Generation of anti-complement "prodrugs" - Cleavable reagents for specific delivery of complement regulators to disease sites

CL Harris*, CE Hughes, AS Williams, [No Value] Goodfellow, DJ Evans, B Caterson, BP Morgan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

Expression of biologically active molecules as fusion proteins with antibody Fc can substantially extend the plasma half-life of the active agent but may also influence function. We have previously generated a number of fusion proteins comprising a complement regulator coupled to Fc and shown that the hybrid molecule has a long plasma half-life and retains biological activity. However, several of the fusion proteins generated had substantially reduced biological activity when compared with the native regulator or regulator released from the Fc following papain cleavage. We have taken advantage of this finding to engineer a prodrug with low complement regulatory activity that is cleaved at sites of inflammation to release active regulator. Two model prodrugs, comprising, respectively, the four short consensus repeats of human decay accelerating factor (CD55) linked to IgG(4) Fc and the three NH2-terminal short consensus repeats of human decay accelerating factor linked to IgG(2) Fc have been developed. In each, specific cleavage sites for matrix metalloproteinases and/or aggrecanases have been incorporated between the complement regulator and the Fc. These prodrugs have markedly decreased complement inhibitory activity when compared with the parent regulator in vitro. Exposure of the prodrugs to the relevant enzymes, either purified, or in supernatants of cytokine-stimulated chondrocytes or in synovial fluid, efficiently cleaved the prodrug, releasing active regulator. Such agents, having negligible systemic effects but active at sites of inflammation, represent a paradigm for the next generation of anti-C therapeutics.

Original languageEnglish
Pages (from-to)36068-36076
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number38
DOIs
Publication statusPublished - 19 Sept 2003

Keywords

  • DECAY-ACCELERATING FACTOR
  • MATRIX-METALLOPROTEINASE CLEAVAGE
  • INTERGLOBULAR DOMAIN
  • RHEUMATOID-ARTHRITIS
  • SYNOVIAL-FLUID
  • CARTILAGE PROTEOGLYCAN
  • MONOCLONAL-ANTIBODIES
  • SEGMENTAL FLEXIBILITY
  • ARTICULAR-CARTILAGE
  • AGGRECANASE SITE

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