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An in silico method to assess antibody fragment polyreactivity.

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.

SUBMITTER: Harvey EP

PROVIDER: S-EPMC9729196 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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An in silico method to assess antibody fragment polyreactivity.

Harvey Edward P EP Shin Jung-Eun JE Skiba Meredith A MA Nemeth Genevieve R GR Hurley Joseph D JD Wellner Alon A Shaw Ada Y AY Miranda Victor G VG Min Joseph K JK Liu Chang C CC Marks Debora S DS Kruse Andrew C AC

Nature communications 20221207 1

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 acc ...[more]

PMID: 36477674

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An in silico method to assess antibody fragment polyreactivity.

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An in silico method to assess antibody fragment polyreactivity.

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