Anti-tumoral effect of active immunotherapy in C57BL/6 mice using a recombinant human VEGF protein as antigen and three chemically unrelated adjuvants.
Following the clinical success of Bevacizumab, a humanized monoclonal antibody that affects the interaction between vascular endothelial growth factor (VEGF) and its receptors, blocking tumor-induced angiogenesis has become one of the most important targets for the development of new cancer therapeutic drugs and procedures. Among the latter, therapeutic vaccination using VEGF as antigen presents itself as very attractive, with the potential of generating not only a growth factor blocking antibody response but also a cellular response against tumor cells and stromal elements, which appear to be a major source of tumor VEGF. In this paper, we report the development of a protein vaccine candidate, based on a human modified VEGF antigen that is expressed at high levels in E. coli. With respect to controls, immunization experiments in C57BL/6 mice using weekly doses of this antigen and three adjuvants of different chemical natures show that time for tumor development after subcutaneous injection of Melanoma B16-F10 cells increases, tumors that develop grow slower, and overall animal survival is higher. Immunization also prevents tumor development in some mice, making them resistant to second tumor challenges. Vaccination of mice with the human modified VEGF recombinant antigen produces antibodies against the human antigen and the homologous mouse VEGF molecule. We also show that sera from immunized mice block human VEGF-induced HUVEC proliferation. Finally, a possible contribution of T cell cytotoxicity to the overall anti-tumor effect is suggested from the results of vaccination experiments where CD8+ lymphocytes were impaired using neutralizing rat antibodies.
Morera
Yanelys
Y
Recombinant Antibody Group, Cancer Research Department, Center for Genetic Engineering and Biotechnology, P.O. Box 6162, Ave 31 and 190 Cubanacán, 10600, Playa, Havana, Cuba.
Bequet-Romero
Mónica
M
Ayala
Marta
M
Lamdán
Humberto
H
Agger
Else-Marie
EM
Andersen
Peter
P
Gavilondo
Jorge V
JV
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies; D000941:Antigens / Q000276:immunology*; D001522:Behavior, Animal / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004926:Escherichia coli; D006801:Humans; D007106:Immune Sera; D016233:Immunotherapy, Active; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000302:isolation & purification / Q000378:metabolism; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D011994:Recombinant Proteins / Q000276:immunology* / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000276:immunology* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000906:Antibodies; D000941:Antigens; D007106:Immune Sera; D050505:Mutant Proteins; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2