodies in diabetes and other autoimmune diseases using a simple radioligand assay", DIABETES, vol. 43, 1 March 1994 (1994-03-01)
PETTERSSON, M.CREWS, C. M.: "In Drug Discovery Today: Technologies", vol. 31, 2019, ELSEVIER BV., article "PROteolysis TArgeting Chimeras (PROTACs) - Past, present and future", pages: 15 - 27
PISSARNITSKI ET AL.: "Discovery of insulin receptor partial agonists MK-5160 and MK-1092 as novel basal insulins with potential to improve therapeutic index", J. MED. CHEM., vol. 65, 14 April 2022 (2022-04-14), pages 5593 - 5605, XP093178658, DOI: 10.1021/acs.jmedchem.1c02073
SABLJIC ET AL.: "Novel flow cytometric immunoassay for detection of proinsulin autoantibodies in diabetes mellitus employing a recombinant autoantigen expressed in E", COLI. FRONT. IMMUNOL., vol. 12, 6 April 2021 (2021-04-06), pages 648021
SAXENAWU: "dvances in therapeutic Fc engineering-modulation of IgG-associated effector functions and serum half-life", FRONTIERS IN IMMUNOLOGY, vol. 7, 2016, pages 580
SAXONMCDERMOTTMICHELS: "Novel management of insulin autoimmune syndrome with rituximab and continuous glucose monitoring", THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 101, no. 5, 1 May 2016 (2016-05-01), pages 1931 - 4
SHIELDS ET AL.: "High resolution mapping of the binding site on human IgG1 for FcyRI, FcyRII, FcγRlll, and FcRn and design of IgG1 variants with improved binding to the FcyR", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 276, no. 9, 2001, pages 6591 - 6604
SMITHPEAKMAN: "Peptide immunotherapy for Type 1 diabetes-clinical advances", FRONT IMMUNOL., vol. 9, 28 February 2018 (2018-02-28), pages 392, XP093063578, DOI: 10.3389/fimmu.2018.00392
STROHL: "Optimization of Fc-mediated effector functions of monoclonal antibodies", CURRENT OPINION IN BIOTECHNOLOGY, vol. 20, no. 6, 2009, pages 685 - 691, XP026778879, DOI: 10.1016/j.copbio.2009.10.011
SUBRAMANIAN ET AL.: "Insulin receptor-insulin interaction kinetics using multiplex surface plasmon resonance", JOURNAL OF MOLECULAR RECOGNITION, vol. 26, no. 12, December 2013 (2013-12-01), pages 643 - 52
TAMMSCHMIDT: "IgG binding sites on human Fcy receptors", INTERNATIONAL REVIEWS OF IMMUNOLOGY, vol. 16, no. 1-2, 1997, pages 57 - 85, XP009071061
TENG ET AL.: "A strategy for the generation of biomimetic ligands for affinity chromatography. Combinatorial synthesis and biological evaluation of an IgG binding ligand", J. MOL. RECOGNITION, vol. 12, 1999, pages 67 - 75, XP001084821, DOI: 10.1002/(SICI)1099-1352(199901/02)12:1<67::AID-JMR443>3.0.CO;2-4
TILMAN ET AL.: "Novel human IgG1 and IgG4 Fc-engineered antibodies with completely abolished immune effector functions", PROTEIN ENGINEERING, DESIGN AND SELECTION, vol. 29, October 2016 (2016-10-01), pages 457 - 466, XP055414310, DOI: 10.1093/protein/gzw040
UTTAMCHANDANI ET AL.: "Microarrays of tagged combinatorial triazine libraries in the discovery of small-molecule ligands of human IgG", J. COMB. CHEM., vol. 6, no. 6, November 2004 (2004-11-01), pages 862 - 8, XP008102342, DOI: 10.1021/cc049900s
VALDEZ ET AL.: "E. A radioligand-binding assay for detecting antibodies specific for proinsulin and insulin using 35S-proinsulin", J. IMMUNOL. METHODS, vol. 279, no. 1-2, August 2003 (2003-08-01), pages 173 - 81, XP004455317, DOI: 10.1016/S0022-1759(03)00197-2
WATANABE ET AL.: "Human soluble phospholipase A2 receptor is an inhibitor of the integrin-mediated cell migratory response to collagen", AM. J. PHYSIOL. CELL PHYSIOL., vol. 315, 2018, pages C398 - C408
WEISS: "Evolution of insulin at the edge of foldability and its medical implications", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (PNAS, vol. 117, no. 47, 2020
WILLIAMS ET AL.: "An artificial intelligence-based deep learning algorithm for the diagnosis of diabetic neuropathy using corneal confocal microscopy: A development and validation study", DIABETOLOGIA, vol. 63, February 2020 (2020-02-01), pages 419 - 30, XP036980700, DOI: 10.1007/s00125-019-05023-4
WILLIAMS ET AL.: "Racial differences in the associations between adiposity, placental growth hormone and inflammatory cytokines in pregnant women", FRONTIERS IN ENDOCRINOLOGY, vol. 14, 17 March 2023 (2023-03-17), pages 1100724
WILLIAMS: "The measurement of autoantibodies to insulin informs diagnosis of diabetes in a childhood population negative for other autoantibodies", FRONTIERS IN ENDOCRINOLOGY, vol. 39, no. 12, December 2022 (2022-12-01), pages 14979
YAMADA ET AL., ANGEW CHEM. INT., ED ENGL., vol. 58, no. 17, 16 April 2019 (2019-04-16), pages 5592 - 5597
YAMADA ET AL.: "Preferential utilization of specific immunoglobulin heavy chain diversity and joining segments in adult human peripheral blood B lymphocytes", J. EXP. MED., vol. 173, 1991, pages 395
YEH ET AL.: "Pathogenic human monoclonal antibody against desmoglein 3", CLINICAL IMMUNOLOGY., vol. 120, no. 1, 2006, pages 68 - 75, XP024911180, DOI: 10.1016/j.clim.2006.03.006
YU ET AL.: "APRIL and TALL-1 and receptors BCMA and TACI: system for regulating humoral immunity", NATURE IMMUNOLOGY., vol. 1, no. 3, September 2000 (2000-09-01), pages 252 - 6, XP000992743, DOI: 10.1038/79802
YU ET AL.: "Distinguishing persistent insulin autoantibodies with differential risk: Nonradioactive bivalent proinsulin/insulin autoantibody assay", DIABETES, vol. 61, no. 1, January 2012 (2012-01-01), pages 179 - 86
YU: "Islet autoantibody detection by electrochemiluminescence (ECL) assay", METHODS IN MOLECULAR BIOLOGY, vol. 1433, 2016, pages 85 - 91
ZALEVSKY ET AL.: "Enhanced antibody half-life improves in vivo activity", NATURE BIOTECHNOLOGY, vol. 28, no. 2, 2010, pages 157 - 159, XP055308991, DOI: 10.1038/nbt.1601

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