With an accumulation of knowledge and expertise in complement therapeutics, Creative Biolabs dedicated to offering a full range of biotherapeutics development services. Based on our advanced antibody engineering platform, protease inhibitor platform, and drug discovery platform, we are fully equipped to provide the services for drug discovery and validation based on the complement system.
Complement System
The complement system is composed of three different simultaneous pathways for the formation of membrane-lysis complex. Being part of the adaptive immunity, the classical pathway is stimulated by antigen-antibody complexes and involved in the activation of the complement system. In contrast to the classical pathway, the alternative pathway is activated by the spontaneous hydrolysis of C3, which increases its reactivity allowing for the binding of Factor B. The lectin pathway initiation is done by the opsonin, mannose-binding lectin or ficolins which in turn activate the associated serine proteases MASP-1 and MASP-2. C1q, C1r, and C1s form a complex called C1 complex when a single pentameric IgM and six IgG initiate the classical pathway. The complex also forms when C1q binds to the surface of the invading pathogen.
Fig 1. Structure of C1-inhibitor.1
Function of C1-inhibitor
C1-inhibitor (also called C1 esterase inhibitor) is a protease inhibitor that belongs to the serpin superfamily. Its main role is to prevent spontaneous activation of the complement system by inhibiting its specific targets (e.g. C1 and mannose-binding lectin). Most serpins have merely one target, but C1-inhibitor has several targets which includes factor XIIa, kallikrein and factor XIa derived from the contact system, activated C1s and C1r derived from the classical pathway, also the proteases MASp-1 and MASP-2 derived from the lectin pathway.
C1-inhibitor Associated Disease
Deficiency of C1-inhibitor is associated with hereditary angioedema (HAE) and acquired angioedema (AAE), both conditions trigger recurrent angioedema which could be life-threatening.
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Hereditary Angioedem(HAE)
HAE is a disorder that leads to the recurrent attacks of severe swelling. This usually has an impact on patients’ arms, legs, face, and intestinal tracts. The genetic defect is ascribed to the heterozygous deficiency of C1-inhibitor. Mutations have been identified and are reported to elicit reduced levels of C1-inhibitor in the blood or lead to the production of C1-inhibitors without normal functionality.
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Acquired Angioedema(AAE)
First described in 1972, AAE is characterized by the acquired deficiency of C1 inhibitor, hyperactivation of the classical pathway of the complement system. The recurrence frequency of angioedema is not predictable. It usually lasts for two to five days and presents disfiguring, non-pruritic edema of the skin. It might affect tissues such as the face, arms genitals, buttocks, stomach, intestines or bladders.
C1-inhibitor Related Therapeutics
So far, C1-inhibitor is the only complement-directed protease inhibitor that is available on the market. C1-inhibitor preparations have been used as the treatment of HAE for several years in Europe. C1-inhibitor is not specific to C1 but inhibits additional proteases in the complement cascades such as MASP-2, plasmin, thrombin, factor Xa and contact systems.
rhC1INH
Recombinant human C1-inhibitor (rhC1INH) (Pharming Group N.Y) is a new drug developed for the patients suffering from the angioedema due to Ci-inhibitor deficiency. During clinical trials into the management of the edema, 190 subjects received recombinant C1-inhibitor intravenously on 714 occasions. The result showed effectiveness for all localization of HAE attacks. The safety studies of rhC1INH based on 300 administrations to healthy subjects or patients with HAE did not show detected form of autoantibodies against rhC1INH for 90 days.
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Reference
1. From Wikipedia: Jfdwolff at the English-language Wikipedia, CC BY-SA 3.0 https://commons.wikimedia.org/wiki/File:C1-inhibitor.png
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Questions & Answer
A: Yes, research suggests that C1 inhibitor therapy might have applications in various inflammatory and autoimmune conditions, such as sepsis, organ transplantation, and autoimmune diseases like lupus and rheumatoid arthritis. The regulatory role of C1 inhibitor in the complement system makes it a potential target for modulating immune responses.
A: Research is ongoing to develop more convenient and effective C1 inhibitor therapies, such as longer-acting formulations that require less frequent dosing. Additionally, efforts continue to explore its potential in various immune and inflammatory disorders.
A: Yes, there are several ongoing research efforts related to C1 inhibitors. More fundamental research is being carried out to understand exactly how C1 inhibitors work, and to identify potential new therapeutic targets. This involves studying the structure of the C1 inhibitor protein, as well as its interactions with other proteins in the body. Pharmaceutical companies and research institutions are continually developing and testing new C1 inhibitors to treat various conditions.
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