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Research Articles: Therapeutics, Targets, and Development

Generation of adenovirus-mediated anti-CD20 antibody and its effect on B-cell deletion in mice and nonhuman primate cynomolgus monkey

¹ Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgical Hospital, and Department of Hematology, Changhai Hospital, The Second Military Medical University; ² Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People's Republic of China; ³ Xinyuan Institute of Medicine and Biotechnology, College of Life Science, Zhejiang Sci-Tech University, Zhejiang, People's Republic of China; ⁴ Institute of Radiation Medicine; and ⁵ Department of Hematology, General Hospital of Chinese PLA, Beijing, People's Republic of China

Requests for reprints: Qijun Qian, Laboratory of Viral and Gene Therapy, Eastern Hepatobiliary Surgical Hospital, The Second Military Medical University, Shanghai, People's Republic of China 200438. Phone: 86-2125070836; Fax: 86-2135030677. E-mail: qianqj{at}sino-gene.cn

Abstract

Therapeutic monoclonal anti-CD20 antibody (Rituxan) is increasingly applied to treat B-cell-related hematologic malignancies and autoimmune disorders with great clinical success, whereas its widespread application is limited by antibody manufacturing capability. Here, we explored a quick and economical adenovirus-mediated anti-CD20 antibody generating system to directly produce anti-CD20 antibody in vivo. We generated a recombinant adenovirus encoding the anti-CD20 antibody gene and found that infection of cells with this recombinant adenovirus led to the generation of anti-CD20 antibody in cells with a similar CD20 binding affinity and specificity as commercial product Rituxan. After one single administration of the anti-CD20-expressing adenoviruses through tail vein at a dose of 1 x 10⁹ plaque-forming units/mouse in nude mice, anti-CD20 antibody in the serum was detectable at day 3, reached to the peak value of 246.34 µg/mL at day 14, and maintained a high serum concentration of >40 µg/mL for 56 days. Furthermore, the in vivo generation of anti-CD20 antibody led a complete elimination of preestablished B-cell lymphoma Raji cells in nude mice, and a single administration of the anti-CD20-expressing adenovirus at a dose of 2.0 x 10⁹ plaque-forming units/kg in cynomolgus monkey led a continuous B-cell deletion in circulation blood and bone marrow. These observations thus suggest that adenovirus-mediated in vivo generation of anti-CD20 antibody may serve as a new strategy to combat B-cell-related hematologic disorders. [Mol Cancer Ther 2008;7(6):1562–8]

Grant support: State 863 High Technology R&D Project of China grant 2007AA021108, National Natural Science Foundation of China grant 30700333, 30671402, and Key Project of ZheJiang Provincial Nature and Science Foundation grant Z205618.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: J. Chen, C. Su, and Q. Lu contributed equally to this work.

Received 3/28/08; accepted 4/19/08.