scholarly journals Anti-C2 Antibody ARGX-117 Inhibits Complement in a Disease Model for Multifocal Motor Neuropathy

2021 ◽  
Vol 9 (1) ◽  
pp. e1107
Author(s):  
Kevin Budding ◽  
Lill Eva Johansen ◽  
Inge Van de Walle ◽  
Kim Dijkxhoorn ◽  
Elisabeth de Zeeuw ◽  
...  
Keyword(s):  
Complement Activation ◽  
Disease Model ◽  
Intervention Strategy ◽  
Multifocal Motor Neuropathy ◽  
Immunoglobulin M ◽  
Regulatory Proteins ◽  
Motor Neuropathy ◽  
Complement Regulatory Proteins ◽  
Igm Antibodies ◽  
Fresh Serum

Background and ObjectivesTo determine the role of complement in the disease pathology of multifocal motor neuropathy (MMN), we investigated complement activation, and inhibition, on binding of MMN patient-derived immunoglobulin M (IgM) antibodies in an induced pluripotent stem cell (iPSC)-derived motor neuron (MN) model for MMN.MethodsiPSC-derived MNs were characterized for the expression of complement receptors and membrane-bound regulators, for the binding of circulating IgM anti-GM1 from patients with MMN, and for subsequent fixation of C4 and C3 on incubation with fresh serum. The potency of ARGX-117, a novel inhibitory monoclonal antibody targeting C2, to inhibit fixation of complement was assessed.ResultsiPSC-derived MNs moderately express the complement regulatory proteins CD46 and CD55 and strongly expressed CD59. Furthermore, MNs express C3aR, C5aR, and complement receptor 1. IgM anti-GM1 antibodies in serum from patients with MMN bind to MNs and induce C3 and C4 fixation on incubation with fresh serum. ARGX-117 inhibits complement activation downstream of C4 induced by patient-derived anti-GM1 antibodies bound to MNs.DiscussionBinding of IgM antibodies from patients with MMN to iPSC-derived MNs induces complement activation. By expressing complement regulatory proteins, particularly CD59, MNs are protected against complement-mediated lysis. Yet, because of expressing C3aR, the function of these cells may be affected by complement activation upstream of membrane attack complex formation. ARGX-117 inhibits complement activation upstream of C3 in this disease model for MMN and therefore represents an intervention strategy to prevent harmful effects of complement in MMN.

Childhood-Onset Multifocal Motor Neuropathy With Immunoglobulin M Antibodies to Gangliosides GM1 and GM2: A Case Report and Review of the Literature

2016 ◽  
Vol 62 ◽  
pp. 51-57 ◽  
Author(s):  
Hidetoshi Ishigaki ◽  
Takuya Hiraide ◽  
Yoshifumi Miyagi ◽  
Taiju Hayashi ◽  
Tomoko Matsubayashi ◽  
...  
Keyword(s):  
Case Report ◽  
Multifocal Motor Neuropathy ◽  
Immunoglobulin M ◽  
Motor Neuropathy ◽  
Review Of The Literature ◽  
Childhood Onset

scholarly journals Human Monoclonal Immunoglobulin M Antibodies to Ganglioside GM1 Show Diverse Cross-Reactivities with Lipopolysaccharides of Campylobacter jejuni Strains Associated with Guillain-Barré Syndrome

1999 ◽  
Vol 67 (7) ◽  
pp. 3698-3701 ◽  
Author(s):  
Martina M. Prendergast ◽  
Hugh J. Willison ◽  
Anthony P. Moran
Keyword(s):  
Campylobacter Jejuni ◽  
Multifocal Motor Neuropathy ◽  
Immunoglobulin M ◽  
Motor Neuropathy ◽  
Ganglioside Gm1 ◽  
Binding Studies ◽  
Monoclonal Immunoglobulin ◽  
Serotype O ◽  
Substantial Heterogeneity ◽  
Lps Binding

ABSTRACT We examined the reactivity of a panel of anti-GM1immunoglobulin M monoclonal antibodies (MAbs) cloned from multifocal motor neuropathy patients with lipopolysaccharides (LPSs) ofCampylobacter jejuni strains, including serotype O:41 strains associated with Guillain-Barré syndrome. The MAbs reacted with ganglioside GM1 to different degrees, and these differences in fine specificities for GM1 were reflected in the different degrees of reactivity with each of the C. jejuni LPSs tested. Antibodies could also be discriminated by the varying patterns of inhibition by cholera toxin (a GM1ligand) in LPS binding studies. These results indicate that there is a substantial heterogeneity among C. jejuni O:41 strains in their expression of GM1-like epitopes and among the fine specificities of different neuropathy-associated anti-GM1antibodies.

