title: Potent in vitro and in vivo activity of an Fc-engineered humanized anti-HM1.24 antibody against multiple myeloma via augmented effector function.
abstract: HM1.24, an immunologic target for multiple myeloma (MM) cells, has not been effectively targeted with therapeutic monoclonal antibodies (mAbs). In this study, we investigated in vitro and in vivo anti-MM activities of XmAb5592, a humanized anti-HM1.24 mAb with Fc-domain engineered to significantly enhance FcγR binding and associated immune effector functions. XmAb5592 increased antibody-dependent cellular cytotoxicity (ADCC) several fold relative to the anti-HM1.24 IgG1 analog against both MM cell lines and primary patient myeloma cells. XmAb5592 also augmented antibody dependent cellular phagocytosis (ADCP) by macrophages. Natural killer (NK) cells became more activated by XmAb5592 than the IgG1 analog, evidenced by increased cell surface expression of granzyme B-dependent CD107a and MM cell lysis, even in the presence of bone marrow stromal cells. XmAb5592 potently inhibited tumor growth in mice bearing human MM xenografts via FcγR-dependent mechanisms, and was significantly more effective than the IgG1 analog. Lenalidomide synergistically enhanced in vitro ADCC against MM cells and in vivo tumor inhibition induced by XmAb5592. A single dose of 20 mg/kg XmAb5592 effectively depleted both blood and bone marrow plasma cells in cynomolgus monkeys. These results support clinical development of XmAb5592, both as a monotherapy and in combination with lenalidomide, to improve patient outcome of MM.
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.forename: Holly M
authors.initials: HM
authors.lastname: Horton
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Kong
authors.forename: Erik
authors.initials: E
authors.lastname: Pong
authors.forename: Hsing
authors.initials: H
authors.lastname: Chen
authors.forename: Saso
authors.initials: S
authors.lastname: Cemerski
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bernett
authors.forename: Duc-Hanh T
authors.initials: DH
authors.lastname: Nguyen
authors.forename: Sher
authors.initials: S
authors.lastname: Karki
authors.forename: Seung Y
authors.initials: SY
authors.lastname: Chu
authors.forename: Greg A
authors.initials: GA
authors.lastname: Lazar
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.forename: John R
authors.initials: JR
authors.lastname: Desjarlais
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Umesh S
authors.initials: US
authors.lastname: Muchhal
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000276:immunology*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D004357:Drug Synergism; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D000077269:Lenalidomide; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008212:Lymphocyte Depletion; D008252:Macaca fascicularis; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000628:therapy*; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000074010:Bone Marrow Stromal Antigen 2
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000970:Antineoplastic Agents; D058851:GPI-Linked Proteins; D007141:Immunoglobulin Fc Fragments; D000077269:Lenalidomide; D013792:Thalidomide; C094572:BST2 protein, human; D000074010:Bone Marrow Stromal Antigen 2