IgE
Several epidemiological studies have suggested a protective effect of
some allergies and IgE antibodies against specific types of
tumours34,35, providing a rationale for exploring the
potential use of mAbs of the IgE isotype as anti-tumour agents. IgE can
mediate its Fc-effector function via two activating receptors - the
high-affinity FcεRI and the low-affinity FcεRII. While predominantly
expressed by mast cells (MC) and basophils, FcεRI expression can also be
found on eosinophils, DCs and myeloid cells, although 10-100 fold lower
than on fully matured and activated MC36. Compared to
the IgG class, IgE offers several advantages that can be of interest for
cancer therapy. For instance, it shows two orders of magnitude higher
affinity for its receptor FcεRI than IgG for its high affinity receptor
FcγRI37. Because of such a high FcɛRI affinity, IgE is
locally retained on the cells expressing FcɛRI and has excellent
bioavailability in tissues, which is of great importance for treatment
of solid tumours. In addition, IgE lacks inhibitory Fc receptors that
could cause immunosuppression such as FcγRIIb in the case of
IgG37. Consequently, use of IgE antibodies in cancer
therapy has been tested both in vitro and in in vivo mouse
models, using transgenic hFcɛRI mice38 as well as
rats.
Side to side studies demonstrated that an IgE mAb targeting
tumour-associated antigen was superior to its IgG1 counterpart in terms
of survival and reduction of tumor growth38–40.
Furthermore, it was found that the main anti-tumour effector function of
IgE antibodies was mediated by myeloid cells40,41, andin vitro experimental data showed that monocytes can mediate IgE
tumour killing via both ADCC through FcɛRI as well as ADCP through
FcɛRII42. Remarkably, the IgE antibodies both
recruited tumour-associated macrophages (TAM) for ADCC and ADCP, but
also differentiated them towards activated M1-like phenotype
characterised by upregulation of a TNFα/MCP-1/IL-10 cytokine signature,
suggesting a potential role of IgE in TME
modification43. Furthermore, IgE has been shown to
facilitate DC cross-presentation of IgE IC-derived antigens, further
supporting the anti-tumour effect by inducing a T cell based anti-tumour
response44–46. An intrinsic concern regarding IgE
therapy is the risk of inducing potentially life-threatening anaphylaxis
triggered by degranulation of MC or basophils. Nevertheless, MC are
predominantly localised within the peri-tumoural surrounding of most
types of tumour and rarely within the tumours themselves. Since MC are
not expected to be found in close proximity to tumour-bound IgE, their
degranulation appears less likely. Furthermore, tumour antigens released
into the blood as monomers are not expected to induce crosslinking of
FcɛR-bound IgE required for degranulation44.
Consistently, no signs of anaphylaxis were found in preclinical models
and safety data was satisfactory in both rodents and
monkeys44,47,48.
In conclusion, the experimental data suggest that IgE might be a rather
attractive Ig isotype to improve the clinical efficacy of
tumour-depleting mAbs and one clinical trial using a tumour-targeting
IgE mAb has already been initiated (NCT02546921).