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Proteomic Profiling Identifies CLDN3 as a Tumor-Selective Therapeutic Target in Small Cell Lung Cancer
Brett A Schroeder1, Jae Choi2, Alejandro A Schäffer3
1Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Abstract:
Small cell lung cancer (SCLC) remains a highly lethal disease with limited targetable surface antigens beyond delta-like ligand 3 (DLL3). We sought to systematically identify and validate tumor-selective cell-surface targets in relapsed SCLC. To this end, we developed an integrated proteogenomic pipeline combining single-cell RNA sequencing, combinatorial optimization, mass spectrometry-based proteomics, and immunohistochemistry to systematically map the SCLC surfaceome of 49 tumors across 25 patients with relapsed SCLC. Using this approach we found claudin-3 (CLDN3) to be a consistently expressed and tumor-selective antigen, with broader coverage than DLL3, which is the current clinical benchmark. CLDN3 was highly expressed across various treatment states, while maintaining low expression in most nonmalignant tissues. Functional validation using a novel CLDN3-specific monoclonal antibody (ABN501) demonstrated NK cell-mediated cytotoxicity in vitro and tumor regression in vivo, as well as a favorable safety profile. These findings support clinical development of CLDN3-directed therapies and demonstrate the utility of integrated proteogenomic approaches for antigen discovery in solid tumors.
Insights
Researchers identified Claudin-3 (CLDN3) as a promising new target for small cell lung cancer (SCLC) therapy. This antigen shows broader tumor selectivity than DLL3, enabling potential new treatments for this lethal disease.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Small cell lung cancer (SCLC) is a highly aggressive malignancy with few effective targeted therapies.
- Current treatment strategies are limited by the scarcity of validated tumor-specific surface antigens, with delta-like ligand 3 (DLL3) being a primary target.
Purpose of the Study:
- To systematically identify and validate novel, tumor-selective cell-surface antigens in relapsed SCLC.
- To discover new therapeutic targets beyond DLL3 for SCLC treatment.
Main Methods:
- Development of an integrated proteogenomic pipeline.
- Utilizing single-cell RNA sequencing, mass spectrometry-based proteomics, and immunohistochemistry.
- Analysis of 49 SCLC tumors from 25 patients with relapsed disease.
Main Results:
- Claudin-3 (CLDN3) was identified as a consistently expressed and tumor-selective antigen in SCLC.
- CLDN3 demonstrated broader tumor coverage compared to DLL3 across various treatment states.
- Functional validation with a CLDN3-specific antibody (ABN501) showed in vitro NK cell-mediated cytotoxicity and in vivo tumor regression with a favorable safety profile.
Conclusions:
- CLDN3 represents a promising therapeutic target for SCLC, potentially offering broader applicability than DLL3.
- Integrated proteogenomic approaches are effective for discovering tumor-specific antigens in solid tumors.
- The findings support the clinical development of CLDN3-directed therapies for SCLC.
