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Targeting the Lymphotoxin-ß Receptor with Agonist Antibodies as a Potential Cancer Therapy

¹ Departments of Immunobiology, Oncopharmacology, Molecular Engineering, Molecular Profiling, Molecular Discovery, Antibody Humanization, and Cellular Engineering, Biogen Idec, Cambridge, Massachusetts; ² Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan; and ³ AntiCancer, Inc., San Diego, California

Requests for reprints: Jeffrey L. Browning, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142. Phone: 617-679-3312; Fax: 617-679-3148; E-mail: jeff.browning{at}biogenidec.com.

The lymphotoxin-ß receptor (LTßR) is a tumor necrosis factor receptor family member critical for the development and maintenance of various lymphoid microenvironments. Herein, we show that agonistic anti-LTßR monoclonal antibody (mAb) CBE11 inhibited tumor growth in xenograft models and potentiated tumor responses to chemotherapeutic agents. In a syngeneic colon carcinoma tumor model, treatment of the tumor-bearing mice with an agonistic antibody against murine LTßR caused increased lymphocyte infiltration and necrosis of the tumor. A pattern of differential gene expression predictive of cellular and xenograft response to LTßR activation was identified in a panel of colon carcinoma cell lines and when applied to a panel of clinical colorectal tumor samples indicated 35% likelihood a tumor response to CBE11. Consistent with this estimate, CBE11 decreased tumor size and/or improved long-term animal survival with two of six independent orthotopic xenografts prepared from surgical colorectal carcinoma samples. Targeting of LTßR with agonistic mAbs offers a novel approach to the treatment of colorectal and potentially other types of cancers. (Cancer Res 2006; 66(19): 9617-24)

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