ES2579987T3 - Polipéptidos interleuquina-2 mutantes - Google Patents

Polipéptidos interleuquina-2 mutantes Download PDF

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Publication number
ES2579987T3
ES2579987T3 ES12702045.1T ES12702045T ES2579987T3 ES 2579987 T3 ES2579987 T3 ES 2579987T3 ES 12702045 T ES12702045 T ES 12702045T ES 2579987 T3 ES2579987 T3 ES 2579987T3
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fab
mice
mutant
polypeptide
interleukin
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Oliver Ast
Peter Bruenker
Anne Freimoser-Grundschober
Sylvia Herter
Thomas U. Hofer
Ralf Hosse
Christian Klein
Ekkehard Moessner
Valeria G. Nicolini
Pablo Umana
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Roche Glycart AG
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Roche Glycart AG
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    • 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
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/54—Interleukins [IL]
    • C07K14/55—IL-2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2013—IL-2
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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    • 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
    • A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
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    • 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
    • A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
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    • 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
    • A61K47/6835—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6853—Carcino-embryonic antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K47/6871—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 the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting an enzyme
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K47/6891—Pre-targeting systems involving an antibody for targeting specific cells
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    • 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
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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    • C07—ORGANIC CHEMISTRY
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    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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Abstract

Polipéptido interleuquina 2 (IL-2) mutante que comprende tres mutaciones de aminoácido que anulan o reducen la afinidad del polipéptido IL-2 mutante para el receptor de IL-2 de alta afinidad y conservan la afinidad del polipéptido IL-2 mutante para el receptor de IL-2 de afinidad intermedia, comparando cada uno con un polipéptido IL- 2 de tipo salvaje, en el que dichas tres mutaciones de aminoácido se encuentran en las posiciones correspondientes a los residuos 42, 45 y 72 de la IL-2 humana (SEC ID nº 1).

Description

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Grupo 7 (9 µg/g)
1 1 32 33 101208 94764 97986
1
5,5 34 35 35766 32359 34062
1
24 36 37 573 588 580
Fab-II2-Fab WT de 4G8
32 31779 37473
5
5,5 33 35 51143 53409
36
13562
1
1
38 39 73326 47953 60639
1
5,5 40 41 12168 14371 13269
Grupo 8 (4.5 µg/g)
1 24 42 43 494 487 490
Fab-II2-Fab mutante de 4G8
5 5,5 40 41 6561 15352 10957
38
608 721
5
24 39 42 543 1298
43
437
1
1
44 45 162970 129862 146416
1
5.5 46 47 20475 29125 24800
Grupo 9 (9 µg/g)
1 24 48 49 478 509 493
Fab-II2-Fab mutante de 4G8
5 5.5 46 47 20504 75557 48031
44
634 703
5
24 45 48 796 661
49
719
Estos datos demuestran que tanto Fab-IL-2 qm-Fab de 4G8 como Fab-IL-2 wt-Fab de 4G8 mostraban propiedades farmacocinéticas comparables con una exposición ligeramente superior para Fab-IL-2 qm-Fab de 4G8.
5 Mortalidad
En el grupo de 9 µg/g de Fab-IL-2 wt-Fab de 4G8 con diana en FAP, se produjo mortalidad relacionada con el tratamiento en un animal previamente a la necropsia, el día 5. Se observaron hipoactividad, piel fría y postura encorvada previamente a la muerte. Este animal probablemente murió debido a una combinación de infiltración
10 celular en el pulmón que se vio acompañada de edema y hemorragia y necrosis marcada de la médula ósea. Se resumen los datos de mortalidad en la Tabla 17.

