TARGETED TGFß INHIBITION

Abstract

This invention relates generally to bifunctional molecules including (a) a TGFβRII or fragment thereof capable of binding TGFβ and (b) an antibody, or antigen binding fragment thereof, that binds to an immune checkpoint protein, such as Programmed Death Ligand 1 (PD-L1), uses of such molecules (e.g., for treating cancer), and methods of making such molecules.

1 . A protein comprising:
 a) human TGFβRII, or a fragment thereof capable of binding TGFβ; and   b) an antibody, or an antigen-binding fragment thereof, that binds human protein Programmed Death Ligand 1 (PD-L1).   
     
     
         2 . A polypeptide comprising:
 a) at least a variable domain of a heavy chain of an antibody that binds human protein Programmed Death Ligand 1 (PD-L1); and   b) human TGFβRII, or a fragment thereof capable of binding TGFβ.   
     
     
         3 . The polypeptide of  claim 2 , further comprising an amino acid linker connecting the C-terminus of the variable domain to the N-terminus of the human TGFβRII or fragment thereof. 
     
     
         4 . The polypeptide of  claim 3 , comprising the amino acid sequence of SEQ ID NO: 3. 
     
     
         5 . A nucleic acid comprising a nucleotide sequence encoding a polypeptide according to  claim 2 . 
     
     
         6 . The nucleic acid of  claim 5 , further comprising a second nucleotide sequence encoding at least a variable domain of a light chain of an antibody which, when combined with the polypeptide, forms an antigen-binding site that binds PD-L1. 
     
     
         7 . The nucleic acid of  claim 6 , wherein the second nucleotide sequence encodes the amino acid sequence of SEQ ID NO: 1 (secreted anti-PD-L1 lambda light chain). 
     
     
         8 . A cell comprising the nucleic acid of  claim 5  and a second nucleic acid encoding at least a variable domain of a light chain of an antibody which, when combined with the polypeptide, forms an antigen-binding site that binds PD-L1. 
     
     
         9 . The cell of  claim 8 , wherein the second nucleic acid encodes the amino acid sequence of SEQ ID NO: 1. 
     
     
         10 . A cell comprising the nucleic acid of  claim 6 . 
     
     
         11 . A method of producing a protein comprising a) TGFβRII, or a fragment thereof capable of binding TGFβ, and b) an antibody, or an antigen-binding fragment thereof, that binds human protein Programmed Death Ligand 1 (PD-L1), the method comprising maintaining a cell according to  claim 8  under conditions permitting expression of the protein. 
     
     
         12 . The method of  claim 11 , further comprising harvesting the protein. 
     
     
         13 . A protein comprising:
 a polypeptide according to  claim 2 ; and   at least a variable domain of a light chain of an antibody which, when combined with the polypeptide, forms an antigen-binding site that binds PD-L1.   
     
     
         14 . The protein of  claim 13 , comprising two polypeptides each having an amino acid sequence consisting of the amino acid sequence of SEQ ID NO: 3, and two additional polypeptides each having an amino acid sequence consisting of the amino acid sequence of SEQ ID NO: 1. 
     
     
         15 - 35 . (canceled)