Michel Friesenhahn

An Effector-Reduced Anti-β-Amyloid (Aβ) Antibody with Unique Aβ Binding Properties Promotes Neuroprotection and Glial Engulfment of Aβ

Passive immunization against β-amyloid (Aβ) has become an increasingly desirable strategy as a therapeutic treatment for Alzheimers disease (AD). However, traditional passive immunization approaches carry the risk of Fcγ receptor-mediated overactivation of microglial cells, which may contribute to an inappropriate proinflammatory response leading to vasogenic edema and cerebral microhemorrhage. Here, we describe the generation of a humanized anti-Aβ monoclonal antibody of an IgG4 isotype, known as MABT5102A (MABT). An IgG4 subclass was selected to reduce the risk of Fcγ receptor-mediated overactivation of microglia. MABT bound with high affinity to multiple forms of Aβ, protected against Aβ1–42 oligomer-induced cytotoxicity, and increased uptake of neurotoxic Aβ oligomers by microglia. Furthermore, MABT-mediated amyloid plaque removal was demonstrated using in vivo live imaging in hAPP(V717I)/PS1 transgenic mice. When compared with a human IgG1 wild-type subclass, containing the same antigen-binding variable domains and with equal binding to Aβ, MABT showed reduced activation of stress-activated p38MAPK (p38 mitogen-activated protein kinase) in microglia and induced less release of the proinflammatory cytokine TNFα. We propose that a humanized IgG4 anti-Aβ antibody that takes advantage of a unique Aβ binding profile, while also possessing reduced effector function, may provide a safer therapeutic alternative for passive immunotherapy for AD. Data from a phase I clinical trial testing MABT is consistent with this hypothesis, showing no signs of vasogenic edema, even in ApoE4 carriers.

The Alzheimer's prevention initiative composite cognitive test score: sample size estimates for the evaluation of preclinical Alzheimer's disease treatments in presenilin 1 E280A mutation carriers.

OBJECTIVE To identify a cognitive composite that is sensitive to tracking preclinical Alzheimers disease decline to be used as a primary end point in treatment trials. METHOD We capitalized on longitudinal data collected from 1995 to 2010 from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the worlds largest known early-onset autosomal dominant Alzheimers disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimers disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimers Prevention Initiatives (API) preclinical Alzheimers disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top-performing combinations, and representation of relevant cognitive domains. RESULTS The optimal test combination included Consortium to Establish a Registry for Alzheimers Disease (CERAD) Word List Recall, CERAD Boston Naming Test (high frequency items), Mini-Mental State Examination (MMSE) Orientation to Time, CERAD Constructional Praxis, and Ravens Progressive Matrices (Set A), with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR = 0.38) or the entire CERAD-Col battery (MSDR = 0.76). A sample size of 75 cognitively normal PSEN1 E280A mutation carriers aged 30 years and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, P = .05). CONCLUSIONS We have identified a composite cognitive test score representing multiple cognitive domains that, compared to the most sensitive single test item, has improved power to track preclinical Alzheimers disease decline in autosomal dominant Alzheimers disease mutation carriers and to evaluate preclinical Alzheimers disease treatments. This API composite cognitive test score will be used as the primary end point in the first API trial in cognitively unimpaired autosomal dominant Alzheimers disease carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset Alzheimers disease, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytic approaches.

A phase ia dose-escalation study of the anti-factor D monoclonal antibody fragment FCFD4514S in patients with geographic atrophy.

Purpose: Multicenter, open-label, single-dose, dose-escalation Phase Ia study to determine the safety, tolerability, maximum tolerated dose, and immunogenicity of FCFD4514S, an antigen-binding fragment from a humanized monoclonal antibody directed against complement factor D, in patients with geographic atrophy. Methods: Eighteen patients with geographic atrophy (lesion size: ≥0.75 disk areas; best-corrected visual acuity: 20/125–20/400 Snellen equivalent) were sequentially enrolled and received 1 of 6 escalating doses of intravitreal FCFD4514S subject to dose-limiting toxicity criteria. Follow-up assessments (clinical examination, best-corrected visual acuity, intraocular pressure) were conducted at postadministration Days 1, 3, 7, 14, 30, 60, and 90. Serum pharmacokinetics, immunogenicity, and complement activity were also evaluated. Results: All patients completed the study with no reported FCFD4514S-related dose-limiting toxicities or ocular or systemic adverse events. The maximum tolerated dose for this study was 10 mg, the highest dose tested. No antitherapeutic antibody response or adverse effects on systemic complement activity were observed. Time to maximum serum concentration was 1 day to 3 days postdosing; serum terminal half-life was 5.9 days. Conclusion: Single-dose intravitreal FCFD4514S administrations were safe and well tolerated and not associated with any study drug–related ocular or systemic adverse events. These data support a multidose safety and tolerability assessment of FCFD4514S in geographic atrophy.

An automated method for nonparametric kinetic analysis of clinical DCE-MRI data: application to glioblastoma treated with bevacizumab.

Here, we describe an automated nonparametric method for evaluating gadolinium‐diethylene triamine pentaacetic acid (Gd‐DTPA) kinetics, based on dynamic contrast‐enhanced–MRI scans of glioblastoma patients taken before and after treatment with bevacizumab; no specific model or equation structure is assumed or used. Tumor and venous blood concentration‐time profiles are smoothed, using a robust algorithm that removes artifacts due to patient motion, and then deconvolved, yielding an impulse response function. In addition to smoothing, robustness of the deconvolution operation is assured by excluding data that occur prior to the plasma peak; an exhaustive analysis was performed to demonstrate that exclusion of the prepeak plasma data does not significantly affect results. All analysis steps are executed by a single R script that requires blood and tumor curves as the sole input. Statistical moment analysis of the Impulse response function yields the area under the curve (AUC) and mean residence time (MRT). Comparison of deconvolution results to fitted Tofts model parameters suggests that

ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease

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A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 2 STUDY TO EVALUATE THE EFFICACY AND SAFETY OF CRENEZUMAB IN PATIENTS WITH MILD TO MODERATE ALZHEIMER'S DISEASE

and AUC of the Impulse response function closely approximate fractional clearance from plasma to tissue (Ktrans) and fractional interstitial volume (ve) . Intervisit variability is shown to be comparable when using the deconvolution method (11% [

METHODS OF TREATING ALZHEIMER'S DISEASE

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Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE)

] and 13%[AUC]) compared to the Tofts model (14%[Ktrans] and 24%[ve]). AUC and

Verfahren zur behandlung von morbus alzheimer

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Méthode de traitement de la maladie d'alzheimer

both exhibit a statistically significant decrease (P < 0.005) 1 day after administration of bevacizumab. Magn Reson Med 63:1366–1375, 2010.