Serum Neurofilament Light Trajectories and Their Relation to Subclinical Radiological Disease Activity in Relapsing Multiple Sclerosis Patients in the APLIOS Trial.

Introduction: Several studies have described prognostic value of serum neurofilament light chain (sNfL) at the group level in relapsing multiple sclerosis (RMS) patients. Here, we aimed to explore the temporal association between sNfL and development of subclinical disease activity as assessed by magnetic resonance imaging (MRI) at the group level and evaluate the potential of sNfL as a biomarker for capturing subclinical disease activity in individual RMS patients.

Methods: In the 12-week APLIOS study, patients (N = 284) received subcutaneous ofatumumab 20 mg.

Serum GFAP and NfL Levels Differentiate Subsequent Progression and Disease Activity in Patients With Progressive Multiple Sclerosis.

Background And Objectives: Neurodegeneration and astrocytic activation are pathologic hallmarks of progressive multiple sclerosis (MS) and can be quantified by serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP). We investigated sNfL and sGFAP as tools for stratifying patients with progressive MS based on progression and disease activity status.

Methods: We leveraged our Comprehensive Longitudinal Investigation of MS at the Brigham and Women's Hospital (CLIMB) natural history study, which includes clinical, MRI data and serum samples collected over more than 20 years.

Prognostic Value of Serum Neurofilament Light Chain for Disease Activity and Worsening in Patients With Relapsing Multiple Sclerosis: Results From the Phase 3 ASCLEPIOS I and II Trials.

Objective: This study aims to confirm the prognostic value of baseline serum neurofilament light chain (sNfL) for on-study disease activity and worsening in patients with relapsing MS (RMS).

Background: Previous studies suggested that sNfL could be a prognostic biomarker in RMS. In the phase 3 ASCLEPIOS I/II trials in which ofatumumab demonstrated better efficacy outcomes than teriflunomide, treatment with ofatumumab also led to significantly reduced sNfL levels compared to teriflunomide treatment.

Blood Neurofilament Light in Progressive Multiple Sclerosis: Post Hoc Analysis of 2 Randomized Controlled Trials.

Background And Objectives: To investigate the potential of plasma neurofilament light (pNfL) as a biomarker of disease progression and treatment response in progressive multiple sclerosis (PMS) with and without acute disease activity.

Methods: A post hoc blinded analysis of pNfL levels in 2 placebo-controlled, phase 3 studies in secondary progressive multiple sclerosis (SPMS; EXPAND) and primary progressive multiple sclerosis (PPMS; INFORMS) using siponimod and fingolimod, respectively, as active compounds was performed. pNfL levels were quantified using a single molecule array (Homebrew Simoa) immunoassay from stored ethylenediaminetetraacetic acid (EDTA) plasma samples of all patients who consented for exploratory biomarker analysis in either study; pNfL levels were divided into high (≥30 pg/mL) and low (<30 pg/mL) at baseline.

Safety of Fingolimod in Patients with Multiple Sclerosis Switched from Natalizumab: Results from TRANSITION-A 2-Year, Multicenter, Observational, Cohort Study.

Multiple sclerosis (MS) patients receiving natalizumab and who are at risk of developing progressive multifocal leukoencephalopathy (PML) often switch to other high-efficacy disease-modifying therapies including fingolimod as a risk mitigation strategy, which could impact treatment safety and effectiveness. The TRANSITION study aimed to evaluate the safety of fingolimod over two years in patients with MS after switching from natalizumab in a real-world setting. The safety and effectiveness were assessed by monitoring serious and other adverse events (SAEs, AEs).

Serum NfL levels in the first five years predict 10-year thalamic fraction in patients with MS.

Background: Serum neurofilament light chain (sNfL) levels are associated with relapses, MRI lesions, and brain volume in multiple sclerosis (MS).

Objective: To explore the value of early serum neurofilament light (sNfL) measures in prognosticating 10-year regional brain volumes in MS.

Methods: Patients with MS enrolled in the Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study within five years of disease onset who had annual blood samples from years 1-10 (n = 91) were studied.

Long-term prognostic value of longitudinal measurements of blood neurofilament levels.

Objective: To assess the long-term prognostic value of an integral of longitudinal measurements of plasma neurofilament light chain levels (NfL) over 12 and 24 months vs single neurofilament light chain (NfL) measurements in patients with relapsing-remitting MS (RRMS) and its additional value when combined with clinical and MRI measures.

