Antibody Therapy Targeting a Novel Neuroblastoma Antigen

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DESCRIPTION (provided by applicant): Neuroblastoma is the most common extracranial solid tumor of childhood. Aggressive chemotherapy and surgery have improved remission rates for young patients, but not for adolescents or adults, in whom neuroblastoma is especially resistant to chemotherapy. Thus, new therapeutic proaches are desperately needed, especially for this difficult to treat patient group. The goal of this proposal is to develop a new therapeutic monoclonal antibody (mAb) directed against a novel neuroblastoma-associated antigen. A panel of 4 - 6 mAbs will be produced and purified from mouse ascites fluid. These mAbs will be characterized in vitro to select the best one or two candidates for further pre-clinical development in Phase II studies. The target cell specificity will be determined by testing the binding of the mAbs to a large anel of neuroblastoma cell lines, as well as a diverse selection of other tumor cell types by immunofluorescence. Evaluation of mAb binding to normal non-transformed cells will also be studied. Immunohistochemical analysis will evaluate mAb binding to neuroblastoma tissues derived from patients, as well as a panel of different normal tissue types. The potential cytotoxic effects of mAbs alone or in the presence of complement or antibodydependent cytotoxic effector cells will be tested against neuroblastoma cell lines in vitro. The ability of the mAbs to internalize into neuroblastoma cell lines will evaluated in vitro. The results of these studies will indicate whether the mAb of choice may be therapeutic alone or whether it should be armed with a toxic moiety to kill neuroblastoma cells in future Phase II animal models. Preliminary results indicating that the novel antigen termed NBA260 is a suitable target for nueroblastoma targeting will be confirmed by purification of NBA260 and amino acid sequencing. The results of this study will demonstrate the validity of a new therapeutic option for neuroblastoma patients and possibly other types of cancer such as ovarian and liver cancer.