Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin.
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.
Wu
Chengbin
C
Department of Biologics, Abbott Bioresearch Center, Worcester, Massachusetts 01605, USA. chengbin.wu@abbott.com
Ying
Hua
H
Grinnell
Christine
C
Bryant
Shaughn
S
Miller
Renee
R
Clabbers
Anca
A
Bose
Sahana
S
McCarthy
Donna
D
Zhu
Rong-Rong
RR
Santora
Ling
L
Davis-Taber
Rachel
R
Kunes
Yune
Y
Fung
Emma
E
Schwartz
Annette
A
Sakorafas
Paul
P
Gu
Jijie
J
Tarcsa
Edit
E
Murtaza
Anwar
A
Ghayur
Tariq
T
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
C526870:1D4.1-325 DVD-Ig protein; D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D007135:Immunoglobulin Variable Region; D020382:Interleukin-18; D018664:Interleukin-12