Conjugation to Albumin‐Binding Molecule Tags as a Strategy to Improve Both Efficacy and Pharmacokinetic Properties of the Complement Inhibitor Compstatin

Reis

Mastellos

et al. 2016

Immunological Reviews

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349

295

Summary As a preformed defense system, complement faces a delicate challenge in providing an immediate, forceful response to pathogens even at first encounter, while sparing host cells in the process. For this purpose, it engages a tightly regulated network of plasma proteins, cell surface receptors, and regulators. Complement component C3 plays a particularly versatile role in this process by keeping the cascade alert, acting as a point of convergence of activation pathways, fueling the amplification of the complement response, exerting direct effector functions, and helping to coordinate downstream immune responses. In recent years, it has become evident that nature engages the power of C3 not only to clear pathogens but also for a variety of homeostatic processes ranging from tissue regeneration and synapse pruning to clearing debris and controlling tumor cell progression. At the same time, its central position in immune surveillance makes C3 a target for microbial immune evasion and, if improperly engaged, a trigger point for various clinical conditions. In our review, we look at the versatile roles and evolutionary journey of C3, discuss new insights into the molecular basis for C3 function, provide examples of disease involvement, and summarize the emerging potential of C3 as a therapeutic target.

Section: Therapeutic Control Of C3 Activationmentioning

confidence: 99%

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

Reis

Mastellos

et al. 2016

Immunological Reviews

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349

295

“…Whereas addition of PEG or albumin-binding moieties to compstatin derivatives has generally been shown to increase their plasma residence [81, 138], C3-saturating drug concentrations can even be achieved via subcutaneous administration of the untagged compstatin analog Cp40 [81]. Subcutaneous injection is currently being considered for many biological complement inhibitors and may allow for patient self-administration in chronic diseases such as PNH.…”

Section: Modulating An Immune Modulator: Reconsidering the Challengesmentioning

confidence: 99%

New milestones ahead in complement-targeted therapy

Lambris

2016

Seminars in Immunology

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125

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.

“…By employing the depot effect of subcutaneous administration, doses as low as 1 mg/kg every 12 hours were shown to maintain target-saturating Cp40 levels in NHP (Risitano et al, 2014). In addition to a modulation of the pharmacokinetic properties by means of PEGylation or albumin-binding entities (Huang et al, 2014; Risitano et al, 2014), even an adjustment of the dose and formulation may extend the injection frequency to a single daily dose (Lambris and Ricklin, unpublished observations), thereby rendering therapeutic options such as patient self-administration in PNH or DDD increasingly realistic. Finally, it is not yet clear whether C3 inhibition needs to be complete or continuous in all indications.…”

Section: Chances and Challenges On The Way To The Clinicmentioning

confidence: 99%

Therapeutic control of complement activation at the level of the central component C3

Lambris

2016

Immunobiology

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The increasing recognition of the complement system’s association with diseases of the inflammatory spectrum and with biomaterial and transplant-related complications has generated growing interest in the therapeutic modulation of this innate immune cascade. As a central functional hub that largely drives the activation, amplification, and effector generation of the complement response, the plasma protein C3 has long been recognized as an attractive target. While pharmacological modulation of C3 activation may offer a powerful opportunity to interfere with or even prevent complement-driven pathologies, the development of C3 inhibitors has often been accompanied by concerns regarding the safety and feasibility of this approach. Although no C3-targeted inhibitors have thus far been approved for clinical use, several promising concepts and candidates have emerged in recent years. At the same time, experiences from preclinical development and clinical trials are slowly providing a more detailed picture of therapeutic complement inhibition at the level of C3. This review highlights the current therapeutic strategies to control C3 activation and discusses the possibilities and challenges on the road to bringing C3-targeted therapeutics to the clinic.