ES2553440T3 - Anticuerpos contra el virus sincitial respiratorio humano (VSR) y método de uso - Google Patents
Anticuerpos contra el virus sincitial respiratorio humano (VSR) y método de uso Download PDFInfo
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- ES2553440T3 ES2553440T3 ES10747357.1T ES10747357T ES2553440T3 ES 2553440 T3 ES2553440 T3 ES 2553440T3 ES 10747357 T ES10747357 T ES 10747357T ES 2553440 T3 ES2553440 T3 ES 2553440T3
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- 125000000539 amino acid group Chemical group 0.000 abstract description 11
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- 108090000288 Glycoproteins Proteins 0.000 description 1
- 108060003393 Granulin Proteins 0.000 description 1
- 101150062179 II gene Proteins 0.000 description 1
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- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1027—Paramyxoviridae, e.g. respiratory syncytial virus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/55—Fab or Fab'
-
- 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
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
Abstract
Un anticuerpo o fragmento de unión a antígeno del mismo que comprende: una CDR1 de VH, que comprende la secuencia de restos de aminoácidos expuesta en SEC ID Nº: 2; una CDR2 de VH, que comprende la secuencia de restos de aminoácidos expuesta en SEC ID Nº: 3; una CDR3 de VH, que comprende la secuencia de restos de aminoácidos expuesta en SEC ID Nº: 4; una CDR1 de VL, que comprende la secuencia de restos de aminoácidos expuesta en SEC ID Nº: 6; una CDR2 de VL, que comprende la secuencia de restos de aminoácidos expuesta en SEC ID Nº: 7; y una CDR3 de VL, que comprende la secuencia de restos de aminoácidos expuesta en SEC ID Nº: 8, en el que el anticuerpo o fragmento de unión a antígeno se une inmunoespecíficamente con la proteína de fusión (F) del Virus Sincitial Respiratorio (VSR) y neutraliza VSR.
Description
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separadas. En los métodos proporcionados en el presente documento, la composición farmacéutica y el agente antiviral pueden administrarse secuencialmente, simultáneamente o intermitentemente.
En algunos ejemplos, una composición farmacéutica proporcionada en el presente documento puede administrarse con una terapia hormonal, inmunoterapia o un agente antiinflamatorio. En algunos ejemplos, una composición farmacéutica proporcionada en el presente documento puede administrarse con uno o más anticuerpos antivirales adicionales o fragmentos de unión a antígeno de los mismos. La composición farmacéutica y el o los anticuerpos antivirales adicionales se formulan como una única composición o como composiciones separadas. La composición farmacéutica y el o los anticuerpos anti VSR adicionales pueden administrarse secuencialmente, simultáneamente o intermitentemente. En algunos ejemplos, el fragmento de unión a antígeno es un fragmento Fv monocatenario (scFv), Fab, Fab’, F(ab’)2, Fv, dsFv, diacuerpo, Fd o Fd’.
En algunos ejemplos, una composición farmacéutica proporcionada en el presente documento puede administrarse con uno o más anticuerpos antivirales adicionales seleccionados de entre anticuerpos anti VSR o fragmentos de unión a antígeno de los mismos, tales como, por ejemplo, palivizumab, motavizumab, AFFF, P12f2, P12f4, P11d4, A1e9, A12a6, A13c4, A17d4, A4B4, A8c7, 1X-493L1, FR H3-3F4, M3H9, Y10H6, DG, AFFF(1), 6H8, L1-7E5, L215B10, A13a11, A1h5, A4B4(1), A4B4L1FR-S28R, A4B4-F52S, rsv6, rsv11, rsv13, rsv19, rsv21, rsv22, rsv23, RF-1, RF-2 o fragmentos de unión a antígeno de los mismos.
En algunos ejemplos, puede administrarse una composición farmacéutica proporcionada en el presente documento con uno o más anticuerpos antivirales adicionales seleccionados de entre un anticuerpo o fragmento de unión a antígeno del mismo que se une inmunoespecíficamente con un antígeno del virus paragripal (PIV) o metaneumovirus humano (hMPV). En algunos ejemplos, el antígeno de PIV es un antígeno de PIV humano de tipo 1, PIV humano de tipo 2, PIV humano de tipo 3 y/o PIV humano de tipo 4. En algunos ejemplos, el antígeno de PIV se selecciona de entre una fosfoproteína de nucleocápsida de PIV, una proteína de fusión (F) de PIV, una fosfoproteína de PIV, una proteína grande (L) de PIV, una proteína de matriz (M) de PIV, una glucoproteína de hemaglutinina-neuraminidasa (HN) de PIV, una ARN polimerasa dependiente de ARN de PIV, una proteína Y1 de PIV, una proteína D de PIV, una proteína C de PIV y variantes alélicas de las mismas. En algunos ejemplos, el antígeno de hMPV es un antígeno de hMPV de tipo A o hMPV de tipo B. En algunos ejemplos, el antígeno de hMPV es un antígeno de hMPV de subtipo A1, hMPV de subtipo A2, hMPV de subtipo B1 o hMPV de subtipo B2. En algunos ejemplos, el antígeno de hMPV se selecciona de entre una nucleoproteína de hMPV, una fosfoproteína de hMPV, una proteína de la matriz de hMPV, una proteína hidrófoba pequeña de hMPV, una ARN polimerasa dependiente de ARN de hMPV, una proteína F de hMPV, una proteína G de hMPV y variantes alélicas de las mismas.
