ES2533480T3 - Uso de biomarcadores para evaluar el tratamiento de trastornos inflamatorios gastrointestinales con antagonistas de la integrina beta7 - Google Patents

Uso de biomarcadores para evaluar el tratamiento de trastornos inflamatorios gastrointestinales con antagonistas de la integrina beta7 Download PDF

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ES2533480T3
ES2533480T3 ES09747765.7T ES09747765T ES2533480T3 ES 2533480 T3 ES2533480 T3 ES 2533480T3 ES 09747765 T ES09747765 T ES 09747765T ES 2533480 T3 ES2533480 T3 ES 2533480T3
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beta7
lymphocytes
treatment
patient
beta7 integrin
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Thomas Richard Gelzleichter
Hajime Hiraragi
Eric Gary Stefanich
Hong Wang
Marna Bromberg Williams
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F Hoffmann La Roche AG
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
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    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70546—Integrin superfamily, e.g. VLAs, leuCAM, GPIIb/GPIIIa, LPAM
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Abstract

Un método para determinar la dosificación de un antagonista de integrina beta7 para el tratamiento de un trastorno gastrointestinal inflamatorio en un paciente, en el que dicho antagonista de la integrina beta7 es un anticuerpo anti-beta7, y el método comprende ajustar la dosis del antagonista de integrina beta7 en base a una comparación de la cantidad de un biomarcador en una muestra obtenida del paciente después de o durante el tratamiento con una dosis o régimen de dosificación del antagonista de integrina beta7, y la cantidad del biomarcador en una muestra obtenida del paciente antes del tratamiento, en el que un cambio en la cantidad del biomarcador después o durante el tratamiento, en comparación con antes del tratamiento, es indicativo de la eficacia o de respuesta a la dosis o régimen de dosificación del antagonista de la integrina beta7 para el tratamiento del trastorno gastrointestinal en el paciente, y en el que el biomarcador se selecciona de un grupo que consiste en linfocitos residentes en el intestino en la sangre periférica del paciente, la ocupación de antagonista de la integrina beta7 en los linfocitos residentes en el intestino, y los receptores de la integrina beta7 en los linfocitos residentes en el intestino, en el que los linfocitos residentes en el intestino son un subgrupo distintivo de linfocitos identificados como CD4+ CD45RA- β7 alto.

