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1.
Mov Disord ; 39(6): 936-944, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38494847

RESUMO

BACKGROUND: Immunotherapy targeting pathological α-synuclein (α-syn) species is a promising strategy for slowing disease progression in neurodegenerative synucleinopathies, including Parkinson's disease (PD). OBJECTIVE: The aim was to evaluate the safety, tolerability, pharmacokinetics, and target engagement of ascending doses of Lu AF82422. METHODS: In this first-in-human study (NCT03611569), healthy participants (18-55 years, cohort A) and patients with PD (40-80 years, Hoehn and Yahr stage ≤3, cohort B) were enrolled in ascending-dose cohorts and randomly assigned to receive single intravenous infusions of Lu AF82422 (cohorts A1-A6: 75, 225, 750, 2250 4500, and 9000 mg, respectively; cohorts B1 and B2: 2250 and 9000 mg, respectively) or placebo. Participants were monitored during a 12-week observational period. RESULTS: Overall, single intravenous infusions of Lu AF82422 were safe and well tolerated, and no serious adverse events (AE) were observed; the most common AEs were related to the study on lumbar punctures, headache, and common infections. Lu AF82422 concentrations (in plasma and cerebrospinal fluid [CSF]) increased in a dose-proportional manner with no observable differences between cohorts; mean plasma half-life was 700 h. Plasma concentrations of Lu AF82422 had an immediate, concentration-dependent lowering effect on the plasma concentration of free α-syn and on the ratio of free to total α-syn in all cohorts and lowered the free-to-total α-syn ratio in CSF in the high-dose PD cohort. CONCLUSIONS: The safety and pharmacokinetic profile of Lu AF82422 were appropriate for further clinical development, and results indicated peripheral target engagement. The central target engagement observed in participants with PD indicates that the doses of Lu AF82422 tested may provide CSF concentrations sufficient to target aggregated forms of α-syn. © 2024 H. Lundbeck A/S. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Doença de Parkinson , alfa-Sinucleína , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Adulto , Doença de Parkinson/tratamento farmacológico , Idoso , Adolescente , Adulto Jovem , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Método Duplo-Cego
2.
MAbs ; 13(1): 1994690, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34709986

RESUMO

Alpha-synuclein is a 15 kDa protein associated with neurodegenerative diseases such as Parkinson disease and multiple-system atrophy where pathological forms of alpha-synuclein aggregate and become neurotoxic. Here we describe the nonclinical program to support a first-in-human (FIH) single ascending dose (SAD) study for Lu AF82422, a human recombinant, anti-alpha-synuclein monoclonal antibody (mAb) in development for treatment of synucleinopathies. Alpha-synuclein is primarily expressed in brain, peripheral nerves and in blood cells. A tissue cross-reactivity assessment showed that Lu AF82422 binding was generally restricted to nervous tissues. Flow cytometry analysis did not show extracellular surface binding of Lu AF82422 to human platelets, erythrocytes, granulocytes, or lymphocytes, but to a low fraction of monocytes, without any functional consequences on activation or phagocytic capacity. A single dose pharmacokinetic (PK) study in cynomolgus monkeys with dose levels of 1-30 mg/kg confirmed PK properties in the expected range for a mAb with a soluble target, and target engagement was shown as a decrease in free alpha-synuclein in plasma. Four-week repeat-dose toxicity studies were conducted in rats and cynomolgus monkeys at doses up to 600 mg/kg administered intravenously every 10 days. Results showed no treatment-related adverse findings and the no-observed-adverse-effect-level was the highest dose tested. Target engagement was shown in plasma and cerebrospinal fluid. Taken together, the nonclinical data indicated no safety signal of concern and provided adequate safety margins between observed safe doses in animals and the planned dose levels in the FIH SAD study.


