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A Novel Raji-Burkitt's Lymphoma Model for Preclinical and Mechanistic Evaluation of CD52-Targeted Immunotherapeutic Agents

Authors' Affiliations: ¹ Division of Hematology-Oncology, Department of Internal Medicine, ² Division of Pharmaceutics, College of Pharmacy, ³ Department of Chemical and Biomolecular Engineering, ⁴ Center for Affordable Nanoengineering of Polymeric Biomedical Devices, ⁵ Department of Pathology, and ⁶ Center for Biostatistics, Ohio State University, Columbus, Ohio

Requests for reprints: Natarajan Muthusamy, 455E, OSU CCC, 410 West 12th Avenue, Ohio State University, Columbus, OH 43210. Phone: 614-292-8135; Fax: 614-293-7526; E-mail: raj.muthusamy{at}osumc.edu.

Purpose: To date, efforts to study CD52-targeted therapies, such as alemtuzumab, have been limited due to the lack of stable CD52 expressing transformed B-cell lines and animal models. We describe generation and utilization of cell lines that stably express CD52 both in vitro and in vivo.

Experimental Design: By limiting dilution, we have established several clones of Raji-Burkitt's lymphoma cell line that express surface CD52. Immunophenotype and cytogenetic characterization of these clones was done. In vivo usefulness of the CD52^high cell line to evaluate the therapeutic efficacy of CD52-directed antibody was investigated using a SCID mouse xenograft model.

Results: Stable expression of CD52 was confirmed in cells cultured in vitro up to 52 weeks of continuous growth. The functional integrity of the expressed CD52 molecule was shown using alemtuzumab, which induced cytotoxic effects in vitro in the CD52^high but not the CD52^low clone. Compared with control antibody, alemtuzumab treatment in CD52^high inoculated mice resulted in significantly increased median survival. Comparable levels of CD52-targeted direct cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cytotoxicity and anti-CD52 immunoliposome-mediated delivery of synthetic oligodeoxyribo nucleotides in CD52^high clone and primary B-chronic lymphocytic leukemia cells implicated potential in vivo application of this model for evaluation of CD52-targeted antibody and immunoliposomes encapsulating therapeutic agents.

Conclusions: These results show the in vitro utility of the cloned Raji cell lines that stably express high levels CD52. The disseminated leukemia-lymphoma mouse model described herein using these stable cell lines can serve as an excellent system for in vivo therapeutic and mechanistic evaluation of existing and novel antibodies directed against CD52 molecule.

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