Valo Health Announces Publication of the Journal of Clinical Investigation of a New Therapeutic Approach to Improve CD8+ T Cell Function

Novel engineered cytokine triggers a unique signaling pathway in preclinical studies

Valo Health, Inc (“Valo”), the technology company focused on transforming the drug discovery and development process using human-centric data and artificial intelligence, announced a proof of concept for using 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).

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The data presented in JCI demonstrates that OPL-0101 (referred to as OMCPmutIL-2 in the paper) triggers improved CD8+ T cell function by utilizing a novel signaling pathway different from any currently available immunotherapy. Such data provides proof of concept that the rational design of immunostimulatory agents, different from currently available checkpoint inhibitors or cytokines, may extend the range of therapeutic options available to cancer patients. The preclinical research found that in both 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 the augmentation of T cell receptor sensitivity and activation of the Nuclear Factor of Activated T Cells (NFAT) pathway of T cell activation. 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 multiple murine preclinical models as well as CAR-modified human T cells, targeting of CD19 expressing malignancies OPL-0101 outperformed both IL-2 and IL-15 for tumor control.  Importantly OPL-0101 synergized with anti-CTLA4 immunotherapy to provide long-term cure of murine lung cancer.

Alexander Sasha Krupnick, MD, Chief of Thoracic Surgery and Surgical Director of the Lung Transplant Program at the University of Maryland School of Medicine, and the senior author of the study and co-inventor of the technology behind OPL-0101, said that the study shows the value of the unique tumor-targeting candidate OPL-0101.

“I believe that the research highlights OPL-0101 as a potential new therapeutic agent in immunotherapy, whose biology and mechanism of action is distinct from currently available check point inhibitors and cytokines,” said Krupnick who is a consultant to Valo. “This agent represents a new class of biologic agents which will aim to form the basis of future novel multimodality therapy for multiple malignancies.”

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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 when it acquired Courier Therapeutics in 2021.  The intent of the underlying design of OPL-0101 is to enable professional killing cells to target cancers with reduced toxicity. The original research and design of OPL-0101 was done by Dr. Krupnick and team at Washington University in St. Louis, where the team sought to harness the signaling properties of a unique cytokine by design, where T cell surface binding and signaling are separated between two different families of receptors. This fusion protein cytokine binds with high affinity to the cytotoxic lymphocyte-defining immunoreceptor NKG2D but signals through the common γ-chain cytokine receptor. Such rational design of separating the binding activating receptors virtually eliminates off target side effects which remain the main barrier to broader use of immunostimulatory agents.

In addition to precise activation of cytotoxic lymphocytes due to NKG2D binding, the research describes that OPL-0101 results in superior activation of both human and murine CD8+ T cells by improving their survival, memory cell generation, and decreasing exhaustion. This functional improvement appears to be the result of altered 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 STAT/AKT signaling intermediates. The novel signaling pathway activates Nuclear Factor of Activated T Cells (NFAT) transcription factor, 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.

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