Prostate-specific membrane antigen binding proteins and related compositions and methods
AssigneeAptevo Research and Development LLC
InventorsJohn W. Blankenship, Elaine Todd Sewell, Philip Tan
Life of this patent
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Abstract
The present invention relates to mono-specific and multi-specific polypeptide therapeutics that specifically target cells expressing prostate-specific membrane antigen (PSMA) and are useful for the treatment of prostate cancer (e.g., castrate-resistant prostate cancer), tumor-related angiogenesis or benign prostatic hyperplasia (BPH). In one embodiment, the multi-specific polypeptide therapeutics bind both PSMA-expressing cells and the T-cell receptor complex on T cells to induce target-dependent T-cell cytotoxicity, activation and proliferation.
Claims14
A heterodimeric PSMA-binding protein comprising
- a first polypeptide comprising, in order from amino-terminus to carboxyl-terminus,
- (a) a first binding domain that specifically binds human PSMA, wherein the first binding domain comprises an immunoglobulin light chain variable region comprising LCDR1, LCDR2, and LCDR3, and an immunoglobulin heavy chain variable region comprising HCDR1, HCDR2, and HCDR3;
- wherein the LCDR1, LCDR2 and LCDR3 have the amino acid sequences set forth in SEQ ID NO:15, 16 and 17, respectively, and the HCDR1, HCDR2, and HCDR3 have the amino acid sequences set forth in SEQ ID NO:
- 9, 10 and 11, respectively, and wherein the first binding domain is an scFv;
- (b) a first hinge region,
- (c) a first immunoglobulin constant region, and
- (d) a second binding domain that specifically binds human CD3, wherein the second binding domain comprises an immunoglobulin light chain variable region comprising LCDR1, LCDR2, and LCDR3, and an immunoglobulin heavy chain variable region comprising HCDR1, HCDR2, and HCDR3;
- wherein the second binding domain comprises an amino acid sequence selected from the group consisting of (i) the amino acid sequence set forth in residues 1-245 of SEQ ID NO:47, and (ii) the amino acid sequence set forth in residues 496-742 of SEQ ID NO:78;
- wherein the first hinge region comprises the amino acid sequence set forth in SEQ ID NO:
- 99;
- wherein the immunoglobulin light chain and heavy chain variable regions of the first binding domain are joined by an amino acid sequence comprising (Gly4Ser)n, wherein n=1-5 (SEQ ID NO:165);
- wherein the immunoglobulin light chain and heavy chain variable regions of the second binding domain are joined by an amino acid sequence comprising (Gly4Ser)n, wherein n=1-5 (SEQ ID NO:165);
- wherein the first immunoglobulin constant region comprises an amino acid sequence that is 100% identical to a wildtype CH2 domain of human IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, or IgD, with the exception of at least one amino acid substitution or deletion relative to the wildtype CH2 domain of human IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, or IgD, wherein the amino acid substitution is at a position selected from 234, 235, 236, 237, 238, 253, 297, 310, 318, 320, 322, or 331 of the wildtype CH2 domain of human IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, or IgD, wherein the deletion comprises a deletion of one or more of amino acids 234-238, wherein the substitution comprises an alanine or a serine substitution of one or more of amino acids 234-238, 253, 310, 318, 320, 322, or 331, or wherein the substitution comprises an alanine substitution of amino acid 297;
- and
- a second polypeptide comprising a binding domain that specifically binds human PSMA.
Dependencies are inferred from the claim text.