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Blood, 29 October 2009, Vol. 114, No. 18, pp. 3864-3871.
Prepublished online as a Blood First Edition Paper on August 26, 2009; DOI 10.1182/blood-2009-06-228890.
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LYMPHOID NEOPLASIA
CD20-targeted tetrameric interferon- , a novel and potent immunocytokine for the therapy of B-cell lymphomas
Edmund A. Rossi1,
David M. Goldenberg2,
Thomas M. Cardillo1,
Rhona Stein2, and
Chien-Hsing Chang1
1 Immunomedics Inc, Morris Plains, NJ; and
2 Center for Molecular Medicine and Immunology, Garden State Cancer Center, Belleville, NJ
Interferon- (IFN-) has direct inhibitory effects on some tumors and is a potent stimulator of both the innate and adaptive immune systems. A tumor-targeting antibody-IFN- conjugate (mAb-IFN-) could kill by direct actions of the monoclonal antibody (mAb) and IFN- on tumor cells and also potentiate a tumor-directed immune response. The modular Dock-and-Lock method (DNL) was used to generate 20-2b, the first immunocytokine having 4 cytokine (IFN-2b) groups that are fused to the humanized anti-CD20 mAb, veltuzumab. Additional mAb-IFN- constructs, each retaining potent IFN-2b biologic activity, also were produced by DNL. The 20-2b shows enhanced antibody-dependent cellular cytotoxicity compared with veltuzumab but lacks complement-dependent cytotoxicity. The 20-2b inhibits in vitro proliferation of lymphoma cells and depletes them from whole human blood more potently than the combination of veltuzumab and a nontargeting, irrelevant, mAb-IFN-. The 20-2b demonstrated superior therapeutic efficacy compared with veltuzumab or nontargeting mAb-IFN- in 3 human lymphoma xenograft models, even though mouse immune cells respond poorly to human IFN-2b. Targeting IFN- with an anti-CD20 mAb makes the immunocytokine more potent than either agent alone. These findings suggest that 20-2b merits clinical evaluation as a new candidate antilymphoma therapeutic.
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