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. 2025 Apr 2;33(4):1621-1641.
doi: 10.1016/j.ymthe.2025.02.029. Epub 2025 Feb 20.

ZP4: A novel target for CAR-T cell therapy in triple negative breast cancer

Lauren K Somes  1 , Jonathan T Lei  2 , Xinpei Yi  2 , Diego F Chamorro  3 , Paul Shafer  3 , Ahmed Z Gad  3 , Lacey E Dobrolecki  4 , Emily Madaras  3 , Nabil Ahmed  3 , Michael T Lewis  4 , Bing Zhang  2 , Valentina Hoyos  3
Affiliations

ZP4: A novel target for CAR-T cell therapy in triple negative breast cancer

Lauren K Somes et al. Mol Ther. .

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: CAR-T cells; ZP4; breast cancer; cellular immunotherapies; monoclonal antibodies; translational research; xenograft models.

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Conflict of interest statement

Declaration of interests V.H. consults for AstraZeneca and owns stock in Marker Therapeutics. V.H., B.Z., J.T.L., X.Y., and L.K.S. have filed a provisional patent for the use of ZP4 antibodies and chimeric antigen receptors (63/382,221). P.S. consults for StimulusBio and Pre-Amp. M.T.L. is a co-founder of, and equity stakeholder in, Tvardi Therapeutics Inc. and a co-founder of, and an uncompensated Limited Partner in StemMed LP, as well as an uncompensated manager in StemMed Holdings LLC, its General Partner. L.E.D. is a compensated employee of StemMed LP. B.Z. received research funding from AstraZeneca and consulting fee from Inotiv. A.Z.G. and N.A. are named inventors on patents and patent applications owned by BCM. N.A. received one-time royalties from Celgene and Cell Medica; consulted in the past for Adaptimmune, Equillium (pro bono) and CARISMA; and continues to consult The Children’s Cancer Hospital of Egypt 57357 in matters of development in medical education, training, and research. None of these relationships conflict with the published work.

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