Anti-lag-3 antibodies

Abstract

Antibodies, or antigen-binding fragments thereof, that bind to Lymphocyte-activation gene-3 (LAG-3) are described, in particular antibodies, or antigen-binding fragments thereof, that are agonists of LAG-3. The antibodies bind to LAG-3 and inhibit antigen-induced CD4 + and/or CD8 + T cell proliferation, or antigen-induced CD4 + and/or CD8 + T cell activation. The antibodies may be used as medicaments, in particular for the treatment of conditions associated with proliferation and/or activation of CD4 + and/or CD8 + T cells, such as inflammatory and autoimmune disorders

1 .- 123 . (canceled) 
     
     
         124 . A method of treating a T cell-mediated immune disorder, which comprises administering to a subject in need of such treatment an effective amount of a humanized antibody, or antigen-binding fragment thereof, that binds to lymphocyte activation gene-3 (LAG-3), wherein the humanized antibody, or antigen-binding fragment thereof, comprises:
 a) an antibody VH region comprising a VH CDR1, a VH CDR2, and a VH CDR3, wherein the VH CDR1 has an amino acid sequence of SEQ ID NO:1, the VH CDR2 has an amino acid sequence of SEQ ID NO:2, and the VH CDR3 has an amino acid sequence of SEQ ID NO:3; and an antibody VL region comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein the VL CDR1 has an amino acid sequence of SEQ ID NO:4, the VL CDR2 has an amino acid sequence of SEQ ID NO:5, and the VL CDR3 has an amino acid sequence of SEQ ID NO:6; or   b) an antibody VH region comprising a VH CDR1, a VH CDR2, and a VH CDR3, wherein the VH CDR1 has an amino acid sequence of SEQ ID NO:21, the VH CDR2 has an amino acid sequence of SEQ ID NO:22, and the VH CDR3 has an amino acid sequence of SEQ ID NO:23; and an antibody VL region comprising a VL CDR1, a VL CDR2, and a VL CDR3, wherein the VL CDR1 has an amino acid sequence of SEQ ID NO:24, the VL CDR2 has an amino acid sequence of SEQ ID NO:25, and the VL CDR3 has an amino acid sequence of SEQ ID NO:26; wherein:   the antibody or antigen binding fragment thereof comprises a humanized light chain framework region which comprises:   a VL framework region 1 (VL FR1) of SEQ ID NO: 68; a VL FR2 of SEQ ID NO: 69; a VL FR3 of SEQ ID NO: 70; and a VL FR4 of SEQ ID NO: 71;   a VL framework region 1 (VL FR1) of SEQ ID NO: 72; a VL FR2 of SEQ ID NO: 73; a VL FR3 of SEQ ID NO: 74; and a VL FR4 of SEQ ID NO: 75;   a VL framework region 1 (VL FR1) of SEQ ID NO: 76; a VL FR2 of SEQ ID NO: 77; a VL FR3 of SEQ ID NO: 78; and a VL FR4 of SEQ ID NO: 79; or   a VL framework region 1 (VL FR1) of SEQ ID NO: 80; a VL FR2 of SEQ ID NO: 81; a VL FR3 of SEQ ID NO: 82; and a VL FR4 of SEQ ID NO: 83; and   wherein the antibody or antigen binding fragment thereof comprises a humanized heavy chain framework region which comprises:   a VH framework region I (VH FR1) of SEQ ID NO: 52; a VH FR2 of SEQ ID NO: 53; a VH FR3 of SEQ ID NO: 54; and a VH FR4 of SEQ ID NO: 55;   a VH framework region 1 (VH FR1) of SEQ ID NO: 56; a VH FR2 of SEQ ID NO: 57; a VH FR3 of SEQ ID NO: 58; and a VH FR4 of SEQ ID NO: 59;   a VH framework region 1 (VH FR1) of SEQ ID NO: 60; a VH FR2 of SEQ ID NO: 61; a VH FR3 of SEQ ID NO: 62; and a VH FR4 of SEQ ID NO: 63; or   a VH framework region 1 (VH FR1) of SEQ ID NO: 64; a VH FR2 of SEQ ID NO: 65; a VH FR3 of SEQ ID NO: 66; and a VH FR4 of SEQ ID NO: 67.   
     
