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Cancer Res. 2011 Feb 15;71(4):1374-84. Epub 2010 Dec 21.. o: q1 Q$ O& `3 A- d9 w6 v' r0 Y
Therapeutic Antibody Targeting of CD47 Eliminates Human Acute Lymphoblastic Leukemia.
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Chao MP, Alizadeh AA, Tang C, Jan M, Weissman-Tsukamoto R, Zhao F, Park CY, Weissman IL, Majeti R.
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/ {0 g" D6 v! G" Z% hAuthors' Affiliations: Institute for Stem Cell Biology and Regenerative Medicine, Stanford Cancer Center, and Ludwig Center at Stanford; Department of Internal Medicine; Divisions of Hematology and Oncology, Department of Pathology, Stanford University, Palo Alto, California; and Departments of Pathology and Clinical Laboratories and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York./ T9 Z: \# q& A% i
Abstract
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Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and constitutes 15% of adult leukemias. Although overall prognosis for pediatric ALL is favorable, high-risk pediatric patients and most adult patients have significantly worse outcomes. Multiagent chemotherapy is standard of care for both pediatric and adult ALL, but is associated with systemic toxicity and long-term side effects and is relatively ineffective against certain ALL subtypes. Recent efforts have focused on the development of targeted therapies for ALL including monoclonal antibodies. Here, we report the identification of CD47, a protein that inhibits phagocytosis, as an antibody target in standard and high-risk ALL. CD47 was found to be more highly expressed on a subset of human ALL patient samples compared with normal cell counterparts and to be an independent predictor of survival and disease refractoriness in several ALL patient cohorts. In addition, a blocking monoclonal antibody against CD47 enabled phagocytosis of ALL cells by macrophages in vitro and inhibited tumor engraftment in vivo. Significantly, anti-CD47 antibody eliminated ALL in the peripheral blood, bone marrow, spleen, and liver of mice engrafted with primary human ALL. These data provide preclinical support for the development of an anti-CD47 antibody therapy for treatment of human ALL. Cancer Res; 71(4); 1374-84. ©2010 AACR. |
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