Abstract
IntroductionSoluble immune aggregates bearing intact Fc fragments are effective treatment for a variety of autoimmune disorders in mice. The better to understand the mechanisms by which Fc-bearing immune complexes suppress autoimmunity, and to develop a platform for clinical translation, we created a series of fully recombinant forms of polyvalent IgG2a Fc, termed stradomers, and tested their efficacy in a therapeutic model of collagen-induced arthritis (CIA) and preventive models of both idiopathic thrombocytopenic purpura (ITP) and graft-versus-host disease (GVHD).MethodsStradomers were created by engineering either the human IgG2 hinge sequence (IgG2H) or the isoleucine zipper (ILZ) onto either the carboxy or amino termini of murine IgG2a Fc. Multimerization and binding to the canonical Fc receptors and the C-type lectin SIGN-RI were evaluated by using sodium dodecylsulfate-polymerase chain reaction (SDS-PAGE) and Biacore/Octet assays. The efficacy of stradomers in alleviating CIA and preventing ITP and GVHD was compared with "gold standard" therapies, including prednisolone and intravenous immune globulin (IVIG).ResultsStradomers exist as both homodimeric and highly ordered sequential multimers. Higher-order multimers demonstrate increasingly stable associations with the canonic Fcγ receptors (FcγRs), and SIGN-R1, and are more effective than Fc homodimers in treating CIA. Furthermore, stradomers confer partial protection against platelet loss in a murine model ITP, but do not prevent GVHD.ConclusionThese data suggest that fully human stradomers might serve as valuable tools for the treatment of selected autoimmune disorders and as reagents to study the function of Fc:FcR interactions in vivo.
Highlights
Soluble immune aggregates bearing intact Fc fragments are effective treatment for a variety of autoimmune disorders in mice
We demonstrate that fully recombinant fusion proteins composed of murine IgG2a Fc and either the human IgG2 hinge sequence (IgG2H) or isoleucine zipper (ILZ) multimerization domain (MD) exist as both monomers and as a surprisingly high percentage of covalently linked highly ordered multimers
Stradomers exist as highly ordered multimers that can be fractionated by size To evaluate the potential of the IgG2 hinge as an MD, we created cDNA constructs in which the hinge region of human IgG2 was linked to either the carboxy (2A-2HC) or amino (2A-2HN) termini of murine IgG2a Fc
Summary
Soluble immune aggregates bearing intact Fc fragments are effective treatment for a variety of autoimmune disorders in mice. We demonstrate that fully recombinant fusion proteins composed of murine IgG2a Fc and either the human IgG2H or isoleucine zipper (ILZ) MDs exist as both monomers (homodimers) and as a surprisingly high percentage of covalently linked highly ordered multimers We called these Fc multimers stradomers to distinguish them from the naturally occurring homodimeric form of intact immunoglobulins. These novel fusion proteins can alleviate collagen-induced arthritis (CIA) and prevent ITP in murine models, raising the possibility that fully human variants may have therapeutic potential for the treatment of a variety of rheumatologic diseases [9,10]
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