Animal models for IgE-meditated cancer immunotherapy

Abstract

Although most monoclonal antibodies developed for cancer therapy are of the IgG class, antibodies of the IgE class have certain properties that make them attractive as cancer therapeutics. These properties include the superior affinity for the Fc epsilon receptors (FcεRs), the low serum level of IgE that minimizes competition of endogenous IgE for FcεR occupancy, and the ability to induce a broad and vigorous immune response through the interaction with multiple cells including mast cells, basophils, monocytes, macrophages, dendritic cells, and eosinophils. Tumor-targeted IgE antibodies are expected to harness the allergic response against tumors and activate a secondary, T-cell-mediated immune response. Importantly, the IgE antibody can be used for passive immunotherapy and as an adjuvant of cancer vaccines. However, there are important limitations in the use of animal models including the fact that human IgE does not interact with rodent FcεRs and that there is a different cellular distribution of FcεRs in humans and rodents. Despite these limitations, different murine models have been used with success to evaluate the in vivo anti-cancer activity of several IgE antibodies. These models include wild-type immunocompetent animals bearing syngeneic tumors, xenograft models using immunocompromised mice bearing human tumors and reconstituted with human effector cells, and human FcεRIα transgenic mice bearing syngeneic tumors. In addition, non-human primates such as cynomolgus monkeys can be potentially used for toxicological and pharmacokinetic studies. This article describes the advantages and disadvantages of these models and their use in evaluating the in vivo properties of IgE antibodies for cancer therapy.

AllergoOncology – the impact of allergy in oncology: EAACI position paper

“…Various animal models have been successfully employed to study the in vivo efficacy of IgE antibodies against cancer , with different limitations.…”

“…Next, humans express FcεRI on a broad range of cells including monocytes, mast cells, basophils, eosinophils, platelets, Langerhans cells and DCs (Table ), whereas murine FcεRI expression has only been confirmed on mast cells and basophils (Table ). Furthermore, also CD23 can be found on numerous human cells, while mice express CD23 on only B cells and certain T cells .…”

A novel IgE antibody targeting the prostate-specific antigen as a potential prostate cancer therapy

“…In vivo studies using human IgE can be hindered due to various limitations as discussed [22], most notably the lack of interaction of human IgE with murine FcεRI [20]. For this reason, BALB/c human FcεRIα transgenic mice were used to evaluate the ability of the anti-PSA IgE to induce degranulation of effector cells in vivo .…”

“…There are two human FcεRs, the FcεRI that binds human IgE with high affinity (K a  = 10 10 M -1 ) and is expressed on human basophils, mast cells, monocytes, macrophages, eosinophils, Langerhans cells, and DC, and the FcεRII (CD23) that binds IgE with lower affinity (K a  = 10 8 M -1 ) and is expressed on human B cells, eosinophils, monocytes, macrophages, and DC [18,20,21]. Importantly, IgE antibodies have been successfully used in animal models as passive cancer immunotherapies and as adjuvants of cancer vaccines [22-25]. …”

IgE Immunotherapy Against Cancer

“…A challenge in the field of IgE-based therapeutics is the lack of appropriate in vivo models to examine the efficacy and toxicity of the therapy [reviewed in Daniels et al (2012b)]. Available models include immunocompetent murine models bearing tumor cell lines from the same genetic background (syngeneic), which can be used to evaluate the efficacy and potential toxicity of mouse IgE-mediated therapy and cancer vaccines, as well as the adaptive immune response induced by these murine antibodies.…”