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[Cancer Research 65, 5898-5906, July 1, 2005]
© 2005 American Association for Cancer Research

Experimental Therapeutics, Molecular Targets, and Chemical Biology

Human Anti-CD40 Antagonist Antibody Triggers Significant Antitumor Activity against Human Multiple Myeloma

Yu-Tzu Tai1, Xianfeng Li1, Xia Tong2, Daniel Santos1, Takemi Otsuki3, Laurence Catley1, Olivier Tournilhac1, Klaus Podar1, Teru Hideshima1, Robert Schlossman1, Paul Richardson1, Nikhil C. Munshi1, Mohammad Luqman2 and Kenneth C. Anderson1

1 Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; 2 Research, Chiron Corporation, Emeryville, California; and 3 Department of Hygiene, Kawasaki Medical School, Okayama, Japan

Requests for reprints: Kenneth C. Anderson, Department of Medical Oncology, Dana-Farber Cancer Institute, M557, 44 Binney Street, Boston, MA 02115. Phone: 617-632-2144; Fax: 617-632-2140; E-mail: kenneth.anderson{at}dfci.harvard.edu.

Monoclonal antibodies (mAb) directed against lineage-specific B-cell antigens have provided clinical benefit for patients with hematologic malignancies, but to date no antibody-mediated immunotherapy is available for multiple myeloma. In the present study, we assessed the efficacy of a fully human anti-CD40 mAb CHIR-12.12 against human multiple myeloma cells. CHIR-12.12, generated in XenoMouse mice, binds to CD138-expressing multiple myeloma lines and freshly purified CD138-expressing cells from >80% multiple myeloma patients, as assessed by flow cytometry. Importantly, CHIR-12.12 abrogates CD40L-induced growth and survival of CD40-expressing patient multiple myeloma cells in the presence or absence of bone marrow stromal cells (BMSC), without altering constitutive multiple myeloma cell proliferation. Immunoblotting analysis specifically showed that PI3-K/AKT, nuclear factor-{kappa}B (NF-{kappa}B), and extracellular signal-regulated kinase activation induced by CD40L (5 µg/mL) was inhibited by CHIR-12.12 (5 µg/mL). Because CD40 activation induces multiple myeloma cell adhesion to both fibronectin and BMSCs, we next determined whether CHIR-12.12 inhibits this process. CHIR-12.12 decreased CD40L-induced multiple myeloma cell adhesion to fibronectin and BMSCs, whereas control human IgG1 did not. Adhesion of multiple myeloma cells to BMSCs induces interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion, and treatment of multiple myeloma cells with CD40L further enhanced adhesion-induced cytokine secretion; conversely, CHIR-12.12 blocks CD40L-enhanced IL-6 and VEGF secretion in cocultures of multiple myeloma cells with BMSCs. Finally, CHIR-12.12 triggered lysis of multiple myeloma cells via antibody-dependent cellular cytotoxicity (ADCC) but did not induce ADCC against CD40-negative multiple myeloma cells, confirming specificity against CD40-expressing multiple myeloma cells. These results provide the preclinical rationale for clinical trials of CHIR-12.12 to improve patient outcome in multiple myeloma.




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