Generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-Ig(TM)) molecule that specifically and potently neutralizes both IL-1? and IL-1?.

ABSTRACT: Interleukin-1 (IL-1) cytokines such as IL-1?, IL-1?, and IL-1Ra contribute to immune regulation and inflammatory processes by exerting a wide range of cellular responses, including expression of cytokines and chemokines, matrix metalloproteinases, and nitric oxide synthetase. IL-1? and IL-1? bind to IL-1R1 complexed to the IL-1 receptor accessory protein and induce similar physiological effects. Preclinical and clinical studies provide significant evidence for the role of IL-1 in the pathogenesis of osteoarthritis (OA), including cartilage degradation, bone sclerosis, and synovial proliferation. Here, we describe the generation and characterization of ABT-981, a dual variable domain immunoglobulin (DVD-Ig) of the IgG1/k subtype that specifically and potently neutralizes IL-1? and IL-1?. In ABT-981, the IL-1? variable domain resides in the outer domain of the DVD-Ig, whereas the IL-1? variable domain is located in the inner position. ABT-981 specifically binds to IL-1? and IL-1?, and is physically capable of binding 2 human IL-1? and 2 human IL-1? molecules simultaneously. Single-dose intravenous and subcutaneous pharmacokinetics studies indicate that ABT-981 has a half-life of 8.0 to 10.4 d in cynomolgus monkey and 10.0 to 20.3 d in rodents. ABT-981 exhibits suitable drug-like-properties including affinity, potency, specificity, half-life, and stability for evaluation in human clinical trials. ABT-981 offers an exciting new approach for the treatment of OA, potentially addressing both disease modification and symptom relief as a disease-modifying OA drug.

SUBMITTER: Lacy SE 

PROVIDER: S-EPMC4622731 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature