18 April 2019 - - US-based biotechnology company Eureka Therapeutics, Inc. has published a proof-of-concept study in OncoImmunology entitled "Depleting T regulatory cells by targeting intracellular Foxp3 with a TCR mimic antibody," the company said.

The study was led by Dr. Cheng Liu, president and chief executive officer of Eureka and Dr. Tao Dao and Dr. David Scheinberg of Memorial Sloan Kettering Cancer Center.

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 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 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.

Eureka Therapeutics 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 bn 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 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.