Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
Preclinical Characterization of CLSP-1025, a First-in-Class, Mutation-Specific T-Cell Engager Targeting a Neoantigen Derived from a Common p53 Mutation.
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Maloney Michael F, Caushi Justina X, Cullen Lenore A, Andrews Alec R, Ford Amanda C, Gizzi Anthony S, Souza Catherine, Stokes Kate L, Dobrev Veselin S, Krapfl Kaleigh, Curtis Siok Madison, Orlando David A, Bingham James, Kingsbury Gillian A
Аннотация
PURPOSE: Targeting intracellular oncogenic mutations with T-cell engagers (TCE) has the potential to expand precision immunotherapy beyond surface antigens. In this study, we describe the preclinical characterization of CLSP-1025, a mutation-specific TCE that targets the p53R175H neoantigen presented by HLA-A*02:01.
EXPERIMENTAL DESIGN: CLSP-1025 binding, selectivity, and functional activity were evaluated using biochemical assays, T-cell activation and cytotoxicity assays, primary human cells, patient-derived tumor organoids, and humanized mouse models. Off-target activity was assessed using broad human leukocyte antigen (HLA) cross-reactivity screens, primary tissue panels, and cytokine release assays. Pharmacokinetic (PK) and pharmacodynamic properties were characterized in rats and human CD3 transgenic mice.
RESULTS: CLSP-1025 bound with nM affinity to both CD3 and the HLA-A*02:01-p53R175H complex, with structural modeling suggesting spacing consistent with a physiologic immune synapse. The molecule mediated potent and mutation-dependent cytotoxicity across tumor cell lines and patient-derived organoids expressing p53R175H, with minimal activity against p53 wild-type targets. Extensive cross-reactivity screening demonstrated a narrow HLA recognition profile and limited off-target T-cell activation. In humanized mouse models, CLSP-1025 induced robust tumor growth inhibition, accompanied by increased intratumoral CD8+ and CD4+ T-cell infiltration. PK analyses showed dose-proportional exposure with an IgG-like half-life, and CD3 receptor occupancy correlated with systemic exposure.
CONCLUSIONS: These data establish CLSP-1025 as a highly selective, mutation-specific TCE and support the feasibility of targeting shared intracellular neoantigens with peptide-HLA-directed immunotherapies. This favorable preclinical activity and specificity support ongoing clinical investigation of CLSP-1025 in HLA-A*02:01+ patients with cancers harboring p53R175H and outline a framework for developing next-generation TCEs against additional driver mutations.
EXPERIMENTAL DESIGN: CLSP-1025 binding, selectivity, and functional activity were evaluated using biochemical assays, T-cell activation and cytotoxicity assays, primary human cells, patient-derived tumor organoids, and humanized mouse models. Off-target activity was assessed using broad human leukocyte antigen (HLA) cross-reactivity screens, primary tissue panels, and cytokine release assays. Pharmacokinetic (PK) and pharmacodynamic properties were characterized in rats and human CD3 transgenic mice.
RESULTS: CLSP-1025 bound with nM affinity to both CD3 and the HLA-A*02:01-p53R175H complex, with structural modeling suggesting spacing consistent with a physiologic immune synapse. The molecule mediated potent and mutation-dependent cytotoxicity across tumor cell lines and patient-derived organoids expressing p53R175H, with minimal activity against p53 wild-type targets. Extensive cross-reactivity screening demonstrated a narrow HLA recognition profile and limited off-target T-cell activation. In humanized mouse models, CLSP-1025 induced robust tumor growth inhibition, accompanied by increased intratumoral CD8+ and CD4+ T-cell infiltration. PK analyses showed dose-proportional exposure with an IgG-like half-life, and CD3 receptor occupancy correlated with systemic exposure.
CONCLUSIONS: These data establish CLSP-1025 as a highly selective, mutation-specific TCE and support the feasibility of targeting shared intracellular neoantigens with peptide-HLA-directed immunotherapies. This favorable preclinical activity and specificity support ongoing clinical investigation of CLSP-1025 in HLA-A*02:01+ patients with cancers harboring p53R175H and outline a framework for developing next-generation TCEs against additional driver mutations.