PEGylation Extends Circulation Half-Life While Preserving In Vitro and In Vivo Activity of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1)

Jyotica Batra, Jessica Robinson, Christine Mehner, Alexandra Hockla, Erin Miller, Derek C Radisky, Evette S Radisky

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Excess proteolytic activity of matrix metalloproteinases (MMPs) contributes to the development of arthritis, cardiovascular diseases and cancer progression, implicating these enzymes as therapeutic targets. While many small molecule inhibitors of MMPs have been developed, clinical uses have been limited, in part by toxicity and off-target effects. Development of the endogenous tissue inhibitors of metalloproteinases (TIMPs) as recombinant biopharmaceuticals represents an alternative therapeutic approach; however, the short plasma half-life of recombinant TIMPs has restricted their potential in this arena. To overcome this limitation, we have modified recombinant human TIMP-1 (rhTIMP-1) by PEGylation on lysine residues. We analyzed a mixture of mono- and di-PEGylated rhTIMP-1 species modified by attachment of 20 kDa mPEG chains (PEG20K-TIMP-1), as confirmed by SELDI-TOF mass spectrometry. This preparation retained complete inhibitory activity toward the MMP-3 catalytic domain and partial inhibitory activity toward full length MMP-9. Pharmacokinetic evaluation showed that PEGylation extended the plasma half-life of rhTIMP-1 in mice from 1.1 h to 28 h. In biological assays, PEG20K-TIMP-1 inhibited both MMP-dependent cancer cell invasion and tumor cell associated gelatinase activity. Overall these results suggest that PEGylated TIMP-1 exhibits improved potential for development as an anti-cancer recombinant protein therapeutic, and additionally may offer potential for clinical applications in the treatment of other diseases.

Original languageEnglish (US)
Article numbere50028
JournalPLoS One
Volume7
Issue number11
DOIs
StatePublished - 2012

Fingerprint

Tissue Inhibitor of Metalloproteinase-1
metalloproteinases
half life
Half-Life
Tissue Inhibitor of Metalloproteinases
Matrix Metalloproteinases
Neoplasms
Cells
Plasmas
Matrix Metalloproteinase 3
Gelatinases
Pharmacokinetics
Matrix Metalloproteinase Inhibitors
Matrix Metalloproteinase 9
therapeutics
Recombinant Proteins
Biological Assay
Lysine
Arthritis
Mass spectrometry

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

PEGylation Extends Circulation Half-Life While Preserving In Vitro and In Vivo Activity of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1). / Batra, Jyotica; Robinson, Jessica; Mehner, Christine; Hockla, Alexandra; Miller, Erin; Radisky, Derek C; Radisky, Evette S.

In: PLoS One, Vol. 7, No. 11, e50028, 2012.

Research output: Contribution to journalArticle

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