Description

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19-03-2015
el intestino y la cantidad de linfocitos residentes en la periferia en una muestra de sangre de dicho paciente con una relación entre la cantidad de linfocitos residentes en el intestino y la cantidad de linfocitos periféricos en una muestra de sangre de un individuo sano, en el que una disminución en la proporción de dicho paciente en comparación con la del individuo sano es indicativo del pronóstico de la enfermedad.
En otro aspecto, la especificación describe un método de identificación de una población de linfocitos que comprenden los linfocitos que expresan la integrina alfaEbeta7 y linfocitos que expresan la integrina alfa4beta7, que comprende unir dichos linfocitos con un anticuerpo aislado que se une al mismo epítopo que un anticuerpo que comprende la secuencia de una región variable de la cadena ligera del Id. de Sec. Nº: 10, y una secuencia de la región variable de la cadena pesada del Id. de Sec. Nº: 11.
En una realización, dichos linfocitos están en la sangre periférica de un paciente diagnosticado con una enfermedad intestinal inflamatoria.
En otro aspecto, dichos linfocitos están en los nódulos linfáticos y los tejidos del intestino de un paciente diagnosticado con una enfermedad intestinal inflamatoria linfático.
Breve descripción de las figuras
La figura 1 muestra subgrupos de linfocitos CD4 + en la sangre periférica de mono cynomolgus.
La figura 2 muestra la media del grupo (± DE) de linfocitos CD4+ CD45RA-beta7alto en sangre periférica después de 12 dosis intravenosas de 5, 15 o 50 mg / kg de rhuMAb Beta7 o 12 dosis intravenosas y subcutáneas de vehículo a mono cynomolgus (recuento absoluto,% LB).
La figura 3 muestra la media del grupo (± DE) de linfocitos CD4+ CD45RA-beta7alto en sangre periférica después de 12 dosis subcutáneas de 15 o 50 mg / kg de rhuMAb Beta7 o 12 dosis intravenosas y subcutáneas de vehículo a mono cynomolgus (recuento absoluto,% LB).
La figura 4 muestra la media del grupo (± DE) de linfocitos CD4+ CD45RA-beta7bajo en sangre periférica después de 12 dosis intravenosas de 5, 15 o 50 mg / kg de rhuMAb Beta7 o 12 dosis intravenosas y subcutáneas de vehículo a mono cynomolgus (recuento absoluto,% LB ).
La figura 5 muestra la media del grupo (± DE) de linfocitos CD4+ CD45RA-beta7bajo en sangre periférica después de 12 dosis subcutáneas de 15 o 50 mg / kg de rhuMAb Beta7 o 12 dosis intravenosas y subcutáneas de vehículo a mono cynomolgus (recuento absoluto,% LB).
beta7intermedio
La figura 6 muestra la media del grupo (± DE) de linfocitos CD4+ CD45RA-en sangre periférica después de 12 dosis intravenosas de 5, 15 o 50 mg / kg de rhuMAb Beta7 o 12 dosis intravenosas y subcutáneas de vehículo a mono cynomolgus (recuento absoluto,% LB).
beta7intermedio
La figura 7 muestra la media del grupo (± DE) de linfocitos CD4+ CD45RA-en sangre periférica después de 12 dosis subcutáneas de 15 o 50 mg / kg de rhuMAb Beta7 o 12 dosis intravenosas y subcutáneas de vehículo a mono cynomolgus (recuento absoluto,% LB).
La Figura 8 muestra aumento transitorio del recuento en la sangre periférica de linfocitos memoria / efectoras “residentes en intestino” CD4+ CD45RA-β7alto después de la administración de rhuMAb Beta7 -4 dosis semanales IV de 25 mg / kg de rhuMAb Beta7 o vehículo (recuentos absolutos,% LB).
La figura 9 (A-D) muestra la concentración en suero de rhuMAb Beta7 (microgramos / microlitro) y la ocupación de los receptores β7 en linfocitos memoria / efectoras CD4+ CD45RA-beta7alto de sangre periférica.
La figura 10 (A-D) muestra que el aumento transitorio en linfocitos memoria / efectoras “residentes en intestino” CD4+
CD45RA-β7alto en sangre periférica se correlaciona con la ocupación de los receptores β7 en linfocitos memoria / β7alto
efectoras CD4+ CD45RA-.
La Figura 11 muestra que rhuMAb Beta7 inhibe la residencia in vivo de los linfocitos en el colon inflamado pero no en el bazo de ratones SCID CD45RBalto reconstituido (modelo de colitis del ratón).
La figura 12A y 12B muestra la alineación de secuencias de las cadenas variables ligeras y pesadas para lo siguiente: secuencia consenso del subgrupo kappa I de la cadena ligera humana (Figura 12A, Id. de Sec. Nº: 12)., secuencia consenso del subgrupo III de la cadena pesada humana (figura 12B, Id. de Sec. Nº: 13), región variable de la cadena ligera del anticuerpo de rata anti-beta7 de ratón (Fib504) (figura 12A, Id. de Sec. Nº: 10), región variable de la cadena pesada del anticuerpo de rata anti-beta7 de ratón (Fib504) (figura 12B, Id. de Sec. Nº: 11), y variantes de anticuerpos humanizados: región variable de la cadena ligera humanizada hu504Kgraft (figura 12A, Id. de Sec. Nº: 14), región variable de la cadena pesada humanizada hu504Kgraft (figura 12B, Id. de Sec. Nº: 15), las
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Claims (1)

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    imagen2
ES09747765.7T 2008-05-16 2009-05-18 Uso de biomarcadores para evaluar el tratamiento de trastornos inflamatorios gastrointestinales con antagonistas de la integrina beta7 Active ES2533480T3 (es)

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US5411508P 2008-05-16 2008-05-16
US54115P 2008-05-16
PCT/US2009/044375 WO2009140684A2 (en) 2008-05-16 2009-05-18 Use of biomarkers for assessing treatment of gastrointestinal inflammatory disorders with beta7integrin antagonists

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US (5) US20100255508A1 (es)
EP (1) EP2279004B1 (es)
JP (4) JP6219556B2 (es)
KR (2) KR101511453B1 (es)
CN (1) CN102124344B (es)
AU (1) AU2009246071B2 (es)
BR (1) BRPI0908665A2 (es)
CA (1) CA2723614C (es)
DK (1) DK2279004T3 (es)
ES (1) ES2533480T3 (es)
IL (1) IL209079A (es)
MX (1) MX2010012368A (es)
PL (1) PL2279004T3 (es)
SI (1) SI2279004T1 (es)
WO (1) WO2009140684A2 (es)

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