A dimeric form of a small-sized protein binder exhibits enhanced anti-tumor activity through prolonged blood circulation

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Small-sized non-antibody scaffolds have attracted considerable interest as alternatives to immunoglobulin antibodies. However, their short half-life is considered a drawback in the development of therapeutic agents. Here we demonstrate that a homo-dimeric form of a repebody enhances the anti-tumor activity than a monomeric form through prolonged blood circulation. Spytag and spycatcher were genetically fused to the C-terminus of a respective human IL-6-specific repebody, and the resulting two repebody constructs were mixed at an equimolar ratio to produce a homo-dimeric form through interaction between spytag and spycatcher. The homo-dimeric repebody was detected as a single band in the SDS-PAGE analysis with an expected molecular size (78 kDa), showing high stability and homogeneity. The dimeric repebody was shown to simultaneously accommodate two hIL-6 molecules, and its binding affinity for hIL-6 was estimated to be comparable to a monomeric repebody. The serum concentration of the dimeric repebody was observed to be about 5.5 times higher than a monomeric repebody, consequently leading to considerably higher tumor suppression effect in human tumor xenograft mice. The present approach can be effectively used for prolonging the blood half-life of small-sized protein binders, resulting in enhanced therapeutic efficacy.
Publisher
ELSEVIER SCIENCE BV
Issue Date
2018-06
Language
English
Article Type
Article
Citation

JOURNAL OF CONTROLLED RELEASE, v.279, pp.282 - 291

ISSN
0168-3659
DOI
10.1016/j.jconrel.2018.04.039
URI
http://hdl.handle.net/10203/244014
Appears in Collection
BS-Journal Papers(저널논문)
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