Therapeutic Antibodies of Complement System

Therapeutic Antibodies of Complement System Background

Following a general trend in the pharmaceutical industry, antibody-based therapeutics appear to be the most rapidly growing drug class against complement-related diseases. Crucial developments in their screening, production and humanization have led to a remarkable boost in the number of therapeutic antibodies. By targeting specific components of the complement system, all stages from the initiation and activation process to single terminal actions can hypothetically be blocked in a selective manner. Current drug candidates in the pipeline focus primarily on the inhibition of downstream processes around C5 and its cleavage fragment, the anaphylatoxin C5a.

Selective inhibition of C5 using monoclonal antibodies (mAb) has been considered a promising therapeutic option for many years. A highly selective mAb against mouse C5 was introduced by Frei et al. two decades ago and was later demonstrated to be effective in a mouse model of rheumatoid arthritis by Alexion Pharmaceuticals. Eculizumab is the first and only approved therapy for Paroxysmal nocturnal hemoglobinuria (PNH), a rare but life-threatening disorder that is characterized by a chronic destruction of red blood cells. A mutation on the X chromosomes of hematopoietic stem cells prevents the proper biosynthesis of the glycosylphosphatidylinositol (GPI) anchor, which leads to a deficiency in membrane-anchored proteins, including DAF and CD59. The survival of PNH erythrocytes is dramatically reduced in PNH patients, to 10% of normal red blood cells. On platelets, the absence of CD59 and increased MAC formation can lead to morphological changes of their surface.

As an anti-C5 antibody that inhibits the generation of both C5b and the anaphylatoxin C5a, the potential indications for eculizumab are certainly not limited to PNH. Consequently, eculizumab has undergone several preclinical and clinical studies for a variety of conditions (e.g., psoriasis, rheumatoid arthritis, systemic lupus erythematosus and transplant rejection). Several companies list anticomplement antibodies in their pipelines. Two of them target the various actions of the anaphylatoxin C5a. Neutrazumab (G2 Therapies, Darlinghurst, NSW, Australia) binds to extracellular loops of C5aR and thereby inhibits the binding of C5a to its major signaling receptor. G2 Therapies recently announced a partnership with Novo Nordisk (Bagsværd, Denmark) with regard to the development of their anti-C5aR antibodies.

Experience with monoclonal antibodies in cancer therapy suggests that induction of cell death through antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity (CDC) may be a major driving force behind their effectiveness (e.g., in the case of the anti-CD20 mAb rituximab from Roche). CDC may generally be induced by therapeutic IgGs (and IgMs), the CDC activity of these reagents may become a crucial parameter in the development of therapeutic antibodies.

Therapeutic Antibodies of Complement System List

Product (company) Activity Stage of development
Eculizumab/ Soliris (Alexion Pharmaceuticals) Humanized long-acting mAb against C5 Marketed (paroxysmal nocturnal hemoglobinuria/PNH), preclinical for other indications
Pexelizumab (Alexion Pharmaceuticals) Humanized short-acting mAb against C5 Clinical phase 3 (acute myocardial infarction/AMI; coronary artery bypass grafting/CABG)
Ofatumumab (Genmab A/S) Humanized anti-CD20 mAb Clinical phase 2
Neutrazumab (G2 Therapies) Antibody blocking the C5a receptor Development/preclinical (rheumatoid arthritis/RA, stroke)
Anti-properdin (Novelmed Therapeutics) Antibody against properdin Antibody against properdin
TA106 (Taligen Therapeutics) Antibody against factor B Development/preclinical
TNX-558(Tanox) Humanized antibody against C5a Development/preclinical (inflammatory diseases)
TNX-234(Tanox) Humanized antibody against factor D Preclinical (wet age-related macular degeneration/AMD)

Therapeutic Antibodies of Complement System References

1. Ricklin D, et al. (2007). Complement-targeted therapeutics. Nature biotechnology, 25(11), 1265-1275.
2. Hajishengallis G, et al. (2013). Complement-targeted therapeutics in periodontitis. In Complement Therapeutics (pp. 197-206). Springer US.