Abstract 598: A novel allosteric CBL-B inhibitor with differentiated immune enhancing activity in preclinical models

Abstract E3 ligase Casitas B-Lineage Lymphoma Proto-Oncogene B (CBL-B) is a key negative modulator of T-cell receptor and co-stimulatory regulation. CBL-B inhibition lowers the threshold of antigen-specific T cell activation, even in absence of co-stimulatory signaling or the presence of an immune suppressive environment. Genetic ablation of Cbl-b or functional inactivation of its E3 ligase activity in mice or primary human T cells enhances immune-mediated tumor growth control. Therefore, CBL-B inhibition may address the suboptimal response to current immunotherapies due to low inflammation, no/low co-stimulation signal or a high immune suppressive environment. We have identified a series of potent allosteric CBL-B inhibitors via the application of our proprietary Smart Allostery࣪ platform. Herein we demonstrate one of our lead CBL-B inhibitors showed superior activity compared to a competitor CBL-B inhibitor (NX-519) in both biochemical and cellular assays. At similar exposures in a syngeneic mouse tumor model (CT26), our CBL-B inhibitor also demonstrated an increase in tumor growth inhibition relative to NX-519. Mechanistically, our CBL-B inhibitor not only enhanced T cell activation, but also re-invigorated exhaustive T cells and caused resistance to T regulatory cell-mediated suppression, both in a concentration-dependent manner. We further demonstrated differentiation of CBL-B inhibition versus anti-PD1 and anti-CTLA4 in the mixed lymphocyte reaction (MLR) assay. Our CBL-B inhibitor significantly promoted T cell proliferation where anti-PD1 alone and anti-CTLA4 alone did not. Both anti-PD1 and CBL-B inhibition increased IFNγ production in this MLR assay, but that effect was further enhanced in combination. Together, the pre-clinical data presented here provided evidence of a differentiated profile of our allosteric CBL-B inhibitors to enhance key parameters associated with T cell activation and reduce susceptibility to immune suppression, supporting their further progression toward clinical development. Citation Format: Yilin Qi, Jun Kuai, Yingzhi Bi, Huadong Sun, Deborah G. Conrady, Rajiv G. Govindaraj, Graham Hone, Rajiah A. Denny, Ken Carson, Timothy Reilly, Geraldine Harriman, Fang Wang. A novel allosteric CBL-B inhibitor with differentiated immune enhancing activity in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 598.