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

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.

• Authors: Chengbin Wu, Hua Ying, Christine Grinnell, Shaughn Bryant, Renee Miller, Anca Clabbers, Sahana Bose, Donna McCarthy, Rong-Rong Zhu, Ling Santora, Rachel Davis-Taber, Yune Kunes, Emma Fung, Annette Schwartz, Paul Sakorafas, Jijie Gu, Edit Tarcsa, Anwar Murtaza, Tariq Ghayur
• Journal: Nature biotechnology (Nat Biotechnol) Vol. 25 Issue 11 Pg. 1290-7 (Nov 2007) ISSN: 1087-0156 [Print] United States
• PMID: 17934452 (Publication Type: Journal Article)

Chemical References

• 1D4.1-325 DVD-Ig protein
• Antibodies, Bispecific
• Antibodies, Monoclonal
• Immunoglobulin Variable Region
• Interleukin-18
• Interleukin-12

Topics

• Animals
• Antibodies, Bispecific (biosynthesis, pharmacokinetics, therapeutic use)
• Antibodies, Monoclonal (biosynthesis, genetics, pharmacokinetics, therapeutic use)
• Arthritis, Experimental (drug therapy, pathology)
• CHO Cells
• Cricetinae
• Cricetulus
• Disease Models, Animal
• Humans
• Immunoglobulin Variable Region (biosynthesis, genetics, metabolism, therapeutic use)
• Interleukin-12 (antagonists & inhibitors, immunology)
• Interleukin-18 (antagonists & inhibitors, immunology)
• Mice
• Protein Engineering
• Protein Structure, Tertiary
• Rats