Human Antibodies to GREM1

Abstract

The present invention provides antibodies that bind to human gremlin-1 (GREM1), and methods of use. According to certain embodiments of the invention, the antibodies are fully human antibodies that bind to GREM1. The antibodies of the invention are useful for inhibiting or neutralizing GREM1 activity, thus providing a means of treating a GREM1-related disease or disorder such as fibrosis and cancer. In some embodiments, the antibodies of the present invention are used in treating at least one symptom or complication of fibrosis of the liver, lungs or kidney.

What is claimed is: 
     
         1 . An isolated human monoclonal antibody or antigen-binding fragment thereof that binds specifically to human gremlin-1 (GREM1). 
     
     
         2 . The isolated human monoclonal antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof blocks GREM1 binding to one of bone morphogenetic protein-2 (BMP2), BMP4, BMP7 or heparin. 
     
     
         3 . An isolated human antibody or antigen-binding fragment thereof that binds specifically to GREM1, wherein the antibody or antigen-binding fragment thereof exhibits one or more properties selected from the group consisting of:
 (a) binds GREM1 at 37° C. with a binding dissociation equilibrium constant (K D ) of less than about 275 nM as measured by surface plasmon resonance;   (b) binds to GREM1 at 37° C. with a dissociative half-life (t½) of greater than about 3 minutes as measured by surface plasmon resonance;   (c) binds GREM1 at 25° C. with a K D  of less than about 280 nM as measured by surface plasmon resonance;   (d) binds to GREM1 at 25° C. with a t½ of greater than about 2 minutes as measured by surface plasmon resonance;   (e) blocks GREM1 binding to BMP4 with an IC 50  of less than about 1.9 nM as measured in a competition ELISA assay at 25° C.;   (f) blocks GREM1-mediated inhibition of BMP signaling and promotes cell differentiation; and   (g) blocks GREM1 binding to heparin.   
     
     
         4 . The isolated antibody or antigen-binding fragment thereof of any one of  claims 1 - 3 , wherein the antibody competes for specific binding to GREM1 with an antibody or antigen-binding fragment comprising the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR), wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 402, 418, 434, 450, 466, 482, 498, 514, 530, 546, 562, and 578; and the 
     
     
         5 . The isolated antibody or antigen-binding fragment thereof of any one of  claims 1 - 4 , wherein the antibody competes for specific binding to GREM1 with an antibody or antigen-binding fragment thereof comprising the CDRs of a light chain variable region (LCVR), wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554, 570, and 586. 
     
     
         6 . An isolated human antibody or antigen-binding fragment thereof that specifically binds to GREM1, wherein the antibody comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within any one of the heavy chain variable region (HCVR) sequences selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 402, 418, 434, 450, 466, 482, 498, 514, 530, 546, 562, and 578; and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within any one of the light chain variable region (LCVR) sequences selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554, 570, and 586. 
     
     
         7 . The isolated human antibody or antigen-binding fragment thereof of  claim 6 , comprising a HCVR having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 402, 418, 434, 450, 466, 482, 498, 514, 530, 546, 562, and 578. 
     
     
         8 . The isolated human antibody or antigen-binding fragment thereof of either  claim 6  or  7 , comprising a LCVR having an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554, 570, and 586. 
     
     
         9 . The isolated human antibody or antigen-binding fragment thereof of any one of  claims 6 - 8 , comprising: (a) a HCVR having an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 402, 418, 434, 450, 466, 482, 498, 514, 530, 546, 562, and 578; and (b) a LCVR having an amino acid sequence selected from the group consisting of SEQ ID NO: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554, 570, and 586. 
     
