Fully recombinant IgG2a Fc multimers (stradomers) effectively treat collagen-induced arthritis and prevent idiopathic thrombocytopenic purpura in mice
1 Division of General and Oncologic Surgery, University of Maryland School of Medicine, 22 South Greene Street, Room S4B12, Baltimore, MD 21201, USA
2 Department of Otorhinolaryngology-Head and Neck Surgery, University of Maryland School of Medicine, 16 S. Eutaw Street, Baltimore, MD 21201, USA
3 Baltimore Veterans Administration Medical Center, 10 N. Greene Street, 5C Surgical Services Area, Baltimore, MD 21201, USA
4 Gliknik Inc., 801 West Baltimore Street, Suite 501A, Baltimore, MD 21201, USA
5 Division of Biostatistics & Bioinformatics, Department of Epidemiology and Public Health & University of Maryland Greenebaum Cancer Center, University of Maryland School of Medicine, 660 W. Redwood Street, Suite 109, Baltimore, MD 21201, USA
6 Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, Suite 385, Baltimore, MD 21201, USA
Arthritis Research & Therapy 2012, 14:R192 doi:10.1186/ar4024Published: 20 August 2012
Soluble 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).
Stradomers 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).
Stradomers 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.
These 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.