NZ740357B2

NZ740357B2 - Anti-LAG-3 Antibodies

Info

Publication number: NZ740357B2
Application number: NZ740357A
Authority: NZ
Inventors: Chrystelle Brignone; Frederic Triebel
Original assignee: Immutep Sas
Filing date: 2016-09-01
Publication date: 2025-09-02

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.

Claims

What I (or we) claim is: 128

1. An isolated agonistic anti-Lymphocyte activation gene-3 (LAG-3) antibody, or antigen-binding fragment thereof, that binds to LAG-3 and inhibits antigen-induced CD4+ and/or CD8+ T cell proliferation, and/or antigen-induced CD4+ and/or CD8+ T cell activation, wherein the isolated antibody, or antigen-binding fragment thereof, comprises: an antibody VH region with complementarity determining regions (CDRs) comprising amino acid sequences of SEQ ID NO:1, 2, and 3, and an antibody VL region with CDRs comprising amino acid sequences of SEQ ID NO:4, 5, and 6; an antibody VH region with CDRs comprising amino acid sequences of SEQ ID NO:21, 22, and 23, and an antibody VL region with CDRs comprising amino acid sequences of SEQ ID NO:24, 25, and 26; an antibody VH region with CDRs comprising amino acid sequences of SEQ ID NO:11, 12, and 13, and an antibody VL region with CDRs comprising amino acid sequences of SEQ ID NO:14, 15, and 16; or an antibody VH region with CDRs comprising amino acid sequences of SEQ ID NO:31, 32, and 33, and an antibody VL region with CDRs comprising amino acid sequences of SEQ ID NO:34, 35, and 36.

2. The isolated antibody, or antigen-binding fragment thereof, according to claim 1, wherein: (i) the isolated antibody, or antigen-binding fragment thereof, inhibits antigen induced CD4+ and antigen-induced CD8+ T cell proliferation; and/or (ii) the isolated antibody, or antigen-binding fragment thereof, inhibits antigen induced CD8+ T cell proliferation more than antigen-induced CD4+ T cell proliferation; and/or (iii) the inhibition of antigen-induced CD8+ T cell proliferation is LAG-3 dependent, and IL-2 independent.

3. which: An isolated antibody, or antigen-binding fragment thereof, according to claim 1 or 2, binds to LAG-3 with higher affinity than monoclonal antibody 17B4; and/or 129 inhibits binding of LAG-3 or IMP321 to MHC class II-positive cells; and/or inhibits LAGinduced antigen-presenting cell (APC) activation, or IMP321-induced monocyte activation; and/or binds to an epitope of LAG-3 that overlaps with the MHC class II binding site of LAG-3.

4. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which comprises: an antibody VH region comprising amino acid sequence SEQ ID NO:7 or amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:7, and/or an antibody VL region comprising amino acid sequence SEQ ID NO:8 or amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:8; optionally which comprises: an antibody VH region comprising amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:7, and an antibody VL region comprising amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:8; an antibody VH region comprising amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:7, and an antibody VL region comprising amino acid sequence SEQ ID NO:8; an antibody VH region comprising amino acid sequence SEQ ID NO:7, and an antibody VL region comprising amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:8; or an antibody VH region comprising amino acid sequence SEQ ID NO:7, and an antibody VL region comprising amino acid sequence SEQ ID NO:8.

5. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which comprises: an antibody VH region comprising amino acid sequence SEQ ID NO:17 or amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:17, and/or an antibody VL region comprising amino acid sequence SEQ ID NO:18 or amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:18; optionally which comprises: 130 an antibody VH region comprising amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:17, and an antibody VL region comprising amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:18; an antibody VH region comprising amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:17, and an antibody VL region comprising amino acid sequence SEQ ID NO:18; an antibody VH region comprising amino acid sequence SEQ ID NO:17, and an antibody VL region comprising amino acid sequence that is at least 60% identical to amino acid sequence SEQ ID NO:18; or an antibody VH region comprising amino acid sequence SEQ ID NO:17, and an antibody VL region comprising amino acid sequence SEQ ID NO:18.

6. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which comprises a monoclonal antibody, or antigen-binding fragment thereof, or a humanized monoclonal antibody, or antigen-binding fragment thereof.

7. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which comprises a humanized light chain framework region; optionally wherein: (i) the humanized light chain framework region comprises an amino acid sequence with any of the amino acid substitutions depicted for VL1, VL2, VL3, or VL4 in Table 27; and/or (ii) the humanized light chain framework region comprises an amino acid sequence of any of SEQ ID NOs: 68 to 83; optionally wherein the isolated antibody, or antigen binding fragment thereof 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 131 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/or (iii) the isolated 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 selected from SEQ ID NO: 4 and 24; a VL FR2 having an amino acid sequence of SEQ ID NO: 69; a VL CDR2 having an amino acid sequence selected from SEQ ID NO: 5 and 25; a VL FR3 having an amino acid sequence of SEQ ID NO: 70; a VL CDR3 having an amino acid sequence selected from SEQ ID NO: 6 and 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: 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 selected from SEQ ID NO: 4 and 24; a VL FR2 having an amino acid sequence of SEQ ID NO: 73; a VL CDR2 having an amino acid sequence selected from SEQ ID NO: 5 and 25; a VL FR3 having an amino acid sequence of SEQ ID NO: 74; a VL CDR3 having an amino acid sequence selected from SEQ ID NO: 6 and 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: 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 132 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 selected from SEQ ID NO: 4 and 24; a VL FR2 having an amino acid sequence of SEQ ID NO: 77; a VL CDR2 having an amino acid sequence selected from SEQ ID NO: 5 and 25; a VL FR3 having an amino acid sequence of SEQ ID NO: 78; a VL CDR3 having an amino acid sequence selected from SEQ ID NO: 6 and 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: 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 selected from SEQ ID NO: 4 and 24; a VL FR2 having an amino acid sequence of SEQ ID NO: 81; a VL CDR2 having an amino acid sequence selected from SEQ ID NO: 5 and 25; a VL FR3 having an amino acid sequence of SEQ ID NO: 82; a VL CDR3 having an amino acid sequence selected from SEQ ID NO: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 83; 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 133 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; and/or (iv) the isolated 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 selected from SEQ ID NO: 14 and 34; a VL FR2 having an amino acid sequence of SEQ ID NO: 69; a VL CDR2 having an amino acid sequence selected from SEQ ID NO: 15 and 35; a VL FR3 having an amino acid sequence of SEQ ID NO: 70; a VL CDR3 having an amino acid sequence selected from SEQ ID NO: 16 and 36; 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: 14; 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: 15; 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: 16; 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: 34; 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: 35; 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: 36; 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 selected from SEQ ID NO: 14 and 34; a VL FR2 having an amino acid sequence of SEQ ID NO: 73; a VL CDR2 having an amino acid sequence selected from SEQ ID NO: 15 and 35; a VL FR3 having an amino acid sequence of SEQ ID NO: 74; a VL CDR3 having an amino acid sequence selected from SEQ ID NO: 16 and 36; 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: 14; 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: 15; 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: 16; 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: 34; a VL FR2 having an amino acid sequence of SEQ ID 134 NO: 73; a VL CDR2 having an amino acid sequence of SEQ ID NO: 35; 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: 36; 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 selected from SEQ ID NO: 14 and 34; a VL FR2 having an amino acid sequence of SEQ ID NO: 77; a VL CDR2 having an amino acid sequence selected from SEQ ID NO: 15 and 35; a VL FR3 having an amino acid sequence of SEQ ID NO: 78; a VL CDR3 having an amino acid sequence selected from SEQ ID NO: 16 and 36; 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: 14; 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: 15; 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: 16; 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: 34; 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: 35; 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: 36; 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 selected from SEQ ID NO: 14 and 34; a VL FR2 having an amino acid sequence of SEQ ID NO: 81; a VL CDR2 having an amino acid sequence selected from SEQ ID NO: 15 and 35; a VL FR3 having an amino acid sequence of SEQ ID NO: 82; a VL CDR3 having an amino acid sequence selected from SEQ ID NO: 16 and 36; and a VL FR4 having an amino acid sequence of SEQ ID NO: 83; 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: 14; 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: 15; 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: 16; 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: 34; 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: 35; a VL FR3 having 135 an amino acid sequence of SEQ ID NO: 82; a VL CDR3 having an amino acid sequence of SEQ ID NO: 36; and a VL FR4 having an amino acid sequence of SEQ ID NO: 83.

8. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which comprises a humanized heavy chain framework region; optionally wherein: (i) the humanized heavy chain framework region comprises an amino acid sequence with any of the amino acid substitutions depicted for VH1, VH2, VH3, or VH4 in Table 26; and/or (ii) the humanized heavy chain framework region comprises an amino acid sequence of any of SEQ ID NOs: 52 to 67; optionally wherein the isolated antibody, or antigen-binding fragment thereof, comprises: a VH framework region 1 (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; and/or (iii) the isolated 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 selected from SEQ ID NO: 1 and 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 53; a VH CDR2 having an amino acid sequence selected from SEQ ID NO: 2 and 22; a VH FR3 having an amino acid sequence of SEQ ID NO: 54; a VH CDR3 having an amino acid sequence selected from SEQ ID NO: 3 and 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: 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: 136 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 selected from SEQ ID NO: 1 and 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 57; a VH CDR2 having an amino acid sequence selected from SEQ ID NO: 2 and 22; a VH FR3 having an amino acid sequence of SEQ ID NO: 58; a VH CDR3 having an amino acid sequence selected from SEQ ID NO: 3 and 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: 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 selected from SEQ ID NO: 1 and 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 61; a VH CDR2 having an amino acid sequence selected from SEQ ID NO: 2 and 22; a VH FR3 having an amino acid sequence of SEQ ID NO: 62; a VH CDR3 having an amino acid sequence selected from SEQ ID NO: 3 and 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: 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 137 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 selected from SEQ ID NO: 1 and 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 65; a VH CDR2 having an amino acid sequence selected from SEQ ID NO: 2 and 22; a VH FR3 having an amino acid sequence of SEQ ID NO: 66; a VH CDR3 having an amino acid sequence selected from SEQ ID NO: 3 and 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 67; 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; and/or (iv) the isolated 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 selected from SEQ ID NO: 11 and 31; a VH FR2 having an amino acid sequence of SEQ ID NO: 53; a VH CDR2 having an amino acid sequence selected from SEQ ID NO: 12 and 32; a VH FR3 having an amino acid sequence of SEQ ID NO: 54; a VH CDR3 having an amino acid sequence selected from SEQ ID NO: 13 and 33; 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: 11; a VH FR2 having an amino acid sequence of SEQ ID 138 NO: 53; a VH CDR2 having an amino acid sequence of SEQ ID NO: 12; 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: 13; 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: 31; 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: 32; 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: 33; 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 selected from SEQ ID NO: 11 and 31; a VH FR2 having an amino acid sequence of SEQ ID NO: 57; a VH CDR2 having an amino acid sequence selected from SEQ ID NO: 12 and 32; a VH FR3 having an amino acid sequence of SEQ ID NO: 58; a VH CDR3 having an amino acid sequence selected from SEQ ID NO: 13 and 33; 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: 11; 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: 12; 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: 13; 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: 31; 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: 32; 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: 33; 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 selected from SEQ ID NO: 11 and 31; a VH FR2 having an amino acid sequence of SEQ ID NO: 61; a VH CDR2 having an amino acid sequence selected from SEQ ID NO: 12 and 32; a VH FR3 having an amino acid sequence of SEQ ID NO: 62; a VH CDR3 having an amino acid sequence selected from SEQ ID NO: 13 and 33; 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: 11; 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: 12; a VH FR3 having 139 an amino acid sequence of SEQ ID NO: 62; a VH CDR3 having an amino acid sequence of SEQ ID NO: 13; 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: 31; 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: 32; 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: 33; 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 selected from SEQ ID NO: 11 and 31; a VH FR2 having an amino acid sequence of SEQ ID NO: 65; a VH CDR2 having an amino acid sequence selected from SEQ ID NO: 12 and 32; a VH FR3 having an amino acid sequence of SEQ ID NO: 66; a VH CDR3 having an amino acid sequence selected from SEQ ID NO: 13 and 33; and a VH FR4 having an amino acid sequence of SEQ ID NO: 67; 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: 11; 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: 12; 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: 13; 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: 31; 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: 32; 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: 33; and a VH FR4 having an amino acid sequence of SEQ ID NO: 67.

9. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which 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 selected from SEQ ID NO: 1 and 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 65; a VH CDR2 having an amino acid sequence selected from SEQ ID NO: 2 and 22; a VH FR3 having an amino acid sequence of SEQ ID NO: 66; a VH CDR3 having an amino acid sequence selected from SEQ ID NO: 3 and 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 selected from SEQ ID NO: 4 and 140 24; a VL FR2 having an amino acid sequence of SEQ ID NO: 77; a VL CDR2 having an amino acid sequence selected from SEQ ID NO: 5 and 25; a VL FR3 having an amino acid sequence of SEQ ID NO: 78; a VL CDR3 having an amino acid sequence selected from SEQ ID NO: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 79; or 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; or 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.