TABLA 17. Mortalidad el día 5.
Grupo
Tipo Dosis (µg/kg) Muertos Sacrificio por toxicidad severa** Total
1
DPBS 0 0/5 0/5 0/5
2
Fab-IL-2 wt-Fab de 4G8 4,5 0/5 5/5 5/5
3
9 1/5* 4/5 4/5
4
Fab-IL-2 qm-Fab de 4G8 4,5 0/5 0/5 0/5
5
9 0/5 0/5 0/5
6
Fab-IL-2 wt-Fab de 4G8 4,5 1/6 5/6 6/6
7
9 2/6 4/6 6/6
8
Fab-IL-2 qm-Fab de 4G8 4,5 0/6 0/6 0/6
9
9
0/6 0/6 0/6
* progresando a necrosis ** el estudio se planificó para que durase siete días, pero todos los ratone tratados con el inmunoconjugado de IL-2 de tipo salvaje resultaron afectados marcadamente llegado el día 5 y se sacrificaron ya que no se esperaba
66
que sobreviviesen.
Observaciones clínicas Se registraron observaciones de hipoactividad, piel fría y postura encorvada en los animales que recibieron 4,5 y 9 µg/g/día de IL-2 wt. Se resumen las observaciones clínicas en la Tabla 18. TABLA 18. Observaciones clínicas el día 5.
Grupo
Tipo Dosis (µg/kg) Postura encorvada Hipoactivo Frío al tacto
1
DPBS 0 0/5 0/5 0/5
2
Fab-IL-2 wt-Fab de 4G8 4,5 4/5 4/5 5/5
3
9 5/5 5/5 5/5
4
Fab-IL-2 qm-Fab de 4G8 4,5 0/5 0/5 0/5
5
9 0/5 0/5 0/5
6
Fab-IL-2 wt-Fab de 4G8 4,5 6/6 2/6 2/6
7
9 6/6 5/6 6/6
8
Fab-IL-2 qm-Fab de 4G8 4,5 0/6 0/6 0/6
9
9
0/6 0/6 0/6
Peso corporal
10 Se observó una reducción moderada del peso corporal tras 5 días de tratamiento en animales que recibieron 4,5 y 9 (9% y 11%, respectivamente) µg/g/día de IL-2 wt. Se observó una ligera reducción del peso corporal tras 5 días de tratamiento en animales que habían recibido 4,5 ó 9 (2% y 1%, respectivamente) µg/g/día de IL-2 qm. También se observó una reducción moderada (9%) de peso corporal en los controles de vehículo tras 5 días de tratamiento. Sin
15 embargo, el porcentaje de reducción había sido de 5% si se hubiese excluido un valor potencialmente atípico (animal nº 3). La pérdida de peso corporal en el grupo de vehículo podría atribuirse a estrés.
Hematología
20 Se observó un recuento reducido de plaquetas en los animales que recibieron 4,5 (de ~4,5 veces) y 9 µg/g/día (de ~11 veces) Fab-IL-2 wt-Fab de 4G8, lo que se correlaciona con un número reducido de megacariocitos en la médula ósea, así como efectos sistémicos de consumo (fibrina) en el bazo y pulmón de estos animales (ver la sección de histopatología, posteriormente). Estos resultados indican que el recuento plaquetario reducido probablemente se debe a los efectos combinados del consumo y reducción de la producción/hiperplasia en la médula ósea debido al
25 incremento de la producción de linfocitos/células mieloides como efecto directo o indirecto de la IL-2.
Los resultados hematológicos de relación incierta con la administración de compuesto consistían de una reducción del recuento absoluto de linfocitos con Fab-IL-2 wt-Fab de 4G8 a las dosis de 4,5 (de ~5 veces) y de 9 µg/g (de ~3 veces) en comparación con el valor medio del grupo de control de vehículo. Estos resultados no presentan una clara 30 dependencia de la dosis, pero podrían considerarse secundarios a los efectos asociados al estrés en las observaciones vitales o una farmacología exagerada del compuesto (migración de los linfocitos al interior de los tejidos). No se produjeron cambios hematológicos relacionados con el tratamiento atribuibles a la administración de Fab-IL-2 qm-Fab de 4G8. Unos cuantos resultados hematológicos aislados eran estadísticamente diferentes de sus controles respectivos. Sin embargo, estos resultados eran de insuficiente magnitud para sugerir una relevancia
35 patológica.
Patología macroscópica e histopatología
Entre los resultados generales relacionados con el tratamiento se incluyen un agrandamiento del bazo, observado 40 en 5/5 y 4/5 de los ratones de los grupos de 4,5 y 9 µg/g de Fab-IL-2 wt-Fab de 4G8, respectivamente, y en 1/5 en los grupos de tratamiento de 4,5 y 9 µg/g de Fab-IL-2 qm-Fab de 4G8.
Se observaron resultados histopatológicos relacionados con el tratamiento en los grupos que recibieron 4,5 y 9 µg/g de Fab-IL-2 wt-Fab de 4G8 y que recibieron 4,5 y 9 µg/g de Fab-IL-2 qm-Fab de 4G8, en pulmón, médula ósea, 45 hígado, bazo y timo, con diferencias de incidencia, gradación de la severidad o naturaleza de los cambios, tal como se informa posteriormente.
Los resultados histopatológicos relacionados con el tratamiento en el pulmón consistían de infiltración mononuclear leve a marcada en 5/5 ratones de los grupos de 4,5 y 9 µg/g de Fab-IL-2 wt-Fab de 4G8 y marginalmente en 5/5 50 ratones de los grupos de 4,5 y 9 µg/g de Fab-IL-2 qm-Fab de 4G8. La infiltración monuclear consistía de linfocitos
67
imagen65
imagen66
imagen67
imagen68
5
10
15
20
25
30
35
40
45
