OXFORD, U.K.—Targeted toward developing first-in-class therapies for autoimmune diseases and immuno-oncology, biotech Pathios Therapeutics has joined hands with Nottingham, U.K.-based contract research organization (CRO) Sygnature Discovery to launch a partnership aimed at accelerating Pathios’ drug discovery and development programs.
The lynchpin of the collaboration hinges on Pathios’ integrated drug discovery program against a novel G protein-coupled receptor (GPCR) target and GPR65, a pH sensing GPCR. Sygnature is providing its expertise in GPCR bioscience and medicinal chemistry and deploying its computational chemistry, library design and synthesis, and medium-throughput screening capability to expand Pathios’ current hit-to-lead program.
Pathios says it brings together “cutting-edge European science” and its development team to modulate the activity of GPR65. This drug target is characteristic of certain T helper 17 (Th17) cell populations which have been shown to contribute significantly to the pathology of autoimmune conditions, such as ankylosing spondylitis and psoriatic arthritis.
“We founded Pathios (in 2017) to build on emerging science that demonstrated GPR65 sits at the nexus of autoimmune disease and immuno-oncology, as this receptor links pathology caused by a low pH environment,” according to Tom McCarthy, executive chairman and co-founder of Pathios.
“The ultimate aim is to block the pathological process that GPR65 initiates without interfering with the physiological role of this receptor,” McCarthy says. “In addition to developing potent and selective drugs to modulate GPR65, we are continuing to broaden the understanding of the fundamental biological processes that link to GPR65’s effects in Th17 cells, TAMs and other cell types.
“Our team has worked closely with Sygnature in the past, and know they have the deep experience, expertise and drug discovery and development infrastructure to drive our program forward. I’m delighted that on this rare occasion, Sygnature also chose to invest in Pathios and expand our GPR65 drug discovery efforts, while we explore Series A funding opportunities from venture capital firms.”
McCarthy told DDNews, “Specifically, we have medicinal chemistry FTEs to build libraries around our current hit molecules and to identify new hit molecules in different chemical spaces. Sygnature is also providing bioscience resource to determine each molecule’s potency and selectivity in vitro. Finally, we are also taking a computational chemistry approach to drugging GPR65.”
In the Unites States alone, 1.3 million people have been diagnosed with ankylosing spondylitis, while approximately 1 million people have been diagnosed with psoriatic arthritis, he adds.
Ankylosing spondylitis (AS) is similar to rheumatoid arthritis (RA) because in both diseases, people often report morning pain and stiffness; they also feel feverish and fatigued and affected joints can feel swollen and tender. Some people with AS also experience eye symptoms, including redness, light sensitivity and blurred vision.
Psoriatic arthritis is a form of arthritis that affects some people who have psoriasis—a condition that features red patches of skin topped with silvery scales. Most people develop psoriasis first, and are later diagnosed with psoriatic arthritis, but the joint pain and swelling problems can sometimes begin before skin lesions appear, the Mayo Clinic reports.
No cure for the diseases exists, so the focus is on controlling symptoms and preventing damage to joints.
Recently published studies have demonstrated GPR65 drives tumor associated macrophages (TAMs) to adopt a phenotype that supports cancer immune evasion, McCarthy says, noting that he was influenced by Hussein Al-Mossawi, an Oxford rheumatologist who identified that GPR65 was highly expressed in pathogenic Th17 cells in the blood and synovial fluid from patients with two particular autoimmune diseases—ankylosing spondylitis and psoriatic arthritis.
Al-Mossawi “showed these GPR65 expressing cells produced multiple cytokines that have been implicated in autoimmune disease, particularly IL17 and GM-CSF,” McCarthy reports. “Although he didn’t set out to identify GPR65, in hindsight there is a logical rationale for why this receptor might drive autoimmune disease as this GPCR signals in response to low pH, which characterizes an inflamed joint.”
Independently, Aviv Regev’s group at the Broad Institute also showed that GPR65 drives Th17 mediated autoimmune disease in a mouse model, and together with GM-CSF are amongst the most highly expressed genes in pathogenic T cells, McCarthy says. Modulating GPR65 offers the potential to treat autoimmune disease by reducing multiple cytokines that are triggered by the low pH environment of an inflamed joint. The other pathology characterized by a low extracellular pH is cancer.
While it has been known for several decades that tumors exist in an acidified microenvironment due to metabolic changes, a 2018 publication from Tobias Bopp’s group in Mainz, Germany showed that low pH signaling through GPR65 polarized tumor associated macrophages to adopt a phenotype that supports immune evasion.
The goal of this collaboration “is to identify potent and selective GPR65 modulators and demonstrate initially in vitro, and eventually in vivo, proof of concept—i.e. that modulation of GPR65 with a small molecule impacts the level of multiple cytokines triggered in a low pH environment,” McCarthy says.
“We want to take a GPR65 modulator into the clinic and demonstrate it delivers a best-in-class and first-in-class treatment for autoimmune disease without significant immune suppression,” he says. “In parallel, we will hopefully show that this same mechanism of action will prevent tumor immune evasion.”
Simon Hirst, CEO of Sygnature, says, “We are extremely pleased to take this exceptional opportunity to partner with, and invest in, Pathios on their drug discovery projects. Based on our diligence activities, we are excited about the potential for GPR65 modulation to be central to new treatments for autoimmune disease and a critical mechanism of action in next-generation immuno-oncology drugs targeting the tumor microenvironment.
“We are excited to have the opportunity to work with Tom and the rest of Pathios’ tremendously talented team again and contribute to the potential positive impact their therapeutics will have on patients’ lives.”