NEW YORK – Following its acquisition of TigaTx earlier this week, Epsilogen is mulling its options for new biomarker-driven cancer therapeutics by leveraging new capabilities across three antibody isotypes.
Epsilogen was founded in 2017 in London to advance antibodies for cancer based on immunoglobulin E (IgE). This focus set it apart from other companies developing antibody therapies, which have overwhelmingly built their drugs using immunoglobulin G (IgG).
When scientists began investigating antibody therapeutics in the 1980s, IgG was favored because it had a long half-life in the blood, according to Epsilogen CEO Tim Wilson. However, at the time, it was not understood that IgG has a very short half-life in tissues. In contrast, Wilson said, "IgE has the opposite profile, a very short half-life in the blood. [This was] one of the first things that pointed away from it back in the day, [but] it was later discovered that it has a very long half-life in the tissue where most solid tumors are."
Another obstacle to incorporating IgE into therapeutics has been its potential to trigger anaphylaxis. Typically, IgE's role is to defend against parasitic infections and venoms, and as such, it leads to a very strong allergic response that can escalate to anaphylaxis in some cases. That has led to an assumption that it would carry a similar risk if used for therapeutic purposes. However, Wilson said a key study carried out by Cancer Research UK of Epsilogen's lead asset MOv18 IgE revealed a solution that can potentially mitigate or entirely eliminate the risk of anaphylaxis during IgE antibody therapy: testing for anaphylaxis risk using a basophil activation test (BAT).
MOv18 IgE is designed to recognize and bind to FRα, a surface antigen commonly found on cancer cells. In the trial, Cancer Research UK enrolled patients with advanced cancer who tested positive for FRα in a tumor sample. The trial generated preliminary evidence of anti-tumor activity for the drug, as six out of 24 evaluable patients with advanced ovarian cancer responded to MOv18 IgE.
The drug also showed a manageable safety profile at doses much lower than those typically required for IgG antibody-based treatments. There was one case of anaphylaxis in the patient group, and that patient was the only one that tested positive for anaphylaxis via BAT.
Wilson said the company believes that a BAT is a simple way to screen people to see if they have a predisposition for anaphylaxis before enrolling them into trials or giving them IgE treatment. Those patients would then be excluded.
Epsilogen licensed MOv18 IgE from King's College London in 2020 and commenced further development of the drug with a £1 million ($1.31 million, as of Oct. 21, 2020) Smart Grant from Innovate UK.
Epsilogen then began a Phase Ib trial of MOv18 IgE in 2024 in patients with platinum-resistant, FRα-expressing ovarian cancer. In the study, researchers are assessing MOv18 IgE in about 45 patients with progressive disease that have had up to four prior lines of therapy. To be eligible for the trial, patients must have FRα-expressing tumors based on the Leica Biosystems BN3.2 antibody test and have immunohistochemistry scores of 1+, 2+, or 3+ representing antigen expression in at least 5 percent of tumor cells. Investigators in the first part of the trial are evaluating the safety and tolerability of MOv18 IgE and are determining both the maximum tolerated dose and a recommended expansion dose. In part two, the researchers will track the drug's anti-tumor activity and disease progression in patients receiving the recommended expansion dose.
So far, Wilson said that Epsilogen has been pleased with early signals on MOv18 IgE's safety and efficacy from the Cancer Research UK trial and animal models. "The dose [used in the trial] was 250th of a typical IgG dose," he said. He attributes the drug's ability to shrink tumors at such a low dose to its very tight binding to FRα. "We've since found that the efficacy in animal models isn't just driven by macrophages. It absolutely requires T cells. … That's fantastic because that suggests that IgE would work with checkpoint inhibitors, and indeed, in animals, it does," he added.
Because IgE can kill tumor cells with very low antigen expression, Wilson said the drug has potential to address patient populations with extremely low levels of protein biomarkers, such as HER2. For example, the company has conducted preclinical experiments in breast cancer models with high, low, and ultralow HER2 expression, finding that an IgE antibody was effective at every level, even in cancers that would be categorized as triple-negative.
"In vivo, the anti-tumor activity of [the IgE antibody] is just the same for [triple-negative breast cancer] as it is for HER2-high breast cancer," Wilson said.
Now, with the acquisition of TigaTx, Epsilogen is adding that company's expertise and assets in therapeutic IgA antibodies to its arsenal. Wilson noted that IgA activates a type of immune cell called polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), an immunosuppressive type of neutrophil, which when used in cancer have tumor cell killing capabilities. "That's counterintuitive because you would think that a cell which is immunosuppressive will be good for the tumor and bad for you," Wilson said. "Actually, what happens is that in the presence of IgA, [PMN-MDSCs] become bad for the tumor."
With the TigaTx acquisition, Epsilogen gains the anti-EGFR IgA antibody EPS 401, for which the firm hopes to begin clinical studies in 2026. The drug has potential in EGFR-expressing cancers, such as colon, lung, and head and neck.
In addition to its IgE and IgA assets, Epsilogen also has capabilities in conventional IgG antibodies and is exploring the utility of a new antibody class it calls IgEG, which combines parts from IgE and IgG antibodies. The company has established in vitro and in vivo proof of concept for its IgEG technology.
Wilson noted that although Epsilogen's antibodies are directed to the same targets as many approved antibody-drug conjugates (ADCs), the company doesn't see them as competition because the mechanism of its treatments is completely different. For example, if Epsilogen decided to develop an IgE therapy targeting HER2 in triple-negative breast cancer, Wilson said that the company would have to establish single-agent activity. "But the next step is to combine it with [a HER2-targeted ADC], for example, and/or checkpoint inhibitors, because we've already got evidence in vivo that that's a great combination," Wilson noted, but added that Epsilogen has not selected a compound to develop for triple-negative breast cancer.
For future development, Epsilogen aims to leverage these three antibody platforms by tailoring the different isotypes to specific cancer indications to optimize responses. "If you can match specific isotypes, a G, or an E, or an A, against a specific cancer, you might have more chance of success," Wilson said.
The possibilities include bispecific antibodies with two different isotypes that can bind antigens from different immune cells simultaneously. Wilson speculated that the company might even experiment with an antibody that contains domains from all three isotypes in the hope that it will "rev up" the immune system even more, though the company hasn't attempted to make such an antibody yet.
"Your immune system is an incredible thing," Wilson said. "Why not exploit it and use it to kill baddies like cancer? That's our philosophy."