VEGFA/Ang2 Compounds
The present invention relates to compounds that bind to human vascular endothelial growth factor A (VEGFA) and human angiopoietin-2 (Ang2), and may be useful for treating angiogenic eye diseases, such as diabetic and other proliferative retinopathies, and for cancer, especially solid tumors driven by VEGFA and Ang2, including gastric, lung, hepatocellular carcinoma, ovarian, colorectal, and breast cancers.
1. A compound, comprising an antibody fused by two linkers to two single chain fragment variable (scFv) polypeptides, wherein: a) the antibody comprises two identical heavy chains (HCs) and two identical light chains (LCs), wherein each HC comprises a heavy chain variable region (HCVR) comprising SEQ ID NO: 1, and wherein each LC comprises a light chain variable region (LCVR) comprising SEQ ID NO: 4, b) the two scFv polypeptides are identical and each comprise an HCVR operably linked to an LCVR, wherein each HCVR has the amino acid sequence of SEQ ID NO: 7, and wherein each LCVR has the amino acid sequence of SEQ ID NO: 8, and c) the two linkers are identical glycine-rich linkers that each operably link the carboxy-terminus of one HC of the antibody to the amino-terminus of one of the scFv polypeptides.
2. The compound of claim 1 , wherein the two scFv polypeptides each comprise the carboxy-terminus of the HCVR of one scFv polypeptide operably linked to the amino-terminus of the LCVR of one scFv polypeptide.
3. The compound of claim 1 , wherein the antibody comprises two heavy chains (HCs) and two light chains (LCs), wherein each HC has the amino acid sequence of SEQ ID NO: 2, and each LC has the amino acid sequence of SEQ ID NO: 5.
4. The compound of claim 3 , wherein each scFv polypeptide has the identical amino acid sequence of SEQ ID NO: 6.
5. A compound comprising two first polypeptides and two second polypeptides wherein each of the first polypeptides has the amino acid sequence of SEQ ID NO: 3, and each of the second polypeptides has the amino acid sequence of SEQ ID NO: 5.
6. The compound of claim 5 , wherein each of the first polypeptides forms an inter-chain disulfide bond with each of the second polypeptides, and the first polypeptide forms two inter-chain disulfide bonds with the other first polypeptide, and each of the first polypeptides forms seven intra-chain disulfide bonds.
7. A mammalian cell comprising a DNA molecule comprising a polynucleotide sequence encoding a first polypeptide comprising the amino acid sequence of SEQ ID NO: 3 and a polynucleotide sequence encoding a second polypeptide comprising the amino acid sequence of SEQ ID NO: 5, wherein the cell is capable of expressing a compound comprising the first polypeptide and the second polypeptide.
8. A process for producing a compound comprising two first polypeptides comprising SEQ ID NO: 3 and two second polypeptides comprising SEQ ID NO: 5, comprising cultivating the mammalian cell of claim 7 under conditions such that the compound is expressed, and recovering the expressed compound.
9. A compound obtainable by the process of claim 8 .
10. A pharmaceutical composition, comprising the compound of claim 1 , and an acceptable carrier, diluent, or excipient.
11. A method of treating cancer, comprising administering to a patient in need thereof, an effective amount of the compound of claim 1 .
12. The method of claim 11 , wherein the cancer is breast cancer, lung cancer, ovarian cancer, gastric cancer, colorectal cancer, or hepatocellular carcinoma.
13. A method of treating proliferative retinopathy, comprising administering to a patient in need thereof, an effective amount of the compound of claim 1 .
14. The method of claim 13 , wherein the proliferative retinopathy is diabetic retinopathy, or retinopathy of prematurity.
15. A method of treating angiogenic eye disease, comprising administering to a patient in need thereof, an effective amount of the compound of claim 1 .
16. The method of claim 15 , wherein the angiogenic eye disease is neovascular glaucoma, age-related macular degeneration, diabetic macular edema, corneal neovascularization, conical graft neovascularization, conical graft rejection, retinal/choroidal neovascularization, neovascularization of the angle (rubeosis), ocular neovascular disease, vascular restenosis, or arteriovenous malformations (AVM).