WORCESTER, Mass.—Metabolic redundancies can be problematic for drug developers. No sooner do scientists develop a therapy to target one part of a disease, when the disease agent (tumor, virus, etc.) does an end run and finds another way to upset the metabolic balance. This challenge motivated scientists at the Abbott Research Center to develop monoclonal antibodies (mAbs) that targeted more than one disease mediator with the goal of providing simultaneous blockade of multiple pathways.
In Nature Biotechnology, the researchers describe tetravalent IgG-like molecules called dual-variable-domain immunoglobulins (DVD-Igs), which they designed by genetically fusing the variable domains of mAbs targeting various signaling molecules, such as IL-12 or IL-18. They then transfected these constructs into stable mammalian cell lines and noted similar protein expression levels as with single-target mAbs. As well, they noted that the DVD-Igs could bind both target antigens simultaneously, whether in vitro (Biacore affinity assay) or in vivo (dosed in rats).
The researchers also found that when given to mice, the DVD-Igs were as effective in reducing downstream cytokine production as a dose of the two single-target mAbs given together. They then engineered a DVD-Ig that targeted both IL-1α and β, molecules involved in a mouse model of rheumatoid arthritis. Therapeutic administration of the DVD-Ig significantly inhibited progression of established arthritis in the animal model.