There are improvements needed to bring to full effectiveness radioimmunotherapy (RIT) in breast cancer. Thus, the following specific aims were chosen: 1) Abrogation of the immune response to radioconjugates in RIT of breast tumors. Efforts in this regard will be directed to provide non- immunogenic MoAbs or interfere with the immune response they could create. The following objectives will be pursued: a) Production of human MoAbs by a novel approach using as a starting point human-mouse hybridomas (from human lymph nodes draining breast tumors vs. mouse myeloma cells), that, through genetic engineering, will be transformed into a stable cell lines producing high titers of human MoAbs for use in RIT. It must be emphasized that these human MoAbs will target the repertoire of antigens and epitopes identified by the human immune response to the breast tumor; b) Engineering of immunoglobulin molecules that are non immunogenic to humans using murine MoAbs as donors of variable regions and CDRs. Two general types of molecules will be produced that will progressively approximate our objective: chimeric and humanized monoclonal antibodies. Initially murine MoAb Mc3 will be produced in its chimeric and humanized form. By molecular engineering approaches fragments of these human and humanized antibodies will be also prepared and then tested vs intact parent Ig. c) Development of an immunocompetent mouse model grafted with syngeneic mammary tumors to study the response to heterologous Ig and different idiotypes in an immunologically intact animal and ways to interfere with it. In this model the serologic response to the potentially immunogenic Ig used in RIT will be studied, since even human MoAbs can induce in patients an anti-idiotypic response that preclude repeated administration of the MoAb. 2) Definitive characterization and experimental testing of human anti- breast tumor MoAb intended for immunotherapy.
This aim will comprise of: a) immunochemical testing; and b) in vivo pre-clinical testing. 3) Identification and testing in preclinical studies of enhancers of radioimmunotherapy (RIT). In recently reported results we showed the successful use of radiosensitizers in RIT. These reagents will increase therapeutic ability of the radioconjugates (RC) on the tumor while decreasing innocent bystander radiation damage to normal cells.
| Ozzello, L; Blank, E W; De Rosa, C M et al. (1998) Conjugation of interferon alpha to a humanized monoclonal antibody (HuBrE-3vl) enhances the selective localization and antitumor effects of interferon in breast cancer xenografts. Breast Cancer Res Treat 48:135-47 |
