A recombinant human IgG1 Fc multimer designed to mimic the active fraction of IVIG in autoimmunity
Xiaoyu Zhang, Jane Owens, Henrik S. Olsen, Edward So, Erin Burch, Mark C. McCroskey, Xianfeng Li, Gregory L. Weber, Donald Bennett, Denis Rybin, Hua Zhou, Haiping Hao, Emmanuel Y. Mérigeon, David S. Block, Gregory LaRosa, Scott E. Strome
Xiaoyu Zhang, Jane Owens, Henrik S. Olsen, Edward So, Erin Burch, Mark C. McCroskey, Xianfeng Li, Gregory L. Weber, Donald Bennett, Denis Rybin, Hua Zhou, Haiping Hao, Emmanuel Y. Mérigeon, David S. Block, Gregory LaRosa, Scott E. Strome
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Research Article

A recombinant human IgG1 Fc multimer designed to mimic the active fraction of IVIG in autoimmunity

Abstract

The antiinflammatory effects of i.v. Ig (IVIG) in the treatment of autoimmune disease are due, in part, to the Fc fragments of Ig aggregates. In order to capitalize on the known antiinflammatory and tolerogenic properties of Ig Fc aggregates, we created a recombinant human IgG1 Fc multimer, GL-2045. In vitro, GL-2045 demonstrated high-avidity binding to Fc receptors, blocked the binding of circulating immune complexes from patients with rheumatoid arthritis to human Fcγ receptors (FcγRs), and inhibited antibody-mediated phagocytosis at log order–lower concentrations than IVIG. In vivo, administration of GL-2045 conferred partial protection against antibody-mediated platelet loss in a murine immune thrombocytopenic purpura (ITP) model. GL-2045 also suppressed disease activity in a therapeutic model of murine collagen-induced arthritis (CIA), which was associated with reduced circulating levels of IL-6. Furthermore, GL-2045 administration to nonhuman primates (NHPs) transiently increased systemic levels of the antiinflammatory cytokines IL-10 and IL-1RA, reduced the proinflammatory cytokine IL-8, and decreased surface expression of CD14 and HLA-DR on monocytes. These findings demonstrate the immunomodulatory properties of GL-2045 and suggest that it has potential as a treatment for autoimmune and inflammatory diseases, as a recombinant alternative to IVIG.

Authors

Xiaoyu Zhang, Jane Owens, Henrik S. Olsen, Edward So, Erin Burch, Mark C. McCroskey, Xianfeng Li, Gregory L. Weber, Donald Bennett, Denis Rybin, Hua Zhou, Haiping Hao, Emmanuel Y. Mérigeon, David S. Block, Gregory LaRosa, Scott E. Strome

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Figure 4

GL-2045 ameliorates histopathological parameters in CIA mice.

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GL-2045 ameliorates histopathological parameters in CIA mice. Joints fro...
Joints from each animal were assessed for changes in histopathology parameters at the end of the treatment study (day 11 after enrollment). (A) Representative photomicrographs of toluidine blue–stained ankle (40× magnification), knee (100× magnification), hind paw (16× magnification), and forepaw (16× magnification) joints from selected groups: naive, diseased vehicle-treated (PBS), diseased dexamethasone-treated (Dex), diseased IVIG-treated 2 g/kg (IVIG i.p.), and diseased GL-2045–treated 50 mg/kg (GL-2045 50 i.v.). w, wrist; s, synovium. Arrows point to affected joints. (B) Box and whisker plots of quantification of histopathological parameters measured in all joints from each treatment group. The bounds of the boxes represent the 25th and 75th percentile, the lines represent median, and top and bottom whiskers represent the 95th and 5th percentile. Naive mice showed no inflammation or joint pathology. Compared with the PBS group, Dex- and GL-2045–treated animals showed significantly less histopathological evidence of disease. *P < 0.05 compared with PBS. Kruskal-Wallis test with Dunn’s post-hoc test. Naive, n = 4; all the other groups, n = 10.