Abstract B020: Creating actionable neoantigens by design with KRAS(G12C) covalent inhibitors

Abstract Covalent inhibitors against KRAS(G12C) represent major breakthroughs in the effort to directly and selectively target oncogenic RAS mutants. However, similar to other targeted therapies, they lack durability. Immune therapy can be curative, and fragments of RAS containing a G12 mutation can be presented by the major histocompatibility complex (MHC) and thus could serve neoantigens. However, it is challenging to achieve selective targeting with minimal differences for RAS G12 mutations in the context of the large MHC molecule. To overcome these challenges and unify targeted and immune therapies, we have established a platform technology that exploits the large changes produced by the conjugation of a covalent inhibitor to create distinct neoantigens that selectively mark cancer cells. We performed proof-of-concept experiments using the FDA-approved covalent inhibitors sotorasib and osimertinib, and we developed “HapImmune” antibodies that bind to drug-peptide conjugate/MHC complexes but not to the free drugs. HapImmune-based bispecific T cell engager selectively and potently kills sotorasib-resistant lung cancer cells upon sotorasib treatment. Notably, it is effective against KRAS(G12C) mutant cells with different HLA supertypes, HLA-A*02, A*03 and A*11, suggesting loosening of MHC restriction. We have determined the structures of several HapImmune antibodies bound to drug-peptide conjugate/MHC complexes using cryo-electron microscopy, which revealed the molecular basis of their antigen recognition and will guide further improvement of their potency and specificity. Furthermore, we have developed additional antibodies to other KRAS(G12C) drugs and other targets, demonstrating the expansive scope of HapImmune approach that can potentially utilize the vast possible combinations of covalent inhibitors and oncoproteins. Citation Format: Lorenzo Maso, Takamitsu Hattori, Kiyomi Araki, Akiko Koide, Epsa Rajak, James Hayman, Padma Akkapeddi, Injin Bang, Benjamin G. Neel, Shohei Koide. Creating actionable neoantigens by design with KRAS(G12C) covalent inhibitors [abstract]. In: Proceedings of the AACR Special Conference: Targeting RAS; 2023 Mar 5-8; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Res 2023;21(5_Suppl):Abstract nr B020.