TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity

Antibodies specific for TNFRSF receptors that bind soluble ligands without getting properly activated generally act as strong agonists upon FcγR binding. Systematic analyses revealed that the FcγR dependency of such antibodies to act as potent agonists is largely independent from isotype, FcγR type,...

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Bibliographic Details
Published in:Cell death & disease 2019-03, Vol.10 (3), p.224-224, Article 224
Main Authors: Medler, Juliane, Nelke, Johannes, Weisenberger, Daniela, Steinfatt, Tim, Rothaug, Moritz, Berr, Susanne, Hünig, Thomas, Beilhack, Andreas, Wajant, Harald
Format: Article
Language:English
Subjects:
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Animals
Antibodies
Antigen-Antibody Reactions
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell surface
Epitopes
Epitopes - immunology
HEK293 Cells
HeLa Cells
HT29 Cells
Humans
Immunoglobulin Fc Fragments - immunology
Immunoglobulin Fc Fragments - metabolism
Immunoglobulins
Immunology
Jurkat Cells
Life Sciences
Ligands
Mice
Proteins
Receptors, IgG - immunology
Receptors, Tumor Necrosis Factor - antagonists & inhibitors
Receptors, Tumor Necrosis Factor - immunology
Receptors, Tumor Necrosis Factor - metabolism
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Summary:Antibodies specific for TNFRSF receptors that bind soluble ligands without getting properly activated generally act as strong agonists upon FcγR binding. Systematic analyses revealed that the FcγR dependency of such antibodies to act as potent agonists is largely independent from isotype, FcγR type, and of the epitope recognized. This suggests that the sole cellular attachment, achieved by Fc domain-FcγR interaction, dominantly determines the agonistic activity of antibodies recognizing TNFRSF receptors poorly responsive to soluble ligands. In accordance with this hypothesis, we demonstrated that antibody fusion proteins harboring domains allowing FcγR-independent cell surface anchoring also act as strong agonist provided they have access to their target. This finding defines a general possibility to generate anti-TNFRSF receptor antibodies with FcγR-independent agonism. Moreover, anti-TNFRSF receptor antibody fusion proteins with an anchoring domain promise superior applicability to conventional systemically active agonists when an anchoring target with localized disease associated expression can be addressed.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-019-1456-x