     
         125 . A method according to  claim 124 , wherein the antibody, or antigen-binding fragment thereof, is a humanized monoclonal antibody, or antigen-binding fragment thereof. 
     
     
         126 . A method according to  claim 124 , wherein the antibody, or antigen-binding fragment thereof, comprises an antibody VL region comprising:
 a VL FR1 having an amino acid sequence of SEQ ID NO: 68; a VL CDR1 having an amino acid sequence of SEQ ID NO: 4; a VL FR2 having an amino acid sequence of SEQ ID NO: 69; a VL CDR2 having an amino acid sequence of SEQ ID NO: 5; a VL FR3 having an amino acid sequence of SEQ ID NO: 70; a VL CDR3 having an amino acid sequence of SEQ ID NO: 6; and a VL FR4 having an amino acid sequence of SEQ ID NO: 71;   a VL FR1 having an amino acid sequence of SEQ ID NO: 68; a VL CDR1 having an amino acid sequence of SEQ ID NO: 24; a VL FR2 having an amino acid sequence of SEQ ID NO: 69; a VL CDR2 having an amino acid sequence of SEQ ID NO: 25; a VL FR3 having an amino acid sequence of SEQ ID NO: 70; a VL CDR3 having an amino acid sequence of SEQ ID NO: 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 71;   a VL FR1 having an amino acid sequence of SEQ ID NO: 72; a VL CDR1 having an amino acid sequence of SEQ ID NO: 4; a VL FR2 having an amino acid sequence of SEQ ID NO: 73; a VL CDR2 having an amino acid sequence of SEQ ID NO: 5; a VL FR3 having an amino acid sequence of SEQ ID NO: 74; a VL CDR3 having an amino acid sequence of SEQ ID NO: 6; and a VL FR4 having an amino acid sequence of SEQ ID NO: 75;   a VL FR1 having an amino acid sequence of SEQ ID NO: 72; a VL CDR1 having an amino acid sequence of SEQ ID NO: 24; a VL FR2 having an amino acid sequence of SEQ ID NO: 73; a VL CDR2 having an amino acid sequence of SEQ ID NO: 25; a VL FR3 having an amino acid sequence of SEQ ID NO: 74; a VL CDR3 having an amino acid sequence of SEQ ID NO: 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 75;   a VL FR1 having an amino acid sequence of SEQ ID NO: 76; a VL CDR1 having an amino acid sequence of SEQ ID NO: 4; a VL FR2 having an amino acid sequence of SEQ ID NO: 77; a VL CDR2 having an amino acid sequence of SEQ ID NO: 5; a VL FR3 having an amino acid sequence of SEQ ID NO: 78; a VL CDR3 having an amino acid sequence of SEQ ID NO: 6; and a VL FR4 having an amino acid sequence of SEQ ID NO: 79;   a VL FR1 having an amino acid sequence of SEQ ID NO: 76; a VL CDR1 having an amino acid sequence of SEQ ID NO: 24; a VL FR2 having an amino acid sequence of SEQ ID NO: 77; a VL CDR2 having an amino acid sequence of SEQ ID NO: 25; a VL FR3 having an amino acid sequence of SEQ ID NO: 78; a VL CDR3 having an amino acid sequence of SEQ ID NO: 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 79;   a VL FR1 having an amino acid sequence of SEQ ID NO: 80; a VL CDR1 having an amino acid sequence of SEQ ID NO: 4; a VL FR2 having an amino acid sequence of SEQ ID NO: 81; a VL CDR2 having an amino acid sequence of SEQ ID NO: 5; a VL FR3 having an amino acid sequence of SEQ ID NO: 82; a VL CDR3 having an amino acid sequence of SEQ ID NO: 6; and a VL FR4 having an amino acid sequence of SEQ ID NO: 83; or   a VL FR1 having an amino acid sequence of SEQ ID NO: 80; a VL CDR1 having an amino acid sequence of SEQ ID NO: 24; a VL FR2 having an amino acid sequence of SEQ ID NO: 81; a VL CDR2 having an amino acid sequence of SEQ ID NO: 25; a VL FR3 having an amino acid sequence of SEQ ID NO: 82; a VL CDR3 having an amino acid sequence of SEQ ID NO: 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 83.   
     
