Identification of isoaspartate-modified transthyretin as potential target for selective immunotherapy of transthyretin amyloidosis.

Autor:	Köppen J; Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Halle (Saale), Germany., Kleinschmidt M; Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Halle (Saale), Germany., Morawski M; Paul Flechsig Institute - Center of Neuropathology and Brain Research, Leipzig, Germany., Rahfeld JU; Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Halle (Saale), Germany., Wermann M; Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Halle (Saale), Germany., Cynis H; Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Halle (Saale), Germany.; Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany., Hegenbart U; Department of Hematology, Oncology and Rheumatology, Amyloidosis Center, University Hospital, Heidelberg, Germany., Daniel C; Department of Nephropathology, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany., Roßner S; Paul Flechsig Institute - Center of Neuropathology and Brain Research, Leipzig, Germany., Schilling S; Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Halle (Saale), Germany.; Faculty of Applied Biosciences and Bioprocess Technology, Anhalt University of Applied Sciences, Köthen, Germany., Schulze A; Department of Drug Design and Target Validation, Fraunhofer Institute for Cell Therapy and Immunology, Halle (Saale), Germany.; Faculty of Applied Biosciences and Bioprocess Technology, Anhalt University of Applied Sciences, Köthen, Germany.
Jazyk:	angličtina
Zdroj:	Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis [Amyloid] 2024 Sep; Vol. 31 (3), pp. 184-194. Date of Electronic Publication: 2024 May 27.
DOI:	10.1080/13506129.2024.2358121
Abstrakt:	Background: Numerous studies suggest a progressive accumulation of post-translationally modified peptides within amyloid fibrils, including isoaspartate (isoD) modifications. Here, we generated and characterised novel monoclonal antibodies targeting isoD-modified transthyretin (TTR). The antibodies were used to investigate the presence of isoD-modified TTR in deposits from transthyretin amyloidosis patients and to mediate antibody-dependent phagocytosis of TTR fibrils. Methods: Monoclonal antibodies were generated by immunisation of mice using an isoD-modified peptide and subsequent hybridoma generation. The antibodies were characterised in terms of affinity and specificity to isoD-modified TTR using surface plasmon resonance, transmission electron microscopy and immunohistochemical staining of human cardiac tissue. The potential to elicit antibody-dependent phagocytosis of TTR fibrils was assessed using THP-1 cells. Results: We developed two mouse monoclonal antibodies, 2F2 and 4D4, with high nanomolar affinity for isoD-modified TTR and strong selectivity over the unmodified epitope. Both antibodies show presence of isoD-modified TTR in human cardiac tissue, but not in freshly purified recombinant TTR, suggesting isoD modification only present in aged fibrillar deposits. Likewise, the antibodies only facilitated phagocytosis of TTR fibrils and not TTR monomers by THP-1 cells. Conclusions: These antibodies label aged, non-native TTR deposits, leaving native TTR unattended and thereby potentially enabling new therapeutic approaches.
Databáze:	MEDLINE
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