Harnessing the power of IgE Technology

Epsilogen is developing novel IgE antibodies to treat cancer. The company’s lead candidate,  MOv18 IgE, is in a Phase I clinical trial in folate receptor alpha positive cancer patients and is the world’s first IgE drug to enter clinical trials. Tim Wilson, CEO talks to Lu Rahman.

Epsilogen was founded in April 2017 based around the IgE expertise of Professor Sophia Karagiannis at King’s College London. The London-based company has received over $25 million in dilutive and non-dilutive financing (including four Innovate UK grants). Epsilogen’s management team has a wealth of experience within the biotechnology industry encompassing everything from basic antibody science and immunology to preclinical and clinical development, intellectual property derivation, biologics manufacturing, private and public financing, business development and company building skills.

LR: Can you provide more detail on how IgES can be used for targetting cancer cells for killing and what research has been carried out in this area?

TW: IgE has evolved to kill tissue-dwelling multicellular parasites endowing it with several key features that make it ideal for the treatment of solid tumours. The epsilon constant region of IgE binds very tightly to its cognate receptor (FcεRI) on the surface of immune effector cells including macrophages, monocytes, basophils and eosinophils. This interaction is up to 10,000 fold greater than the gamma chain of IgG has for its equivalent receptor and allows IgE to bind to immune effector cells in the absence of antigen. This, in turn, facilitates immunosurveillance by immune effector cells which travel through the body primed and ready to destroy cells expressing the relevant tumour antigen. To enable this activity, IgE has evolved to have a much longer tissue half-life than IgG, 2 weeks versus two – three days for IgG.

IgE also enhances tumour penetration by macrophages, as compared to IgG, and can stimulate significantly greater levels of both ADCP (antibody-dependent cell-mediated phagocytosis) and ADCC (antibody-dependent cell-mediated cytotoxicity), the two main mechanisms by which immune effector cells can kill tumour cells. As a consequence, IgE is able to kill tumour cells expressing very low levels of antigen, an attribute of real clinical significance.

Lastly, IgE is able to repolarise macrophages towards an M1-like, anti-tumoural, phenotype and away from the M2, pro-tumoural, phenotype. IgE-mediated crosslinking of FcεRI receptors on the surface of M2 macrophages directly converts them to an M1-like phenotype as defined by expression of various pro-inflammatory cytokines and chemokines such as TNF⍺and MCP-1. The net effect of all of these changes is to warm up the Tumour Microenvironment (TME), a key goal of immunooncology.

Although IgE is very potent at activating myeloid immune effector cells, there are certain functions it lacks which IgG possesses including the ability to activate Natural Killer (NK) cells and fix complement. IgG also has a significantly longer serum half life than IgE by virtue of its ability to bind the FcRn receptor. Epsilogen has created IgE/IgG fusion antibodies (IGEGs) in which these IgG functions are added to an IgE molecule. IGEG antibodies were created by fusing the CH2-CH3 domains plus the hinge region of IgG to the C terminus of an IgE molecule. They have performed very well in a variety of preclinical tests and are now being assessed in in vivo efficacy models.

LR: Describe MOv18 IgE and its potential.

TW: Epsilogen’s lead product candidate is MOv18 IgE, an IgE antibody that targets folate receptor alpha (FRα), a clinically-validated antigen in ovarian cancer. This is the first therapeutic IgE antibody to enter man. Preclinical data in a variety of models found MOv18 IgE to possess significant anticancer activity in excess of the IgG version of the antibody.

Data from a 24 patient, single agent, multiple ascending dose Phase I trial was released at AACR 2020. MOv18 IgE was found to possess an acceptable safety profile with urticaria reported as the most frequent adverse event. This trial was not designed to show efficacy but early signs of activity were seen. One patient experienced radiographically-defined tumour shrinkage with accompanying CA125 drop, ascites resolution and restoration of appetite. Promising activity was seen in other patients.

The dose levels used in the Phase I trial are at least two orders of magnitude lower than those used for a typical anticancer IgG antibody. MOv18 IgE activity was also consistent with preclinical data showing IgE is able to kill cancer cells regardless of antigen expression level. Both of these observations reflect the enhanced potency of IgE. A Phase I/IIa trial in ovarian cancer patients is scheduled to begin in March 2022.

LR: What opportunities does this create for the research sector and the wider oncology field?

TW: IgE represents a new multi-faceted anti-cancer modality with a broad panoply of actions that contrasts to the mono-functional characteristics of other approaches such as ADCs, CAR-T, T cell engagers and checkpoint inhibitors. By harnessing the potency of the IgE-mediated immune response it is hoped that we can provide patients with new safe and effective treatment options for many serious diseases.

Epsilogen’s encouraging Phase I data builds on compelling preclinical data and provides the strongest suggestion to date that IgE antibodies can viably form the basis of an efficacious new class of biologic. IgE antibody therapeutics potentially offer significant advantages over those based on IgG, which currently account for over $120bn in worldwide drug sales – especially in the treatment of solid tumours. These include greater potency, better tumour access and longer tissue half-life.

Volume 22, Issue 2 – Spring 2021

Biography

Tim Wilson is Chief Executive Officer, Epsilogen. His career has encompassed start-ups, venture capital, investment banking and equity research. He has held senior positions at a number of firms including NM Rothschild, Hambrecht and Quist, UBS, SG Cowen and Pacific Growth Equities. In 2013 he founded Longcross Advisers, a life science-focused corporate finance firm. He gained his PhD from the MRC’s Laboratory of Molecular Biology in Cambridge and a BSc (Hons) in biochemistry from Imperial College, London.

 

 

 

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