Here, we have described a selection of cancer types related to complement regulators, based on the extent to which they have been studied in humans. diseases often result in red blood cell destruction or occur in the eye, kidney or brain, which are tissues known for aberrant complement activity or regulation. In addition, complement regulators have also been associated with different types of cancer, although their mechanisms here have not been elucidated yet. In most of these pathologies, treatments are limited and do not prevent the complement system from attacking host cells, but rather fight the consequences of the complement-mediated damage, using for example blood transfusions in anemic patients. Currently only few drugs targeting the complement system are used in the clinic. With further demand for therapeutics rising linked to the wide range of complement-mediated disease we should broaden our horizon towards treatments that can actually protect the host cells against complement. Here, we will discuss the latest insights on how complement regulators can benefit therapeutics. Such therapeutics are currently being developed extensively, and can be categorized into full-length complement regulators, engineered complement system regulators and antibodies targeting complement regulators. In conclusion, this review provides an overview of the complement regulatory proteins PF-03394197 (oclacitinib) and their links to disease, together with their potential in the development of novel therapeutics. antibody-binding, recognition of specific sugar patterns or spontaneous C3 hydrolysis, all resulting in formation of a C3 convertase. C3 convertases cleave C3, resulting in opsonization of pathogens and formation of C5 convertases. With C5 convertases the terminal pathway is initiated which will result in chemotaxis and formation of the membrane attack complex (MAC) (3). Although all three complement pathways result in the formation of a C3 convertase, their initiation and intermediate actions differ (Physique 1). The CP is mainly initiated by antibody binding to target cells. The C1 complex consists of C1q, C1r and C1s. C1q is the pattern recognition molecule, and upon surface binding of C1q, the protease C1r is usually activated, cleaving and activating C1s. C1s can then cleave C2 and C4, which leads to the formation of C3 convertase C4bC2a (3, 5, 6). The LP is usually activated in a similar way, with ficolin and mannose-binding lectin (MBL) acting as pattern recognition molecules. These molecules recognize microbial carbohydrate structures. Upon recognition, the MBL-associated serine proteases (MASPs), can cleave BMP10 C2 and C4, to form the C4bC2a C3 convertase (5C7). Lastly, the AP is usually activated by C3b coming from the other two pathways. In addition, constant background spontaneous hydrolysis of C3 results in formation of C3(H2O) which also serves as a platform for the AP. C3b or C3(H2O) will bind Factor B (FB), which is usually cleaved by the protease Factor D (FD), leading to the formation of C3bBb, another C3 convertase (5, 8). The AP mechanisms enable it to work as an amplification loop for the CP and LP (9, 10). Open in a separate window Physique 1 The complement system. Three pathways can lead to complement activation: the classical pathway (CP), the lectin pathway (LP) and the alternative pathway (AP). Activation of the CP (left) starts with binding of C1q to target cells, often antibodies. Binding of C1q leads to cleavage of C1r, which in turn cleaves C1s. The proteolytic activity of C1s results in the cleavage of C2 and C4. These components form the C3 convertase of the CP, C4bC2a. Activation of the LP (middle) starts with the binding of MBL or ficolins to carbohydrate structures on target cell surfaces. As a result, the proteases of the LP, MASPs, cleave C2 and C4, also leading to the formation of C4bC2a. The AP pathway (right) is usually activated by spontaneous hydrolysis of PF-03394197 (oclacitinib) C3, which leads to the formation of C3(H2O), or by C3b from the CP or LP. After assembly of C3b, FB binds to C3b or C3(H2O) and is cleaved by protease PF-03394197 (oclacitinib) FD. This results in the formation of the C3 convertases of the AP, C3bBb or C3(H2O)Bb. C3 convertases of the CP/LP and the AP cleave C3 into C3b and C3a. Usage of C3b in the AP causes an amplification loop, which can amplify the CP and LP. In addition,.