Efficacy of anti-cancer monoclonal antibodies (mAbs) is limited by the exhaustion of effector mechanisms. IgG mAbs mediate cellular effector functions via FcγRs expressed on effector cells. We have recently shown that IgA mAbs can also induce efficient tumor killing both in vitro and in vivo. IgA mAbs recruit FcαRI-expressing effector cells, and therefore initiate different effector mechanisms in vivo compared to IgG. Here we studied killing of tumor cells co-expressing EGFR and HER2 by IgG mAbs cetuximab and trastuzumab and their IgA variants. In the presence of a heterogeneous population of effector cells (leukocytes), the combination of IgG and IgA anti-tumor mAbs against two different tumor targets (EGFR and HER2) led to enhanced cytotoxicity compared to each isotype alone. Combination of two IgGs or two IgAs or IgG and IgA against the same target did not enhance cytotoxicity. Increased cytotoxicity relied on the presence of both the peripheral blood mononuclear cell and the polymorphonuclear (PMN) fraction. Purified NK cells were only cytotoxic with IgG, whereas cytotoxicity induced by PMNs was strong with IgA and poor with IgG. Monocytes, which co-express FcγRs and FcαRI, also displayed increased cytotoxicity by the combination of IgG and IgA in an overnight killing assay. Co-injection of cetuximab and IgA2-HER2 resulted in increased anti-tumor effects compared to either mAb alone in a xenograft model with A431-luc2-HER2 cells. Thus, the combination of IgG and IgA isotypes optimally mobilizes cellular effectors for cytotoxicity, representing a promising novel strategy to improve mAb therapy.
- Received April 10, 2015.
- Revision received July 1, 2015.
- Accepted July 3, 2015.
- Copyright © 2015, American Association for Cancer Research.