Optimized synthesis, polymer conjugation, and proof-of-concept studies of the gd-IgA1 epitope for antibody-scavenging therapies in IgA nephropathy

Chem Biol Drug Des. 2023 Sep;102(3):580-586. doi: 10.1111/cbdd.14258. Epub 2023 Apr 26.

Abstract

IgA nephropathy (IgAN) is the most common glomerular autoimmune disease and has severe long-term consequences for patients, with 40% of the patients eventually progressing to end-stage renal disease. Despite the severity, no causal treatment is currently available. While the pathogenesis of IgAN is complex, disease severity is linked to autoantibodies against the gd-IgA1 epitope, a stretch in the hinge region of IgA1 that lacks O-glycans and is found in the characteristic immune complexes deposited in the kidneys of IgAN patients. One elegant, causal approach would be to remove the anti-gd-IgA1 autoantibodies and consequently reduce the immune complex burden on the kidneys. The administration of synthetic polymers that present autoantigens in a multivalent manner have been established as promising therapeutic strategies in other autoimmune diseases and may be applied to IgAN. We here present an improved protocol for the synthesis of the gd-IgA1 epitope, its successful coupling to a poly-L-lysine polymer and proof-of-concept experiments that the polymer-bound synthetic glycopeptide is able to capture the IgAN autoantibodies, making this approach a promising way forward for developing a targeted treatment option for IgAN patients.

Keywords: IgA nephropathy; antibody scavenging; autoantibodies; gd-IgA1; glycopeptide; glycopolymer.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen-Antibody Complex
  • Autoantibodies
  • Epitopes
  • Galactose
  • Glomerulonephritis, IGA* / drug therapy
  • Glomerulonephritis, IGA* / pathology
  • Humans
  • Immunoglobulin A

Substances

  • Epitopes
  • Immunoglobulin A
  • Autoantibodies
  • Antigen-Antibody Complex
  • Galactose