Cited by 124Monoclonal and Polyclonal Antibodies Researchvaccines and immunoinformatics approachesMachine Learning in Bioinformatics

Humanization of antibodies using a machine learning approach on large-scale repertoire data

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Marks, Claire, Hummer, Alissa M, Chin, Mark, Deane, Charlotte M·2021·Bioinformatics

Published version of a preprint

Abstract

MOTIVATION: Monoclonal antibody (mAb) therapeutics are often produced from non-human sources (typically murine), and can therefore generate immunogenic responses in humans. Humanization procedures aim to produce antibody therapeutics that do not elicit an immune response and are safe for human use, without impacting efficacy. Humanization is normally carried out in a largely trial-and-error experimental process. We have built machine learning classifiers that can discriminate between human and non-human antibody variable domain sequences using the large amount of repertoire data now available. RESULTS: Our classifiers consistently outperform the current best-in-class model for distinguishing human from murine sequences, and our output scores exhibit a negative relationship with the experimental immunogenicity of existing antibody therapeutics. We used our classifiers to develop a novel, computational humanization tool, Hu-mAb, that suggests mutations to an input sequence to reduce its immunogenicity. For a set of therapeutic antibodies with known precursor sequences, the mutations suggested by Hu-mAb show substantial overlap with those deduced experimentally. Hu-mAb is therefore an effective replacement for trial-and-error humanization experiments, producing similar results in a fraction of the time. AVAILABILITY AND IMPLEMENTATION: Hu-mAb (humanness scoring and humanization) is freely available to use at opig.stats.ox.ac.uk/webapps/humab. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

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  • The Deane group used nearly 2 billion antibody sequences available in OAS across organisms, labeling all human sequences as positive and others as negative, and trained a random forest classifier model to produce a 'humanness score'.

    “Moreover, the Deane group used nearly 2 billion antibody sequences, available in OAS, across organisms where all human sequences were labeled as positive class, while others were labeled as negative class, and trained a random forest classifier model to produce a 'humanness score'.”
  • The random forest classifier consists of 200 decision trees and each decision tree individually separates the input sequences into classes (human or other species) using their features.

    “The random forest classifier consists of 200 decision trees and each decision tree individually separates the input sequences into classes (human or other species) using their features.”
  • The score was used to construct a humanization tool called Hu-mAb, which suggests mutations to reduce immunogenicity risk.

    “Furthermore, the score was used to construct a humanization tool called Hu-mAb, which suggests mutations to reduce immunogenicity risk [32].”
  • The output score not only distinguishes human V genes from non-human sequences in the variable region but also indicates the level of immunogenicity risks.

    “The output score not only distinguishes human V genes from non-human sequences in the variable region but also indicates the level of immunogenicity risks [32].”

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Authors
Marks, C., Hummer, A. M., Chin, M., & Deane, C. M.
Affiliations
University of Oxford (GB)
Corresponding author
Deane, Charlotte M
Venue
Bioinformatics
Published
2021-06-10
Volume
37
Issue
22
Pages
4041-4047
ISSN
  • 1367-4803 (ISSN-L)
  • 1367-4811
OpenAlex
W3169434891
Cited by
124
References
24
Citations by year
2026: 24 · 2025: 32 · 2024: 31 · 2023: 19 · 2022: 14 · 2021: 4
FWCI
8.94
Type
journal article
Language
en
Open access
Locations
  • Bioinformatics (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Medical Research Council (MR/N013468/1)
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Machine Learning in Bioinformatics
Keywords
antibody humanization, monoclonal antibodies, immunogenicity, murine antibodies, antibody variable domains, machine learning classification, mutation prediction, therapeutic antibodies
MeSH terms
Machine Learning, Animals, Antibodies, Monoclonal, Mice

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