Using the K/BxN mouse model of endogenous, chronic, rheumatoid arthritis for the evaluation of potential immunoglobulin-based therapeutic agents, including IVIg and Fc-μTP-L309C, a recombinant IgG1 Fc hexamer

Abstract

BackgroundHigh-dose intravenous immunoglobulin (IVIg), and more recently, subcutaneously-delivered Ig (SCIg), are used to treat a variety of autoimmune diseases; however, there are challenges associated with product production, availability, access and efficacy. These challenges have provided incentives to develop a human recombinant Fc as a more potent alternative to IVIg and SCIg for the treatment of autoimmune diseases. Recently, a recombinant human IgG1 Fc hexamer (Fc-μTP-L309C) was shown to be more efficacious than IVIg in a variety of autoimmune mouse models. We have now examined its efficacy compared to IVIg and SCIg in the K/BxN mouse model of endogenous, chronic rheumatoid arthritis (RA).ResultUsing the serum-transfer K/BxN model and the endogenous autoimmune model, amelioration of the arthritis was achieved. Effective treatment required high and frequent doses of IVIg, SCIg and Fc-μTP-L309C. However, Fc-μTP-L309C was efficacious at 10-fold lower doses that IVIg/SCIg. Also, arthritis could be prevented when Fc-μTP-L309C was given prior to onset of the arthritis in both the endogenous model and in the serum transfer model.ConclusionsOur results show that Fc-μTP-L309C is a powerful treatment for the prevention and amelioration of severe, chronic arthritis in a true autoimmune mouse model of RA. Thus, the K/BxN endogenous arthritis model should be useful for testing potential therapeutics for RA. Our findings provide rationale for further examination of the treatment efficacy of immunoglobulin-based therapeutics in rheumatoid arthritis.

Engineering of Fc Multimers as a Protein Therapy for Autoimmune Disease

“…This compound exhibits greater affinity for the FcγRs than IVIG and upon internalization, is associated with preferential degradation of the activating FcγRs and protects mice from platelet loss for up to 3 days after dosing (80). Studies with analogous compounds demonstrate clinical efficacy in both CIA and in the K/BxN model of chronic arthritis (81). These data lend credence to the idea that structurally distinct ICs can have anti-inflammatory properties.…”

Isoagglutinin‐reduced immunoglobulin retains efficacy in mouse models of immune thrombocytopenia and rheumatoid arthritis and is less likely to cause intravenous immunoglobulin–associated hemolysis

“…However, our in vitro assay does not predict whether the chromatographic procedure to remove the isoagglutinins has affected the efficacy of the isoagglutinin‐reduced Ig to ameliorate autoimmune disease. Thus, we tested and compared the efficacy of isoagglutinin‐reduced Ig to nonreduced Ig with two different mouse models of autoimmune disease: ITP and the K/BxN of RA …”

“…In brief, for ITP, BALB/c and C57BL/6 mice were injected daily with escalating doses of rat monoclonal anti‐mouse glycoprotein IIb antibody (anti‐CD41; clone MWReg30) to induce ITP . For RA, we used the passive serum‐transfer model (K/BxN) of RA, which has been extensively studied and has many characteristics with human RA . Detailed procedures can be found in previous publications and Appendix S1, available as supporting information in the online version of this paper.…”

Mouse Models of Rheumatoid Arthritis for Studies on Immunopathogenesis and Preclinical Testing of Fc Receptor-Targeting Biologics

“…There has been an increasing amount of evidence that IVIg works to treat RA in various mouse models through the FcγR blockade [22,89,[110][111][112]. However, the numerous challenges associated with IVIg production and its application has provided incentives to develop an alternative therapy with similar efficacy but with improved characteristics.…”

“…This particularly applies for indications where the effector mechanism(s) of IVIg are dependent on the Fc of IgG. The mechanism of IVIg in mouse models of RA has been proposed to be mediated by the Fc of IgG [22,89,[110][111][112]. Accordingly, many researchers have investigated recombinant Fcs as a replacement for IVIg.…”