A universal chimeric antigen receptor (CAR)–fragment antibody binder (FAB) split system for cancer immunotherapy

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-07-04 DOI:10.1126/sciadv.adv4937

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

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引用次数: 0

Abstract

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.

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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

嵌合抗原受体（CAR） T细胞疗法在治疗血液病方面显示出非凡的效果，但面临着抗原丢失、毒性和复杂制造等挑战。与传统的CAR结构相比，通用和模块化的CAR结构提供了更高的灵活性、安全性和成本效益。我们提出了一种基于工程蛋白G变体（GA1）和Fab支架的car片段抗体结合物（Fab）平台。GA1CAR在人CD8+ T细胞上的表达导致抗原识别和T细胞效应功能，可以根据CAR对Fab和Fab对靶标的亲和力来调节。GA1CAR - T细胞可以识别乳腺癌和卵巢癌细胞系上的多种fab -抗原对。过继性转移的GA1CAR - T细胞在乳腺癌异种移植模型中控制肿瘤，它们的靶向可以使用不同的fab快速重定向。这种多功能的“即插即用”CAR - T平台在个性化治疗、防止抗原丢失变异逃逸、降低毒性和增加可及性方面具有应用潜力。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

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.