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Bivalent Llama Single-Domain Antibody Fragments against Tumor Necrosis Factor Have Picomolar Potencies due to Intramolecular Interactions

descriptionPublicationkeyboard_double_arrow_right Article , Other literature type 31 Jul 2017Publisher:Frontiers Media SAJournal:Frontiers in Immunology, volume 8 (eissn: 1664-3224, Copyright policy )
Authors: Els Beirnaert; Aline Desmyter; Aline Desmyter; Silvia Spinelli; Silvia Spinelli; Marc Lauwereys; Lucien Aarden; +8 Authors

doi: 10.3389/fimmu.2017.00867

pmid: 28824615

pmc: PMC5534440

Bivalent Llama Single-Domain Antibody Fragments against Tumor Necrosis Factor Have Picomolar Potencies due to Intramolecular Interactions

Abstract

The activity of tumor necrosis factor (TNF), a cytokine involved in inflammatory pathologies, can be inhibited by antibodies or trap molecules. Herein, llama-derived variable heavy-chain domains of heavy-chain antibody (VHH, also called Nanobodies™) were generated for the engineering of bivalent constructs, which antagonize the binding of TNF to its receptors with picomolar potencies. Three monomeric VHHs (VHH#1, VHH#2, and VHH#3) were characterized in detail and found to bind TNF with sub-nanomolar affinities. The crystal structures of the TNF-VHH complexes demonstrate that VHH#1 and VHH#2 share the same epitope, at the center of the interaction area of TNF with its TNFRs, while VHH#3 binds to a different, but partially overlapping epitope. These structures rationalize our results obtained with bivalent constructs in which two VHHs were coupled via linkers of different lengths. Contrary to conventional antibodies, these bivalent Nanobody™ constructs can bind to a single trimeric TNF, thus binding with avidity and blocking two of the three receptor binding sites in the cytokine. The different mode of binding to antigen and the engineering into bivalent constructs supports the design of highly potent VHH-based therapeutic entities.

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Keywords

crystal structure, [SDV.BIO]Life Sciences [q-bio]/Biotechnology, Tumor necrosis factor, [SDV.BBM.BS] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, tumor necrosis factor, Molecular Biology/Biochemistry [q-bio.BM], Immunology, Intramolecular binding, VHH, Vhh, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, cytokine, structural biology, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity, X-ray crystallography, intramolecular binding, [SDV.MHEP.ME] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Molecular Biology/Structural Biology [q-bio.BM], [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, RC581-607, 540, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, [SDV.BIO] Life Sciences [q-bio]/Biotechnology, CYTOKINE, nanobody, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, inflammation, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Nanobody, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immunologic diseases. Allergy, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Tumor Necrosis Factor (TNF)

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selected citations
These citations are derived from selected sources.
This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Citations provided by BIP!
popularity
This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.
BIP!Popularity provided by BIP!
influence
This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).
BIP!Influence provided by BIP!
impulse
This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.
BIP!Impulse provided by BIP!
82
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