Assuntos
Doença de Parkinson , Sinucleinopatias , Animais , Anticorpos Monoclonais/farmacocinética , Imunoglobulina G , Ratos , alfa-Sinucleína
3.
J Neurosci ; 33(11): 4923-34, 2013 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-23486963

RESUMO

The Alzheimer's disease (AD) process is understood to involve the accumulation of amyloid plaques and tau tangles in the brain. However, attempts at targeting the main culprits, neurotoxic Aß peptides, have thus far proven unsuccessful for improving cognitive function. Recent clinical trials with passively administrated anti-Aß antibodies failed to slow cognitive decline in mild to moderate AD patients, but suggest that an immunotherapeutic approach could be effective in patients with mild AD. Using an AD mouse model (Tg2576), we tested the immunogenicity (cellular and humoral immune responses) and efficacy (AD-like pathology) of clinical grade Lu AF20513 vaccine. We found that Lu AF20513 induces robust "non-self" T-cell responses and the production of anti-Aß antibodies that reduce AD-like pathology in the brains of Tg2576 mice without inducing microglial activation and enhancing astrocytosis or cerebral amyloid angiopathy. A single immunization with Lu AF20513 induced strong humoral immunity in mice with preexisting memory T-helper cells. In addition, Lu AF20513 induced strong humoral responses in guinea pigs and monkeys. These data support the translation of Lu AF20513 to the clinical setting with the aims of: (1) inducing therapeutically potent anti-Aß antibody responses in patients with mild AD, particularly if they have memory T-helper cells generated after immunizations with conventional tetanus toxoid vaccine, and (2) preventing pathological autoreactive T-cell responses.


Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/química , Epitopos de Linfócito T/imunologia , Fragmentos de Peptídeos/química , Vacinação/métodos , Fatores Etários , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Análise de Variância , Animais , Anticorpos Anti-Idiotípicos/sangue , Anticorpos Anti-Idiotípicos/farmacologia , Formação de Anticorpos/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta Imunológica , Ensaio de Imunoadsorção Enzimática , Epitopos de Linfócito B/imunologia , Epitopos de Linfócito B/metabolismo , Feminino , Cobaias , Humanos , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/imunologia , Macaca fascicularis , Masculino , Camundongos , Camundongos Transgênicos , Mutação/genética , Neuroglia/efeitos dos fármacos , Neuroglia/imunologia , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Ligação Proteica/imunologia , Ressonância de Plasmônio de Superfície , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Vacinas/imunologia
6.
Neurochem Int ; 53(5): 137-47, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18656513

RESUMO

Although a large number of signalling cascades are known to be activated downstream of NCAM, only little is known regarding the hierarchical relationship between the involved molecules in the individual cascades and the level of cross talk between the cascades. Here, we evaluated the requirement of putative upstream signalling cascades for the phosphorylation of the kinases extracellular signal-regulated kinase (ERK) and Akt and the transcription factor cyclic adenosine monophosphate (cAMP) response-element binding protein (CREB) following stimulation of NCAM in rat cerebellar granule neurons with an NCAM ligand, the C3d peptide. NCAM-mediated ERK phosphorylation depended on activation of the fibroblast growth factor receptor (FGFR), Src-family kinases, MEK (MAP and ERK kinase) and G(0)/G(i)-proteins, whereas NCAM-mediated CREB phosphorylation depended on the activity of Src-family kinases and MEK. NCAM-specific Akt phosphorylation depended on cyclic guanosine monophosphate (cGMP) and phosphatidylinositide 3-kinase (PI3K). All three phosphorylation events were independent of activation of the signalling molecules phospholipase C, protein kinase C, protein kinase A, and CamKII, which all have been demonstrated previously to be involved in NCAM signalling. For comparison, we also evaluated the role of upstream signalling cascades on fibroblast growth factor 2 (FGF2)-mediated phosphorylation of ERK, Akt, and CREB and found that FGF2 required the activity of both FGFR and Src-family kinases for phosphorylation of ERK, Akt, and CREB. MEK was required for phosphorylation of ERK and CREB, but not Akt, whereas G(0)/G(i)-proteins were necessary for phosphorylation of Akt and CREB, and cGMP was necessary for Akt phosphorylation. We thus demonstrate that even though NCAM and FGF2 have many signalling features in common, and even though both are known to activate FGFR, there are a number of differences in the intracellular signalling network activated by the NCAM ligand C3d and the FGFR ligand FGF2.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fator 2 de Crescimento de Fibroblastos/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Células Cultivadas , Cerebelo/citologia , Neurônios/metabolismo , Fosforilação , Ratos , Ratos Wistar , Transdução de Sinais
8.
J Neurosci Res ; 86(4): 727-43, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17975827

