title: Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma.
abstract: B-cell maturation antigen (BCMA), highly expressed on malignant plasma cells in human multiple myeloma (MM), has not been effectively targeted with therapeutic monoclonal antibodies. We here show that BCMA is universally expressed on the MM cell surface and determine specific anti-MM activity of J6M0-mcMMAF (GSK2857916), a novel humanized and afucosylated antagonistic anti-BCMA antibody-drug conjugate via a noncleavable linker. J6M0-mcMMAF specifically blocks cell growth via G2/M arrest and induces caspase 3-dependent apoptosis in MM cells, alone and in coculture with bone marrow stromal cells or various effector cells. It strongly inhibits colony formation by MM cells while sparing surrounding BCMA-negative normal cells. J6M0-mcMMAF significantly induces effector cell-mediated lysis against allogeneic or autologous patient MM cells, with increased potency and efficacy compared with the wild-type J6M0 without Fc enhancement. The antibody-dependent cell-mediated cytotoxicity and apoptotic activity of J6M0-mcMMAF is further enhanced by lenalidomide. Importantly, J6M0-mcMMAF rapidly eliminates myeloma cells in subcutaneous and disseminated mouse models, and mice remain tumor-free up to 3.5 months. Furthermore, J6M0-mcMMAF recruits macrophages and mediates antibody-dependent cellular phagocytosis of MM cells. Together, these results demonstrate that GSK2857916 has potent and selective anti-MM activities via multiple cytotoxic mechanisms, providing a promising next-generation immunotherapeutic in this cancer.
authors.affiliation: The Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.affiliation: Oncology Research & Development, GlaxoSmithKline, Collegeville, PA;
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Mayes
authors.affiliation: The Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Chirag
authors.initials: C
authors.lastname: Acharya
authors.affiliation: The Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Mike Y
authors.initials: MY
authors.lastname: Zhong
authors.affiliation: The Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Michele
authors.initials: M
authors.lastname: Cea
authors.affiliation: The Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Antonia
authors.initials: A
authors.lastname: Cagnetta
authors.affiliation: Biopharm Discovery, GlaxoSmithKline, Stevenage, United Kingdom;
authors.forename: Jenny
authors.initials: J
authors.lastname: Craigen
authors.affiliation: Biopharm Discovery, GlaxoSmithKline, Stevenage, United Kingdom;
authors.forename: John
authors.initials: J
authors.lastname: Yates
authors.affiliation: Biopharm Discovery, GlaxoSmithKline, Stevenage, United Kingdom;
authors.forename: Louise
authors.initials: L
authors.lastname: Gliddon
authors.affiliation: Platform Technology & Science Research & Development, GlaxoSmithKline, Collegeville, PA;
authors.forename: William
authors.initials: W
authors.lastname: Fieles
authors.affiliation: Platform Technology & Science Research & Development, GlaxoSmithKline, Collegeville, PA;
authors.forename: Bao
authors.initials: B
authors.lastname: Hoang
authors.affiliation: Platform Technology & Science Research & Development, GlaxoSmithKline, Collegeville, PA;
authors.forename: James
authors.initials: J
authors.lastname: Tunstead
authors.affiliation: Lurie Family Imaging Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; and.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Christie
authors.affiliation: Department of Pediatrics, Columbia University Medical Center, New York, NY.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.affiliation: The Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.affiliation: The Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: The Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA;
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000627:therapeutic use; D053301:B-Cell Maturation Antigen / Q000276:immunology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology / Q000627:therapeutic use; D000922:Immunotoxins / Q000276:immunology / Q000627:therapeutic use*; D000077269:Lenalidomide; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013792:Thalidomide / Q000031:analogs & derivatives / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053301:B-Cell Maturation Antigen; D007155:Immunologic Factors; D000922:Immunotoxins; D013792:Thalidomide; D000077269:Lenalidomide