LONDON – Immuno-oncology specialist Grey Wolf Therapeutics Ltd. arrived on the scene Monday, armed with a $14 million series A round to take small-molecule modulators of the antigen presentation pathway into the clinic.

The aim is to directly alter tumor cells by "illuminating" them for attack and destruction by the immune system. Data from mice models show the approach is effective as a monotherapy and also works in combination with approved checkpoint inhibitor drugs.

Oxford, U.K.-based Grey Wolf has discovered small molecules that target endoplasmic reticulum aminopeptidases (ERAPs), which are key proteins in the antigen presentation pathway. That opens up the possibility of changing the neoantigen repertoire in tumors, increasing the number and range of neoantigens presented on tumor cells that are available to engage an immune response.

"The technology arose from a couple of areas," said Peter Joyce, co-founder and CEO. "First is the finding that tumor visibility is key to if checkpoint inhibitors work or not," he said. "That combined with research published in 2013 by researcher Edd James at Southampton University on ERAP proteins and their role in antigen presentation," Joyce told BioWorld.

James' in vivo mouse data showing antigen presentation can be controlled has since been replicated by other research groups. "The coming together of the two things seeded the idea," said Joyce.

In the lead up to the series A, Grey Wolf has done de novo discovery and has two programs aimed at ERAP1 and ERAP2, the two homologues of ERAP.

"The animal data is based on a compound from Edd's group and we are now in the process of generating animal data on our own molecules," Joyce said. The $14 million funding will enable Grey Wolf to flesh out the in vivo work and have a candidate ready for IND.

ERAP1 and ERAP2 are involved in loading major histocompatibility (MHC) class 1 molecules with antigenic peptides derived from viral, bacterial or mutated proteins, for presentation to the immune system.

The two homologues act by trimming peptides that are too long to the correct length for MHC class 1 loading, thus playing a critical role in defining the repertoire of peptides available for presentation. Modulating ERAP activity in established tumors in vivo results in extended survival and reduced tumor burden in mice.

"The recent breakthroughs in immunotherapy have fundamentally changed the treatment landscape in oncology, but the fact remains that current approaches only target the minority of tumors that are visible to the immune system," said Joyce.

"There is strong validation for targeting ERAPs to increase tumor visibility, and with these funds we are now positioned to build on our existing work and collaborations to deliver a clinical candidate in the coming two to three years."

Data in the literature and also some unpublished research by James indicate modulating ERAP would be effective as a monotherapy. "There is also data to show it combines with anti-PD-1 [drugs] and would work in synergy," Joyce said.

It also is expected that the approach will be effective across a number of cancer types. "We think [ERAP] can have a relatively broad effect," said Joyce. "The potential is there, and that's what we are trying to confirm."

While immuno-oncology is an increasingly crowded field, the majority of the focus is in acting directly on the immune system. "What appealed to me in this, and made me jump into setting up the company, is that we are focused on the tumor," said Joyce. "No other company is doing this from the perspective of tackling the tumor visibility problem with a small molecule."

Before forming Grey Wolf, Joyce was project leader at Vertex Pharmaceuticals Inc. His co-founder is Tom McCarthy, former CEO of neuropathic pain specialist Spinifex Pharmaceuticals, of Melbourne, Australia.

(For anyone curious about the name, Joyce's hobby is fly fishing, and the company is named after the Grey Wulff mayfly, which, he said, "has been lucky for me.")

The series A was led by Andera Partners (formerly Edmond de Rothschild Investment Partners), with Canaan. The U.S. venture capital firm was making its first investment in the U.K. biotech sector.

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