Novel complement inhibitor limits severity of experimentally myasthenia gravis.
OBJECTIVE
Complement mediated injury of the neuromuscular junction is considered a primary disease mechanism in human myasthenia gravis and animal models of experimentally acquired myasthenia gravis (EAMG). We utilized active and passive models of EAMG to investigate the efficacy of a novel C5 complement inhibitor rEV576, recombinantly produced protein derived from tick saliva, in moderating disease severity.


METHODS
Standardized disease severity assessment, serum complement hemolytic activity, serum cytotoxicity, acetylcholine receptor (AChR) antibody concentration, IgG subclassification, and C9 deposition at the neuromuscular junction were used to assess the effect of complement inhibition on EAMG induced by administration of AChR antibody or immunization with purified AChR.


RESULTS
Administration of rEV576 in passive transfer EAMG limited disease severity as evidenced by 100% survival rate and a low disease severity score. In active EAMG, rats with severe and mild EAMG were protected from worsening of disease and had limited weight loss. Serum complement activity (CH(50)) in severe and mild EAMG was reduced to undetectable levels during treatment, and C9 deposition at the neuromuscular junction was reduced. Treatment with rEV576 resulted in reduction of toxicity of serum from severe and mild EAMG rats. Levels of total AChR IgG, and IgG(2a) antibodies were similar, but unexpectedly, the concentration of complement fixing IgG(1) antibodies was lower in a group of rEV576-treated animals, suggesting an effect of rEV576 on cellular immunity.


CONCLUSIONS
Inhibition of complement significantly reduced weakness in two models of EAMG. C5 inhibition could prove to be of significant therapeutic value in human myasthenia gravis.
Soltys
Jindrich
J
Department of Neurology & Psychiatry, Saint Louis University, St. Louis, MO, USA.
Kusner
Linda L
LL
Young
Andrew
A
Richmonds
Chelliah
C
Hatala
Denise
D
Gong
Bendi
B
Shanmugavel
Vaithesh
V
Kaminski
Henry J
HJ
D000818:Animals; D000906:Antibodies / Q000009:adverse effects; D060829:Arthropod Proteins; D045744:Cell Line, Tumor; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D003186:Complement C9 / Q000378:metabolism; D003169:Complement Inactivator Proteins / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D007074:Immunoglobulin G / Q000097:blood / Q000145:classification; D019476:Insect Proteins / Q000276:immunology / Q000627:therapeutic use; D053580:Muscle Strength / Q000187:drug effects; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000276:immunology; D012208:Rhabdomyosarcoma / Q000378:metabolism / Q000473:pathology; D012471:Salivary Proteins and Peptides / Q000097:blood / Q000276:immunology / Q000627:therapeutic use; D012720:Severity of Illness Index; D013997:Time Factors; D015431:Weight Loss / Q000187:drug effects
D000906:Antibodies; D060829:Arthropod Proteins; D003182:Complement C5; D003186:Complement C9; D003169:Complement Inactivator Proteins; D007074:Immunoglobulin G; D019476:Insect Proteins; D011950:Receptors, Cholinergic; D012471:Salivary Proteins and Peptides; C539676:rEV576 protein, tick