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 3

GL-2045 effect in preventing platelet loss in ITP and ameliorating disease activity in CIA.

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GL-2045 effect in preventing platelet loss in ITP and ameliorating disea...
(A) GL-2045 effects on platelet loss in a murine model of ITP. Mice were pretreated with GL-2045 i.v./i.p., M-045 i.v., IVIG i.p., or Albumin i.p. 1 day before platelet depletion with anti-CD41 Ab. The percent of platelets in total cells was analyzed on day 4. Data are shown as dot plot with mean ± SEM. n = 15 mice per group. (B) GL-2045 effects on arthritis score in murine CIA. The treatments were initiated after the onset of arthritis, and arthritis scores were evaluated daily after initiation of the treatment. (C) The body weight changes on day 11 after enrollment from baseline were compared among different treatment groups. At the initiation of treatment, individual paws were classified as noninflamed (arthritis score = 0) and inflamed (arthritis score ≥ 1). AUC arthritis scores were calculated and were compared among different treatment groups on noninflamed (D) and inflamed paws (E). (C–E) Data are shown as box and whisker plots (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). CIA data show naive (n = 4), diseased (n = 10), and treated (n = 10). Units for the test compounds: mg/kg. *P < 0.05, **P < 0.01, ***P < 0.001, compared with Albumin group (A) or PBS group (C–E). One-way ANOVA with Dunnett’s correction (A, C, D, and E).