Abstract C059: Development of a Differentiated, Best-in-Class Oral Cbl-b Inhibitor with Robust Immune Activation and Favourable Safety for Cancer Immunotherapy

Abstract Cbl-b, a key intracellular immune checkpoint, negatively regulates T cell and NK cell function, making it a compelling target for cancer immunotherapy. We report the discovery and preclinical characterization of structurally distinct, best in class, oral small molecule Cbl-b inhibitors that demonstrate excellent potency, functional activity, and superior efficacy. Our lead compound demonstrates strong and specific target engagement, as evidenced by its high-affinity binding to Cbl-b and a favourable dissociation profile. Functional assays conducted in both human and mouse immune cells demonstrate robust cytokine induction and dose-dependent tumor cell killing, mediated by both T and NK cells. In vivo, our compound induces significant pharmacodynamic modulation, including pro-inflammatory cytokine induction in CD3/CD28-stimulated mice. In tumor bearing model, it enhances infiltration of activated immune cells into tumor microenvironment and promotes upregulation of immune cell activation markers, as confirmed by nanostring transcriptomic analysis. In vitro safety profiling reveals no non-specific binding to muscarinic receptors or 5HT serotonin receptors, a liability observed with clinical stage Cbl-b inhibitor molecules. The compound also shows no hERG liability and no cardiovascular toxicity in vitro, supporting favourable safety profile. It has also demonstrated excellent liver microsomal and hepatocyte stability that translated into excellent oral bioavailability across tested rodent species, outperforming other known clinical stage Cbl-b inhibitors reported to show suboptimal oral exposure in rodents. In syngeneic tumor models, the in-house Cbl-b inhibitor demonstrated robust antitumor efficacy as a monotherapy and achieved tumor regression when administered in combination with an anti-PD-1 antibody. This combination not only significantly prolonged survival but also triggered durable anti-tumor immune responses, showing that the compound works in synergy with approved Immune checkpoint inhibitors. In summary, our novel Cbl-b inhibitor is structurally distinct with enhanced immune activation, favourable safety and PK profiles, and robust in vivo efficacy. These attributes position it as a differentiated and promising candidate for clinical development in cancer immunotherapy. Citation Format: Chandregowda Venkateshappa, Sandeep Patil, Kalisankar Bera, Nagaraju A, Vakkapatla Durga Prasad, Swaroop S. G, Sachin Jotiba. Rajaikar, Shilpa S. Nayak, Sivapriya Marappan, Vaishnavi Shivaji. Khamkar, Raghavendra N. R, Sachin M, Aravind A. B, Elli Narvi, Sakari Pöysti, Olli Törmäkangas, Laura Ravanti, Anil Thotakura, Samiulla D. S, Girish Daginakatte, Kavitha Nellore, Murali Ramachandra, Susanta Samajdar. Development of a Differentiated, Best-in-Class Oral Cbl-b Inhibitor with Robust Immune Activation and Favourable Safety for Cancer Immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C059.