Improving activating-to-inhibitory (A/I) ratio
One of the common approaches to improve the IgG Fc-effector functions is
to optimise A/I ratio by increasing the affinity for the activating
FcγRs on one hand and decreasing the binding to the inhibitory FcγRIIb
on the other. Improved A/I ratio was successfully achieved by
glycoengineering. The most relevant modification is afucosylation of
N297 glycan which significantly increased the affinity for FcγRIIIa
improving the ADCC effect in vitro 17, which was
mirrored by improved in vivo anti-tumour responses in mouse
models18. Two afucosylated mAbs already received
marketing approval (mogamulizumab19,
obinutuzumab20) and several others are currently in
clinical trials21. Another commonly used strategy to
improve A/I ratio is the introduction of point mutations in the Fc
tail16. The most promising mAb in this group is
margetuximab, an anti-HER2 antibody featuring five point-mutations in
its Fc tail resulting in improved binding to FcγRIIIa and FcγRIIa, as
well as a decreased FcγRIIb binding22. This translated
into improved ADCC in vitro 22, enhanced
anti-tumour activity in vivo 22 and higher
response rate and progression-free survival in HER2-positive metastatic
breast cancer when compared to its non-Fc-engineered analogue
trastuzumab23. Therefore, glyco- and Fc- engineered
IgG1 mAbs with optimised A/I ratio are superior to non-engineered IgG1,
most likely due to enhanced ADCC.