Complement inhibitors are therapeutic agents designed to block specific components or signaling steps within the complement system, an important part of innate immunity. By inhibiting complement activation at different points, these therapies can reduce complement-mediated inflammation, opsonization, and cell lysis.

Complement inhibitors can target different components of the complement cascade, including C1s, C3, C5, Factor B, Factor D, and the C5a receptor (C5aR1). Depending on the target, complement inhibition can act on the classical, lectin and alternative pathways.  This therapeutic approach has led to approved treatments for diseases such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), myasthenia gravis, geographic atrophy, and other complement-mediated disorders. 

FDA Approved Complement Inhibitors

Now, there are 15 complement inhibitors are approved by FDA, including C1 inhibitor Berinert, Cinryze, Ruconest and Enjaymo (sutimlimab), C3 inhibitor Empaveli (pegcetacoplan), SYFOVRE™ (pegcetacoplan injection) , and C5 inhibitor, Zilbrysq (Zilucoplan), Veopoz (Pozelimab), Izervay (avacincaptad pegol), Soliris (Eculizumab), Ultomiris (ravulizumab) and Tavneos (avacopan), factor B inhibitor Fabhalta (Iptacopan) and factor D inhibitor Voydeya (Danicopan).

Table. FDA Approved Complement Inhibitors

PEGylated Complement Inhibitors

PEGylation has played an important role in the development of complement-targeted therapeutics. Several complement-targeted therapies illustrate how PEG chemistry can be incorporated into different therapeutic modalities.

Pegcetacoplan is a PEGylated cyclic peptide targeting C3, while avacincaptad pegol is a PEGylated RNA aptamer targeting C5. Zilucoplan uses a lipid-containing structure with a short PEG linker to support its pharmacokinetic properties.

Pegcetacoplan (Empaveli / Syfovre)

In May 2021, the FDA approved Empaveli (pegcetacoplan), the world's first targeted C3 therapy for the treatment of Paroxysmal nocturnal hemoglobinuria (PNH). pegcetacoplan is a synthetic cyclic peptide conjugated to a polyethylene glycol (PEG) polymer that specifically binds C3 and C3b. On 17 Feb, 2023, the FDA has approved SYFOVRE™ (pegcetacoplan injection) for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). SYFOVRE is the first and only FDA-approved treatment for GA,

Pegcetacoplan is a highly pegylated peptide with a chemical structure that resembles that of peginesatide. Thus, both molecules contain two copies of a disulfide cyclic peptide (13 aa for pegcetacoplan and 20 aa for peginesatide) and 40 kDa PEG (two units of 20 kDa for peginesatide).

Avacincaptad pegol (IZERVAY™)

On August 4, 2023, the FDA approved IZERVAY™ (avacincaptad pegol), a complement C5 inhibitor, for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). IZERVAY, is a ribonucleic acid (RNA) aptamer, covalently bound to an approximately 43-kiloDalton (kDa) branched polyethylene glycol (PEG) molecule.

Avacincaptad pegol (IZERVAY™)

On October 18, 2023, the FDA approved ZILBRYSQ® (zilucoplan) for the treatment of generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody-positive. With the approval, zilucoplan becomes the first once-daily subcutaneous C5 complement inhibitor available for adults with generalized myasthenia gravis.  

Zilucoplan is a fully synthetic macrocyclic peptide developed through a targeted screen using the innovative extreme diversity mRNA display platform (10–12). It is composed of a 15-amino acid macrocyclic peptide, including four unnatural amino acids, designed to inhibit TCC activation (13). The addition of a C16 lipid via a short monodisperse polyethylene glycol (PEG24) linker  provides a pharmacokinetic (PK) profile consistent with daily dosing in humans.

Conclusion

The development of drugs targeting the complement system is gaining momentum. However, there are still many difficulties in the development of these drugs.

On the one hand, although the role of complement in the human body is widely recognized, how it mediates disease and how it affects pathogenesis is unknown. On the other hand, the complement system is a complex network of proteins with a large number of pathways that play regulatory roles. Even if one of the complement pathways is blocked, the complement system can "redirect" to another pathway through regulatory mechanisms, protecting the body from pathogens, but also eliminating the expected clinical effect of target inhibitors. Therefore, the development of drugs that effectively block the complement pathway has become a major challenge, including the selection of indications, the screening of complement system targets, and the selection of drug types (e.g., monoclonal antibodies, small molecules, peptides, etc.).

In addition, complement proteins are widely present in the body, accounting for about 10% of total serum proteins, and are metabolized at a very fast rate. Once the complement protein is activated in the body, it will need to be blocked with high frequency and high dose of drugs. Therefore, the frequency and dose of complement drugs have become a major consideration in drug development.

PEG Derivatives for Complement Inhibitor Research

The development of PEGylated complement inhibitors requires PEG derivatives with appropriate molecular weight, architecture, linker chemistry, and functional groups. Depending on the therapeutic modality and conjugation strategy, researchers may select monofunctional PEGs, heterobifunctional PEG linkers, lipid-PEG conjugates, or other functional PEG derivatives.

Biopharma PEG provides monodispersed and polydispersed PEG derivatives, including amine, carboxyl, maleimide, thiol, NHS ester, azide, and other functional PEGs for peptide, protein, oligonucleotide, and bioconjugation research. We also provide custom PEG derivative synthesis for research and development applications, supporting the design and preparation of PEG structures with customized molecular weights, functional groups, linker configurations, and molecular architectures.

References:
[1] Kim BJ, Mastellos DC, Li Y, Dunaief JL, Lambris JD. Targeting complement components C3 and C5 for the retina: Key concepts and lingering questions. Prog Retin Eye Res. 2021 Jul;83:100936. doi: 10.1016/j.preteyeres.2020.100936. Epub 2020 Dec 13. PMID: 33321207; PMCID: PMC8197769.
[2]
Wioleta M Zelek, Long Xie, B Paul Morgan, Claire L Harris,, Compendium of current complement therapeutics, Molecular Immunology, Volume 114, 2019, Pages 341-352, ISSN 0161-5890, https://doi.org/10.1016/j.molimm.2019.07.030.
[3] Morgan BP, Harris CL. Complement, a target for therapy in inflammatory and degenerative diseases. Nat Rev Drug Discov. 2015;14(12):857-877. doi:10.1038/nrd4657 

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