# US 9,751,932 B2 · Anti-big-endothelin-1 (big-ET-1) antibodies and uses thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,751,932 B2 - Document ID: US9751932B2 - Status: Granted - Kind: B2 - Application number: 13/774,695 - Filed: 2013-02-22 - Published: 2013-08-22 - Granted: 2017-09-05 - Earliest claimed: 2012-02-22 - Assignees: Regeneron Pharmaceuticals, Inc. - Applicants: Regeneron Pharmaceuticals, Inc. - Inventors: Lori C. Morton; Douglas MacDonald - Web page: https://patentgrep.com/patent/US9751932B2 ## CPC - C07K 16/18: against material from animals or humans - A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics - A61P 3/10: for hyperglycaemia, e.g. antidiabetics - A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure - A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis - A61P 9/12: Antihypertensives - A61P 11/00: Drugs for disorders of the respiratory system - A61P 13/12: of the kidneys - A61P 17/00: Drugs for dermatological disorders - A61P 25/04: Centrally acting analgesics, e.g. opioids - A61P 27/00: Drugs for disorders of the senses - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61P 29/02: without antiinflammatory effect - A61P 35/00: Antineoplastic agents - A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection - C07K 16/26: against hormones {; against hormone releasing or inhibiting factors} - A61K 2039/505: {comprising antibodies} - C07K 2317/52: Constant or Fc region; Isotype - C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding - 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) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - 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) ## Abstract The present invention provides antibodies that bind big-endothelin-1 (“big-ET-1”), and methods of using same. According to certain embodiments of the invention, the antibodies specifically bind human big-ET-1 but do not bind human small-ET-1 (i.e., the active form of endothelin-1 that results from proteolytic cleavage of big-ET-1 by endothelin-converting enzyme-1 [ECE-1]). According to certain embodiments of the invention, the anti-big-ET-1 antibodies are capable of blocking cleavage of big-ET-1 by ECE-1. The antibodies of the invention are useful for the treatment of big-ET-1-related disorders, including hypertension disorders, fibrotic disorders, neurodegenerative disorders, retinal disorders, pain and cancers. ## Claims ### Claim 1 An isolated human antibody or antigen-binding fragment thereof that specifically binds human big-endothelin-1 (big-ET-1) (SEQ ID NO:434), and does not bind small-endothelin-1 (small-ET-1) (SEQ ID NO:435), wherein the antibody or antigen-binding fragment thereof blocks cleavage of big-ET-1 by endothelin-converting enzyme-1 (ECE-1) and comprises the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) having the amino acid sequence selected from the group consisting of SEQ ID NO:2, 18, 34, 50, 66, 146, 162, 194, 210, 226, 242, 258, 274, 290, 322, 338, 370, and 386, and the CDRs of a light chain variable region (LCVR) having the amino acid sequence selected from the group consisting of SEQ ID NO:10, 26, 42, 58, 74, 154, 170, 202, 218, 234, 250, 266, 282, 298, 330, 346, 378, and 394. ### Claim 2 (depends on 1) The isolated antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment thereof binds human big-ET-1 (SEQ ID NO:434) but not mouse big-ET-1. ### Claim 3 (depends on 1) The isolated antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment thereof binds human big-ET-1 (SEQ ID NO:434) and mouse big-ET-1. ### Claim 4 (depends on 1) The isolated antibody or antigen-binding fragment of claim 1, wherein said antibody or antigen-binding fragment thereof comprises heavy and light chain CDRs of the HCVR/LCVR sequence pair selected from the group consisting of SEQ ID NOs:2/10, 18/26, 34/42, 50/58, 66/74, 146/154, 162/170, 194/202, 210/218, 226/234, 242/250, 258/266, 274/282, 290/298, 322/330, 338/346, 370/378, and 386/394. ### Claim 5 (depends on 4) The isolated antibody or antigen-binding fragment of claim 4, wherein the antibody or antigen-binding fragment thereof comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, selected from the group consisting of SEQ ID NOs: 4-6-8-12-14-16; 20-22-24-28-30-32; 36-38-40-44-46-48; 52-54-56-60-62-64; 68-70-72-76-78-80; 148-150-152-156-158-160; 164-166-168-172-174-176; 196-198-200-204-206-208; 212-214-216-220-222-224; 228-230-232-236-238-240; 244-246-248-252-254-256; 260-262-264-268-270-272; 276-278-280-284-286-288; 292-294-296-300-302-304; 324-326-328-332-334-336; 340-342-344-348-350-352; 372-374-376-380-382-384; and 388-390-392-396-398-400. ### Claim 6 (depends on 5) The isolated antibody or antigen-binding fragment of claim 5, wherein said antibody or antigen-binding fragment thereof comprises the HCVR/LCVR amino acid sequence pair selected from the group consisting of SEQ ID NOs:2/10, 18/26, 34/42, 50/58, 66/74, 146/154, 162/170, 194/202, 210/218, 226/234, 242/250, 258/266, 274/282, 290/298, 322/330, 338/346, 370/378, and 386/394. ### Claim 7 (depends on 6) A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 6 and a pharmaceutically acceptable carrier or diluent. ### Claim 8 (depends on 1) A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 1 and a pharmaceutically acceptable carrier or diluent. ### Claim 9 (depends on 1) The isolated antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDRs of the HCVR/LCVR sequence pair of SEQ ID NOs: 242/250. ### Claim 10 (depends on 9) The isolated antibody or antigen-binding fragment of claim 9, wherein the antibody or antigen-binding fragment thereof comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, of SEQ ID NOs: 244-246-248-252-254-256. ### Claim 11 (depends on 10) The isolated antibody or antigen-binding fragment of claim 10, wherein the antibody or antigen-binding fragment thereof comprises the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 242/250. ### Claim 12 (depends on 11) A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 11 and a pharmaceutically acceptable carrier or diluent. ### Claim 13 (depends on 1) The isolated antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDRs of the HCVR/LCVR sequence pair of SEQ ID NOs: 18/26. ### Claim 14 (depends on 13) The isolated antibody or antigen-binding fragment of claim 13, wherein the antibody or antigen-binding fragment thereof comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, of SEQ ID NOs: 20-22-24-28-30-32. ### Claim 15 (depends on 14) The isolated antibody or antigen-binding fragment of claim 14, wherein the antibody or antigen-binding fragment thereof comprises the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 18/26. ### Claim 16 (depends on 15) A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 15 and a pharmaceutically acceptable carrier or diluent. ### Claim 17 (depends on 1) The isolated antibody or antigen-binding fragment of claim 1, wherein the antibody or antigen-binding fragment thereof comprises heavy and light chain CDRs of the HCVR/LCVR sequence pair of SEQ ID NOs: 162/170. ### Claim 18 (depends on 17) The isolated antibody or antigen-binding fragment of claim 17, wherein the antibody or antigen-binding fragment thereof comprises HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 domains, respectively, of SEQ ID NOs: 164-166-168-172-174-176. ### Claim 19 (depends on 18) The isolated antibody or antigen-binding fragment of claim 18, wherein the antibody or antigen-binding fragment thereof comprises the HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 162/170. ### Claim 20 (depends on 19) A pharmaceutical composition comprising the antibody or antigen-binding fragment of claim 19 and a pharmaceutically acceptable carrier or diluent.