Eureka Therapeutics Announces Publication of Preclinical Study Demonstrating Selective Depletion of Tregs Using Foxp3 Targeting TCR-mimic Antibody
The efficacy of checkpoint therapies such as PD-1 has demonstrated the importance of reducing immunosuppressive pathways in tumors as a strategy for successful immunotherapy. However, regulatory T-cell (Tregs), are powerful inhibitors of anti-tumor immunity and a critical barrier to successful immunotherapy. Depletion of Tregs in the tumor microenvironment is therefore a promising cancer immunotherapy strategy.
The study demonstrated that Tregs could be depleted by targeting the Foxp3 protein with a TCR-mimic (TCRm) antibody developed from Eureka’s proprietary E-ALPHA® antibody discovery platform. Foxp3 is found in a subset of Tregs that constitute 5-10% of T-cells. Typically, Tregs suppress inappropriate immune activity and autoimmune diseases, however, their presence in tumors can prove deleterious and promote progression of many types of human cancers. In such cases, Tregs prevent anti-tumor responses by stopping the body’s conventional immune cells from attacking the cancerous cells.
Current strategies to deplete Tregs by using monoclonal antibodies (mAbs) to target cell surface proteins such as CD25 and GITR have demonstrated mixed results, perhaps because CD25 and GITR are also expressed in CD4 and CD8 effector T-cells, resulting in the mAbs killing both the Tregs and the effector T-cells.
In the study, investigators used a novel TCRm antibody to selectively target the Foxp3-derived epitope/HLA-A2 complex on Tregs and deplete the Treg cell via antibody dependent cellular cytotoxicity. Researchers engineered the TCRm antibody in both bispecific T-cell engager and full-length antibody formats and demonstrated that the TCRm antibody induces peptide-specific killing activities against Foxp3+ human Treg in both in vitro and in vivo settings.
“The depletion of Tregs by use of a Foxp3 targeting TCRm antibody represents an innovative and novel approach in the next iteration of antibody-based or CAR-T and other T-cell-based immunotherapies,” said Dr. David Scheinberg, Chair of the Molecular Pharmacology Program in the Sloan Kettering Institute, Director of the Experimental Therapeutics Center at MSK, and Scientific Advisory Board member at Eureka. “Foxp3 has also been reported to be expressed in certain forms of pancreatic cancers and lymphomas so the application of this TCRm approach could potentially go beyond depleting Tregs.”
“Using a TCRm antibody to selectively deplete Tregs adds to our arsenal of strategies to combat the challenging solid tumor microenvironment,” said Dr. Cheng Liu, President and Chief Executive Officer of Eureka Therapeutics. “To tackle solid tumors, we previously engineered a TCRm antibody onto our proprietary ARTEMIS™ AbTCR receptor to target the intracellular antigen AFP in patients with advanced liver cancer. We have also co-expressed a PD-1 inhibiting antibody on a T-cell which allowed the engineered T-cell to localize around the tumor site. We look forward to leveraging all of these approaches to our developmental pipeline.”
ABOUT EUREKA THERAPEUTICS, INC.
Eureka Therapeutics, Inc. is a privately held clinical stage biotechnology company developing antibody-TCR (AbTCR) T-Cell Therapies for solid and hematological malignancies. Its core technology centers around its proprietary ARTEMIS™ AbTCR T-cell receptor platform and E-ALPHA® antibody discovery platform for the discovery and development of potentially safer and more effective T-cell therapies for the treatment of multiple solid and hematologic tumors. The E-ALPHA platform comprises a highly diverse human-derived antibody phage library, containing over 100 billion clones with unique antibody sequences, and a robust workflow to develop highly specific antibodies against target antigens.
Eureka’s lead asset, ET140202, utilizes Eureka’s proprietary ARTEMIS™ T-cell receptor platform engineered with a proprietary human TCR-mimic (TCRm) antibody to target an AFP-peptide/HLA-A2 complex on HCC cancer cells. Data presented in September 2018 from Eureka’s ongoing first-in-human study of ET140202 in China demonstrated a favorable safety profile with no observed cytokine release syndrome or drug-related neurotoxicity. The Company plans to initiate its Phase 1/2 US multicenter clinical trial in the first half of 2019.
Eureka Therapeutics, Inc. is headquartered in the San Francisco Bay Area. For more information on Eureka, please visit www.eurekatherapeutics.com.
Source: Eureka Therapeutics, Inc.