Anti-garp protein and uses thereof

Abstract

The present invention relates to a protein binding to GARP in the presence of TGF-β and uses thereof.

1 . An antibody binding to an epitope of a complex formed by human GARP and TGF-β, said epitope comprising at least one of the residues 137, 138, or 139 of GARP (SEQ ID NO: 1) and at least one residue of TGF-β (SEQ ID NO: 53). 
     
     
         2 . The antibody binding to an epitope of a complex formed by human GARP and TGF-β according to  claim 1 , said epitope comprising at least one of the residues 137, 138, or 139 of GARP (SEQ ID NO: 1) and at least one residue from the Latency associated peptide (LAP) of TGF-β (SEQ ID NO: 54) and at least one residue from mature TGF-β (SEQ ID NO: 55). 
     
     
         3 . The antibody binding to an epitope of a complex formed by human GARP and TGF-β according to  claim 1 , said epitope comprising residues 137, 138 and 139 of GARP (SEQ ID NO: 1) and at least one residue of TGF-β (SEQ ID NO: 53). 
     
     
         4 . The antibody binding to an epitope of a complex formed by human GARP and TGF-β according to  claim 1 , said epitope comprising residues 137, 138 and 139 of GARP (SEQ ID NO: 1) and at least one residue from the Latency associated peptide (LAP) of TGF-β (SEQ ID NO: 54) and at least one residue from mature TGF-β (SEQ ID NO: 55). 
     
     
         5 . The antibody binding to an epitope of a complex formed by human GARP and TGF-β according to  claim 1 , said epitope comprising at least one of residues 137, 138 or 139 of GARP (SEQ ID NO: 1) and at least one residue from the Latency associated peptide (LAP) of TGF-β selected from the group of residues 58, 100, 146, 269, 270, 271, 272, and 273 of TGF-β (SEQ ID NO: 53) and at least one residue from mature TGF-β (SEQ ID NO: 55). 
     
     
         6 . The antibody binding to an epitope of a complex formed by human GARP and TGF-β according to  claim 1 , said epitope comprising at least one of residues 137, 138 or 139 of GARP (SEQ ID NO: 1) and at least one residue from the Latency associated peptide (LAP) of TGF-β (SEQ ID NO: 54) and at least one residue from mature TGF-β selected from the group of residues 284, 336, 337, 338, 341, and 345 of TGF: 13 (SEQ ID NO: 53). 
     
     
         7 . The antibody binding to an epitope of a complex formed by human GARP and TGF-β according to  claim 1 , said epitope comprising at least one of residues 137, 138 or 139 of GARP (SEQ ID NO: 1) and at least one residue from the Latency associated peptide (LAP) of TGF-β selected from the group of residues 58, 100, 146, 269, 270, 271, 272, and 273 of TGF-β (SEQ ID NO: 53) and at least one residue from mature TGF-β selected from the group of residues 284, 336, 337, 338, 341, and 345 of TGF: 13 (SEQ ID NO: 53). 
     
     
         8 . The antibody binding to an epitope of a complex formed by human GARP and TGF-β according to  claim 1 , said epitope comprising residues 137, 138 and 139 of GARP (SEQ ID NO: 1) and at least one residue from the Latency associated peptide (LAP) of TGF-β selected from the group of residues 58, 100, 146, 269, 270, 271, 272, and 273 of TGF-β (SEQ ID NO: 53) and at least one residue from mature TGF-β selected from the group of residues 284, 336, 337, 338, 341, and 345 of TGF: 13 (SEQ ID NO: 53). 
     
     
         9 . The antibody binding to an epitope of a complex formed by human GARP and TGF-β according to  claim 1 , said epitope comprising at least one of residues 137, 138 or 139 of GARP (SEQ ID NO: 1) and at least one residue from TGF-β selected from the group of residues 58, 100, 146, 269, 270, 271, 272, 273, 284, 336, 337, 338, 341, and 345 of TGF-β (SEQ ID NO: 53). 
     
     
         10 . The antibody binding to an epitope of a complex formed by human GARP and TGF-β according to  claim 1 , said epitope comprising residues 137, 138 and 139 of GARP (SEQ ID NO: 1) and at least one residue selected from the group of residues 113, 114, 116, 117, 118, 119, 140, 142, 143, 144, 145, 146, 162, 163, 165, 166, 167, 170 and 189 of GARP (SEQ ID NO: 1) and at least one residue from the Latency associated peptide (LAP) of TGF-β (SEQ ID NO: 54) and at least one residue from mature TGF-β (SEQ ID NO: 55). 
     
