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.

Keywords: AMY-101; C3 convertase; Clinical efficacy; Complement dysregulation; Peptidic C3 inhibitors; Primate models.

Figure 1

(Panel A) A simplified schematic overview of the complement cascade with points of therapeutic intervention by clinically developed C3 inhibitors. Complement activation on foreign surfaces (e.g. microbial, transplants, biomaterials) or damaged/transformed self surfaces can be triggered by any of the three pathways (classical, lectin, alternative). All pathways converge at the cleavage of the central component, C3, by the C3 convertases. Amplification of the AP is considered a pivotal pathogenic driver in many complement-mediated diseases. Activation of C5 by C5 convertases of both the classical and alternative pathway leads to the release of the proinflammatory mediator C5a and the assembly of the cell-perforating MAC (C5b-9). Convertase-independent cleavage of C3 and C5 by coagulation and fibrinolytic proteases (e.g. plasmin, thrombin) has been implicated as a bypass pathway of complement activation in certain pathophysiological contexts. C3-targeted inhibitors (e.g. Cp40, AMY-101) can provide effective and broad therapeutic control of the cascade by targeting all pathways at the level of C3 and blocking downstream complement effector responses (e.g. C5a generation, MAC assembly). Abbreviations: AP, alternative pathway; MBL, mannose-binding lectin; MASPs, mannose-binding lectin associated proteases; FP, properdin; FB, factor B; FD factor D; MAC, membrane attack complex. (Panel B) Concepts and illustrative examples of C3-targeted therapeutic modulation. Several inhibitory approaches have been developed and are currently in clinical evaluation as C3-targeted therapeutics for various indications. These include: a) systemic or local complement modulation at the level of C3 (e.g. compstatin analogs), b) surface-targeting of fluid-phase complement regulators ( e.g. FH) acting at the level of the AP C3 convertase (e.g. mini-FH variants, CR2-FH fusion constructs:TT30) and c) targeting moieties that recruit endogenous C3 regulators to the complement-opsonized surface (e.g. FH-binding peptides, 5C6). Blue arrows indicate ways by which AP C3 convertase activity can be regulated by natural, chimeric or small-sized C3 inhibitors.