title: Genetic alteration of a bispecific ligand-directed toxin targeting human CD19 and CD22 receptors resulting in improved efficacy against systemic B cell malignancy.
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.
authors.affiliation: University of Minnesota Cancer Center, Section on Molecular Cancer Therapeutics, Department of Therapeutic Radiology-Radiation Oncology, Minneapolis, MN 55455, USA. valle001@umn.edu
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Vallera
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Sicheneder
authors.forename: Angela
authors.initials: A
authors.lastname: Panoskaltsis-Mortari
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Taras