The development of a bicistronic plasmid DNA vaccine for B-cell lymphoma.
Tumor vaccines are a promising alternative to chemotherapy for the treatment of metastatic cancer. To be effective and safe, a therapeutic cancer vaccine should specifically target antigens expressed only on metastatic tumor cells. A vaccine directed against the unique surface immunoglobulin or idiotype expressed on non-Hodgkin's B-cell lymphoma fulfills these criteria, as both primary and metastatic tumor cells express tumor specific immunoglobulins. Using the murine 38C13 B-cell lymphoma tumor as a model system, a plasmid DNA vaccine was designed to express a bicistronic mRNA encoding both the light and heavy tumor immunoglobulin (idiotype) proteins expressed on the surface of the 38C13 tumor. To increase the immunogenicity of the plasmid DNA vaccine, each of the murine variable domains (light and heavy) were fused to their respective human immunoglobulin constant domains. In addition, a eukaryotic expression cassette was constructed to effect both high-level expression of the mouse/human chimeric immunoglobulin, and to elicit a protective immune response in vivo. Unique Sfi I restriction sites were used for the rapid cloning of any tumor specific immunoglobulin idiotype domains and a series of plasmid constructs were made to test changes to the J domain and/or the human C domain to insert the Sfi I restriction sites. Such changes were found to have significant effects on both expression and immunogenicity. Vaccination of mice with prototype idiotype vaccines was found to generate a protective immune response to the 38C13 tumor. This study indicates that a novel bicistronic plasmid DNA-based vaccine can be used to develop a tumor specific vaccine against B-cell lymphoma.
Singh
Gita
G
Department of Molecular Biology, Vical Incorporated, 9373 Towne Centre Dr. Suite 100, San Diego, CA 92121, USA.
Parker
Suezanne
S
Hobart
Peter
P
D000818:Animals; D000912:Antibodies, Neoplasm / Q000235:genetics* / Q000276:immunology; D001483:Base Sequence; D019496:Cancer Vaccines / Q000276:immunology*; D005260:Female; D005796:Genes; D005822:Genetic Vectors; D006801:Humans; D007114:Immunization; D007130:Immunoglobulin Idiotypes / Q000235:genetics* / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D010957:Plasmids; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured; D019444:Vaccines, DNA / Q000276:immunology*
D000912:Antibodies, Neoplasm; D019496:Cancer Vaccines; D007130:Immunoglobulin Idiotypes; D019444:Vaccines, DNA