10. An isolated antibody, or antigen-binding fragment thereof, according to any one of the preceding claims, which: is a chimeric antibody molecule, or antigen-binding fragment thereof; optionally which comprises variable region amino acid sequence of an antibody according to any one of the preceding claims, and human constant region amino acid sequence; and/or which lacks complement-dependent cytotoxicity (CDC) and antibody-dependent cell mediated cytotoxicity (ADCC); and/or 141 which binds to a human LAG-3 protein (or a human LAG-3Ig protein) with a dissociation constant (KD) of no more than 100 pM, no more than 90 pM, no more than 80 pM, no more than 70 pM, no more than 60 pM, no more than 50 pM, no more than 40 pM, no more than 30 pM, or no more than 25 pM, for example as determined by Biacore analysis; and/or which is an agonistic anti-LAG-3 antibody, or an antigen-binding fragment thereof; and/or which does not bind to the 30 amino acid extra-loop sequence (SEQ ID NO: 40) of the first N-terminal D1 domain of human LAG-3 protein.

11. An isolated antibody, or antigen-binding fragment thereof, according to any one of claims 1-4, 6, 7(i), 7(ii), 7(iii), 8(i), 8(ii), or 10, which comprises: 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 selected from SEQ ID NO: 4 and 24; a VL FR2 having an amino acid sequence of SEQ ID NO: 77; a VL CDR2 having an amino acid sequence selected from SEQ ID NO: 5 and 25; a VL FR3 having an amino acid sequence of SEQ ID NO: 78; a VL CDR3 having an amino acid sequence selected from SEQ ID NO: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 79; and 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 selected from SEQ ID NO: 1 and 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 53; a VH CDR2 having an amino acid sequence selected from SEQ ID NO: 2 and 22; a VH FR3 having an amino acid sequence of SEQ ID NO: 54; a VH CDR3 having an amino acid sequence selected from SEQ ID NO: 3 and 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 55; or a modified version of the antibody, or antigen-binding fragment thereof, which comprises one or more amino acid substitutions that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site.

12. An isolated antibody, or antigen-binding fragment thereof, according to any one of claims 1-4, 6, 7(i), 7(ii), 7(iii), 8(i), 8(ii), or 10, which comprises: an antibody VL region comprising: 142 a VL FR1 having an amino acid sequence of SEQ ID NO: 76; a VL CDR1 having an amino acid sequence selected from SEQ ID NO: 4 and 24; a VL FR2 having an amino acid sequence of SEQ ID NO: 77; a VL CDR2 having an amino acid sequence selected from SEQ ID NO: 5 and 25; a VL FR3 having an amino acid sequence of SEQ ID NO: 78; a VL CDR3 having an amino acid sequence selected from SEQ ID NO: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 79; and an antibody VH region comprising: a VH CDR1, a VH CDR2, and a VH CDR3, wherein the VH CDR1 has an amino acid sequence selected from SEQ ID NO:1 and 21, the VH CDR2 has an amino acid sequence selected from SEQ ID NO:2 and 22, and the VH CDR3 has an amino acid sequence selected from SEQ ID NO:3 and 23; and a humanized heavy chain framework region comprising an amino acid sequence of any of SEQ ID Nos: 52 to 67.

13. A nucleic acid comprising a nucleotide sequence encoding an antibody, or antigen binding fragment thereof, according to any one of the preceding claims; or a nucleotide sequence of any of SEQ ID NOs:9, 10, 19, or 20, or a nucleotide sequence that is at least 80% identical to the nucleotide sequence of any of SEQ ID NOs: 9, 10, 19, or 20.

14.

15. A recombinant vector comprising a nucleic acid of claim 13. An isolated recombinant cell comprising the nucleic acid of claim 13, or the recombinant vector of claim 14.

16. A pharmaceutical composition comprising an isolated antibody, or antigen-binding fragment thereof, according to any one of claims 1 to 12, and a pharmaceutically acceptable carrier, excipient, or diluent.

17. Use of an isolated antibody, or antigen-binding fragment thereof, according to any one of claims 1 to 12, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for the treatment of a T cell-mediated immune disorder.

18. Use according to claim 17, wherein the T-cell-mediated immune disorder is an inflammatory disease, or an autoimmune disorder.

19. Use according to claim 17, 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 143 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.