CD123-SPECIFIC CHIMERIC ANTIGEN RECEPTOR REDIRECTED T CELLS AND METHODS OF THEIR USE

摘要

A family of chimeric antigen receptors (CARs) containing a CD123 specific scFv was developed to target different epitopes on CD123. In some embodiments, such a CD123 chimeric antigen receptor (CD123CAR) gene includes an anti-CD123 scFv region fused in frame to a modified IgG4 hinge region comprising an S228P substitution, an L235E substitution, and optionally an N297Q substitution; a costimulatory signaling domain; and a T cell receptor (TCR) zeta chain signaling domain. When expressed in healthy donor T cells (CD4/CD8), the CD123CARs redirect T cell specificity and mediated potent effector activity against CD123+ cell lines as well as primary AML patient samples. Further, T cells obtained from patients with active AML can be modified to express CD123CAR genes and are able to lyse autologous AML blasts in vitro. Finally, a single dose of 5.0×106 CAR123 T cells results in significantly delayed leukemic progression in mice. These results suggest that CD123CAR-transduced T cells may be used as an immunotherapy for the treatment of high risk AML.

主权项

1. A CD123 chimeric antigen receptor (CD123CAR) gene, comprising an anti-CD123 scFv region fused in frame to
a modified IgG4 hinge region comprising a nucleotide sequence that encodes an S228P amino acid substitution and an L235E amino acid substitution; and a T cell receptor (TCR) zeta chain signaling domain.