Antibody - Pretargeted Cytokine Therapy of Cancer

Abstract : We hypothesized that the selective accumulation of systemically administered cytokines at tumor sites can alter tumor microenvironments to favor the induction of anti-tumor immune responses. We further hypothesized that this can be accomplished by pre-targeting tumors with antibody-streptavidin immunoconjugates and then administering biotinylated cytokines. The purpose of this research program was to identify antibody-pretargeted cytokine therapy strategies that lead to tumor-selective cytokine accumulation, the development of host inflammatory cell infiltrates in tumor, and the induction of tumor-specific immunity. The ultimate goal of this research was to identify candidate strategies for clinical development, alone or in combination with tumor vaccines. In the first year of this award we made significant progress toward achieving these goals. Interleukin-2 (IL-2) was biotinylated, and its biological properties were thoroughly characterized. We obtained a streptavidin-conjugated monoclonal antibody that recognized the Ep-CAM tumor antigen that is frequently overexpressed in breast cancer specimens. Animal experiments to characterize the biodistribution properties of the antibody - streptavidin conjugate and of the conjugate admixed with biotinylated IL-2 were performed in year 2. Because biodistribution results did not suggest that the previously used streptavidin-biotin system would yield therapeutic results we redirected efforts in the final year on developing new systems employing bispecific minibodies that contain anti-tumor binding domains and domains that bind to a metal chelate that can serve as a universal acceptor for metal-conjugated cytokines.