Technicians in Creative Biolabs’ experienced team provides complement therapeutic services ranging from therapeutic antibodies, protease inhibitors, soluble complement regulators, complement component inhibitors to anaphylatoxin receptor antagonists. We help our clients discover novel drugs, avoid the pitfalls of variability in assays and benefit from the efficiency and accuracy of a dedicated facility.
Complement System
The complement system is a biological process in the serum. It’s most well-known function is undoubtedly the role to clear away the pathogens such as bacteria, viruses, fungi or parasites. It is now also known that the complement system mainly consists of three pathways which maintain the complement homeostasis, the classical pathway, the lectin pathway, and the alternative pathway. The complement system approximately possesses 30 proteins. Some of the components are proteases, cofactors, inhibitors, and others are membrane-associated proteins. When one of these cascades is initiated, a series of cleavage events will occur, followed by an amplification of the immune responses and the formation of the membrane-lysis complex. However, inappropriate activation of complement cascade may implicate numerous diseases. C3a may lead to pathological activation of other phagocytes. The anaphylatoxin C5a triggers glucosylceramide accumulation and tissue inflammation in Gaucher disease. In addition, the complement system is reported to be implicated in the disease of nervous system such as Alzheimer’s disease.
Fig. 1 An illustration of the current complement therapeutics.1
Complement Therapeutic Services
Nowadays, numerous promising approaches for the clinical studies and trials of complement have been developed. Based on diverse mechanism of action, the current complement therapeutics can be classified into five major categories.
Serine Protease Inhibitors
The complement system is a proteolytic cascade where the serine proteases activate the consecutive cleavage of each other by limited proteolysis in a strictly ordered manner. Serine proteases are crucial in both the initiation and the amplification processes. Since the dysfunction and dysregulation of the serine proteases in the complement cascade contributes to the development of the complement-related diseases, suppressing the activities of the serine proteases can be an attractive approach and has drawn much attention in the clinical trials. Serpins are one major type of serine protease inhibitors in the blood, which undergo the conformational change, when binding to target proteases, and lead to the formation of irreversible complexes.
Soluble Complement Regulators
In addition to serine proteases, the complement regulators in the system play an important role, preventing the host cell from being invaded by the pathogen. These regulators are taken into consideration for therapeutic applications since the early stages of complement drug discovery and validation. Complement receptor type 1 (CR 1) that binds to the C3b and C4b is a big breakthrough for complement strategies. It features both decay accelerator and cofactor activity and had a high potency in suppressing both classical and alternative pathways. It has been shown to act as an excellent inhibitor of in vitro and in vivo activation of human and many other species.
Therapeutic Antibodies in Complement Therapeutic
Antibody-based therapeutics seems to be one of the most rapidly-developed drug class. Because of their robust features, antibodies superbly suited to be developed into the complement therapeutics with appropriate stimulatory or inhibitory activities. C5, one of the components in the complement cascade, is proved to be associated with several diseases. One of these diseases is paroxysmal nocturnal hemoglobinuria (PHN), which is a rare but life-threatening disorder and characterized by a chronic destruction of erythrocytes. For the people with PHN, inhibition with the anti-C5 antibody has yielded encouraging results, decreasing the need for blood transfusions.
Complement Component Inhibitors
Antibodies might be regarded as the archetype of site-blocking compound. Small compounds such peptides, nucleotides and synthetic molecules might also have the potential impact on interrupting protein functions by steric hindrance of conformational changes. With the advantages such as ease of production and the potential for oral administration, small compounds expected to be suited to the drug development efforts in terms of oral bioavailability and better administration routes.
Anaphylatoxin Receptor Antagonists
Anaphylatoxins such as C3a and C5a are among the strongest modulators generated by the complement cascade. They induce chemotaxis, cell activation, and inflammatory signaling when binding to their respective G-protein-coupled receptors (GPCR), which are C3aR and C5aR. In view of the strong inflammatory effects and the potential drugability, C5a has been a driving force behind a great many complement-related disorders and its receptors (e.g. C5aR) have been identified as attractive and promising drug targets reversing the complement-associated pathogenesis. Anti-C5 antibodies and aptamers for inhibiting C5a generation have shed light on neutralizing C5a-CaR interaction by shielding the binding sites. C5aR antagonists have designed to prevent the C5a-CaR interaction by binding the receptor with high affinity.
Creative Biolabs is confident in providing best-in-class complement-associated services through our excellent platform, aiming to help our clients with novel complement related drug discovery and validation. If you are interested in our service, please contact us for more detail information.
Reference
1. Morgan, B. Paul, and Claire L. Harris. "Complement, a target for therapy in inflammatory and degenerative diseases." Nature reviews Drug discovery 14.12 (2015): 857-877.
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