Antibody Engineering for Optimized Immunotherapy in Alzheimer's Disease

Sumner, Isabelle L.; Edwards, Ross A.; Asuni, Ayodeji A.; Teeling, Jessica L.

doi:10.3389/fnins.2018.00254

Cited by 22 publications

(17 citation statements)

References 109 publications

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“…Treatment with different doses of bapineuzumab was tested in participants with mild to moderate AD to asses PK, safety, and tolerability profile. Based on these observations, bapineuzumab successfully reached phase III clinical trial . However, all bapineuzumab studies after concluding the results were terminated in August 2012, due to the evidence of low efficacy and increased the occurrence of magnetic resonance imaging (MRI) abnormalities, known as amyloid‐related imaging abnormalities attributed to edema or effusion (ARIA‐E) with high doses of bapineuzumab and APOE‐ε4 gene carriers …”

Section: Alternative Interventions To Prevent Aβ Accumulation By Immumentioning

confidence: 99%

“…Based on these observations, bapineuzumab successfully reached phase III clinical trial. 119 However, all bapineuzumab studies after concluding the results were terminated in August 2012, 112 due to the evidence of low efficacy and increased the occurrence of magnetic resonance imaging (MRI) abnormalities, known as amyloid-related imaging abnormalities attributed to edema or effusion (ARIA-E) with high doses of bapineuzumab and APOE-ε4 gene carriers. 120,121 Another first-generation Aβ passive immunotherapy is solanezumab (LY2062430, Eli Lilly), an IgG1 mAb that is humanized from the parent murine antibody m266.…”

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confidence: 99%

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BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

230

175

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Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.

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Section: Alternative Interventions To Prevent Aβ Accumulation By Immumentioning

confidence: 99%

mentioning

confidence: 99%

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

Moussa-Pacha

Abdin

Omar

et al. 2019

Medicinal Research Reviews

230

175

View full text Add to dashboard Cite

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“…Alterations of microglial motility have been documented in AD, with (i) microglial clusters identified around Aβ plaques indicating movement of microglia as part of their response to Aβ aggregation [16,57], (ii) in AD mouse models, impairment of directed motility and phagocytic activity [23], and (iii) morphological changes in plaque-associated cells [38]. Aβimmunotherapy is one of the major current therapeutic approaches being investigated in AD [51]. The first clinical trial of Aβ immunotherapy in humans involved active immunisation with a full-length synthetic Aβ42 compound named AN1792 [3].…”

Section: Introductionmentioning

confidence: 99%

P2‐196: MICROGLIAL MOTILITY IN ALZHEIMER'S DISEASE AND AFTER Aβ42 IMMUNOTHERAPY: A HUMAN POSTMORTEM STUDY

Franco-Bocanegra

George

Lau

et al. 2019

Alzheimer's & Dementia

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Microglial function is highly dependent on cell motility, with baseline motility required for homeostatic surveillance activity and directed motility to migrate towards a source of injury. Experimental evidence suggests impaired microglial motility in Alzheimer's disease (AD) and therefore we have investigated whether the expression of proteins associated with motility is altered in AD and affected by the Aβ immunotherapy using post-mortem brain tissue of 32 controls, 44 AD cases, and 16 AD cases from our unique group of patients immunised against A β 42 (iAD). Sections of brain were immunolabelled and quantified for (i) the motility-related microglial proteins Iba1, cofilin 1 (CFL1), coronin-1a (CORO1A) and P2RY12, and (ii) pan-A β , A β 42 and phosphorylated (p)tau. The neuroinflammatory environment was characterised using Meso Scale Discovery multiplex assays. The expression of all four motility-related proteins was unmodified in AD compared with controls, whereas Iba1 and P2RY12, the homeostatic markers, were increased in the iAD group compared with AD. Iba1 and P2RY12 showed significant positive correlations with A β in controls but not in AD or iAD groups. Pro-and anti-inflammatory proteins were increased in AD, whereas immunotherapy appears to result in a slightly less pro-inflammatory environment. Our findings suggest that as Aβ appears during the ageing process, the homeostatic Iba1 and P2RY12-positive microglia respond to Aβ, but this response is absent in AD. Aβ-immunisation promoted increased Iba1 and P2RY12 expression, likely reflecting increased baseline microglial motility but without restoring the profile observed in controls.

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“…6,9,12,13,15,16,19 However, such antibodies, injected in finite dose, may be captured away by the vast amount of monomers, leaving potentially neurotoxic species like oligomers and protofilaments undegraded. 20 In addition, targeting Aβ monomers may actually be harmful, as data suggest that these are involved in physiological function such as maintenance of the bloodbrain-barrier, antimicrobial and even neuronal protection. 21 In contrast, antibodies with ongoing clinical potential like Aducanumab (Biogen) and BAN2401 (Eisei/Bioartic Neurosciene) have considerably higher selectivity for aggregated vs monomeric Aβ forms (around 10 000-fold in case of Aducanumab).…”

Section: Introductionmentioning

confidence: 99%

From monomer to fibril: Abeta‐amyloid binding to Aducanumab antibody studied by molecular dynamics simulation

Frost

Zacharias

2020

Proteins

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Alzheimer's disease is one of the most common causes of dementia. It is believed that the aggregation of short Aβ-peptides to form oligomeric and protofibrillar amyloid assemblies plays a central role for disease-relevant neurotoxicity. In recent years, passive immunotherapy has been introduced as a potential treatment strategy with anti-amyloid antibodies binding to Aβ-amyloids and inducing their subsequent degradation by the immune system. Although so far mostly unsuccessful in clinical studies, the high-dosed application of the monoclonal antibody Aducanumab has shown therapeutic potential that might be attributed to its much greater affinity to Aβ-aggregates vs monomeric Aβ-peptides. In order to better understand how Aducanumab interacts with aggregated Aβ-forms compared to monomers, we have generated structural model complexes based on the known structure of Aducanumab in complex with an Aβ 2 − 7-eptitope. Structural models of Aducanumab bound to full-sequence Aβ 1 − 40-monomers, oligomers, protofilaments and mature fibrils were generated and investigated using extensive molecular dynamics simulations to characterize the flexibility and possible additional interactions. Indeed, an aggregate-specific N-terminal binding motif was found in case of Aducanumab binding to oligomers, protofilaments and fibrils that is located next to but not overlapping with the epitope binding site found in the crystal structure with Aβ 2 − 7. Analysis of binding energetics indicates that this motif binds weaker than the epitope but likely contributes to Aducanumab's preference for aggregated Aβspecies. The predicted aggregate-specific binding motif could potentially serve as a basis to reengineer Aducanumab for further enhanced preference to bind Aβaggregates vs monomers.

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Antibody Engineering for Optimized Immunotherapy in Alzheimer's Disease

Cited by 22 publications

References 109 publications

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease

P2‐196: MICROGLIAL MOTILITY IN ALZHEIMER'S DISEASE AND AFTER Aβ42 IMMUNOTHERAPY: A HUMAN POSTMORTEM STUDY

From monomer to fibril: Abeta‐amyloid binding to Aducanumab antibody studied by molecular dynamics simulation

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