RESUMO

The neural cell adhesion molecule (NCAM) plays a crucial role in neuronal development, synaptic plasticity, and regeneration. NCAM works as "smart glue" that not only mediates cell-cell adhesion but also induces activation of a complex network of intracellular signaling cascades on homophilic or heterophilic binding. Stimulation of NCAM by homophilic interactions induces neuronal differentiation through activation of a number of signaling molecules, including the fibroblast growth factor receptor, non-receptor kinases Fyn and focal adhesion kinase, growth-associated protein-43, the mitogen-activated protein kinase pathway, intracellular Ca(2+), and protein kinases A, C, and G. This review presents and discusses the current knowledge in the area of NCAM signaling with a focus on the events involved in NCAM-mediated neurite outgrowth.


Assuntos
Moléculas de Adesão de Célula Nervosa/fisiologia , Neuritos/metabolismo , Transdução de Sinais/fisiologia , Animais , Humanos
9.
Eur J Neurosci ; 25(6): 1678-84, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17408429

RESUMO

Stimulation of the neural cell adhesion molecule (NCAM) by homophilic interactions is known to lead to neurite outgrowth as well as to neuronal survival. Whereas a complex network of signalling molecules is known to be of importance to NCAM-mediated neurite extension, only limited information is available regarding signalling underlying NCAM-mediated neuroprotection. Here, we present data suggesting a difference in the signalling events required for survival of rat dopaminergic neurons as compared with neurite outgrowth from the same cell type. Whereas Fyn, fibroblast growth factor receptor, mitogen-activated protein and ERK kinase, protein kinase A and protein kinase C are required for both responses to NCAM-induced signalling, phospholipase C and Ca(2+)-calmodulin-dependent kinase II are only necessary for the neurite outgrowth response, but dispensable for neuroprotection.


Assuntos
Dopamina/metabolismo , Moléculas de Adesão de Célula Nervosa/metabolismo , Neurônios/fisiologia , Transdução de Sinais/fisiologia , Adrenérgicos/toxicidade , Análise de Variância , Animais , Contagem de Células/métodos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , Complemento C3d/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Mesencéfalo/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxidopamina/toxicidade , Ratos , Ratos Wistar , Tirosina 3-Mono-Oxigenase/metabolismo
10.
J Neurosci Res ; 85(4): 703-11, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17279552

RESUMO

The neural cell adhesion molecule (NCAM) plays a crucial role in neuronal development, regeneration, and synaptic plasticity associated with learning and memory consolidation. Homophilic binding of NCAM leads to neurite extension and neuroprotection in various types of primary neurons through activation of a complex network of signalling cascades, including fibroblast growth factor receptor, Src-family kinases, the mitogen-activated protein kinase pathway, protein kinase C, phosphatidylinositol-3 kinase, and an increase in intracellular Ca(2+). Here we present data indicating an involvement of cyclic GMP in NCAM-mediated neurite outgrowth in both hippocampal and dopaminergic neurons and in NCAM-mediated neuroprotection of dopaminergic neurons. In addition, evidence is presented suggesting that NCAM mediates activation of cGMP via synthesis of nitric oxide (NO) by NO synthase (NOS) and activation of soluble guanylyl cyclase by NO, leading to an increased synthesis of cGMP and activation by cGMP of protein kinase G.


