Intact natalizumab pharmacokinetics is impacted by endogenous IgG4 concentration.

Background: Natalizumab (NAT) pharmacokinetics and pharmacodynamics are complicated by arm exchange with endogenous IgG4, resulting in a mixture of a more potent intact, bivalent form and a less potent, functionally monovalent form. Total NAT and endogenous IgG4 concentrations vary considerably across patients. This study assessed the concentration of intact NAT, and how it relates to total NAT and endogenous IgG4 levels in blood and saliva.

Accurate prediction of serum antibody levels from noninvasive saliva/nasal samples.

The importance of easily accessible, noninvasive samples, such as saliva, to effectively monitor serum antibody levels has been underscored by the SARS-CoV-2 (COVID-19) pandemic. Although a correlation between saliva and serum antibody titers has been observed, the ability to predict serum antibody levels from measurements in saliva is not well established. Herein, the authors demonstrate that measurements of SARS-CoV-2 antibody levels in both saliva and nasal specimens can be used to accurately determine serum levels by utilizing endogenous total IgG as an internal calibrator.

Peptide Mimotope-Enabled Quantification of Natalizumab Arm Exchange During Multiple Sclerosis Treatment.

Background: Natalizumab, a therapeutic antibody used to treat multiple sclerosis, undergoes in vivo Fab arm exchange to form a monovalent bispecific antibody. Although highly efficacious, the immunosuppressive activity of natalizumab has been associated with JC polyomavirus-driven progressive multifocal leukoencephalopathy (PML). Development of assays that can distinguish between and quantify bivalent (unexchanged) and monovalent (exchanged) forms of natalizumab in clinical samples may be useful for optimizing extended interval dosing and reducing the risk of PML.

Formation of gelsolin amyloid fibrils in the rough endoplasmic reticulum of skeletal muscle in the gelsolin mouse model of inclusion body myositis: comparative analysis to human sporadic inclusion body myositis.

Sporadic inclusion body myositis has a significant impact on the life of the elderly. Despite some similarities to other myopathies with established genetic defects, little is known about mechanisms of its development and no effective treatment is available. Therefore, there is a need for animal models that can faithfully reconstitute important aspects of this human disease.

Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention.

Protein misassembly into aggregate structures, including cross-β-sheet amyloid fibrils, is linked to diseases characterized by the degeneration of post-mitotic tissue. While amyloid fibril deposition in the extracellular space certainly disrupts cellular and tissue architecture late in the course of amyloid diseases, strong genetic, pathological and pharmacologic evidence suggests that the process of amyloid fibril formation itself, known as amyloidogenesis, likely causes these maladies. It seems that the formation of oligomeric aggregates during the amyloidogenesis process causes the proteotoxicity and cytotoxicity characteristic of these disorders.

Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis leading to the intracellular aggregation of proteins.

Familial amyloidosis of Finnish type (FAF) is a systemic amyloid disease associated with the deposition of proteolytic fragments of mutant (D187N/Y) plasma gelsolin. We report a mouse model of FAF featuring a muscle-specific promoter to drive D187N gelsolin synthesis. This model recapitulates the aberrant endoproteolytic cascade and the aging-associated extracellular amyloid deposition of FAF.

Metalloendoprotease cleavage triggers gelsolin amyloidogenesis.

Amyloid diseases like Alzheimer's disease and familial amyloidosis of Finnish type (FAF) stem from endoproteolytic cleavage of a precursor protein to generate amyloidogenic peptides that accumulate as amyloid deposits in a tissue-specific manner. FAF patients deposit both 8 and 5 kDa peptides derived from mutant (D187Y/N) plasma gelsolin in the extracellular matrix (ECM). The first of two aberrant sequential proteolytic events is executed by furin to yield a 68 kDa (C68) secreted fragment.

Ca2+ binding protects against gelsolin amyloidosis.

Amyloid diseases occur when native or mutant polypeptides misfold and aggregate to form deposits in the extracellular space. There are at least 20 proteins associated with amyloid diseases, including the well-known amyloid-beta peptide that is the causative agent for Alzheimer's disease (AD). This review describes familial amyloidosis of Finnish type (FAF), an amyloid disease caused by mutations in plasma gelsolin, a secreted protein that contains multiple Ca2+-binding domains.

Gelsolin domain 2 Ca2+ affinity determines susceptibility to furin proteolysis and familial amyloidosis of finnish type.

Mutation of aspartic acid 187 to asparagine (D187N) or tyrosine (D187Y) in domain 2 of the actin-modulating protein gelsolin causes the neurodegenerative disease familial amyloidosis of Finnish type (FAF). These mutations render plasma gelsolin susceptible to aberrant proteolysis by furin in the trans-Golgi network, the initial proteolytic event in the formation of 71 and 53 residue fragments that assemble into amyloid fibrils. Ca(2+) binding stabilizes wild-type domain 2 gelsolin against denaturation and proteolysis, but the FAF variants are unable to bind and be stabilized by Ca(2+).