How do the four human IgG subclasses differ, and why does the choice matter?

Why

The subclasses are more than 90 percent identical in amino acid sequence, yet behave very differently, because the differences sit in the hinge and the upper Fc where receptors and complement bind. Vidarsson and colleagues tabulate the contrasts. IgG1 is the most abundant in serum, IgG3 has a long hinge with many inter-chain disulfide bonds and is the strongest complement activator, and IgG2 and IgG4 bind Fc gamma receptors and C1q weakly.

IgG1, IgG2 and IgG4 have a half-life of about 21 days, while most IgG3 allotypes are closer to 7 days. For a therapeutic, the subclass is therefore a design decision. A molecule meant to kill a target cell usually uses IgG1.

A molecule meant only to block a ligand often uses IgG4 or IgG2 to avoid killing the cells it binds. IgG4 brings its own quirk. Its hinge allows Fab-arm exchange with other IgG4 molecules in the body, which creates bispecific, functionally monovalent antibodies, and the S228P substitution is used to stabilize the hinge and prevent it.