The nature of the IgG isotype
Different capabilities for the recruitment and activation of the different immune effector functions are naturally found in the Fc regions of the human IgG subclasses. Thus, to achieve a desired MOA, the different IgG subclasses are important starting points for the selection and engineering of the optimal mAb Fc. IgG1 is, in many ways, a proinflammatory or “effector‐active” subclass, as it can initiate the complement cascade and is a “universal” FcγR ligand.74 Notwithstanding it is also a ligand for the inhibitory FcγRIIb, IgG1 elicits proinflammatory responses through all activating‐type FcγRs, including ADCC, ADCP and cytokine release.
Because of their more restricted FcγR‐binding profile, IgG2 and IgG4 have offered some choice in potentially avoiding FcR effector function without the need for Fc engineering. They have been used as the backbone for therapeutic mAbs either because recruitment of patients’ effector functions was unlikely to be necessary for the primary MOA of the mAb or is possibly detrimental to the desired therapeutic effect.75 However, the use of these unmodified “inert” subclasses is not without consequences and underscores the need for Fc engineering to modify FcγR interactions—See the “Attenuating and ablating FcγR related functions of IgG” section.
Thus, the choice of IgG subclass for therapeutic mAb engineering is an important first step for engineering of novel mAbs of improved specificity, potency and safety.