Targeted TGFβ inhibitors
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 first polypeptide comprising:
a) at least a variable region of a heavy chain of an antibody that binds human protein Programmed Death Ligand 1 (PD-L1); and
b) human Transforming Growth Factor β Receptor II (TGFβRII), or a fragment thereof capable of binding Transforming Growth Factor β (TGFβ); and
a second polypeptide comprising at least a variable region of a light chain of an antibody that binds PD-L1,
wherein the first polypeptide comprises the amino acid sequence of SEQ ID NO: 3,
wherein the second polypeptide comprises the amino acid sequence of SEQ ID NO: 1, and wherein the heavy chain of the first polypeptide and the light chain of the second polypeptide, when combined, form an antigen binding site that binds PD-L1.
2. The protein of claim 1 , 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.
3. A nucleic acid comprising a first nucleotide sequence encoding the first polypeptide according to claim 1 , and a second nucleotide sequence encoding the second polypeptide according to claim 1 .
4. An isolated cell comprising the nucleic acid of claim 3 .
5. 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 4 under conditions permitting expression of the protein.
6. The method of claim 5 , further comprising harvesting the protein.