BAFF blockade prevents anti-drug antibody formation in a mouse model of Pompe disease

Clin Immunol. 2015 Jun;158(2):140-7. doi: 10.1016/j.clim.2015.03.022. Epub 2015 Apr 1.

Abstract

Antibodies formed against the therapeutic protein are a life-threatening complication that arises during enzyme replacement therapy for Pompe disease (acid α-glucosidase deficiency; GAA). To provide an effective alternative to current practices, we investigated the capacity of anti-B-cell activating factor (BAFF) as a novel drug candidate to prevent antibody formation in a Pompe disease mouse model. A BAFF-neutralizing antibody was administered prophylactically and with maintenance doses in association with enzyme replacement therapy using recombinant human GAA in Gaa(-/-) mice. BAFF blockade delayed antibody production and increased GAA activity within tissues with protection from anaphylaxis. Anti-BAFF also resolved antibody formation during an immune response and precluded the maturation of antibody secreting cells from entering the bone marrow compartment. This treatment modality may therefore be a viable alternative for the clinical management of antibody formation for Pompe disease and has potential use against antibody formation in other protein replacement therapies.

Keywords: Acid alpha-glucosidase; BAFF; BLyS; Enzyme replacement therapy; Pompe disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / immunology*
  • B-Cell Activating Factor / antagonists & inhibitors*
  • Disease Models, Animal
  • Enzyme Replacement Therapy*
  • Female
  • Gene Deletion
  • Gene Expression Regulation, Enzymologic
  • Genetic Therapy / methods
  • Glucan 1,4-alpha-Glucosidase / genetics
  • Glucan 1,4-alpha-Glucosidase / immunology
  • Glucan 1,4-alpha-Glucosidase / metabolism
  • Glucan 1,4-alpha-Glucosidase / therapeutic use*
  • Glycogen Storage Disease Type II / drug therapy
  • Glycogen Storage Disease Type II / immunology*
  • Male
  • Mice
  • Mice, Knockout
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / genetics
  • Tumor Necrosis Factor Ligand Superfamily Member 13 / metabolism

Substances

  • Antibodies
  • B-Cell Activating Factor
  • Tnfsf13 protein, mouse
  • Tnfsf13b protein, mouse
  • Tumor Necrosis Factor Ligand Superfamily Member 13
  • Glucan 1,4-alpha-Glucosidase