title: 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.affiliation: Department of Biologics, Abbott Bioresearch Center, Worcester, Massachusetts 01605, USA. chengbin.wu@abbott.com
authors.forename: Chengbin
authors.initials: C
authors.lastname: Wu
authors.forename: Hua
authors.initials: H
authors.lastname: Ying
authors.forename: Christine
authors.initials: C
authors.lastname: Grinnell
authors.forename: Shaughn
authors.initials: S
authors.lastname: Bryant
authors.forename: Renee
authors.initials: R
authors.lastname: Miller
authors.forename: Anca
authors.initials: A
authors.lastname: Clabbers
authors.forename: Sahana
authors.initials: S
authors.lastname: Bose
authors.forename: Donna
authors.initials: D
authors.lastname: McCarthy
authors.forename: Rong-Rong
authors.initials: RR
authors.lastname: Zhu
authors.forename: Ling
authors.initials: L
authors.lastname: Santora
authors.forename: Rachel
authors.initials: R
authors.lastname: Davis-Taber
authors.forename: Yune
authors.initials: Y
authors.lastname: Kunes
authors.forename: Emma
authors.initials: E
authors.lastname: Fung
authors.forename: Annette
authors.initials: A
authors.lastname: Schwartz
authors.forename: Paul
authors.initials: P
authors.lastname: Sakorafas
authors.forename: Jijie
authors.initials: J
authors.lastname: Gu
authors.forename: Edit
authors.initials: E
authors.lastname: Tarcsa
authors.forename: Anwar
authors.initials: A
authors.lastname: Murtaza
authors.forename: Tariq
authors.initials: T
authors.lastname: Ghayur
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000096:biosynthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000473:pathology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000276:immunology; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D051381:Rats
chemical_list: C526870:1D4.1-325 DVD-Ig protein; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D007135:Immunoglobulin Variable Region; D020382:Interleukin-18; D018664:Interleukin-12