On August 3, 2022 Eureka Therapeutics, Inc., a clinical-stage biotechnology company developing novel T cell therapies to treat solid tumors, reported the publication of a study in Nature’s Scientific Reports entitled "Validation and promise of a TCR mimic antibody for cancer immunotherapy of hepatocellular carcinoma" (Press release, Eureka Therapeutics, AUG 3, 2022, View Source [SID1234617415]). The study was led by Dr. Cheng Liu, President and Chief Executive Officer of Eureka, Dr. Brian M. Baker and Dr. Moumita Dasgupta of the University of Notre Dame, and Dr. Chang Liu of The First Affiliated Hospital of Xi’an Jiaotong University.
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T cell receptor mimic (TCRm) antibodies represent a novel approach to address one of the limitations of immunotherapy. Whereas traditional therapeutics antibodies are limited to targeting cell surface antigens, TCRm antibodies can target intracellular antigens presented by cell surface major histocompatibility complex (MHC) proteins, which enables the targeting of otherwise undruggable cancer antigens.
Alpha-fetoprotein (AFP) is an intracellular antigen found in hepatocellular carcinoma (HCC), the predominant type of liver cancer. In a previous study, Eureka reported that an engineered TCRm targeting alpha-fetoprotein (AFP)-MHC complex can effectively redirect CAR-T cells against liver cancer cells.
In this study, the crystal structure showed the AFP-MHC targeting TCRm antibody binding directly over the center of the HLA protein. Unlike natural TCRs, the TCRm antibody interfaced with the AFP/HLA-A*02 complex by engaging the AFP peptide along its entire length, contacting most of the amino acids and interacting rigidly with the target complex. The significant interactions with the peptide likely confers the high affinity and specificity of the TCRm to AFP/HLA-A*02 observed in vitro and in animal studies when compared to natural TCRs. Moreover, no off-target effects were observed in the pre-clinical studies.
"TCR mimic antibodies represent a novel way to target the subset of cancer antigens found intracellularly," said Dr. Brian M. Baker, Coleman Professor of Life Sciences at the University of Notre Dame. "The details seen in the structural and biochemical data and the resulting high specificity and affinity for this TCRm could address some of the previous safety concerns about non-specific or off-target recognition in humans."
Eureka fused the binding domain of the TCRm to the γ and δ subunits of a TCR, and co-expressed a co-stimulatory molecule to create its proprietary ARTEMIS T cell receptor. The engineered T cells showed potent killing activity against AFP-positive cancer cell lines in vitro and in vivo, with no off-target reactivity observed.
A first-in-human safety assessment of anti-AFP targeting ARTEMIS T cells was conducted over a 17-month period on 6 HCC patients at the First Affiliated Hospital of Xi’an Jiaotong University in China. The anti-AFP targeting ARTEMIS T cells demonstrated a favorable safety profile with no significant treatment-related adverse events. T cell expansion after infusions and a commensurate drop in serum AFP were detected in most patients in this study.
Eureka is currently conducting two clinical trials (ARYA-1 and ARYA-2) in the United States targeting AFP in patients with liver cancer using TCRm antibodies engineered onto ARTEMIS T cells (ET140203). A third trial (ARYA-3) targets the GPC3 protein, also found on liver cancer cells, with ARTEMIS T cells (ECT204). All three trials were granted Orphan Drug Designation by the U.S. Food and Drug Administration. For more information, visit www.eurekaconnectme.com.