With complements: C3 inhibition in the clinic

Summary C3 is a key complement protein, located at the nexus of all complement activation pathways. Extracellular, tissue, cell‐derived, and intracellular C3 plays critical roles in the immune response that is dysregulated in many diseases, making it an attractive therapeutic target. However, challe...

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Bibliographic Details
Published in:Immunological reviews Vol. 313; no. 1; pp. 358 - 375
Main Authors: Kolev, Martin, Barbour, Tara, Baver, Scott, Francois, Cedric, Deschatelets, Pascal
Format: Journal Article
Language:English
Published: England Wiley Subscription Services, Inc 01.01.2023
Subjects:
blood
Blood levels
C3‐targeted therapeutics
Cell activation
Complement
Complement Activation
Complement C3 - metabolism
Complement C3 - pharmacology
Complement C5 - pharmacology
Complement C5 - therapeutic use
Complement component C3
Complement component C5
Complement Inactivating Agents - pharmacology
Complement Inactivating Agents - therapeutic use
complement system
complement‐mediated disease
compstatin
Drug development
Health risks
hemoglobinuria
Hemoglobinuria, Paroxysmal - drug therapy
Humans
Immune response
mechanism of action
Paroxysmal nocturnal hemoglobinuria
pegcetacoplan
risk
Therapeutic targets
therapeutics
C3
compstatin
complement-mediated disease
complement system
pegcetacoplan
C3-targeted therapeutics
ISSN:0105-2896, 1600-065X, 1600-065X
Online Access:Get full text
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Summary:Summary C3 is a key complement protein, located at the nexus of all complement activation pathways. Extracellular, tissue, cell‐derived, and intracellular C3 plays critical roles in the immune response that is dysregulated in many diseases, making it an attractive therapeutic target. However, challenges such as very high concentration in blood, increased acute expression, and the elevated risk of infections have historically posed significant challenges in the development of C3‐targeted therapeutics. This is further complicated because C3 activation fragments and their receptors trigger a complex network of downstream effects; therefore, a clear understanding of these is needed to provide context for a better understanding of the mechanism of action (MoA) of C3 inhibitors, such as pegcetacoplan. Because of C3's differential upstream position to C5 in the complement cascade, there are mechanistic differences between pegcetacoplan and eculizumab that determine their efficacy in patients with paroxysmal nocturnal hemoglobinuria. In this review, we compare the MoA of pegcetacoplan and eculizumab in paroxysmal nocturnal hemoglobinuria and discuss the complement‐mediated disease that might be amenable to C3 inhibition. We further discuss the current state and outlook for C3‐targeted therapeutics and provide our perspective on which diseases might be the next success stories in the C3 therapeutics journey.
Bibliography:This article is part of a series of reviews covering The Alternative Pathway or Amplification Loop of Complement appearing in Volume 313 of
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Immunological Reviews
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ISSN:0105-2896
1600-065X
1600-065X
DOI:10.1111/imr.13138