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US-12617858-B2 - Anti-Müllerian hormone receptor 2 antibodies and methods of use

US12617858B2US 12617858 B2US12617858 B2US 12617858B2US-12617858-B2

Abstract

Provided herein are anti-Anti-Müllerian Hormone Receptor 2 (AMHR2) antibodies and methods of using such antibodies, for example, in the treatment of cancer.

Inventors

  • Vincent K. Tuohy
  • Suparna Mazumder
  • Justin M. Johnson

Assignees

  • THE CLEVELAND CLINIC FOUNDATION

Dates

Publication Date
20260505
Application Date
20210129

Claims (16)

  1. 1 . An isolated antibody, wherein said antibody comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein a) CDR-H1 comprises the sequence shown in SEQ ID NO: 1, b) CDR-H2 comprises the sequence shown in SEQ ID NO: 2, c) CDR-H3 comprises the sequence shown in SEQ ID NO: 3, d) CDR-L1 comprises the sequence shown in SEQ ID NO: 4, e) CDR-L2 comprises the sequence shown in SEQ ID NO: 5, and f) CDR-L3 comprises the sequence shown in SEQ ID NO: 6.
  2. 2 . The isolated antibody of claim 1 , wherein the VH chain sequence comprises the sequence shown in SEQ ID NO: 7.
  3. 3 . The isolated antibody of claim 1 , wherein the VL chain sequence comprises the sequence show in SEQ ID NO: 8.
  4. 4 . The isolated antibody of claim 1 , wherein the antibody is a humanized or chimeric antibody.
  5. 5 . The isolated antibody of claim 1 , wherein the antibody is a monoclonal antibody.
  6. 6 . A method of treating cancer in a subject in need thereof, comprising administering to the subject the anti-AMHR2 antibody of claim 1 , wherein said subject has an AMHR2-expressing cancer.
  7. 7 . The method of claim 6 , wherein the antibody has antibody-dependent cell-mediated cytotoxicity (ADCC) activity, antibody-mediated cellular phagocytosis (ADCP) activity, and/or complement-dependent cytotoxicity (CDC) activity.
  8. 8 . The method of claim 6 , wherein the subject is human.
  9. 9 . The method of claim 6 , wherein the cancer is a solid cancer.
  10. 10 . The method of claim 6 , wherein the cancer is ovarian cancer.
  11. 11 . The method of claim 10 , wherein the ovarian cancer is stage I, stage IA, stage IB, stage IC, stage II, stage IIA, stage IIB, stage III, stage IIIA1, stage IIIA2, stage IIIB, stage IIIC, stage IV, stage IVA, or stage IVB ovarian cancer.
  12. 12 . The method of claim 6 , wherein the antibody is effective at reducing a cancer volume as compared to the cancer volume prior to administration of the antibody.
  13. 13 . An isolated polynucleotide or set of polynucleotides encoding: a) an antibody that comprises a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein: i) CDR-H1 comprises the sequence shown in SEQ ID NO: 1, ii) CDR-H2 comprises the sequence shown in SEQ ID NO: 2, iii) CDR-H3 comprises the sequence shown in SEQ ID NO: 3, iv) CDR-L1 comprises the sequence shown in SEQ ID NO: 4, v) CDR-L2 comprises the sequence shown in SEQ ID NO: 5, and iv) CDR-L3 comprises the sequence shown in SEQ ID NO: 6, b) a VH of said antibody, c) a VL of said antibody, d) a light chain of said antibody, e) a heavy chain of said antibody, or f) an antigen-binding portion of said antibody.
  14. 14 . The isolated polynucleotide or set of polynucleotides of claim 13 , wherein said isolated polynucleotide or set of polynucleotides comprise cDNA.
  15. 15 . The isolated polynucleotide or set of polynucleotides of claim 13 , wherein said isolated polynucleotide encodes said VH of said antibody.
  16. 16 . The isolated polynucleotide or set of polynucleotides of claim 13 , wherein said isolated polynucleotide encodes said VL of said antibody.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119 of U.S. provisional application No. 62/968,840, filed Jan. 31, 2020, wherein the contents are incorporated herein by reference in their entirety. BACKGROUND Epithelial ovarian carcinoma (EOC) is the most prevalent and lethal form of ovarian cancer representing ˜85% of all ovarian cancers. An array of non-definitive symptoms associated with EOC onset and the lack of effective biomarkers for early detection often results in late diagnoses at advanced diseased stages resulting in high rates of disease recurrence and poor prognoses following current standard of care. AMHR2 is a serine/threonine