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

Köppen J, Kleinschmidt M, Morawski M, Rahfeld JU, Wermann M, Cynis H, Hegenbart U, Daniel C, Roβner S, Schilling S, Schulze A (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Amyloid-Journal of Protein Folding Disorders Informa Healthcare

DOI: 10.1080/13506129.2024.2358121

Abstract

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.

Authors with CRIS profile

Christoph Daniel Department of Nephropathology

Involved external institutions

Fraunhofer-Institut für Zelltherapie und Immunologie (IZI) DE Germany (DE) Universitätsklinikum Leipzig DE Germany (DE) Universitätsklinikum Heidelberg DE Germany (DE)

How to cite

APA:

Köppen, J., Kleinschmidt, M., Morawski, M., Rahfeld, J.U., Wermann, M., Cynis, H.,... Schulze, A. (2024). Identification of isoaspartate-modified transthyretin as potential target for selective immunotherapy of transthyretin amyloidosis. Amyloid-Journal of Protein Folding Disorders. https://doi.org/10.1080/13506129.2024.2358121

MLA:

Köppen, Janett, et al. "Identification of isoaspartate-modified transthyretin as potential target for selective immunotherapy of transthyretin amyloidosis." Amyloid-Journal of Protein Folding Disorders (2024).

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