# US 9,518,129 B2 · Thrombin-binding antibody molecules 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 9,518,129 B2 - Document ID: US9518129B2 - Status: Granted - Kind: B2 - Application number: 14/363,514 - Filed: 2012-12-14 - Published: 2014-12-18 - Granted: 2016-12-13 - Earliest claimed: 2011-12-14 - Assignees: Janssen Pharmaceuticals, Inc. - Applicants: Janssen Pharmaceuticals, Inc. - Inventors: James Andrew Huntington; Trevor Baglin; Jonathan Langdown - Web page: https://patentgrep.com/patent/US9518129B2 ## CPC - C07K 16/40: against enzymes - A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors - A61P 7/04: Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents - 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 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia - A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] - A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics - A61P 35/00: Antineoplastic agents - A61P 35/04: specific for metastasis - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07K 16/36: against blood coagulation factors - C07K 2317/21: from primates, e.g. man - C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues - C07K 2317/55: Fab or Fab' - C07K 2317/565: Complementarity determining region [CDR] - C07K 2317/70: characterized by effect upon binding to a cell or to an antigen - C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding - C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value - 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 ## Abstract This invention relates to isolated antibodies which recognize the exosite 1 epitope of thrombin and selectively inhibit thrombin without promoting bleeding. These antibody molecules may be useful in the treatment and prevention of thrombosis, embolism and other conditions mediated by thrombin. ## Claims ### Claim 1 A recombinant antibody molecule, comprising a VH domain having the amino acid sequence of SEQ ID NO: 2, a VL domain, and an IgG constant region, wherein the recombinant antibody molecule specifically binds to the exosite 1 region of thrombin. ### Claim 2 (depends on 1) An antibody molecule according to claim 1 that inhibits thrombin activity. ### Claim 3 (depends on 2) An antibody molecule according to claim 2, wherein the antibody does not inhibit hemostasis and does not cause bleeding in vivo. ### Claim 4 (depends on 1) An antibody molecule according to claim 1, wherein the VL domain comprises an LCDR1 having the amino acid sequence of SEQ ID NO: 7, an LCDR2 having the amino acid sequence of SEQ ID NO: 8, and an LCDR3 having the amino acid sequence of SEQ ID NO: 9. ### Claim 5 (depends on 1) An antibody molecule according to claim 1, wherein the VL domain has the amino acid sequence of SEQ ID NO: 6 or the amino acid sequence of SEQ ID NO: 6 with one or more amino acid substitutions. ### Claim 6 (depends on 4) An antibody molecule according to claim 4, wherein the VL domain has the amino acid sequence of SEQ ID NO: 6. ### Claim 7 A recombinant antibody molecule, comprising a VH domain comprising an HCDR3 having the amino acid sequence of SEQ ID NO: 5, an HCDR2 having the amino acid sequence of SEQ ID NO: 4, and an HCDR1 having the amino acid sequence of SEQ ID NO: 3, a VL domain comprising an LCDR1 having the amino acid sequence of SEQ ID NO: 7 or the amino acid sequence of SEQ ID NO: 7 with one or two amino acid substitutions, an LCDR2 having the amino acid sequence of SEQ ID NO: 8, and an LCDR3 having the amino acid sequence of SEQ ID NO: 9, and an IgG constant region, wherein the recombinant antibody molecule specifically binds to the exosite 1 region of thrombin. ### Claim 8 (depends on 1) An antibody molecule according to claim 1, wherein the antibody molecule is a monoclonal antibody. ### Claim 9 (depends on 1) An antibody molecule according to claim 1, wherein the antibody molecule is a minibody. ### Claim 10 (depends on 1) A pharmaceutical composition, comprising the antibody molecule according to claim 1 and a pharmaceutically acceptable carrier or excipient. ### Claim 11 (depends on 1) The antibody molecule according to claim 1, wherein the IgG constant region is an IgG1 or IgG4 constant region. ### Claim 12 (depends on 1) The antibody molecule according to claim 1, wherein the antibody molecule is a human antibody. ### Claim 13 (depends on 5) The antibody molecule according to claim 5, wherein the VL comprise an amino acid substitution at Asn28 of SEQ ID NO: 6 or an amino acid substitution at Ser30 of SEQ ID NO: 6. ### Claim 14 (depends on 7) An antibody molecule according to claim 7 that inhibits thrombin activity. ### Claim 15 (depends on 14) An antibody molecule according to claim 14 which does not inhibit hemostasis and does not cause bleeding in vivo. ### Claim 16 (depends on 7) The antibody molecule according to claim 7, wherein the LCDR1 has the amino acid sequence of SEQ ID NO: 7. ### Claim 17 (depends on 7) The antibody molecule according to claim 7, wherein the LCDR1 has the amino acid sequence of SEQ ID NO: 7 with an amino acid substitution at Asn5 of SEQ ID NO: 7 or has the amino acid sequence of SEQ ID NO: 7 with an amino acid substitution at Ser7 of SEQ ID NO: 7. ### Claim 18 (depends on 7) The antibody molecule according to claim 7, wherein the VL domain has the amino acid sequence of SEQ ID NO: 6. ### Claim 19 (depends on 7) The antibody molecule according to claim 7, wherein the VL domain has the amino acid sequence of SEQ ID NO: 6 with an amino acid substitution at Asn28 or an amino acid substitution at Ser30. ### Claim 20 (depends on 7) The antibody molecule according to claim 7, wherein the LCDR1 has the amino acid sequence of SEQ ID NO: 7 with one amino acid substitution. ### Claim 21 (depends on 7) The antibody molecule according to claim 7, wherein the antibody molecule is a monoclonal antibody. ### Claim 22 (depends on 7) The antibody molecule according to claim 7, wherein the antibody molecule is a minibody. ### Claim 23 (depends on 7) The antibody molecule according to claim 7, wherein the IgG constant region is an IgG1 or IgG4 constant region. ### Claim 24 (depends on 7) The antibody molecule according to claim 7, wherein the antibody molecule is a human antibody. ### Claim 25 (depends on 7) A pharmaceutical composition, comprising the antibody molecule according to claim 7 and a pharmaceutically acceptable carrier or excipient.