240. A Recombinant Adenovirus Type 35 Fiber Knob Protein Sensitizes Lymphoma Cells to Rituximab Therapy

Abstract

Many tumors, including lymphomas, up-regulate expression of CD46 to escape destruction by complement. Tumor cells are therefore relatively resistant to therapy by monoclonal antibodies, which act through complement-dependent cytotoxicity (CDC). From an Escherichia coli expression library of adenovirus type 35 fiber knob mutants, we selected a variant (Ad35K++) that had a higher affinity to CD46 than did the natural Ad35 fiber knob. We demonstrated that incubation of lymphoma cells with recombinant Ad35K++ protein resulted in transient removal of CD46 from the cell surface. Preincubation of lymphoma cells with Ad35K++ sensitized cells to CDC, triggered by the CD20-specific monoclonal antibody rituximab. In xenograft models with human lymphoma cells, preinjection of Ad35K++ dramatically increased the therapeutic effect of rituximab. Blood cell counts and organ histology were normal after intravenous injection of Ad35K++ into mice that express human CD46. The presence of polyclonal anti-Ad35K++ antibodies did not affect the ability of Ad35K++ to enhance rituximab-mediated CDC in in vitro assays. The Ad35K++-based approach has potential implications in monoclonal antibody therapy of malignancies beyond the combination with rituximab.