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

MAbs
Susan E LacyRajesh V Kamath

Abstract

Interleukin-1 (IL-1) cytokines such as IL-1α, IL-1β, 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-1α and IL-1β 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-1α and IL-1β. In ABT-981, the IL-1β variable domain resides in the outer domain of the DVD-Ig, whereas the IL-1α variable domain is located in the inner position. ABT-981 specifically binds to IL-1α and IL-1β, and is physically capable of binding 2 human IL-1α and 2 human IL-1β 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...Continue Reading

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Datasets Mentioned

BETA
ABT-981

Methods Mentioned

BETA
enzyme-linked
size
surface
surface plasmon resonance
ELISA
biosensor
chip
infrared spectroscopy
differential scanning calorimetry
size exclusion chromatography

Software Mentioned

NBCI Blast
Softmax
IDBS XLfit4
WinNonlin
Biaevaluation

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