HotSpot Therapeutics Presents Pre-Clinical Data on CBL-B Program at American Association for Cancer Research Annual Meeting 2022

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Apr 08, 2022, 16:05 ET

In Vitro and In Vivo Data for CBL-B Inhibitor Demonstrated Differentiated Immune Enhancing Activity

BOSTON, April 8, 2022 /PRNewswire/ -- 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.

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.

"Our CBL-B inhibitor program exemplifies the immense potential of our Smart Allostery™ drug discovery platform, as our proprietary technology has enabled the development of a potent and selective allosteric inhibitor of this target that has proven difficult to drug using traditional, active site-directed small molecule drug discovery," said Jonathan Montagu, Co-Founder and Chief Executive Officer of HotSpot Therapeutics. "We look forward to continuing to expand our pipeline of allosteric modulators as we execute on our goal of delivering therapies to address areas of true unmet need."

About HotSpot Therapeutics, Inc.
HotSpot Therapeutics is targeting naturally occurring pockets on proteins called "natural hotspots" that are decisive in the control of cellular protein function. Largely unexploited by industry, these pockets are highly attractive for drug discovery and enable the systematic design of highly potent and selective small molecules that exhibit novel pharmacology. The Company's Smart Allostery™ technology platform utilizes AI-driven data mining of large and highly diverse data sets to identify pockets that matter on proteins, integrated with a tailored pharmacology toolkit and bespoke chemistry to rapidly deliver superior hotspot-targeted small molecules. The Company has successfully exploited natural hotspots across multiple classes, including E3 ligases, kinases, and transcription factors. HotSpot has established a product pipeline of ﬁrst-in-class small molecules for the treatment of cancer and autoimmune diseases, each enabled by precision and patient-targeted clinical design. To learn more, visit www.hotspotthera.com.

SOURCE HotSpot Therapeutics