Mechanism of action of tumour antigen-targeting mAbs
The first generation of mAbs approved for clinical application - and still the most common group of mAbs in cancer therapy – consisted of mAbs directly targeting tumour antigens. These tumour antigens are, to a greater or lesser extent, important for the growth, survival and invasiveness of the tumour. The interference with tumour cell signalling pathways affects cell proliferation and leads to tumour cell death (e.g. anti-HER2, anti-EGFR)3,4. However, several observations in humans and mice suggest that Fc-mediated activation of immune cells is an important additional mechanism of action of many of these mAbs4,5 (fig.2) . Tumour cell bound antibodies can bind with their Fc tail to activating FcRs present on effector cells such as natural killer (NK) cells, macrophages or neutrophils, which then mediate tumour cell lysis5. This can occur via release of cytotoxic mediators (antibody-dependent cell-mediated cytotoxicity - ADCC) or via phagocytosis of tumour cells (antibody-dependent cell-mediated phagocytosis - ADCP). In addition, with their Fc tail, antibodies can activate the complement cascade through binding of C1q which can result in tumour cell lysis via several different mechanisms6. These include the formation of membrane attack complex (MAC) that directly induces the lysis of target cells (CDC) or the attraction of immune cells through the chemo-attractive activity of the complement components C3a, C4a and C5. Furthermore, the opsonisation by C3b and C4b marks the target cells for complement-dependent cell-mediated cytotoxicity (CDCC) by NK cells, macrophages/monocytes and granulocytes, or for complement-dependent cell-mediated phagocytosis (CDCP) by myeloid cells6. Antibody-mediated cell death also leads to the release of tumour antigens and formation of immune complexes (IC) which facilitates the initiation of anti-tumour T cell responses, sustaining the tumour control and rejection. During this process, binding to FcγRs and activation of complement have been shown to play a critical role in the uptake of IC and cross-presentation of IC-derived tumour antigens by dendritic cells (DCs) in vivo 7–9.
In conclusion, in addition to blocking important signalling pathways in tumour cells with their Fab arm, tumour-targeting antibodies furthermore deliver their effect through Fc-mediated ADCC, ADCP and CDC. Therefore, an antibody isotype with the highest capacity to induce these effects should show improved clinical efficacy. We will discuss different strategies to improve IgG Fc-effector functions, as well as the potential use of alternative isotypes such as IgE and IgA (fig.4a ).