Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Celiac disease (CeD), caused by immune reactions to cereal gluten, is treated with gluten -elimination diets. Within hours of gluten exposure, either perorally or extraorally by intradermal injection, treated patients experience gastrointestinal symptoms. To test whether gluten exposure leads to systemic cytokine production time -related to symptoms, series of multiplex cytokine measurements were obtained in CeD patients after gluten challenge. Peptide injection elevated at least 15 plasma cytokines, with IL-2, IL-8, and IL-10 being most prominent (fold-change increase at 4 hours of 272, 11, and 1.2, respectively). IL-2 and IL-8 were the only cytokines elevated at 2 hours, preceding onset of symptoms. After gluten ingestion, IL-2 was the earliest and most prominent cytokine (15-fold change at 4 hours). Supported by studies of patient-derived gluten-specific T cell clones and primary lymphocytes, our observations indicate that gluten-specific CD4+ T cells are rapidly reactivated by antigen -exposure likely causing CeD-associated gastrointestinal symptoms.

SUMMARY Background Gluten-free diet (GFD) is the only management available for celiac disease (CeD), a permanent immune intolerance to gluten. Nexvax2® is the first therapeutic vaccine designed to treat CeD. The adjuvant-free formulation of peptides is intended to engage and render gluten-specific CD4+ T cells unresponsive to further antigenic stimulation. We have assessed safety and pharmacodynamics of Nexvax2® in patients with CeD on GFD. Methods In two randomized, double-blind, placebo-controlled, phase 1 studies at 12 community sites in Australia, New Zealand and the United States, we screened for HLA-DQ2·5+ CeD patients (aged 18–70 years) on GFD. The screening and post-treatment periods included either a crossover, placebo-controlled, oral gluten challenge (OGC) to mobilize and assess T cells responsive to Nexvax2 or, for the final cohort in each study, endoscopy and duodenal histology without OGC. Participants and study staff were masked to the gluten content of food provided for each interval of the OGCs. One of two sequences of active and placebo challenges was assigned (1:1) by central randomization using a simple block method. The sequence of challenges was active/placebo then active/placebo, or placebo/active then active/placebo for the OGCs in the screening and post-treatment periods, respectively. Participants with a negative interferon (IFN)-γ release assay (IGRA) to Nexvax2 peptides after the screening OGC, or Marsh score >1 were discontinued before dosing. There was temporal allocation of participants to sequential cohorts assessing multiple fixed intradermal doses of Nexvax2 (60µg, 90µg, or 150µg weekly in the 3-dose study; or 150µg, or 300µg two-times weekly in the 16-dose study) in 0.1 mL 0.9% sodium chloride. A maximum tolerated dose (MTD) was administered in the final biopsy cohort in each study. Participants within each cohort were assigned to receive Nexvax2 or placebo by central randomization (2:1, respectively) using simple block method in SAS software Version 9·2. Participants, investigators, and study staff were masked to the treatment assignment, except for the study pharmacist. The primary endpoint was the number and percentage of adverse events in the treatment period. Other safety outcomes included duodenal histology, gastrointestinal symptoms, plasma cytokines, and immune cell frequencies. The main pharmacodynamic endpoint was IGRA to Nexvax2 peptides. All participants who received Nexvax2 or placebo, the safety population, were included in an intention to treat analysis for the primary endpoint. Additional post hoc analyses were also performed. Both trials were completed and closed before data analysis. Trials were registered with Australian New Zealand Clinical Trials Registry, numbers ACTRN12612000355875 and ACTRN12613001331729. Findings Participants were screened from November 28, 2012 to August 14, 2014, and August 3, 2012 to September 10, 2013, for the 3-dose and 16-dose studies respectively. Across both studies, 136 (80%) of 169 volunteers met initial eligibility crite...

IntroductionAducanumab (BIIB037), a human monoclonal antibody selective for aggregated forms of amyloid beta, is being investigated as a disease-modifying treatment for Alzheimer's disease (AD).MethodsThis randomized, double-blind, placebo-controlled single ascending-dose study investigated the safety, tolerability, and pharmacokinetics (PK) of aducanumab in patients with mild-to-moderate AD. Eligible patients were sequentially randomized 6:2 to aducanumab (0.3, 1, 3, 10, 20, 30, and 60 mg/kg) or placebo.ResultsThe primary outcome was safety and tolerability. Doses ≤30 mg/kg were generally well tolerated with no severe or serious adverse events (SAEs). All three patients who received 60 mg/kg aducanumab developed SAEs of symptomatic amyloid-related imaging abnormalities, which completely resolved by weeks 8–15. Aducanumab Cmax, AUC0–last, and AUCinf increased in a dose-proportional manner.DiscussionIn this single-dose study, aducanumab demonstrated an acceptable safety and tolerability profile and linear PK at doses ≤30 mg/kg (clinicaltrials.govNCT01397539).

Summary Cytokines have been extensively studied in coeliac disease, but cytokine release related to exposure to gluten and associated symptoms has only recently been described. Prominent, early elevations in serum interleukin (IL)‐2 after gluten support a central role for T cell activation in the clinical reactions to gluten in coeliac disease. The aim of this study was to establish a quantitative hierarchy of serum cytokines and their relation to symptoms in patients with coeliac disease during gluten‐mediated cytokine release reactions. Sera were analyzed from coeliac disease patients on a gluten free‐diet (n = 25) and from a parallel cohort of healthy volunteers (n = 25) who underwent an unmasked gluten challenge. Sera were collected at baseline and 2, 4 and 6 h after consuming 10 g vital wheat gluten flour; 187 cytokines were assessed. Confirmatory analyses were performed by high‐sensitivity electrochemiluminescence immunoassay. Cytokine elevations were correlated with symptoms. Cytokine release following gluten challenge in coeliac disease patients included significant elevations of IL‐2, chemokine (C‐C motif) ligand 20 (CCL20), IL‐6, chemokine (C‐X‐C motif) ligand (CXCL)9, CXCL8, interferon (IFN)‐γ, IL‐10, IL‐22, IL‐17A, tumour necrosis factor (TNF)‐α, CCL2 and amphiregulin. IL‐2 and IL‐17A were earliest to rise. Peak levels of cytokines were generally at 4 h. IL‐2 increased most (median 57‐fold), then CCL20 (median 10‐fold). Cytokine changes were strongly correlated with one another, and the most severely symptomatic patients had the highest elevations. Early elevations of IL‐2, IL‐17A, IL‐22 and IFN‐γ after gluten in patients with coeliac disease implicates rapidly activated T cells as their probable source. Cytokine release after gluten could aid in monitoring experimental treatments and support diagnosis.