Genetic alteration of a bispecific ligand-directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy

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70 Scopus citations

Abstract

A bispecific ligand-directed toxin (BLT) called DT2219ARL consisting of two scFv ligands recognizing CD19 and CD22 and catalytic DT390 was genetically enhanced for superior in vivo anti-leukemia activity. Genetic alterations included reverse orienting VH-VL domains and adding aggregation reducing/stabilizing linkers. In vivo, these improvements resulted in previously unseen long-term tumor-free survivors measured in a bioluminescent xenograft imaging model in which the progression of human Raji Burkitt's lymphoma could be tracked in real time and in a Daudi model as well. Studies showed DT2219ARL was potent (IC50s 0.06-0.2 nM range) and selectively blockable. Imaging studies indicated the highly invasive nature of this B cell malignancy model and showed it likely induced pre-terminal hind limb paralysis because of metastasis to spinal regions prevented by DT2219ARL. DT2219ARL represents a new class of bispecific biological that can be continually improved by genetic mutation.

Original languageEnglish (US)
Pages (from-to)1233-1242
Number of pages10
JournalLeukemia research
Volume33
Issue number9
DOIs
StatePublished - Sep 2009

Bibliographical note

Funding Information:
This work was supported in part by the US Public Health Service Grants RO1-CA36725 and RO1-CA082154 awarded by the NCI and the NIAID, DHHS and Children's Cancer Research Fund, the Lion's Children's Cancer Fund, and the William Lawrence and Blanche Hughes Fund.

Keywords

  • Anti-CD19 sFv
  • Anti-CD22 sFv
  • Diphtheria toxin
  • Immunotoxin
  • Leukemia
  • Lymphoma
  • Scid model

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