     
         127 . A method according to  claim 124 , wherein the antibody, or antigen-binding fragment thereof, comprises an antibody VH region comprising:
 a VH FR1 having an amino acid sequence of SEQ ID NO: 52; a VH CDR1 having an amino acid sequence of SEQ ID NO: 1; a VH FR2 having an amino acid sequence of SEQ ID NO: 53; a VH CDR2 having an amino acid sequence of SEQ ID NO: 2; a VH FR3 having an amino acid sequence of SEQ ID NO: 54; a VH CDR3 having an amino acid sequence of SEQ ID NO: 3; and a VH FR4 having an amino acid sequence of SEQ ID NO: 55;   a VH FR1 having an amino acid sequence of SEQ ID NO: 52; a VH CDR1 having an amino acid sequence of SEQ ID NO: 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 53; a VH CDR2 having an amino acid sequence of SEQ ID NO: 22; a VH FR3 having an amino acid sequence of SEQ ID NO: 54; a VH CDR3 having an amino acid sequence of SEQ ID NO: 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 55;   a VH FR1 having an amino acid sequence of SEQ ID NO: 56; a VH CDR1 having an amino acid sequence of SEQ ID NO: 1; a VH FR2 having an amino acid sequence of SEQ ID NO: 57; a VH CDR2 having an amino acid sequence of SEQ ID NO: 2; a VH FR3 having an amino acid sequence of SEQ ID NO: 58; a VH CDR3 having an amino acid sequence of SEQ ID NO: 3; and a VH FR4 having an amino acid sequence of SEQ ID NO: 59;   a VH FR1 having an amino acid sequence of SEQ ID NO: 56; a VH CDR1 having an amino acid sequence of SEQ ID NO: 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 57; a VH CDR2 having an amino acid sequence of SEQ ID NO: 22; a VH FR3 having an amino acid sequence of SEQ ID NO: 58; a VH CDR3 having an amino acid sequence of SEQ ID NO: 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 59;   a VH FR1 having an amino acid sequence of SEQ ID NO: 60; a VH CDR1 having an amino acid sequence of SEQ ID NO: 1; a VH FR2 having an amino acid sequence of SEQ ID NO: 61; a VH CDR2 having an amino acid sequence of SEQ ID NO: 2; a VH FR3 having an amino acid sequence of SEQ ID NO: 62; a VH CDR3 having an amino acid sequence of SEQ ID NO: 3; and a VH FR4 having an amino acid sequence of SEQ ID NO: 63;   a VH FR1 having an amino acid sequence of SEQ ID NO: 60; a VH CDR1 having an amino acid sequence of SEQ ID NO: 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 61; a VH CDR2 having an amino acid sequence of SEQ ID NO: 22; a VH FR3 having an amino acid sequence of SEQ ID NO: 62; a VH CDR3 having an amino acid sequence of SEQ ID NO: 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 63;   a VH FR1 having an amino acid sequence of SEQ ID NO: 64; a VH CDR1 having an amino acid sequence of SEQ ID NO: 1; a VH FR2 having an amino acid sequence of SEQ ID NO: 65; a VH CDR2 having an amino acid sequence of SEQ ID NO: 2; a VH FR3 having an amino acid sequence of SEQ ID NO: 66; a VH CDR3 having an amino acid sequence of SEQ ID NO: 3; and a VH FR4 having an amino acid sequence of SEQ ID NO: 67; or   a VH FR1 having an amino acid sequence of SEQ ID NO: 64; a VH CDR1 having an amino acid sequence of SEQ ID NO: 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 65; a VH CDR2 having an amino acid sequence of SEQ ID NO: 22; a VH FR3 having an amino acid sequence of SEQ ID NO: 66; a VH CDR3 having an amino acid sequence of SEQ ID NO: 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 67.   
     
