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.