450. Anti-CD22 Immunolipoplexes Enhance Transduction of Adenovirus in B Lymphoma Cells Independent on Adenovirus' Receptor but Do Not Enhance the Cytotoxicity of Oncolytic Adenovirus

Abstract

Adenovirus vectors have several features that make them attractive for potential use in gene therapy, and attention has focused particularly on replication-competent adenoviruses for cancer applications. These have been evaluated extensively in epithelial tumours but only recently in lymphoid malignancies, mainly due to the known resistance of the lymphoid lineage to adenovirus infection. However, we and other groups have shown that this resistance is not absolute and that adenovirus can infect primary chronic lymphocytic leukaemia (CLL) and B-cell lymphoma lines, and that infection with replication-competent human adenovirus results in cytotoxicity that varies among different patients and different lymphoma cell lines. We found that the cytotoxicity of Adenovirus to Burkitt's lymphoma cells correlates with the infectability of these cells to adenovirus, which depends on the expression of adenovirus receptors such as CAR and heparan sulfate glycosaminoglycans. In a panel of lymphoma cell lines including Jiyoye, Raji, Daudi/ICRF, Daudi/100k, P3HR1, BL-74 and CA-46, only Jiyoye and Raji showed a significant cytotoxicity and Adenovirus receptor expression. Most of these cell lines show a very low or no cytotoxicity to replication-competent adenovirus due to low expression of adenovirus receptors. Most lymphoma cells exhibit high expression of CD22, a membrane protein that is endocytosed when anti-CD22 antibody binds the protein. Based on these observations, an adenovirus-retargeting system was developed for CD22-mediated cell entry: adenovirus-containing immunolipoplexes formed with monoclonal anti-CD22 antibody were tested for enhanced transduction of adenovirus receptor-negative lymphoma cell lines (BL-74 and CA-46). The results demonstrate that the method increased adenovirus transduction by 95.4% (anti-CD22-immunolipoplexes vs naked adenovirus) and 62.3% (anti-CD22-immunolipoplexes vs lipid-adenovirus complex) in CA-46 cells, and 38.2% (anti-CD22-immunolipoplexes vs naked adenovirus) and 27.1% (anti-CD22-immunolipoplexes vs lipid-adenovirus complex) in BL-74 cells, respectively. However, the method did not increase the cytotoxicity of replication-competent adenovirus to these cells. In conclusion, this study demonstrates that anti-CD22 immunolipoplexes represent an efficient strategy to enhance adenovirus transduction independent of adenovirus receptor status. This protocol may have an impact on cancer therapy for lymphomas.