Abstract 1616: CLSP-5282, a first-in-class T cell engager targeting KRasG12V mutant peptide presented on HLA-A*03:01

Abstract Background: Mutant KRas is one of the most common driver oncogenes in solid tumors. Approximately 25% of pancreatic cancer, 9% of colorectal cancer (CRC), and 5% of non-small cell lung cancer (NSCLC) tumors harbor KRasG12V mutations. We describe the nonclinical characterization of CLSP-5282, a first-in-class T cell engager that selectively targets the KRasG12V[7-16] mutant peptide presented on HLA-A*03:01. Methods: Functional activity was assessed in vitro in co-culture assays of T cells and target cells expressing KRasG12V and HLA-A*03:01, including models with acquired resistance to Ras-targeted small molecule inhibitors. Since CLSP-5282 does not cross react with any preclinical toxicology species, an extensive panel of secondary pharmacology and in vitro toxicology studies was performed. A Jurkat reporter assay with a positional scanning peptide library was used to identify potential cross-reactivity to other peptides presented on HLA-A*03:01. Specificity was further assessed by T cell reactivity with a panel of normal human tissues and a panel of the most common Class I HLA alleles, and cytokine release in high density PBMC cultures was determined to evaluate CRS risk. In vivo anti-tumor activity of CLSP-5282 was investigated in PBMC engrafted mouse models. Results: CLSP-5282 induces T cell activation and target cell killing specifically against cells expressing KRasG12V and HLA-A*03:01, but not wild-type KRas. Cell lines with acquired resistance to KRas inhibitors maintain sensitivity to CLSP-5282, suggesting continued presentation of the KRasG12V neoantigen. In vitro studies did not identify potential cross-reactivity to any peptides presented on HLA-A:03:01 and showed minimal T cell reactivity or cytokine release with a panel of normal human tissues, a panel of the 50 most common Class I HLA alleles, or in high-density PBMC cultures. In vivo, CLSP-5282 induces regression of established tumors in a humanized mouse model. Conclusions: These preclinical data support clinical evaluation of CLSP-5282 in HLA-A*03:01 positive patients with solid tumors harboring the KRasG12V mutation. CLSP-5282 is expected to be the first TCE in the clinic directed against mutant KRas, providing tumor targeting without the risk of on-target, off-tumor toxicity. Our data demonstrate the potential for CLSP-5282 to be efficacious even in the context of resistance to small molecule KRas inhibitors. Citation Format: Amanda Ford, Lenore Cullen, Alec R. Andrews, Justina X. Caushi, Catherine Souza, Veselin S. Dobrev, Raffaello Verardi, Hayden Jones, Brena Williams, Kai Li Tan, Michael Alloway, Anthony S. Gizzi, James Bingham, Gillian A. Kingsbury, Jessica Kohler. CLSP-5282, a first-in-class T cell engager targeting KRasG12V mutant peptide presented on HLA-A*03:01 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1616.