ES2494921T3 - Anticuerpo que sustituye la función del factor VIII de coagulación sanguínea - Google Patents

Anticuerpo que sustituye la función del factor VIII de coagulación sanguínea Download PDF

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ES2494921T3
ES2494921T3 ES06730769.4T ES06730769T ES2494921T3 ES 2494921 T3 ES2494921 T3 ES 2494921T3 ES 06730769 T ES06730769 T ES 06730769T ES 2494921 T3 ES2494921 T3 ES 2494921T3
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coagulation factor
a44fr
pcagg
a44lr3
a44lf3
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Tetsuo Kojima
Kunihiro Hattori
Tetsuhiro Soeda
Taro Miyazaki
Hiroyuki Saito
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Chugai Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/36—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against blood coagulation factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/46—Hybrid immunoglobulins
    • C07K16/468—Immunoglobulins having two or more different antigen binding sites, e.g. multifunctional antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/75—Agonist effect on antigen

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Abstract

Un anticuerpo biespecífico que puede sustituir funcionalmente al factor VIII de coagulación y que presenta la actividad para mejorar la activación del factor X, que comprende: un primer dominio que reconoce al factor de coagulación IX y/o al factor de coagulación IX activado; y un segundo dominio que reconoce al factor de coagulación X, donde el primer dominio comprende un primer polipéptido que comprende la cadena H de un anticuerpo contra el factor de coagulación IX y/o el factor de coagulación IX activado; el segundo dominio comprende un segundo polipéptido que comprende la cadena H de un anticuerpo contra el factor de coagulación X; y tanto el primero como el segundo dominio comprenden un tercer polipéptido que comprende una cadena L compartida en común de un anticuerpo contra el factor de coagulación IX, el factor de coagulación IX activado o el factor de coagulación X, donde el tercer polipéptido comprende un sitio de unión a antígenos que comprende las CDR1, 2 y 3 seleccionadas individualmente de CDR1, 2 y 3 de cada cadena L de dos o más anticuerpos;

