With complements: C3 inhibition in the clinic

Abstract

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 complementmediated 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.

Paroxysmal nocturnal hemoglobinuria: Where we stand

“…3,9,10,84,113 It took, however, more than 10 years from the initial observations of the inescapable C3-fraction binding on C5 inhibitor shielded erythrocytes to the final development of the first approved proximal C3-targeted inhibitor pegcetacoplan. 114 Pegcetacoplan is a further development of a second generation compstatin analog. 115 Compstatin, a cyclic peptide was found to specifically bind and block C3.…”

Reeling in complement in transplant‐associated thrombotic microangiopathy: You're going to need a bigger boat

“…C3 plays a critical role the dysregulated immune response of many diseases, making it a viable therapeutic target in TA‐TMA 49 . C3 inhibition could potentially be effective in alleviating calcineurin inhibitor (CNI) induced TMAs since renal podocytes produce and secrete C3 that can influence local glomerular complement activation 50 .…”

“…C3 plays a critical role the dysregulated immune response of many diseases, making it a viable therapeutic target in TA-TMA. 49 C3 inhibition could potentially be effective in alleviating calcineurin inhibitor (CNI)…”

The complement alternative pathway in health and disease—activation or amplification?

“…Kolev et al describe the evolution of molecules that block complement at the level of C3 with a particular focus on pegcetacoplan, the only C3‐blocker currently approved for clinical use (EMPAVELI™ for PNH) 51 . Pegcetacoplan binds to native and activated C3, blocking amplification, but it does not block C3(H 2 O) generation nor the proteolytic cleavage of C3 by non‐convertase enzymes.…”

“…Kolev et al describe the evolution of molecules that block complement at the level of C3 with a particular focus on pegcetacoplan, the only C3-blocker currently approved for clinical use (EMPAVELI™ for PNH). 51 Pegcetacoplan binds to native and activated C3, blocking amplification, but it does not block C3(H 2 O) generation nor the proteolytic cleavage of C3 by non-convertase enzymes. Intriguingly, the authors suggest that pegcetacoplan modulates disease while retaining significant hemolytic activity, as measured by ex vivo hemolysis assays; residual activity of the classical pathway is striking (CH50).…”