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Syntonix Pharmaceuticals, Waltham, MA 02451
The neonatal FcR (FcRn) plays a critical role in IgG homeostasis by protecting it from a lysosomal degradation pathway. It has been shown that IgG has an abnormally short half-life in FcRn-deficient mice and that FcRn blockade significantly increases the catabolism of serum IgG in mice. Therefore, reduction of serum IgG half-life may have therapeutic benefits in Ab-mediated autoimmune diseases. We have studied the therapeutic effects of an anti-rat FcRn mAb, 1G3, in two rat models of myasthenia gravis, a prototypical Ab-mediated autoimmune disease. Passive experimental autoimmune myasthenia gravis was induced by administration of an anti-acetylcholine receptor (AChR) mAb, and it was shown that treatment with 1G3 resulted in dose-dependent amelioration of the disease symptoms. In addition, the concentration of pathogenic Ab in the serum was reduced significantly. The effect of 1G3 was also studied in an active model of experimental autoimmune myasthenia gravis in which rats were immunized with AChR. Treatment with 1G3 significantly reduced the severity of the disease symptoms as well as the levels of total IgG and anti-AChR IgG relative to untreated animals. These data suggest that FcRn blockade may be an effective way to treat Ab-mediated autoimmune diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Liming Liu, Syntonix Pharmaceuticals, 9 Fourth Avenue, Waltham, MA 02451. E-mail address: lliu{at}syntnx.com
2 Current address: Boston Biomedical Research Institute, 64 Grove Street, Watertown, MA 02472.
3 Current address: Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139.
4 Abbreviations used in this paper: MG, myasthenia gravis; AChR, acetylcholine receptor; EAMG, experimental autoimmune MG; SNMG, seronegative MG; FcRn, neonatal FcR; SPF, specific pathogen free; CR3, complement receptor 3; Dex, dexamethasone; 
2m, 2-microglobulin; SPR, surface plasmon resonance; mIgG1, murine IgG1; Ctrl, Control.
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  A. R. Mezo, K. A. McDonnell, C. A. T. Hehir, S. C. Low, V. J. Palombella, J. M. Stattel, G. D. Kamphaus, C. Fraley, Y. Zhang, J. A. Dumont, et al. Reduction of IgG in nonhuman primates by a peptide antagonist of the neonatal Fc receptor FcRn PNAS, February 19, 2008; 105(7): 2337 - 2342. [Abstract] [Full Text] [PDF]
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