From orphan drugs to adopted therapies: Advancing C3-targeted intervention to the clinical stage

Abstract

Complement dysregulation is increasingly recognized as an important pathogenic driver in a number of clinical disorders. Complement-triggered pathways intertwine with key inflammatory and tissue destructive processes that can either increase the risk of disease or exacerbate pathology in acute or chronic conditions. The launch of the first complement-targeted drugs in the clinic has undeniably stirred the field of complement therapeutic design, providing new insights into complement's contribution to disease pathogenesis and also helping to leverage a more personalized, comprehensive approach to patient management. In this regard, a rapidly expanding toolbox of complement therapeutics is being developed to address unmet clinical needs in several immune-mediated and inflammatory diseases. Elegant approaches employing both surface-directed and fluid-phase inhibitors have exploited diverse components of the complement cascade as putative points of therapeutic intervention. Targeting C3, the central hub of the system, has proven to be a promising strategy for developing biologics as well as small-molecule inhibitors with clinical potential. Complement modulation at the level of C3 has recently shown promise in preclinical primate models, opening up new avenues for therapeutic intervention in both acute and chronic indications fueled by uncontrolled C3 turnover. This review highlights recent developments in the field of complement therapeutics, focusing on C3-directed inhibitors and alternative pathway (AP) regulator-based approaches. Translational perspectives and considerations are discussed, particularly with regard to the structure-guided drug optimization and clinical advancement of a new generation of C3-targeted peptidic inhibitors.

Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

“…Cinryze, Shire) target peripheral steps such as initiation or effector generation. Fortunately, several candidate drugs acting at the level of C3 activation are currently in development; they either act on C3 itself or on the C3 convertase (Figure ) …”

Complement C3-Targeted Therapy: Replacing Long-Held Assertions with Evidence-Based Discovery

“…C5 blockade has not only provided an effective therapeutic handle for treating diseases with complement-mediated pathophysiology but has also revealed new pathogenic mechanisms that remain unaddressed by this clinically available anti-complement therapy (e.g., C3-mediated extravascular lysis of erythrocytes in patients suffering from paroxysmal nocturnal hemoglobinuria [PNH], a form of acquired hemolytic anemia) [13,14]. The strategic positioning of C3 at the intersection of all complement activation pathways and its pivotal role in coordinating crosstalk with multiple immune and inflammatory networks have galvanized efforts to develop C3-based therapies [15]. Accumulating evidence suggests that C3-targeted intervention may hold clinical promise as a viable therapeutic entity alongside anti-C5 therapeutics.…”

“…Interestingly, the genetic absence or pharmacologic inhibition of C3 in certain animal models can even attenuate the spread of infection, implying a more complex impact of complement on host-pathogen interactions [64,65]. Further lines of evidence supporting the safety and clinical feasibility of prolonged pharmacologic C3 intervention are extensively discussed in recent reviews [15,16, 21]. …”

Anti-Immune Strategies of Pathogenic Fungi

“…However, two complement-targeted drugs for non-fungal diseases have been introduced in the clinic: the therapeutic anti-C5 antibody eculizumab (Soliris; Alexion Pharmaceuticals) and various preparations of the physiological regulator C1 esterase inhibitor (C1-INH). In addition, several new candidate drugs targeting various components of the complement cascade are in different stages of clinical development (Ricklin and Lambris, 2013; Morgan and Harris, 2015; Reis et al, 2015; Mastellos et al, 2016). …”