Arina Ainhoa, Arauz Edwin, Masoumi Elham, Warzecha Karolina W, Sääf Annika, Widło Łukasz, Slezak Tomasz, Zieminska Aleksandra, Dudek Karolina, Schaefer Zachary P, Lecka Maria, Usatyuk Svitlana, Weichselbaum Ralph R, Kossiakoff Anthony A
Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, USA.
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA.
Sci Adv. 2025 Jul 4;11(27):eadv4937. doi: 10.1126/sciadv.adv4937.
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.
嵌合抗原受体(CAR)T细胞疗法在治疗血液系统癌症方面已显示出非凡的效果,但面临着抗原丢失、毒性和复杂制造等挑战。通用型和模块化CAR构建体比传统CAR构建体具有更高的灵活性、安全性和成本效益。我们基于工程化蛋白G变体(GA1)和Fab支架提出了一种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,可根据CAR对Fab以及Fab对靶标的亲和力进行调节。GA1CAR T细胞能够识别乳腺癌和卵巢癌细胞系上的多个Fab-抗原对。过继转移的GA1CAR T细胞可控制乳腺癌异种移植模型中的肿瘤,并且使用不同的Fab可快速重新定向其靶向。这种多功能的“即插即用”CAR T平台在个性化治疗、防止抗原丢失变体逃逸、降低毒性以及增加可及性方面具有应用潜力。
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