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Eur Heart J. 2020 Mar 21;41(12):1260-1270. doi: 10.1093/eurheartj/ehz695.

A novel monoclonal antibody targeting aggregated transthyretin facilitates its removal and functional recovery in an experimental model.

Author information

1
Heart Center, Kaplan Medical Center, Pasternak St., 1, Rehovot 76100, Israel.

Abstract

AIMS:

Cardiac amyloidosis typically manifests as heart failure with preserved left ventricular function due to extracellular plaques comprising aggregated TTR. Despite recent success in halting disease progression with a TTR stabilizer and encouraging preliminary findings with TTR silencers, these agents are not targeting preexisting plaques. Herein, we report the development of a novel monoclonal antibody capable of attenuating experimental cardiac amyloidosis.

METHODS AND RESULTS:

We generated an IgG1 monoclonal antibody against aggregated TTR that immunoprecipitated the protein in the sera of patients with wild-type ATTR (wtATTR) and robustly stained cardiac plaques from patients. The antibody was shown to facilitate aggregated-TTR uptake by various myeloid cells and to protect cardiomyocytes from TTR-inducible toxicity. In a novel in vivo model of wtATTR amyloidosis, the antibody enhanced the disappearance of the pyrophosphate signals attesting for a rapid amyloid deposit removal and degradation and also exhibited improved echocardiographic measures of cardiac performance. Importantly, a capture ELISA developed based on the antibody exhibited higher levels of aggregated TTR in the sera of wtATTR amyloidosis patients as compared to control patients with heart failure suggesting a potential applicability in diagnosis and pharmacodynamic guidance of dosing.

CONCLUSION:

We developed a proprietary antibody targeting aggregated TTR that exhibits beneficial effects in a novel experimental wtATTR model and also possesses a potential diagnostic utility. The antibody could potentially be tested as a disease modifying agent in ATTR amyloidosis.

KEYWORDS:

Amyloidosis; Animal model; Heart failure; Monoclonal antibody; Transthyretin

PMID:
31865366
DOI:
10.1093/eurheartj/ehz695

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