Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
J Immunother Cancer. 2024 May 20;12(5):e009013. doi: 10.1136/jitc-2024-009013.
CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking.
We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice.
We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both low antigen density and clinically relevant patient-derived xenograft models. Increased activation and enhanced polyfunctionality led to enhanced efficacy.
Showing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models.
CD33 是嵌合抗原受体（CAR）T 细胞治疗急性髓细胞白血病（AML）的一个可行靶点，但临床效果不佳。
我们开发了 3P14HLh28Z，这是一种新型 CD33 导向的 CD28/CD3Z 为基础的 CAR T 细胞，源自在人源化小鼠中通过膜近端片段免疫获得的高亲和力结合物。
我们发现，在人源化小鼠中鉴定膜近端结合物时，仅免疫 CD33 的膜近端结构域是必要的。与针对远端 CD33 表位的临床验证的 lintuzumab 为基础的 CAR T 细胞相比，3P14HLh28Z 显示出增强的体外功能，以及在低抗原密度和临床相关患者来源异种移植模型中更好的肿瘤控制和增加的总生存期。增强的激活和多功能性导致了增强的疗效。
首次表明在 CD33 靶向治疗中，膜近端 CAR 优于膜远端 CAR，我们的结果证明了用高亲和力结合物靶向膜近端表位的原理。我们还证明了在低抗原密度和临床相关的患者来源模型中优化 CAR T 细胞功能的重要性。
