ES2491743T3 - Haptenos, conjugados de haptenos, composiciones de los mismos y método para su preparación y uso - Google Patents

Haptenos, conjugados de haptenos, composiciones de los mismos y método para su preparación y uso Download PDF

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ES2491743T3
ES2491743T3 ES12151520.9T ES12151520T ES2491743T3 ES 2491743 T3 ES2491743 T3 ES 2491743T3 ES 12151520 T ES12151520 T ES 12151520T ES 2491743 T3 ES2491743 T3 ES 2491743T3
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conjugates
fluorescence microscopy
haptens
haptenos
compositions
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Jerry W. Kosmeder
Mark Lefever
Donald Johnson
Michael Farrell
Zhanna Zhilina
Christopher Bieniarz
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Ventana Medical Systems Inc
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Ventana Medical Systems Inc
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    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
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Abstract

Un anticuerpo anti-hapteno que se une específicamente a un hapteno que es un nitroarilo, que puede ser un mono- o dinitro pirazol

Description

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Recientemente se han desarrollado Citrina y Venus, dos versiones brillantes de un mutante de la GFP que emite luz amarilla (YFP) que maduran eficazmente.
Dos variedades recientemente desarrolladas de DsRed, conocidas como T1 y E57, despliegan una maduración
mejorada, lo que hace que resulten preferibles para su uso en experimentos a dos colores.
5 La fluorescencia de algunas variantes de GFP puede ser "fotoactivada" mediante una iluminación específica, que ofrece la ventaja de que la fluorescencia se puede activar en un punto temporal seleccionado. Se han desarrollado tres proteínas fluorescentes que se someten a modificación fotoquímica en el cromóforo o cerca de este, PA-GFP, Kaede y KFP1, que permiten la activación selectiva de señales de fluorescencia tras una iluminación específica y que se pueden utilizar para marcar por fluorescencia células, organelos o proteínas individuales.
10 La Tabla 1 proporciona otros ejemplos de fracciones generadoras de señales y conjugados que comprenden estas fracciones.
Tabla 1
Ejemplos de conjugados de etiqueta detectable de anticuerpo
15
Etiqueta de conjugado de anticuerpo
Recomendado para Color emitido Excitación de etiqueta Emisión de etiqueta
Lake Placid Blue (EviTag™ Quantum Dot)
Citometría de flujo, inmunoblots y microscopía de fluorescencia <450 490
Fluoresceína (es decir, FITC)
Citometría de flujo, incl. sistemas BD FAC y Guava System, y microscopía de fluorescencia 494 518
Adirondack Green (EviTag™ Quantum Dot)
Citometría de flujo, inmunoblots y microscopía de fluorescencia <450 520
Rhodamine Green
Microscopía de fluorescencia 502 527
Catskill Green (EviTag™ Quantum Dot)
Microscopía de fluorescencia <450 540
Rodamina 6G
Citometría de flujo, inmunoblots y microscopía de fluorescencia 525 555
Hops Yellow (EviTag™ Quantum Dot)
Citometría de flujo, inmunoblots y microscopía de fluorescencia <450 560
Amersham Cy3
Microscopía de fluorescencia 550 565
R-Phycoerythrin (PE)
Citometría de flujo, sistemas Luminex® y Guava, ensayos de FRET, electroforesis capilar y uso (495)565 575
75
con FITC para doble etiquetado
Rhodamine Red
Citometría de flujo, microscopía de fluorescencia 560 580
Birch Yellow (EviTag™ Quantum Dot)
Microscopía de fluorescencia <450 580
Amersham Cy3.5
Microscopía de fluorescencia 581 596
Fort Orange (EviTag™ Quantum Dot)
Citometría de flujo, inmunoblots y microscopía de fluorescencia <450 600
SulfoRhodamine (Alias Texas Red®)
Citometría de flujo y microscopía de fluorescencia 596 615
Amersham Cy5
Immunoblot, incl. Amersham Typhoon System, y aplicaciones inmunofluorescentes 650 670
Allophycocyanin (APC)
Ensayos FRET y ensayos HTRF 652 670
Amershani Cy5.5
Immunoblot, especialmente sistemas LI-COR Odyssey 675 694
Biotina
Citometría de flujo y otras aplicaciones fluorescentes -
Muchas de estas etiquetas se pueden utilizar con múltiples anticuerpos que no interreaccionan para crear ensayos multiplexados personalizados.
VII. Procesos para la formación de conjugados de hapteno -Esquemas de reacción
5 Los siguientes esquemas proporcionan ejemplos de realizaciones de un método útil para producir conjugados de la presente realización. Otras metodologías sintéticas también resultan útiles para producir estos conjugados y no se deberá interpretar que los esquemas siguientes limitan el método a las metodologías sintéticas concretas ilustradas.
1. Conjugados de nitropirazol
El Esquema 1 ilustra un método adecuado para acoplar ejemplos de haptenos de nitropirazol a un conector de óxido 10 de alquileno y posteriormente a un vehículo de proteína.
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tampón de fosfatos (PBS) 0,15 molar. La concentración de BSA-dPEG8-benzofurazano fue de 2 µg/ml, y la concentración por pocillo de 50 µL. Estas muestras se incubaron a 4 ˚C hasta el día siguiente. Se utilizó leche en polvo desnatada (NFDM) al 1% (10 mg/mL, 300 µL/por pocillo) como reactivo de bloqueo, seguido de incubación a 37 ˚C durante 120 minutos. Las placas se lavaron, cuando se consideró necesario, utilizando 0,15 M PBS que
5 contenía un 0,05% de Tween 20. A continuación se utilizó cada hapteno testado para producir antisuero de ratón. Se utilizó una concentración total de 80 [micro]l por pocillo de antisuero de ratón diluido con un 1% de NFDM en 0,15 M PBAS, utilizando el protocolo de diluciones y de diseño de placas que se indica más adelante en la Tabla 6. Las placas se incubaron a continuación a 37 ˚C durante 150 minutos. Se utilizó un conjugado de peroxidasa de rábanoanticuerpo de cabra anti-ratón (Gt-α-Mu-HRP, Pierce) como anticuerpo secundario a una concentración de 1:10,000
10 en 0.15 M PBS con un 0,05% de Tween 20 para obtener un volumen total de 50 µL/por pocillo. A continuación, las placas se incubaron durante 60 minutos a 37 ˚C. La configuración y los resultados del ELISA se resumen en la Tabla 2 siguiente.
Tabla 2
Resultados del ensayo ELISA
Adhesión:
Cliente Muestra testada Suero antiratón
500421
Ventana
Parámetros del ensayo
Paso
Reactivo Dilución en serie Solución tampón de dilución Concentración Volumen/pocillo Incubación
Revestimient o de Ag.
VMSI1357-98 0,15M PBS 2µg/ml 50µl ON@4C
Bloqueo
1% NFDM 0,15M PBS 10µg/ml 300 µl 2hr @37C
Dilución de la muestra
Véase debajo 5 x 1% NFDM en 0,15m PBS Partida @1,50 80 µl 2,5hr. @ 37C
Ac secundario
Gt-α-Mu-HRP ,15M PBS w/0,05% Tween 20 1 (10000) 50µl 1hr @ 37c
Diseño de la placa
Dilución de la muestra
1:50 1:250 1:1250 1:6250 1:31250 1:156250
1
2 3 4 5 6 7 8 9 10 11 12
Mu#1
A 1,8 9 0,0 1 1,8 1 0,0 0 1,8 2 0,0 0 1,60 0,00 1,06 0,0 0 0,5 6 0,0 0
Mu#2
B 1,7 6 0,0 1 1,8 7 0,0 0 1,7 3 0,0 0 1,25 0,00 0,60 0,0 0 0,2 5 0,0 0
Mu#3
C 1,7 0 0,0 1 1,8 3 0,0 0 1,8 7 0,0 0 1,50 0,00 0,95 0,0 1 0,3 7 0,0 0
Mu#4
D 1,7 5 0,0 1 1,7 3 0,0 0 1,8 3 0,0 0 1,49 0,01 0,98 0,0 0 0,4 2 0,0 0
Mu#5
E 1,6 2 0,0 1 1,5 8 0,0 0 1,7 2 0,0 0 1,35 0,00 ,074 0,0 0 0,3 3 0,0 0
Concentrad o premezcla (PbP)
F 0 ,06 0,0 1 0,0 1 0,0 0 0,0 0 0,0 1 0,00 0,00 0,00 0,0 0 0,0 0 0,0 0
x
x
x
x
x
x
Antígeno
VMSI-1357-98 Lot#C05081610 x = en blanco (sin antígeno)
Solución tampón de
0,15M PBS con 0,05% Tween 20 NFDM = leche en polvo desnatada
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5
10
15
20
25
30
35
1992 ; Pluckthun, Biotechnology 9:545, 1991 ; Huse et al., Science 246:1275, 1989 y Ward et al., Nature 341:544, 1989, incorporados todos al presente por referencia.
A menudo, las proteínas heterólogas funcionales de E. coli u otras bacterias se aíslan de los cuerpos de inclusión y exigen una solubilización utilizando potentes desnaturalizantes y su posterior repliegue. Durante el paso de solubilización, como se sabe en la técnica, debe estar presente un agente reductor para separar los enlaces disulfuro. Un ejemplo de solución tampón con un agente reductor es el siguiente: 0.1 M Tris pH 8, 6 M guanidina, 2 mM EDTA, 0,3 M DTE (ditioeritritol). La reoxidación de los enlaces disulfuro se puede producir en presencia de reactivos de tiol de bajo peso molecular en forma reducida y oxidada, tal como se describe en Saxena et al., Biochemistry 9: 5015-5021, 1970, incorporado al presente por referencia, y especialmente tal como se describe en Buchner et al., supra.
