ES2537015T3 - Proteína de unión del receptor de NOGO - Google Patents

Proteína de unión del receptor de NOGO Download PDF

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Publication number
ES2537015T3
ES2537015T3 ES10171533.2T ES10171533T ES2537015T3 ES 2537015 T3 ES2537015 T3 ES 2537015T3 ES 10171533 T ES10171533 T ES 10171533T ES 2537015 T3 ES2537015 T3 ES 2537015T3
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lrr
binding protein
receptor binding
nogo receptor
control
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Sha Mi
John Mccoy
R. Blake Pepinsky
Daniel H. S. Lee
Alexey A. Lugovskoy
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Biogen MA Inc
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    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
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    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
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    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
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    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
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    • C12N5/0602—Vertebrate cells
    • C12N5/0618—Cells of the nervous system
    • C12N5/0619—Neurons
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5058—Neurological cells
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Abstract

Uso de un anticuerpo o fragmento de unión a antígeno del mismo que se unen al polipéptido del SEQ ID NO: 2 para la preparación de un medicamento para tratar una enfermedad o trastorno neurodegenerativos, en los que la extensión axonal sería beneficiosa en un mamífero, en donde el anticuerpo o fragmento son capaces de disminuir la inhibición del crecimiento axonal de una neurona del sistema nervioso central (SNC).

Description

imagen1
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E10171533
14-05-2015
La FIG. 8 es un gráfico que resume los datos de un experimento que demuestra que Sp35-Fc administrado intratecalmente mejora la recuperación funcional después de la hemisección dorsal en una rata. La puntuación BBB locomotora se midió como una función del tiempo después de la hemisección dorsal en ratas de control (IgG) o tratadas con Sp35-Fc (8 animales por grupo). El tratamiento se inició en el momento de la lesión de la médula
5 espinal.
La FIG. 9 es un gráfico que muestra las puntuaciones BBB de los animales individuales en la semana cuatro en el experimento resumido en la FIG. 8.
Descripción detallada de la invención
El Sp35 humano de origen natural es una proteína específica del SNC glicosilada que contiene 614 aminoácidos
10 (FIG. 2; SEQ ID NO: 2). El polipéptido Sp35 de tipo salvaje completo, humano contiene un dominio LRR que consta de 14 repeticiones ricas en leucina (incluyendo protecciones N-y C-terminales), un dominio Ig, una región transmembrana, y un dominio citoplásmico (FIG. 3) . El dominio citoplásmico contiene un sitio de fosforilación canónico de tirosina. Además, la proteína Sp35 de origen natural contiene una secuencia señal, una región alcalina corta entre el LRRCT y el dominio Ig, y una región transmembrana entre el dominio Ig y el dominio citoplásmico (FIG.
15 3). El gen de Sp35 humano contiene codones de inicio de la traducción alternativos, de modo que seis aminoácidos adicionales, es decir, MQVSKR (SEQ ID NO: 9) pueden estar presentes o no en el extremo N-terminal de la secuencia señal de Sp35. La Tabla 1 enumera los dominios Sp35 y otras regiones, de acuerdo con el número de residuos de aminoácido, basándose en la secuencia en la FIG. 2 (SEQ ID NO: 2).
Tabla 1
Dominio o Región
Residuo de Comienzo Residuo de Finalización
Secuencia Señal
1 33
LRRNT
34 64
LRR
66 89
LRR
90 113
LRR
114 137
LRR
138 161
LRR
162 185
LRR
186 209
LRR
210 233
LRR
234 257
LRR
258 281
LRR
282 305
LRR
306 329
LRR
330 353
LRRCT
363 416
Alcalino
417 424
6
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E10171533
14-05-2015
Tabla 2
En ausencia de sp35-Fc
sustrato secado:
OMgp/Nogo/MAG/mielina Control de Fc
extensión de neuritas
corta distorsionada larga extendida
morfología del cuerpo celular
redondeada diseminada
materiales nucleares
condensados claros
número de neuronas al final del expt
reducido igual que Fc de control
imagen23
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En presencia de sp35-Fc
sustrato secado:
OMgp/Nogo/MAG/mielina Control de Fc
extensión de neuritas
larga extendida larga extendida
morfología del cuerpo celular
diseminada diseminada
materiales nucleares
claros claros
número de neuronas al final del expt
menos reducido que FC de control igual que Fc de control
Estos datos indican que una forma soluble de Sp35, p. ej., Sp35-Fc, posee actividad neuroprotectora.
En ratas con médula espinal hemi-transectada (T9, SCT), la tinción de tubulina βIII de las secciones de médula
5 espinal mostró una pérdida sustancial de neuronas en el sitio de la lesión. Se utilizó un virus recombinante que expresaba sp35 para infectar los animales SCT en el sitio de la lesión. La tinción histológica de estas médulas espinales mostró un aumento del número de neuronas alrededor del sitio de la lesión en comparación con el grupo de control que se había infectado con el virus vector. Esto es congruente con los descubrimientos experimentales in vitro descritos anteriormente, e indica adicionalmente las propiedades neuroprotectoras asociadas con Sp35.
10 Ejemplo 17: Sp35 en modelo animal de lesión de la médula espinal
Puesto que Sp35-Fc reduce la inhibición de la proyección de las neuritas causada por OMgp, Nogo-66 y MAG in vitro, los autores de la presente invención esperaban que la molécula promoviera la recuperación funcional de las lesiones del SNC in vivo. Para confirmar esto, los autores de la presente invención administraron Sp35-Fc a ratas con la médula espinal hemiseccionada, es decir, un modelo animal de traumatismo agudo del SNC. Como se
15 muestra en la FIG. 8 y la FIG. 9, las ratas tratadas con Sp35-Fc demostraron una recuperación funcional significativamente mejorada, en comparación con las ratas de control tratadas con IgG.
La lesión de la médula espinal y el análisis de comportamiento se realizaron de la siguiente manera. Todos los procedimientos quirúrgicos se realizaron de acuerdo con las directrices del Biogen Institutional Animal Use and Care Comittee. Se anestesiaron ratas Long Evans hembra (190-210 g, Charles River, Wilmington, MA) utilizando 2,5 20 mg/kg de midazolam, IP y Fluotano al 2-3% en O2. Se realizó una laminectomía dorsal a nivel espinal T6 y T7. Se realizó una hemisección dorsal, interrumpiendo completamente los componentes del conducto corticoespinal (CST) dorsomedial principal y dorsolateral minoritario. Inmediatamente después de la transección CST se insertó un catéter intratecal en el espacio subaracnoideo en T7 y se conectó a una bomba mini-osmótica cebada (modelo Alzet 2004) insertada en el espacio subcutáneo. Las bombas mini-osmóticas suministraron la proteína de control de isotipo de 25 Hu IgG (5 mg/ml, n = 5, Pharmingen), PBS (n = 3), proteína de fusión Hu Sp35-Ig soluble (4,3 mg/ml, n = 8) a una velocidad de 0,25 µl/h. Después de la cirugía, el sitio de la laminectomía se suturó y la herida de la piel se suturó con grapas. Los cuidados postoperatorios incluyen analgesia (buprenorfina 0,05 mg/kg sc) durante 3 días y tratamiento con antibióticos (ampicilina 100 mg/kg sc dos veces al día) durante 7 días después de la cirugía. Las vejigas se exprimieron manualmente dos veces al día durante la duración del estudio (28 días) o hasta el regreso de la función
25
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Claims (1)

  1. imagen1
ES10171533.2T 2003-03-19 2004-03-17 Proteína de unión del receptor de NOGO Expired - Lifetime ES2537015T3 (es)

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