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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We thank Gerald Carson, Yun Zhang, Liqiang Zhou, Randolph Huelsman, Limary Medina, Michelle Babineau, Shaona Fang, Wendy Gion, Cheryl Thibault, Baofu Ni, Adriana Bajardi-Taccioli, and Elizabeth O'Connor of Abbott Bioresearch Center, for their technical contributions; Jochen Salfeld, Trudi Veldman, Andrew Goodearl, Lisa Olson, Lisa Schopf, Susan Lacy, Robert Hickman, Catherine Tripp, and Peter Isakson of Abbott Bioresearch Center for their support. We also acknowledge, with their permission, Lori Lush, PharmD, of JK Associates, Inc., and Michael Nissen, ELS, of Abbott Laboratories, for their editing and formatting assistance in the development of this manuscript. Type II porcine collagen (lyophilized) was obtained from Marie Griffiths at the University of Utah.
This study was supported by Abbott Laboratories, Abbott Park, Illinois. The authors are employees of Abbott Laboratories and may own Abbott stock or stock options.
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Wu, C., Ying, H., Grinnell, C. et al. Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin. Nat Biotechnol 25, 1290–1297 (2007). https://doi.org/10.1038/nbt1345
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