Data highlights the ability of GPR65 inhibition to bring about a robust Type I/II interferon (IFN) gene signature and reduce tumor burden in a renal cell carcinoma (RCC) PDX model.
This demonstrates the promise of Pathios’ Macrophage Conditioning approach in reversing the immunosuppressive polarization of human macrophages brought about an acidic microenvironment.
In vivo proof of concept data will be presented during the Immuo Week conference on July 9, 2021.
OXFORD, UK 8th JULY 2021: Pathios Therapeutics Limited (“Pathios”), an innovative biotech company focused on the development of first-in-class therapies for cancer, today announced the presentation of preclinical data establishing in vivo proof of concept for its small molecule GPR65 inhibitor programme. The data will be presented during the Immuno Week meeting which is being held virtually from July 6-9th, 2021, and will form part of a session entitled “Macrophage Drug Development”.
In the research presented, Pathios evaluated the impact of PTT-3196, an orally bioavailable, potent and selective GPR65 inhibitor, on expression of key immune-related genes and tumor growth in a highly glycolytic RCC PDX model implanted in NCG mice that had been reconstituted with human immune cells. The key findings of the study were:
- A dose-dependent increase in a host of genes known to be predictive of a successful response to T cell checkpoint inhibitors in the clinic including CD3D, CD3E, IL2RG, CCL5 and CXCL10
- Prominent increases in a range of other genes comprising a Type I/II interferon signature including CD40, STAT1, TAP1, TAP2 and components of the inducible immunoproteasome (PSMB8, PSMB9 and PSMB10)
- A reduction in tumor volume commensurate with the gene expression changes highlighted above
- A suppression of pro-tumorigenic genes including TGFB, IL10 and ADORA2A
“We are extremely excited about these results. PTT-3196 is able to robustly activate the human innate immune system in a highly glycolytic, patient derived tumor microenvironment, reversing many of the pro-tumorigenic macrophage gene expression changes that result from chronic exposure to an acidic environment,” commented Stuart Hughes, Chief Executive Officer of Pathios Therapeutics.
“The ability to bring about a gene expression signature that is predictive of clinical success with T cell checkpoint inhibitors is especially encouraging and fully validates the concept that GPR65 inhibitors counteract a critical innate immune checkpoint that we believe prevents the majority of solid cancers being able to respond to currently approved immunotherapies,” he added.
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. To date, Pathios has secured a total of US$13.2M in Series A funding from the leading venture capital firms, Canaan Partners and Brandon Capital. 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. The acidic tumour 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 tumour 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. The importance of the GPR65 pathway in cancer is underscored by the presence of a genetic coding variant in the GPR65 gene in a small proportion of the population that reduces receptor signalling and which is linked to increased survival across a range of cancer types. Pathios is headquartered in Oxford, UK.
Title: “GPR65 Is A Critical Innate Immune Checkpoint In Tumour Associated Macrophages: Human Genetic Validation And Discovery Of Potent And Selective GPR65 Antagonists”
Session type: Oral presentation
Date and Time: July 9, 2021, 2:00 p.m. – 2:20 p.m. BST
Presenting Author: Stuart Hughes, PhD. Chief Executive Officer, Pathios Therapeutics
Stuart Hughes, Chief Executive Officer, +44 1865 292 039