The complement system is an entire functionally related system comprising at least 20 distinct plasma proteins that is the effector not only of cytolysis but also of other biologic functions.
Inflammation in general terms, is a rapid highly amplified, controlled humeral and cellular response involving the complement, kinin/kallikrein coagulation and fibrinolytic cascade systems which are triggered together with activation of different cells. Loss of the control mechanisms in these systems or an exaggerated response may lead to locally chronic inflammation or whole body inflammation with subsequent tissue damage.
Activation of the complement system is associated with several diseases and conditions but may also be triggered by pharmaceuticals. Terminal pathway activation leads to formation of the potent anaphylatoxin C5a and SC5b-9/MAC (membrane attack complex) which have the ability to activate basophils, mast cells, platelets and endothelial cells and stimulate the release of multiple pro-inflammatory mediators. The activation of granulocytes by C5a leads to formation of toxic oxygen radicals, which may be involved in tissue damage. A number of studies have shown that inhibition of the complement system is beneficial in reducing the tissue injury observed in several conditions.
Particular diseases with which complement activation is associated include multiple organ failure, myocardial, intestinal or skeletal liver ischaemia reperfusion, xenograft rejection, thermal injury, extracorporeal circulation, respiratory distress syndrome, rheumatoid arthritis, post streptococcal glomerulonephritis and atherosclerosis.
Complement activation occurs mainly be two pathways, the classical and alternative pathways. The classical pathway is the main antibody-directed mechanism for the activation of complement (IgG- and IgM-complexes) but this pathway may also be activated in an antibody independent process, by polyanions and certain microorganisms as mycoplasma and some viruses. The proteins of the classical and common terminal pathway are assigned a C followed by a number, and reacts in the following order: C1q, C1r, C1s, C4, C2, C3, C5, C6, C7, C8, and C9. The alternative pathway is most effectively activated by many strains of microorganisms, but also by substances like dextran sulphate, different carbohydrates and foreign surfaces. The proteins of the alternative pathway are usually identified by single letters e.g. B, meaning factor B. Both pathways lead to the formation of a convertase that cleaves C3 to C3a and C3b. The two C3-convertases may be turned into a C5-convertase, which is the first step in the common terminal pathway of complement, leading to formation of the membrane attack complex. The complement system is a cascade system where many of the complement proteins are zymogens (pro-enzymes), which require proteolytic cleavage to become active. The cleavage products are distinguished from the parent molecule by suffix letters e.g. C3a and C3b. Activation of complement by either pathways leads to formation of several biologically active compounds that act as anaphylatoxins, opsonins and chemotactic factors. The membrane attack complex may result in the lysis of target cells. Due to its many potentially harmful effects, the complement system is well regulated. The regulatory proteins are identified with abbreviation usually from a “functional name” as DAF (decay accelerating factor). The complement receptors are named either according to their ligand or using the cluster of differentiation (CD) system. In addition there is a numbering system based on the receptors of the major fragments of C3, complement receptor types 1 to 4 (CR1–CR4).
A number of compounds have previously been proposed for their ability to inhibit activation of the complement system. Such compounds include soluble forms of the complement receptors such as sCR1; naturally-occurring complement blockers such as CD59 and synthetic complement blockers.
There clearly remains a need to develop further complement blockers since such agents may have utility in the treatment of or prevention of diseases such as respiratory distress syndrome or the prevention of reperfusion injury following myocardial infarction as discussed above.
USPTO Backgrounds
USPTO Backgrounds