Targeting the membrane-proximal C2-set domain of CD33 for improved CAR T cell therapy.

ABSTRACT: Current CD33-targeted immunotherapies typically recognize the membrane-distal V-set domain of CD33. Here, we show that decreasing the distance between T cell and leukemia cell membrane increases the efficacy of CD33 chimeric antigen receptor (CAR) T cells. We therefore generated and optimized second-generation CAR constructs containing single-chain variable fragments from antibodies raised against the membrane-proximal C2-set domain, which bind CD33 regardless of whether the V-set domain is present (CD33^PAN antibodies). CD33^PAN CAR T cells resulted in efficient tumor clearance and improved survival of immunodeficient mice bearing human AML cell xenografts and, in an AML model with limited CD33 expression, forced escape of CD33^neg leukemia. Compared to CD33<

SUBMITTER: Fiorenza S 

PROVIDER: S-EPMC11367471 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature