Ovarian Cancer Immunotherapy Using Redirected Endogenous Anti-Gal Antibody

摘要

We proposed that decorating ovarian tumor cells with alphaGal (using RGD*-alphaGal) will lead to their destruction by patients' naturally occurring antibody against alphaGal. This past year we developed an in vitro assay to measure antibody-specific complement-dependent cytotoxicity (CDC) of tumors expressing alphaGal. We showed in mice that human serum containing anti- alphaGal antibody induced specific regression of alphaGal -expressing B16 melanoma far more than the effects against alphaGal nonexpressing B16. In order to increase the amount of alphaGal that could be expressed on the surface of human tumors, we collaborated with Dr. Kiessling to modify a humanized anti-GD2 mAb by directly conjugating it with alphaGal. We showed this modified mAb (hu14.18K322A- alphaGal9) bound well to GD2+ tumors. It also delivered alphaGal to their membranes, as detected using an alphaGal -specific lectin. The hu14.18K322A- alphaGal9 mAb also appeared to deliver enough alphaGal to the surface of GD2+ tumors to enable detection of anti-Gal IgM antibody, found in human serum. However, despite the detection of alphaGal delivery to the surfaces of these tumor cells, we have not yet been able to reproducibly show sufficient levels of antibody and complement mediated killing to enable translation into clinical treatment simulation in vitro or in mice. These results suggest that we should pursuing means to further augment the alphaGal expression and the immune recognition of it by anti-Gal antibody. The studies planned for this next year in our and Dr. Kiessling's lab are jointly directed towards these goals.