New Data Highlight the Potential of Neoantigen-Generating ERAP1 Inhibitors to Drive a Differentiated T Cell Response, Leading to Tumor Growth Inhibition
Proprietary Neoantigen Generation Technology Platform Represents Potential New Pillar in Oncology Therapeutics
OXFORD, United Kingdom, Nov. 12, 2021 /PRNewswire/ -- Grey Wolf Therapeutics, a biotechnology company spearheading a new therapeutic approach to immuno-oncology driven by targeted neoantigen generation, today announced the presentation of promising preclinical in vivo data on the company's first-in-class inhibitors of ERAP1 at the 36th Annual Meeting of the Society for Immunotherapy of Cancer (SITC). The results are featured in a poster presentation (#553) entitled, "First-in-Class Inhibitors of ERAP1 Alter the Immunopeptidome of Cancer, Driving a Differentiated T Cell Response Leading to Tumor Growth Inhibition," at the SITC conference, being held November 10-14, 2021 in Washington, D.C., as well as virtually.
Grey Wolf Therapeutics' first-of-its-kind immuno-oncology approach is centered on dramatically increasing the visibility of tumors to allow for their identification and destruction by the body's immune system. This is achieved through targeted inhibition of the endoplasmic reticulum aminopeptidases (ERAP1 and ERAP2), causing the generation and presentation of novel and potent neoantigens to the surface of tumor cells. The appearance of these neoantigens uncloaks the tumor cells, illuminating them for the immune system and setting in motion powerful, differentiated T cell responses against the tumor. Importantly, this unique approach is orthogonal to a broad range of other cancer therapy modalities, including, but not limited to, immunotherapy.
The presented findings at the SITC conference provide compelling evidence for several key elements of the company's therapeutic hypothesis for ERAP1 inhibition in the treatment of cancer. These include the ability of the company's ERAP1 inhibitors to drive neoantigen creation, differentiated T cell responses, and tumor growth inhibition.
Key highlights from the company's presentation include:
Researchers highlighted study results demonstrating that ERAP1 inhibition triggered clear generation of novel neoantigens, as well as increased expression of existing neoantigens, across various species, cell types and genetic backgrounds in vitro and in vivo. For example, targeted ERAP1 inhibition within the HCT116 colorectal cancer cell line led to increased surface expression of key cancer antigens including MAGE3 and PBK, as well as the generation of an entirely new neoantigen (ATAD2) within the tumor. This neoantigen generation is believed to make the tumor significantly more visible to the immune system, allowing for the desired differentiated T cell response.
Differentiated T Cell Response
Presented findings highlighted three different data sets supporting the ability of ERAP1 inhibition to drive a differentiated T cell response.
First, results demonstrated a statistically significant increase in T cell receptor (TCR) diversity across a range of timepoints following treatment with an ERAP1 inhibitor and an anti-PD-1 antibody in the CT26 tumor model. Second, data demonstrated that the combination of an ERAP1 inhibitor and anti-PD-1 in the CT26 model drove a significant increase in T cell infiltration into the tumor in conjunction with elevated intra-tumoral Granzyme. Finally, the treatment combination led to a significant elevation of a broad range of translationally relevant immune markers that have been shown to correlate with patient response to anti-PD-1 treatment, including CXCL9, CXCL10, IFNg and IL-7R.
It is important to note that this impact on immune markers is tumor-specific as it was only observed within tumors and not in the periphery, suggesting that ERAP1 inhibition is driving an entirely novel, cancer-specific response.
Tumor Growth Inhibition
The ability of ERAP1 inhibition to drive neoantigen creation and the subsequent differentiated T cell response resulted in a meaningful impact on tumor growth. Presented study results demonstrated clear tumor growth inhibition and improved overall survival in multiple syngeneic mouse models following treatment with ERAP1 inhibitors in combination with an anti-PD-1 antibody, as compared to vehicle. Significantly, in the CT26 syngeneic mouse model, each of the findings demonstrating a differentiated T cell response (i.e., TCR repertoire changes, T cell infiltration and upregulation of translationally relevant immune markers) correlates with tumor growth inhibition providing compelling evidence for neoantigen creation driving anti-tumor responses.
"The totality of these presented data provides compelling support for our belief that the generation of novel neoantigens through targeted inhibition of ERAP1 represents a promising, entirely new approach to the oncology drug development space. While we have previously shown the potential of our ERAP1 inhibitors to generate neoantigens that drive anti-tumor responses, these new data presented today clearly demonstrate that the anti-tumor responses are due to a novel and differentiated T cell response," said Peter Joyce, Ph.D., chief executive officer of Grey Wolf Therapeutics. "While these promising results were achieved by combining our ERAP1 inhibitors with an anti-PD-1 antibody, it is important to note that we believe our unique approach will be orthogonal to a broad range of other cancer therapy modalities, including, but not limited to, immunotherapy. Based on these data, we continue to progress our lead ERAP1 inhibitor drug candidate through preclinical development, with the goal of advancing into the clinic in the second half of 2022."
Grey Wolf Therapeutics is developing a portfolio of ERAP inhibitors that it believes represents the first ever application of direct neoantigen generation to the treatment of cancer. GRWD5769, the company's lead ERAP1 inhibitor development candidate, is expected to enter the clinic in the second half of 2022.
About Grey Wolf Therapeutics
Grey Wolf Therapeutics is a UK-based drug discovery biotechnology company spearheading a new therapeutic approach to immuno-oncology driven by targeted neoantigen generation. The company's first-of-its-kind immuno-oncology approach is centered on dramatically increasing the visibility of tumors to allow for their identification and destruction by the body's immune system. Based on this approach, the company is developing a portfolio of first-in-class small molecules that inhibit the endoplasmic reticulum aminopeptidases (ERAP1 and ERAP2), which play a key role in the antigen presentation pathway. The company's lead development candidate, GRWD5769 is an ERAP1 inhibitor that is expected to enter the clinic in the second half of 2022. A second program, focused on ERAP2 inhibition, is advancing through early discovery work and toward preclinical development.
For more information, please visit: www.greywolftherapeutics.com
Grey Wolf Therapeutics
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SOURCE Grey Wolf Therapeutics