Abstract 3512: Development of a novel T cell engager for solid tumors presenting KRAS G12V mutant peptide in HLA-A*11:01

Abstract Background: KRAS neoantigens present on the surface of tumors as peptide-HLA complexes are promising targets for immunotherapy. Here, we describe preclinical development of a half-life extended T cell engager, MA022-2037, designed to redirect T cells to kill solid tumors driven by KRAS G12V mutation in HLA-A*11:01-positive patients. Methods: The antibody discovery platform, Retained Display (ReD), was used to isolate fully human single chain variable fragments (scFv) selectively recognizing a 10-mer peptide derived from KRAS G12V in the context of HLA-A*11:01, while avoiding the corresponding wildtype KRAS peptide differing by a single amino acid. Target selectivity was assessed in bead-based binding assays involving arrays of irrelevant peptide-HLA-A*11:01 complexes and HLA-A*11:01-restricted peptides with sequence homology to the target peptide. Scanning mutagenesis was used to map specific binding motifs for prediction of cross-reactive peptides. Following conversion to T cell engager format, activity was assessed in co-cultures of in vitro expanded T cells isolated from donor PBMC with HLA-A*11:01-positive tumor cell lines with or without KRAS G12V mutation. The pharmacokinetics of half-life extended MA022-2037 was assessed in animals prior to evaluation of efficacy in tumor-bearing mice engrafted with donor PBMC. Results: MA022-2037 binding was restricted to KRAS G12V/HLA-A*11:01, with no binding observed to any other HLA-A*11:01-restricted peptide examined, including those with similarity to the target peptide. No cross-reactive peptides from the known human proteome were predicted to bind MA022-2037 based on analysis of its specific binding motif. MA022-2037 mediated robust killing of HLA-A*11:01-positive, KRAS G12V mutant tumor models in the presence of donor T cells in vitro, while KRAS wildtype or KRAS mutation-mismatched tumors were spared. As a half-life extended T cell engager, MA022-2037 displayed a favorable pharmacokinetic profile with a half-life of ∼20 days, enabling in vivo evaluation of efficacy. Conclusions: Our preclinical data support continued development of MA022-2037 for HLA-A*11:01-positive patients with KRAS G12V mutant tumors and IND-enabling studies are in progress. We anticipate delivery of a new precision immunotherapy for patients whose high unmet need is not currently addressed by molecularly targeted inhibitors. Citation Format: Lauren Pitt, Rasika Premaratne, Rebecca Wood, Ruban Kannan, Shereen Jabar, Dylan James, Brendan Eames, Kal Gunarathne, Nicole Church, Zac Rosenes, Fiona Gracey, Idris Bello, Eleanor Leung, Brad McColl, Ben Kiefel, Matt Beasley. Development of a novel T cell engager for solid tumors presenting KRAS G12V mutant peptide in HLA-A*11:01 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3512.