IL-7R-alpha specific antibodies for treating acute lymphoblastic leukemia

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  • Publication Date:
    September 07, 2021
  • Additional Information
    • Patent Number:
      11111,306
    • Appl. No:
      16/459396
    • Application Filed:
      July 01, 2019
    • Abstract:
      Antibodies and antigen binding fragments that specifically bind to IL-7Rα are disclosed. Nucleic acids encoding the antibodies and antigen binding fragments, and vectors including the nucleic acid molecules are also provided. Methods for detecting a ca cancer or a cell that expresses IL-7Rα using the antibodies and antigen binding fragments are disclosed, as is the use of the antibodies and antigen binding fragments to prevent and/or treat a subject with a cancer that expresses IL-7Rα, such as acute lymphoblastic leukemia.
    • Inventors:
      The United States of America, as represented by the Secretary, Department of Health and Human Services (Bethesda, MD, US); University of Maryland, College Park (College Park, MD, US)
    • Assignees:
      The United States of America, as represented by the Secretary, Department of Health and Human Services (Bethesda, MD, US), University of Maryland, College Park (College Park, MD, US)
    • Claim:
      1. A method of treating a subject with an IL-7Rα positive cancer or with an autoimmune disease, comprising: administering to the subject a therapeutically effective amount of: (A) a monoclonal antibody that specifically binds to an extracellular domain of IL-7Rα, the monoclonal antibody comprising: a heavy chain variable region (V H) comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3 of the V H set forth as SEQ ID NO: 1 (4A10 V H) and a light chain variable region (V L) comprising a light chain complementarity determining region (LCDR)1, a LCDR2, and a LCDR3 of the V L set forth as SEQ ID NO: 2 (4A10 V L), or a V H comprising a HCDR1, a HCDR2, and a HCDR3 of the V H set forth as SEQ ID NO: 3 (2B8 V H) and a V L comprising a LCDR1, a LCDR2, and a LCDR3 of the V L set forth as SEQ ID NO: 4 (2B8 V L); (B) an antigen binding fragment of the monoclonal antibody; or (C) a bispecific antibody comprising the monoclonal antibody or the antigen binding fragment; and administering to the subject a therapeutically effective amount of an additional agent, thereby treating the IL-7Rα positive cancer or the autoimmune disease in the subject.
    • Claim:
      2. The method of claim 1 , wherein the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2, and the LCDR3 comprise the amino acid sequences set forth as SEQ ID NOs: 5, 6, 7, 8, 9, and 10, respectively (4A10 kabat CDRs) or the amino acid sequences set forth as SEQ ID NOs: 11, 12, 13, 14, 15, and 16, respectively (2B8 kabat CDRs).
    • Claim:
      3. The method of claim 1 , wherein the V H and V L comprise the amino acid sequences set forth as SEQ ID NOs: 1 and 2, respectively, or the amino acid sequences set forth as SEQ ID NOs: 3 and 4, respectively.
    • Claim:
      4. The method of claim 1 , wherein the monoclonal antibody comprises human framework regions and/or a human constant region.
    • Claim:
      5. The method of claim 1 , wherein the monoclonal antibody is an IgG, IgM, or IgA.
    • Claim:
      6. The method of claim 1 , wherein the monoclonal antibody is an IgG1 and comprises a human constant region.
    • Claim:
      7. The method of claim 6 , wherein the monoclonal antibody comprises a heavy chain and a light chain comprising the amino acid sequences set forth as SEQ ID NOs: 21 and 22, respectively, or SEQ ID NOs: 23 and 24, respectively.
    • Claim:
      8. The method of claim 1 , wherein the monoclonal antibody comprises a constant region comprising a modification that increases binding to the neonatal Fc receptor and/or increases antibody-dependent cell cytotoxicity (ADCC).
    • Claim:
      9. The method of claim 1 , wherein the monoclonal antibody mediates ADCC killing of IL-7Rα positive cells.
    • Claim:
      10. The method of claim 1 , wherein the monoclonal antibody inhibits IL-7 signaling in IL-7Rα positive cells.
    • Claim:
      11. The method of claim 1 , comprising treating the subject with the IL-7Rα positive cancer.
    • Claim:
      12. The method of claim 1 , wherein the monoclonal antibody or antigen binding fragment comprises an Fc domain with one or more glycosylation sites.
