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Anti-VEGF Single-Chain Antibody GLAF-1 Encoded by Oncolytic Vaccinia Virus Significantly Enhances Antitumor Therapy
Alexa Frentzen, Yong A. Yu, Nanhai Chen, Qian Zhang, Stephanie Weibel, Viktoria Raab, Aladar A. Szalay and George Klein
Proceedings of the National Academy of Sciences of the United States of America
Vol. 106, No. 31 (Aug. 4, 2009), pp. 12915-12920
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/40484625
Page Count: 6
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We previously reported that the replication-competent vaccinia virus (VACV) GLV-1h68 shows remarkable oncolytic activity and efficacy in different animal models as a single treatment modality and also in combination with chemotherapy [Yu YA, et al. (2009) Mol Cancer Ther 8: 141-151]. Here, we report the construction of 3 VACV strains encoding GLAF-1, a previously undescribed engineered single-chain antibody (scAb). This unique scAb is transcribed from 3 vaccinia promoters (synthetic early, early/late, and late) and directed against both human and murine VEGFs. The expression of GLAF-1 was demonstrated in cell cultures. Also, the replication efficiency of all GLAF-1-expressing VACV strains in cell culture was similar to that of the parental GLV-1h68 virus. Successful tumor-specific delivery and continued production of functional scAb derived from individual VACV strains were obtained in tumor xenografts following a single intravenous injection of the virus. The VACV strains expressing the scAb exhibited significantly enhanced therapeutic efficacy in comparison to treatment of human tumor xenografts with the parental virus GLV-1h68. This enhanced efficacy was comparable to the concomitant treatment of tumors with a one-time i. v. injection of GLV-1h68 and multiple i.p. injections of Avastin. Taken together, the VACV-mediated delivery and production of immunotherapeutic anti-VEGF scAb in colonized tumors may open the way for a unique therapy concept: tumor-specific, locally amplified drug therapy in humans.
Proceedings of the National Academy of Sciences of the United States of America © 2009 National Academy of Sciences