The history of monoclonal antibody development – Progress, remaining challenges and future innovations

Liu, Justin K.H.

Targets for improving antibody efficacy include: immunogenicity, antigen-binding affinity, effector functions and pharmacokinetics. Immunogenicity involves minimising non-human sequences by creating chimeric, humanised or human versions of the antibodies with as few T-lymphocyte epitopes as possible [18] . Antibody fragments are usually less immunogenic due to a lack of Fc domain [19] . Antigen-binding affinity can be improved by using phage display libraries to isolate antibodies with strong affinities for the antigen. However, sometimes antibodies with a lower affinity for the antigen may be required to allow better penetration of a tumour [20] . Effector functions can be improved by genetically engineering the Fc region to contain point mutations or glycan modifications. Yamane-Ohnuki and Satoh review and discuss the development of defucosylated antibodies which have increased affinities for the FcgRIIIa receptor and enhanced antibodydependent cell-mediated cytotoxicity (ADCC) [21] . A particularly interesting aspect of antibody efficacy is its unique pharmacokinetic characteristics once inside the body. For example, it has been noted that the bioavailability of IgG in plasma is partially dependent on its interaction with the neonatal Fc/Brambell receptor (FcRn) [22] . The FcRn functions as a salvage receptor that leads to the rescue of IgG internalised in cells from degradation by lysosomes and causes recycling of antibodies into the plasma, thus prolonging its half-life [23] . The plasma half-life of IgG can also be increased by developing antibodies (e.g. through phage display) with increased affinity for FcRn [24] . Antibody fragments treated with polyethylene gycol (PEGylation) have also been shown to have an increased plasma half-life [25] .