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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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Submitted April 12, 2007
Accepted March 4, 2008

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

Mohammad Luqman*, Sha Klabunde, Karen Lin, Georgios V. Georgakis, Anu Cherukuri, Jocelyn Holash, Cheryl Goldbeck, Xiaomei Xu, Edward E. Kadel III, Sang Hoon Lee, Sharon Lea Aukerman, Bahija Jallal, Natasha Aziz, Wen-Kai Weng, William Wierda, Susan OBrien, and Anas Younes

Disease Area Oncology, Novartis Institutes for Biomedical Research, Emeryville, CA, United States
Dept. of Leukemia, UT MD Anderson Cancer Center, Houston, TX, United States
Department of Internal Medicine, Stanford University Medical Center, Palo Alto, CA, United States
Lymphoma and Myeloma, UT MD Anderson Cancer Center, Houston, TX, United States

* Corresponding author; email: mohammad.luqman{at}novartis.com.

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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