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

Waleed Haso, Daniel 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

Research output: Contribution to journalArticle

Abstract

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 3500 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 mAb, which targets a proximal CD22 epitope demonstrated superior antileukemic activity compared with those incorporating other binding domains, and addition of a 4-1BB signaling domain to CD28.CD3l 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 second-generation m971 mAb-derived anti-CD22 CARs are promising novel therapeutics that should be tested in BCP-ALL.

Original languageEnglish (US)
Pages (from-to)1165-1171
Number of pages7
JournalBlood
Volume121
Issue number7
DOIs
StatePublished - Feb 14 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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  • Cite this

    Haso, W., Lee, D. W., Shah, N. N., Stetler-Stevenson, M., Yuan, C. M., Pastan, I. H., Dimitrov, D. S., Morgan, R. A., FitzGerald, D. J., Barrett, D. M., Wayne, A. S., MacKall, C. L., & Orentas, R. J. (2013). Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia. Blood, 121(7), 1165-1171. https://doi.org/10.1182/blood-2012-06-438002