MABS 2021 | VOL. 13 | NO. 1 | 1 DEC 2021

Andre Azevedo Reis Teixeira, Michael Frank Erasmus, Sara D’Angelo, Leslie Naranjo, Fortunato Ferrara, Camila Leal-Lopes, Oliver Durrant, Cecile Galmiche, Aleardo Morelli, Anthony Scott-Tucker & Andrew Raymon Morton Bradbury


Therapeutic antibodies must have “drug-like” properties. These include high affinity and specificity for the intended target, biological activity, and additional characteristics now known as “developability properties”: long-term stability and resistance to aggregation when in solution, thermodynamic stability to prevent unfolding, high expression yields to facilitate manufacturing, low self-interaction, among others. Sequence-based liabilities may affect one or more of these characteristics. Improving the stability and developability of a lead antibody is typically achieved by modifying its sequence, a time-consuming process that often results in reduced affinity. Here we present a new antibody library format that yields high-affinity binders with drug-like developability properties directly from initial selections, reducing the need for further engineering or affinity maturation. The innovative semi-synthetic design involves grafting natural complementarity-determining regions (CDRs) from human antibodies into scaffolds based on well-behaved clinical antibodies. HCDR3s were amplified directly from B cells, while the remaining CDRs, from which all sequence liabilities had been purged, were replicated from a large next-generation sequencing dataset. By combining two in vitro display techniques, phage and yeast display, we were able to routinely recover a large number of unique, highly developable antibodies against clinically relevant targets with affinities in the subnanomolar to low nanomolar range. We anticipate that the designs and approaches presented here will accelerate the drug development process by reducing the failure rate of leads due to poor antibody affinities and developability.


Monoclonal antibodies are becoming progressively more important as therapeutics, comprising six of the top 10 bestselling drugs in the United States. As is the case with rules applying to many small-molecule drugs (e.g., Lipinski’s rule of five), it has been proposed that therapeutic antibodies should similarly adhere to strict criteria regarding pharmacodynamics, kinetics and formulation. Once antibodies are produced against a given target, ensuring they have “druglike” characteristics appears to greatly improve chances of therapeutic success (Suppl. Figure S1). In addition to high affinity, therapeutic success also depends on “developability”, a term coined to describe a favorable set of in vitro biophysical characteristics such as reduced aggregation propensity and polyreactivity, which tend to be associated with improved in vivo properties.

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