A novel antibody against human factor B that blocks formation of the C3bB proconvertase and inhibits complement activation in disease models

Marta Subías, Agustín Tortajada, Sara Gastoldi, Miriam Galbusera, Andrés López-Perrote, Lucia De Juana Lopez, Fernando Ataúlfo González-Fernández, Ana Villegas-Martínez, Mercedes Dominguez, Oscar Llorca, Marina Noris, B. Paul Morgan, Santiago Rodríguez De Córdoba

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)5567-5575
Number of pages9
JournalJournal of Immunology
Volume193
Issue number11
DOIs
Publication statusPublished - Dec 1 2014

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Complement Factor B
Complement Activation
Alternative Pathway Complement C3 Convertase
Complement Inactivating Agents
Hemolysis
Antibodies
Autoimmune Experimental Myasthenia Gravis
Erythrocytes
Alternative Complement Pathway
Complement Membrane Attack Complex
Paroxysmal Hemoglobinuria
Critical Pathways
Autoantibodies
Adenosine Diphosphate
Epitopes
Sheep
Theoretical Models
Animal Models
Pharmacology
Pathology

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

A novel antibody against human factor B that blocks formation of the C3bB proconvertase and inhibits complement activation in disease models. / Subías, Marta; Tortajada, Agustín; Gastoldi, Sara; Galbusera, Miriam; López-Perrote, Andrés; De Juana Lopez, Lucia; González-Fernández, Fernando Ataúlfo; Villegas-Martínez, Ana; Dominguez, Mercedes; Llorca, Oscar; Noris, Marina; Morgan, B. Paul; De Córdoba, Santiago Rodríguez.

In: Journal of Immunology, Vol. 193, No. 11, 01.12.2014, p. 5567-5575.

Research output: Contribution to journalArticle

Subías, M, Tortajada, A, Gastoldi, S, Galbusera, M, López-Perrote, A, De Juana Lopez, L, González-Fernández, FA, Villegas-Martínez, A, Dominguez, M, Llorca, O, Noris, M, Morgan, BP & De Córdoba, SR 2014, 'A novel antibody against human factor B that blocks formation of the C3bB proconvertase and inhibits complement activation in disease models', Journal of Immunology, vol. 193, no. 11, pp. 5567-5575. https://doi.org/10.4049/jimmunol.1402013
Subías, Marta ; Tortajada, Agustín ; Gastoldi, Sara ; Galbusera, Miriam ; López-Perrote, Andrés ; De Juana Lopez, Lucia ; González-Fernández, Fernando Ataúlfo ; Villegas-Martínez, Ana ; Dominguez, Mercedes ; Llorca, Oscar ; Noris, Marina ; Morgan, B. Paul ; De Córdoba, Santiago Rodríguez. / A novel antibody against human factor B that blocks formation of the C3bB proconvertase and inhibits complement activation in disease models. In: Journal of Immunology. 2014 ; Vol. 193, No. 11. pp. 5567-5575.
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AU - Galbusera, Miriam

AU - López-Perrote, Andrés

AU - De Juana Lopez, Lucia

AU - González-Fernández, Fernando Ataúlfo

AU - Villegas-Martínez, Ana

AU - Dominguez, Mercedes

AU - Llorca, Oscar

AU - Noris, Marina

AU - Morgan, B. Paul

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