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Synthesis and characterization of a thermally-responsive tumor necrosis factor antagonist.

Publication ,  Journal Article
Shamji, MF; Chen, J; Friedman, AH; Richardson, WJ; Chilkoti, A; Setton, LA
Published in: J Control Release
August 7, 2008

Numerous antagonists of tumor necrosis factor alpha (TNFalpha) have been developed to attenuate inflammation and accompanying pain in many disease processes. Soluble TNF receptor type II (sTNFRII) is one such antagonist that sequesters TNFalpha away from target receptors and attenuates its activity. Systemic delivery of soluble TNF receptors or other antagonists may have deleterious side effects associated with immune suppression, so that strategies for locally targeted drug delivery are of interest. Elastin-like polypeptides (ELPs) are biopolymers capable of in situ drug depot formation through thermally-driven supramolecular complexes at physiological temperatures. A recombinant fusion protein between ELP and sTNFRII was designed and evaluated for retention of bivalent functionality. Thermal sensitivity was observed by formation of supramolecular submicron-sized particles at 32 degrees C, with gradual resolubilization from the depot observed at physiological temperatures. In vitro refolding of the sTNFRII domain was required and the purified product exhibited an equilibrium dissociation constant for interacting with TNFalpha that was seven-fold higher than free sTNFRII. Furthermore, anti-TNF activity was observed in inhibiting TNFalpha-mediated cytotoxicity in the murine L929 fibrosarcoma assay. Potential advantages of this ELP-sTNFRII fusion protein as an anti-TNFa drug depot include facility of injection, in situ depot formation, low endotoxin content, and functionality against TNFalpha.

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Published In

J Control Release

DOI

EISSN

1873-4995

Publication Date

August 7, 2008

Volume

129

Issue

3

Start / End Page

179 / 186

Location

Netherlands

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Temperature
  • Solubility
  • Recombinant Fusion Proteins
  • Receptors, Tumor Necrosis Factor, Type II
  • Protein Structure, Tertiary
  • Protein Renaturation
  • Pharmacology & Pharmacy
  • Peptides
  • Mice
 

Citation

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Shamji, M. F., Chen, J., Friedman, A. H., Richardson, W. J., Chilkoti, A., & Setton, L. A. (2008). Synthesis and characterization of a thermally-responsive tumor necrosis factor antagonist. J Control Release, 129(3), 179–186. https://doi.org/10.1016/j.jconrel.2008.04.021
Shamji, Mohammed F., Jun Chen, Allan H. Friedman, William J. Richardson, Ashutosh Chilkoti, and Lori A. Setton. “Synthesis and characterization of a thermally-responsive tumor necrosis factor antagonist.J Control Release 129, no. 3 (August 7, 2008): 179–86. https://doi.org/10.1016/j.jconrel.2008.04.021.
Shamji MF, Chen J, Friedman AH, Richardson WJ, Chilkoti A, Setton LA. Synthesis and characterization of a thermally-responsive tumor necrosis factor antagonist. J Control Release. 2008 Aug 7;129(3):179–86.
Shamji, Mohammed F., et al. “Synthesis and characterization of a thermally-responsive tumor necrosis factor antagonist.J Control Release, vol. 129, no. 3, Aug. 2008, pp. 179–86. Pubmed, doi:10.1016/j.jconrel.2008.04.021.
Shamji MF, Chen J, Friedman AH, Richardson WJ, Chilkoti A, Setton LA. Synthesis and characterization of a thermally-responsive tumor necrosis factor antagonist. J Control Release. 2008 Aug 7;129(3):179–186.
Journal cover image

Published In

J Control Release

DOI

EISSN

1873-4995

Publication Date

August 7, 2008

Volume

129

Issue

3

Start / End Page

179 / 186

Location

Netherlands

Related Subject Headings

  • Tumor Necrosis Factor-alpha
  • Temperature
  • Solubility
  • Recombinant Fusion Proteins
  • Receptors, Tumor Necrosis Factor, Type II
  • Protein Structure, Tertiary
  • Protein Renaturation
  • Pharmacology & Pharmacy
  • Peptides
  • Mice