Complement System

Three routes start the cascade: the classical pathway from C1q binding antibody complexes or C-reactive protein, the lectin pathway from mannose-binding lectin recognising carbohydrate patterns, and the alternative pathway from continuous low-level hydrolysis of C3 that samples every surface it meets. All three build a C3 convertase, splitting C3 into the opsonin C3b and the anaphylatoxin C3a, then a C5 convertase yielding the chemoattractant C5a and C5b, seed of the C5b-9 membrane attack complex. Host cells survive that constant sampling only because regulators such as factor H, CD55 and CD59 shut the cascade down on self surfaces.

Losing that protection is the disease. In paroxysmal nocturnal haemoglobinuria, red cells lack the GPI anchor holding CD55 and CD59 in place and are lysed by their own complement. Eculizumab, an anti-C5 antibody approved in 2007, and ravulizumab block the terminal pathway; pegcetacoplan, a PEGylated cyclic peptide derived from compstatin that binds C3 itself, was approved for the same condition in 2021 and, as an intravitreal formulation, for geographic atrophy in 2023.

A short disulfide-cyclised sequence carrying a PEG chain is a marketed complement drug, showing the whole engineering stack in one molecule: cyclisation for protease resistance, PEGylation for half-life. It also frames a real design choice, since intercepting at C3 removes opsonisation as well as lysis while stopping at C5 preserves upstream function.

Blocking the terminal pathway removes the specific mechanism that clears Neisseria, which is why approved C5 inhibitors carry a boxed warning for meningococcal disease and a risk management programme requiring vaccination first. Laboratory interpretation trips people the other way: C3, C4 and CH50 are consumption measurements, and normal systemic values are compatible with vigorous local activation in tissue.