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 Blood, 1 August 2008, Vol. 112, No. 3, pp. 711-720.
Prepublished online as a Blood First Edition Paper on May 22, 2008; DOI 10.1182/blood-2007-04-084756.

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NEOPLASIA

The antileukemia activity of a human anti-CD40 antagonist antibody, HCD122, on human chronic lymphocytic leukemia cells

Mohammad Luqman1, Sha Klabunde1, Karen Lin1, Georgios V. Georgakis2, Anu Cherukuri1, Jocelyn Holash1, Cheryl Goldbeck1, Xiaomei Xu1, Edward E. Kadel, III1, Sang Hoon Lee1, Sharon Lea Aukerman1, Bahija Jallal1, Natasha Aziz1, Wen-Kai Weng3, William Wierda2, Susan O'Brien2, and Anas Younes4

1 Disease Area Oncology, Novartis Institutes for BioMedical Research, Emeryville, CA; 2 Leukemia Department, University of Texas M. D. Anderson Cancer Center, Houston; 3 Department of Internal Medicine, Stanford University School of Medicine, Palo Alto, CA; and 4 Department of Lymphoma/Myeloma, University of Texas M. D. Anderson Cancer Center, Houston

B-cell chronic lymphocytic leukemia (B-CLL) is a lymphoproliferative disorder characterized by the surface expression of CD20, CD5 antigens, as well as the receptor CD40. Activation of CD40 by its ligand (CD40L) induces proliferation and rescues the cells from spontaneous and chemotherapy-induced apoptosis. CD40 activation also induces secretion of cytokines, such as IL-6, IL-10, TNF-{alpha}, IL-8, and GM-CSF, which are involved in tumor cell survival, migration, and interaction with cells in the tumor microenvironment. Here we demonstrate that in primary B-CLL tumor cells, the novel antagonist anti-CD40 monoclonal antibody, HCD122, inhibits CD40L-induced activation of signaling pathways, proliferation and survival, and secretion of cytokines. Furthermore, HCD122 is also a potent mediator of antibody-dependent cellular cytotoxicity (ADCC), lysing B-CLL cells more efficiently than rituximab in vitro, despite a significantly higher number of cell surface CD20 binding sites compared with CD40. Unlike rituximab, however, HCD122 (formerly CHIR-12.12) does not internalize upon binding to the cells. Our data suggest that HCD122 may inhibit B-CLL growth by blocking CD40 signaling and by ADCC-mediated cell lysis.


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