Methods: This analysis included continuously fingolimod-treated patients with RRMS from the 24-month FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS)/12-month Trial Assessing Injectable Interferon vs FTY720 Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) phase 3 trials and their long-term extension, LONGTERMS. Patients were classified into high (≥30 pg/mL, n = 110) and low (<30 pg/mL, n = 164) NfL categories based on the baseline (BL) NfL value or the geometric mean NfL calculated over 12 and 24 months to predict disability-related outcomes and brain volume loss (BVL).

Serum neurofilament light chain and optical coherence tomography measures in MS: A longitudinal study.

Objective: To study the association between serum neurofilament light chain (sNfL) and multiple optical coherence tomography (OCT) measures in patients with MS and healthy controls (HCs).

Methods: In this prospective study, 110 patients with MS were recruited, together with 52 age- and sex-matched HCs. Clinical evaluation and spectral domain OCT and sNfL were obtained at baseline and after 5.

Serum neurofilament light chain is a useful biomarker in pediatric multiple sclerosis.

Objective: To investigate serum neurofilament light chain (sNfL) as a potential biomarker for disease activity and treatment response in pediatric patients with multiple sclerosis (MS).

Methods: In this retrospective cohort study, sNfL levels were measured in a pediatric MS cohort (n = 55, follow-up 12-105 months) and in a non-neurologic pediatric control cohort (n = 301) using a high-sensitivity single-molecule array assay. Association of sNfL levels and treatment and clinical and MRI parameters were calculated.

A multimodal approach to assess the validity of atrophied T2-lesion volume as an MRI marker of disease progression in multiple sclerosis.

Background: Atrophied T2-lesion volume (LV) is a novel MRI marker representing brain-lesion loss due to atrophy, able to predict long-term disability progression and conversion to secondary-progressive multiple sclerosis (MS).

Objective: To better characterize atrophied T2-LV via comparison with other multidisciplinary markers of MS progression.

Methods: We studied 127 MS patients (85 relapsing-remitting, RRMS and 42 progressive, PMS) and 20 clinically isolated syndrome (CIS) utilizing MRI, optical coherence tomography, and serum neurofilament light chain (sNfL) at baseline and at 5-year follow-up.

Serum neurofilament light chain level associations with clinical and cognitive performance in multiple sclerosis: A longitudinal retrospective 5-year study.

Background: A limited number of studies investigated associations between serum neurofilament light chain (sNfL) and cognition in persons with multiple sclerosis (PwMS).

Objective: To assess cross-sectional and longitudinal associations between sNfL levels, clinical, and cognitive performance in PwMS and age-matched healthy controls (HCs).

Materials: One hundred twenty-seven PwMS (85 relapsing-remitting MS/42 progressive MS), 20 clinically isolated syndrome patients, and 52 HCs were followed for 5 years.

Serum neurofilament light chain levels associations with gray matter pathology: a 5-year longitudinal study.

Background: Gray matter (GM) pathology is closely associated with physical and cognitive impairment in persons with multiple sclerosis (PwMS). Similarly, serum neurofilament light chain (sNfL) levels are related to MS disease activity and progression.

Objectives: To assess the cross-sectional and longitudinal associations between sNfL and MRI-derived lesion and brain volume outcomes in PwMS and age-matched healthy controls (HCs).

Blood neurofilament light as a potential endpoint in Phase 2 studies in MS.

Objectives: To assess whether neurofilament light chain (NfL) could serve as an informative endpoint in Phase 2 studies in patients with relapsing-remitting multiple sclerosis (RRMS) and estimate the sample size requirements with NfL as the primary endpoint.

Methods: Using data from the Phase 3 FREEDOMS study, we evaluated correlation of NfL at Month 6 with 2-year outcomes: relapses, confirmed disability worsening (CDW), new or enlarging T2 lesions (active lesions), and brain volume loss (BVL). We compared the proportion of treatment effect (PTE) on 2-year relapses and BVL explained by 6-month log-transformed NfL levels with the PTE explained by the number of active lesions over 6 months.

Blood neurofilament light chain as a biomarker of MS disease activity and treatment response.

Objective: To assess the value of blood neurofilament light chain (NfL) as a biomarker of recent, ongoing, and future disease activity and tissue damage and its utility to monitor treatment response in relapsing-remitting multiple sclerosis.

Methods: We measured NfL in blood samples from 589 patients with relapsing-remitting multiple sclerosis (from phase 3 studies of fingolimod vs placebo, FREEDOMS and interferon [IFN]-β-1a, TRANSFORMS) and 35 healthy controls and compared NfL levels with clinical and MRI-related outcomes.

