Despite their pre-clinical safety data, Mellor says, “We had to go in at a really, really low dose.” The first two volunteers received only 70 micrograms of protein. Then, the team “aggressively but safely” increased the dosage, the final two participants receiving 6 and 12 milligrams, respectively – still a relatively low dose for an antibody drug.
The official protocol safeguarded volunteers against allergic reactions by mandating skin-prick test that checked for reactions to MOv18. In parallel, however, Karagiannis’s team developed several novel new screening assays. “We put them to the test in the trial,” she says, “We didn’t know which would parallel the clinical picture.”
Several people receiving MOv18 briefly developed skin rashes that could be controlled with medication. One person did, though, experience moderate anaphylaxis. The reaction was resolved in the hospital setting but is clearly undesirable.
When Karagiannis checked this person’s readouts on her new assays, she saw that before she’d received the drug, she had tested positive in one. Termed the basophil activation test, this BAT assay was then used to screen future volunteers. “It became a clinical tool,” says Karagiannis. One other person who tested positive on it was denied access to the trial.
“With a phase one trial, my priority is to study safety, and make a decision of ‘go or no- go’ based on that,” says Spicer. “We’ve demonstrated for the first time that IgE as a therapeutic is potentially safe.”
In one participant – given 700 micrograms of MOv18, a dose that Spicer calls “homeopathic from an IgG point of view” – the drug showed distinct anticancer activity.
Karagiannis was at Lisbon airport, returning from a conference, when Spicer called and asked if she was sitting down. He told her that this person’s tumour had shrunk, and their ascites volume had fallen along with a sharp decrease in some important cancer markers. Spicer told Karagiannis. “You know this never happens on its own. Something has happened there.”
Karagiannis suspects that some patients may have just the right complement of immune cells and tissues conditions to allow even small amounts of a drug to have an effect. “But I think going up the doses,” she says, “there will be a dose where most people will have enough engagement of this antibody with immune cells to trigger a beneficial effect.”
The team now eagerly awaits a next trial in which doses will be elevated further.
That trial will be conducted by Epsilogen, a company that Karagiannis and Spicer co-founded in 2017. “It was never my dream to just sit there and learn about something and then publish it and get a nice career and a nice position at a university,” says Karagiannis of this venture. “I felt that if we get a company off the ground, then there is a chance that this will be made available to everybody who’s dying of ovarian cancer today or any other cancers.”
Founded principally on the licensing of a second IgE from Kargiannis, which targets melanoma, Epsilogen also secured first refusal on MOv18 contingent on the outcomes of this trial – which it has now exercised.
“If we can get a company to take it on and take it forward, then that’s success for us,” says the CDD’s Mellor. “Our goal was to get it through to the end of phase one and pull together a package of data that was appealing to somebody.”
Spicer and Karagiannis maintain their respective academic and clinical roles while working closely with Epsilogen. Whether it is MOv18 itself or follow-on molecules, Spicer says he hopes the company will “establish a whole new therapeutic class, which is what we hope this particular trial heralds.”
What types of cancer will respond best to IgE treatment remains to be seen, says Karagiannis. “Selecting a good target that feeds the IgE biology and immunology is important,” she says. “I would go for solid tumours because there’s where IgE does its best functions, activating tissue resident immune cells.”
She hopes that IgG and IgE drugs will prove to be complementary. “We’re not here to abolish IgG in any way. We’re here to add to the toolbox we need to have for patients with cancer,” she says.
This project – 25 years in the making – has forged firm friendships between the various protagonists.
“Without CRUK,” Karagiannis says, “we would not have been where we are today, if it wasn’t for all the wonderful work we’ve done together. Even the preclinical work that we did together was pioneering and groundbreaking.”
“If we didn’t have CRUK it was going to be a bigger uphill struggle by far. And I have no idea what would have happened. CRUK took on the difficult part.”
