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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Podrobná bibliografia
Vydané v:	Immunological reviews Ročník 313; číslo 1; s. 358 - 375
Hlavní autori:	Kolev, Martin, Barbour, Tara, Baver, Scott, Francois, Cedric, Deschatelets, Pascal
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	England Wiley Subscription Services, Inc 01.01.2023
Predmet:	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
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Popis
Shrnutí:	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.
Bibliografia:	This article is part of a series of reviews covering The Alternative Pathway or Amplification Loop of Complement appearing in Volume 313 of . Immunological Reviews ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Review-3 content type line 23
ISSN:	0105-2896 1600-065X 1600-065X
DOI:	10.1111/imr.13138