Abstract 1126: CLSP-1025, a first-in-class precision T cell engager for the treatment of p53 mutant cancers
Authors: Michael F. Maloney, Justina X. Caushi, Alec R. Andrews, James B. Bingham, Ronald Copeland, Lenore Cullen, Julie DeSander, Shannon Devens, Veselin S. Dobrev, Amanda Ford, Anthony S. Gizzi, Lauren C. Harshman, Gillian A. Kingsbury, Kaleigh Krapfl, David Orlando, Julia Shepherd, Madison Curtis Siok, Catherine Souza, Kate L. Stokes, Stuart A. Underwood, Vipin Suri, Kristen McEachern
Journal: Cancer Research (2025)

Abstract Oncogenic driver mutations in p53 occur frequently in cancer. T cell engagers that specifically target tumor cells harboring p53 mutations have the potential to enable durable efficacy while sparing normal tissue. CLSP-1025 leverages this specificity by targeting tumors that express the p53 R175H mutant protein in HLA-A*02:01 positive patients. The preclinical characterization provides a foundation for advancing CLSP-1025 to a first-in-human (FIH) study.CLSP-1025 is a half-life extended single-chain diabody IgG4 Fc fusion protein that binds to the p53(R175H)168-176 peptide presented by HLA-A*02:01 on cancer cells and to CD3ε on T cells with nM affinity. Preclinical studies show that CLSP-1025 induces potent and targeted T cell activation (EC50 = 0.8 nM), leading to effective tumor cell killing in vitro (EC90 = 10 nM) and regression of KMS-26 tumor xenografts in vivo.The safety assessment of CLSP-1025 included various in vitro and ex vivo assays using human cells and tissues. CLSP-1025 did not show significant reactivity towards any non-target HLA-A*02:01-presented human proteome derived peptide. In an evaluation of cross-reactivity to other HLA alleles, CLSP-1025 cross reacted with 8 of 264 HLA alleles tested and patients with these alleles will be excluded in the FIH study. In a tissue cross-reactivity study, CLSP-1025 demonstrated no off-target binding to the 39 normal human tissues tested. Additionally, assays with human whole blood and PBMCs revealed no significant CLSP-1025-dependent T-cell activation, cytokine production, or platelet activation.To define the addressable patient population, genomic data was analyzed from over 180, 000 tumor samples (AACR Project GENIE Consortium, v16.1) to determine the frequency of the p53 R175H mutation. Overall, the mutation was present in 2% of patient samples, with gastrointestinal cancers having the highest frequencies: colorectal (6.3%), pancreatic (4.3%), and esophageal (4.9%). Gynecological cancers also showed notable frequencies, with ovarian at 2.8% and endometrial at 2.4%. The population frequency of HLA-A*02:01 in the US is ∼41% (Gragert 2013).A mechanistically based, CLSP-1025-specific quantitative systems pharmacology (QSP) model incorporating target binding affinities, CD3 receptor occupancy, in vitro pharmacodynamics, and in vivo rodent PK profiles was developed to predict an efficacious dose range to inform the FIH study. The model predicted a terminal half-life for CLSP-1025 of approximately 16 days and the potential for tumor regression at target peptide-HLA densities as low as 2 molecules/cell.Clinical evaluation of CLSP-1025 will be initiated in early 2025 in the GUARDIAN-101 study, a FIH dose escalation and expansion trial to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of CLSP-1025 in HLA-A*02:01 positive patients with advanced solid tumors harboring the p53 R175H mutation. Citation Format: Michael F. Maloney, Justina X. Caushi, Alec R. Andrews, James B. Bingham, Ronald Copeland, Lenore Cullen, Julie DeSander, Shannon Devens, Veselin S. Dobrev, Amanda Ford, Anthony S. Gizzi, Lauren C. Harshman, Gillian A. Kingsbury, Kaleigh Krapfl, David Orlando, Julia Shepherd, Madison Curtis Siok, Catherine Souza, Kate L. Stokes, Stuart A. Underwood, Vipin Suri, Kristen McEachern. CLSP-1025, a first-in-class precision T cell engager for the treatment of p53 mutant cancers [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 1126.