Results: At baseline, NfL levels (pg/mL) were higher in patients than in healthy controls (30.

Neurofilament light chain serum levels correlate with 10-year MRI outcomes in multiple sclerosis.

Objective: To assess the value of annual serum neurofilament light (NfL) measures in predicting 10-year clinical and MRI outcomes in multiple sclerosis (MS).

Methods: We identified patients in our center's Comprehensive Longitudinal Investigations in MS at Brigham and Women's Hospital (CLIMB) study enrolled within 5 years of disease onset, and with annual blood samples up to 10 years ( = 122). Serum NfL was measured using a single molecule array (SIMOA) assay.

Perspectives on Subcutaneous Route of Administration as an Immunogenicity Risk Factor for Therapeutic Proteins.

An increasing number of therapeutic proteins are being developed for delivery through the subcutaneous (SC) route of administration. Relative to intravenous (IV) administration, the SC route offers more convenience to patients, flexibility in dosing, and potential to reduce health care costs. There is a perception that SC administration can pose a higher immunogenicity risk than IV administration for a given protein.

The effects of intrathecal rituximab on biomarkers in multiple sclerosis.

Objectives: Clinical trials of IV-rituximab have proved successful. It is unclear whether intrathecal (IT)-rituximab is more efficacious at lower doses. We examine its effects on B-cell biomarkers.

T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation.

Protein therapeutics hold a prominent and rapidly expanding place among medicinal products. Purified blood products, recombinant cytokines, growth factors, enzyme replacement factors, monoclonal antibodies, fusion proteins, and chimeric fusion proteins are all examples of therapeutic proteins that have been developed in the past few decades and approved for use in the treatment of human disease. Despite early belief that the fully human nature of these proteins would represent a significant advantage, adverse effects associated with immune responses to some biologic therapies have become a topic of some concern.

A simple whole blood bioassay detects cytokine responses to anti-CD28SA and anti-CD52 antibodies.

Introduction: In 2006 the anti-CD28 superagonistic IgG4 TGN1412, having passed pre-clinical safety screens, caused a severe 'cytokine storm' in 6 healthy volunteers. Others have shown that for TGN1412 to induce an inflammatory signal in human peripheral blood mononuclear cells (PBMCs) or in human diluted blood, endothelial cells or bound monoclonal antibody (mAb) is required as part of a bioassay complex. These types of protocols rely on different donor cells and therefore have limitations as bioassays for pre-clinical testing.

Taking immunogenicity assessment of therapeutic proteins to the next level.

Therapeutic proteins provide innovative and effective therapies for numerous diseases. However, some of these products are associated with unwanted immunogenicity that may lead to clinical consequences such as reduced or loss of efficacy, altered pharmacokinetics (PK), general immune and hypersensitivity reactions, and neutralisation of the natural counterpart (e.g.

The safety and side effects of monoclonal antibodies.

Monoclonal antibodies (mAbs) are now established as targeted therapies for malignancies, transplant rejection, autoimmune and infectious diseases, as well as a range of new indications. However, administration of mAbs carries the risk of immune reactions such as acute anaphylaxis, serum sickness and the generation of antibodies. In addition, there are numerous adverse effects of mAbs that are related to their specific targets, including infections and cancer, autoimmune disease, and organ-specific adverse events such as cardiotoxicity.

Evaluation of the immuno-stimulatory potential of stopper extractables and leachables by using dendritic cells as readout.

Recombinant protein pharmaceuticals may bear some risks and undesirable side effects, such as the appearance of immunogenic reactions. The increased incidence of antibody-mediated pure red cell aplasia (PRCA) outside the United States after administration of a human serum albumin (HSA)-free EPREX (recombinant human erythropoietin alpha) formulation was explained with the generation of rubber stopper related leachables, possibly acting as immunogenic adjuvants. In our study, we have investigated the potential of extractable and leachable preparations of three different pharmaceutical relevant stoppers to generate a "danger signal" in a dendritic cell assay.

Overview of cell-based tools for pre-clinical assessment of immunogenicity of biotherapeutics.

With the increasing number of biotherapeutic drugs entering clinical trials, drug-induced immunogenicity becomes more and more a topic in immunotoxicology of drug development. Immunogenicity relies on the induction or presence of antibodies recognizing a biotherapeutic protein after its administration. Anti-drug antibodies (ADA) that may either bind to a protein drug and/ or neutralize its potency may modulate the pharmacokinetics of therapeutic proteins or evoke adverse events, ranging from hypersensitivity to autoimmune reactions.