Antibodies and methods of use thereof

Abstract

The present disclosure provides multispecific (e.g., bispecific) antibodies that specifically bind to human GITR and/or human OX40 as well as compositions comprising such antibodies. In a specific aspect, the multispecific antibodies specifically bind to human GITR and OX40 and modulate GITR and/or OX40 activity, e.g., enhance, activate, or induce GITR and/or OX40 activity, or reduce, deactivate, or inhibit GITR and/or OX40 activity. The present disclosure also provides methods for treating disorders, such as cancer, by administering a multispecific antibody that specifically binds to human GITR and/or OX40 and modulates GITR and/or OX40 activity, e.g., enhances, activates, or induces GITR and/or OX40 activity. Also provided are methods for treating autoimmune or inflammatory diseases or disorders, by administering a multispecific antibody that specifically binds to human GITR and/or OX40 and modulates GITR and/or OX40 activity, e.g., reduces, deactivates, or inhibits GITR and/or OX40 activity.

1 - 29 . (canceled) 
     
     
         30 . A multispecific antibody comprising:
 (a) a first antigen-binding region that specifically binds to human OX40 comprising
 (i) a VH-CDR1 comprising the amino acid sequence of SEQ ID NO: 47; 
 (ii) a VH-CDR2 comprising the amino acid sequence of SEQ ID NO: 48; 
 (iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 49; 
 (iv) a VL-CDR1 comprising the amino acid sequence of SEQ ID NO: 50; 
 (v) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 51; and 
 (vi) a VL-CDR3 comprising the amino acid sequence of SEQ ID NO: 52 or 53; and 
   (b) a second antigen-binding region that specifically binds to human GITR comprising
 (i) a VH-CDR1 comprising the amino acid sequence of X 1 YX 2 MX 3  (SEQ ID NO: 87), wherein X 1  is D, E or G; X 2  is A or V; and X 3  is Y or H; 
 (ii) a VH-CDR2 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: 88), 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; 
 (iii) a VH-CDR3 comprising the amino acid sequence of SEQ ID NO: 3; 
 (iv) a VL-CDR1 comprising the amino acid sequence of KSSQSLLNSX 1 NQKNYLX 2 (SEQ ID NO: 90), wherein X 1  is G or S; and X 2  is T or S; 
 (v) a VL-CDR2 comprising the amino acid sequence of SEQ ID NO: 5; and 
 (vi) a VL-CDR3 comprising the amino acid sequence of QNX 1 YSX 2 PYT (SEQ ID NO: 92), wherein X 1  is D or E; and X 2  is Y, F or S, 
   wherein the VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 of the second antigen-binding region do not comprise the amino acid sequences of SEQ ID NOs: 7, 10, 3, 14, 5, and 16, respectively.   
     
     
         31 . The multispecific antibody of  claim 30 , wherein the second antigen-binding region comprises VH-CDR1, VH-CDR2, VH-CDR3, VL-CDR1, VL-CDR2, and VL-CDR3 comprising the amino acid sequences of SEQ ID NOs: 8, 11, 3, 15, 5, and 17; 9, 12, 3, 14, 5, and 16; or 9, 13, 3, 14, 5, and 16, respectively. 
     
     
         32 . The multispecific antibody of  claim 30 , wherein:
 (a) the first antigen-binding region comprises a VH comprising the amino acid sequence of SEQ ID NO: 54, and/or a VL comprising the amino acid sequence of SEQ ID NO: 55 or 56; and/or   (b) the second antigen-binding region comprises a VH comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 20, 22, 24, and 25, and/or a VL comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 21, 23, and 26.   
     
     
         33 . The multispecific antibody of  claim 30 , wherein the second antigen-binding region comprises a VH and a VL comprising the amino acid sequences of SEQ ID NOs: 20 and 21; 22 and 23; 24 and 23; or 25 and 26, respectively. 
     
     
         34 . The multispecific antibody of  claim 30 , wherein the first antigen-binding region and/or the second antigen-binding region comprises a heavy chain constant region selected from the group consisting of human IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 . 
     
     
         35 . The multispecific antibody of  claim 34 , wherein the heavy chain constant region is an IgG 1  heavy chain constant region. 
     
     
         36 . The multispecific antibody of  claim 35 , wherein the heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 126. 
     
     
         37 . The multispecific antibody of  claim 35 , wherein:
 (a) the first antigen-binding region comprises a first heavy chain constant region comprising serine, alanine, and valine at amino acid positions 366, 368, and 407, respectively, and the second antigen-binding region comprises a second heavy chain constant region comprising tryptophan at amino acid position 366; or   (b) the first antigen-binding region comprises a first heavy chain constant region comprising tryptophan at amino acid position 366, and the second antigen-binding region comprises a second heavy chain constant region comprising serine, alanine, and valine at amino acid positions 366, 368, and 407, respectively,   numbered according to the EU numbering system.   
     
     
         38 . The multispecific antibody of  claim 37 , wherein the first heavy chain constant region and/or the second heavy chain constant region comprises aspartate, leucine, and glutamate at amino acid positions 239, 330, and 332, respectively, numbered according to the EU numbering system. 
     
     
         39 . The multispecific antibody of  claim 30 , wherein the first antigen-binding region comprises a first heavy chain comprising the amino acid sequence of SEQ ID NO: 54, and/or the second antigen-binding region comprises a second heavy chain comprising the amino acid sequence of SEQ ID NO: 25. 
     
     
         40 . The multispecific antibody of  claim 30 , wherein the first antigen-binding region and/or the second antigen-binding region comprises a light chain constant region selected from the group consisting of a human kappa light chain constant region or a human lambda light chain constant region. 
     
     
         41 . The multispecific antibody of  claim 30 , wherein the first antigen-binding region comprises a first light chain comprising the amino acid sequence of SEQ ID NO: 55, 56, 67, or 69, and/or the second antigen-binding region comprises a second light chain comprising the amino acid sequence of SEQ ID NO: 26. 
     
     
         42 . A pharmaceutical composition comprising the multispecific antibody of  claim 30  and a pharmaceutically acceptable excipient.