Author:
Hutchinson Mark,Ruffolo Jeffrey A.,Haskins Nantaporn,Iannotti Michael,Vozza Giuliana,Pham Tony,Mehzabeen Nurjahan,Shandilya Harini,Rickert Keith,Croasdale-Wood Rebecca,Damschroder Melissa,Fu Ying,Dippel Andrew,Gray Jeffrey J.,Kaplan Gilad
Abstract
AbstractOver the last two decades, therapeutic antibodies have emerged as a rapidly expanding domain within the field biologics. In silico tools that can streamline the process of antibody discovery and optimization are critical to support a pipeline that is growing more numerous and complex every year. In this study, DeepAb, a deep learning model for predicting antibody Fv structure directly from sequence, was used to design 200 potentially stabilized variants of an anti-hen egg lysozyme (HEL) antibody. We sought to determine whether DeepAb can enhance the stability of these antibody variants without relying on or predicting the antibody-antigen interface, and whether this stabilization could increase antibody affinity without impacting their developability profile. The 200 variants were produced through a robust highthroughput method and tested for thermal and colloidal stability (Tonset, Tm, Tagg), affinity (KD) relative to the parental antibody, and for developability parameters (non-specific binding, aggregation propensity, self-association). In the designed clones, 91% and 94% exhibited increased thermal and colloidal stability and affinity, respectively. Of these, 10% showed a significantly increased affinity for HEL (5-to 21-fold increase), with most clones retaining the favorable developability profile of the parental antibody. These data open the possibility ofin silicoantibody stabilization and affinity maturation without the need to predict the antibody-antigen interface, which is notoriously difficult in the absence of crystal structures.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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