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Acute Leukemias

Macrophage and NK-mediated killing of precursor-B acute lymphoblastic leukemia cells targeted with a-fucosylated anti-CD19 humanized antibodies

Leukemia volume 27, pages 1263–1274 (2013)Cite this article

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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.

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Acknowledgements

KM-W received salary support from LLS, P50/GM065794 and the UNM Pediatrics Department. We thank UNM Pediatric Hematology/Oncology division for acquiring consented pre-B ALL samples and Anna Holmes for technical assistance. We acknowledge Flow Cytometry, Fluorescent Microscopy, Human Tissue Repository and Animal Resource Facilities at UNM.

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Authors and Affiliations

  1. Department of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

    K Matlawska-Wasowska & B S Wilson

  2. Department of Pediatrics, Division of Hematology/Oncology, University of New Mexico Health Sciences Center, Albuquerque, NM, USA

    K Matlawska-Wasowska, S Stevens & S S Winter

  3. Department of Research, Respiratory, Inflammation, and Autoimmunity, MedImmune, LLC, Gaithersburg, MD, USA

    E Ward, Y Wang & R Herbst

  4. LU-R1 program, Lawrence University, Appleton, WI, USA

    S Stevens

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  1. K Matlawska-Wasowska
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Correspondence to B S Wilson.

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KM-W, SSW, BSW and SS have no relevant financial conflicts to disclose. RH, YW and EW are employees of MedImmune.

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Author contributions

KM-W designed and performed the research, analyzed data and wrote the manuscript. EW prepared Medi-551 for research. SS genotyped human cells. YW participated in designing the research. SSW provided pre-B ALL samples and designed the research. RH originated the project. BSW originated, supervised the project and wrote the manuscript. All authors reviewed the manuscript.

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Matlawska-Wasowska, K., Ward, E., Stevens, S. et al. Macrophage and NK-mediated killing of precursor-B acute lymphoblastic leukemia cells targeted with a-fucosylated anti-CD19 humanized antibodies. Leukemia 27, 1263–1274 (2013). https://doi.org/10.1038/leu.2013.5

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