See also Applications of Cregs: 

Complement Receptor 1 (CR1; CD35; C3b/C4b receptor): is present on erythrocytes, monocytes/macrophages, granulocytes, B cells, some T cells, splenic follicular dendritic cells and glomerular pdocytes. CR1 specifically binds C3b, C4b, and ic3B. A soluble form of the receptor has been found in plasma that has ligand binding activity and the same MW as membrane-associated CR1. CR1 binds C3b and C4b that have covalently attached to immune complexes and other complement activators, and the consequences of these interactions depend upon the cell type bearing the receptor. CR1 can also inhibit the classical and alternative pathway C3/C5 convertases and act as a cofactor for the cleavage of C3b and C4b by factor I, indicating that CR1 also has complement regualtory functions in addition to serving as a receptor (Fearon, 5,472,939).  CR1 possesses decay-accelerating activity for both C3 and C5 convertases in both the classical and alternative pathways, as well as factor I cofactor activity for the degradation of both C3b and C4b.

Factor H: is a glycoprotein that circulates in high concentrations and is a potent inhibitor of the AP pathway. Factor H competes with factor B for binding to C3b. Binding of C3b to Factor H also leads to degradation of C3b by factor I to the inactive form C3bi (also designated iC3b), thus exerting a further check on complement activation. Several regions within the factor H protein bind to anionic surfaces such as membranes rich in heparin sulfate or sialic acid, as well as to C3b on the surface.

The ability of factor H to discriminate between host cells and invasive pathogens has been attributed to binding of factor H to negatively charged molecules such as sialic acid and glycosaminoglycans that are displayed on the surface of host cells (S. Meri et al., Proc. Nat’l Acad. Sci. USA (1990) 87: 3982-3986. Distinct tissues express different combinations of the membrane boudn complement inhibitors and factor H likely has different affinities for various cell types.

–Structure: FH is a single polypeptide chain plasma glycoprotein composed of 20 repetitive SCR domains of about 60 amino acids arranged in a continous fasion like a string of 20 beads. FH has at least 3 distinct binding domains for C3b, which are located within SCR 1-4, SCR5-8, and SCR 19-20. Each site of factor H binds to a distinct region within the C3b protein. The N-terminal sites bind to native C3b; the second site, located in the middle region of FH, binds to the C3c fragment and the site located within SCR19 and 20 binds to the C3d region. In addition, FH contains binding sties for heparin, which are located within SCR7, SCR5-12 and SCR20 and overalp with that of the C3b binding site. Structural and functional analyses have shown that the doamins for the complement inhibitory activity of FH are located within the first 4 N-temrinal SCR domains (Gilkeson, WO/2007/14/9567). 

Knoell (EP1336618) discloses that complement regulation is generally considered to be species specific and that rat FH is not interchangeable with human FH. This fact supports the unpredictability of taking sequences sharing sequence homology and expecting those sequences to have similar complement regulatory activity in different species. 

Thurman (US 13/120125, now US 8937046) disclose that factor H binds to annexin A2 in post ischemic kidneys and that mice that do not express annexin A2 develop more severe injury after renal I/R. 

Membrane Cofactor Protein (MCP; CD46): Mature human CD46 protein is composed of 392 amino acids and is found in leukocytes, platelets, epithelial cells, sperm cells and fibroblasts. Numerous transcript variants encoding different isoforms have been identified. MCP has four SCR sequences and serine/threonine enriched region in which heavy O-linked glycosylation occurs. MCP has a transmembrane and cytoplasmic domain. MCP works by binding to the C3b and C4b present on the cell surface thereby targeting the protien for degradation by factor I, a plasma protease, and thereby destroying any C3 or C4 convertase activity. Thus, MCP is said to have “cofactor activity”. Because MCP is localized on the cell surface, it protects only the cells on which it is present and therefore is said to act in an intrinsic manner. Portions of the mature MCP sequence can be deleted and yet the protein retains complement inhibiting activity. Examples of portions that can be deleted include the cytoplasmic tail and the transmembrane domain.  (WO 96/34965).  

Decay Accelerating Factor (DAF; CD55): DAF controls the early part of the complement system by regulating the activity of the C3 and C5 convertases. DAF is composed of 4 SCRs plus a serine/threonine-enriched domain that is capable of extensive O-linked glycosylation. DAF is attached to cell membranes by a glycosyl phosphatidyl inositol and through its ability to bind C4b and C3b, it acts by dissociating the C3 and C5 convertases in both the classical and alternative pathways. The human CD55 protein is uniformly GPI-anchored which is referred to as DAF-GPI or GPI-DAF or CD55a. Mice possess two closely related genes, termed decay-accelerating factor 1 (DAF1) and decay-accelerating factor 2 (DAF2), also referred to as CD55b. These genes share 93% identity in their coding regions.

As with MCP, DAF regulates complement in an intrinsic manner, thus protecting only the cells on which DAF is located. Portion of DAF such as the GPI-anchor domain can be deleted and yet the protein retain complement inhibiting activity (WO 96/34965).

CD59: is a membrane inhibitor of complement that inhibits MAC formation by binding C8 and/or C9, and inhibiting C9 polymerisation during MAC formation. CD59 appears to function by competing with C9 for binding to C8 in the C5b-8 complex, thereby decreasing the formation of the C5b-9 membrane attack complex. Like DAF, CD59 is anchored in the cell membrane by a glycosylphosphatidylinositol (GPI) anchor, which is attached to an asparagine at amino aicd 102.

CD59 is a 18-20 kDa glycosyl phosphatidylinositol (GPI)-anchored membrane glycoprotein. The CD59 antigen has been well characterized by amino acid analysis and NMR. It consists of 128 amino acids, of which the first 25 comprise a signal siequence. Tehre are 10 cysteine resiudes, which result in a tightly folded molecule. The asparagine resiude at position 18 is known to be N-glycosylated, while the asparagine resiude at position 77 is linked to the GPI anchor. The C-terminuys residues are characteristic of GPi anchored proteins Young, (US 2006/0140963). 

Analysis of the physical association of CD59 with components of MAC suggested that separate bidning sites for CD59 are contained within the alpha chain of human C8 and C9. The complement inhibitory activity of CD59 is species selective and is most effective towards C9 direvied from human or other primate plasma. (Sims (US2003/0166565). 

Vitronectin (complement S-protein): is a multifunctional gyocoprotein that inhibits complement mediated cytolysis at two identified stages of terminal complement complex formation: blocking of C5b-7 membrane binding and prevention of C9 polymerization (Sheehan, Clin Exp Immunol. 1995, 101(1) 136-41). Vitronectin occupies the metastable membrane binding site of the nascent precursor complex C5b-7, so that the newly formed SC5b-7 is unable to insert into cell membranes. Vitronectin has also been shown to inhibit C9 binding to the terminal complement complex thereby directly affecting lytic pore formation.