An in silico method to assess antibody fragment polyreactivity

Edward P. Harvey, Jung-Eun Shin, Meredith A. Skiba, Genevieve R. Nemeth, Joseph D. Hurley, Alon Wellner, Ada Y. Shaw, Victor G. Miranda, Joseph K. Min, Chang C. Liu, Debora S. Marks () and Andrew C. Kruse ()
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Edward P. Harvey: Harvard Medical School
Jung-Eun Shin: Harvard Medical School
Meredith A. Skiba: Harvard Medical School
Genevieve R. Nemeth: Harvard Medical School
Joseph D. Hurley: Harvard Medical School
Alon Wellner: University of California
Ada Y. Shaw: Harvard Medical School
Victor G. Miranda: Harvard Medical School
Joseph K. Min: Harvard Medical School
Chang C. Liu: University of California
Debora S. Marks: Harvard Medical School
Andrew C. Kruse: Harvard Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-15

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. Here, we design 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 test our models’ performance on three independent nanobody scaffolds, where over 90% of predicted substitutions successfully reduced polyreactivity. Importantly, the models allow us to diminish the polyreactivity of an angiotensin II type I receptor antagonist nanobody, without compromising its functional properties. We provide a companion web-server that offers a straightforward means of predicting polyreactivity and polyreactivity-reducing mutations for any given nanobody sequence.

Date: 2022
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DOI: 10.1038/s41467-022-35276-4

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