Hua Ying

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.

Molecular construction and optimization of anti-human IL-1α/β dual variable domain immunoglobulin (DVD-IgTM) molecules

Signal transduction through the interleukin-1 receptor (IL-1R) pathway mediates a strong pro-inflammatory response, which contributes to a number of human diseases such as rheumatoid arthritis. Within the IL-1 family, IL-1α and IL-1β are both agonistic ligands for IL-1R, whereas IL-1 receptor antagonist (IL-1ra) is an endogenous antagonist that binds to IL-R, but does not signal. Therefore, the ideal therapeutic strategy would be blocking both IL-1α and IL-1β, but not IL-1ra. However, due to low sequence homology between the three members of the family, it has been exceedingly difficult to identify potent therapeutic agents, e.g., monoclonal antibodies (mAbs), that selectively recognize both IL-1α and IL-1β, but not IL-1ra. Currently, several anti-IL-1 therapeutic agents in clinical development either inhibit only IL-1β (i.e. anti-IL-1β mAb), or recognize all three ligands (i.e. anti-IL-1R mAb or IL-1R Trap). We have recently developed a novel dual variable domain immunoglobulin (or DVD-IgTM) technology that enables engineering the distinct specificities of two mAbs into a single functional, dual-specific, tetravalent IgG-like molecule. Based on this approach, we have developed anti-human IL-1α/b DVD-IgTM molecules using several pairs of monoclonal antibodies with therapeutic potential, and present a case study for optimal design of a DVD-IgTM agent for a specific target pair combination.