An in silico method to assess antibody fragment polyreactivity

Citations Over Time

Abstract

ABSTRACT Antibodies are essential biological research tools and important therapeutic agents, but some exhibit non-specific binding to off-target proteins and other biomolecules. Such polyreactive antibodies compromise screening pipelines, lead to incorrect and irreproducible experimental results, and are generally intractable for clinical development. We designed a set of experiments using a diverse naïve synthetic camelid antibody fragment (‘nanobody’) library to enable machine learning models to accurately assess polyreactivity from protein sequence (AUC > 0.8). Moreover, our models provide quantitative scoring metrics that predict the effect of amino acid substitutions on polyreactivity. We experimentally tested our model’s performance on three independent nanobody scaffolds, where over 90% of predicted substitutions successfully reduced polyreactivity. Importantly, the model allowed us to diminish the polyreactivity of an angiotensin II type I receptor antagonist nanobody, without compromising its pharmacological properties. We provide a companion web-server that offers a straightforward means of predicting polyreactivity and polyreactivity-reducing mutations for any given nanobody sequence.

Related Papers

• → G protein-coupled receptors: In silico drug discovery in 3D(2004)146 cited
• → In silico identification of functional regions in proteins(2005)57 cited
• → In Silico Identification and Characterization of Effector Catalogs(2011)13 cited
• → In Silico Expression Analysis(2016)1 cited
• Two novel alternatively spliced transcripts of Prkar 1b gene of mouse: Identification using a novel approach of In-silico and molecular biology techniques(2011)