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Disruption of Cell-Cell Adhesion Enhances Antibody-dependent Cellular Cytotoxicity

Implications for Antibody-based Therapeutics of Cancer¹

Molecular and Cellular Biology Research, Sunnybrook and Women’s College Health Sciences Center, Toronto, Ontario, Canada, M4N 3M5 [S. K. G., R. S. K.]; Department of Medical Biophysics, University of Toronto, Ontario, Canada, M5S 1A1 [S. K. G., R. S. K.]; and Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York 10021 [M. C. I. K., J. V. R.]

Resistance to antibody-based anticancer approaches has become of considerable interest because of the rapidly growing clinical use of several different monoclonal antibodies as therapeutic agents, coupled with the recent finding that their efficacy may be attributable in part to their participation in host antibody-dependent cellular cytotoxicity. In this proof-of-concept study, we demonstrate the novel ability of an antiadhesive antibody (SHE78–7), targeted at the potent homophilic cell adhesion molecule E-cadherin, to play a dual role as participant in, and sensitizing agent for, host immune-mediated antitumor activity. SHE78–7 disrupted preformed multicellular aggregates (spheroids) of HT29 colon carcinoma cells both in vitro and in vivo in an ascites tumor xenograft model, but had no direct antitumor effect in vitro. In vivo, however, i.p. injection of SHE78–7 significantly prolonged the survival of nude mice carrying established i.p. HT29 xenografts, most notably when injections were given biweekly. This antitumor effect was dependent on the antiadhesive effect of SHE78–7 and could be effectively recapitulated via treatment with a combination of nondisruptive anti-hMHC-I antibodies, capable of recruiting an F_c-mediated immune response but ineffective as a monotherapy and antiadhesive F(ab')₂ fragments of SHE78–7. Furthermore, additional therapy experiments using such F(ab')₂ fragments, or mice lacking activating F_cRIII receptors or inhibitory F_cRIIB, unequivocally indicated a role for host antibody-dependent cellular cytotoxicity, mediated by F_cRIII and negatively regulated by F_cRIIB. Taken together, the results suggest a possible means of improving antibody-based therapies of cancer, namely targeting antigens, selectively expressed or up-regulated by target cancer cells, which mediate cell-cell adhesive functions.

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