A Novel Antibody Against Human Factor B That Blocks Formation of the C3bB Proconvertase and Inhibits Complement Activation in Disease Models

J Immunol. 2014 Dec 1;193(11):5567-75. doi: 10.4049/jimmunol.1402013. Epub 2014 Oct 29.

Abstract

The alternative pathway (AP) is critical for the efficient activation of complement regardless of the trigger. It is also a major player in pathogenesis, as illustrated by the long list of diseases in which AP activation contributes to pathology. Its relevance to human disease is further emphasized by the high prevalence of pathogenic inherited defects and acquired autoantibodies disrupting components and regulators of the AP C3-convertase. Because pharmacological downmodulation of the AP emerges as a broad-spectrum treatment alternative, there is a powerful interest in developing new molecules to block formation and/or activity of the AP C3-convertase. In this paper, we describe the generation of a novel mAb targeting human factor B (FB). mAb FB48.4.2, recognizing with high affinity an evolutionary-conserved epitope in the Ba fragment of FB, very efficiently inhibited formation of the AP C3-proconvertase by blocking the interaction between FB and C3b. In vitro assays using rabbit and sheep erythrocytes demonstrated that FB28.4.2 was a potent AP inhibitor that blocked complement-mediated hemolysis in several species. Using ex vivo models of disease we demonstrated that FB28.4.2 protected paroxysmal nocturnal hemoglobinuria erythrocytes from complement-mediated hemolysis and inhibited both C3 fragment and C5b-9 deposition on ADP-activated HMEC-1 cells, an experimental model for atypical hemolytic uremic syndrome. Moreover, i.v. injection of FB28.4.2 in rats blocked complement activation in rat serum and prevented the passive induction of experimental autoimmune Myasthenia gravis. As a whole, these data demonstrate the potential value of FB28.4.2 for the treatment of disorders associated with AP complement dysregulation in man and animal models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Blocking / immunology*
  • Antibodies, Blocking / isolation & purification
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / isolation & purification
  • Antibody-Dependent Cell Cytotoxicity / drug effects
  • Atypical Hemolytic Uremic Syndrome / immunology
  • Atypical Hemolytic Uremic Syndrome / therapy*
  • Cattle
  • Cell Line
  • Complement C3 Convertase, Alternative Pathway / metabolism
  • Complement C3b / metabolism*
  • Complement Factor B / genetics
  • Complement Factor B / immunology
  • Complement Factor B / metabolism*
  • Complement Pathway, Alternative / drug effects
  • Disease Models, Animal
  • Female
  • Hemoglobinuria, Paroxysmal / immunology
  • Hemoglobinuria, Paroxysmal / therapy*
  • Humans
  • Mice
  • Mice, Knockout
  • Myasthenia Gravis, Autoimmune, Experimental / immunology
  • Myasthenia Gravis, Autoimmune, Experimental / therapy*
  • Protein Binding / drug effects
  • Rabbits
  • Rats
  • Rats, Inbred Lew
  • Sheep

Substances

  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Complement C3b
  • Complement C3 Convertase, Alternative Pathway
  • Complement Factor B