ES2564092T3 - Exotoxinas de pseudomonas mutadas con antigenicidad reducida - Google Patents

Exotoxinas de pseudomonas mutadas con antigenicidad reducida Download PDF

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ES2564092T3
ES2564092T3 ES10179539.1T ES10179539T ES2564092T3 ES 2564092 T3 ES2564092 T3 ES 2564092T3 ES 10179539 T ES10179539 T ES 10179539T ES 2564092 T3 ES2564092 T3 ES 2564092T3
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essay
exotoxins
pes
mutated
reduced antigenicity
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Ira H. Pastan
Masanori Onda
Satoshi Nagata
David Fitzgerald
Robert Kreitman
Byungkook Lee
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US Department of Health and Human Services
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • A61K47/6829—Bacterial toxins, e.g. diphteria toxins or Pseudomonas exotoxin A
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/21—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Pseudomonadaceae (F)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Toxicology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Exotoxina A de Pseudomonas ("PE") aislada, en la que dicha PE tiene una sustitución de alanina, glicina, serina o glutamina en lugar del resto aminoacídico E548, en la que el resto aminoacídico E548 se define en referencia a la secuencia de aminoácidos de la PE nativa (SEQ ID NO:1).

Description

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los promotores T7, trp, lac o λ, un sitio de unión a ribosomas y preferentemente una señal de terminación de la transcripción. Para células eucariotas, las secuencias de control pueden incluir un promotor y preferentemente un potenciador derivado de genes de inmunoglobulinas, SV40, citomegalovirus y una señal de poliadenilación y pueden incluir secuencias donadoras y aceptoras de corte y empalme. Las casetes de la invención pueden transferirse a la
5 célula hospedadora elegida por procedimientos bien conocidos como la transformación por cloruro de calcio o la electroporación para E. coli y el tratamiento con fosfato de calcio, la electroporación o la lipofección para células de mamíferos. Las células transformadas con las casetes pueden seleccionarse por la resistencia a antibióticos conferida por genes contenidos en las casetes, como los genes amp, gpt, neo e hyg.
10 [00127] El experto reconocerá que es posible hacer modificaciones en un ácido nucleico que codifica un polipéptido de la presente invención (es decir, PE o un inmunoconjugado formado a partir de una PE de la invención) sin disminuir su actividad biológica. Algunas modificaciones pueden hacerse para facilitar la clonación, la expresión, o la incorporación de la molécula de reconocimiento en una proteína de fusión. Tales modificaciones son bien conocidas para los expertos en la técnica e incluyen, por ejemplo, codones de terminación, una metionina añadida al extremo
15 amino para proporcionar un sitio de iniciación, aminoácidos adicionales colocados en cualquiera de los extremos para crear sitios de restricción localizados convenientemente o aminoácidos adicionales (como poli-His) para facilitar las etapas de purificación.
[00128] Además de mediante procedimientos recombinantes, los inmunoconjugados y las PE de la presente
20 invención pueden construirse también en parte o en su totalidad mediante síntesis peptídica estándar. La síntesis en fase sólida de los polipéptidos de la presente invención de menos de 50 aminoácidos de longitud puede realizarse mediante la unión del aminoácido C-terminal de la secuencia a un soporte insoluble, seguida de la adición secuencial de los aminoácidos restantes de la secuencia. Las técnicas para la síntesis en fase sólida se describen en Barany y Merrifield, THE PEPTIDES: ANALYSIS, SYNTHESIS, BIOLOGY. Vol. 2: SPECIAL METHODS IN
