Studies on Superantigens and Antibody Directed Enzyme Prodrug Therapy for Tolerable Targeted Cancer Treatment

Conventional cancer therapies such as Radiotherapy, chemotherapy and surgery are often associated with severe side effects due to the lack of specificity to tumor cells. Targeted Cancer therapies overcome these limitations. Our work focuses on improving two tumor targeting strategies, the first is Tumor Targeted Superantigens (TTS) and the second is Antibody Directed Enzyme Prodrug Therapy (ADEPT). Superantigens are potent T-cell activators and therefore it is used in targeted cancer immunotherapy. Superantigen, however, causes severe hypotension. Thus, we measure vasodilatory effect of different superantigens. We identified region(s) on SPEA superantigen which are involved in vasodilation effect. Our new data would lead to the construction of Tumor targeted Superantigens, using the new variant of superantigen lacking the regions responsible for vasodilation for safer cancer treatment. The second part of the work deals with the antibody directed enzyme prodrug therapy. The ADEPT is a technique that uses enzyme to convert a prodrug into a toxic drug in the vicinity of the tumor. Repeated cycles of ADEPT induce severe immune response which lowers the efficiency of ADEPT. To reduce the immunogenicity effect, we successfully carried out the following: 1. Isolation and molecular characterization of new carboxypeptidase G2 enzyme variant (Xen CPG2) with different epitopes to be used consecutively with the wild type CPG2.2. Production of three “biobetter” CPG2 variants with enhanced enzyme activities than the wild type.3. Production of novel variants of Xen CPG2 with long acting activities by the conjugation with the two life extenders, PEG and HSA