title: Macrophage and NK-mediated killing of precursor-B acute lymphoblastic leukemia cells targeted with a-fucosylated anti-CD19 humanized antibodies.
abstract: This work reports the tumoricidal effects of a novel investigational humanized anti-CD19 monoclonal antibody (Medi-551). An a-fucosylated antibody with increased affinity for human FcγRIIIA, Medi-551 is shown to mediate both antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). Medi-551/CD19 complexes internalize slowly (>5 h) and thus remain accessible to effector cells for prolonged periods. We evaluated in vitro ADCC and ADCP activities of primary human natural killer (NK) cells and macrophages against precursor-B (pre-B) acute lymphoblastic leukemia (ALL) cell lines and pediatric patient blasts. Fluorescent imaging studies document immunological synapses formed between anti-CD19-bound target leukemia cells and effector cells and capture the kinetics of both NK-mediated killing and macrophage phagocytosis. Genetic polymorphisms in FcγRIIIA-158F/V modulate in vitro activities of effector cells, with FcγRIIIA-158V homozygotes or heterozygotes showing the strongest activity. Medi-551 treatment of severe combined immunodeficiency (SCID) mice engrafted with human pre-B cells led to prolonged animal survival and markedly reduced disease burden in blood, liver and bone marrow. These data show that anti-CD19 antibodies effectively recruit immune cells to pre-B ALL cells and support a move forward to early phase trials in this disease.
authors.affiliation: Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131-0001, USA.
authors.forename: K
authors.initials: K
authors.lastname: Matlawska-Wasowska
authors.forename: E
authors.initials: E
authors.lastname: Ward
authors.forename: S
authors.initials: S
authors.lastname: Stevens
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: R
authors.initials: R
authors.lastname: Herbst
authors.forename: S S
authors.initials: SS
authors.lastname: Winter
authors.forename: B S
authors.initials: BS
authors.lastname: Wilson
mesh_terms: D000208:Acute Disease; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000378:metabolism; D000920:Antibody-Dependent Cell Cytotoxicity; D018941:Antigens, CD19 / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D005455:Fluorescent Antibody Technique; D005643:Fucose / Q000378:metabolism; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D015448:Leukemia, B-Cell / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D014183:Transplantation, Heterologous
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018941:Antigens, CD19; D005643:Fucose