Novel complement inhibitors.
The complement system provides natural immunity against microbes and is an effector arm of antibody-mediated humoral immunity. It promotes the inflammatory process by activating cells and facilitates microbial destruction through opsonisation and lysis. Given this tissue damaging potential, it is not surprising that nearly half of the proteins of the complement system are regulators. The complement system can mediate undesirable cellular damage in autoantibody-mediated conditions, for example myasthenia gravis, immune-complex excess syndromes, such as systemic lupus erythaematosus, ischaemia-reperfusion states, hyperacute rejection of transplants, organ failure conditions (e.g., adult respiratory distress syndrome [ARDS]), Alzheimer's disease (AD) and related neurodegenerative disorders. A complement inhibitor has been lacking in the therapeutic arsenal. However, there are now several such agents being assessed in clinical trials and others under development. Current approaches include soluble versions of membrane regulatory proteins, humanised antibodies to components, small molecule inhibitors at various stages of the pathway and transgenic animals expressing human complement regulators for xenotransplantation. These and other strategies should lead to an effective means with which to inhibit complement activation in clinical medicine.
Department of Medicine, Washington University School of Medicine, 660 South Euclid, Box 8045, St Louis, MO 63110, USA.
M K
MK
Liszewski
J P
JP
Atkinson