Language
English
Publication Date
4-2-2025
Journal
Molecular Therapy
DOI
10.1016/j.ymthe.2025.02.029
PMID
39980195
PMCID
PMC11997509
PubMedCentral® Posted Date
2-20-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Triple-negative breast cancer (TNBC) remains one of the most challenging subtypes of breast cancer to treat due to a lack of effective targeted therapies. Chimeric antigen receptor (CAR)-T cells hold promise, but their efficacy in solid tumors is often limited by on-target/off-tumor toxicities. Through comprehensive bioinformatic analysis of public RNA and proteomic data, we identified zona pellucida glycoprotein 4 (ZP4) as a novel target for TNBC. ZP4 RNA and protein were detected in a subset of TNBC patient samples and patient-derived xenograft (PDX) models, with expression otherwise restricted to oocytes. We generated 89 ZP4-specific novel monoclonal antibodies and used the single-chain variable fragment (scFv) antigen binding domains from the top three candidates to engineer CAR constructs. ZP4 CAR-T cells demonstrated efficacy against ZP4-expressing TNBC cells and PDX models. Additionally, we found that variations in the scFv antigen binding domain significantly influence CAR-T cell function.
Keywords
Triple Negative Breast Neoplasms, Humans, Animals, Female, Immunotherapy, Adoptive, Mice, Xenograft Model Antitumor Assays, Cell Line, Tumor, Receptors, Chimeric Antigen, Zona Pellucida Glycoproteins, Single-Chain Antibodies, Disease Models, Animal
Published Open-Access
yes
Recommended Citation
Somes, Lauren K; Lei, Jonathan T; Yi, Xinpei; et al., "ZP4: A Novel Target for Car-T Cell Therapy in Triple Negative Breast Cancer" (2025). Faculty, Staff and Students Publications. 7070.
https://digitalcommons.library.tmc.edu/baylor_docs/7070
Graphical Abstract