Mapping binding epitopes of monoclonal antibodies targeting major histocompatibility complex class I chain-related A (MICA) with hydrogen/deuterium exchange and electron-transfer dissociation mass spectrometry

Major histocompatibility complex class I chain-related A and B (MICA/B) are cell-surface proteins that act as ligands to natural killer cell receptors, NKG2D, expressed on immune cells. Prevention of proteolytic shedding of MICA/B to retain their integrity on the cell surface has become a therapeuti...

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Published in:Analytical and bioanalytical chemistry 2020-03, Vol.412 (7), p.1693-1700
Main Authors: Huang, Richard Y.-C., Kuhne, Michelle, Deshpande, Shrikant, Rangan, Vangipuram, Srinivasan, Mohan, Wang, Yun, Chen, Guodong
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Analytical Chemistry
Antibodies, Monoclonal - chemistry
Antibodies, Monoclonal - immunology
Antigenic determinants
Binding
Biochemistry
Cancer immunotherapy
Cell surface
Chains
Characterization and Evaluation of Materials
Chemical compounds
Chemistry
Chemistry and Materials Science
Deuterium
Deuterium Exchange Measurement - methods
Drug discovery
Electron Transport
Epitope mapping
Epitope Mapping - methods
Exchanging
Food Science
Health aspects
Histocompatibility Antigens Class I - immunology
Humans
Immune system
Immunoglobulins
Instrument industry
Killer cells
Laboratory Medicine
Major histocompatibility complex
Mapping
Mass spectrometry
Mass Spectrometry - methods
Mass spectroscopy
Monitoring/Environmental Analysis
Monoclonal antibodies
Natural killer cells
Oncology
Pharmaceutical industry
Pharmacology
Proteins
Proteolysis
Receptors
Research Paper
Scientific imaging
Shedding
Spectroscopy
Spectrum analysis
Structural analysis
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Summary:Major histocompatibility complex class I chain-related A and B (MICA/B) are cell-surface proteins that act as ligands to natural killer cell receptors, NKG2D, expressed on immune cells. Prevention of proteolytic shedding of MICA/B to retain their integrity on the cell surface has become a therapeutic strategy in immuno-oncology. Given the unique mechanism of MICA/B shedding, structural characterization of MICA/B and therapeutic agent interaction is important in the drug discovery process. In this study, we describe the practical utility of hydrogen/deuterium exchange mass spectrometry (HDX-MS) in epitope mapping studies of a cohort of four monoclonal antibodies targeting MICA in a rapid manner. HDX-MS followed by electron-transfer dissociation allows high-resolution refinement of binding epitopes. This integrated strategy offers, for the first time, molecular-level understanding of MICA’s conformational dynamics in solution as well as the unique mechanism of actions of these antibodies in targeting MICA. Graphical abstract
ISSN:1618-2642
1618-2650
DOI:10.1007/s00216-020-02409-x