An Effector-Reduced Anti- -Amyloid (A ) Antibody with Unique A Binding Properties Promotes Neuroprotection and Glial Engulfment of A (original) (raw)
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Immunotherapy for Alzheimer's disease
Biochemical Pharmacology, 2014
Alzheimer's disease (AD) is the most common cause of dementia worldwide. In AD the normal soluble amyloid β (sAβ) peptide is converted into oligomeric/fibrillar Aβ. The oligomeric forms of Aβ are thought to be the most toxic, while fibrillar Aβ becomes deposited as amyloid plaques and congophilic angiopathy, which serve as neuropathological markers of the disease. In addition the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat AD. Among the more exciting and advanced of these approaches is vaccination. Active and passive Immunotherapy targeting only Aβ has been successful in many AD model animal trials; however, the more limited human data has shown much less benefit so far, with encephalitis occurring in a minority of patients treated with active immunization and vasogenic edema or amyloid-related imaging abnormalities (ARIA) being a complication in some passive immunization trials. Therapeutic intervention targeting only tau has been tested only in mouse models; and no approaches targeting both pathologies concurrently has been attempted, until very recently. The immune approaches tried so far were targeting a self-protein, albeit in an abnormal conformation; however, effective enhanced clearance of the disease associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation. The design of future more effective immunomodulatory approaches will need to target all aspects of AD pathology, as well as specifically targeting pathological oligomeric conformers, without the use of any self-antigen.
Antibody Engineering for Optimized Immunotherapy in Alzheimer's Disease
Frontiers in Neuroscience, 2018
There are nearly 50 million people with Alzheimer's disease (AD) worldwide and currently no disease modifying treatment is available. AD is characterized by deposits of Amyloid-β (Aβ), neurofibrillary tangles, and neuroinflammation, and several drug discovery programmes studies have focussed on Aβ as therapeutic target. Active immunization and passive immunization against Aβ leads to the clearance of deposits in humans and transgenic mice expressing human Aβ but have failed to improve memory loss. This review will discuss the possible explanations for the lack of efficacy of Aβ immunotherapy, including the role of a pro-inflammatory response and subsequent vascular side effects, the binding site of therapeutic antibodies and the timing of the treatment. We further discuss how antibodies can be engineered for improved efficacy.
Current Alzheimer Research
Background: Alzheimer's disease (AD) is associated with age-associated central nervous system degeneration and dementia. This decline in the function correlates with deposition of Aβ peptide containing plaques and associated reactive gliosis. The inflammatory phenotype of microglia, in particular, is often considered detrimental to cognitive function in AD. In addition to the changes in the CNS, altered immune changes in the periphery have recently been observed in AD suggesting a critical immune-related communication between the periphery and the brain.
Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies
Acta neuropathologica, 2015
Immunotherapy is a promising strategy for the treatment of Alzheimer's disease (AD). Antibodies directed against Amyloid Beta (Aβ) are able to successfully clear plaques and reverse cognitive deficits in mouse models. Excitement towards this approach has been tempered by high profile failures in the clinic, one key issue has been the development of inflammatory side effects in the brain (ARIAs). New antibodies are entering the clinic for Alzheimer's disease; therefore, it is important to learn all we can from the current generation. In this study, we directly compared 3 clinical candidates in the same pre-clinical model, with the same effector function, for their ability to clear plaques and induce inflammation in the brain. We produced murine versions of the antibodies: Bapineuzumab (3D6), Crenezumab (mC2) and Gantenerumab (chGantenerumab) with an IgG2a constant region. 18-month transgenic APP mice (Tg2576) were injected bilaterally into the hippocampus with 2 µg of each an...
Amyloid-β Immunotherapy for Alzheimers Disease
Cns & Neurological Disorders-drug Targets, 2010
Alzheimer's disease (AD) is a progressive, degenerative disorder of the brain and the most common form of dementia among the elderly. As the population grows and lifespan is extended, the number of AD patients will continue to rise. Current clinical therapies for AD provide partial symptomatic benefits for some patients, however, none of them modify disease progression. Amyloid-β (Aβ) peptide, the major component of senile plaques in AD patients, is considered to play a crucial role in the pathogenesis of AD thereby leading to Aβ as a target for treatment. Aβ immunotherapy has been shown to induce a marked reduction in amyloid burden and an improvement in cognitive function in animal models. Although preclinical studies were successful, the initial human clinical trial of an active Aβ vaccine was halted due to the development of meningoencephalitis in ~ 6% of the vaccinated AD patients. Some encouraging outcomes, including signs of cognitive stabilization and apparent plaque clearance, were obtained in subset of patients who generated antibody titers. These promising preliminary data support further efforts to refine Aβ immunotherapy to produce highly effective and safer active and passive vaccines for AD. Furthermore, some new human clinical trials for both active and passive Aβ immunotherapy are underway. In this review, we will provide an update of Aβ immunotherapy in animal models and in human beings, as well as discuss the possible mechanisms underlying Aβ immunotherapy for AD.
