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, 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.