Anti-VEGF-A and anti-ANG2 antibodies and uses thereof
The present invention relates to bispecific antibodies having activity against a vascular endothelial growth factor (VEGF) and an angiopoietin (ANG), and methods of making and using such bispecific antibodies.
1. A bispecific antibody comprising a first binding domain comprising heavy chain complementarity determining regions 1-3 (HCDR1, HCDR2, and HCDR3) and light chain complementarity determining regions 1-3 (LCDR1, LCDR2, and LCDR3), wherein the first binding domain HCDR1, HCDR2, and HCDR3 and LCDR1, LCDR2, and LCDR3 comprise SEQ ID NOs: 17-22, respectively, and a second binding domain comprising an HCDR1, HCDR2, and HCDR3 and an LCDR1, LCDR2, and LCDR3, wherein the second binding domain HCDR1, HCDR2, and HCDR3 and LCDR1, LCDR2, and LCDR3 comprise SEQ ID NOs: 23-28, respectively.
2. The bispecific antibody of claim 1 , wherein the first binding domain comprises a heavy chain and a light chain comprising SEQ ID NOs: 3 and 9, respectively, and wherein the second binding domain comprises a heavy chain and a light chain comprising SEQ ID NOs: 5 and 11, respectively.
3. The bispecific antibody of claim 1 , wherein the heavy chain amino acid sequence comprises SEQ ID NO: 1 and the light chain amino acid sequence comprises SEQ ID NO: 7.
4. The bispecific antibody of claim 1 , wherein the bispecific antibody comprises a formula having the parts VH-CH1-H-CH2-CH3, VL-CL, and one or more scFv, L1, or optionally L2, wherein the individual part are VH=a heavy chain variable domain; CH1=a heavy chain constant region domain 1; H=a hinge region; CH2=a heavy chain constant region domain 2; CH3=a heavy chain constant region domain 3; VL=a variable light chain domain; CL=a light chain constant domain; L1=a linker; and L2=a linker independent of L1, wherein the formula can be:
a. VH-CH1-CH2-CH3 and scFv-L1-VL-CL;
b. scFv-L1-VH-CH1-CH2-CH3 and VL-CL;
c. VH-CH1-CH2-CH3-L1-scFv and VL-CL;
d. VH-CH1-CH2-CH3-L1-scFv-L2 and VL-CL, wherein L1 and L2 are covalently bound to CH3;
e. VH-CH1-L1-scFv-L2-CH2-CH3 and VL-CL, the heavy chain can contain a hinge region or be hingeless.
5. The bispecific antibody of claim 4 comprising the formula VH-CH1-CH2-CH3-L1-scFv and VL-CL.
6. The bispecific antibody of claim 5 wherein the scFv comprises the amino acid sequence of SEQ ID NO: 13.
7. A method of reducing angiogenesis in a subject in need thereof comprising providing a bispecific antibody of claim 1 to the subject, wherein the subject exhibits aberrant or unwanted angiogenesis.