Anti-GITR antibodies and methods of use thereof
The present disclosure provides antibodies that specifically bind to human glucocorticoid-induced TNFR family related receptor (GITR) and compositions comprising such antibodies. In a specific aspect, the antibodies specifically bind to human GITR and modulate GITR activity, e.g., enhance, activate or induce GITR activity, utilizing such antibodies. The present disclosure also provides methods for treating disorders, such as cancer and infectious diseases, by administering an antibody that specifically binds to human GITR and modulates GITR activity e.g., enhances, activates or induces GITR activity.
1. An isolated antibody that specifically binds to human glucocorticoid-induced TNFR-related protein (GITR), comprising:
(a) a heavy chain variable region (VH) CDR1 comprising the amino acid sequence of X 1 YX 2 MX 3 (SEQ ID NO: 7), wherein
X 1 is D, E or G;
X 2 is A or V; and
X 3 is Y or H;
(b) a VH CDR 2 comprising the amino acid sequence of X 1 IX 2 TX 3 SGX 4 X 5 X 6 YNQKFX 7 X 8 (SEQ ID NO: 8), wherein
X 1 is V or L;
X 2 is R, K or Q;
X 3 is Y or F;
X 4 is D, E or G;
X 5 is V or L;
X 6 is T or S;
X 7 is K, R or Q; and
X 8 is D, E or G;
(c) a VH CDR3 comprising the amino acid sequence of SEQ ID NO: 9;
(d) a light chain variable region (VL) CDR1 comprising the amino acid sequence of KSSQSLLNSX 1 NQKNYLX 2 (SEQ ID NO: 10), wherein
X 1 is G or S; and
X 2 is T or S;
(e) a VL CDR2 comprising the amino acid sequence of SEQ ID NO: 11; and
(f) a VL CDR3 comprising the amino acid sequence of QNX 1 YSX 2 PYT (SEQ ID NO: 12), wherein
X 1 is D or E; and
X 2 is Y, F or S.
2. The antibody of claim 1 , wherein the antibody comprises:
(a) a VH having human derived framework regions;
(b) a VH framework region that is or is derived from an amino acid sequence encoded by a human gene, wherein said amino acid sequence is selected from the group consisting of IGHV1-2*02 (SEQ ID NO: 601), IGHV1-3*01 (SEQ ID NO: 602), IGHV1-46*01 (SEQ ID NO: 603), IGHV1-18*01 (SEQ ID NO: 604), IGHV1-69*01 (SEQ ID NO: 605), and IGHV7-4-1*02 (SEQ ID NO: 606); and/or
(c) a VH framework region that is derived from amino acid sequence SEQ ID NO: 601 and wherein at least one amino acid in amino acid sequence SEQ ID NO: 601 is substituted with an amino acid in an analogous position in a corresponding non-human heavy chain variable framework region, optionally wherein the amino acid substitution is at an amino acid position selected from the group consisting of 24, 48, 67, 71, 73, and 94, according to Kabat numbering.
3. The antibody of claim 1 , wherein the antibody comprises:
(a) a VL having human derived framework regions;
(b) a VL framework region that is or is derived from an amino acid sequence encoded by a human gene, wherein said amino acid sequence is selected from the group consisting of IGKV4-1*01 (SEQ ID NO: 607) and IGKV3-7*02 (SEQ ID NO: 608); and/or
(c) a VL framework region that is derived from an amino acid sequence selected from the group consisting of IGKV4-1*01 (SEQ ID NO: 607) and IGKV3-7*02 (SEQ ID NO: 608) and at least one amino acid in amino acid sequence SEQ ID NO: 607 or SEQ ID NO: 608 is substituted with an amino acid in an analogous position in a corresponding non-human light chain variable framework region, optionally wherein the amino acid substitution is at amino acid position 87, according to Kabat numbering.
4. The antibody of claim 1 , further comprising a heavy and/or a light chain constant region, wherein:
(a) the heavy chain constant region is a human IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , or IgA 2 constant region; and/or
(b) the light chain constant region is a human kappa light chain constant region or a human lambda light chain constant region.
5. The antibody of claim 4 , wherein:
(a) the IgG 1 constant region is non-fucosylated;
(b) the amino acid sequence of the IgG 1 constant region comprises an N297A or an N297Q mutation;
(c) the amino acid sequence of the IgG4 constant region comprises an S228P mutation; or
(d) the amino acid sequence of the IgG2 constant region comprises a C127S mutation.
6. The antibody of claim 4 , wherein:
(a) the heavy chain constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 557-562, 583 and 584; and/or
(b) the light chain constant region comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 563-566, and 588-591.
7. The antibody of claim 1 , wherein the antibody comprises:
(a) a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 553, 554, 568-570, 581 and 582; and/or
(b) a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 555, 556, and 571-575.
8. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier or excipient.