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Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin
Chengbin Wu1, Hua Ying1, Christine Grinnell2, Shaughn Bryant3, Renee Miller1, Anca Clabbers1, Sahana Bose1, Donna McCarthy1, Rong-Rong Zhu4, Ling Santora1, Rachel Davis-Taber1, Yune Kunes1, Emma Fung1, Annette Schwartz2, Paul Sakorafas1, Jijie Gu1, Edit Tarcsa2, Anwar Murtaza3 & Tariq Ghayur1
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.
Specifically targeting a single molecule with monoclonal antibody (mAb) therapy has emerged as an important therapeutic modality for human diseases. In most biologic systems, however, multiple disease mediators are involved in pathogenesis by either playing redundant roles in inducing the same signaling cascade, such as interleukin-1
(IL-1) and IL-1
1, or stimulating two independent cellular pathways in a disease process, such as tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF) in rheumatoid arthritis2. Therefore, simultaneous blockade of these effector molecules is likely to provide better clinical efficacy and/or reach a broader patient population than inhibition of a single target. The utility of combining two mAbs1, 3 has already been demonstrated in preclinical models, and such an approach is also being investigated in the clinic4. However, the option of using approved mAbs for combination therapy is limited, owing to the small number of therapeutic mAbs currently on the market. In addition, the preclinical safety and efficacy of the combination of the marketed mAbs have probably not been adequately addressed. Therefore, testing these combinations directly in humans may have safety risks, and additional preclinical and clinical studies may be necessary. A different approach is to develop pairs of mAbs as combination therapies, which is costly and subject to substantial regulatory hurdles. Therefore, additional approaches to address multi-specificity issues for antibody-based therapeutics are needed.
During the last decade, genetic engineering has led to the development and optimization of various multi-specific antibody formats5, 6, 7. Although multi-specificity has been achieved at the molecular level, two major hurdles still remain: manufacturing efficiency and in vivo drug-like properties (pharmacokinetics, efficacy), the absence of which has hampered clinical use of these molecules as therapeutics, particularly for prolonged treatment of chronic diseases. Herein, we describe the design of a DVD-Ig, which can be engineered from any two mAbs of distinct specificities. The DVD-Ig protein is an IgG-like molecule that can be efficiently produced by conventional mammalian expression systems as a single species for easy manufacturing and purification, while maintaining the affinities and potencies of the two parental mAbs. In addition, it is highly stable and exhibits excellent, IgG-like physicochemical and pharmacokinetic properties.
