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).