期刊
LEUKEMIA RESEARCH
卷 33, 期 9, 页码 1233-1242出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.leukres.2009.02.006
关键词
Immunotoxin; Diphtheria toxin; Leukemia; Lymphoma; Scid model; Anti-CD19 sFv; Anti-CD22 sFv
资金
- US Public Health Service [R01-CA36725, R01-CA082154]
- NCI
- MAID
- DHHS
- Children's Cancer Research Fund
- Lion's Children's Cancer Fund
- William Lawrence and Blanche Hughes Fund
- NATIONAL CANCER INSTITUTE [R01CA082154, R01CA036725] Funding Source: NIH RePORTER
A bispecific ligand-directed toxin (BIT) called DT2219ARL consisting of two scFv ligands recognizing CD19 and CD22 and catalytic DT(390) 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 (IC(50)s 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. (C) 2009 Elsevier Ltd. All rights reserved.
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