# US 12,214,049 B2 · Anti-angiogenic antibody-drug conjugates > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,214,049 B2 - Document ID: US12214049B2 - Status: Granted - Kind: B2 - Application number: 17/065,901 - Filed: 2020-10-08 - Published: 2021-02-04 - Granted: 2025-02-04 - Earliest claimed: 2016-02-04 - Assignees: ADS Therapeutics LLC - Applicants: ADS Therapeutics LLC - Inventors: Jinsong Ni; Rong Yang - Web page: https://patentgrep.com/patent/US12214049B2 ## CPC - A61K 47/6803: {Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates} - A61K 9/0048: {Eye, e.g. artificial tears} - A61K 9/08: Solutions {(composition of solutions A61K47/00)} - A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin - A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines} - A61K 47/6845: {the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon} - A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant} - A61P 17/00: Drugs for dermatological disorders - A61P 19/02: for joint disorders, e.g. arthritis, arthrosis - A61P 27/02: Ophthalmic agents - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07K 16/00: Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies - C07K 16/22: against growth factors {; against growth regulators} - A61K 47/46: Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts - C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## Abstract A method of producing synergistic and enhanced efficacy in treating a disease in a subject includes providing an antibody, the antibody being a classic antibody or a modified biologic molecule that blocks a first target in the subject; providing a drug, the drug being a small molecule agent that blocks the first target or a second target in the subject; connecting the antibody and the drug with a linker to form an Antibody-Drug Synergism (ADS) compound; and treating the disease with the ADS compound. The linker is hydrolyzed in the subject over a certain time so that both the antibody and the drug exert their functions simultaneously, and the ADS compound confers better efficacy than either the antibody or the drug alone due to a synergism of the ADS compound. ## Claims ### Claim 1 A method of treating an ocular disease in a subject, comprising: delivering to the subject a compound comprising: bevacizumab or ranibizumab; a small molecule anti-angiogenesis inhibitor; and a linker that links the small molecule anti-angiogenesis inhibitor to the bevacizumab or ranibizumab, wherein the linker comprises a bond that can be hydrolyzed in vitreous humor, and wherein the linker is hydrolyzed in the subject over time such that both the bevacizumab or ranibizumab and the small molecule exert their functions in the subject. ### Claim 2 (depends on 1) The method of claim 1, wherein the ocular disease is a neovascular disease. ### Claim 3 (depends on 1) The method of claim 1, wherein: the small molecule anti-angiogenesis inhibitor is selected from the group consisting of axitinib, cediranib, linifanib, motesanib, nintedanib, pazopanib, ponatinib, regorafenib, sorafenib, sunitinib, tivozanib, vatalanib, LY2874455, and SU5402; and the linker comprises an ester, an amide, a carbamate, a carbonate, an imine, an ether, a phosphate, or a hydrozone bond. ### Claim 4 (depends on 1) The method of claim 1, wherein the compound is delivered or injected into an eye of the subject through intravitreal, intracameral, suprachoroidal, subconjunctival, subtenon, or topical ocular delivery. ### Claim 5 (depends on 1) The method of claim 1, wherein the small molecule anti-angiogenesis inhibitor is squalamine, and the linker comprises an ester, an amide, a carbamate, a carbonate, an imine, an ether, a phosphate, or a hydrozone bond. ### Claim 6 (depends on 1) The method of claim 1, wherein the compound is delivered or injected into an eye of the subject through intravitreal, intracameral, suprachoroidal, subconjunctival, subtenon, or topical ocular delivery. ### Claim 7 A method of treating an ocular disease in a subject, comprising: delivering to the subject a compound comprising: ramucirumab; a small molecule anti-angiogenesis inhibitor; and a linker that links the small molecule anti-angiogenesis inhibitor to the ramucirumab, wherein the linker comprises a bond that can be hydrolyzed in vitreous humor, and wherein the linker is hydrolyzed in the subject over time such that both the ramucirumab and the small molecule exert their functions in the subject. ### Claim 8 (depends on 7) The method of claim 7, wherein the ocular disease is a neovascular disease. ### Claim 9 (depends on 7) The method of claim 7, wherein: the small molecule anti-angiogenesis inhibitor is selected from the group consisting of axitinib, cediranib, linifanib, motesanib, nintedanib, pazopanib, ponatinib, regorafenib, sorafenib, sunitinib, tivozanib, vatalanib, LY2874455, and SU5402; and the linker comprises an ester, an amide, a carbamate, a carbonate, an imine, an ether, a phosphate, or a hydrozone bond. ### Claim 10 (depends on 7) The method of claim 7, wherein the small molecule anti-angiogenesis inhibitor is squalamine, and the linker comprises an ester, an amide, a carbamate, a carbonate, an imine, an ether, a phosphate, or a hydrozone bond. ### Claim 11 A method of treating an ocular disease in a subject, comprising: delivering to the subject a compound comprising: aflibercept or conbercept; a small molecule anti-angiogenesis inhibitor; and a linker that links the small molecule anti-angiogenesis inhibitor to the aflibercept or conbercept, wherein the linker comprises a bond that can be hydrolyzed in vitreous humor, and wherein the linker is hydrolyzed in the subject over time such that both the aflibercept or conbercept and the small molecule exert their functions in the subject. ### Claim 12 (depends on 11) The method of claim 11, wherein the ocular disease is a neovascular disease. ### Claim 13 (depends on 11) The method of claim 11, wherein: the small molecule anti-angiogenesis inhibitor is selected from the group consisting of axitinib, cediranib, linifanib, motesanib, nintedanib, pazopanib, ponatinib, regorafenib, sorafenib, sunitinib, tivozanib, vatalanib, LY2874455, and SU5402; and the linker comprises an ester, an amide, a carbamate, a carbonate, an imine, an ether, a phosphate, or a hydrozone bond. ### Claim 14 (depends on 11) The method of claim 11, wherein the compound is delivered or injected into an eye of the subject through intravitreal, intracameral, suprachoroidal, subconjunctival, subtenon, or topical ocular delivery. ### Claim 15 (depends on 11) The method of claim 11, wherein the small molecule anti-angiogenesis inhibitor is squalamine, and the linker comprises an ester, an amide, a carbamate, a carbonate, an imine, an ether, a phosphate, or a hydrozone bond.