Dataset Information

2A4 binds soluble and insoluble light chain aggregates from AL amyloidosis patients and promotes clearance of amyloid deposits by phagocytosis †.

ABSTRACT: Amyloid light chain (AL) amyloidosis is characterized by misfolded light chain (LC) (amyloid) deposition in various peripheral organs, leading to progressive dysfunction and death. There are no regulatory agency-approved treatments for AL amyloidosis, and none of the available standard of care approaches directly targets the LC protein that constitutes the amyloid. NEOD001, currently in late-stage clinical trials, is a conformation-specific, anti-LC antibody designed to specifically target misfolded LC aggregates and promote phagocytic clearance of AL amyloid deposits. The present study demonstrated that the monoclonal antibody 2A4, the murine form of NEOD001, binds to patient-derived soluble and insoluble LC aggregates and induces phagocytic clearance of AL amyloid in vitro. 2A4 specifically labeled all 21 fresh-frozen organ samples studied, which were derived from 10 patients representing both ? and ? LC amyloidosis subtypes. 2A4 immunoreactivity largely overlapped with thioflavin T-positive labeling, and 2A4 bound both soluble and insoluble LC aggregates extracted from patient tissue. Finally, 2A4 induced macrophage engagement and phagocytic clearance of AL amyloid deposits in vitro. These findings provide further evidence that 2A4/NEOD001 can effectively clear and remove human AL-amyloid from tissue and further support the rationale for the evaluation of NEOD001 in patients with AL amyloidosis.

SUBMITTER: Renz M

PROVIDER: S-EPMC5152553 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

2A4 binds soluble and insoluble light chain aggregates from AL amyloidosis patients and promotes clearance of amyloid deposits by phagocytosis <sup>†</sup>.

Renz Mark M Torres Ronald R Dolan Philip J PJ Tam Stephen J SJ Tapia Jose R JR Li Lauri L Salmans Joshua R JR Barbour Robin M RM Shughrue Paul J PJ Nijjar Tarlochan T Schenk Dale D Kinney Gene G GG Zago Wagner W

Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 20160805 3

Amyloid light chain (AL) amyloidosis is characterized by misfolded light chain (LC) (amyloid) deposition in various peripheral organs, leading to progressive dysfunction and death. There are no regulatory agency-approved treatments for AL amyloidosis, and none of the available standard of care approaches directly targets the LC protein that constitutes the amyloid. NEOD001, currently in late-stage clinical trials, is a conformation-specific, anti-LC antibody designed to specifically target misfo ...[more]

PMID: 27494229

Similar Datasets

Project description:Background Both light-chain (AL) amyloidosis and transthyretin (ATTR) amyloidosis are types of cardiac amyloidosis (CA) that require accurate prognostic stratification to plan therapeutic strategies and follow-ups. Cardiac biomarkers, e.g., N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (Hs-cTnT), remain the cornerstone of the prognostic assessment. An increased level of soluble suppression of tumorigenesis-2 (sST2) is predictive of adverse events [all-cause death and heart failure (HF) hospitalizations] in patients with HF. This study aimed to evaluate the prognostic value of circulating sST2 levels in AL-CA and ATTR-CA. Methods We carried out a multicenter study including 133 patients with AL-CA and 152 patients with ATTR-CA. During an elective outpatient visit for the diagnosis of CA, Mayo Clinic staging [NT-proBNP, Hs-cTnT, differential of free light chains (DFLCs)] and sST2 were assessed for all AL patients. Gillmore staging [including estimated glomerular filtration rate (eGFR), NT-proBNP] and Grogan staging (including NT-proBNP and Hs-cTnT) were assessed for TTR-CA patients. Results The median age was 73 years [interquartile range (IQR) 61–81], and 53% were men. The endpoint was the composite of all-cause death or first HF-related hospitalization. The median follow-up was 20 months (IQR 3–34) in AL amyloidosis and 33 months (6–45) in TTR amyloidosis. The primary outcome occurred in 70 (53%) and 99 (65%) of AL and TTR patients, respectively. sST2 levels were higher in patients with AL-CA than in patients with ATTR-CA: 39 ng/L (26–80) vs. 32 ng/L (21–46), p < 0.001. In AL-CA, sST2 levels predicted the outcome regardless of the Mayo Clinic score (HR: 2.16, 95% CI: 1.17–3.99, p < 0.001). In TTR-CA, sST2 was not predictive of the outcome in multivariate models, including Gillmore staging and Grogan staging (HR: 1.17, CI: 95% 0.77–1.89, p = 0.55). Conclusion sST2 level is a relevant predictor of death and HF hospitalization in AL cardiac amyloidosis and adds prognostic stratification on top of NT-proBNP, Hs cTnT, and DFLC.

Dataset Information

2A4 binds soluble and insoluble light chain aggregates from AL amyloidosis patients and promotes clearance of amyloid deposits by phagocytosis †.

Publications

2A4 binds soluble and insoluble light chain aggregates from AL amyloidosis patients and promotes clearance of amyloid deposits by phagocytosis <sup>†</sup>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets