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Published on: July 25, 2020
Preclinical characterization of CLSP-1025, a first-in-class, mutation-specific T-cell engager targeting a neoantigen
Michael F Maloney1, Justina X Caushi1, Lenore A Cullen1
1Clasp Therapeutics, Inc Cambridge United States.
Purpose:
Targeting intracellular oncogenic mutations with T-cell engagers has the potential to expand precision immunotherapy beyond surface antigens. Here, we describe the preclinical characterization of CLSP-1025, a mutation-specific T-cell engager 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 HLA cross-reactivity screens, primary tissue panels, and cytokine release assays. Pharmacokinetic 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. Pharmacokinetic 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 T-cell engager and support the feasibility of targeting shared intracellular neoantigens with pHLA-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.
Insights
CLSP-1025, a novel T-cell engager, effectively targets the intracellular p53R175H mutation in cancer cells. This highly selective immunotherapy shows promising preclinical results for precision treatment.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Precision immunotherapy aims to expand treatment options beyond surface antigens by targeting intracellular oncogenic mutations.
- T-cell engagers offer a promising approach for directing T-cell activity against cancer cells.
Purpose of the Study:
- To characterize CLSP-1025, a novel mutation-specific T-cell engager targeting the intracellular p53R175H neoantigen presented by HLA-A*02:01.
- To evaluate the preclinical efficacy and safety of CLSP-1025 for potential cancer immunotherapy.
Main Methods:
- Biochemical and cellular assays were used to assess CLSP-1025 binding, selectivity, and functional activity.
- Cytotoxicity assays, primary human cells, patient-derived tumor organoids, and humanized mouse models were employed for efficacy evaluation.
- Off-target activity, pharmacokinetics, and pharmacodynamics were rigorously assessed.
Main Results:
- CLSP-1025 demonstrated nM affinity for CD3 and the HLA-A*02:01-p53R175H complex, facilitating T-cell engagement.
- Potent and mutation-dependent cytotoxicity was observed in cancer cells and organoids expressing p53R175H.
- In vivo studies showed robust tumor growth inhibition and increased T-cell infiltration, with a favorable safety profile.
Conclusions:
- CLSP-1025 is a highly selective, mutation-specific T-cell engager with significant preclinical anti-tumor activity.
- These findings support the development of pHLA-directed immunotherapies for targeting intracellular neoantigens.
- CLSP-1025 warrants further clinical investigation for patients with p53R175H-mutated cancers.
