Antibody engineering for increased potency, breadth and half-life

Sievers, Stuart A.; Scharf, Louise; West, Anthony P.; Bjorkman, Pamela J.

Strategies being used to improve properties such as poor solubility and aggregation profiles that could lead to polyreactivity include switching the IgG isotype, inserting N-linked glycosylation sites, and making targeted mutations to reduce surfaceexposed hydrophobic residues [92] [93] [94] [95] [96] [97] . For example, in the engineering of VRC07-523, variants such as VRC07-G54W not only showed increased breadth and potency, but also polyreactivity and poor pharmacokinetics [54 && ]. Similar characteristics were observed for NIH45-46 G54W [94] . In both cases, a histidine substitution (G54H) reduced polyreactivity [54 && ,94] . Similarly, several mutations intended to eliminate clashes with the gp120 V5 loop resulted in VRC07 variants with increased polyreactivity, but mutations were identified that yielded a variant exhibiting a favorable pharmacokinetic profile [54 && ]. In another study, a structurebased approach guided by cataloguing variations in solubility in clonal relatives of 10E8 was used to improve the solubility of 10E8 nearly 10-fold while maintaining comparable potency, an important step towards making this antibody useful clinically [98] .