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 Blood, 1 February 2005, Vol. 105, No. 3, pp. 1114-1120.
Prepublished online as a Blood First Edition Paper on October 14, 2004; DOI 10.1182/blood-2004-07-2561.

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IMMUNOBIOLOGY

Anti–human CTLA-4 monoclonal antibody promotes T-cell expansion and immunity in a hu-PBL-SCID model: a new method for preclinical screening of costimulatory monoclonal antibodies

Kenneth F. May, Jr, Sameek Roychowdhury, Darshna Bhatt, Ergun Kocak, Xue-Feng Bai, Jin-Qing Liu, Amy K. Ferketich, Edward W. Martin, Jr, Michael A. Caligiuri, Pan Zheng, and Yang Liu

From the Department of Pathology, Division of Cancer Immunology; Department of Internal Medicine, Division of Hematology/Oncology; Division of Epidemiology and Biometrics; and Department of Surgery, Division of Surgical Oncology, The Ohio State University Medical Center and Comprehensive Cancer Center, Columbus.

When adopting basic principles learned in mice to clinical application in humans, it is often difficult to distinguish whether a "translation" fails because of an invalid target in the human disease or because the therapeutic agents are not optimal for the human target. It is, therefore, desirable to develop preclinical models to optimize therapies for human targets using in vivo settings. Although anti–mouse CTLA-4 antibodies are known to enhance immune responses in vivo, their effect on T-cell activation in vitro ranges from enhancement to inhibition. Here we use the hu-PBL-SCID mouse model of Epstein-Barr virus (EBV)–associated lymphoma development to screen a panel of anti–human CTLA-4 monoclonal antibodies (mAbs) for their effect on human lymphocytes in an in vivo "humanized" environment. We report significant heterogeneity of anti–human CTLA-4 mAbs in enhancing the expansion of human T cells in mice, and this heterogeneity cannot be attributed to immunoglobulin isotypes or affinity for CTLA-4. These data validate the development of additional screening tools, such as the one described, to further characterize functional activity of antihuman antibodies before proceeding with clinical translation to human studies.


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