25 PEPTIDE SYNTHESIS, parte A, págs. 3-284; Merrifield y col., J. Am. Chem. Soc. 85: 2149-2156 (1963) y Stewart y col., SOLID PHASE PEPTIDE SYNTHESIS, 2a edición, Pierce Chem. Co., Rockford, IL, EE. UU. (1984). Es posible sintetizar proteínas de mayor longitud por condensación de los extremos amino y carboxilo de fragmentos más cortos. Los procedimientos para formar enlaces peptídicos por activación de un extremo carboxilo terminal (p. ej., mediante el agente de acoplamiento N, N’-diciclohexilcarbodiimida) son conocidos para los expertos.
30
B. Purificación
[00129] Una vez expresados, los inmunoconjugados y PE recombinantes de la presente invención pueden purificarse según procedimientos estándar de la técnica, como precipitación con sulfato de amonio, columnas de
35 afinidad, cromatografía en columna y similares (véase generalmente R. Scopes, PROTEIN PURIFICATION, Springer-Verlag, NY, EE. UU. (1982). Se prefieren composiciones sustancialmente puras con una homogeneidad de al menos aproximadamente el 90-95% y una homogeneidad del 98 al 99% es la más preferida para usos farmacéuticos. Una vez purificados, parcialmente o hasta homogeneidad, según se desee, si han de usarse terapéuticamente, los polipéptidos no deberán contener sustancialmente ninguna endotoxina.
40 [00130] Los procedimientos para la expresión de anticuerpos de una sola cadena y/o su plegamiento para obtener una forma activa apropiada, incluidos los anticuerpos de una sola cadena de bacterias como E. coli , han sido descritos y son bien conocidos y aplicables a los anticuerpos de esta invención. Véase Buchner y col., Anal. Biochem. 205: 263-270 (1992); Pluckthun, Biotechniology 9: 545 (1991); Huse y col., Science 246: 1275 (1989) y
45 Ward y col., Nature 341: 544 (1989), todos ellos incorporados por referencia en este documento.
[00131] Frecuentemente, las proteínas heterólogas funcionales de E. coli o de otras bacterias se aíslan de cuerpos de inclusión y requieren la solubilización mediante desnaturalizantes fuertes y un subsiguiente plegamiento. Durante la etapa de solubilización, tal como es bien conocido en la técnica, debe haber presente un agente reductor para
50 separar los puentes disulfuro. Un tampón de ejemplo con un agente reductor es: Tris 0,1 M pH 8, guanidina 6 M, EDTA 2 mM, DTE (ditioeritritol) 0,3 M. La reoxidación de los puentes disulfuro puede tener lugar en presencia de reactivos tiólicos de bajo peso molecular en forma reducida y oxidada, tal como se describe en la publicación de Saxena y col., Biochemistry 9: 5015-5021 (1970), incorporada por referencia en este documento, y especialmente tal como describen Buchner y col., cita anterior.
55 [00132] Típicamente la renaturalización se consigue por dilución (p. ej., 100 veces) de la proteína desnaturalizada y reducida en el tampón de plegamiento. Un tampón de ejemplo es Tris 0,1 M pH 8,0, L-arginina 0,5 M, glutatión oxidado 8 mM y EDTA 2 mM.
20
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Fusión Inmunización Refuerzo Ratón Título Procedimiento Número de final de cribado clones finales (c) 14 M1-ip x 4 D553E-ip C3H Hej 3 x 104 ICC con 0 CD30 15 M1-ipx3+ III-ip A/J 3x105 ICCcon30 3 D553E x 2 16 M1-ip x 3 + D553E-ip A/J 3 x 105 ICC con 13 D553E x 2 CD30
(c) Los clones se seleccionan por su alta afinidad relativa en ICC-ELISA con M40-3 como estándar. M1: M1(dsFv)-PE38, D553E: mutante de LMB-2 con D553E, R276G: mutante de M1(scFv)PE38 con R276G, III: dominio III
