[P1–074]: PRECLINICAL DISCOVERY AND DEVELOPMENT OF MEDI1814, a MONOCLONAL ANTIBODY SELECTIVELY TARGETING BETA‐AMYLOID 42 (Aβ42)

Billinton, Andy; Newton, Philip M.; Lloyd, Chris J.; Groves, Maria; Welsh, Fraser; Bogstedt, Anna; Eketjäll, Susanna; McFarlane, Mary; Perkinton, Michael S.; Narwal, Rajesh; Tan, Keith; Dudley, Amanda; Vaughan, Tristan J.; Chessell, Iain P.

doi:10.1016/j.jalz.2017.06.141

Cited by 9 publications

(7 citation statements)

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“…Recent works have been studying the MEDI1814, a monoclonal antibody as a potential disease-modifying treatment for Alzheimer’s disease. This strategy is based on the ability of MEDI1814 to selectively target β-amyloid 42 [128], which is highly associated with Alzheimer’s disease [129]. As early trials have proved that MEDI1814 can reduce the levels of the β-amyloid 42, AstraZeneca and Lily are co-developing it as part of the BACE alliance.…”

Section: Nanomedicine In Central Nervous System Disordersmentioning

confidence: 99%

Neuronanomedicine: An Up-to-Date Overview

et al. 2019

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The field of neuronanomedicine has recently emerged as the bridge between neurological sciences and nanotechnology. The possibilities of this novel perspective are promising for the diagnosis and treatment strategies of severe central nervous system disorders. Therefore, the development of nano-vehicles capable of permeating the blood–brain barrier (BBB) and reaching the brain parenchyma may lead to breakthrough therapies that could improve life expectancy and quality of the patients diagnosed with brain disorders. The aim of this review is to summarize the recently developed organic, inorganic, and biological nanocarriers that could be used for the delivery of imaging and therapeutic agents to the brain, as well as the latest studies on the use of nanomaterials in brain cancer, neurodegenerative diseases, and stroke. Additionally, the main challenges and limitations associated with the use of these nanocarriers are briefly presented.

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Section: Nanomedicine In Central Nervous System Disordersmentioning

confidence: 99%

Neuronanomedicine: An Up-to-Date Overview

et al. 2019

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“…The antibody appears to be selective to low molecular weight species, primarily monomers. In the CSF of rats and monkeys, MEDI-1814 reduced free, antibody-unbound levels of A β 42 , while increasing total A β 42 ( Billinton et al (2017) ), indicating target engagement. There is no co-crystal structure reported to date.…”

Section: Passive Immunotherapies For a βmentioning

confidence: 99%

Section: Passive Immunotherapies For a βmentioning

confidence: 99%

“…MEDI-1814 is a fully human antibody optimized from a clone identified from phage library selections against A β 42 ( Billinton et al (2017) ). MEDI-1814 binds selectively to the C-terminus of A β 42 with very high affinity ≈50-300 pM ( Billinton et al (2017) ). The epitope is broadly characterized between residues 29–42 ( Groves et al (2014) ), but selective to A β 42 in that the antibody does not engage A β 40 ( Bogstedt et al (2015) ).…”

Section: Passive Immunotherapies For a βmentioning

confidence: 99%

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Passive immunotherapies targeting Aβ and tau in Alzheimer's disease

Plotkin

Cashman

2020

Neurobiology of Disease

106

111

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Amyloid- β (A β ) and tau proteins currently represent the two most promising targets to treat Alzheimer's disease. The most extensively developed method to treat the pathologic forms of these proteins is through the administration of exogenous antibodies, or passive immunotherapy. In this review, we discuss the molecular-level strategies that researchers are using to design an effective therapeutic antibody, given the challenges in treating this disease. These challenges include selectively targeting a protein that has misfolded or is pathological rather than the more abundant, healthy protein, designing strategic constructs for immunizing an animal to raise an antibody that has the appropriate conformational selectivity to achieve this end, and clearing the pathological protein species before prion-like cell-to-cell spread of misfolded protein has irreparably damaged neurons, without invoking damaging inflammatory responses in the brain that naturally arise when the innate immune system is clearing foreign agents. The various solutions to these problems in current clinical trials will be discussed.

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“…Gantenerumab, a fully human monoclonal antibody that binds aggregated A␤ and removes A␤ plaques by Fc receptor-mediated phagocytosis, is in the Phase III recruiting stage [121,122]. Some other monoclonal antibodies which are recently observed are BAN-2401 [123,124]; UB-311 [125,126]; Crenezumab [127,128]; Ponezumab [129,130]; Octagam [131,132]; SAR-228810 [133,134]; MEDI-1814 [135]; KHK-6640 [136,137]; Lu-AF-20513 [138][139][140] and TTP4000 [133,141]. Some approaches to inhibition of enzymes, i.e., ␤and ␥-secretases involved in A␤PP cleavage, resulted in A␤ peptide formation.…”

Section: Anti-amyloid Drugs In Clinical Trialsmentioning

confidence: 99%

Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

Duggal

Mehan

2019

ADR

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Neuronal microtubule (MT) tau protein provides cytoskeleton to neuronal cells and plays a vital role including maintenance of cell shape, intracellular transport, and cell division. Tau hyperphosphorylation mediates MT destabilization resulting in axonopathy and neurotransmitter deficit, and ultimately causing Alzheimer's disease (AD), a dementing disorder affecting vast geriatric populations worldwide, characterized by the existence of extracellular amyloid plaques and intracellular neurofibrillary tangles in a hyperphosphorylated state. Pre-clinically, streptozotocin stereotaxically mimics the behavioral and biochemical alterations similar to AD associated with tau pathology resulting in MT assembly defects, which proceed neuropathological cascades. Accessible interventions like cholinesterase inhibitors and NMDA antagonist clinically provides only symptomatic relief. Involvement of microtubule stabilizers (MTS) prevents tauopathy particularly by targeting MT oriented cytoskeleton and promotes polymerization of tubulin protein. Multiple in vitro and in vivo research studies have shown that MTS can hold substantial potential for the treatment of AD-related tauopathy dementias through restoration of tau function and axonal transport. Moreover, anti-cancer taxane derivatives and epothiolones may have potential to ameliorate MT destabilization and prevent the neuronal structural and functional alterations associated with tauopathies. Therefore, this current review strictly focuses on exploration of various clinical and pre-clinical features available for AD to understand the neuropathological mechanisms as well as introduce pharmacological interventions associated with MT stabilization. MTS from diverse natural sources continue to be of value in the treatment of cancer, suggesting that these agents have potential to be of interest in the treatment of AD-related tauopathy dementia in the future.

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[P1–074]: PRECLINICAL DISCOVERY AND DEVELOPMENT OF MEDI1814, a MONOCLONAL ANTIBODY SELECTIVELY TARGETING BETA‐AMYLOID 42 (Aβ42)

Cited by 9 publications

References 0 publications

Neuronanomedicine: An Up-to-Date Overview

Neuronanomedicine: An Up-to-Date Overview

Passive immunotherapies targeting Aβ and tau in Alzheimer's disease

Neuroprotective Approach of Anti-Cancer Microtubule Stabilizers Against Tauopathy Associated Dementia: Current Status of Clinical and Preclinical Findings

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