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

Adolfsson, Oskar; Pihlgren, Maria; Toni, Nicolas; Varisco, Yvan; Buccarello, Anna Lucia; Antoniello, Katia; Lohmann, Sophie; Piorkowska, Kasia; Gafner, Valérie; Atwal, Jasvinder K.; Maloney, Janice; Chen, Mark; Gogineni, Alvin; Weimer, Robby M.; Mortensen, Deborah L.; Friesenhahn, Michel; Ho, Carole; Paul, Robert; Pfeifer, Andrea; Muhs, Andreas; Watts, Ryan J.

doi:10.1523/jneurosci.4742-11.2012

Cited by 278 publications

(270 citation statements)

References 54 publications

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“…Passive immunization approaches using monoclonal antibodies against Aβ1-40 [103], Aβ1-42 [104], pyroglutamate Aβ [105], oligomers [106], or protofibrils [107][108][109] have been developed. Currently, clinical trials with the antibodies BAN2401 (recognizing protofibrils) [75], crenezumab (aggregated species) [76], gantenerumab (fibrils) [78][79][80], and solanezumab (Aβ mid-domain) [81,82] are ongoing (Table 1). However, other programs using antibodies such as bapinezumab (N-terminus) [110] and ponezumab (Cterminus) [111] have been discontinued as they did not meet expected goals.…”

Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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Disease-modifying alternatives are sorely needed for the treatment of neurodegenerative disorders, a group of diseases that afflict approximately 50 million Americans annually. Immunotherapy is one of the most developed approaches in this direction. Vaccination against amyloid-β, α-synuclein, or tau has been extensively explored, specially as the discovery that these proteins may propagate cell-to-cell and be accessible to antibodies when embedded into the plasma membrane or in the extracellular space. Likewise, the use of passive immunization approaches with specific antibodies against abnormal conformations of these proteins has also yielded promising results. The clinical development of immunotherapies for Alzheimer's disease, Parkinson's disease, frontotemporal dementia, dementia with Lewy bodies, and other neurodegenerative disorders is a field in constant evolution. Results to date suggest that immunotherapy is a promising therapeutic approach for neurodegenerative diseases that progress with the accumulation and prion-like propagation of toxic protein aggregates. Here we provide an overview of the most novel and relevant immunotherapeutic advances targeting amyloid-β in Alzheimer's disease, α-synuclein in Alzheimer's disease and Parkinson's disease, and tau in Alzheimer's disease and frontotemporal dementia.

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Section: Immunotherapy Targeting Aβmentioning

confidence: 99%

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

2016

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“…Traditionally p38 α kinase is considered to be an inflammation‐related target as microglial p38 α promotes production of proinflammatory cytokines6 and modulates microglial activation state,7, 8 and in the healthy state p38 α expression within neurons is low 9. However, more recent findings indicate that neuronal p38 α is increased in disease and under stress, and neuronal p38 α expression has been implicated in amyloid‐beta and/or inflammation‐induced synaptic dysfunction,10, 11, 12, 13, 14 specifically impaired synaptic plasticity.…”

Section: Introductionmentioning

confidence: 99%

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

Scheltens

Prins

Lammertsma

et al. 2018

Ann Clin Transl Neurol

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ObjectiveThe aim of this study was to preliminarily evaluate an oral small molecule p38α kinase inhibitor in patients with early Alzheimer's disease (AD) for the effects on brain amyloid plaque load and episodic memory function, and to establish pharmacokinetic–pharmacodynamics correlations if any effects identified on these parameters.MethodsSixteen patients with early AD received a highly selective p38α inhibitor (neflamapimod) for 84 days (12 weeks). To obtain a broad range of plasma drug exposures, subjects randomized to receive either 40 mg (n = 9) or 125 mg (n = 7) twice daily. Dynamic, 11C‐PiB positron emission scans were performed at baseline and at Day 84 and quantitatively analyzed by reference parametric mapping. Episodic memory assessed as Wechsler Memory Scale (WMS) immediate and delayed recall composites.ResultIn the 11C‐PiB analyses there were no main group level effects, though in the prespecified responder analysis (>7% reduction in 11C‐PiB signal) there were three responders in the 40 mg, and one in the 125 mg group. There were statistically significant increases from baseline in mean WMS immediate recall score and WMS delayed recall at both day 28 (P = 0.03 and P = 0.001) and day 84 (P = 0.001 and P < 0.001). Individual subject plasma drug concentration profiles were significantly positively correlated with the change in combined WMS immediate and delayed recall (P < 0.0001, r 2= 0.70). Within‐subject effect size was 0.59 for immediate recall and 0.67 for delayed recall.InterpretationSelective p38α inhibition in patients with early AD may improve episodic memory and potentially impact β‐amyloid production. These preliminary clinical findings support conduct of a longer duration placebo‐controlled study, particularly to confirm the effects on episodic memory function.

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“…Such IgGs exert competing favorable and unfavorable effects (7,8). Whereas the A␤-IgG immune complexes are cleared via the Fc receptor-dependent uptake pathway by phagocytic cells (the microglia) (4), the activated cells release inflammatory mediators and neurotoxic factors (5,9). Moreover, A␤-binding monoclonal IgGs clear parenchymal A␤42, but they induce increased A␤40 deposition in blood vessel walls, enhancing the incidence of microhemorrhages and CAA (6,7) thought to be correlated with cognitive impairments (10).…”

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confidence: 99%

Specific Amyloid β Clearance by a Catalytic Antibody Construct

Planque

Nishiyama

Sonoda

et al. 2015

Journal of Biological Chemistry

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Background: Naturally occurring catalytic antibodies (catabodies) can hydrolyze peptide bonds. Results: A catabody engineered from innate immunity principles hydrolyzed amyloid ␤ (A␤) specifically, dissolved A␤ aggregates, and cleared brain A␤ deposits without evident toxicity. Conclusion:The catabody could potentially be developed as a therapy for Alzheimer disease. Significance: The innate catabody repertoire may be a source of useful catabodies to toxic amyloids.

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

Cited by 278 publications

References 54 publications

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

Immunotherapeutic Approaches Targeting Amyloid-β, α-Synuclein, and Tau for the Treatment of Neurodegenerative Disorders

An exploratory clinical study of p38α kinase inhibition in Alzheimer's disease

Specific Amyloid β Clearance by a Catalytic Antibody Construct

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