In depth scientific analysis has shown that GPR65’s ability to sense low pH leads multiple immune cells to adopt a pro-tumorigenic, immunosuppressed phenotype. Unlike other approaches, which seek to artificially activate immune cells within the tumor, inhibition of GPR65 addresses the root cause of dysfunctional immune cells within the TME
Science
The acidic TME inherent to all solid cancers causes a profound alteration of tumor-infiltrating immune cells. This occurs through the activation of the acid-sensing GPCR, GPR65, leading to a disarming of the anti-cancer immune response and rendering current immunotherapies ineffective. The detrimental impact of low pH acting via GPR65 occurs across a range of different immune cell subtypes including cytotoxic T cells, natural killer (NK) cells, dendritic cells (DCs) and macrophages. In the case of macrophages this signalling can explain all of the cardinal features of tumor associated macrophages (TAMs) thus constituting a fundamental and ubiquitous piece of pro-tumorigenic causal biology.
Pathios has unique insights into the science of inhibiting GPR65 and will be the first company in the world to advance this novel mechanism into cancer patients with its lead asset, PTT-4256. PTT-4256 is an orally-bioavailable, highly potent and selective GPR65 inhibitor with the potential to be a first-in-class treatment in the cancer immunotherapy space.
PTT-4256 is a first-in-class GPR65 inhibitor that reverses the immuno-suppressive effects of acidic pH in macrophages, activates anti-tumorigenic pathways in the tumour microenvironment and displays single agent anti-tumour efficacy in mice.
