1. The MFHR1 Fusion Protein Is a Novel Synthetic Multitarget Complement Inhibitor with Therapeutic Potential.
- Author
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Michelfelder S, Fischer F, Wäldin A, Hörle KV, Pohl M, Parsons J, Reski R, Decker EL, Zipfel PF, Skerka C, and Häffner K
- Subjects
- Animals, Atypical Hemolytic Uremic Syndrome genetics, Atypical Hemolytic Uremic Syndrome immunology, Complement C3 metabolism, Complement C3-C5 Convertases antagonists & inhibitors, Complement C3-C5 Convertases metabolism, Complement C3b antagonists & inhibitors, Complement C3b Inactivator Proteins deficiency, Complement C5 metabolism, Complement Factor H genetics, Complement Inactivating Agents isolation & purification, Complement Inactivating Agents therapeutic use, Complement Membrane Attack Complex biosynthesis, Complement Pathway, Alternative, Drug Design, Drug Evaluation, Preclinical, Kidney Glomerulus chemistry, Kidney Glomerulus pathology, Mice, Mice, Knockout, Protein Domains, Recombinant Fusion Proteins isolation & purification, Recombinant Fusion Proteins therapeutic use, Atypical Hemolytic Uremic Syndrome blood, Blood Proteins deficiency, Complement C3b Inactivator Proteins genetics, Complement Inactivating Agents pharmacology, Molecular Targeted Therapy, Recombinant Fusion Proteins pharmacology
- Abstract
The complement system is essential for host defense, but uncontrolled complement system activation leads to severe, mostly renal pathologies, such as atypical hemolytic uremic syndrome or C3 glomerulopathy. Here, we investigated a novel combinational approach to modulate complement activation by targeting C3 and the terminal pathway simultaneously. The synthetic fusion protein MFHR1 links the regulatory domains of complement factor H (FH) with the C5 convertase/C5b-9 inhibitory fragment of the FH-related protein 1. In vitro , MFHR1 showed cofactor and decay acceleration activity and inhibited C5 convertase activation and C5b-9 assembly, which prevented C3b deposition and reduced C3a/C5a and C5b-9 generation. Furthermore, this fusion protein showed the ability to escape deregulation by FH-related proteins and form multimeric complexes with increased inhibitory activity. In addition to substantially inhibiting alternative and classic pathway activation, MFHR1 blocked hemolysis mediated by serum from a patient with aHUS expressing truncated FH. In FH-/- mice, MFHR1 administration augmented serum C3 levels, reduced abnormal glomerular C3 deposition, and ameliorated C3 glomerulopathy. Taking the unique design of MFHR1 into account, we suggest that the combination of proximal and terminal cascade inhibition together with the ability to form multimeric complexes explain the strong inhibitory capacity of MFHR1, which offers a novel basis for complement therapeutics., (Copyright © 2018 by the American Society of Nephrology.)
- Published
- 2018
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