     
         11 . The antibody binding to an epitope of a complex formed by human GARP and TGF-β according to  claim 1 , said epitope comprising residues 137, 138 and 139 of GARP (SEQ ID NO: 1) and at least one residue selected from the group of residues 113, 114, 116, 117, 118, 119, 140, 142, 143, 144, 145, 146, 162, 163, 165, 166, 167, 170 and 189 of GARP (SEQ ID NO: 1) and at least one residue from the Latency associated peptide (LAP) of TGF-β selected from the group of residues 58, 100, 146, 269, 270, 271, 272, and 273 of TGF-β (SEQ ID NO: 53) and at least one residue from mature TGF-β (SEQ ID NO: 55). 
     
     
         12 . The antibody binding to an epitope of a complex formed by human GARP and TGF-β according to  claim 1 , said epitope comprising residues 137, 138 and 139 of GARP (SEQ ID NO: 1) and at least one residue selected from the group of residues 113, 114, 116, 117, 118, 119, 140, 142, 143, 144, 145, 146, 162, 163, 165, 166, 167, 170 and 189 of GARP (SEQ ID NO: 1) and at least one residue from the Latency associated peptide (LAP) of TGF-β (SEQ ID NO: 54) and at least one residue from mature TGF-β selected from the group of residues 284, 336, 337, 338, 341, and 345 of TGF: 13 (SEQ ID NO: 53). 
     
     
         13 . The antibody binding to an epitope of a complex formed by human GARP and TGF-β according to  claim 1 , said epitope comprising residues 137, 138 and 139 of GARP (SEQ ID NO: 1) and at least one residue selected from the group of residues 113, 114, 116, 117, 118, 119, 140, 142, 143, 144, 145, 146, 162, 163, 165, 166, 167, 170 and 189 of GARP (SEQ ID NO: 1) and at least one amino acid from the Latency associated peptide (LAP) of TGF-β selected from the group of residues 58, 100, 146, 269, 270, 271, 272, and 273 of TGF-β (SEQ ID NO: 53) and at least one residue from mature TGF-β selected from the group of residues 284, 336, 337, 338, 341, and 345 of TGF: 13 (SEQ ID NO: 53). 
     
     
         14 . The antibody of  claim 1 , wherein the antibody is selected from the group consisting of a whole antibody, a humanized antibody, a single chain antibody, a dimeric single chain antibody, a Fv, a Fab, a F(ab)′2, a defucosylated antibody, a bi-specific antibody, a diabody, a triabody, a tetrabody; or an antibody fragment selected from the group consisting of a unibody, a domain antibody, and a nanobody; or an antibody mimetic selected from the group consisting of an affibody, an affilin, an affitin, an adnectin, an atrimer, an evasin, a DARPin, an anticalin, an avimer, a fynomer, a versabody and a duocalin. 
     
     
         15 . The antibody of  claim 1 , wherein the antibody inhibits TGF-β signaling. 
     
     
         16 . The antibody of  claim 1 , wherein the antibody prevents the release of active TGF-β from GARP/TGF-β. 
     
     
         17 . A method for inhibiting TGF-β signaling comprising administering an antibody according to  claim 1 . 
     
     
         18 . A method for treating a TGF-β related disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody according to  claim 1 . 
     
     
         19 . The method according to  claim 18 , wherein the TGF-β related disorder is selected from the group consisting of inflammatory diseases, chronic infection, cancer, fibrosis, cardiovascular diseases, cerebrovascular disease, and neurodegenerative diseases. 
     
     
         20 . A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody according to  claim 1  in combination with another treatment for cancer or another immunotherapeutic agent. 
     
     
         21 . The method according to  claim 20 , wherein the immunotherapeutic agent is a tumor vaccine or an immunostimulatory antibody. 
     
     
         22 . The method according to  claim 20 , wherein the method reduces immunosuppression in the tumor environment. 
     
     
         23 . A method for boosting the immune system in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody according to  claim 1  in combination with another treatment for cancer or another immunotherapeutic agent. 
     
     
         24 . A method for inhibiting the immune suppressive function of human Tregs in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody according to  claim 1  in combination with another treatment for cancer or another immunotherapeutic agent.