Fully recombinant IgG2a Fc multimers (stradomers) effectively treat collagen-induced arthritis and prevent idiopathic thrombocytopenic purpura in mice.
BACKGROUND
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).


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Ajay
A
Jain
Henrik S
HS
Olsen
Ravi
R
Vyzasatya
Erin
E
Burch
Yukimi
Y
Sakoda
Emmanuel Y
EY
Mérigeon
Ling
L
Cai
Changwan
C
Lu
Ming
M
Tan
Koji
K
Tamada
Dan
D
Schulze
David S
DS
Block
Scott E
SE
Strome
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D007074:Immunoglobulin G / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000378:metabolism / Q000517:prevention & control*; D011897:Random Allocation; D017452:Receptors, IgG / Q000378:metabolism / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use; D016896:Treatment Outcome
D007074:Immunoglobulin G; D017452:Receptors, IgG; D011994:Recombinant Proteins