BR112020011308A2 - imunógenos peptídicos de il-31 e formulações dos mesmos para tratamento e/ou prevenção de dermatite atópica - Google Patents

imunógenos peptídicos de il-31 e formulações dos mesmos para tratamento e/ou prevenção de dermatite atópica Download PDF

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BR112020011308A2
BR112020011308A2 BR112020011308-5A BR112020011308A BR112020011308A2 BR 112020011308 A2 BR112020011308 A2 BR 112020011308A2 BR 112020011308 A BR112020011308 A BR 112020011308A BR 112020011308 A2 BR112020011308 A2 BR 112020011308A2
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Brazil
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phosphorylation
pstat3
petition
lys
seq
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BR112020011308-5A
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English (en)
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Chang Yi Wang
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Ubi Ip Holdings
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    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/35—Allergens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55505—Inorganic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55561—CpG containing adjuvants; Oligonucleotide containing adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55566—Emulsions, e.g. Freund's adjuvant, MF59
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55577—Saponins; Quil A; QS21; ISCOMS
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6018—Lipids, e.g. in lipopeptides
    • 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
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

Abstract

A presente invenção refere-se a construtos de imunógeno peptídico individuais direcionados a porções da proteína Interleucina-31 (IL-31) para o tratamento e/ou prevenção de uma condição pruriginosa e/ou condição alérgica, tal como a dermatite atópica. A presente invenção se refere também a composições contendo os construtos de imunógeno peptídico, métodos de produção e uso dos construtos de imunógeno peptídico e anticorpos produzidos pelos construtos de imunógeno peptídico.

Description

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%) *% 1 Q%*$%BG7 9% $:/"7. "$#$9%9 9 /: 7"&8 /87 9 :/"7.!"$7 ;8<9$#7 9 =/:%"7 @ K ' 6 A : 7 S/$"=7& 9% "9$% : 7 :/*%BE & 9 X*8$;*7& 7:;7" "8 & 82/ =/:%"% G-2 - @ K ' 51A <8/*7 U 97 V 97 :/"7.!"$7 9O/Q%"8 7. 6 . /;7 %"$:%* 6W W 2W 5W +W 1W + G, 0 ., ,0G,. /0. / H0.,G H0H H /0.G, s + G/ 0 G 0-+/ H0/GH H0.,G H0+.G + GH 0 .. 0 /0 H H0- H0/ /0G/G + G- 0 ., 0 H0,,/ H0 -H H0G/H H0./ , K + G+ 0 +H 0 /0+G H0 .+ /0HH /0, - + G. 0 +H 0 0,./ H0,-, /0 +, /0H + GG 0 .. 0 ,+ /0.GG H0H+ H0 H. /0+ - / K/ + G 0 +G /0 G+ H0. , -0 H0G,+ H0.HH + 0 +H 0 ,0HG. /0 . /0//+ /0 H. + 0 /, H0- + H0G / H0 / H0GH. H0G + H '4 - ;K + , 0 G- /0. , H0+HG H0.H- H0. G H0/+ - -U# + / 0 , H0 -- H0G.H H0 H, H0 -+ -0 ./ &P !@ 2dR2RRR2 + H 0 +G 0 . /0H+ H0.+ H0+ / /0G - 82/ =/:%"% G-2 - 4 E 2 @ + - 0 . ,0-G/ H0+ H H0 ,- H0.., H0- . - + + 0 ./ ,0 G+ H0 ., H0/ H /0G /0/ G 'A ( \ + . 0 ++ H0 - -0H-H +0 H+ -0H G -0,/ '4 - ;K V + + G 0 +H H0./H -0/G +0-+. -0G- -0/
K + 0 . H0G+/ -0,,G +0,GG -0.+ -0,,G . 0 G/ 0+., H0HG+ H0.G/ H0+ H0+ G 4 E 2 @ V . . 0 +. ,0-. H0,-- H0./ H0H H0 GH
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Claims (4)