kinase receptor homologous to type II receptors of the transforming growth factor-beta (TGFβ) superfamily. Anti-Müllerian hormone (AMH) is the cognate ligand of AMHR2, and binding of AMH to the extracellular domain of AMHR2 (AMHR2-ED) signals cell cycle arrest and programmed cell death resulting in regression of the Müllerian ducts during male development and regulation of oocyte development, and control of ovarian reserve and fertility in adult females. AMHR2 is overexpressed in the majority of human EOCs. Accordingly, there is an urgent need for need for new and effective therapies for treating and managing cancer, especially EOC, including therapies targeting AMHR2. SUMMARY The invention is based, in part, on the discovery of anti-AMHR2 antibodies and AMHR2 vaccine formulations that are useful in the treatment of cancers, for example, ovarian cancer. In one aspect, provided is an isolated antibody that binds to human Anti-Müllerian Hormone Receptor II (AMHR2), wherein the antibody binds within residues 11-32 (SEQ ID NO: 12) of the AMHR2 extracellular domain (SEQ ID NO: 11). In some embodiments, the antibody binds within residues 20-26 (SEQ ID NO: 13) of the AMHR2 extracellular domain (SEQ ID NO: 11). In some embodiments, the antibody binds within residues 22-26 (SEQ ID NO: 14) of the AMHR2 extracellular domain (SEQ ID NO: 11). In one aspect, provided is an isolated antibody that binds to human AMHR2 (SEQ ID NO: 9), wherein the antibody competes for binding to human AMHR2 with Anti-Müllerian Hormone (AMH). In one aspect, provided is an isolated antibody that binds to human AMHR2 (SEQ ID NO: 9), wherein the antibody competes for binding to human AMHR2 with an antibody disclosed herein. In one aspect, provided is an isolated antibody comprising a heavy chain comprising a variable heavy (VH) chain sequence comprising three heavy chain CDR sequences, CDR-H1, CDR-H2, and CDR-H3, and a light chain comprising a variable light (VL) chain sequence comprising three light chain CDR sequences, CDR-L1, CDR-L2, and CDR-L3, wherein CDR-H1 comprises the sequence shown in SEQ ID NO: 1, CDR-H2 comprises the sequence shown in SEQ ID NO: 2, CDR-H3 comprises the sequence shown in SEQ ID NO: 3, CDR-L1 comprises the sequence shown in SEQ ID NO: 4, CDR-L2 comprises the sequence shown in SEQ ID NO: 5, and CDR-L3 comprises the sequence shown in SEQ ID NO: 6. In some embodiments of any of the foregoing antibodies, the VH chain sequence comprises the sequence shown in SEQ ID NO: 7, and/or the VL chain sequence comprises the sequence show in SEQ ID NO: 8. In some embodiments, the VH chain sequence consists essentially of the sequence shown in SEQ ID NO: 7, and/or the VL chain sequence consists essentially of the sequence show in SEQ ID NO: 8. In some embodiments, the VH chain sequence consists of the sequence shown in SEQ ID NO: 7, and/or the VL chain sequence consists of the sequence show in SEQ ID NO: 8. In some embodiments of any of the foregoing antibodies, the antibody binds to human AMHR2 with a KD of less than or equal to about 0.1, 0.2, 0.5, 1, 2, 3, 4, or 5×10−9 M, as measured by surface plasmon resonance (SPR). In some embodiments of any of the foregoing antibodies, the antibody is a humanized, human, or chimeric antibody. For example, in some embodiments, the heavy chain and light chain CDRs are interposed between human or humanized immunoglobulin framework regions. In some embodiments, the antibody is a monoclonal antibody. In some embodiments of any of the foregoing antibodies, the antibody comprises a heavy chain human constant region or a human Fc region of a class selected from IgG, IgA, IgD, IgE, and IgM. In some embodiments, the heavy chain human constant region or the human Fc region is of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4, e.g., the antibody comprises a wild-type human IgG1 Fc region. In some embodiments, the heavy chain human constant region or the human Fc region comprise one or more amino acid substitutions, wherein the one or more substitutions result in increased antibody half-life, increased ADCC activity, increased ADCP activity, or increased CDC activity compared with the constant region or Fc without the one or more substitutions. In some embodiments, the heavy chain human constant regio