Abstract A039: Towards the discovery of a panKRAS binder via the use of antibody derivatives

Abstract Antibodies and antibody derivatives, such as single-chain variable fragments (scFvs), usually possess higher binding affinities and selectivity for their targets than small molecules. However, poor plasma stability and cell permeability limit their use as therapeutics. Our research group has developed a technology that utilizes the epitope of a protein, bound to an antibody derivative, as a template to discover small molecule binders of that protein. Therefore, given a protein-scFv pair, a small molecule library can be screened for compounds that disrupt the protein-protein interaction between the target and the scFv. This method leads to the discovery and development of antibody-derived (Abd) compounds. These compounds retain the selectivity of the scFv due to the common binding site on the target, but feature improved physicochemical characteristics, resulting in a drug-like pharmacokinetic profile. Following an scFv phage display screening, we identified an scFv (referred to as P2E2) that selectively binds to KRAS, while sparing H- and NRAS. To date, P2E2 binding has also been confirmed on several KRAS mutants. Currently, the P2E2-KRASwt pair is being used to screen a library of ∼12k small molecules via an AlphaScreen assay. This assay detects compounds that interfere with the P2E2-KRASwt interaction, yielding chemical matter for the development of Abd compounds. These newly discovered molecules hold the potential to be pan-KRAS binders and could be deployed to develop pan-KRAS inhibitors and heterobifunctional degraders. Citation Format: Davide Cardella, Nikki Sereesongsaeng, Terence Howard. Rabbitts. Towards the discovery of a panKRAS binder via the use of antibody derivatives [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A039.