Ainhoa Arina, Edwin Arauz, Elham Masoumi, Karolina W. Warzecha, Annika Sääf, Łukasz Widło, Tomasz Slezak, Aleksandra Zieminska, Karolina Dudek, Zachary P. Schaefer, Maria Lecka, Svitlana Usatyuk, Ralph R. Weichselbaum, Anthony A. Kossiakoff
{"title":"用于肿瘤免疫治疗的通用嵌合抗原受体(CAR) -片段抗体结合物(FAB)分裂系统","authors":"Ainhoa Arina, Edwin Arauz, Elham Masoumi, Karolina W. Warzecha, Annika Sääf, Łukasz Widło, Tomasz Slezak, Aleksandra Zieminska, Karolina Dudek, Zachary P. Schaefer, Maria Lecka, Svitlana Usatyuk, Ralph R. Weichselbaum, Anthony A. Kossiakoff","doi":"10.1126/sciadv.adv4937","DOIUrl":null,"url":null,"abstract":"<div >Chimeric antigen receptor (CAR) T cell therapy has shown extraordinary results in treating hematological cancer but faces challenges like antigen loss, toxicity, and complex manufacturing. Universal and modular CAR constructs offer improved flexibility, safety, and cost-effectiveness over conventional CAR constructs. We present a CAR–fragment antibody binder (Fab) platform on the basis of an engineered protein G variant (GA1) and Fab scaffolds. Expression of GA1CAR on human CD8<sup>+</sup> T cells leads to antigen recognition and T cell effector function that can be modulated according to the affinity of the CAR for the Fab and of the Fab for the target. GA1CAR T cells can recognize multiple Fab-antigen pairs on breast and ovarian cancer cell lines. Adoptively transferred GA1CAR T cells control tumors in breast cancer xenograft models, and their targeting can be quickly redirected using different Fabs. This versatile “plug-and-play” CAR T platform has potential for application in personalized therapy, preventing antigen loss variant escape, decreasing toxicity, and increasing access.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 27","pages":""},"PeriodicalIF":11.7000,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adv4937","citationCount":"0","resultStr":"{\"title\":\"A universal chimeric antigen receptor (CAR)–fragment antibody binder (FAB) split system for cancer immunotherapy\",\"authors\":\"Ainhoa Arina, Edwin Arauz, Elham Masoumi, Karolina W. Warzecha, Annika Sääf, Łukasz Widło, Tomasz Slezak, Aleksandra Zieminska, Karolina Dudek, Zachary P. Schaefer, Maria Lecka, Svitlana Usatyuk, Ralph R. Weichselbaum, Anthony A. Kossiakoff\",\"doi\":\"10.1126/sciadv.adv4937\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >Chimeric antigen receptor (CAR) T cell therapy has shown extraordinary results in treating hematological cancer but faces challenges like antigen loss, toxicity, and complex manufacturing. Universal and modular CAR constructs offer improved flexibility, safety, and cost-effectiveness over conventional CAR constructs. We present a CAR–fragment antibody binder (Fab) platform on the basis of an engineered protein G variant (GA1) and Fab scaffolds. Expression of GA1CAR on human CD8<sup>+</sup> T cells leads to antigen recognition and T cell effector function that can be modulated according to the affinity of the CAR for the Fab and of the Fab for the target. GA1CAR T cells can recognize multiple Fab-antigen pairs on breast and ovarian cancer cell lines. Adoptively transferred GA1CAR T cells control tumors in breast cancer xenograft models, and their targeting can be quickly redirected using different Fabs. This versatile “plug-and-play” CAR T platform has potential for application in personalized therapy, preventing antigen loss variant escape, decreasing toxicity, and increasing access.</div>\",\"PeriodicalId\":21609,\"journal\":{\"name\":\"Science Advances\",\"volume\":\"11 27\",\"pages\":\"\"},\"PeriodicalIF\":11.7000,\"publicationDate\":\"2025-07-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.science.org/doi/reader/10.1126/sciadv.adv4937\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Advances\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/sciadv.adv4937\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Advances","FirstCategoryId":"103","ListUrlMain":"https://www.science.org/doi/10.1126/sciadv.adv4937","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
A universal chimeric antigen receptor (CAR)–fragment antibody binder (FAB) split system for cancer immunotherapy
Chimeric antigen receptor (CAR) T cell therapy has shown extraordinary results in treating hematological cancer but faces challenges like antigen loss, toxicity, and complex manufacturing. Universal and modular CAR constructs offer improved flexibility, safety, and cost-effectiveness over conventional CAR constructs. We present a CAR–fragment antibody binder (Fab) platform on the basis of an engineered protein G variant (GA1) and Fab scaffolds. Expression of GA1CAR on human CD8+ T cells leads to antigen recognition and T cell effector function that can be modulated according to the affinity of the CAR for the Fab and of the Fab for the target. GA1CAR T cells can recognize multiple Fab-antigen pairs on breast and ovarian cancer cell lines. Adoptively transferred GA1CAR T cells control tumors in breast cancer xenograft models, and their targeting can be quickly redirected using different Fabs. This versatile “plug-and-play” CAR T platform has potential for application in personalized therapy, preventing antigen loss variant escape, decreasing toxicity, and increasing access.
期刊介绍:
Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.