Journal of Alzheimer's disease : JAD, 2012
The amyloid-β lowering capacity of anti-Aβ antibodies has been demonstrated in transgenic models of Alzheimer's disease (AD) and in AD patients. While the mechanism of immunotherapeutic amyloid-β removal is controversial, antibody-mediated sequestration of peripheral Aβ versus microglial phagocytic activity and disassembly of cerebral amyloid (or a combination thereof) has been proposed. For successful Aβ immunotherapy, we hypothesized that high affinity antibody binding to amyloid-β plaques and recruitment of brain effector cells is required for most efficient amyloid clearance. Here we report the generation of a novel fully human anti-Aβ antibody, gantenerumab, optimized in vitro for binding with sub-nanomolar affinity to a conformational epitope expressed on amyloid-β fibrils using HuCAL(®) phage display technologies. In peptide maps, both N-terminal and central portions of Aβ were recognized by gantenerumab. Remarkably, a novel orientation of N-terminal Aβ bound to the compl...
Alzheimer disease immunotherapeutics: Then and now
Human vaccines & immunotherapeutics, 2014
D ementia is a public health priority and one of the major contributors to morbidity and global non-communicable disease burden, thus necessitating the need for significant health-care interventions. Alzheimer disease (AD) is the most common cause of dementia and may contribute to 60-70% of cases. The cause and progression of AD are not well understood but have been thought to be due at least in part to protein misfolding (proteopathy) manifest as plaque accumulation of abnormally folded bamyloid and tau proteins in brain. There are about 8 million new cases per year. The total number of people with dementia is projected to almost double every 20 years, to 66 million in 2030 and 115 million in 2050. Immunotherapy in AD aimed at b-amyloid covers 2 types of vaccination: active vaccination against Ab42 in which patients receive injections of the antigen itself, or passive vaccination in which patients receive injections of monoclonal antibodies (mAb) against Ab42. Three of the peptide vaccines for active immunizations, CAD106, ACC001, and Affitope, are in phase 2 clinical trials. Three of the mAbs solanezumab, gantenerumab, and crenezumab, are or were in phase 2 and 3 clinical studies. While the phase 3 trials failed, one of these may have shown a benefit at least in mild forms of AD. There is a need for a greater initiative in the development of immunotherapeutics. Several avenues have been explored and still to come.
Treating Alzheimer’s disease with monoclonal antibodies: current status and outlook for the future
Alzheimer's Research & Therapy, 2013
In the past decade, Alzheimer's disease drug discovery has been directed at 'disease modifying drugs' that are able to counteract the progression of Alzheimer's disease by intervening in specific parts of its neuropathological process. Passive immunization with monoclonal antibodies (mAbs) may be able to clear toxic amyloid-β species either directly or through microglia or complement activation, thereby halting the amyloid cascade and preventing neurodegeneration and cognitive and functional decline. Thus far, results from two large phase 3 trial programs with bapineuzumab and solaneuzumab, respectively, have brought rather disappointing results. Possible explanations could be that these compounds were either targeting the wrong amyloid-β species, or were given too late in the disease process. Several new mAbs targeting various amyloid-β epitopes are now being tested in ongoing phase 2 and 3 clinical trials. The present review discusses the various mAbs aimed at amyloid-β, summarizes trial results and provides an outlook for the future.
J Neuroinflamm, 2010
Background: Purified intravenous immunoglobulin (IVIG) obtained from the plasma of healthy humans is indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. IVIG contains naturally occurring auto-antibodies, including antibodies (Abs) against β-amyloid (Aβ) peptides accumulating in the brains of Alzheimer's disease (AD) patients. IVIG has been shown to alleviate AD pathology when studied with mildly affected AD patients. Although its mechanisms-of-action have been broadly studied, it remains unresolved how IVIG affects the removal of natively formed brain Aβ deposits by primary astrocytes and microglia, two major cell types involved in the neuroinflammatory responses. Methods: We first determined the effect of IVIG on Aβ toxicity in primary neuronal cell culture. The mechanismsof-action of IVIG in reduction of Aβ burden was analyzed with ex vivo assay. We studied whether IVIG solubilizes natively formed Aβ deposits from brain sections of APP/PS1 mice or promotes Aβ removal by primary glial cells. We determined the role of lysosomal degradation pathway and Aβ Abs in the IVIG-promoted reduction of Aβ. Finally, we studied the penetration of IVIG into the brain parenchyma and interaction with brain deposits of human Aβ in a mouse model of AD in vivo. Results: IVIG was protective against Aβ toxicity in a primary mouse hippocampal neuron culture. IVIG modestly inhibited the fibrillization of synthetic Aβ1-42 but did not solubilize natively formed brain Aβ deposits ex vivo. IVIG enhanced microglia-mediated Aβ clearance ex vivo, with a mechanism linked to Aβ Abs and lysosomal degradation. The IVIG-enhanced Aβ clearance appears specific for microglia since IVIG did not affect Aβ clearance by astrocytes. The cellular mechanisms of Aβ clearance we observed have potential relevance in vivo since after peripheral administration IVIG penetrated to mouse brain tissue reaching highest concentrations in the hippocampus and bound selectively to Aβ deposits in co-localization with microglia. Conclusions: Our results demonstrate that IVIG promotes recognition and removal of natively formed brain Aβ deposits by primary microglia involving natural Aβ Abs in IVIG. These findings may have therapeutic relevance in vivo as IVIG penetrates through the blood-brain barrier and specifically binds to Aβ deposits in brain parenchyma.