HotSpot Therapeutics, Inc., a biotechnology company pioneering the discovery and development of first- and best-in-class small molecule allosteric therapies targeting regulatory sites on proteins referred to as “natural hotspots,” today announced the presentation of additional pre-clinical data on the Company’s Casitas B-lineage lymphoma proto-oncogene (CBL-B) program in a poster presentation at the American Association for Cancer Research (AACR) Annual Meeting 2022.
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CBL-B acts as a gatekeeper in immune cell activation, and its inhibition holds the potential to address several key mechanisms where translational data supports a causative role in suboptimal response to current immunotherapies. Targeting CBL-B represents a novel therapeutic approach because inhibition of CBL-B lowers the threshold for T cell and NK cell activation, even in the absence of co-stimulatory signals, potentially bringing benefit to patients with low antigen levels (e.g., low TMB), low inflammation (e.g., low PDL-1) and/or sub-par co-stimulation (e.g., low CD28).
“CBL-B represents a promising immunotherapy target given its role as a master regulator of T cells and NK cells. Its inhibition may address the limitations of current immunotherapies and, in turn, expand the benefits of I-O to more patients,” said Geraldine Harriman, Ph.D., Co-Founder and Chief Scientific Officer of HotSpot Therapeutics. “Using one of our potent small molecule CBL-B inhibitors identified from our Smart Allostery™ platform, we demonstrated an ability to enhance T cell activation and reduce susceptibility to immune suppression, supporting the potential therapeutic utility of a CBL-B inhibitor. We look forward to continuing to advance our lead CBL-B inhibitor candidate, HST-1011, toward clinical studies.”
The presentation describes compelling data for a HotSpot compound designed as a novel, allosteric, small molecule inhibitor of CBL-B E3 ubiquitin ligase activity.
- The HotSpot CBL-B inhibitor drove potent immunostimulatory activity both in vitro and in vivo in a CT26 tumor mouse model with superior potency observed when comparing the HotSpot CBL-B inhibitor to a reference CBL-B inhibitor.
- When added to exhausted T cell cultures or to effector T cells in the presence of regulatory T cells in vitro, the HotSpot CBL-B inhibitor demonstrated an ability to reduce the effects of suppressive mechanisms.
- In the mixed lymphocyte reaction (MLR) assay that is a strong predictive correlate of the clinical activity of I-O therapies, the HotSpot CBL-B inhibitor demonstrated clear activity as monotherapy and was synergistic with anti-PD1 in enhancing T cell proliferation and cytokine secretion.