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EP-3817770-B1 - ANTI-STEAP1 ANTIGEN-BINDING PROTEIN

EP3817770B1EP 3817770 B1EP3817770 B1EP 3817770B1EP-3817770-B1

Inventors

  • NOLAN-STEVAUX, Olivier
  • LI, CONG
  • MURAWSKY, Christopher, M.
  • ALBA, BENJAMIN, M.
  • AGRAMAL, Neeraj Jagdish
  • GRAHAM, KEVIN
  • STEVENS, Jennitte, LeAnn
  • MOORE, GREGORY

Dates

Publication Date
20260506
Application Date
20190702

Claims (20)

  1. An antigen-binding protein that binds STEAP1 of SEQ ID NO: 2 and comprises: (a) a variable heavy domain comprising SEQ ID NO: 182 and a variable light domain comprising SEQ ID NO: 183; or (b) a variable heavy domain comprising SEQ ID NO: 184 and a variable light domain comprising SEQ ID NO: 183.
  2. The antigen-binding protein of claim 1, wherein the antigen-binding protein is an antibody, optionally a monoclonal antibody, or a chimeric antibody.
  3. The antigen-binding protein of claim 1 or 2, wherein the antigen-binding protein is an antigen-binding antibody fragment or comprises a single chain antibody, a diabody, a triabody, or a tetrabody.
  4. A pharmaceutical composition comprising the antigen-binding protein of any one of claims 1-3 and a physiologically acceptable carrier.
  5. The pharmaceutical composition of claim 4, further comprising an anti-PD-1 antigen-binding protein comprising a vhCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 189, a vhCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 190, a vhCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 191, a vlCDR1 comprising the amino acid sequence set forth in SEQ ID NO: 192, a vlCDR2 comprising the amino acid sequence set forth in SEQ ID NO: 193, and a vlCDR3 comprising the amino acid sequence set forth in SEQ ID NO: 194.
  6. The antigen-binding protein of any one of claims 1-3 for use in treating cancer in a subject in need thereof, wherein the antigen-binding protein is optionally administered with an anti-PD-1 antigen-binding protein.
  7. A polynucleotide comprising a nucleic acid sequence encoding the light chain variable domain and heavy chain variable domain of the antigen-binding protein of any one of claims 1-3, wherein the polynucleotide is optionally present in an expression vector.
  8. A composition comprising a polynucleotide comprising a nucleic acid sequence encoding the light chain variable domain of the antigen-binding protein of any one of claims 1-3 and a polynucleotide comprising a nucleic acid sequence encoding the heavy chain variable domain of the antigen-binding protein of any one of claims 1-3.
  9. A method of making an antigen-binding protein, the method comprising contacting a host cell with the polynucleotide of claim 7 or the composition of claim 8 under conditions that allow expression of the light chain variable domain and the heavy chain variable domain.
  10. A bispecific antigen-binding protein comprising the antigen-binding protein of any one of claims 1-3.
  11. The bispecific antigen-binding protein of claim 10, which binds STEAP1 and CD3.
  12. The bispecific antigen-binding protein of claim 11, comprising a CD3 binding domain comprising CDR sequences vhCDR1 SEQ ID NO: 170, vhCDR2 SEQ ID NO: 171, vhCDR3 SEQ ID NO: 172, vlCDR1 SEQ ID NO: 174, vlCDR2 SEQ ID NO:175, and vlCDR3 SEQ ID NO: 176.
  13. A heterodimeric antibody comprising: a) a first monomer comprising a first heavy chain comprising: 1) a first variable heavy domain; 2) a first constant heavy chain comprising a first CH1 domain and a first Fc domain; 3) a scFv that binds human CD3 and comprises a scFv variable light domain, an scFv linker and a scFv variable heavy domain; wherein said scFv is covalently attached between the C-terminus of said CH1 domain and the N-terminus of said first Fc domain using domain linker(s); b) a second monomer comprising a second heavy chain comprising a second variable heavy domain and a second constant heavy chain comprising a second Fc domain; and c) a common light chain comprising a variable light domain and a constant light domain; wherein said first variable heavy domain and said variable light domain bind human STEAP1, said second variable heavy domain and said variable light domain bind human STEAP1, and wherein (i) the first variable heavy domain and the second variable heavy domain comprise SEQ ID NO: 182 and the variable light domain comprises SEQ ID NO: 183; or (ii) the first variable heavy domain and the second variable heavy domain comprise SEQ ID NO: 184 and the variable light domain comprises SEQ ID NO: 183.
  14. The heterodimeric antibody of claim 13, wherein the first monomer comprises amino acid substitutions E233P, L235V, G236A, S267K, R292C, N297G, V302C, E357Q, and S364K; the second monomer comprises the amino acid substitutions N208D, E233P, L235V, G236A, S267K, R292C, Q295E, N297G, V302C, L368D, K370S, N384D, Q418E, and N421D; and both monomers comprise a deletion at position 234.
  15. The heterodimeric antibody of claim 13 or claim 14, wherein said scFv comprises (i) a variable heavy domain comprising heavy chain CDRs comprising the amino acid sequences vhCDR1 SEQ ID NO: 170, vhCDR2 SEQ ID NO: 171, and vhCDR3 SEQ ID NO: 172, and a variable light domain comprising light chain CDRs comprising the amino acid sequences vlCDR1 SEQ ID NO: 174, vlCDR2 SEQ ID NO: 175, and vlCDR3 SEQ ID NO: 176; or (ii) a variable heavy domain comprising an amino acid sequence at least 90% identical to SEQ ID NO:169 and comprising the CDR amino acid sequences of (i) and a variable light domain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 173 and comprising the CDR amino acid sequences of (i).
  16. The heterodimeric antibody of claim 13 or claim 14, wherein said scFv comprises a variable heavy region and a variable light region comprising SEQ ID NO: 169 and SEQ ID NO:173, respectively.
  17. The heterodimeric antibody of any one of claims 13-16, wherein said scFv has a charged scFv linker, optionally having a positive charge from 3 to 8 and selected from the group consisting of SEQ ID NOs: 143 to 153, and preferably comprising SEQ ID NO: 152.
  18. The heterodimeric antibody of any one of claims 13-16, wherein said scFv comprises the sequence of SEQ ID NO: 44.
  19. The heterodimeric antibody of any of claims 13-18, comprising the amino acid substitution N67Q and/or a substitution at one or more of positions 292, 297, or 302.
  20. The heterodimeric antibody of claim 13, wherein the first monomer comprises the sequence of SEQ ID NO: 19, the second monomer comprises the sequence of SEQ ID NO: 18, and the common light chain comprises the sequence of SEQ ID NO: 17.

