New engineered cytokine triggers unique signaling pathway in preclinical studies
BOSTON, June 2, 2022 /PRNewswire/ — Valo Health, Inc. (“Valo”), the technology company focused on transforming the drug discovery and development process using human-centric data and artificial intelligence, has announced a proof of concept for the use of its preclinical asset, OPL-0101, to target CD8+ T cells, in the current issue and featured on the cover of the Journal of Clinical Investigation Insight (JCI).
Data presented in JCI demonstrate that OPL-0101 (referred to as OMCPmutIL-2 in the article) triggers enhanced CD8+ T cell function using a novel signaling pathway unlike any currently available immunotherapy. These data provide proof of concept that the rational design of immunostimulatory agents, different from currently available checkpoint inhibitors or cytokines, can expand the range of therapeutic options available to cancer patients. Preclinical research revealed that in murine and human CD8+ T cells, OPL-0101 improved CD8+ T cell viability, increased memory cell generation, and decreased exhaustion. This appears to be the result of increased T cell receptor sensitivity and activation of the nuclear factor activated T cell (NFAT) activated T cell pathway. Valo believes that OPL-0101 thus offers the potential to enhance T-cell receptor recognition of low-affinity antigens, such as cancer neoantigens, as a mechanism to overcome tumor immunoevasion. In several preclinical mouse models as well as in human CAR-modified T cells, targeting of malignant tumors expressing CD19 OPL-0101 outperformed both IL-2 and IL-15 for tumor control. Importantly, OPL-0101 was synergized with anti-CTLA4 immunotherapy to provide long-term cure of murine lung cancer.
Alexander Sacha KrupnickMD, Chief of Thoracic Surgery and Surgical Director of the Lung Transplant Program at University of Maryland School of Medicineand the study’s lead author and co-inventor of the technology behind OPL-0101, said the study shows the value of the unique tumor-targeting candidate OPL-0101.
“I believe the research highlights OPL-0101 as a potential new therapeutic agent in immunotherapy, whose biology and mechanism of action are distinct from currently available checkpoint inhibitors and cytokines,” said Krupnick, consultant at Valo. “This agent represents a new class of biological agents that will aim to form the basis of future novel multimodality therapy for multiple malignancies.”
OPL-0101 is a protein therapeutic design for cell targeting and to drive specific biological responses in targeted cells. Valo acquired the exclusive license to OPL-0101 through the acquisition of Courier Therapeutics in 2021. The underlying design intent of OPL-0101 is to enable professional killer cells to target cancers with reduced toxicity. The original research and design of the OPL-0101 was carried out by Dr. Krupnick and the team at University of Washington in Saint Louis, where the team sought to exploit the signaling properties of a single cytokine by design, where T cell surface binding and signaling is separated between two different families of receptors. This fusion protein cytokine binds with high affinity to the NKG2D immunoreceptor defining cytotoxic lymphocytes, but signals via the common γ-chain cytokine receptor. Such a rational design for separation of binding-activating receptors virtually eliminates off-target side effects which remain the main obstacle to wider use of immunostimulatory agents.
In addition to the precise activation of cytotoxic lymphocytes due to NKG2D binding, research describes that OPL-0101 results in superior activation of human and murine CD8+ T cells by enhancing their survival, generation of memory cells and decreasing the ‘exhaustion. This functional enhancement appears to be the result of impaired signal transduction based on the reorganization of surface membrane lipid rafts that lead to Janus Kinase-3 (JAK-3)-mediated phosphorylation of the T cell receptor (TCR) rather than to STAT/AKT signaling. intermediaries. The novel signaling pathway activates the nuclear factor transcription factor of activated T cells (NFAT), leading to increased mitochondrial biogenesis and increased CD8+ T cell responses to low-affinity antigens, creating an opportunity to specifically catalyze activity against cancer neoantigens.
About Valo Health
Valo Health, Inc (“Valo”) is a technology company created to transform the drug discovery and development process using human-centered data and artificial intelligence-based calculations. As a digitally native company, Valo aims to fully integrate human-centric data across the drug development lifecycle into a single unified architecture, accelerating the discovery and development of life-changing drugs. while simultaneously reducing cost, time and failure rates. The company’s Opal computing platform™ is an integrated set of features designed to transform data into valuable insights that can accelerate discovery and enable Valo to advance a strong portfolio of programs in cardiovascular, metabolic, renal, oncology and neurodegenerative diseases. Founded by Flagship Pioneering and based in Boston, MAValo also has offices in San Francisco, California, New York, NY, Lexington, MAand Branford, Connecticut. To learn more, visit www.valohealth.com.
Investors: Graeme BellCFO [email protected]
Media: Jennifer Hanleyvice president of corporate communications [email protected]
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SOURCEValo Health LLC