Complement Factor H-Based Therapeutics: A Comprehensive Overview

The complement system is a key component of innate immunity, modulating immunological processes to maintain proper homeostasis. However, dysregulation of the complement can lead to severe pathologies. Complement therapeutics strive to reduce and lower the risk of breakthrough complement activation, and the field has been growing steadily since the first complement-regulating compound was introduced to the clinic in 2007, with many complement-regulating strategies currently under development. This review focuses on therapeutic developments surrounding factor H (FH), which is a critical and native regulator of complement. FH is a complement inhibitor that controls the self-amplifying alternative pathway (AP). It functions by destabilizing C3 and C5 AP convertases through decay-accelerating activity, mainly via competition with factor B for binding to C3b. Additionally, FH acts as a cofactor for factor I, which cleaves C3b into iC3b. The classical and lectin pathways converge at the C3 level, triggering the AP self-amplification loop. Independently, the AP is triggered by a tick-over mechanism that is continuously activated. Both the amplification loop and the tick-over mechanism of the AP are controlled by FH. Consequently, enhancing FH function in a dysregulated system represents a promising therapeutic approach. FH-driven therapeutic strategies include replenishing FH via plasma-derived or recombinantly produced full-length FH. On top of that, protein-engineered constructs that contain FH fragments both with and without targeting mechanisms are under development, as well as modulating moieties such as antibodies and peptides that bind and potentiate FH. In this review, we provide an extensive overview of these developments, discuss the underlying rationale of each strategy, and evaluate their status in the therapeutic pipeline.