See also therapeutic antibodies against specific complement components in the “antibodies” section. 

See also CR2 targetting of complement inhibitors for treatment of disease under “pharmacology”  

See also specific diseases throughout ypatent for the role which complement plays in these diseases. 

The complement system has been implicated in many autoimmune diseases such a rheumatoid arthritis, systemic lupus erythemaosus, renal diseases, myocarditis, multiple sclerosis, Type I diabetes mellitus and asthma. Individuals with inherited deficiency of any of the complement molecules prior to C5 are vulnerable to both pyogenic organisms and to autoimmune disorders. In contrast, deficiency of any of the molecules after C5 remarkably has little phenotype except for an increased risk of infection by encapsulated organisms, namely, Haemophilus influenza, Neisseria meningitides and N gonorrhea.

Inherited deficiencies have been recognized in humans for nearly every complement component. Deficiencies of components of the same pathway cause similar clinical problems. Classical pathway component deficiencies (C1, C4, C2) commonly cause infections by a variety of pyrogenic organisms and immune complex diseases, as does defieincy of C3. Alternative pathway component deficiences (P, D) often results in Neisserial infections. (US 2003/0198636). 

Unpredictability in the Art: 

The activation of the complement system may cause substantial injury when activated inappropriately and that while complement activaiton is probably not the primary etiology of many diseases such as those which affect the cardiovascular, the damage to tissues in certain conditions is clearly complement mediated (p. 59, 1st #s1-2). Key constituents of the formation of the AP is the association of factor B with C3b, and adminsitration of antibodies against components of the AP such as C5 are therapeutic approaches for blocking AP pathways and thus complement actiation. Makrides (“therapeutic inhibition of the complement system” Pharmacological Reviews, 60(1), 1998).

Still, succcessful marketing of complement targeted drugs has proved to be more difficult than initially expected, and many strategies have been discontinued. In light of these complications, most of the major pharmaceutical companies seem to have abandoned their initial efforts to develop drugs that target complement. Despite numerous attempts to inhibit or modulate complement therapeutically, the success rate has been disappointly low. The multifaceted nature of both the cascade and its disease involvement may be one central problem. Many questions about the exact disease related mechanisms of complement, both at the molecular and clinical level are still unresolved, and this lack fo clarity complicates specific targetting. Inhibition of a single pathway may be insuffcient for many diseases. (Ricklin “Complement-targeted therapeutics” Nat Biotechnol. 2007, 25(11); 1265-1276). 

One of skill in the art would recognize that a particular complement inhibitor which may be effective for one type of complement mediated disorder may not be effective in a different complement mediator disorder and that treatment of any one particular disorder will depend upon not only the particular complement inhibitor being administered but also the complement component and organ being targeted. For example, C3a protects neurons against glutamate-induced excitoxicity and induces the production of nerve grwoth factor and anti-inflammatory hormones, while targeted expression in the brain proteins against endotoxic short, indicating that “complemet therapeutics may be highly disease specific in practice (Stahel, Expert Rev. Clin. Immunol. 2(3), p. 451, 2nd column, lines 4-16, (2006).

The development of mice deficient in elements of the complement system are stimulating investigators to study the role of different complement components in systemic injury. Such experiments suggest that not all components of the complement system may enhance injury but some may in fact be beneficial. (Yang, “the role of complement C3 in intracerebral hemorrhage-induced brain injury” J. Cerebral Blood Flow & Metabolism (2006), 26, 1490-1495).

Role in Specific Diseases 

Ischemia/Reperfusion Injury (IRI):  Activation of the complement cascade represents an important event during ischemia/reperfuion injury (IRI). Fondevilla, (Liver Transpl. 2008, 14(8): 1133-1141).

–Hepatic IRI: 

Fondevilla (Liver Transpl. 2008, 14(8): 1133-1141) discloses that terminal products of the complement system are essential in the mechanism of hepatic IRI. Using a clinically relevant liver cold ischemia model, they show that local MAC inhibition attenuates IRI cascade in orthotopic liver transplantation recipients. 

–Intestinal IRI:

Huang (J. Immunology, 2008, 181: 8068-8076) discloses that the alternative pathway of complement plays a role in intestine ischemia/eperfusion injury. 

Pulmonary diseases:

Francois (US14/052545 and US8,580,735) teaches administration of compstatin analogs for treatment of respiratory diseases.

Levin (WO94/17822) discloses pulmonary administration of a complement inhibitory protein by inhalation for the therapeutic treatment of diseases involving complement. Deseases include bronchoconstriction and inhibitors are directed to tComplement receptors.

Wang (WO2004022096) discloses method of treating asthma which a complement inhbitiory such as an antibody.