Anti-CD22-chimeric antigen receptors targeting B cell precursor acute lymphoblastic leukemia

Waleed Haso, Damiel W. Lee, Nirali N. Shah, Maryalice Stetler-Stevenson, Constance M. Yuan, Ira H. Pastan, Dimiter S. Dimitrov, Richard A. Morgan, David J. FitzGerald, David M. Barrett, Alan S. Wayne, Crystal L. Mackall and Rimas J. Orentas


Immune targeting of B cell malignancies using chimeric antigen receptors (CARs) is a promising new approach, but critical factors impacting CAR efficacy remain unclear. To test the suitability of targeting CD22 on precursor B cell acute lymphoblastic leukemia (BCP-ALL), lymphoblasts from 111 patients with BCP-ALL were assayed for CD22 expression and all were found to be CD22 positive, with median CD22 expression levels of 3,500 sites/cell. Three distinct binding domains targeting CD22 were fused to various TCR signaling domains ± an IgG heavy chain constant domain (CH2CH3) to create a series of vector constructs suitable to delineate optimal CAR configuration. CARs derived from the m971 anti-CD22 moAb, which targets a proximal CD22 epitope demonstrated superior anti-leukemic activity compared to those incorporating other binding domains, and addition of a 4-1BB signaling domain to CD28.CD3ζ constructs diminished potency, whereas increasing affinity of the anti-CD22 binding motif, and extending the CD22 binding domain away from the membrane via CH2CH3 had no effect. We conclude that 2nd generation m971 derived anti-CD22-CARs are promising novel therapeutics that should be tested in BCP-ALL.

  • Submitted June 20, 2012.
  • Accepted November 26, 2012.