IgE Class Antibody Engagement and Activation of Human Monocyte and Macrophage Subsets for Cancer Immunotherapy

The human immune system produces five types, or classes, of antibodies and practically all endeavours to use them for cancer therapy have made use of just one class, IgG (most often the IgG1 isotype). IgG antibodies are the most common antibody found in the human circulation. However, IgG antibodies have limited half-life in tissues (2-3 days), relatively low affinity to their Fc receptors on immune effector cells and the disadvantage of interaction with inhibitory Fcy receptors, abundant in the tumour microenvironment. IgE class antibodies on the other hand are the least abundant in the blood, with very short serum half-lives, but long residence times in solid tissues, for which they have a very high affinity. Although IgE antibodies are common in people with allergies. Importantly, IgE antibodies are thought to give protection against parasites. IgE class antibodies may offer new options for cancer therapy, based on high affinity for their cognate FcE receptors present on different often tumour-resident immune effector cells such as macrophages and mast cells, and lack inhibitory IgE Fc receptors. Thus, it has been suggested that the IgE mediated tissue surveillance functions known to play roles in "allergic" or "pathogen/parasite-clearing" responses could be re-directed against tissue-resident tumours. Our goal is to develop more effective treatments for solid tumours using IgE antibodies and we are the first to have developed a therapeutic IgE antibody designed to attack a tumour-associated antigen produced almost exclusively in tissue cancers, such as those of the ovary, breast and skin. Our first in class IgE antibody against the tumour associated antigen folate receptor a (FRa) has been demonstrated to induce superior immune responses in disparate animal models of cancer, especially in the context of ovarian carcinomas many of which express FRa. This first-in-class IgE antibody is now undergoing an early phase clinical trial for patients with cancer (Co-supervisor, Spicer, NCT02546921, www.clinicaltrials.gov). Antibodies are multifunctional molecules. By activating immune cells through their Fc-regions (effector functions), antibodies can confer protection from pathogens and cancer. The signalling mechanisms that control these properties are not well-understood, and this remains the case for IgE class antibodies. In our laboratory, we have already demonstrated that IgE antibodies recognising cancer cells could activate human macrophages, which are normally found in tumours to engulf and kill cancer cells. We have also found that macrophages, including those often found in solid tumours, re-educated by IgE towards activated states. We have generated preliminary phosphoprotein and cytokine profiling data demonstrating molecular and immunological signatures associated with specific tumour cell killing by monocytes with the in-house engineered antibody. These suggest potent and widely-applicable functionality for this agent in activating human monocytes and in triggering Fc receptor signalling pathways in the cancer context.
Although findings in our laboratory point to monocytes and macrophages as key immune cells recruited by IgE against tumours and may play important roles in IgE-mediated anti-tumour efficacy, the underlying mechanisms of how IgE exerts anti-tumour immunity by engaging different subsets of these effector cells are not fully characterized. In this project we aim to gain an insight into the pathways that control IgE-mediated immune effector functions, by characterising antibody-mediated activation of human monocytes and macrophages subsets against cancer. We will study the monocyte-and macrophage-mediated functions of four in-house generated IgE antibodies recognising different tumour antigens, which we are developing for the treatment of melanomas, ovarian and breast carcinomas.