Human ex vivo data demonstrates the promise of Pathios’ ‘Macrophage Conditioning’ approach in reversing the immunosuppressive polarization of macrophages brought about by an acidic microenvironment
Preclinical study results show the ability of GPR65 inhibition to inhibit tumor growth and increase infiltration of key effector cell populations
OXFORD, UK – April 12 2022 – Pathios Therapeutics Limited (“Pathios”), a biotech company focused on the development of first-in-class therapies for cancer, today announced that new data on PTT-3213, the company’s orally bioavailable, potent and selective GPR65 inhibitor, were reported in a podium presentation at the American Association for Cancer Research (AACR) Annual Meeting 2022. Presented findings from human genetic and ex vivo human cellular studies demonstrated that GPR65, a pH-sensing, G protein-coupled receptor, serves as a critical innate immune checkpoint in the human tumor microenvironment. Furthermore, data showed that inhibition of GPR65 with PTT-3213 resulted in significantly reduced tumor growth in the MC38 mouse syngeneic cancer model. The AACR conference is being held April 8-13, 2022 in New Orleans, Louisiana.
Stuart Hughes, Ph.D., Pathios’ chief executive officer, delivered the podium presentation as part of the conference’s “Cancer Biology and Tumor Immunity” mini-symposium. The key findings presented included:
- In response to acidic pH, human macrophages undergo profound alterations in gene expression that render them indistinguishable from a typical immunosuppressive tumor associated macrophage. Pathios’ small molecule GPR65 inhibitors are able to fully counteract this polarization and re-establish an anti-tumorigenic phenotype
- In vivo studies in the MC38 colon cancer syngeneic mouse model demonstrated that once weekly oral dosing with PTT-32131 provided equivalent efficacy to dosing twice weekly with a murine anti-PD-1 antibody
- The combination of PTT-3213 and anti-PD-1 therapy provided greater efficacy than either agent gave alone in the MC38 colon cancer syngeneic mouse model
- Inhibition of GPR65 by PTT-3213 was associated with significant increases in tumor-infiltrating CD8+ T cells and natural killer T (NKT) cells, both cell types with critical tumor cell killing capabilities. There was a clear correlation between the increased infiltration of these cells and decreased tumor volume across combination groups
“These are powerful findings as they firmly demonstrate the substantial clinical promise of GPR65 inhibition as a novel immuno-oncology strategy in a range of solid cancers. Importantly, these data further validate our long-held view that low pH acting on GPR65 is a critical innate immune checkpoint and the key determinant of immunosuppressive myeloid cells in the tumor microenvironment,” commented Dr. Hughes. “As highlighted during our AACR presentation, we have now assembled a robust collection of data on the associations between the human genetics of GPR65 and cancer outcomes, including ex vivo studies in human cells. Additionally, we have now shown that weekly dosing of a small molecule GPR65 inhibitor is able to provide equivalent efficacy to anti-PD-1. We look forward to continuing research into this novel immuno-oncology target as we build on this data and complete further candidate nomination studies through 2022.”
About Acidity in the Tumor Microenvironment
The acidic tumor microenvironment, inherent to many cancers, causes a profound immunosuppression of infiltrating immune cells. This environment disarms the anti-cancer immune response and negates the effectiveness of current immunotherapies. This is particularly evident in tumor associated macrophages (TAM), where acidity is sensed by the cell-surface receptor GPR65, leading to an induction of the transcriptional repressor ICER (inducible cAMP early repressor) and the widespread suppression of a host of pro-inflammatory mediators and anti-tumorigenic genes.
About Pathios Therapeutics
Launched in 2017, Pathios is a drug discovery and development company focused on translating innovative science into new medicines. Pathios was founded by a team of experienced biotech and pharmaceutical industry professionals, entrepreneurs and clinicians. The company is focused on developing small-molecule inhibitors of the pH-sensing G protein-coupled receptor GPR65 to target immunosuppressive macrophages in advanced cancers. To date, Pathios has secured a total of US$33M in Series A funding from the leading venture capital firms, Canaan Partners and Brandon Capital. Pathios is headquartered at the Innovation Centre on Milton Park, a key science precinct south of Oxford, UK. For more information, please visit www.pathios.com.
1. PTT-3213 co-dosed with the CYP inhibitor 1-ABT to prolong compound exposure
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