Fig 4. Optimal Ig isotypes for therapeutic mAbs
- 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.
- 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.
- 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.