Antitumor immune effector mechanisms recruited by phage display-derived fully human IgG1 and IgA1 monoclonal antibodies

We have constructed a recombinant, fully human IgA1 monoclonal antibody, UB S-54/IgA1, against the tumor-associated Ep-CAM molecule and compared its tu mor-killing capacity with its IgG1 counterpart in in vitro assays. The data show that phage display-derived fully human IgA1 antibodies efficiently re cruit immune effector cells that express the Fe receptor for IgA, Fc alpha RI (CD89), UBS-54/IgA1-mediated killing of tumor cells by isolated polymorp honuclear cells (PMNs) and in whole blood was found to proceed without the necessity to preactivate effector cells with cytokines. In addition, the Ig A1 anti-Ep-CAM human monoclonal antibody (huMab) triggered phagocytosis of tumor cells by monocyte-derived macrophages, Strikingly, simultaneous addit ion of IgA1 and IgG1 anti-Ep-CAM antibodies did not result in enhancement o f tumor cell killing unless the effector cells were stimulated with granulo cyte colony-stimulating factor, The lack of an additive effect could be att ributed to an inhibitory effect of IgG on IgA-mediated tumor cell killing t hrough binding of IgG1 to the inhibitory Fc gamma RIIb receptor expressed b y PMN's, These results shun that IgA1 antitumor huMabs are capable of recru iting the large population of peripheral blood PMNs for tumor cell killing. This population is not effectively recruited by IgG type antibodies, curre ntly the antibodies most frequently used for clinical application. In addit ion, the data suggest that a combination of IgG1 and IgA1 antitumor huMabs may collaborate in tumor cell killing in patients treated with granulocyte colony-stimulating factor.