     
         10 . The isolated human antibody or antigen-binding fragment thereof of any one of  claims 6 - 9 , comprising:
 (a) a HCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 20, 36, 52, 68, 84, 100, 116, 132, 148, 164, 180, 196, 212, 228, 244, 260, 276, 292, 308, 324, 340, 356, 372, 388, 404, 420, 436, 452, 468, 484, 500, 516, 532, 548, 564, and 580;   (b) a HCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 6, 22, 38, 54, 70, 86, 102, 118, 134, 150, 166, 182, 198, 214, 230, 246, 262, 278, 294, 310, 326, 342, 358, 374, 390, 406, 422, 438, 454, 470, 486, 502, 518, 534, 550, 566, and 582;   (c) a HCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 24, 40, 56, 72, 88, 104, 120, 136, 152, 168, 184, 200, 216, 232, 248, 264, 280, 296, 312, 328, 344, 360, 376, 392, 408, 424, 440, 456, 472, 488, 504, 520, 536, 552, 568, and 584;   (d) a LCDR1 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 28, 44, 60, 76, 92, 108, 124, 140, 156, 172, 188, 204, 220, 236, 252, 268, 284, 300, 316, 332, 348, 364, 380, 396, 412, 428, 444, 460, 476, 492, 508, 524, 540, 556, 572, and 588;   (e) a LCDR2 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 14, 30, 46, 62, 78, 94, 110, 126, 142, 158, 174, 190, 206, 222, 238, 254, 270, 286, 302, 318, 334, 350, 366, 382, 398, 414, 430, 446, 462, 478, 494, 510, 526, 542, 558, 574, and 590; and   (f) a LCDR3 domain having an amino acid sequence selected from the group consisting of SEQ ID NOs: 16, 32, 48, 64, 80, 96, 112, 128, 144, 160, 176, 192, 208, 224, 240, 256, 272, 288, 304, 320, 336, 352, 368, 384, 400, 416, 432, 448, 464, 480, 496, 512, 528, 544, 560, 576, and 592.   
     
     
         11 . The isolated human antibody or antigen-binding fragment of any one of  claims 6 - 10 , comprising a 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, 82/90, 98/106, 114/122, 130/138, 146/154, 162/170, 178/186, 194/202, 210/218, 226/234, 242/250, 258/266, 274/282, 290/298, 306/314, 322/330, 338/346, 354/362, 370/378, 386/394, 402/410, 418/426, 434/442, 450/458, 466/474, 482/490, 498/506, 514/522, 530/538, 546/554, 562/570, and 578/586. 
     
     
         12 . An isolated antibody or antigen-binding fragment thereof that binds the same epitope on GREM1 as an antibody or antigen-binding fragment comprising the complementarity determining regions (CDRs) of a heavy chain variable region (HCVR), wherein the HCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs: 2, 18, 34, 50, 66, 82, 98, 114, 130, 146, 162, 178, 194, 210, 226, 242, 258, 274, 290, 306, 322, 338, 354, 370, 386, 402, 418, 434, 450, 466, 482, 498, 514, 530, 546, 562, and 578; and the CDRs of a light chain variable region (LCVR), wherein the LCVR has an amino acid sequence selected from the group consisting of SEQ ID NOs: 10, 26, 42, 58, 74, 90, 106, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522, 538, 554, 570, and 586. 
     
     
         13 . A pharmaceutical composition comprising an isolated human antibody or antigen-binding fragment thereof that binds to GREM1 according to any one of  claims 1 - 12 , and a pharmaceutically acceptable carrier or diluent. 
     
     
         14 . A method for treating fibrosis comprising administering an effective amount of an antibody or an antigen-binding fragment thereof according to any of  claims 1 - 12 ; or a pharmaceutical composition according to  claim 13  to a patient in need thereof. 
     
     
         15 . The method of  claim 14 , wherein the antibody or antigen-binding fragment thereof, or the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, is administered to the patient in combination with a second therapeutic agent. 
     
     
         16 . The method of  claim 15 , wherein the second therapeutic agent is selected from the group consisting of an anti-fibrotic agent, an anti-inflammatory drug, a corticosteroid, a nutritional supplement, an anti-hypertensive agent, an antibiotic, another antibody to GREM1, an antibody to a cytokine such as IL-1, IL-6, or TGF-β, and any other palliative therapy. 
     
