A handful of monoclonal antibodies have been introduced for treatment of hematopoietic malignant neoplasms and solid tumors. The complement system is a major effector arm activated following antibody binding to its target cell. However, cancer cells express several defense mechanisms from complement-dependent cytotoxicity (CDC). They block activation of the complement cascade with membrane regulatory proteins (CD46, CD55, CD59) and they rapidly remove the C5b-9 membrane attack complex from their surface by endocytosis and exo-vesiculation. The pivotal cellular proteins that mediate enhanced cancer cell resistance to CDC were identified and are now subjects to investigation as potential targets in cancer immunotherapy. Our results have implicated mortalin/GRP75, the mitochondrial heat shock protein 70, in the elimination of the C5b-9 complexes from the cell surface. Mortalin has a postulated role against cell senescence and is over-expressed in cancer. In vitro experiments showed that mortalin siRNA and a mortalin synthetic inhibitor amplify the cytotoxic effect of anti-cancer antibodies and complement. Mortalin silencing in tumor cells in vitro by siRNA followed by injection of the cells into mice, led to reduced tumor growth, relative to cells pretreated with scrambled siRNA. The effect of the mortalin siRNA and inhibitor was tested in SCID mice bearing Raji (human B lymphoma) subcutaneous tumors and combined with treatment with Rituximab anti-CD20 antibodies. Targeting of mortalin in the tumor in vivo significantly enhanced the protective capacity of Rituximab. It decreased tumor growth, reduced tumor blood supply and extended mice survival. Blocking of CD59 on Raji cells also improved the therapeutic effect of Rituximab in mice. Thus, mortalin and CD59 inhibition in cancer cells apparently has a potent adjuvant effect on antibody-based cancer therapy. Such adjuvants will likely harness the cytotoxic complement system to better suppress cancer growth and spreading.
