HDX-MS-Guided computational modeling for rapid and accurate antibody-antigen interface mapping.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος:	HDX-MS-Guided computational modeling for rapid and accurate antibody-antigen interface mapping.
Συγγραφείς:	McMahon W; Analytical Sciences, Biopharmaceutical Development, AstraZeneca, Gaithersburg, MD, USA., Zhang H; Biologics Engineering, R&D, AstraZeneca, Gaithersburg, MD, USA., Li X; Biologics Engineering, R&D, AstraZeneca, Gaithersburg, MD, USA., Oganesyan V; Biologics Engineering, R&D, AstraZeneca, Gaithersburg, MD, USA., Payne S; Biologics Engineering, R&D, AstraZeneca, Gaithersburg, MD, USA., Mehzabeen N; Biologics Engineering, R&D, AstraZeneca, Gaithersburg, MD, USA., Dyk NV; Biologics Engineering, R&D, AstraZeneca, Gaithersburg, MD, USA., Liu W; Biologics Engineering, R&D, AstraZeneca, Gaithersburg, MD, USA., Howard W; Analytical Sciences, Biopharmaceutical Development, AstraZeneca, Gaithersburg, MD, USA., Zhao P; Analytical Sciences, Biopharmaceutical Development, AstraZeneca, Gaithersburg, MD, USA., Zhang Y; Analytical Sciences, Biopharmaceutical Development, AstraZeneca, Gaithersburg, MD, USA., Fang M; Analytical Sciences, Biopharmaceutical Development, AstraZeneca, Gaithersburg, MD, USA., Chen X; Analytical Sciences, Biopharmaceutical Development, AstraZeneca, Gaithersburg, MD, USA., Mazor Y; Biologics Engineering, R&D, AstraZeneca, Gaithersburg, MD, USA., Shi Y; Analytical Sciences, Biopharmaceutical Development, AstraZeneca, Gaithersburg, MD, USA.
Πηγή:	MAbs [MAbs] 2026 Dec; Vol. 18 (1), pp. 2722455. Date of Electronic Publication: 2026 Sep 11.
Τύπος έκδοσης:	Journal Article
Γλώσσα:	English
Στοιχεία περιοδικού:	Publisher: Taylor & Francis Country of Publication: United States NLM ID: 101479829 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1942-0870 (Electronic) Linking ISSN: 19420862 NLM ISO Abbreviation: MAbs Subsets: MEDLINE
Imprint Name(s):	Publication: 2015- : Philadelphia, PA : Taylor & Francis Original Publication: Austin, TX : Landes Bioscience
Ιατρικοί όροι (MeSH):	Hydrogen Deuterium Exchange-Mass Spectrometry/methods , Epitope Mapping/methods , Epitopes/chemistry , Epitopes/immunology , Antigen-Antibody Complex/chemistry , Antigen-Antibody Complex/immunology, Immunoglobulin Fab Fragments/chemistry ; Humans ; Models, Molecular ; Crystallography, X-Ray
Περίληψη:	Accurate mapping of paratopes and epitopes at antibody-antigen (Ab-Ag) interfaces is essential for the rational design of therapeutic antibodies in early drug development. Traditional methods for determining high-resolution Ab-Ag complex structures, such as X-ray crystallography and cryo-electron microscopy, are labor-intensive and require substantial time and resources. Although recent computational approaches have increased throughput, prediction accuracy and reliability remain limited, particularly without experimental structural constraints. Here, we present a hydrogen-deuterium exchange mass spectrometry (HDX-MS)-guided structural modeling workflow for efficient and accurate epitope and paratope mapping across three prospective case studies in therapeutic protein discovery and engineering. Across these systems, peptide-level HDX-MS data were sufficient to guide docking and structural modeling, whereas targeted electron transfer dissociation (ETD) HDX-MS was applied in one system as a higher-resolution, orthogonal approach to further localize critical binding residues. The workflow was applied to diverse Ab-Ag architectures spanning Fab and VHH binders and homodimeric and heterodimeric antigen ectodomains, and HDX-MS data were integrated with HADDOCK, AlphaFold2, and Protenix to generate Ab-Ag complex models. Comparison with subsequently obtained in-house X-ray crystal structures, used here as orthogonal high-resolution reference structures, showed strong agreement in overall binding orientation and interface placement. These results demonstrate the robustness and practical utility of this integrative approach for structure-informed antibody engineering in therapeutic protein discovery.
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Contributed Indexing:	Keywords: Antibody-antigen interface mapping; HDX-MS; computational modeling
Substance Nomenclature:	0 (Immunoglobulin Fab Fragments) 0 (Epitopes) 0 (Antigen-Antibody Complex)
Entry Date(s):	Date Created: 20260911 Date Completed: 20260911 Latest Revision: 20260917
Update Code:	20260917
PubMed Central ID:	PMC13577250
DOI:	10.1080/19420862.2026.2722455
PMID:	42725674
Βάση Δεδομένων:	MEDLINE

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ISSN:	1942-0870
DOI:	10.1080/19420862.2026.2722455