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

Xinfang Xie, Jingyi Li, Pan Liu, Manliu Wang, Li Gao, Feng Wan, Jicheng Lv, Hong Zhang and Jing Jin
JASN May 2022, 33 (5) 918-935; DOI: https://doi.org/10.1681/ASN.2021030372
Xinfang Xie
1Department of Medicine, Division of Nephrology and Hypertension, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
2Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Jingyi Li
3Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease; Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
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Pan Liu
1Department of Medicine, Division of Nephrology and Hypertension, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Manliu Wang
3Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease; Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
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Li Gao
1Department of Medicine, Division of Nephrology and Hypertension, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
4Department of Cardiovascular Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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Feng Wan
3Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease; Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
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Jicheng Lv
3Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease; Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
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Hong Zhang
3Renal Division, Peking University First Hospital; Peking University Institute of Nephrology; Key Laboratory of Renal Disease; Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
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Jing Jin
1Department of Medicine, Division of Nephrology and Hypertension, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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Significance Statement

IgA nephropathy is the most common glomerulonephritis worldwide and a leading cause of kidney failure. The disease often progresses through episodes of flare-ups that require effective treatments to tame inflammation. We followed a rational design strategy to construct a recombinant fusion IgA protease derived from commensal gut microbiota Clostridium ramosum. The fusion protease, referred to as Fc-AK183, showed week-long activity in mice to completely obliterate IgA in circulation and clear pathologic deposits in the kidney. Therefore, the recombinant enzyme is a promising drug candidate for future treatment of IgA nephropathy.

Abstract

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.

  • IgA nephropathy
  • IgA protease
  • AK183
  • Clostridium ramosum
  • Fc-fusion protein
  • neonatal Fc receptor/FcRn
  • recombinant biologics
  • Copyright © 2022 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 33 (5)
Journal of the American Society of Nephrology
Vol. 33, Issue 5
May 2022
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Chimeric Fusion between Clostridium Ramosum IgA Protease and IgG Fc Provides Long-Lasting Clearance of IgA Deposits in Mouse Models of IgA Nephropathy
Xinfang Xie, Jingyi Li, Pan Liu, Manliu Wang, Li Gao, Feng Wan, Jicheng Lv, Hong Zhang, Jing Jin
JASN May 2022, 33 (5) 918-935; DOI: 10.1681/ASN.2021030372

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Chimeric Fusion between Clostridium Ramosum IgA Protease and IgG Fc Provides Long-Lasting Clearance of IgA Deposits in Mouse Models of IgA Nephropathy
Xinfang Xie, Jingyi Li, Pan Liu, Manliu Wang, Li Gao, Feng Wan, Jicheng Lv, Hong Zhang, Jing Jin
JASN May 2022, 33 (5) 918-935; DOI: 10.1681/ASN.2021030372
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Keywords

  • IgA nephropathy
  • IgA protease
  • AK183
  • Clostridium ramosum
  • Fc-fusion protein
  • neonatal Fc receptor/FcRn
  • recombinant biologics

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