Potential to Improve Efficacy of T-cell and Immune Checkpoint Blockade
Therapies in Solid Tumors
EMERYVILLE, Calif.–(BUSINESS WIRE)–Eureka
Therapeutics, Inc., a clinical stage biotechnology company
developing novel T-cell therapies that harness the evolutionary power of
the immune system, today announced the publication of a proof-of-concept
study in OncoImmunology entitled “Depleting
T regulatory cells by targeting intracellular Foxp3 with a TCR mimic
antibody.” The study was led by Dr. Cheng Liu, President & Chief
Executive Officer of Eureka and Dr. Tao Dao and Dr. David Scheinberg of
Memorial Sloan Kettering Cancer Center (MSK).
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
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.
Eureka Therapeutics, Inc.