Complement, a target for therapy in inflammatory and degenerative diseases

Abstract

The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies.

A fully recombinant human IgG1 Fc multimer (GL-2045) inhibits complement-mediated cytotoxicity and induces iC3b

“…52,53 As with other drug candidates in development, such as C1INH proteins, anti-C1s mAbs, and anti-MASP2 mAbs, GL-2045 inhibits complement-mediated activation on the cell surface. 54 Unlike these more "traditional" drug candidates, GL-2045 induces self-limited complement activation, resulting in the generation of proteins with long-lasting anti-inflammatory properties (Figure 7). Ongoing in vivo studies in nonhuman primates will help further define the influence of GL-2045 on complement function.…”

Antibodies That Efficiently Form Hexamers upon Antigen Binding Can Induce Complement-Dependent Cytotoxicity under Complement-Limiting Conditions

“…The complement cascade terminates with the insertion of multiple copies of the membrane attack complex (MAC, C5b-9) which pierces the cell membrane. A threshold level of MAC binding promotes plasma membrane permeability and influx of water and ions that kills the targeted cell (13)(14)(15)(16)(17)(18). Increasing evidence indicates that under physiologic conditions, as a consequence of this permeabilization, the rapid rise in the concentration of intracellular Ca 2+ poisons the cell and is the most proximate mediator of MAC-induced cell death (12,(19)(20)(21)(22).…”

Structural Basis for Simvastatin Competitive Antagonism of Complement Receptor 3

“…Recent progress supports the clinical significance of these strategies. Nevertheless, there are still considerable unmet clinical needs for short and long term modulation of leukocyte responses to complement activation (1,2).…”