Fig 4. Optimal Ig isotypes for therapeutic mAbs
  1. Tumour antigen-targeting antibodies are mostly of IgG1 isotype which can be further improved by optimising their A/I ratio and complement activation through Fc- and glyco-engineering. Recently, interest in IgE, IgA and cross-isotype chimeras is rising as they can offer alternative immune responses against tumor cells and the chimeras combine the advantages of two different isotypes.
  2. For checkpoint inhibitors, a functional Fc tail may be either beneficial (anti-CTLA-4) or detrimental (anti-PD-1). If Fc-effector function is needed, isotype selection is similar to depleting antibodies (a). If Fc-mediated effects are unwanted, optimal isotypes are IgG4 (low A/I ratio) or IgG1 with abrogated FcR and C1q binding, for instance via LALA-PG mutation75.
  3. Agonistic antibodies target different receptors of the TNFR family, which require receptor clustering for initiation of their signaling cascade. Different strategies for achieving receptor clustering are available. In addition, Fc-mediated cell depletion plays an important role in some cases. Prior to selecting the optimal isotype, the need for a functional Fc tail should be considered.