title: 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.
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 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.
authors.affiliation: a AbbVie Bioresearch Center; Global Biologics ; Worcester , MA USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Lacy
authors.forename: Chengbin
authors.initials: C
authors.lastname: Wu
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Ambrosi
authors.forename: Chung-Ming
authors.initials: CM
authors.lastname: Hsieh
authors.forename: Sahana
authors.initials: S
authors.lastname: Bose
authors.forename: Renee
authors.initials: R
authors.lastname: Miller
authors.forename: Donna M
authors.initials: DM
authors.lastname: Conlon
authors.forename: Edit
authors.initials: E
authors.lastname: Tarcsa
authors.forename: Ravi
authors.initials: R
authors.lastname: Chari
authors.forename: Tariq
authors.initials: T
authors.lastname: Ghayur
authors.forename: Rajesh V
authors.initials: RV
authors.lastname: Kamath
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D000915:Antibody Affinity; D000918:Antibody Specificity; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D007135:Immunoglobulin Variable Region / Q000737:chemistry* / Q000276:immunology / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000276:immunology; D051379:Mice
chemical_list: D057134:Antibodies, Neutralizing; C508584:IL1A protein, human; C508585:IL1B protein, human; D007074:Immunoglobulin G; D007135:Immunoglobulin Variable Region; D053582:Interleukin-1alpha; D053583:Interleukin-1beta
keywords: ABT-981; ADA, Anti-drug antibodies; CDR, complementarity-determining region; CEC, cation exchange chromatography; Cyno, cynomolgus monkey; DVD-Ig, dual variable domain immunoglobulin; ED50, efficacious dose at 50% response; ED80, efficacious dose at 80% response; ; DVD-Ig; IL-1 antagonist; IL-1α; IL-1β; osteoarthritis