Assuntos
GMP Cíclico/metabolismo , Moléculas de Adesão de Célula Nervosa/fisiologia , Neuritos/fisiologia , Neurônios/citologia , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Análise de Variância , Animais , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Células Cultivadas , GMP Cíclico/análogos & derivados , GMP Cíclico/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Embrião de Mamíferos , Inibidores Enzimáticos/farmacologia , Fibroblastos , Hipocampo/citologia , Mesencéfalo/citologia , Camundongos , Ratos , Ratos Wistar
11.
J Neurochem ; 91(4): 920-35, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15525346

RESUMO

The Neural Cell Adhesion Molecule (NCAM) plays a crucial role in development of the central nervous system regulating cell migration, differentiation and synaptogenesis. NCAM mediates cell-cell adhesion through homophilic NCAM binding, subsequently resulting in activation of the fibroblast growth factor receptor (FGFR). NCAM-mediated adhesion leads to activation of various intracellular signal transduction pathways, including the Ras-mitogen activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K)-Akt pathways. A synthetic peptide derived from the second fibronectin type III module of NCAM, the FGL peptide, binds to and induces phosphorylation of FGFR without prior homophilic NCAM binding. We here present evidence that this peptide is able to mimic NCAM heterophilic binding to the FGFR by inducing neuronal differentiation as reflected by neurite outgrowth through a direct interaction with FGFR in primary cultures of three different neuronal cell types all expressing FGFR subtype 1: dopaminergic, hippocampal and cerebellar granule neurons. Moreover, we show that the FGL peptide promotes neuronal survival upon induction of cell death in the same three cell types. The effects of the FGL peptide are shown to depend on activation of FGFR and the MAPK and PI3K intracellular signalling pathways, all three kinases being necessary for the effects of FGL on neurite outgrowth and neuronal survival.


Assuntos
Moléculas de Adesão de Célula Nervosa/metabolismo , Moléculas de Adesão de Célula Nervosa/farmacologia , Neuritos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores de Fatores de Crescimento de Fibroblastos/agonistas , Animais , Apoptose/efeitos dos fármacos , Caspase 3 , Caspases/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cerebelo/citologia , Dopamina/metabolismo , Ativação Enzimática/efeitos dos fármacos , Hipocampo/citologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Mesencéfalo/citologia , Moléculas de Adesão de Célula Nervosa/química , Neuritos/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Fragmentos de Peptídeos/química , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , RNA Mensageiro/biossíntese , Ratos , Ratos Wistar , Receptores de Fatores de Crescimento de Fibroblastos/genética , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo
12.
Neurochem Res ; 28(1): 127-41, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12587671

RESUMO

Cell adhesion molecules are known to play far more complex roles than mechanically attaching one cell to an adjacent cell or to components of the extracellular matrix. Thus, important roles for cell adhesion molecules in the regulation of intracellular signaling pathways have been revealed. In this review, we discuss the present knowledge about signaling pathways activated upon homophilic binding of the neural cell adhesion molecule (NCAM). Homophilic NCAM binding leads to activation of a signal transduction pathway involving Ca2+ through activation of the fibroblast growth factor receptor, and to activation of the mitogen-activated protein kinase pathway. In addition, cyclic adenosine monophosphate and protein kinase A are involved in NCAM-mediated signaling. Among these pathways the possibility exists of cross talk or convergence, of which different possible mediators have been suggested. Finally, several downstream effector molecules leading to NCAM-mediated cellular endpoints have been demonstrated, including transcription factors and regulators of the cytoskeleton.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Receptores de Fatores de Crescimento de Fibroblastos/metabolismo , Transdução de Sinais , Animais , AMP Cíclico/metabolismo , Sistema de Sinalização das MAP Quinases , Proteína Quinase C/metabolismo
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