Understanding the complex behavior of effector cells such as monocytes or macrophages in regulating cancerous growth is of central importance for cancer immunotherapy. Earlier studies using CD20-specific antibodies have demonstrated that the Fcγ receptor (FcγR)-mediated transfer of the targeted receptors from tumor cells to these effector cells through trogocytosis can enable escape from antibody therapy, leading to the viewpoint that this process is pro-tumorigenic. In the current study we demonstrate that persistent trogocytic attack results in the killing of HER2-overexpressing breast cancer cells. Further, antibody engineering to increase FcγR interactions enhances this tumoricidal activity. These studies extend the complex repertoire of activities of macrophages to trogocytic-mediated cell death of HER2-overexpressing target cells and have implications for the development of effective antibody-based therapies.

Multiple autoimmune diseases are characterized by the involvement of autoreactive antibodies in pathogenesis. Problems associated with existing therapeutics such as the delivery of intravenous immunoglobulin (IVIG) have led to interest in developing alternative approaches using recombinant or synthetic methods. Towards this aim, in the current study we demonstrate that the use of Fc-engineered antibodies (Abdegs, for antibodies that enhance IgG degradation) to block FcRn through high affinity, Fc region binding is an effective strategy for the treatment of antibody-mediated disease. Specifically, Abdegs can be used at low, single doses to treat disease in the K/BxN serum-transfer model of arthritis using BALB/c mice as recipients. 25–50 fold higher doses of IVIG are required to induce similar therapeutic effects. Importantly, we show that FcRn blockade is a primary contributing factor towards the observed reduction in disease severity. The levels of albumin, which is also recycled by FcRn, are not affected by Abdeg delivery. Consequently, Abdegs do not alter FcRn expression levels or subcellular trafficking behavior. The engineering of antibody constant regions to generate potent FcRn blockers therefore holds promise for the therapy of antibody-mediated autoimmunity.

The neonatal Fc receptor, FcRn, is related to MHC class I with respect to its structure and association with β2microglobulin (β2m). However, by contrast with MHC class I molecules, FcRn does not bind to peptides, but interacts with the Fc portion of IgGs and belongs to the Fc receptor family. Unlike the 'classical' Fc receptors, however, the primary functions of FcRn include salvage of IgG (and albumin) from lysosomal degradation through the recycling and transcytosis of IgG within cells. The characteristic feature of FcRn is pH-dependent binding to IgG, with relatively strong binding at acidic pH (<6.5) and negligible binding at physiological pH (7.3-7.4). FcRn is expressed in many different cell types, and endothelial and hematopoietic cells are the dominant cell types involved in IgG homeostasis in vivo. FcRn also delivers IgG across cellular barriers to sites of pathogen encounter and consequently plays a role in protection against infections, in addition to regulating renal filtration and immune complex-mediated antigen presentation. Further, FcRn has been targeted to develop both IgGs with extended half-lives and FcRn inhibitors that can lower endogenous antibody levels. These approaches have implications for the development of longer lived therapeutics and the removal of pathogenic or deleterious antibodies.