IL-2 de tipo salvaje (wt) o mutante cuádruple (qm), en ratones Black 6 inmunocompetentes libres de tumor. Los ratones Black 6 hembra (Charles River, Alemania), de 8 a 9 semanas de edad al inicio del experimento, se mantuvieron bajo condiciones libres de patógenos específicos con ciclos diarios de 12 horas de luz/12 horas de oscuridad de acuerdo a directrices acordadas (GV-Solas, Felasa, TierschG). El protocolo del estudio experimental fue revisado y autorizado por el gobierno local (P 2008016). Tras la llegada, los animales se mantuvieron durante una semana para aclimatarse al nuevo entorno y para su observación. Se llevó a cabo un seguimiento continuo de su salud de manera periódica.
Los ratones recibieron inyecciones i.v. una vez al día durante 7 días de Fab-IL2 wt-Fab de 4G8 a dosis de 60, 80 y 100 µg/ratón o de Fab-IL2 qm-Fab de 4G8 a dosis de 100, 200, 400, 600 y 1.000 µg/ratón. Todos los ratones recibieron inyecciones i.v. de 200 µl de la solución apropiada. Con el fin de obtener la cantidad correcta de inmunoconjugado por cada 200 µl, las soluciones madre se diluyeron con PBS en caso necesario.
La figura 40 muestra que la MTD (dosis máxima tolerada) para Fab-IL2 qm-Fab era 10 veces mayor para Fab-IL2 wt-Fab, es decir 600 µg/ratón diariamente durante 7 días para Fab-IL2 qm-Fab frente a 60 µg/ratón diarios durante 7 días para Fab-IL2 wt-Fab.
TABLA 19
Compuesto
Dosis Tampón de formulación concentración (mg/ml)
60,
Fosfato potásico 25 mM, 3,32 (=solución madre)
Fab-IL-2 wt-Fab de
80, NaCl 125 mM,
4G8
100 µg Glicina 100 mM,
pH 6,7
Fab-IL-2 qm-Fab de 4G8
100, 200, 400, 600, 1.000 µg Fosfato potásico 25 mM, NaCl 125 mM, Glicina 100 mM, pH 6,7 4,25 (=solución madre)
Ejemplo 16
Farmacocinética de una única dosis de IgG-IL2 wt y qm dirigidos a FAP y sin diana
Se llevó a cabo un estudio farmacocinético (PK) de una sola dosis en ratones 129 inmunocompetentes libres de tumor para inmunoconjugados IgG-IL2 con diana en FAP que comrpendían IL-2 de tipo salvaje o mutante cuádruple e inmunoconjugados IgG-IL2 sin diana que comprendían IL-2 de tipo salvaje o mutante cuádruple.
Los ratones Black 129 hembra (Harlan, Reino Unido), de 8 a 9 semanas de edad al inicio del experimento, se mantuvieron bajo condiciones libres de patógenos específicos con ciclos diarios de 12 horas de luz/12 horas de oscuridad de acuerdo a directrices acordadas (GV-Solas, Felasa, TierschG). El protocolo del estudio experimental fue revisado y autorizado por el gobierno local (P 2008016). Tras su llegada, los animales se mantuvieron durante una semana para que se aclimatasen al nuevo entorno y para su observación. Se llevó a cabo un seguimiento continuo periódico de su estado de salud.
Los ratones recibieron inyecciones i.v. una vez con IgG-IL2 wt de 28H1 (2,5 mg/kg) con diana en FAP o IgG-IL2 qm de 28H1 (5 mg/kg) o IgG-IL2 wt DP47G2 sin diana (5 mg/kg) o IgG-IL2 qm DP47GS (5 mg/kg). Todos los ratones recibieron inyecciones i.v. de 200 µl de la solución apropiada. Con el fin de obtener la cantidad correcta de inmunoconjugado por cada 200 µl, las soluciones madre se diluyeron con PBS en caso necesario.
Se sangraron los ratones a las 1, 8, 24, 48, 72 y 96 horas y posteriormente cada 2 días durante 3 semanas. Se extrajeron los sueros y se almacenaron a -20ºC hasta la realización de los análisis ELISA. Se determinaron las concentraciones de inmunoconjugados en suero utilizando una ELISA para la cuantificación del anticuerpo de inmunoconjugado de IL-2 (Roche-Penzberg). Se midió la absorbancia utilizando una longitud de onda de medición de 405 nm y una longitud de onda de referencia de 492 nm (lector de microplacas regulable VersaMax, Molecular Devices). La figura 41 muestra la farmacocinética de dichos inmunoconjugados de IL-2. Los constructos IgG-IL2 tanto con diana en FAP (A) como sin dianas (B) presentaban una vida media en suero más prolongada (aproximadamente 30 horas) que los constructos IgG-IL2 wt correspondientes (aproximadamente 15 horas).
TABLA 20
imagen69
72
imagen70

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IL269687A (en) 2019-11-28
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US10323098B2 (en) 2019-06-18
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RS57767B1 (sr) 2018-12-31
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PE20140303A1 (es) 2014-03-22
RS54802B1 (sr) 2016-10-31
US10184009B2 (en) 2019-01-22
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ZA201305282B (en) 2016-07-27
ES2883371T3 (es) 2021-12-07
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CO6741186A2 (es) 2013-08-30
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