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Complement System

The complement system is a sophisticated part of the immune system that enhances the ability of antibodies and phagocytic cells to clear microbes and damaged cells, promotes inflammation, and attacks the pathogen's cell membrane. This system is named for its capacity to "complement" the killing of pathogens by antibodies.

Comprising over 30 small proteins produced by the liver, the complement system circulates in the blood serum and within tissues throughout the body. These proteins are normally inactive but become sequentially activated in response to a pathogen. Activation can occur via three pathways: the classical pathway, which is triggered by antibodies bound to a pathogen; the lectin pathway, which is activated by mannose-binding lectin attaching to the pathogen surface; and the alternative pathway, which can be initiated directly by pathogen surfaces.

Each pathway leads to the cleavage of the protein C3, generating C3a and C3b fragments. C3b binds to the pathogen surface and can lead to direct opsonization—tagging the pathogen for destruction by phagocytes. C3a, along with other small fragments released during complement activation, acts as a chemoattractant to recruit immune cells to the site of infection and promote inflammation.

The final common step of the complement activation pathways is the assembly of the membrane attack complex (MAC). This complex forms a pore in the membrane of the target cell, leading to cell lysis and death. The MAC is particularly effective against gram-negative bacteria.

Regulation of the complement system is crucial, as overactivation can damage host cells. Regulators are present in blood plasma and on cell surfaces, ensuring the system is directed only at pathogens or damaged cells.

The complement system plays a crucial role not only in innate immunity but also as a bridge to adaptive immunity. It assists in clearing immune complexes and apoptotic cells, and in enhancing the humoral response and immune memory.

Understanding and manipulating the complement system has therapeutic potential for numerous diseases, including those that involve excessive or inappropriate activation of the complement pathways.

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  1. A24463
    Lanoracopan

    Complement factor B inhibitor

    Lanoracopan is a potent inhibitor of complement factor B, with an IC₅₀ of 1.2 μM. It is suitable for research in inflammation- and immunity-related diseases.
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  2. A24462
    CP-289,503

    C5a receptor inhibitor

    CP-289,503 is an inhibitor of the complement C5a receptor, with an IC₅₀ of 1 μM. The C5a receptor mediates pro-inflammatory signaling by binding to C5a, a complement activation product that stimulates leukocyte and phagocyte activation, upregulates integrins, and induces degranulation of inflammatory cells, contributing to endothelial damage. By blocking C5a signaling, CP-289,503 may be useful in the treatment of various inflammatory diseases.
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  3. A24351
    ADH-503

    CD11b agonist.

    ADH-503 ((Z)-Leukadherin-1 choline) is an orally active, allosteric agonist of CD11b, an integrin subunit expressed on myeloid cells. By activating CD11b, ADH-503 promotes the repolarization of tumor-associated macrophages (TAMs) toward a pro-inflammatory phenotype, reduces the infiltration of immunosuppressive myeloid cells into tumors, and enhances dendritic cell responses. These immunomodulatory effects support its potential use in cancer immunotherapy.
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  4. A24350
    JR14a

    complement C3a antagonist

    JR14a is a potent thiophene-based antagonist of the human complement C3a receptor (C3aR). It exhibits high selectivity for C3aR over the C5a receptor and effectively suppresses C3aR-mediated inflammatory responses. JR14a is a valuable tool for studying the role of C3aR in immune regulation and inflammation-related diseases.
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  5. A24349
    Phaseoloidin
    Phaseoloidin is a homogentisic acid glucoside isolated from *Nicotiana attenuata* trichomes. It plays a defensive role in the plant's resistance against lepidopteran herbivores by significantly reducing the growth of both specialist (*Manduca sexta*) and generalist (*Spodoptera littoralis*) larvae. In addition to its insect-deterrent properties, phaseoloidin also exhibits anti-complement activity, suggesting potential immunomodulatory applications.
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  6. A64236
    Ascuprubart

    Anti-Complement C5 Antibody

    Ascuprubart is a monoclonal antibody specifically designed to target human Complement C5. By inhibiting the activity of C5, this antibody plays a crucial role in modulating the complement pathway, making it instrumental in research related to immune response and inflammation. Ascuprubart is suitable for applications in studies focused on complement-mediated diseases and therapeutic development.
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