Se proporcionan en el presente documento métodos para detectar infección por VSR, que implican (a) ensayar el nivel de antígeno de VSR en una muestra de fluido, celular o tisular usando un anticuerpo o fragmentos de unión a antígeno del mismo proporcionados en el presente documento; (b) comparar el nivel ensayado de antígeno de VSR con un nivel de control por lo que un aumento en el nivel ensayado de antígeno de VSR en comparación con el nivel de control del antígeno de VSR es indicativo de una infección por VSR. En algunos ejemplos, la muestra celular o tisular se obtiene de un sujeto humano. En algunos ejemplos, la muestra celular o tisular es una muestra de sangre, orina, saliva, esputo pulmonar, lavado o linfa.
Se proporcionan en el presente documento ácidos nucleicos aislados que codifican el polipéptido, anticuerpo o fragmentos de unión a antígeno del mismo proporcionados en el presente documento. Se proporcionan en el presente documento vectores que contienen un ácido nucleico que codifica el polipéptido, anticuerpo o fragmentos de unión a antígeno del mismo proporcionados en el presente documento.
Se proporcionan en el presente documento células aisladas que contienen un anticuerpo o fragmento de unión a antígeno del mismo proporcionado en el presente documento, un ácido nucleico proporcionado en el presente documento o un vector proporcionado en el presente documento. Las células proporcionadas en el presente documento pueden ser, por ejemplo, células procariotas o eucariotas. También se proporcionan en el presente documento animales transgénicos que contienen un ácido nucleico proporcionado en el presente documento o un vector proporcionado en el presente documento. También se proporcionan en el presente documento métodos para expresar un anticuerpo aislado o fragmento de unión a antígeno del mismo, que implican cultivar las células aisladas proporcionadas en el presente documento en condiciones que expresan el anticuerpo codificado o por aislamiento del anticuerpo o fragmento de unión a antígeno del animal transgénico proporcionado en el presente documento. En algunos ejemplos, el anticuerpo o fragmento de unión a antígeno se aísla del suero o la leche del animal transgénico.
Se proporcionan en el presente documento kits que contienen un polipéptido, anticuerpo o fragmento de unión a antígeno proporcionado en el presente documento, un anticuerpo multivalente proporcionado en el presente documento, o una combinación proporcionada en el presente documento, en uno o más recipientes, e instrucciones para su uso.
7
convencional descrita en J. Biol. Chem., 243: 3557-59 (1968) y adoptada en 37 C.F.R. §§. 1.821 -1.822, se muestran las abreviaturas para restos de aminoácidos en la Tabla 1:
TABLA 1 -Tabla de correspondencia
- SÍMBOLO
- 1 Letra
- 3 Letras AMINOÁCIDO
- I
- Tyr Tirosina
- G
- Gly Glicina
- F
- Phe Fenilalanina
- M
- Met Metionina
- A
- Ala Alanina
- S
- Ser Serina
- I
- Ile Isoleucina
- L
- Leu Leucina
- T
- Thr Treonina
- V
- Val Valina
- P
- Pro Prolina
- K
- Lys Lisina
- H
- His Histidina
- Q
- Gln Glutamina
- E
- Glu Ácido glutámico
- Z
- Glx Ácido Glutámico y/o Glutamina
- W
- Trp Triptófano
- R
- Arg Arginina
- D
- Asp Ácido aspártico
- N
- Asn Asparagina
- B
- Asx Ácido aspártico y/o Asparagina
- C
- Cys Cisteína
- X
- Xaa Desconocido u otro
5 Todas las secuencias de restos de aminoácidos representadas en el presente documento por una fórmula tienen una orientación de izquierda a derecha en la dirección convencional de extremo amino terminal a extremo carboxilo terminal. Además, se define que la frase “resto de aminoácido” incluye los aminoácidos enumerados en la Tabla de Correspondencia (Tabla 1), aminoácidos modificados, no naturales y poco habituales. Además, un guion al
10 comienzo o final de una secuencia de restos de aminoácidos indica un enlace peptídico con una secuencia adicional de uno o más restos de aminoácidos o con un grupo amino terminal tal como NH2 o con un grupo carboxilo terminal tal como COOH.
