RESUMEN
This corrects the article DOI: 10.1038/nature21361.
RESUMEN
Alzheimer's disease (AD) is characterized by deposition of amyloid-ß (Aß) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aß to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aß. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aß, and reduce soluble and insoluble Aß in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aß in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Anticuerpos Monoclonales Humanizados/uso terapéutico , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Amiloide/efectos de los fármacos , Amiloide/metabolismo , Péptidos beta-Amiloides/química , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ensayos Clínicos Fase III como Asunto , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Modelos Biológicos , Placa Amiloide/patología , Agregación Patológica de Proteínas/tratamiento farmacológico , SolubilidadRESUMEN
The prodrug [(2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxy)methyl]-2-oxido-[1,3,2]-dioxaphosphonane (MB07811)] of a novel phosphonate-containing thyroid hormone receptor agonist [3,5-dimethyl-4-(4'-hydroxy-3'-isopropylbenzyl)phenoxylmethylphosphonic acid (MB07344)] is the first application of the HepDirect liver-targeting approach to a non-nucleotide agent. The disposition of MB07811 was characterized in rat, dog, and monkey to assess its liver specificity, which is essential in limiting the extrahepatic side effects associated with this class of lipid-lowering agents. MB07811 was converted to MB07344 in liver microsomes from all species tested (CL(int) 1.23-145.4 microl/min/mg). The plasma clearance and volume of distribution of MB07811 matched or exceeded 1 l/h/kg and 3 l/kg, respectively. Although absorption of prodrug was good, its absolute oral bioavailability as measured systemically was low (3-10%), an indication of an extensive hepatic first-pass effect. This effect was confirmed by comparison of systemic exposure levels of MB07811 after portal and jugular vein administration to rats, which demonstrated a hepatic extraction ratio of >0.6 with liver CYP3A-mediated conversion to MB07344 being a major component. The main route of elimination of MB07811 and MB07344 was biliary, with no evidence for enterohepatic recirculation of MB07344. Similar metabolic profiles of MB07811 were obtained in liver microsomes across the species tested. Tissue distribution and whole body autoradiography confirmed that the liver is the major target organ of MB07811 and that conversion to MB07344 was high in the liver relative to that in other tissues. Hepatic first-pass extraction and metabolism of MB07811, coupled with possible selective distribution of MB07811-derived MB07344, led to a high degree of liver targeting of MB07344.
Asunto(s)
Organofosfonatos/farmacocinética , Profármacos/farmacocinética , Receptores de Hormona Tiroidea/agonistas , Receptores de Hormona Tiroidea/metabolismo , Animales , Perros , Sistemas de Liberación de Medicamentos/métodos , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos ICR , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Organofosfonatos/administración & dosificación , Profármacos/administración & dosificación , Conejos , Ratas , Ratas Sprague-DawleyRESUMEN
INTRODUCTION: Aducanumab (BIIB037), a human monoclonal antibody selective for aggregated forms of amyloid beta, is being investigated as a disease-modifying treatment for Alzheimer's disease (AD). METHODS: This randomized, double-blind, placebo-controlled single ascending-dose study investigated the safety, tolerability, and pharmacokinetics (PK) of aducanumab in patients with mild-to-moderate AD. Eligible patients were sequentially randomized 6:2 to aducanumab (0.3, 1, 3, 10, 20, 30, and 60 mg/kg) or placebo. RESULTS: The primary outcome was safety and tolerability. Doses ≤30 mg/kg were generally well tolerated with no severe or serious adverse events (SAEs). All three patients who received 60 mg/kg aducanumab developed SAEs of symptomatic amyloid-related imaging abnormalities, which completely resolved by weeks 8-15. Aducanumab Cmax, AUC0-last, and AUCinf increased in a dose-proportional manner. DISCUSSION: In this single-dose study, aducanumab demonstrated an acceptable safety and tolerability profile and linear PK at doses ≤30 mg/kg (clinicaltrials.govNCT01397539).
RESUMEN
The heptapeptide 1, NAc-Gly-Val-DIle-Thr-Arg-Ile-ArgNHEt, a structurally modified fragment derived from the second type-1 repeat of thrombospondin-1 (TSP-1), is known to possess antiangiogenic activity. However, therapeutic utility could not be demonstrated because this peptide has a very short half-life in rodents. To optimize the PD/PK profile of 1, we initiated a systematic SAR study. The initial structural modifications were performed at positions 5 and 7 of peptide 1 and at the N- and C-termini. Out of several hundred peptides synthesized, the nonapeptide 5 (ABT-526) emerged as a promising lead. ABT-526 inhibited VEGF-induced HMVEC cell migration and tube formation in the nanomolar range and increased apoptosis of HUAEC cells. ABT-526 showed acceptable PK in rodents, dog, and monkey. ABT-526, when incorporated in an angiogenic pellet implanted in the rat cornea at 10 microM, reduced neovascularization by 92%. Substitution of DalloIle in place of DIle in ABT-526 provided nonapeptide 6 (ABT-510), which was 30-fold less active than ABT-526 in the EC migration but 20-fold more active in the tube formation assay. In comparison to ABT-526, ABT-510 has increased water solubility and slower clearance in dog and monkey. Radiolabeled ABT-510 demonstrated saturable binding to HMVEC cells at 0.02-20 nM concentrations and was displaceable by TSP-1. ABT-510 and ABT-526 were shown to significantly increase apoptosis of HUAEC cells. ABT-510 was effective in blocking neovascularization in the mouse Matrigel plug model and inhibited tumor growth in the mouse Lewis lung carcinoma model. Previous studies had shown that ABT-510 was effective in inhibiting the outgrowth of murine melanoma metastases in syngeneic mice and in blocking the growth of human bladder carcinoma implanted in nude mice. It had been also shown that ABT-510 could regress tumor lesions in pet dogs or cause unexpected stabilization of the disease in advanced canine cancer. ABT-526 and ABT-510 are the first compounds in the class of potent inhibitors of angiogenesis that mimic the antiangiogenic function of TSP-1. ABT-510 is currently in phase II clinical studies.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Oligopéptidos/síntesis química , Trombospondina 1/química , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Apoptosis , Capilares/citología , Quimiotaxis/efectos de los fármacos , Córnea/irrigación sanguínea , Córnea/efectos de los fármacos , Perros , Células Endoteliales/efectos de los fármacos , Células Endoteliales/fisiología , Endotelio Vascular/citología , Femenino , Haplorrinos , Humanos , Técnicas In Vitro , Inyecciones Intravenosas , Ratones , Ratones Endogámicos C57BL , Imitación Molecular , Neovascularización Fisiológica/efectos de los fármacos , Oligopéptidos/farmacocinética , Oligopéptidos/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Cordón Umbilical/citología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Following a single oral or intravenous administration of the R,R(+) and S,S(-) (14)C-pseudoracemate of (+/-)-(1'R*,3R*)-3-phenyl-1-[(1',2',3',4'-tetrahydro-5',6'-methylene-dioxy-1'-naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200/I) to dogs, a total of six (R,R[+]) and eight (S,S[-]) metabolites were identified by high-pressure liquid chromatography/mass spectral techniques. Greater than 99% of the dose was eliminated as metabolites indicating that the clearance of I was predominantly metabolic. The catechol was the major excreted metabolite (fecal), whereas the urine and bile predominantly contained metabolites resulting from secondary biotransformation of the catechol via O-methylation, glucuronidation, and sulfation. After a single 12 mg/kg oral dose of racemic I to dogs, the mean area under the plasma curve (AUC(0-24h)) averaged 4.55 micro g. h/ml, with an apparent plasma clearance value of 2.70 l/h. kg. After 14 daily doses, the apparent plasma clearance was 3.5-fold lower (0.78 l/h. kg) and the AUC(0-24h) about 4-fold higher (18.58 micro g. h/ml). Isolation of liver microsomes from these animals indicated that a cytochrome p450 (p450)-metabolite complex (MI complex) was formed in the liver after both single and multiple dosing. The mean concentration of the MI complex 24 h after a single dose averaged 31 pmol/mg of microsomal protein, whereas the amount in the animals given multiple doses of I averaged 163 pmol/mg. There was a positive correlation (R(2) = 0.993) between the plasma AUC for I and the amount of the MI complex found in the liver of each animal. Formation of the MI complex was demonstrated in vitro in control dog liver microsomes, was NADPH-dependent, and was dissociated from p450 with 2-methylbenzimidazole. In vitro preincubation studies indicated that I was a mechanism-based inhibitor and that formation of the complex inhibited catechol formation. These results demonstrate that the liver p450s that metabolize I form an inhibitory MI complex after in vivo administration in dogs. Formation of the complex increases during multiple dosing and inhibits the enzymes from further metabolism of I resulting in nonlinear pharmacokinetics.