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

• Published in: Molecular cancer therapeutics 2008-06, Vol.7 (6), p.1562-1568
• Main Authors: Chen, Jie, Su, Changqing, Lu, Qiujun, Shi, Wenfang, Zhang, Qi, Wang, Xinghua, Long, Ju, Yang, Qin, Li, Linfang, Jia, Xiaoyuan, Wang, Jianming, Da, Wanming, Liu, Xinyuan, Wu, Mengchao, Qian, Qijun
• Format: Article
• Language: English
• Subjects: Adenoviridae - genetics; Adenoviridae - metabolism; Adenovirus; Animals; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal, Murine-Derived; antibody therapy; Antigens, CD20 - immunology; Antineoplastic Agents - pharmacology; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; Blotting, Western; CD20 antibody; Cell Line, Tumor; cynolmugus monkey; Cynomolgus; gene therapy; Humans; Lymphocyte Depletion; Macaca fascicularis - immunology; Male; Mice; Mice, Inbred BALB C; Primates; Rituximab
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-08-0297

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 × 10 9 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 × 10 9 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]