Multiple‐dose ponezumab for mild‐to‐moderate Alzheimer's disease: Safety and efficacy

Landen, Jaren W.; Cohen, Sharon; Billing, Clare B.; Cronenberger, Carol; Styren, Scot; Burstein, Aaron H.; Sattler, Catherine; Lee, Jae Hong; Jack, Clifford R.; Kantarci, Kejal; Schwartz, Pamela F.; Duggan, William; Zhao, Qinying; Sprenger, Ken; Bednar, Martin M.; Binneman, Brendon

doi:10.1016/j.trci.2017.04.003

Cited by 52 publications

(48 citation statements)

References 14 publications

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“…The high antibody titers of ~ 400 μg/ml would be difficult to maintain over prolonged time periods using intravenous injection of monoclonal antibodies, which typically results in 100–200 μg/ml serum levels that drop sharply within weeks in humans (Sevigny et al , ; Landen et al , ). Low antibody trough levels and development of anti‐drug antibodies are known to limit the long‐term efficacy of antibody therapy in oncology and inflammatory diseases (Mazor et al , ; Kverneland et al , ).…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, the more advanced clinical trials with active and passive immunotherapy targeting extracellular Aβ aggregates in patients with AD were largely disappointing despite great promise from mouse models (Schenk et al , ; Sevigny et al , ). The key insights from these studies are as follows: (i) Antibodies can penetrate the blood–brain barrier at low levels that may be sufficient to affect the target (Schenk et al , ; Orgogozo et al , ; Landen et al , ). (ii) Clearance of Aβ load correlates with the antibody titer (Sevigny et al , ).…”

Section: Introductionmentioning

confidence: 99%

“…(iii) Unwanted T‐cell responses to active vaccination caused severe meningoencephalitis in a subset of AD patients but may be prevented by careful choice of the epitope (Schenk et al , ; Orgogozo et al , ; Axelsen et al , ). (iv) Limited cognitive improvement despite efficient clearance of Aβ in patients suggests disease mechanisms change and therapy should be started very early, maybe even in the prodromal phase, which is difficult in a mainly sporadic disease (Landen et al , ).…”

Section: Introductionmentioning

confidence: 99%

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Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model

et al. 2019

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The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non-canonical translation of the expanded repeat results in abundant poly-GA inclusion pathology throughout the CNS. (GA) 149 -CFP expression in mice triggers motor deficits and neuroinflammation. Since poly-GA is transmitted between cells, we investigated the therapeutic potential of anti-GA antibodies by vaccinating (GA) 149 -CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin-(GA) 10 conjugates and pre-aggregated carrier-free (GA) 15 . Only ovalbumin-(GA) 10 immunization induced a strong anti-GA response. The resulting antisera detected poly-GA aggregates in cell culture and patient tissue. Ovalbumin-(GA) 10 immunization largely rescued the motor function in (GA) 149 -CFP transgenic mice and reduced poly-GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin-(GA) 10 -immunized poly-GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/ macrophages. Moreover, cytoplasmic TDP-43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model

et al. 2019

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“…61 Ponezumab binds the C-terminal of Aβ but did not affect CSF Aβ or decline of cognition in AD. 56,57,62 MEDI1814 also binds the C-terminal of Aβ; initial clinical tests are ongoing. 56,57 Epitopes of some therapeutic Aβ antibodies are conformations of Aβ.…”

Section: Vaccination For Admentioning

confidence: 99%

Rationale for the development of an Alzheimer’s disease vaccine

Kwan

Konno

Chan

et al. 2019

Human Vaccines & Immunotherapeutics

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Vaccination traditionally has targeted infectious agents and thus has not heretofore been used to prevent neurodegenerative illness. However, amyloid β (Aβ) or tau, which can act like infectious proteins, or prions, might induce Alzheimer's disease (AD). Furthermore, evidence suggests that traditional infectious agents, including certain viruses and bacteria, may trigger AD. It is therefore worth exploring whether removing such targets could prevent AD. Although failing to treat AD patients who already display cognitive impairment, Aβ monoclonal antibodies are being tested in pre-symptomatic, at-risk individuals to prevent dementia. These antibodies might become the first AD therapeutics. However, their high cost will keep them out of the arms of the vast majority of patients, who increasingly live in developing countries. Because vaccines produce antibodies internally at much lower cost, vaccination might be the most promising approach to reducing the global burden of dementia.

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“…In the past decade, a tremendous amount of effort has been put into translating immunotherapies into cognitive benefits in human clinical trials (Graham, Bonito‐Oliva, & Sakmar, 2017; Long & Holtzman, 2019). However, a number of clinical trials failed because of serious side effects or inadequate therapeutic efficacy (Gilman et al, 2005; Landen et al, 2017; Pasquier et al, 2016; Salloway et al, 2014; Schneeberger et al, 2015; Vandenberghe et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Vaccines targeting the primary amino acid sequence and conformational epitope of amyloid‐β had distinct effects on neuropathology and cognitive deficits in EAE/AD mice

Zhu

Liu

et al. 2020

British J Pharmacology

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Background and Purpose:Immunotherapeutic intervention is one of the most promising strategies for the prevention and treatment of Alzheimer's disease (AD). Although they showed great success in AD mouse models, the clinical trials of many immune approaches failed due to low efficacy and safety. Thus, an animal model which can show the potential side effects of vaccines or antibodies is urgently needed. In this study, we generated EAE/AD mice by crossing APP/PS1 mice with experimental autoimmune encephalomyelitis (EAE) mice. We then investigated the efficacy and safety of two vaccines: the immunogens of which were Aβ1-42 aggregates (Aβ42 vaccine) and an oligomer-specific conformational epitope (AOE1 vaccine), respectively.Experimental Approach: EAE/AD mice were immunized with the Aβ42 vaccine or AOE1 vaccine five times at biweekly intervals. After the final immunization, cognitive function was evaluated by the Morris water maze, Y maze, and object recognition tests.Neuropathological changes in the mouse brains were analysed by immunohistochemistry and ELISA. Key Results:In contrast to previous findings in conventional AD animal models, Aβ42 immunization promoted neuroinflammation, enhanced Aβ levels and plaque burden, and failed to restore cognitive deficits in EAE/AD mice. By contrast, AOE1 immunization dramatically attenuated neuroinflammation, reduced Aβ levels, and improved cognitive performance in EAE/AD mice. Conclusion and Implications:These results suggest that the EAE/AD mouse model can exhibit the potential side effects of AD immune approaches that conventional AD animal models fail to display. Furthermore, strategies specifically targeting Aβ oligomers may be safe and show clinical benefit for AD treatment.

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Multiple‐dose ponezumab for mild‐to‐moderate Alzheimer's disease: Safety and efficacy

Cited by 52 publications

References 14 publications

Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model

Active poly‐GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model

Rationale for the development of an Alzheimer’s disease vaccine

Vaccines targeting the primary amino acid sequence and conformational epitope of amyloid‐β had distinct effects on neuropathology and cognitive deficits in EAE/AD mice

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