Cancer Combining Antibody Forces

Elizabeth M. Adler

Science Signaling, AAAS, Washington, DC 20005, USA

When combined with conventional chemotherapy, rituximab, a monoclonal antibody directed against the B cell protein CD20, substantially improves long-term survival of individuals with CD20-positive B cell non-Hodgkin lymphoma (NHL). Used alone, however, rituximab, which acts in part by engaging Fc receptors (FcRs) on immune effector cells and stimulating their functions, is not curative. Noting that phagocytosis by macrophages and dendritic cells is inhibited by activation of signal regulatory protein (SIRP) by the commonly found transmembrane protein CD47, Chao et al. postulated that combining rituximab with an antibody that blocks CD47 might have synergistic effects on the ability of phagocytic immune effector cells to act against target lymphoma cells. Flow cytometry analysis revealed that a large subset of human lymphoma samples (of various B cell NHL subtypes) showed increased CD47 abundance compared with normal peripheral blood and germinal center B cells; moreover, high expression of CD47 mRNA correlated with a worse clinical prognosis in some subtypes. In vitro phagocytosis assays showed that anti-CD47 blocking antibodies (B6H12.2 or BRIC126) promoted phagocytosis of lymphoma cells by human or mouse macrophages, as did rituximab, and that the combination of rituximab with an anti-CD47 antibody was more effective at stimulating lymphoma cell phagocytosis than either alone. Ex vivo coating of human lymphoma cell lines or primary specimens with anti-CD47 antibody or rituximab inhibited their engraftment in SCID (severe combined immunodeficiency) mice. Moreover, combination therapy with anti-CD47 antibody plus rituximab eliminated lymphoma in a substantial fraction of disseminated or localized xenotransplants, involving transplantation of human Raji lymphoma cells, into NSG (for NOD scid gamma) mice, which lack T cells, B cells, and NK cells, as well as xenotransplants of primary human lymphoma cells. The synergistic antitumor activity of anti-CD47 antibody and rituximab depended on macrophages, but not NK cells or complement, and involved increased phagocytosis through the stimulation of FcR-dependent and FcR-independent mechanisms. The authors propose that a therapeutic strategy of combining a blocking antibody directed against CD47 with a separate antibody that activates FcR signaling might be broadly applicable in cancer therapy.

M. P. Chao, A. A. Alizadeh, C. Tang, J. H. Myklebust, B. Varghese, S. Gill, M. Jan, A. C. Cha, C. K. Chan, B. T. Tan, C. Y. Park, F. Zhao, H. E. Kohrt, R. Malumbres, J. Briones, R. D. Gascoyne, I. S. Lossos, R. Levy, I. L. Weissman, R. Majeti, Anti-CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-Hodgkin lymphoma. Cell 142, 699–713 (2010). [PubMed]

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