Developing a membrane-proximal CD33-targeting CAR T cell.
J Immunother Cancer
; 12(5)2024 May 20.
Article
em En
| MEDLINE
| ID: mdl-38772686
ABSTRACT
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Imunoterapia Adotiva
/
Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Immunother Cancer
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos