Article
作者: Daniyan, Anthony F ; Souness, Sydney ; Boelens, Jaap Jan ; Lorenz, Ivo C ; Shahid, Sanam ; Mathew, Serena C ; Levine, Ross L ; Um, Jasmine S ; Yoo, Sarah ; Tanaka, Kento ; Dunbar, Andrew ; Park, Young ; Hosszu, Kinga K ; McAvoy, Devin ; Cai, Winson ; Khan, Abdul G ; Burns, Erin R ; Brentjens, Renier J ; Freeman, Ruby
Background:CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking.
Methods: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.
Results: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.
Conclusions: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.