    • Claim:
      13. The method of claim 12 , wherein the monoclonal antibody lacks fucose attached to the Fc domain.
    • Claim:
      14. The method of claim 12 , wherein the monoclonal antibody comprises fucose from 1% to 80%, as measured by calculating the average amount of fucose within the sugar chain at Asn297 of the CH2 domain of the Fc domain.
    • Claim:
      15. The method of claim 12 , wherein the monoclonal antibody comprises a biantennary oligosaccharide attached to the Fc region.
    • Claim:
      16. The method of claim 12 , wherein the monoclonal antibody comprises a galactose in a carbohydrate attached to the Fc domain.
    • Claim:
      17. The method of claim 1 , comprising treating the subject with the autoimmune disease.
    • Claim:
      18. The method of claim 17 , wherein the additional agent comprises an adrenocorticosteroid.
    • Claim:
      19. The method of claim 18 , wherein the adrenocorticosteroid is prednisone.
    • Claim:
      20. A method of treating a subject with an IL-7Rα positive cancer, comprising: administering to the subject a therapeutically effective amount of: (A) a monoclonal antibody that specifically binds to an extracellular domain of IL-7Rα, the monoclonal antibody comprising: a heavy chain variable region (V H) comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3 of the V H set forth as SEQ ID NO: 1 (4A10 V H) and a light chain variable region (V L) comprising a light chain complementarity determining region (LCDR)1, a LCDR2, and a LCDR3 of the V L set forth as SEQ ID NO: 2 (4A10 V L), or a V H comprising a HCDR1, a HCDR2, and a HCDR3 of the V H set forth as SEQ ID NO: 3 (2B8 V H) and a V L comprising a LCDR1, a LCDR2, and a LCDR3 of the V L set forth as SEQ ID NO: 4 (2B8 V L); (B) an antigen binding fragment of the monoclonal antibody; or (C) a bispecific antibody comprising the monoclonal antibody or the antigen binding fragment; and administering to the subject a therapeutically effective amount of an additional agent, wherein the additional agent comprises a chemotherapeutic agent, an alkylating agent, an antimetabolite, a vinca alkaloid, an epipodophyllotoxin, an antibiotic, an adrenocorticosteroid, or a C—X—C chemokine receptor type 4 (CXCR4) antagonist, thereby treating the IL-7Rα positive cancer.
    • Claim:
      21. The method of claim 20 , wherein the chemotherapeutic agent is vincristine, daunorubicin, fludarabine, doxorubicin, or idarubicin.
    • Claim:
      22. The method of claim 20 , wherein the IL-7Rα positive cancer comprises a mutation in the IL-7 pathway that increases proliferation of lymphocytes.
    • Claim:
      23. The method of claim 22 , wherein the mutation is a gain-of-function mutation in the gene encoding IL-7Rα that leads to increased phosphorylation of Stat5b compared to control.
    • Claim:
      24. The method of claim 23 , wherein the IL-7Rα positive cancer is an acute lymphoblastic leukemia (ALL).
    • Claim:
      25. The method of claim 24 , wherein the ALL is B-ALL.
    • Claim:
      26. The method of claim 25 , wherein the ALL is T-ALL.
    • Claim:
      27. The method of claim 20 , wherein the adrenocorticosteroid is prednisone.
    • Claim:
      28. The method of claim 20 , wherein the adrenocorticosteroid is prednisone.
    • Claim:
      29. The method of claim 20 , wherein the vinca alkaloid is L-asparaginase.
    • Claim:
      30. The method of claim 20 , wherein the alkylating agent is cyclophosphamide.
    • Claim:
      31. The method of claim 20 , wherein the antimetabolite is methotrexate, cytarabine, mercaptopurine, or thioguanine.
    • Patent References Cited:
      2011/0206698 August 2011 Lin et al.
      2583980 April 2013
      WO 2010/017468 February 2010
      WO 2013/056984 April 2013
      WO 2014/102430 July 2014
































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    • Assistant Examiner:
      Hamud, Fozia M
    • Primary Examiner:
      Bunner, Bridget E
    • Attorney, Agent or Firm:
      Klarquist Sparkman, LLP
    • Accession Number:
      edspgr.11111306