Evaluation of the effects of VEGF-binding anti-anti-bevacizumab idiotype antibodies on the expression of angiogenic mediators in human tumor and endothelial cell lines

Abstract

Immunotherapy has become an important topic of many cancer treatment protocols. It is known that tumor cells secrete factors critically involved in the formation and maintenance of angiogenesis. Among the most expressed, it is the vascular endothelial growth factor (VEGF). Bevacizumab is the first and most promising humanized anti-VEGF monoclonal antibody (mAb) approved for the treatment of various types of cancer. However, undesirable effects detected mainly when using the antibody in high doses have been described. As an alternative approach to the use of bevacizumab, our laboratory proposed the development of the anti-bevacizumab idiotype (Id) mAb 10.D7 to be used as a therapeutic vaccine. The mAb 10.D7, when used as an immunogen, stimulates VEGF-binding anti-anti-Id antibody response, inhibits tumor growth, and reduces tumor vascular density. We recently developed the single-chain variable fragment scFv 10.D7 to evaluate its use as a gene vaccine and the results were comparable to those obtained with the hole mAb 10.D7 protein molecule. In the present project, we intend to evaluate the anti-anti-Id antibodies, generated from the gene vaccination of mice, in types of human tumors that respond to treatment with bevacizumab in clinical practice, or those that have already received indication, but with controversial results, and in some VEGF-dependent ones without indication. The evaluation of the effects of antibodies will be carried out by analyzing the expression of genes related to angiogenesis in tumor cells and in endothelial cell line cultured in the presence of supernatants from cultures of treated tumor cells. It is of interest to identify whether there is gene expression of any factor(s) involved in angiogenesis that is common to tumor cells that respond or not to treatment and whether the response to anti-anti-Id is always comparable to that seen with bevacizumab. It is worth mentioning that not all VEGF-dependent tumors respond to therapy with bevacizumab and the response, when present, is not homogeneous, even for patients with the same type of tumor. (AU)