La renaturalización se realiza típicamente mediante dilución (por ejemplo, 100 veces) de la proteína desnaturalizada y reducida en solución tampón de replegado. Un ejemplo de solución tampón es 0,1 M Tris, pH 8.0, 0,5 M L-arginina, 8 mM glutatión oxidado (GSSG), y 2 mM EDTA.
Como modificación del protocolo de purificación de anticuerpos de doble cadena, las regiones de la cadena pesada y ligera se solubilizan y reducen por separado y, a continuación, se combinan en la solución de replegado. Un ejemplo de rendimiento se obtiene cuando estas dos proteínas se mezclan en un ratio molar de forma que no se supera un exceso molar de 5 veces de una proteína con respecto a la otra. Se recomienda añadir glutatión oxidado en exceso u otros compuestos oxidantes de bajo peso molecular a la solución de replegado una vez que se haya completado el intercambio-redox.
Además de los métodos recombinantes, los anticuerpos divulgados en el presente también se pueden producir, en su totalidad o en parte, utilizando la síntesis peptídica estándar. La síntesis en fase sólida de los polipéptidos de menos de unos 50 aminoácidos de longitud se puede realizar uniendo el aminoácido C-terminal de la secuencia con un soporte insoluble, seguido de la adición secuencial de los restantes aminoácidos de la secuencia. Las técnicas para la síntesis en fase sólida se describen en Barany & Merrifield, The Peptides: Analysis, Synthesis, Biology. Vol.
2: Special Methods in Peptide Synthesis, Part A. pp. 3-284 ; Merrifield et al., J. Am. Chem. Soc. 85:2149-2156, 1963 , y Stewart et al., Solid Phase Peptide Synthesis, 2ª ed., Pierce Chem. Co., Rockford, Ill., 1984 . Las proteínas de mayor longitud se pueden sintetizar mediante condensación de los términos amino y carboxilo de los fragmentos más cortos. Los métodos para formar enlaces peptídicos mediante activación de un extremo carboxi-terminal (como mediante el uso del reactivo de acoplamiento N,N'-diciclohexilcarbodiimida) son conocidos en la técnica.
XII. Antígenos
Algunos ejemplos de antígenos de interés incluyen los que se recogen a continuación:
Tabla 1
Ejemplos de antígenos de interés (antígenos diana)
Antígenos diana virales
Ejemplos de secuencias de antígenos diana de los antígenos diana SEC. ID. Nº:
BK
TLYKKMEQDVKVAHQ GNLPLMRKAYLRKCK TFSRMKYNICMGKCI 1 22 23
JC
SITEVECFL 2
Epstein-Barr (EBV)
QPRAPIRPI 3
citomegalovirus (CMV)
NLVPMVATV 4
HPV
YMLDLQPET(T) 5
Influenza A
GILGFVFTL 6
Antígenos diana del tumor y sus péptidos derivados
PRAME
LYVDSLFFL 7
136
WT1
RMFPNAPYL 8
Survivin
ELTLGEFLKL 9
AFP
GVALQTMKQ 10
ELF2M
ETVSEQSNV 11
proteinasa 3 y su péptido PR1
VLQELNVTV 12
elastasa de neutrófilos
VLQELNVTV 13
MAGE
EADPTGHSY 14
MART
AAGIGILTV 15
tirosinasa
RHRPLQEVYPEANAPIGHNRE 16
GP100
WNRQLYPEWTEAQRLD 17
NY-Eso-1
VLLKEFTVSG 18
Herceptin
KIFGSLAFL 19
antígeno carcinoembrionario (CEA)
HLFGYSWYK 20
PSA
FLTPKKLQCV 21
Antígeno diana fúngico
Blastomyces dermatitidis
CELDNSHEDYNWNLWFKWCSGHGR TGHGKHFYDCDWDPSHGDYSWYLW DPSHGDYSWYLWDYLCGNGHHPYD DYLCGNGHHPYDCELDNSHEDYSW DPYNCDWDPYHEKEKYDWDLWNKWCN KYDWDLWNKWCNKDPYNCDWDPYH 24 25 26 27 28 29
Tabla 2 Ejemplos de tumores y sus antígenos tumorales
Tumor
Antígenos diana asociados al tumor
Leucemia mielógena aguda
Tumor de Wilms 1 (WT1), preferiblemente antígeno de melanoma expresado (PRAME), PR1, proteinasa 3, elastasa catepsina G
Leucemia mielógena crónica
WT1, PRAME, PR1, proteinasa 3, elastasa, catepsina G
Síndrome mielodisplásico
WT1, PRAME, PR1, proteinasa 3, elastasa, catepsina G
Leucemia linfoblástica aguda
PRAME
Leucemia linfocítica crónica
Superviviente
Linfoma no Hodgkin
Superviviente
Mieloma múltiple
Nueva York esofágico 1 (NY-Eso-1)
Melanoma maligno
MAGE, MART, Tirosinasa, PRAME GP100
Cáncer de mama
WT1, herceptina
Cáncer de pulmón
WT1
Cáncer de próstata
Antígeno prostático específico (PSA)
137
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