Presentation: Anti-IL-1α/β Dual Variable Domain Immunoglobulin (DVD-Ig), a Novel Inhibitor of IL-1α and IL-1β is Efficacious in Mouse Collagen-Induced Arthritis Model (2007)

135 Anti-IL-1α/β Dual Variable Domain Immunoglobulin (DVD-Ig), a Novel Inhibitor of IL-1α and IL-1β is Efficacious in Mouse Collagen-Induced Arthritis Model

Purpose: Rheumatoid arthritis (RA) is an autoimmune disease with an interplay of multiple pathogenic mechanisms that result in chronic inflammatory synovitis of the peripheral joints, leading to cartilage destruction and bone erosions. Anti-tumor necrosis factor (anti-TNF) therapy has revolutionized the treatment of RA; however, a significant percentage of patients do not fully respond to this therapy. Thus, there is a strong medical need to develop novel agents that can target 2 or more pathogenic processes simultaneously. Such agents are expected to have improved efficacy over the monospecific agents and can also be useful for treating patients that do not respond to monotherapy. For a proof of concept of this approach, a dual-variable domain immunoglobulin (DVD-Ig) containing the variable domains from mouse anti-mouse IL-1α (9H10.2C2.E2) and anti-mouse IL-1β (10G11.B.11) antibodies was constructed. This novel molecule could neutralize both IL-1α and IL-1β simultaneously in in vitro assays. The in vivo efficacy of the anti-IL-1α/β DVD-Ig was evaluated in the mouse collagen-induced arthritis (CIA) model.
Methods: A dual-specific Ig-like molecule was generated from 2 different monospecific mouse anti-IL-1α (clone 9H10.2C2.E2) and anti-IL-1β (clone 10G11.B.11) antibodies by combining the sequences of the 2 variable domains from the light and heavy chains in tandem via a linker and co-expressing in mammalian cells. Anti-IL-1α/β DVD-Ig neutralized both IL-1α and IL-1β in vitro. The efficacy of the DVD-Ig along with the parental monospecific anti-IL-1α and anti-IL-1β antibodies were evaluated in the standard mouse CIA model. The monospecific antibodies and the anti-IL-1α DVD-Ig were dosed therapeutically 2 or 3 times per week, respectively, for 8 days. The impact of treatment on disease was evaluated by mean arthritic score (MAS) and paw swelling.
Results: Our results demonstrate that therapeutic treatment with the anti-IL-1α/β DVD-Ig resulted in a profound inhibition of arthritis as assessed by MAS (p<0.05, by Mann Whitney) and paw swelling (p<0.05, by Student t test). Moreover, the anti-IL-1α/β DVD-Ig showed a similar efficacy to the monospecific anti-IL-1α and anti-IL-1β antibodies in combination. Furthermore, the anti-IL-1α/β DVD-Ig had a comparable impact on synovial hyperplasia, bone damage, and cartilage damage compared with the monospecific anti-IL-1α and anti-IL-1β antibodies in combination.
Conclusions: A novel anti-IL-1α/β DVD-Ig that simultaneously blocked IL-1α and IL-1β in vitro showed comparable efficacy in the mouse CIA to monospecific anti-IL-1α and anti-IL-1β antibodies in combination. Based on the in vivo efficacy of this novel anti-IL-1α/β inhibitor, DVD technology has potential for developing novel next-generation biologics that block 2 pathogenic mechanisms simultaneously.

  A. Murtaza, Abbott Bioresearch Center, 1; Abbott Bioresearch Center, 3; S. Bryant, Abbott Bioresearch Center, 1; Abbott Bioresearch Center, 3; S. Mathieu, Abbott Bioresearch Center, 1; Abbott Bioresearch Center, 3; C. Wu, Abbott Bioresearch Center, 1; Abbott Bioresearch Center, 3; T. Ghayur, Abbott Bioresearch Center, 1; Abbott Bioresearch Center, 3; L. Olson, Abbott Bioresearch Center, 1; Abbott Bioresearch Center, 3; L. Schopf, Abbott Bioresearch Center, 1; Abbott Bioresearch Center, 3.