Description

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E06730769
22-08-2014
GAAGCGATCAGGGACTCCACTGTACCGGTAGGATGCCGAGTAAATCAGTAGTTTAGG B26LF4_A44fr (SEQ ID NO: 61) CTGGCAGATTATCTCTGTCAGCAATATAACAGCTATCCACTCACGTTCGGTGGTGGGA CC A69LR1_A44fr (SEQ ID NO: 62)
5 GGCTACAGCAGTACTCACATCCTGACTGGCCTTGCAGGTGATGCTGACCCTGTCTCCT ACTGATGTGGA A5OLF4_A44fr (SEQ ID NO: 63) CTGGCAGATTATCTCTGTCAGCAATATAGCAGCTATTTAACGTTCGGTGGTGGGACC scback (SEQ ID NO: 64) TTACTCGCGGCCCAGCCGGCCATGGCGGACTACAAAG
10 scfor (SEQ ID NO: 65) GGAATTCGGCCCCCGAG Se mezcló 1 µL de cada oligo ADN sintetizado preparado a 10 µM en la combinación que se muestra en la tabla 1, y
se prepararon 45 µL de las soluciones de reacción que comprenden 1x de tampón agregado de enzimas, 0,33 mM de dNTPs, 2,5 unidades de Proof Start Polymerase (Qiagen) o LATaq (TAKARA). Después de calentar a 94°C
15 durante 5 minutos, se llevaron a cabo 7 ciclos de reacciones a 94°C durante un minuto y 63 °C durante 4 minutos, posteriormente se agregaron 5 µL cada solución de 5 µM de scback y 5 µM de scfor, y se llevaron a cabo 30 ciclos de reacciones a 94°C durante 30 segundos, 55°C durante 30 segundos, y 72°C durante 30 segundos para amplificar el gen VL.
BBA :
B26LR1_A44fr B26LR2_A44fr A44LF4 A44LF1 A44LF2 A44LF3 A44LR3 A44LR4
BAA :
B26LR1_A44fr A44LR2 A44LF4 A44LF1 A44LF2 A44LF3 A44LR3 A44LR4
ABA :
A44LR1 B26LR2_A44fr A44LF4 A44LF1 A44LF2 A44LF3 A44LR3 A44LR4
AAA :
A44LR1 A44LR2 A44LF4 A44LF1 A44LF2 A44LF3 A44LR3 A44LR4
AAa :
A44LR1 A44LR2 A50LF4_A44fr A44LF1 A44LF2 A44LF3 A44LR3 A44LR4
BAa :
B26LR1_A44fr A44LR2 A50LF4_A44fr A44LF1 A44LF2 A44LF3 A44LR3 A44LR4
ABa :
A44LR1 B26LR2_A44fr A50LF4_A44fr A44LF1 A44LF2 A44LF3 A44LR3 A44LR4
BBa :
B26LR1_A44fr B26LR2_A44fr A50LF4_A44fr A44LF1 A44LF2 A44LF3 A44LR3 A44LR4
aAA :
A69LR1_A44fr A44LR2 A44LF4 A44LF1 A44LF2 A44LF3 A44LR3 A44LR4
aBA :
A69LR1_A44fr B26LR2_A44fr A44LF4 A44LF1 A44LF2 A44LF3 A44LR3 A44LR4
BBA(G) :
B26LR1_A44fr B26LR2_A44fr A44LF4 A44LF1 A44LF2 A44LF3 A44LR3 A44LR4Gly
BAA(G) :
B26LR1_A44fr A44LR2 A44LF4 A44LF1 A44LF2 A44LF3 A44LR3 A44LR4Gly
ABA(G) :
A44LR1 B26LR2_A44fr A44LF4 A44LF1 A44LF2 A44LF3 A44LR3 A44LR4Gly
AAA(G) :
A44LR1 A44LR2 A44LF4 A44LF1 A44LF2 A44LF3 A44LR3 A44LR4Gly
AAa(G) :
A44LR1 A44LR2 A50LF4_A44fr A44LF1 A44LF2 A44LF3 A44LR3 A44LR4Gly
Baa(G) :
B26LR1_A44fr A44LR2 A50LF4_A44fr A44LF1 A44LF2 A44LF3 A44LR3 A44LR4Gly
ABa(G) :
A44LR1 B26LR2_A44fr A50LF4_A44fr A44LF1 A44LF2 A44LF3 A44LR3 A44LR4Gly
BBa(G) :
B26LR1_A44fr B26LR2_A44fr A50LF4_A44fr A44LF1 A44LF2 A44LF3 A44LR3 A44LR4Gly
aAA(G) :
A69LR1_A44fr A44LR2 A44LF4 A44LF1 A44LF2 A44LF3 A44LR3 A44LR4Gly
aBA(G) :
A69LR1_A44fr B26LR2_A44fr A44LF4 A44LF1 A44LF2 A44LF3 A44LR3 A44LR4Gly
32
E06730769
22-08-2014
Después de la realización de la PCR, los productos se purificaron a partir de todas las soluciones de la reacción mediante el uso del kit de purificación de PCR QIAquick (Qiagen) a través del procedimiento descrito en el manual de instrucciones adjunto, y se eluyeron mediante el uso de agua esterilizada. Después de que se digirieron los fragmentos con la enzima de restricción Sfi I (TOYOBO), se sometieron a electroforesis en gel de agarosa al 2%. 5 Los fragmentos de amplificación que tienen aproximadamente 0,4 kb se purificaron mediante el uso del kit de extracción en gel QIAquick (QIAGEN) a través del procedimiento descrito en el manual de instrucciones adjunto y se eluyeron mediante el uso de agua esterilizada. Los fragmentos obtenidos se ligaron mediante el uso de alta ligación (TOYOBO) con el vector de expresión de cadena L descrito anteriormente pCAGG-κ que se había digerido con Sfi I. Se utilizó parte de cada solución de reacción para transformar la cepa DH5 α E. coli (TOYOBO). Se determinaron las 10 secuencias de nucleótidos y se confirmaron mediante el uso del kit de secuenciación BigDye Terminator Cycle (Applied Biosystems) con el secuenciador de ADN ABI PRISM 3700 DNA Sequencer (Applied Biosystems) de conformidad con el procedimiento descrito en el manual de instrucciones adjunto. pCAGG-A44BBA se obtuvo mediante inserción del fragmento BBA y otros vectores de expresión se obtuvieron de forma similar mediante inserción de otros fragmentos VL. Las secuencias de región variable de anticuerpos correspondientes se describen 15 en las siguientes SEQ ID NO. Tabla 2
SEQ ID NO de nucleótidos:
SEQ ID NO de aminoácidos:
(1) AAA
(pAGG-A44L) 66 67
(2) BBA
(pCAGG-A44BBA) 68 69
(3) BAA
(pCAGG-A44BAA) 70 71
(4) ABA
(pCAGG-A44ABA) 72 73
(5) AAa
(pCAGG-A44AAa) 74 75
(6) BAa
(pCAGG-A44BAa) 76 77
(7) ABa
(pCAGG-A44ABa) 78 79
(8) BBa
(pCAGG-A44BBa) 80 81
(9) aAA
(pCAGG-A44aAA) 82 83
(10) aBA
(pCAGG-A44aBA) 84 85
(11) AAA (G)
(pCAGG-A44LG) 86 87
(12) BBA (G)
(pCAGG-A44BBAG) 88 89
(13) BAA (G)
(pCAGG-A44BAAG) 90 91
(14) ABA (G)
(pCAGG-A44ABAG) 92 93
(15) AAa (G)
(pCAGG-A44AAaG) 94 95
(16) BAa (G)
(pCAGG-A44BAaG) 96 97
(17) ABa (G)
(pAGG-A44ABaG) 98 99
(18) BBa (G)
(pCAGG-A44BBaG) 100 101
(19) aAA (G)
(pCAGG-A44aAAG) 102 103
(20) aBA (G)
(pAGG-A44aBAG) 104 105

