Comparison of in vitro antibody-targeted cytotoxicity using mouse, rat andhuman effectors

Antibodies can direct tumor cell lysis by activating complement-mediated an d cell-mediated cytoxicities (antibody-dependent cell-mediated cytotoxicity , ADCC). Clinical translation of these effects into successful cancer thera py has been slow. Choosing an appropriate animal model to test new therapeu tic strategies is difficult because of species differences in immunological effector functions. In previous work, we found that an unmodified anti-gan glioside mouse IgG3 monoclonal antibody (mAb), 3F8, could successfully trea t clinical tumors in humans and experimental tumors in rats but not experim ental tumors in mice. We explored the reasons for this species difference b y performing in vitro antibody-dependent cytotoxicity assays comparing the potency of polymorphonuclear neutrophils (PMN), natural killer (NK) cells a nd complement from the three species: mouse, rat and human. 3F8-dependent c omplement-mediated cytotoxicity produced more than 70% specific release whe n human and rat sera were used and only 20% with mouse serum. PMN-mediated ADCC was 35%-70% with human effecters, 25%-60% with rat and undetectable wi th mouse. Human eosinophils did not contribute to this ADCC. Cytotoxicity u tilizing interleukin-2-activated NK cells was antibody-independent in all t hree species but the specific release was 60%-70% with human and rat NK cel ls and 10% with mouse NK cells. These data suggest that, for mouse IgG3, th e rat may provide a more relevant rodent model than the mouse for testing t he in vivo antitumor effects of monoclonal antibodies.