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

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.

Wild-type TTR amyloidosis among patients with unexplained heart failure and systolic LV dysfunction

“…Traditionally, extracellular deposition of misfolded aggregated TTR is viewed as a space occupying process that impairs cardiac relaxation. However, we have recently shown, that aggregated TTR has a direct proapoptotic/toxic effect on cardiomyocytes suggesting that long term in-situ exposure could reduce cardiac mass and result in reduced function [ 40 ].…”

The long and winding road to target protein misfolding in cardiovascular diseases

“…147 In TTR amyloidosis, a variety of monoclonal antibodies targeting epitopes exposed on abnormal TTR protein have shown the protective effects to prevent TTR fibrils formation while promoting the clearance of organ amyloid deposits via phagocytosis. [148][149][150] The efficacy and safety of these antibodies in patients with amyloidosis need to be evaluated in the future. In light of these advances, monoclonal antibodies represent an essential step forward in the treatment of patients with cardiac amyloidosis.…”

“…Moreover, monoclonal antibodies targeting B cells (rituximab) 143 or plasma cells (daratumumab) 144 have shown clinical benefits by inducing haematologic and cardiac responses with safety profile in AL patients who received either daratumumab alone or in combination with other monoclonal antibody (birtamimab), 145 immunomodulatory drugs 146 or dexamethesone 147 . In TTR amyloidosis, a variety of monoclonal antibodies targeting epitopes exposed on abnormal TTR protein have shown the protective effects to prevent TTR fibrils formation while promoting the clearance of organ amyloid deposits via phagocytosis 148–150 . The efficacy and safety of these antibodies in patients with amyloidosis need to be evaluated in the future.…”

Transthyretin amyloid cardiomyopathy: An uncharted territory awaiting discovery

“… Patisiran (APOLLO, 2018) [45] SiRNA Multicentre, double-blind, placebo controlled 2:1 randomization 0.3 mg/kg iv vs. placebo once every 3 weeks for 18 months TTRv-related polyneuropathy Subgroup with cardiomyopathy ( n = 126, 56%) Slower LV functional deterioration and promotion of favourable remodelling: decreased LV volumes, wall thickness, RWT, mass and NT-proBNP. FDA: TTRv-related polyneuropathy EMA: Stages I–II TTRv-related polyneuropathy Inotersen (2018) [46] ASO Multicentre, double-blind, placebo controlled 2:1 randomization 300 mg sc vs. placebo for 64 weeks TTRv-related polyneuropathy – Stages I–II Subgroup with cardiomyopathy ( n = 108, 63%) Slower progression in neuropathy, no effect on echocardiographic parameters (including GLS) FDA: TTRv-related polyneuropathy EMA: Stages I–II TTRv-related polyneuropathy PRX004 (NCT03336580) mAb Phase I, single centre, open-label, dose escalation 0.1 mg/kg iv once every 28 days TTRv amyloidosis (estimated n = 36) Aim: determine the safety, tolerability, PK, PD and MTD Prematurely terminated because of COVID 19 pandemic Ab-A (2020) [47] mAb Single centre, open label, murine model 10 mg/kg vs. 5 mg/kg vs. 0.1 mg/kg vs. sham TTRwt amyloidosis Promoting clearance and degradation of aggregated TTR by cardiac macrophages Protecting cardiomyocytes from aggregated TTR- mediated toxicity – Legend : 6MWT, Six Minute Walking Test; AC, Amyloid Cardiomyopathy; ASO, Antisense Oligonucleotide; CV, Cardiovascular; EMA, European Medicine Agency; FDA, Food and Drug Administration; GLS, Global Longitudinal, Strain; KCCQ-OS, Kansas City Cardiomyopathy Questionnaire Overall Summary; LV, Left Ventricular; mAb, Monoclonal Antibody; MTD, Maximum Tolerated Dose; NT-proBNP, N- terminal Brain Natriuretic Peptide; PD, Pharmacodynamics; PK, Pharmacokinetics; RWT, Relative Wall Thickness, siRNA, small interfering RNA; TTR, Transthyretin; TTRv, mutated Transthyretin; TTRwt, wild-type Transthyretin. …”