[Ejemplo 19] Preparación de anticuerpos
Las células de la cepa HEK293 derivadas de células de carcinoma renal fetal humanas se suspendieron en medio DMEM (Invitrogen) que contenía FCS al 10% (Moregate), 6 x 106 células se colocaron en platos de 10 cm de 20 diámetro para células adherentes (Coming) y se cultivaron en una incubadora de CO2 (37°C, CO2 al 5%) durante la noche. Cualquiera de los vectores de expresión de cadena L del ejemplo 18, dos tipos del vector de expresión de cadena H (30 µg) de pCAGG-chiB26-g4b y pCAGG-chiA44-g4a o pCAGG-chiA69-g4a del ejemplo 17, y 1,5 mL de medio OPTI-MEMI se agregaron a la mezcla de 60 µL de reactivo de transfección Lipofectamine 2000 (Invitrogen) y 1,5 mL de medio Opti-MEM I (Invitrogen) y se dejó reposar a temperatura ambiente durante 20 minutos, y la mezcla
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Claims (1)

  1. imagen1
    imagen2
ES06730769.4T 2005-04-08 2006-03-31 Anticuerpo que sustituye la función del factor VIII de coagulación sanguínea Expired - Lifetime ES2494921T3 (es)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2005112514 2005-04-08
JP2005112514 2005-04-08
PCT/JP2006/306821 WO2006109592A1 (ja) 2005-04-08 2006-03-31 血液凝固第viii因子の機能代替抗体

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ES2494921T3 true ES2494921T3 (es) 2014-09-16

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ID=37086871

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ES06730769.4T Expired - Lifetime ES2494921T3 (es) 2005-04-08 2006-03-31 Anticuerpo que sustituye la función del factor VIII de coagulación sanguínea

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US (16) US20100003254A1 (es)
EP (2) EP2824183B1 (es)
JP (3) JP4917024B2 (es)
CA (2) CA2603264C (es)
CY (1) CY1115702T1 (es)
DK (2) DK1876236T3 (es)
ES (1) ES2494921T3 (es)
NO (1) NO348522B1 (es)
PL (1) PL1876236T3 (es)
PT (1) PT1876236E (es)
SI (1) SI1876236T1 (es)
TW (1) TW200714313A (es)
WO (1) WO2006109592A1 (es)

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