Complement Inhibitors

sCR1 refers to the naturally occurring soluble form of the C3b-C4b cell surface receptor, CR1 (see earlier discussion). Because CR1 can both bind and act as a cofactor in the degradation of these two cell bound foci of further complement activation, sCR1 is a potent complement inhibitor in solution. sCR1 has now been bioengineered into a drug. It is in Phase 2 trials as an agent that can lessen the amount of heart muscle killed during a heart attack.

CAB2 refers to a recombinant protein that combines the active sites of DAF and MCP (see earlier discussion). As such, it would be expected to have a similar activity to sCR1 and be a potent inhibitor of complement activation at the C3 step. Initial designs for clinical trials are underway, the drug having shown promising activity in rodents. Both sCR1 and CAB2 suffer a potential flaw in that the development of an antibody to the drug(s) in a patient could lead to hemolytic anemia, arising from interference with the parent, critical proteins.

Monoclonal anti-C5 is the furthest in clinical development. In theory, interference at this step would prevent neutrophil chemotaxis to a site of injury, and so prevent any deleterious effects to be caused by neutrophil activation. Furthermore, as will be noted later, C5a is thought to cause much of the lung dysfunction associated with major injury, and an anti-C5 could prevent that. Finally, this agent would prevent endothelial activation from injury by preventing the formation of MACs. In large Phase 2 trials, it may improve the outcomes after cardiac surgery.

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