A newly developed immunoglobulin E (IgE) antibody stimulates the immune system to target cancer cells and slow tumour growth, a study finds, potentially offering new therapy options for treatment-resistant breast and ovarian cancers.
Anti-human epidermal growth factor receptor 2 (HER2) immunoglobulin G1 (IgG1)-based antibody therapies, such as trastuzumab and pertuzumab, were first-line therapy for patients with high tumour expression of HER2.
However, tumours could be resistant to the fragment antigen-binding (Fab)-mediated effects of these IgG1-based antibody therapies, limiting clinical response.
This resistance has prompted researchers at King’s College London to find alternative ways to activate the immune microenvironment. Given these resistant tumours usually retained detectable cell surface levels of HER2 it was thought they would respond to a different type of anti-HER2 therapy, the researcher wrote in the Journal for ImmunoTherapy of Cancer.
Previous studies have shown immunoglobulin E (IgE)-based therapies, which harnesses a distinct arm of the immune system, could significantly reduce tumour burden in in vivo clinical models, including melanoma and ovarian cancer.
In 2023, a clinical trial of a first-in-class IgE antibody known as Mov18 IgE indicated tolerability, with evidence of anticancer activity in one patient with ovarian cancer.
Potential for IgE as a new therapy
In this latest study, the researchers generated anti-HER2 trastuzumab-equivalent and pertuzumab-equivalent IgE antibodies and conducted both in vitro and ex vivo assessments where they were able to observe immune-mediated and immunomodulatory functions of IgE.
As part of the investigations, they also analysed the effects of the therapies in two trastuzumab-resistant HER2 tumour xenograft models in mice, finding the trastuzumab-equivalent anti-HER2 IgE restricted tumour growth.
Treatment was associated with enriched classical monocyte and lower alternatively-activated macrophage infiltration, they reported, and higher densities of activated CD4+ T-cells and favourable effector T-cell to regulatory T-cell ratios in tumours.
‘Collectively, anti-HER2 IgE maintains Fab-mediated antitumor activity, induces Fc-mediated effects against HER2-expressing tumour cells, and stimulates remodelling of the immune microenvironment in tumours to promote pro-inflammatory cell phenotypes which could translate to improved outcomes for patients,’ the researchers wrote.
Senior study author Dr Heather Bax, postdoctoral research fellow at St John’s Institute of Dermatology at King’s College London, said around 20% of breast and ovarian cancers expressed HER2 and therefore IgE has potential as a new therapy, particularly fot those whose cancers don’t respond to existing therapies.
‘By generating anti-HER2 IgE antibodies equivalent to the clinically used IgGs, for the first time we demonstrate that IgEs harness unique mechanisms to reprogramme the immune microenvironment, switching immune cells to effectively target HER2-expressing cancers, including those resistant to existing therapies,’ she said.
Use in clinical practice in five years?
‘Our findings indicate that IgE antibodies could offer a potential new therapy option for patients with HER2-expressing cancer.’
Study co-author Professor Sophia Karagiannis, professor of translational cancer immunology and immunotherapy at the same institution, said after generating a panel of IgE antibodies and studying them in different tumour types, the team consistently found that the human immune system reacted in the presence of IgE to restrict the growth of cancer.
‘The findings of our latest study speak to the potential of applying IgE to stimulate effective responses against hard-to-treat solid tumours,’ she said.
‘This new class of drugs holds promise to benefit different patient groups and opens a new frontier in the battle against cancer.’
The researchers believe that, with the right investment and development, this approach could be used in humans in as soon as three to five years.