     
         17 . The method of any of  claims 14 - 16 , wherein the antibody or antigen-binding fragment thereof is administered subcutaneously, intravenously, intradermally, orally, or intramuscularly. 
     
     
         18 . The method of any of  claims 14 - 17 , wherein the antibody or antigen-binding fragment is administered at a dose of about 0.1 mg/kg of body weight to about 100 mg/kg of body weight of the patient. 
     
     
         19 . The method of any of  claims 14 - 18 , wherein the fibrosis is present in liver, lungs or kidney. 
     
     
         20 . The method of any of  claims 14 - 19 , wherein the fibrosis is selected from the group comprising pulmonary fibrosis, pulmonary hypertension, idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis, diabetic nephropathy, ischemic renal injury, nephrosclerosis and nephrotoxicity. 
     
     
         21 . A method for treating cancer comprising administering an effective amount of an antibody or an antigen-binding fragment thereof according to any of  claims 1 - 12 ; or a pharmaceutical composition according to  claim 13  to a patient in need thereof. 
     
     
         22 . The method of  claim 21 , wherein the antibody or antigen-binding fragment thereof, or the pharmaceutical composition comprising the antibody or antigen-binding fragment thereof, is administered to the patient in combination with a second therapeutic agent. 
     
     
         23 . The method of  claim 22 , wherein the second therapeutic agent is selected from the group consisting of another antibody to GREM1, a VEGF antagonist, a cytotoxic agent, a chemotherapeutic agent, radiation, surgery, an anti-inflammatory drug, a corticosteroid, a nutritional supplement, and any other palliative therapy. 
     
     
         24 . The method of  claim 23 , wherein the VEGF antagonist is an anti-VEGF antibody or a VEGF-inhibiting fusion protein. 
     
     
         25 . The method of  claim 23 , wherein the VEGF antagonist is aflibercept. 
     
     
         26 . A method for inhibiting angiogenesis comprising administering an effective amount of an antibody or an antigen-binding fragment thereof according to any of  claims 1 - 12 ; or a pharmaceutical composition according to  claim 13  to a patient in need thereof. 
     
     
         27 . The method of  claim 26 , wherein the antibody is administered to a patient with cancer. 
     
     
         28 . The method of  claim 26 , wherein the antibody is administered in combination with a second therapeutic agent. 
     
     
         29 . The method of  claim 28 , wherein the second therapeutic agent is another antibody to GREM1 or a VEGF antagonist. 
     
     
         30 . An antibody or antigen-binding fragment thereof of any one of  claims 1 - 12  for use in promoting BMP signaling and cell differentiation. 
     
     
         31 . A composition comprising one or more antibodies or antigen-binding fragments thereof of any one of  claims 1 - 12  for use in inhibiting heparin-mediated angiogenesis. 
     
     
         32 . The composition of  claim 31 , wherein the one or more antibodies or antigen-binding fragments thereof comprise a HCVR selected from the group consisting of SEQ ID NOs: 66, 210, 418 and 434; and a LCVR selected from the group consisting of SEQ ID NOs: 74, 218, 426 and 442. 
     
     
         33 . An antibody or antigen-binding fragment thereof of any one of  claims 1 - 12  for use in treating a patient with fibrosis or cancer. 
     
     
         34 . Use of the isolated antibody or antigen-binding fragment thereof of any one of  claims 1 - 12  in the manufacture of a medicament for treating a patient with fibrosis or cancer. 
     
     
         35 . A method of blocking interaction of (a) a polypeptide comprising the amino acid sequence of SEQ ID NO: 594 or SEQ ID NO: 595 with (b) heparin, the method comprising exposing a mixture comprising (a) and (b) to the antibody of any one of  claims 1 - 12 , or to the composition of  claim 32 .