VEGFR2/Ang2 Compounds

Abstract

The present invention relates to compounds that bind to human vascular endothelial growth factor receptor-2 (VEGFR2) and human angiopoietin-2 (Ang2), and may be useful for treating cancer, especially solid tumors driven by VEGFR2 and Ang2, including gastric, hepatocellular carcinoma, ovarian, colorectal, non-small cell lung, biliary tract, and breast cancers.

1 - 27 . (canceled) 
     
     
         28 . A compound, comprising an antibody fused by two linkers to two single chain fragment variable (scFv) polypeptides, wherein:
 i. the antibody comprises two identical heavy chains (HCs) and two identical light chains (LCs), wherein each HC comprises a heavy chain variable region (HCVR) whose amino acid sequence is given in SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3, and wherein each LC comprises a light chain variable region (LVCR) whose amino acid sequence is given in SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO: 15,   ii. the two scFv polypeptides are identical and each comprise an HCVR operably linked to an LCVR, wherein each HCVR has the amino acid sequence given in SEQ ID NO: 21, or SEQ ID NO: 22, and wherein each LCVR has the amino acid sequence given in SEQ ID NO: 23, and   iii. 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.   
     
     
         29 . The compound of  claim 28 , wherein the two scFv polypeptides each comprise the carboxy-terminus of the LCVR of one scFv polypeptide operably linked to the amino-terminus of the HCVR of one scFv polypeptide. 
     
     
         30 . The compound of  claim 28 , wherein each HCVR of the antibody has the amino acid sequence given in SEQ ID NO: 1, each LCVR of the antibody has the amino acid sequence given in SEQ ID NO: 13, the HCVR of each of the scFv polypeptides has the amino acid sequence given in SEQ ID NO: 21, and the LCVR of each of the scFv polypeptides has the amino acid sequence given in SEQ ID NO: 23. 
     
     
         31 . The compound of  claim 28 , wherein each HCVR of the antibody has the amino acid sequence given in SEQ ID NO: 2, each LCVR of the antibody has the amino acid sequence given in SEQ ID NO: 14, the HCVR of each of the scFv polypeptides has the amino acid sequence given in SEQ ID NO: 21, and the LCVR of each of the scFv polypeptides has the amino acid sequence given in SEQ ID NO: 23. 
     
     
         32 . The compound of  claim 28 , wherein each HCVR of the antibody has the amino acid sequence given in SEQ ID NO: 3, each LCVR of the antibody has the amino acid sequence given in SEQ ID NO: 15, the HCVR of each of the scFv polypeptides has the amino acid sequence given in SEQ ID NO: 21, and the LCVR of each of the scFv polypeptides has the amino acid sequence given in SEQ ID NO: 23. 
     
     
         33 . The compound of  claim 28 , wherein the antibody comprises two heavy chains (HCs) and two light chains (LCs), wherein each HC has the amino acid sequence given in one of SEQ ID NO: 5, SEQ ID NO: 6, or SEQ ID NO: 7, and each LC has the amino acid sequence given in one of SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18. 
     
     
         34 . The compound of  claim 33 , wherein each HC of the antibody has the amino acid sequence given in SEQ ID NO: 5, and each LC of the antibody has the amino acid sequence given in SEQ ID NO: 16. 
     
     
         35 . The compound of  claim 33 , wherein each HC of the antibody has the amino acid sequence given in SEQ ID NO: 6, and each LC of the antibody has the amino acid sequence given in SEQ ID NO: 17. 
     
     
         36 . The compound of  claim 33 , wherein each HC of the antibody has the amino acid sequence given in SEQ ID NO: 7, and each LC of the antibody has the amino acid sequence given in SEQ ID NO: 18. 
     
     
         37 . The compound of  claim 28 , wherein each scFv polypeptide has the identical amino acid sequence given in SEQ ID NO: 19. 
     
     
         38 . 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: 9, SEQ ID NO: 10, or SEQ ID NO: 11, and each of the second polypeptides has the amino acid sequence of SEQ ID NO: 16, SEQ ID NO: 17, or SEQ ID NO: 18. 
     
     
         39 . The compound of  claim 38 , wherein each of the first polypeptides has the amino acid sequence of SEQ ID NO: 9, and each of the second polypeptides has the amino acid sequence of SEQ ID NO: 16. 
     
     
         40 . The compound of  claim 38 , wherein each of the first polypeptides has the amino acid sequence of SEQ ID NO: 10, and each of the second polypeptides has the amino acid sequence of SEQ ID NO: 17. 
     
     
         41 . The compound of  claim 38 , wherein each of the first polypeptides has the amino acid sequence of SEQ ID NO: 11, and each of the second polypeptides has the amino acid sequence of SEQ ID NO: 18. 
     
     
         42 . The compound of  claim 38 , 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 an intra-chain disulfide bond. 
     
     
         43 . A mammalian cell comprising a DNA molecule comprising a polynucleotide sequence a encoding a polypeptide selected from the group consisting of a polypeptide consisting of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11 and a polynucleotide sequence encoding a polypeptide selected from the group consisting of a polypeptide consisting of SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18, wherein the cell is capable of expressing a compound comprising a first polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11 and a second polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18. 
     
     
         44 . A process for producing a compound comprising two first polypeptides selected from the group consisting of SEQ ID NO: 9, SEQ ID NO: 10, and SEQ ID NO: 11 and two second polypeptides selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 17, and SEQ ID NO: 18, comprising cultivating the mammalian cell of  claim 43  under conditions such that the compound is expressed, and recovering the expressed compound. 
     
     
         45 . A compound obtainable by the process of  claim 44 . 
     
     
         46 . A pharmaceutical composition, comprising the compound of  claim 28 , and an acceptable carrier, diluent, or excipient. 
     
     
         47 . A method of treating cancer, comprising administering to a patient in need thereof, an effective amount of the compound of  claim 28 . 
     
     
         48 . The method of  claim 47 , wherein the cancer is breast cancer, ovarian cancer, gastric cancer, colorectal cancer, non-small cell lung cancer, biliary tract cancer, or hepatocellular carcinoma.