Simultaneous Targeting of FcγRs and FcαRI Enhances Tumor Cell Killing

Abstract

Efficacy of anticancer monoclonal antibodies (mAb) is limited by the exhaustion of effector mechanisms. IgG mAbs mediate cellular effector functions through FcgRs expressed on effector cells. IgA mAbs can also induce efficient tumor killing both in vitro and in vivo. IgA mAbs recruit FcaRI-expressing effector cells and therefore initiate different effector mechanisms in vivo compared with IgG. Here, we studied killing of tumor cells coexpressing EGFR and HER2 by the 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 mAbs to two different tumor targets (EGFR and HER2) led to enhanced cytotoxicity compared with 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 natural killer cells were only cytotoxic with IgG, whereas cytotoxicity induced by PMNs was strong with IgA and poor with IgG. Monocytes, which coexpress FcgRs and FcaRI, also displayed increased cytotoxicity by the combination of IgG and IgA in an overnight killing assay. Coinjection of cetuximab and IgA2-HER2 resulted in increased antitumor effects compared with 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.

Progress in tumor-associated macrophage (TAM)-targeted therapeutics

“…To further improve ADCP activity, the Fc region of tumor-targeted antibodies could be engineered to increase its interaction with activatory Fc receptors, most importantly FcγRIIa, on macrophages [95]. While development of clinical antibodies is primarily focused on IgG, therapeutic potentials of other Ig isotypes (IgA and IgE) are being investigated in several pre-clinical studies where monocytes/macrophages are also important in effecting the ADCC/ADCP functions [96][97]. …”

Neutrophils in Cancer: Two Sides of the Same Coin

“…IgA2 EGFR was more effective than cetuximab in vivo against EGFR-transfected Ba/F3 target cells [ 221 ]. Very recently, it was also shown that the combination of IgG and IgA mAbs to two different tumor targets (EGFR and HER2) led to enhanced cytotoxicity compared with each isotype alone [ 222 ].…”

Neutrophils in cancer

“…When comparing neutrophil‐mediated ADCC through either FcγRs or FcαRI, it was found that FcαRI is the most effective FcR in triggering ADCC and inducing migration of neutrophils into tumor colonies . Interestingly, a recent article described the use of a combination of both IgG and IgA mAbs in the targeting of two different tumor antigens, EGFR and Her2/Neu, on A431 cells in a xenograft tumor model in mice, leading to increased cytotoxicity compared to each isotype alone . The use of IgA mAbs furthermore could create opportunities for treatment of specific types of cancers, for instance B‐cell lymphomas, in which IgG‐mediated treatments have been previously found less effective.…”