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Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin.

Authors
  • Wu, Chengbin
  • Ying, Hua
  • Grinnell, Christine
  • Bryant, Shaughn
  • Miller, Renee
  • Clabbers, Anca
  • Bose, Sahana
  • McCarthy, Donna
  • Zhu, Rong-Rong
  • Santora, Ling
  • Davis-Taber, Rachel
  • Kunes, Yune
  • Fung, Emma
  • Schwartz, Annette
  • Sakorafas, Paul
  • Gu, Jijie
  • Tarcsa, Edit
  • Murtaza, Anwar
  • Ghayur, Tariq
Type
Published Article
Journal
Nature biotechnology
Publication Date
Nov 01, 2007
Volume
25
Issue
11
Pages
1290–1297
Identifiers
PMID: 17934452
Source
Medline
License
Unknown

Abstract

For complex diseases in which multiple mediators contribute to overall disease pathogenesis by distinct or redundant mechanisms, simultaneous blockade of multiple targets may yield better therapeutic efficacy than inhibition of a single target. However, developing two separate monoclonal antibodies for clinical use as combination therapy is impractical, owing to regulatory hurdles and cost. Multi-specific, antibody-based molecules have been investigated; however, their therapeutic use has been hampered by poor pharmacokinetics, stability and manufacturing feasibility. Here, we describe a generally applicable model of a dual-specific, tetravalent immunoglobulin G (IgG)-like molecule--termed dual-variable-domain immunoglobulin (DVD-Ig)--that can be engineered from any two monoclonal antibodies while preserving activities of the parental antibodies. This molecule can be efficiently produced from mammalian cells and exhibits good physicochemical and pharmacokinetic properties. Preclinical studies of a DVD-Ig protein in an animal disease model demonstrate its potential for therapeutic application in human diseases.

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