Tabla 2. Lista de MAb estudiados
Nombre
Epítopo Isotipo Título (log µl/µg) Afinidad (nM)
IP43
1a γ/I 2,6 0,10
IP62
1a γ/I 2,5 0,2
IP57
1a γ/I 1,9 0,00039
IP11
1b γ/I 2,6 6*
IP39
1b γ/I 2,8 0,93*
IP47
1b γ/I 2,8 0,47*
IP70
1b γ/I 2,5 58*
IP48
1b γ/I 2,7 3,3*
IP1
1b γ/I 2,6 5,80
IP35
1b γ/I 2,8 3,70
IP36
1b γ/I 2,6 3,60
IP42
1b γ/I 2,5 43
IP34
2a γ/I 2,7 0,11*
IP29
2b γ/I 2,8 20
IP63
2b γ/I 2,7 5
IP2
2b γ/I 2,7 0,30
IP15
2c γ/I 2,6 5,3
IP22
2c γ/I 2,6 3,4*
IP51
2c γ/I 2,2 3,10
IP76
2c γ/I 3,0 0,19
IP83
2c γ/I 2,5 0,43
IP9
3a γ/I 2,4 4,80
IP18
3a γ/I 2,5 0,09*
IP16
3a γ/I 2,5 0,24*
IP32
3a γ/I 2,7 33
IP44
3b γ/I 2,5 0,14
IP45
3b γ/I 2,9 0,47
IP58
3b γ/I 2,4 0,24
IP7
4a γ/I 2,7 0,04
IP10
4a γ/I 2,1 0,04
IP31
4a γ/I 2,9 0,27*
IP37
4a γ/I 2,7 1,40
IP49
4a γ/I 1,7 2,60
IP3
4a γ/I 2,6 0,00038
IP27
4a γ/I 2,7 16*
IP72
4a γ/I 2,8 4,4*
IP14
4b γ/I 2,6 81
IP82
4b γ/I 2,7 11*
IP86
4b γ/I 2,9 0,41*
IP13
5 γ/I 2,6 1,2
IP20
5 γ/I 2,3 0,1
29
imagen27
Tabla 4. CI50 de las inmunotoxinas preparadas por mutación de la PE en restos que afectan a la unión a diferentes epítopos
Ensay o n° 14
0,7
Ensay o n° 13
0,44
Ensay o n° 12
1,8
Ensay o n° 11
1,0
Ensay o n° 10
0,9 0,7 0,7
Ensay o n° 9
0,7 0,55 30 >100 0,4
Ensay o n° 8
2,0 1,9(?) 4,4 5,0/6,2
Ensay o n° 7
0,2 0,45
Ensay o n° 6
4 6 5 10
Ensay o n° 5
3,3 3,7 4,2 6,5
Ensay o n° 4
3,4 4,5
Ensay o n° 3
1,0 1,0
Ensay o n° 2
1,0 2,0 1,1 3,0
Ensay o n° 1
1,2ng/ml 3,0 0,72 0,72 1,5 2,1
N° de MAb bloqueados al mutar este resto
8 8 8 3 3 3 3 3/3 8 3 3 3
N° de MAb en este grupo epitópico
37 8 3 3 3 3/3 8 3 3 3
Epítopo
1 1 1 2c 5 2c 1/5/7 7 5/7 5/1 5/2/7 1 5 2 7
IT con los res tos designados mutados en la secuencia de la PE
InmunotoxinaHA22(control) N314A* N314S Q332A R467A R490A R538A* Q332A R490AK590A/K606A/613del* K590A R490AK590A* Q332AR490A* K606A* R490A R538AK590A* Q332S R490S* R538S* K590S
31 32
(continuación) */ La mutación redujo la citotoxicidad en más del 50%
Ensay o n° 14
0,9 0,8
Ensay o n° 13
0,7
Ensay o n° 12
1,0 0,8
Ensay o n° 11
0,75 0,6
Ensay o n° 10
0,8
Ensay o n° 9
Ensay o n° 8
Ensay o n° 7
Ensay o n° 6
Ensay o n° 5
Ensay o n° 4
Ensay o n° 3
Ensay o n° 2
Ensay o n° 1
N° de MAb bloqueados al mutar este resto
17 22 5
N° de MAb en este grupo epitópico
(5) 6
Epítopo
1/2c/5/7 3/1/2c/5/7 3/1/4a/2c/5/7 3/1/4a/2c/5/6/7 3/1/4a/2c/5/6/6/7
IT con los res tos designados mutados en la secuencia de la PE
Q332S R467AR490A K590S R313A Q332SR467A R490AK590S R313A Q332SR432G R467AR490A K590S R313A Q332SR432G R467AR490A R513AK590S R313A Q332SR432G R467AR490A R513AE548S K590S
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Claims (1)

  1. imagen1
ES10179539.1T 2005-07-29 2006-07-25 Exotoxinas de pseudomonas mutadas con antigenicidad reducida Active ES2564092T3 (es)

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ES06788523T Active ES2372537T3 (es) 2005-07-29 2006-07-25 Exotoxinas de pseudomonas mutadas con antigenicidad reducida.
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ES15191395.1T Active ES2660026T3 (es) 2005-07-29 2006-07-25 Exotoxinas de pseudomonas mutadas con antigenicidad reducida
ES10179539.1T Active ES2564092T3 (es) 2005-07-29 2006-07-25 Exotoxinas de pseudomonas mutadas con antigenicidad reducida
ES15191391.0T Active ES2659039T3 (es) 2005-07-29 2006-07-25 Exotoxinas de pseudomonas mutadas con antigenicidad reducida
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EP (6) EP3006458B1 (es)
AT (1) ATE524489T1 (es)
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CA (2) CA2616987C (es)
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PL (3) PL3006456T3 (es)
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