Complement component C5b-9 complex (MAC)

Molecular Classification

Protein complex, Immune system effector, Pore-forming complex, part of the MACPF/CDC superfamily (Membrane Attack Complex/Perforin/Cholesterol Dependent Cytolysin)

Other Names

Membrane Attack Complex, Terminal complement complex, TCC, C5b-9 complex, MAC

Disease Roles

Infection, especially increased susceptibility to Neisseria in cases of MAC component deficiencyInflammatory diseasesNeurological injury (implicated in traumatic brain injury)

Complement component C5b-9 complex Overview

The complement component C5b-9 (Membrane Attack Complex, MAC) is the terminal effector of the complement cascade, composed of C5b, C6, C7, C8, and multiple C9 molecules assembled on target cell membranes[1][6][7]. Upon assembly, the MAC forms a transmembrane pore, leading to osmotic imbalance and lysis of pathogens or 'non-self' cells. While vital for defense against certain bacteria, especially Neisseria, its dysregulation or overactivation is linked to a spectrum of diseases ranging from rare hematological and renal disorders to neuroinflammatory conditions. The complex exists in membrane-bound and soluble forms (sC5b-9), both of which serve as biomarkers for systemic complement activation[4]. Several therapeutic agents target MAC formation by inhibiting upstream components, particularly C5, to control unwanted complement-mediated damage. Tight regulatory mechanisms, such as CD59 on host cells, prevent uncontrolled MAC activity[6][2]. Host risks include increased susceptibility to infections and potential for self-tissue injury if regulation fails.

Mechanism of Action

Inhibition of C5 cleavage or MAC assembly blocks pore formation, preventing cell lysis and downstream inflammatory damage. These drugs act upstream at C5 or block the incorporation of C9.

Biological Functions

Cell lysis (targeting pathogens and damaged cells)

Immune response (innate immunity)

Apoptosis and cell death

Regulation of inflammation (both direct and via C5a release)

Disease Associations

Infection, especially increased susceptibility to Neisseria in cases of MAC component deficiency

Inflammatory diseases

Neurological injury (implicated in traumatic brain injury)

Cancer (MAC formation and sublytic activities)

Paroxysmal nocturnal haemoglobinuria

Atypical hemolytic uremic syndrome

Safety Considerations

Increased risk of infections, especially by Neisseria species, due to impaired terminal complement activity
Potential impact on normal immune surveillance
Host tissue damage if MAC formation is insufficiently controlled

Interacting Drugs

Eculizumab (targets C5 to inhibit MAC formation)

Ravulizumab (targets C5)

Other anti-complement drugs in development

Associated Biomarkers

Biomarker
sC5b-9 (soluble C5b-9) is measured in plasma/serum as a marker of complement activation
C5 functional assays
measurement of other complement activation fragments