The rapidly evolving nature of antibody drug development has resulted in the generation of large numbers (hundreds to thousands) of lead antibody candidates during early discovery. These candidates must be rapidly pared down to identify the most drug-like candidates for in-depth analysis of their safety and efficacy, which can only be performed on a limited number of antibodies due to time and resource requirements. One key biophysical property of successful antibody therapeutics is high specificity, as defined by low levels of non-specific binding (polyspecificity) because non-specific binding is correlated with rapid antibody clearance rates and suboptimal pharmacokinetic profiles. Therefore, we have sought to develop high-throughput methods for rapidly evaluating antibody polyspecificity using minimal amounts of purified protein and widely accessible experimental methods. Our flow cytometry approach – which is amenable to multiple polyspecificity reagents – is well correlated with other methods for evaluating antibody specificity as well as with assays used for identifying antibodies with abnormal clearance rates <i>in vivo</i>. In addition, our approach can be applied to various emerging antibody formats such as multispecifics and multi-domain antibodies. We expect that these results will improve the rapid evaluation of key antibody biophysical properties linked to their developability and thereby improve the drug development process.

High-throughput evaluation of antibody polyspecificity using flow cytometry

ACS Fall 2021

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