Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma

Mark P. Chao; Ash A. Alizadeh; Chad Tang; June H. Myklebust; Bindu Varghese; Saar Gill; Max Jan; Adriel C. Cha; Charles K. Chan; Brent T. Tan; Christopher Y. Park; Feifei Zhao; Holbrook E. Kohrt; Raquel Malumbres; Javier Briones; Randy D. Gascoyne; Izidore S. Lossos; Ronald Levy; Irving L. Weissman; Ravindra Majeti

doi:10.1016/j.cell.2010.07.044

Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma

Mark P. Chao, Ash A. Alizadeh, Chad Tang, June H. Myklebust, Bindu Varghese, Saar Gill, Max Jan, Adriel C. Cha, Charles K. Chan, Brent T. Tan, Christopher Y. Park, Feifei Zhao, Holbrook E. Kohrt, Raquel Malumbres, Javier Briones, Randy D. Gascoyne, Izidore S. Lossos, Ronald Levy, Irving L. Weissman, Ravindra Majeti

Medicine

Research output: Contribution to journal › Article

475 Scopus citations

Abstract

Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.

Original language	English (US)
Pages (from-to)	699-713
Number of pages	15
Journal	Cell
Volume	142
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2010.07.044
State	Published - Sep 3 2010

Keywords

Cellimmuno
Humdisease

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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Chao, M. P., Alizadeh, A. A., Tang, C., Myklebust, J. H., Varghese, B., Gill, S., Jan, M., Cha, A. C., Chan, C. K., Tan, B. T., Park, C. Y., Zhao, F., Kohrt, H. E., Malumbres, R., Briones, J., Gascoyne, R. D., Lossos, I. S., Levy, R., Weissman, I. L., & Majeti, R. (2010). Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma. Cell, 142(5), 699-713. https://doi.org/10.1016/j.cell.2010.07.044

Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma. / Chao, Mark P.; Alizadeh, Ash A.; Tang, Chad; Myklebust, June H.; Varghese, Bindu; Gill, Saar; Jan, Max; Cha, Adriel C.; Chan, Charles K.; Tan, Brent T.; Park, Christopher Y.; Zhao, Feifei; Kohrt, Holbrook E.; Malumbres, Raquel; Briones, Javier; Gascoyne, Randy D.; Lossos, Izidore S.; Levy, Ronald; Weissman, Irving L.; Majeti, Ravindra.

In: Cell, Vol. 142, No. 5, 03.09.2010, p. 699-713.

Research output: Contribution to journal › Article

Chao, MP, Alizadeh, AA, Tang, C, Myklebust, JH, Varghese, B, Gill, S, Jan, M, Cha, AC, Chan, CK, Tan, BT, Park, CY, Zhao, F, Kohrt, HE, Malumbres, R, Briones, J, Gascoyne, RD, Lossos, IS, Levy, R, Weissman, IL & Majeti, R 2010, 'Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma', Cell, vol. 142, no. 5, pp. 699-713. https://doi.org/10.1016/j.cell.2010.07.044

Chao, Mark P. ; Alizadeh, Ash A. ; Tang, Chad ; Myklebust, June H. ; Varghese, Bindu ; Gill, Saar ; Jan, Max ; Cha, Adriel C. ; Chan, Charles K. ; Tan, Brent T. ; Park, Christopher Y. ; Zhao, Feifei ; Kohrt, Holbrook E. ; Malumbres, Raquel ; Briones, Javier ; Gascoyne, Randy D. ; Lossos, Izidore S. ; Levy, Ronald ; Weissman, Irving L. ; Majeti, Ravindra. / Anti-CD47 Antibody Synergizes with Rituximab to Promote Phagocytosis and Eradicate Non-Hodgkin Lymphoma. In: Cell. 2010 ; Vol. 142, No. 5. pp. 699-713.

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abstract = "Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.",

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