Chimeric Fusion between Clostridium Ramosum IgA Protease and IgG Fc Provides Long-Lasting Clearance of IgA Deposits in Mouse Models of IgA Nephropathy

J Am Soc Nephrol. 2022 May;33(5):918-935. doi: 10.1681/ASN.2021030372. Epub 2022 Feb 16.


Background: IgA nephropathy is a common primary glomerulonephritis caused by mesangial deposition of poly-IgA complexes. The disease follows a variable course of clinical progression, with a high risk of kidney failure. Although no specific therapy is available, enzymatic strategies to clear IgA deposits are being considered for the treatment of rapidly progressive IgA nephropathy.

Methods: We chose an IgA protease of commensal bacterium Clostridium ramosum, termed AK183, as the template for constructing a recombinant biologic. To extend the t1/2 in blood, we fused AK183 to the Fc segment of human IgG1. Activities of this Fc-AK183 fusion protein toward the cleavage and subsequent clearance of IgA were tested in mouse models.

Results: First, we discovered an autocleavage activity of AK183 that separates the N-terminal protease from its C-terminal autotransporter β domain. Therefore, we grafted Fc to the N terminus of AK183 and demonstrated its week-long enzymatic activity in mice. In addition, the proteolytic fragments of IgA generated in the reaction with Fc-AK183 were effectively removed from circulation via kidney filtration. The combined actions of Fc-AK183-mediated cleavage and subsequent renal clearance of IgA resulted in a lasting obliteration of blood IgA, as demonstrated in a human IgA-injection model and in a humanized α1KI transgenic model. Fc-AK183 was also able to remove chronic IgA and associated complement C3 deposits in the glomerulus.

Conclusion: We constructed a chimeric fusion of IgA protease with Fc and demonstrated its long-lasting efficacy as a promising targeted therapy for IgA nephropathy in mouse models.

Keywords: AK183; Clostridium ramosum; Fc-fusion protein; IgA nephropathy; IgA protease; neonatal Fc receptor/FcRn; recombinant biologics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Disease Models, Animal
  • Female
  • Firmicutes
  • Glomerulonephritis, IGA* / therapy
  • Humans
  • Immunoglobulin A / metabolism
  • Immunoglobulin G
  • Male
  • Mice
  • Receptors, Fc
  • Serine Endopeptidases


  • Immunoglobulin A
  • Immunoglobulin G
  • Receptors, Fc
  • Serine Endopeptidases
  • IgA-specific serine endopeptidase

Supplementary concepts

  • Erysipelatoclostridium ramosum