Question 7 of 20 Fundamentals Concept
What do the Fab and Fc parts of an IgG antibody each do?
Short answer
The two Fab arms carry the variable domains and bind antigen. The Fc stem binds Fc gamma receptors, complement C1q and the neonatal Fc receptor, so it decides effector functions and circulating half-life.
Why
An IgG is two heavy chains and two light chains. Each Fab arm pairs a light chain with the first two heavy-chain domains, and the six loops at its tip form the binding site. The Fc is the pair of lower heavy-chain domains below the hinge.
Vidarsson and colleagues describe how the Fc region binds Fc gamma receptors on immune cells, which can trigger phagocytosis or antibody-dependent cellular cytotoxicity, and binds C1q to start the classical complement pathway. The same region carries the binding site for the neonatal Fc receptor (FcRn), which is responsible for the long half-life of IgG, for placental transfer and for transport across mucosal surfaces. FcRn binding happens only at acidic pH below about 6.5, as found in endosomes, and the antibody is released again at the neutral pH outside the cell.
This split explains most engineering choices. Change the Fab to change what the molecule recognizes, and change the Fc, its subclass or its glycan to change what happens after binding and how long the molecule lasts.
A strong answer covers
- Fab arms bind antigen through the variable domains
- Fc binds Fc gamma receptors and C1q to drive effector functions
- Fc binds FcRn, which extends half-life and moves IgG across barriers
- FcRn binding is pH dependent and happens in endosomes
- Engineering targets Fab for specificity and Fc for function and half-life
Common mistakes
- Thinking the Fc has no role beyond holding the two arms together
- Assuming any IgG kills target cells regardless of subclass
- Treating half-life as a property of the antigen-binding site
The interviewer might ask next
Why does FcRn binding need to be strong at acidic pH and weak at neutral pH?