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Many drugs for many targets: novel treatments for complement-mediated glomerular disease
1Department of Medicine, Division of Nephrology and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA.
Insights
Complement activation drives glomerular injury, with varied triggers across diseases. New drugs targeting complement pathways offer potential therapeutic strategies for kidney diseases.
Area of Science:
- Nephrology
- Immunology
- Pharmacology
Background:
- Complement activation is implicated in glomerular injury across diverse kidney diseases.
- Specific complement pathways (classical, alternative, mannose-binding lectin) are activated through distinct mechanisms.
- Eculizumab, a C5 inhibitor, shows promise beyond atypical hemolytic uremic syndrome.
Purpose of the Study:
- To review the rationale for targeting various complement cascade proteins.
- To discuss novel anti-complement drugs in development.
- To identify challenges in clinical translation of these therapies.
Main Methods:
- Review of experimental and clinical evidence on complement activation in glomerulonephritis.
- Analysis of approved and investigational complement inhibitors.
- Discussion of therapeutic strategies and clinical development hurdles.
Main Results:
- Evidence supports complement's role in various glomerular diseases.
- Different complement pathways are activated by distinct triggers.
- Emerging complement inhibitors target diverse points in the cascade.
Conclusions:
- Targeting specific complement proteins offers a promising therapeutic avenue for glomerular diseases.
- Development of new anti-complement drugs is advancing.
- Clinical implementation requires addressing specific challenges.
Abstract:
There is a large body of experimental and clinical evidence that complement activation contributes to glomerular injury in multiple different diseases. However, the underlying mechanisms that trigger complement activation vary from disease to disease. Immune complexes activate the classical pathway of complement in many types of glomerulonephritis, whereas the alternative pathway and mannose-binding lectin pathways are directly activated in some diseases. Eculizumab is an inhibitory antibody to C5 that has been approved for the treatment of atypical hemolytic uremic syndrome, and case reports suggest that it is also effective in other types of glomerulonephritis. Furthermore, new complement-inhibitory drugs are being developed that target additional proteins within the complement cascade, raising the possibility of blocking the specific complement proteins involved in a given disease. This review examines the rationale for targeting different proteins within the complement cascade, the new anti-complement drugs currently in development and some of the challenges that investigators will face in bringing these drugs to the clinic.