En un péptido o una proteína, los expertos en la materia conocen sustituciones conservativas adecuadas de
15 aminoácidos y en general pueden realizarse sin alterar una actividad biológica de una molécula resultante. Los expertos en la materia reconocen que, en general, las sustituciones de aminoácidos individuales en regiones no esenciales de un polipéptido no alteran sustancialmente la actividad biológica (véase, por ejemplo, Watson et al., Molecular Biology of the Gene, 4ª Edición, 1987, The Benjamin/Cummings Pub. co., p.224).
20 Dichas sustituciones pueden realizarse de acuerdo con las expuestas en la Tabla 2 a continuación:
17
pCALCL(T)-R (20 µM) 0,25 Pfx50 0,5
25
Para la reacción de PCR, se implementó un enfoque touchdown para añadir especificidad a la amplificación de reacción. En cada etapa touchdown, la temperatura de hibridación se reduce en 1 ºC en cada ciclo. Las condiciones de termociclador de PCR fueron las siguientes. 5 1) 94 ºC durante 2 minutos 2) 10 ciclos de:
-94 ºC durante 15 segundos; 62 ºC durante 20 segundos (Touchdown); 68 ºC durante 1 minuto 10 3) 25 ciclos de:
94 ºC durante 15 segundos; 52 ºC durante 20 segundos; 68 ºC durante 1 minuto
15 4) 68 ºC durante 3 minutos 5) mantenimiento a 4 ºC
Las mezclas de reacción resultantes se usaron como ADN molde para la Etapa II (véase a continuación) sin ninguna purificación adicional. 20
- Tabla 3A. Cebadores de Etapa I para amplificar genes de cadena pesada de IgG
- Grupo de cebadores directos VH:
- SEC ID Nº
- VH1a
- GGATCCTCTTCTTGGTGGCAGCAG 26
- VH1b
- GCATCCTTTTCTTGGTGGCAGCAC 27
- VH1c
- GGGTCTTCTGCTTGCTGGCTGTAG 28
- VH1d
- GGATCCTCTTCTTGGTGGGAGCAG 29
- VH2a
- CTGACCATCCCTTCATGGCTCTTG 30
- VH2b
- CTGACCACCCCTTCCTGGGTCTTG 31
- VH3a
- GCTATTTTARAAGGTGTCCAGTGT 32
- VH3b
- GCTCTTTTAAGAGGTGTCCAGTGT 33
- VH3c
- GCTATTTAAAAAGGTGTCCAATGT 34
- VH4a
- CTGGTGGCAGCTCCCAGATGGGTC 35
- VH5a
- CTCCTGGCTGTTCTCCAAGGAGTC 36
- Grupo de cebadores inversos VH:
- SEC ID Nº
- VH-g 1-INV
- ACAAGATTTGGGCTCAACTTTCTTGTCC 37
- VH-g 2-INV
- TTTGCGCTCAACTGTCTTGTCCACCTTG 38
- VH-g 3-INV
- TTTGAGCTCAACTCTCTTGTCCACCTTG 39
- VH-g 4-INV
- ATATTTGGACTCAACTCTCTTGTCCACC 40
- Tabla 3B. Cebadores de Etapa I para amplificar genes de cadena ligera lambda
- Grupo de cebadores directos VH:
- SEC ID Nº
- 5’ L Vλ 1
- GGTCCTGGGCCCAGTCTGTGCTG 1631
- 5’ L Vλ 2
- GGTCCTGGGCCCAGTCTGCCCTG 1632
- 5’ L Vλ 3
- GCTCTGTGACCTCCTATGAGCTG 1633
- 5’ L Vλ 4/5
- GGTCTCTCTCSCAGCYTGTGCTG 1634
- 5’ L Vλ 6
- GTTCTTGGGCCAATTTTATGCTG 1635
- 5’ L Vλ 7
- GGTCCAATTCYCAGGCTGTGGTG 1636
- 5’ L Vλ 8
- GAGTGGATTCTCAGACTGTGGTG 1637
- Cebador inverso:
- SEC ID Nº
- pCALCL(T)-R
-
imagen88 80
Etapa II. Amplificación de genes de cadena pesada y cadena ligera lambda de IgG
En la Etapa II, las mezclas de reacción de cadena pesada y cadena ligera lambda de la Etapa I se usaron como 25 moldes para reacciones de PCR de segundo ciclo con grupos de cebadores directos e inversos que amplifican de la región marco conservada 1 de cada cadena al final de la primera región constante (CH1 para cadena pesada, CL para cadena ligera).
