Anti-PSMA antibodies, bispecific antigen-binding molecules that bind PSMA and CD3, and uses thereof
Inventors
Kirshner, Jessica R. • Crawford, Alison • Thurston, Gavin • Smith, Eric • Haber, Lauric • Dudgeon, Drew • Rafique, Ashique
Assignees
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Publication Number
US-12344677-B2
Publication Date
2025-07-01
Expiration Date
Abstract
The present invention provides antibodies that bind to prostate-specific membrane antigen (PSMA), bispecific antibodies that bind to PSMA and CD3, and methods of using the same. According to certain embodiments, the antibodies of the invention bind human PSMA with high affinity and bind CD3 to induce human T cell proliferation. The invention includes antibodies that bind PSMA and CD3 and induce T cell-mediated killing of PSMA-expressing tumor cells. According to certain embodiments, the present invention provides bispecific antigen-binding molecules comprising a first antigen-binding domain that specifically binds human CD3, and a second antigen-binding molecule that specifically binds human PSMA. In certain embodiments, the bispecific antigen-binding molecules of the present invention are capable of inhibiting the growth of prostate tumors expressing PSMA. The antibodies and bispecific antigen-binding molecules of the invention are useful for the treatment of diseases and disorders in which an upregulated or induced targeted immune response is desired and/or therapeutically beneficial. For example, the antibodies of the invention are useful for the treatment of various cancers.
Core Innovation
The invention relates to treating a human prostate specific membrane antigen (PSMA)-expressing cancer in a human subject by administering a bispecific antigen-binding molecule. The molecule comprises a first antigen-binding domain that specifically binds human CD3 and a second antigen-binding domain that specifically binds human PSMA, with the CD3-binding and PSMA-binding domains defined by heavy chain complementarity determining regions and light chain complementarity determining regions within heavy chain variable regions and light chain variable regions.
The CD3-binding domain comprises A1-HCDR1, A1-HCDR2, and A1-HCDR3 within an HCVR having an amino acid sequence of SEQ ID NO: 1514 or SEQ ID NO: 1618, and LCDR1, LCDR2, and LCDR3 within an LCVR having an amino acid sequence of SEQ ID NO: 1386. The PSMA-binding domain comprises A2-HCDR1, A2-HCDR2, and A2-HCDR3 within an HCVR having an amino acid sequence of SEQ ID NO: 66, and LCDR1, LCDR2, and LCDR3 within an LCVR having an amino acid sequence of SEQ ID NO: 1386.
The disclosed approach is directed to CD3- and PSMA-targeted T-cell activation leading to PSMA-expressing tumor killing. The document further addresses treatment of prostate cancer and castrate-resistant prostate cancer, and includes functional evaluation in vivo and ex vivo settings.
Claims Coverage
The claim set includes three independent claims centered on administering a bispecific antigen-binding molecule or isolated bispecific antibody that binds human CD3 and human PSMA. The inventive scope is defined by specific heavy chain and light chain complementarity determining regions and corresponding variable-region sequence identifiers, with three inventive features reflected across the independent claims.
Bispecific CD3- and PSMA-binding antigen-binding molecule for treating PSMA-expressing cancer
A method for treating a human PSMA-expressing cancer in a human subject by administering a bispecific antigen-binding molecule comprising a first antigen-binding domain specifically binding human CD3 and a second antigen-binding domain specifically binding human PSMA, with the CD3-binding domain comprising A1-HCDR1, A1-HCDR2, and A1-HCDR3 within an HCVR of SEQ ID NO: 1514 or SEQ ID NO: 1618 and LCDR1, LCDR2, and LCDR3 within an LCVR of SEQ ID NO: 1386, and the PSMA-binding domain comprising A2-HCDR1, A2-HCDR2, and A2-HCDR3 within an HCVR of SEQ ID NO: 66 and LCDR1, LCDR2, and LCDR3 within an LCVR of SEQ ID NO: 1386.
Isolated bispecific antibody with defined CD3 and PSMA CDR amino-acid sequences
A method for treating a human PSMA-expressing cancer in a human subject by administering an isolated bispecific antibody comprising a first antigen-binding domain specifically binding human CD3 and a second antigen-binding domain specifically binding human PSMA, where the first antigen-binding domain comprises A1-HCDR1, A1-HCDR2, A1-HCDR3 comprising amino acid sequences of SEQ ID NOs: 1516, 1518 and 1520, and LCDR1, LCDR2 and LCDR3 comprising amino acid sequences of SEQ ID NOs: 1388, 1390 and 1392, and where the second antigen-binding domain comprises A2-HCDR1, A2-HCDR2 and A2-HCDR3 comprising amino acid sequences of SEQ ID NOs: 68, 70 and 72, and LCDR1, LCDR2 and LCDR3 comprising amino acid sequences of SEQ ID NOs: 1388, 1390 and 1392.
Isolated bispecific antibody with alternative defined CD3 CDR amino-acid sequences and defined PSMA CDR sequences
A method for treating a human PSMA-expressing cancer in a human subject by administering an isolated bispecific antibody comprising a first antigen-binding domain specifically binding human CD3 and a second antigen-binding domain specifically binding human PSMA, where the first antigen-binding domain comprises A1-HCDR1, A1-HCDR2 and A1-HCDR3 comprising amino acid sequences of SEQ ID NOs: 1620, 1622 and 1624, and LCDR1, LCDR2 and LCDR3 comprising amino acid sequences of SEQ ID NOs: 1388, 1390 and 1392, and where the second antigen-binding domain comprises A2-HCDR1, A2-HCDR2 and A2-HCDR3 comprising amino acid sequences of SEQ ID NOs: 68, 70 and 72, and LCDR1, LCDR2 and LCDR3 comprising amino acid sequences of SEQ ID NOs: 1388, 1390 and 1392.
Across the independent claims, the coverage is directed to treating a human PSMA-expressing cancer by administering a bispecific molecule or isolated bispecific antibody that specifically binds human CD3 and human PSMA. The main inventive features are the specified HCDR and LCDR definitions, the corresponding HCVR and LCVR sequence identifiers, and the alternative disclosed CDR amino-acid sequences, with a further limitation in some claims that the human PSMA target comprises SEQ ID NO: 1651.
Stated Advantages
Inhibits tumor growth in PSMA-expressing settings as described in the patent content.
Induces transient dose-dependent cytokine increases as described in the patent content.
Suppresses tumor growth of established xenografts as described in the patent content.
Induces T-cell activation leading to T-cell mediated killing as described in the patent content.
Documented Applications
Treating a human PSMA-expressing cancer in a human subject by administering PSMAxCD3 bispecific antigen-binding molecules or isolated bispecific antibodies.
Treating prostate cancer, including castrate-resistant prostate cancer, as described in the dependent claim refinements.
Functional evaluation in immunocompromised and immunocompetent mouse xenograft models using PSMAxCD3 bispecifics.
Ex vivo functional evaluation using human PBMCs and related cellular assays.
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