title: Anti-CD22-chimeric antigen receptors targeting B-cell precursor acute lymphoblastic leukemia.
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.CD3 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.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research (CCR), National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
authors.forename: Waleed
authors.initials: W
authors.lastname: Haso
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lee
authors.forename: Nirali N
authors.initials: NN
authors.lastname: Shah
authors.forename: Maryalice
authors.initials: M
authors.lastname: Stetler-Stevenson
authors.forename: Constance M
authors.initials: CM
authors.lastname: Yuan
authors.forename: Ira H
authors.initials: IH
authors.lastname: Pastan
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
authors.forename: David J
authors.initials: DJ
authors.lastname: FitzGerald
authors.forename: David M
authors.initials: DM
authors.lastname: Barrett
authors.forename: Alan S
authors.initials: AS
authors.lastname: Wayne
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
authors.forename: Rimas J
authors.initials: RJ
authors.lastname: Orentas
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000628:therapy*; D011948:Receptors, Antigen, T-Cell / Q000037:antagonists & inhibitors* / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C497867:CD22 protein, human; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D051918:Sialic Acid Binding Ig-like Lectin 2