     
         128 . A method of treating a T cell-mediated immune disorder, which comprises administering to a subject in need of such treatment an effective amount of a humanized antibody, or antigen-binding fragment thereof, that binds to lymphocyte activation gene-3 (LAG-3), wherein the humanized antibody, or antigen-binding fragment thereof, comprises:
 an antibody VH region comprising: a VH FR1 having an amino acid sequence of SEQ ID NO: 64; a VH CDR1 having an amino acid sequence of SEQ ID NO: 1; a VH FR2 having an amino acid sequence of SEQ ID NO: 65; a VH CDR2 having an amino acid sequence of SEQ ID NO: 2; a VH FR3 having an amino acid sequence of SEQ ID NO: 66; a VH CDR3 having an amino acid sequence of SEQ ID NO: 3; and a VH FR4 having an amino acid sequence of SEQ ID NO: 67; and   an antibody VL region comprising: a VL FR1 having an amino acid sequence of SEQ ID NO: 76; a VL CDR1 having an amino acid sequence of SEQ ID NO: 4; a VL FR2 having an amino acid sequence of SEQ ID NO: 77; a VL CDR2 having an amino acid sequence of SEQ ID NO: 5; a VL FR3 having an amino acid sequence of SEQ ID NO: 78; a VL CDR3 having an amino acid sequence of SEQ ID NO: 6; and a VL FR4 having an amino acid sequence of SEQ ID NO: 79.   
     
     
         129 . A method of treating a T cell-mediated immune disorder, which comprises administering to a subject in need of such treatment an effective amount of a humanized antibody, or antigen-binding fragment thereof, that binds to lymphocyte activation gene-3 (LAG-3), wherein the humanized antibody, or antigen-binding fragment thereof, comprises:
 an antibody VH region comprising: a VH FR1 having an amino acid sequence of SEQ ID NO: 64; a VH CDR1 having an amino acid sequence of SEQ ID NO: 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 65; a VH CDR2 having an amino acid sequence of SEQ ID NO: 22; a VH FR3 having an amino acid sequence of SEQ ID NO: 66; a VH CDR3 having an amino acid sequence of SEQ ID NO: 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 67; and   an antibody VL region comprising: a VL FR1 having an amino acid sequence of SEQ ID NO: 76; a VL CDR1 having an amino acid sequence of SEQ ID NO: 24; a VL FR2 having an amino acid sequence of SEQ ID NO: 77; a VL CDR2 having an amino acid sequence of SEQ ID NO: 25; a VL FR3 having an amino acid sequence of SEQ ID NO: 78; a VL CDR3 having an amino acid sequence of SEQ ID NO: 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 79.   
     
     
         130 . A method according to  claim 124 , wherein the antibody, or antigen-binding fragment thereof, lacks complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) activity. 
     
     
         131 . A method according to  claim 124 , wherein the T-cell-mediated immune disorder is an inflammatory disease, or an autoimmune disorder. 
     
     
         132 . A method according to  claim 124 , wherein the T-cell-mediated immune disorder is selected from the group consisting of infections (viral, bacterial, fungal and parasitic), endotoxic shock associated with infection, sepsis, arthritis, rheumatoid arthritis, asthma, COPD, pelvic inflammatory disease, Alzheimer's Disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Peyronie's Disease, coeliac disease, gallbladder disease, Pilonidal disease, peritonitis, psoriasis, vasculitis, surgical adhesions, stroke, Type I Diabetes, lyme disease, arthritis, meningoencephalitis, autoimmune uveitis, immune mediated inflammatory disorders of the central and peripheral nervous system such as multiple sclerosis, lupus (such as systemic lupus erythematosus) and Guillain-Barré syndrome, Atopic dermatitis, autoimmune hepatitis, fibrosing alveolitis, Grave's disease, IgA nephropathy, idiopathic thrombocytopenic purpura, Meniere's disease, pemphigus, primary biliary cirrhosis, sarcoidosis, scleroderma, Wegener's granulomatosis, other autoimmune disorders, pancreatitis, trauma (surgery), graft-versus-host disease, transplant rejection, heart disease including ischaemic diseases such as myocardial infarction as well as atherosclerosis, intravascular coagulation, bone resorption, osteoporosis, osteoarthritis, periodontitis and hypochlorhydia, or infertility related to lack of fetal-maternal tolerance.