New milestones ahead in complement-targeted therapy

Abstract

The complement system is a powerful effector arm of innate immunity that typically confers protection from microbial intruders and accumulating debris. In many clinical situations, however, the defensive functions of complement can turn against host cells and induce or exacerbate immune, inflammatory, and degenerative conditions. Although the value of inhibiting complement in a therapeutic context has long been recognized, bringing complement-targeted drugs into clinical use has proved challenging. This important milestone was finally reached a decade ago, yet the clinical availability of complement inhibitors has remained limited. Still, the positive long-term experience with complement drugs and their proven effectiveness in various diseases has reinvigorated interest and confidence in this approach. Indeed, a broad variety of clinical candidates that act at almost any level of the complement activation cascade are currently in clinical development, with several of them being evaluated in phase 2 and phase 3 trials. With antibody-related drugs dominating the panel of clinical candidates, the emergence of novel small-molecule, peptide, protein, and oligonucleotide-based inhibitors offers new options for drug targeting and administration. Whereas all the currently approved and many of the proposed indications for complement-targeted inhibitors belong to the rare disease spectrum, these drugs are increasingly being evaluated for more prevalent conditions. Fortunately, the growing experience from preclinical and clinical use of therapeutic complement inhibitors has enabled a more evidence-based assessment of suitable targets and rewarding indications as well as related technical and safety considerations. This review highlights recent concepts and developments in complement-targeted drug discovery, provides an overview of current and emerging treatment options, and discusses the new milestones ahead on the way to the next generation of clinically available complement therapeutics.

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

“…The expanding landscape of complement-mediated diseases continues to fuel recent efforts to develop targeted complement inhibitors with clinical potential [9–11]. Thus far, clinical experience has been gained with the sole complement-specific drug, eculizumab (Soliris, Alexion Pharmaceuticals), a therapeutic antibody that targets C5 activation, blocking the generation of downstream effectors (C5a, the membrane attack complex (MAC)) [12].…”

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

“…From a different standpoint, strategies targeting the central protein, C3, offer a broader and more comprehensive interception by blunting amplification and downstream receptor-triggered effector mechanisms, as exemplified by compstatin-based C3 inhibitors and engineered versions of natural C3 regulators (Ricklin and Lambris, 2016b). Such a broadly inhibiting approach may have greater therapeutic leverage in clinical conditions associated with systemic complement activation.…”

“…Other elegant approaches exploiting biologics as potential PPI inhibitors include recombinant fusion proteins encompassing regulatory (CCP) modules of natural regulators (e.g., TT30, miniFH) (Fridkis-Hareli et al , 2011;Schmidt et al , 2013), parasite-secreted immune evasion proteins (e.g., OmCI; (Roversi et al , 2007), recombinant protein scaffolds (e.g. SOBI002) (Swedish Orphan Biovitrum, 2016), and oligonucleotide-based ligands such as aptamers (e.g., Zimura), liver-targeted RNAi therapeutics (ALN-CC5, Alnylam), or Spiegelmers (e.g., NOX-D21) (Ricklin and Lambris, 2016b). The development of highly potent peptidic inhibitors has defined a unique class of small-sized complement therapeutics that have shown great promise for clinical translation in various indications.…”

“…This surface-targeted approach may also be beneficial in conditions in which persistent C3 opsonic turnover fuels a vicious cycle of inflammation on malignantly transformed surfaces (e.g., tumor cells), transplants, or biomaterials (Ekdahl et al , 2011). Indeed, promising examples of this surface-directed therapeutic approach include fusion proteins (e.g., TT30 [FH-CR2]), condensed versions of AP regulators with enhanced surface recognition and inhibitory potency (e.g., mini-FH), and targeting moieties that recruit soluble regulators to biomaterial surfaces, thereby attenuating AP activation and C3 opsonization (e.g., FH-binding peptides) [reviewed in (Ricklin and Lambris, 2016b)]. New insights into the unique surface selectivity of this new class of C3-targeted inhibitors and the therapeutic prospects emerging from their preclinical evaluation are discussed below.…”

“…Whereas a Phase I trial of TT30 has proved successful in untreated PNH patients, further clinical development of this inhibitor has not yet been reported (Risitano et al , 2015). Interestingly, this therapeutic concept of opsonin targeting has been extended to other regulators such as CR1 (i.e., TT32) and has also inspired a diversified spectrum of chimeric inhibitors/regulators (e.g., FH-MAP1, FH-CRIg, and CD59-CRIg [reviewed in (Ricklin and Lambris, 2016b)]).…”