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 Blood, 1 February 2007, Vol. 109, No. 3, pp. 1185-1192.
Prepublished online as a Blood First Edition Paper on October 12, 2006; DOI 10.1182/blood-2006-07-034017.

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NEOPLASIA

Engineered anti-CD70 antibody with multiple effector functions exhibits in vitro and in vivo antitumor activities

Julie A. McEarchern1, Ezogelin Oflazoglu1, Leigh Francisco1, Charlotte F. McDonagh1, Kristine A. Gordon1, Ivan Stone1, Kerry Klussman1, Eileen Turcott1, Nico van Rooijen2, Paul Carter1, Iqbal S. Grewal1, Alan F. Wahl1, and Che-Leung Law1

1 Seattle Genetics, Seattle, WA; 2 Department of Molecular Cell Biology, Vrije Universiteit, Amsterdam, the Netherlands

Antigens expressed on malignant cells in the absence of significant expression on normal tissues are highly desirable targets for therapeutic antibodies. CD70 is a TNF superfamily member whose normal expression is highly restricted but is aberrantly expressed in hematologic malignancies including non-Hodgkin lymphoma (NHL), Hodgkin disease, and multiple myeloma. In addition, solid tumors such as renal cell carcinoma, nasopharyngeal carcinoma, thymic carcinoma, meduloblastoma, and glioblastoma express high levels of this antigen. To functionally target CD70-expressing cancers, a murine anti-CD70 monoclonal antibody was engineered to contain human IgG1 constant domains. The engineered antibody retained the binding specificity of the murine parent monoclonal antibody and was shown to induce Fc-mediated effector functions including antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis in vitro. Further, administration of this antibody significantly prolonged survival of severe combined immunodeficient (SCID) mice bearing CD70+ disseminated human NHL xenografts. Survival of these mice was dependent upon the activity of resident effector cells including neutrophils, macrophages, and natural killer (NK) cells. These data suggest that an anti-CD70 antibody, when engineered to contain human IgG1 constant domains, possesses effector cell–mediated antitumor activity and has potential utility for anticancer therapy.


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