期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-11886-7
关键词
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资金
- National Research Program for Biopharmaceuticals, Ministry of Science and Technology, Taipei, Taiwan [MOST 105-2325-B-037-002, MOST 105-2325-B-037-001, MOST 105-2325-B-041-001, MOST 105-2314-B-037-010-MY3]
- Kaohsiung Medical University [KMU-DK106002, D08-00005]
- KMU Aim for the Top 500 Universities Grant [KMU-TP105C00, KMU-DT106003]
- Program for Translational Innovation of Biopharmaceutical Development - Technology Supporting Platform Axis
- Grant of Biosignature in Colorectal Cancers, Academia Sinica, Taiwan [BM10501010045]
- Taiwan Ministry of Health and Welfare [MOHW105-TDU-B-212-134007, MOHW106-TDU-B-212-144007]
- Health and welfare surcharge of tobacco products
Systemic injection of therapeutic antibodies may cause serious adverse effects due to on-target toxicity to the antigens expressed in normal tissues. To improve the targeting selectivity to the region of disease sites, we developed protease-activated pro-antibodies by masking the binding sites of antibodies with inhibitory domains that can be removed by proteases that are highly expressed at the disease sites. The latency-associated peptide (LAP), C2b or CBa of complement factor 2/B were linked, through a substrate peptide of matrix metalloproteinase-2 (MMP-2), to an anti-epidermal growth factor receptor (EGFR) antibody and an anti-tumor necrosis factor-alpha (TNF-alpha) antibody. Results showed that all the inhibitory domains could be removed by MMP-2 to restore the binding activities of the antibodies. LAP substantially reduced (53.8%) the binding activity of the anti-EGFR antibody on EGFR-expressing cells, whereas C2b and CBa were ineffective (21% and 9.3% reduction, respectively). Similarly, LAP also blocked 53.9% of the binding activity of the anti-TNF-alpha antibody. Finally, molecular dynamic simulation showed that the masking efficiency of LAP, C2b and CBa was 33.7%, 10.3% and -5.4%, respectively, over the binding sites of the antibodies. This strategy may aid in designing new protease-activated pro-antibodies that attain high therapeutic potency yet reduced systemic on-target toxicity.
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