scholarly journals Complement in hemolytic anemia

Blood ◽  
2015 ◽  
Vol 126 (22) ◽  
pp. 2459-2465 ◽  
Author(s):  
Robert A. Brodsky
Keyword(s):  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Reticuloendothelial System ◽  
Immunoglobulin M ◽  
Regulatory Proteins ◽  
Cold Agglutinin Disease ◽  
Complement Regulatory Proteins ◽  
Uremic Syndrome ◽  
Alternative Pathway Of Complement

Abstract Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed. In cold agglutinin disease (CAD), immunoglobulin M autoantibodies fix complement on the surface of red cells, resulting in extravascular hemolysis by the reticuloendothelial system. Drugs that inhibit complement activation are increasingly being used to treat these diseases. This article discusses the pathophysiology, diagnosis, and therapy for PNH, aHUS, and CAD.

scholarly journals Complement in hemolytic anemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 385-391 ◽  
Author(s):  
Robert A. Brodsky
Keyword(s):  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Reticuloendothelial System ◽  
Immunoglobulin M ◽  
Regulatory Proteins ◽  
Cold Agglutinin Disease ◽  
Complement Regulatory Proteins ◽  
Uremic Syndrome ◽  
Alternative Pathway Of Complement

Abstract Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed. In cold agglutinin disease (CAD), immunoglobulin M autoantibodies fix complement on the surface of red cells, resulting in extravascular hemolysis by the reticuloendothelial system. Drugs that inhibit complement activation are increasingly being used to treat these diseases. This article discusses the pathophysiology, diagnosis, and therapy for PNH, aHUS, and CAD.

Complement in hemolytic anemia

Hematology ◽  
2015 ◽  
Vol 2015 (1) ◽  
pp. 385-391 ◽  
Author(s):  
Robert A. Brodsky
Keyword(s):  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Alternative Pathway ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Reticuloendothelial System ◽  
Immunoglobulin M ◽  
Regulatory Proteins ◽  
Cold Agglutinin Disease ◽  
Complement Regulatory Proteins ◽  
Uremic Syndrome ◽  
Alternative Pathway Of Complement

Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed. In cold agglutinin disease (CAD), immunoglobulin M autoantibodies fix complement on the surface of red cells, resulting in extravascular hemolysis by the reticuloendothelial system. Drugs that inhibit complement activation are increasingly being used to treat these diseases. This article discusses the pathophysiology, diagnosis, and therapy for PNH, aHUS, and CAD.

Improving the detection of IgM antibodies against glycolipids complexes of GM1 and Galactocerebroside in Multifocal Motor Neuropathy using glycoarray and ELISA assays

2015 ◽  
Vol 278 ◽  
pp. 159-161 ◽  
Author(s):  
Emilien Delmont ◽  
Susan Halstead ◽  
Francesc Galban-Horcajo ◽  
Denggao Yao ◽  
Claude Desnuelle ◽  
...  
Keyword(s):  
Multifocal Motor Neuropathy ◽  
Motor Neuropathy ◽  
Igm Antibodies

Childhood-onset multifocal motor neuropathy with IgM antibodies to GM2 and GalNac-GD1a

2020 ◽  
Vol 42 (1) ◽  
pp. 88-92
Author(s):  
Hiroshi Maeda ◽  
Ryotaro Ishii ◽  
Susumu Kusunoki ◽  
Tomohiro Chiyonobu
Keyword(s):  
Multifocal Motor Neuropathy ◽  
Motor Neuropathy ◽  
Childhood Onset ◽  
Igm Antibodies

Multifocal motor neuropathy: Association of anti-GM1 IgM antibodies with clinical features

Neurology ◽  
2010 ◽  
Vol 75 (22) ◽  
pp. 1961-1967 ◽  
Author(s):  
E. A. Cats ◽  
B. C. Jacobs ◽  
N. Yuki ◽  
A. P. Tio-Gillen ◽  
S. Piepers ◽  
...  
Keyword(s):  
Clinical Features ◽  
Multifocal Motor Neuropathy ◽  
Motor Neuropathy ◽  
Igm Antibodies
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