A functional role for spontaneously occurring natural anti-transthyretin antibodies from patients with transthyretin cardiac amyloidosis

Introduction

Transthyretin cardiac amyloidosis (ATTR-CA) is a progressive disease that results from the accumulation of transthyretin (TTR) fibrils in the extracellular space of the myocardium, leading to heart failure.¹ The pathogenesis of ATTR-CA results from a reduction in cardiac compliance due to amyloid fibril deposition, but recent observations suggest that soluble TTR intermediate oligomers are toxic to cardiomyocytes and contribute to myocardial functional compromise.²

Recently, proof-of-mechanism and proof-of-concept have been established for the ability of monoclonal antibodies to induce Fc gamma-mediated clearance of extracellular beta-amyloid in patients with Alzheimer's disease.³ This led to the Food and Drug Administration approval of a drug that clears amyloid plaques and attenuates cognitive decline.³ In pre-clinical studies, several monoclonal antibodies have been shown to mediate Fc gamma-dependent clearance of aggregated TTR by macrophages in experimental models.^4-6 Very recently, an initial phase I study demonstrated the safety of this approach and provided initial hints of efficacy in reducing imaging-related pathology via magnetic resonance imaging and scintigraphy.⁷

In a recent preliminary observation, antibodies binding to TTR were described for the first time in two patients with ATTR-CA, and were associated with spontaneous clinical recovery and regression of imaging-related findings.⁸ However, this intriguing finding has not yet established a mechanistic role for these naturally occurring antibodies in facilitating amyloid removal.

We aimed to characterize in detail the spontaneously occurring purified antibodies to TTR oligomers and fibrils and test their related functional activities in vitro and in cellular and experimental models, supporting their potential involvement in the spontaneous regression of ATTR amyloidosis.