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PreprintCited by 32Monoclonal and Polyclonal Antibodies Researchvaccines and immunoinformatics approachesProtein Structure and Dynamics

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Biophysical cartography of the native and human-engineered antibody landscapes quantifies the plasticity of antibody developability

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Bashour, Habib, Smorodina, Eva, Pariset, Matteo, Zhong, Jahn, Akbar, Rahmad, Chernigovskaya, Maria, Quý, Khang Lê, Snapkov, Igor, Rawat, Puneet, Krawczyk, Konrad, Sandve, Geir Kjetil, Gutierrez-Marcos, Jose, Gutierrez, Daniel Nakhaee-Zadeh, Andersen, Jan Terje, Greiff, Victor·2023·Communications Biology
DOI 10.1101/2023.10.26.563958PMC PMC11291509

Preprint — published as 10.1038/s42003-024-06561-3 · Paper page

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Abstract

Designing effective monoclonal antibody (mAb) therapeutics faces a multi-parameter optimization challenge known as “developability”, which reflects an antibody’s ability to progress through development stages based on its physicochemical properties. While natural antibodies may provide valuable guidance for mAb selection, we lack a comprehensive understanding of natural developability parameter (DP) plasticity (redundancy, predictability, sensitivity) and how the DP landscapes of human-engineered and natural antibodies relate to one another. These gaps hinder fundamental developability profile cartography. To chart natural and engineered DP landscapes, we computed 40 sequence- and 46 structure-based DPs of over two million native and human-engineered single-chain antibody sequences. We found lower redundancy among structure-based compared to sequence-based DPs. Sequence DP sensitivity to single amino acid substitutions varied by antibody region and DP, and structure DP values varied across the conformational ensemble of antibody structures. Sequence DPs were more predictable than structure-based ones across different machine-learning tasks and embeddings, indicating a constrained sequence-based design space. Human-engineered antibodies were localized within the developability and sequence landscapes of natural antibodies, suggesting that human-engineered antibodies explore mere subspaces of the natural one. Our work quantifies the plasticity of antibody developability, providing a fundamental resource for multi-parameter therapeutic mAb design.

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Metadata

Authors
Bashour, H., Smorodina, E., Pariset, M., Zhong, J., Akbar, R., Chernigovskaya, M., Quý, K. L., Snapkov, I., Rawat, P., Krawczyk, K., Sandve, G. K., Gutierrez-Marcos, J., Gutierrez, D. N.-Z., Andersen, J. T., & Greiff, V.
Affiliations
  • Oslo University Hospital (NO)
  • University of Oslo (NO)
Corresponding author
  • Bashour, Habib
  • Greiff, Victor
ORCID
Venue
Communications Biology
Publisher
openRxiv
Published
2023-10-30
Volume
7
Issue
1
Pages
922-922
ISSN
2399-3642 (ISSN-L)
DOI
10.1101/2023.10.26.563958
PMC
PMC11291509
OpenAlex
W4401165032
Cited by
32
References
1
Citations by year
2026: 12 · 2025: 14 · 2024: 6
FWCI
8.12
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Communications Biology (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Warwick Research Archive Portal (University of Warwick) (acceptedVersion, cc-by-nc-nd)
  • Duo Research Archive (University of Oslo) (acceptedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Leona M. and Harry B. Helmsley Charitable Trust (#2019PG-T1D011)
  • Stiftelsen Kristian Gerhard Jebsen (SKGJ‐MED‐017)
  • Università degli Studi di Siena
  • European Federation of Pharmaceutical Industries and Associations
  • European Commission (101007799, HORIZON2020, 825821)
  • Norges Forskningsråd (331890, 311341, 300 740)
  • Biotechnology and Biological Sciences Research Council (BB/V011065/1)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › 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 › Protein Structure and Dynamics
Keywords
antibody developability, therapeutic monoclonal antibodies, natural antibodies, single-chain antibody
MeSH terms
Antibodies, Monoclonal, Humans, Protein Conformation, Protein Engineering, Single-Chain Antibodies

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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