Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors

Autor: David Hargeaves, Elizabeth England, Robert M. Woods, Michael Fung, Caroline Colley, Paul Warrener, Liz Flavell, Sudharsan Sridharan, Judit E. Debreczeni, Jessica Bonnell, Claire Dobson, Jingying Zha, Bryan M. Edwards, Ling-Ling An, Laura Eghobamien, Ulf Sivars, Joanne Arnold, Jonathan Renshaw, Bojana Popovic, Kate F. Wickson, Tristan J. Vaughan, Trevor Wilkinson
Jazyk: angličtina
Rok vydání: 2017
Předmět:
0301 basic medicine
antibody co–crystal structure
complement C5a receptor
medicine.drug_class
Protein Conformation
Immunology
Antibody Affinity
chemical and pharmacologic phenomena
Complement C5a
Immune receptor
Monoclonal antibody
Protein Engineering
Epitope
03 medical and health sciences
Epitopes
Structure-Activity Relationship
0302 clinical medicine
Antibody Specificity
Report
C5a neutralization
medicine
Immunology and Allergy
Humans
Anaphylatoxin
Receptor
Receptor
Anaphylatoxin C5a
C5a epitope
Linear epitope
biology
C5a crystal structure
Chemistry
Antibodies
Monoclonal
hemic and immune systems
respiratory system
Molecular biology
Cell biology
C5aR2
030104 developmental biology
Epitope mapping
C5aR1
HEK293 Cells
030220 oncology & carcinogenesis
biology.protein
Receptors
Chemokine
human monoclonal antibody
Binding Sites
Antibody
Antibody
Epitope Mapping
Protein Binding
Zdroj: mAbs
'mAbs ', vol: 10, pages: 104-117 (2018)
ISSN: 1942-0870
1942-0862
Popis: C5a is a potent anaphylatoxin that modulates inflammation through the C5aR1 and C5aR2 receptors. The molecular interactions between C5a–C5aR1 receptor are well defined, whereas C5a–C5aR2 receptor interactions are poorly understood. Here, we describe the generation of a human antibody, MEDI7814, that neutralizes C5a and C5adesArg binding to the C5aR1 and C5aR2 receptors, without affecting complement–mediated bacterial cell killing. Unlike other anti–C5a mAbs described, this antibody has been shown to inhibit the effects of C5a by blocking C5a binding to both C5aR1 and C5aR2 receptors. The crystal structure of the antibody in complex with human C5a reveals a discontinuous epitope of 22 amino acids. This is the first time the epitope for an antibody that blocks C5aR1 and C5aR2 receptors has been described, and this work provides a basis for molecular studies aimed at further understanding the C5a–C5aR2 receptor interaction. MEDI7814 has therapeutic potential for the treatment of acute inflammatory conditions in which both C5a receptors may mediate inflammation, such as sepsis or renal ischemia–reperfusion injury.
Databáze: OpenAIRE
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