Week 3, May 2025: Engineering IgE Antibodies to Overcome Tumor Immune Suppression

Recent studies highlight the leveraging of distinct immunological functions of IgE to augment or replace conventional IgG1-based therapies, particularly for treatment-resistant solid tumors. Building on growing evidence of IgE’s pro-inflammatory, tumor-reprogramming capabilities, novel hybrid antibodies combining IgE and IgG1 effector functions (IgEGs) have been developed to simultaneously engage multiple immune pathways. This week's insights converge on the development, functional characterization, and therapeutic implications of IgEGs, as well as deeper exploration into IgE-driven immune modulation within the tumor microenvironment (TME).

Engineering IgEG Hybrids for Dual Immune Engagement

In a recent study led by researchers from King’s College London and Epsilogen, hybrid antibodies were constructed using variable domains from trastuzumab and a novel anti-HER2 clone, yielding Tras IgEG and 26 IgEG, respectively. These constructs were shown to express efficiently in mammalian cells, retained high solubility and stability, and were amenable to purification via standard Protein A chromatography. Critically, they preserved both FcεRI and FcγRI binding capabilities, demonstrating robust dual-isotype functionality including FcεR-mediated degranulation and FcγR-mediated ADCC in vitro. 

Despite achieving dual functionality, IgEGs exhibited pharmacokinetic profiles distinct from conventional IgG1 antibodies. Although capable of FcRn binding at acidic pH similar to IgG1, their serum half-life was notably shorter. This disparity may be attributable to altered glycosylation patterns rather than Fv-region charge distribution. Nevertheless, in vivo experiments demonstrated that both Tras IgEG and 26 IgEG retained anti-tumor efficacy comparable to their IgE counterparts in HER2-low xenograft models, though no synergistic advantage was observed at equivalent dosing levels. These findings suggest that while IgEGs are functionally competent, their potential additive benefits in vivo may be masked by current model limitations.

IgE Antibodies Rewire the Tumor Immune Microenvironment

Meanwhile, there is a new type of antibody which stimulates the immune system to target cancer cells slows tumour growth, according to new research. in HER2-expressing, treatment-resistant breast and ovarian cancer models, anti-HER2 IgE antibodies reduced tumor growth and elicited a shift from an immunosuppressive to immunostimulatory environment. These changes were characterized by enhanced infiltration of cytotoxic CD8+ T cells and decreased regulatory T cell (Treg) populations, reflecting a rebalanced effector-to-suppressor cell ratio. Importantly, these immunologic transformations occurred in tumor types unresponsive to conventional IgG1 treatments, underscoring the unique therapeutic value of IgE.

MOv18 IgE Reprograms Macrophages to Overcome Immune Suppression in Ovarian Cancer

Further mechanistic insights into IgE-driven TME modulation were provided by studies of MOv18 IgE in ovarian cancer. Patient-derived macrophages, which typically exhibit immunosuppressive phenotypes and support Treg expansion, underwent robust pro-inflammatory repolarization upon MOv18 engagement. This reprogramming limited Treg-promoting interactions and enabled expansion of CD8+ T cells—an immune signature associated with favorable prognosis. RNA-seq and flow cytometry analyses confirmed emergence of a hyperinflammatory macrophage subset. Evidence from patient biopsies in a Phase I clinical trial supported these ex vivo findings, confirming increased CD68+ macrophage and CD3+ T cell infiltration post-treatment.

Broader Immunoregulatory Roles of IgE in Adaptive Immunity

Beyond immediate effector functions, IgE also exerts long-term regulatory effects on adaptive immunity. As reviewed in a recent publication from the University Hospital of Bern, IgE can function as a physiological adjuvant, enhancing antigen-specific secondary responses. Regulatory mechanisms, including autoantibodies against IgE and post-translational modifications such as glycosylation, influence its immunogenicity and persistence. These underexplored features could inform next-generation designs of IgE-based or IgEG hybrid therapeutics aimed at sustained immune activation.

Designing Next-Generation Immunotherapeutics

Collectively, these findings illuminate the potential of IgE in oncology, both as a standalone therapeutic and as part of hybrid constructs like IgEG. However, the full utility of IgEGs remains constrained by preclinical models that inadequately reflect human immune complexity, particularly with respect to mast cell and macrophage representation. The development of improved humanized models and Fc-engineered variants may develop their synergistic capabilities.