Refractory acute myeloid leukemia (AML) remains an incurable malignancy despite the clinical use of novel targeted therapies, new antibody-based therapies, and cellular therapeutics. Here, we describe the preclinical development of a novel cell therapy that targets the antigen CLEC12A with a biparatopic bridging protein. Bridging proteins are designed as “CAR-T cell engagers,” with a CAR-targeted protein fused to antigen binding domains derived from antibodies. Here, we created a CD19-anti-CLEC12A bridging protein that binds to CAR19 T cells and to the antigen CLEC12A. Biparatopic targeting increases the potency of bridging protein-mediated cytotoxicity by CAR19 T cells. Using CAR19 T cells that secrete the bridging protein we demonstrate potent activity against aggressive leukemic cell lines in vivo . This CAR-engager platform is facile and modular, as illustrated by activity of a dual-antigen bridging protein targeting CLEC12A and CD33, designed to counter tumor heterogeneity and antigen escape, and created without the need for extensive CAR T-cell genetic engineering. CAR19 T cells provide an optimal cell therapy platform with well-understood inherent persistence and fitness characteristics. This article is featured in Highlights of This Issue, [p. 1755][1] [1]: /lookup/volpage/20/1755?iss=10

中文翻译：

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分泌双互补位抗 CLEC12A 桥接蛋白的抗 CD19 CAR T 细胞在体外和体内对高度侵袭性急性髓性白血病具有有效活性

尽管临床上使用了新型靶向疗法、新型抗体疗法和细胞疗法，但难治性急性髓性白血病 (AML) 仍然是一种无法治愈的恶性肿瘤。在这里，我们描述了一种新型细胞疗法的临床前开发，该疗法以具有双互补位桥接蛋白的抗原 CLEC12A 为靶点。桥接蛋白被设计为“CAR-T 细胞接合器”，其中 CAR 靶向蛋白融合到源自抗体的抗原结合域。在这里，我们创建了一种 CD19 抗 CLEC12A 桥接蛋白，它与 CAR19 T 细胞和抗原 CLEC12A 结合。双互补位靶向增加了 CAR19 T 细胞桥接蛋白介导的细胞毒性的效力。使用分泌桥接蛋白的 CAR19 T 细胞，我们展示了对体内侵袭性白血病细胞系的有效活性。这个 CAR-engager 平台是简单的和模块化的，如针对 CLEC12A 和 CD33 的双抗原桥接蛋白的活性所示，旨在对抗肿瘤异质性和抗原逃逸，并且不需要广泛的 CAR T 细胞基因工程就可以创建。CAR19 T 细胞提供了一个最佳的细胞治疗平台，具有众所周知的固有持久性和适应性特征。这篇文章刊登在本期要闻中，[p。1755][1][1]:/lookup/volpage/20/1755?iss=10 这篇文章刊登在本期要闻中，[p。1755][1][1]:/lookup/volpage/20/1755?iss=10 这篇文章刊登在本期要闻中，[p。1755][1][1]:/lookup/volpage/20/1755?iss=10