Factor B as a therapeutic target for the treatment of complement-mediated diseases

Abstract

The complement system, consisting of three initiating pathways-classical, lectin and alternative, is an important part of innate immunity. Dysregulation of the complement system is implicated in the pathogenesis of several autoimmune and inflammatory diseases. Therapeutic inhibition of the complement system has been recognized as a viable approach to drug development and has been successful with the approval of a small number of complement inhibitors for diseases such as paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, neuromyelitis optica, myasthenia gravis and geographic atrophy. More recently, therapies selectively targeting the alternative pathway (AP), which drives the amplification of the complement responses, are being evaluated for these complement-mediated diseases. Complement Factor B, a serine protease, is a unique component of the AP that is essential for the catalytic activity of AP C3 convertase and AP C5 convertase. Inhibition of Factor B blocks the activity of the alternative pathway and the amplification loop, and subsequent generation of the membrane attack complex downstream; however, it has no effect on the initial activation mediated by the classical and lectin complement pathways. Therefore, Factor B is an attractive target for diseases in which the AP is overactivated. In this review, we provide an overview of Factor B and its critical role in the AP, discuss the benefit-risk of Factor B inhibition as a targeted therapeutic strategy, and describe the various Factor B inhibitors that are approved and/or in clinical development.

Keywords: alternative pathway; complement; factor B; inhibitors; pharmacological treatment; therapeutic target.

Figure 1

An overview of the three pathways of the complement system and complement regulators. (Figure adapted from Morgan BP et al. Front Cell Neurosci. 2021;14:600656 (https://doi.org/10.3389/fncel.2020.600656). Copyright 2021 Morgan, Gommerman and Ramaglia, CC BY (101). C1-INH, serum protein C1 inhibitor; C4Bp, complement inhibitor C4b binding protein; CR1, complement receptor type 1; DAF, decay accelerating factor (CD55); FI, factor I; FH, factor H; MAC, membrane attack complex; MBL, mannose-binding lectin; MCP, membrane cofactor protein (CD46); TCC, terminal complement complex.

Figure 2

Structure of FB (A) and a schematic representation of its domains (B, C) Location of various polymorphic variants in FB reported in aHUS (red), C3G (black); MPGN (purple), and deficiency of FB (green). Slow-fast polymorphism variants R32Q (fast A) associated with reduced risk of age-related macular degeneration) and R32W (fast B) are in blue. *Iptacopan binds to the active site of FB containing the catalytic triad (HIS 526, Ser 699 and Asp576) in the serine protease domain of the Bb subunit (numbering according to UniProt (P00751). (Image A from RCSB PDB of 2OK5 created using Pymol: an open-source molecular visualization system. Figure B and C adapted with permission from Laskowski J, Thurman JM. Chapter 14 - Factor B. The Complement FactsBook: Academic Press; 2018. p. 135-46. Copyright 2018 by Elsevier) (30). CCP, complement control protein module; VWA, von Willebrand factor type A domain.

Figure 3

AP C3 convertase (C3bBb) formation. Binding of FB to C3b results in conformational changes in FB, with the serine protease domain dynamically oscillating between a “closed” and “open” form that allows the binding of FD and cleavage of the scissile bond to liberate the Ba fragment (1, 30). (Figure adapted from Merle NS, Church SE, Fremeaux-Bacchi V, Roumenina LT. Complement System Part I - Molecular Mechanisms of Activation and Regulation. Front Immunol. 2015;6:262, doi: 10.3389/fimmu.2015.00262. Copyright 2015 Merle, Church, Fremeaux-Bacchi and Roumenina. CC BY 4.0) (1). AP, alternative pathway; FB, Factor B; FD, Factor D.

Figure 4

Potential pharmacodynamic effects of FB inhibition on complement activation. The effect of an inhibitor that inhibits catalytic activity of FB (and hence of C3/C5 convertase) is depicted here. Inhibition of FB abolishes cleavage of C3 by the AP C3 convertase and eventually inhibits the amplification loop as well as the downstream formation of AP C5 convertase. *An ASO (or siRNA) targeting FB would lead to reduction in the levels of circulating FB and its fragments in addition to the other effects described here. ^†Particularly likely to be evident in conditions that result in C3 hypocomplementemia such as C3G. AP, alternative pathway, ASO, antisense oligonucleotide; C3G, C3 glomerulopathy; DAF, decay accelerating factor; FB, factor B; FD, factor D; FH, factor H; MCP, membrane cofactor protein; sC5b-9, soluble C5b-9; siRNA, small interfering RNA.

Figure 5

(A) Chemical structure of iptacopan (Figure A reprinted from PubChem. https://pubchem.ncbi.nlm.nih.gov/compound/lnp023. In public domain) and (B) Crystal structure showing iptacopan (magenta) bound to the catalytic domain of human FB. The image on the right shows the indole moiety and the piperidine core of iptacopan binding into the S1 pocket and the S3 pocket, respectively; and the key hydrogen bonds. (Figure B reprinted from Schubart A et al. Immunol Rev. 2023; 313(1):339-357, doi: 10.1111/imr.v313. Copyrights 2022 Novartis Pharma AG. Immunological Reviews published by John Wiley & Sons Ltd. CC BY-NC-ND 4.0) (3).