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A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells.

ABSTRACT: Transthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive analyses of memory B cell repertoires derived from healthy elderly subjects. NI301A binds selectively with high affinity to the disease-associated ATTR aggregates of either wild-type or variant ATTR related to sporadic or hereditary disease, respectively. It does not bind physiological transthyretin. NI301A removes ATTR deposits ex vivo from patient-derived myocardium by macrophages, as well as in vivo from mice grafted with patient-derived ATTR fibrils in a dose- and time-dependent fashion. The biological activity of ATTR removal involves antibody-mediated activation of phagocytic immune cells including macrophages. These data support the evaluation of safety and tolerability of NI301A in an ongoing phase 1 clinical trial in patients with ATTR cardiomyopathy.

SUBMITTER: Michalon A

PROVIDER: S-EPMC8149704 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells.

Michalon Aubin A Hagenbuch Andreas A Huy Christian C Varela Evita E Combaluzier Benoit B Damy Thibaud T Suhr Ole B OB Saraiva Maria J MJ Hock Christoph C Nitsch Roger M RM Jan Grimm

Nature communications 20210525 1

Transthyretin amyloid (ATTR) cardiomyopathy is a debilitating disease leading to heart failure and death. It is characterized by the deposition of extracellular ATTR fibrils in the myocardium. Reducing myocardial ATTR load is a therapeutic goal anticipated to translate into restored cardiac function and improved patient survival. For this purpose, we developed the selective anti-ATTR antibody NI301A, a recombinant human monoclonal immunoglobulin G1. NI301A was cloned following comprehensive anal ...[more]

PMID: 34035264

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Project description:BackgroundTransthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.ObjectivesThe goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.MethodsDemographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189).ResultsU.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival.ConclusionsIn the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745).

Project description:Treatment of cardiac amyloidosis is determined by the amyloid type and degree of involvement. Two types of amyloid commonly infiltrate the heart: immunoglobulin light-chain amyloid (AL), and transthyretin amyloid (ATTR), that encompasses other two forms, a hereditary form (hATTR), and a sporadic, age-related wild-type (wtATTR). The prevalence is expected to increase with aging population. The natural history of ATTR cardiomyopathy includes progressive heart failure (HF), complicated by arrhythmias and conduction system disease. New therapies options have been approved or are under investigation. We performed a narrative literature review, manually-searched the reference lists of included articles and relevant reviews. Treatment for cardiac ATTR should be directed towards alleviation of HF symptoms and to slow or stop progressive amyloid deposition. Conventional HF medications are poorly tolerated and may not alter the disease progression or symptoms, except perhaps with the administration of diuretics. There are three approaches of therapy for ATTR cardiomyopathy: tetramer stabilizers, inhibition of ATTR protein synthesis and clearance of deposited fibrils. Tafamidis diminishes the progression of cardiomyopathy, functional parameters, improves overall outcome in patients with early disease stages, irrespective of ATTR status and is well tolerated. Diflunisal has shown promising results in early studies, but at the expense of significant side effects. Two new agents, antisense oligonucleotides, patisiran and inotersen are under investigation in cardiac amyloidosis. Patisiran appears to be the most effective treatment for hATTR, although evidence is limited, with a relatively small cardiac subpopulation. Therapies considering clearance of amyloid fibrils from tissue remain experimental. In conclusion, tafamidis is the only approved agent for the treatment of ATTR cardiomyopathy although multiple other agents have shown promising early results and are undergoing clinical trials. Careful consideration of the type of ATTR, comorbidities and disease stage will be key in deciding the optimal therapy for ATTR patients.

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A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells.

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A human antibody selective for transthyretin amyloid removes cardiac amyloid through phagocytic immune cells.

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