Los cebadores directos de cadena pesada (véase Tabla 4) se diseñaron para introducir un sitio de restricción SfiI 30 (SEC ID Nº: 41). Las condiciones de reacción fueron las siguientes:
91
Después de la amplificación, los productos de reacción de PCR se separaron en un gel de agarosa al 1 % y la banda correspondiente a la cadena pesada (675 pb) y la cadena ligera (650 pb) se purificaron por extracción en gel (Kit de Extracción en Gel Qiagen; Cat. n.º 28706). Los productos de PCR se eluyeron en 30 µl.
- Tabla 4. Cebadores para amplificar genes de cadena pesada IgG
- Grupo de cebadores directos
- SEC ID Nº
- pCa130 VH1a
- 42
- pCa130 VH1b
- 43
- pCa130 VH1c
- 44
- pCa130 VH1d
- 45
- pCa130 VH2a
-
imagen90 46
- pCa130 VH3a
- 47
- pCa130 VH4a
- 48
- pCa130 VH4b
- 49
- pCa130 VH5a
-
imagen91 50
- pCa130 VH6
- 51
- pCa130 VH6
- 52
- Grupo de cebadores inversos
- SEC ID Nº
- VHII-g1-Inv
- 53
- VHII-g2-Inv
- 54
- VHII-g3-Inv
-
imagen92 55
- VHII-g4-Inv
- 56
- Tabla 5. Cebadores para amplificar genes de cadena ligera kappa
- Grupo de cebadores directos
- SEC ID Nº
- VK1a
- AAggcccagccggccatggccgccggtGACATCCAGATGACCCAG 57
- VK1b
- AAggcccagccggccatggccgccggtGACATCCAGTTGACCCAG 58
- VK1c
- AAggcccagccggccatggccgccggtGCCATCCGGTTGACCCAG 59
- VK2a
- AAggcccagccggccatggccgccggtGATATTGTGATGACYCAG 60
- VK3a
- AAggcccagccggccatggccgccggtGAAATTGTGTTGACGCAG 61
- VK3b
- AAggcccagccggccatggccgccggtGAAATTGTGTTGACACAG 62
- VK3c
- AAggcccagccggccatggccgccggtGAAATAGTGATGACGCAG 63
- VK4a
- AAggcccagccggccatggccgccggtGACATCGTGATGACCCAG 64
- VK5a
- AAggcccagccggccatggccgccggtGAAACGACACTCACGCAG 65
- VK6a
- AAggcccagccggccatggccgccggtGAAATTGTGCTGACTCAG 66
- VK6b
- AAggcccagccggccatggccgccggtGATGTTGTGATGACACAG 67
- Cebador inverso
- SEC ID Nº
- pCALCK(G)L
- 68
- Tabla 6. Cebadores para amplificar genes de cadena ligera lambda
- Grupo de cebadores directos
- SEC ID Nº
- VL1-F
- 69
- VL2-F
- 70
- VL3A-F
- 71
- VL3B-F
- 72
- VL3C-F
-
imagen93 73
93
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IN2012DN01328A (es) | 2015-06-05 |
US9365638B2 (en) | 2016-06-14 |
JP2013501527A (ja) | 2013-01-17 |
EA023179B1 (ru) | 2016-05-31 |
HK1172350A1 (zh) | 2013-04-19 |
CN102656189B (zh) | 2014-10-08 |
KR20120050480A (ko) | 2012-05-18 |
IL217977A0 (en) | 2012-03-29 |
CA2770737A1 (en) | 2011-02-17 |
BR112012003064B8 (pt) | 2021-05-25 |
BR112012003064A2 (pt) | 2017-11-14 |
DK2464664T3 (da) | 2016-01-18 |
US20110076268A1 (en) | 2011-03-31 |
JP5762408B2 (ja) | 2015-08-12 |
ZA201201007B (en) | 2019-08-28 |
IL217977A (en) | 2016-06-30 |
KR101778317B1 (ko) | 2017-09-13 |
US8568719B2 (en) | 2013-10-29 |
EA201200277A1 (ru) | 2012-09-28 |
PL2464664T3 (pl) | 2016-02-29 |
EP2464664B1 (en) | 2015-09-23 |
CN102656189A (zh) | 2012-09-05 |
US20140044719A1 (en) | 2014-02-13 |
AU2010282312A1 (en) | 2012-02-23 |
CA2770737C (en) | 2020-05-12 |
BR112012003064B1 (pt) | 2021-03-16 |
MX2012001882A (es) | 2012-04-11 |
SG178335A1 (en) | 2012-03-29 |
NZ597996A (en) | 2014-02-28 |
WO2011020079A1 (en) | 2011-02-17 |
EP2464664A1 (en) | 2012-06-20 |
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