Using synthetic activity to design ultra-potent antibody cocktails

摘要: Drugs which independently inhibit a shared target or pathway can have synthetic activities that result in multiplicative instead of merely additive potencies. This characteristic of drug combinations can be quantified by expressing the potency of the combination as if it were a single agent. We show that by optimizing this quantity we can prospectively design drug cocktails with apparent potencies that far exceed any of its individual components. We illustrate the power of this approach, which is based on statistical design of experiments to select optimal drug combinations, and response surface methodology to determine optimal drug ratios, by building a drug cocktail comprised of three antibodies for treating C. difficile infection that is almost 1000-fold more potent than the current, clinically approved antibody monotherapy. High synthetic activities do not require unusual drug interactions, and therefore may be achievable much more readily than generally appreciated.