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 ).