Description

TECHNICAL FIELD The disclosure provides a novel antigen-binding protein that binds Six Transmembrane Epithelial Antigen of the Prostate 1 (STEAP1) and uses thereof. BACKGROUND Prostate cancer remains one of the most common cancers among men in the United States. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999-2014 Incidence and Mortality Web-based Report. Atlanta (GA): Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute; 2017. While the survival rate for prostate cancer is relatively high compared to other cancer types, current treatment options are accompanied by risk and unwanted side effects. For example, surgery is accompanied by risk of nerve damage and impotence, and radiation therapy can increase the risk of development bladder or gastrointestinal cancers. Traditional chemotherapy is associated with a host of side effects that limit the patient's quality of life during treatment. Antibody-based therapeutics have been successful in treating a variety of diseases, including cancer and autoimmune/inflammatory disorders. Prostate cancer is believed to be particularly amenable to antibody-based therapy due, at least in part, to the existence of prostate cancer-specific antigens. Despite recent progress in elucidating the underlying biological mechanism of carcinogenesis and potential biomarkers, there exists a need for alternative antibody-based therapeutic options for cancer, including prostate cancer. Tamura et al., 2009, J. Biomed. Biotechnol. 60(23):6568-6569 describes the production of antibodies against multipass membrane proteins expressed in human tumor cells using dendritic cell immunization. Williams et al., 2016, Oncotarget 7(18): 25103-25112 describes that ImmunoPET helps predict the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1. WO 2008/052187 A1 describes anti-STEAP-1 antibodies and immunoconjugates and methods of using anti-STEAP-1 antibodies and immunoconjugates thereof. WO 2017/147368 A1 describes agents that specifically bind tumor-associated antigens (TAA) and comprise an exogenous polypeptide or peptide that can be presented by a tumor cell and methods of using the agents for redirecting an existing immune response against tumor cells and/or treatment of diseases such as cancer. SUMMARY The invention is defined by the appended claims. Any part of the description which does not fall under the scope of the appended claims is for illustrative purposes only. In particular, any subject-matter referred to as "disclosure" which is not falling under the scope of the appended claims does not form part of the invention. Any references in the description to methods of treatment refer to the antibodies or pharmaceutical compositions of the present invention for use in a method of treatment of the human (or animal) body by therapy. The invention provides an antigen-binding protein that binds STEAP1 of SEQ ID NO: 2 and comprises: (a) a variable heavy domain comprising SEQ ID NO: 182 and a variable light domain comprising SEQ ID NO: 183; or (b) a variable heavy domain comprising SEQ ID NO: 184 and a variable light domain comprising SEQ ID NO: 183. The antigen-binding protein comprises a vhCDR1 comprising SEQ ID NO: 14, a vhCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 21, a vhCDR3 comprising SEQ ID NO: 16, a vlCDR1 comprising SEQ ID NO: 11, a vlCDR2 comprising SEQ ID NO: 12, and a vlCDR3 comprising SEQ ID NO: 13. The invention further provides a heterodimeric antibody comprising a first monomer comprising a first heavy chain comprising: 1) a first variable heavy domain; 2) a first constant heavy chain comprising a first CH1 domain and a first Fc domain; and 3) a scFv that binds human CD3 and comprises a scFv variable light domain, an scFv linker, and a scFv variable heavy domain; wherein said scFv is covalently attached between the C-terminus of said CH1 domain and the N-terminus of said first Fc domain using domain linker(s). The heterodimeric antibody further comprises a second monomer comprising a second heavy chain comprising a second variable heavy domain and a second constant heavy chain comprising a second Fc domain; and a common light chain comprising a variable light domain and a constant light domain. The first variable heavy domain and the variable light domain bind human STEAP1, the second variable heavy domain and the variable light domain bind human STEAP1, and wherein (i) the first variable heavy domain and the second variable heavy domain comprise SEQ ID NO: 182 and the variable light domain comprises SEQ ID NO: 183; or (ii) the first variable heavy domain and the second variable heavy domain comprise SEQ ID NO: 184 and the variable light domain comprises SEQ ID NO: 183. The first variable heavy domain and the second variable heavy domain comprise CDR sequences: vhCDR1 comprising SEQ ID NO: 14, vhCDR2 comprising SEQ ID NO: 15 or SEQ ID NO: 21, and vhCDR3 comprising SEQ ID NO: 16;