REIVINDICAÇÕES
1. Construto de imunógeno peptídico de IL-31, caracteri- zado pelo fato de que é representado pela fórmula: (Th)m–(A)n–(fragmento de IL-31)–X ou (fragmento de IL-31)–(A)n–(Th)m–X em que Th é um epítopo heterólogo de T helper; A é um espaçador heterólogo; (fragmento de IL-31) é um epítopo de célula B tendo cerca de 15 a cerca de 75 resíduos de aminoácidos da SEQ ID NO: 1 ou SEQ ID NO: 2; X é um α-COOH ou α-CONH2 de um aminoácido; m é de 1 a cerca de 4; e n é 0 a cerca de 10.
2. Construto de imunógeno peptídico de IL-31, de acordo com a reivindicação 1, caracterizado pelo fato de que o fragmento de IL-31 é selecionado do grupo que consiste em SEQ ID NOs: 1-13 e 93-
98.
3. Construto de imunógeno peptídico de IL-31, de acordo com a reivindicação 1 ou 2, caracterizado pelo fato de que o epítopo Th é selecionado do grupo que consiste em SEQ ID NOs: 14-42.
4. Construto de imunógeno peptídico de IL-31, de acordo com a reivindicação 1, caracterizado pelo fato de que o construto de imunógeno peptídico é selecionado do grupo que consiste em SEQ ID NOs: 43-90 e 99-105.
5. Construto de imunógeno peptídico de IL-31, caracteri- zado pelo fato de que compreende: um epítopo de célula B compreendendo de cerca de 15 a cerca de 75 resíduos de aminoácidos da sequência completa da prote-
ína IL-31 da SEQ ID NO: 1 ou SEQ ID NO: 2; um epítopo de T helper compreendendo uma sequência de aminoácidos selecionada do grupo que consiste em SEQ ID NOs: 14- 42; e um espaçador heterólogo opcional selecionado do grupo consistindo em um aminoácido, Lys-, Gly-, Lys-Lys-Lys-, (α, ε-N)Lys, e ε-N-Lys-Lys-Lys-Lys (SEQ ID NO: 91), em que o epítopo de célula B é covalentemente ligado ao epítopo de T helper diretamente ou através do espaçador heterólogo opcional.
6. Construto de imunógeno peptídico de IL-31, de acordo com a reivindicação 5, caracterizado pelo fato de que o epítopo de célula B é selecionado do grupo que consiste em SEQ ID NOs: 1-13 e 93-98.
7. Construto de imunógeno peptídico de IL-31, de acordo com a reivindicação 5, caracterizado pelo fato de que o epítopo de T helper é selecionado do grupo que consiste em SEQ ID NOs: 14-42.
8. Construto de imunógeno peptídico de IL-31, de acordo com a reivindicação 5, caracterizado pelo fato de que o espaçador heterólogo opcional é (α, ε-N)Lys ou ε-N-Lys-Lys-Lys-Lys (SEQ ID NO: 91).
9. Construto de imunógeno peptídico de IL-31, de acordo com a reivindicação 5, caracterizado pelo fato de que o epítopo de T helper é covalentemente ligado ao terminal amino do epítopo de célula B.
10. Construto de imunógeno peptídico de IL-31, de acordo com a reivindicação 5, caracterizado pelo fato de que o epítopo de T helper é covalentemente ligado ao terminal amino do epítopo de célula B através do espaçador heterólogo opcional.
11. Composição, caracterizada pelo fato de que compre-
ende um construto de imunógeno peptídico como definido em qualquer uma das reivindicações 1 a 4.
12. Composição farmacêutica, caracterizada pelo fato de que compreende: a. um construto de imunógeno peptídico como definido em qualquer uma das reivindicações 1 a 4; e b. e um veículo de distribuição e/ou adjuvante farmaceuti- camente aceitável.
13. Composição farmacêutica, de acordo com a reivindica- ção 12, caracterizada pelo fato de que a. o construto de imunógeno peptídico de IL-31 é selecio- nado do grupo que consiste em SEQ ID NOs: 43-90 e 99-105; e b. o construto de imunógeno peptídico de IL-31 é misturado com um oligodesoxinucleotídeo (ODN) com CpG para formar um com- plexo imunoestimulador estabilizado.
14. Anticorpo isolado ou fragmento de ligação ao epítopo do mesmo, caracterizado pelo fato de que se liga especificamente ao epítopo de célula B do construto de imunógeno peptídico de IL-31 co- mo definido em qualquer uma das reivindicações 1 a 10.
15. Composição, caracterizada pelo fato de que compre- ende o anticorpo isolado ou fragmento de ligação ao epítopo do mes- mo como definido na reivindicação 14.
Figura 1A Sequência sinal Hélice A
Petição 870200083618, de 06/07/2020, pág. 114/147 Hélice B Hélice C Hélice D
Figura 1B 1/33
Figura 2
Petição 870200083618, de 06/07/2020, pág. 115/147 Fator de Diluição (Log10) Fator de Diluição (Log10) Fator de Diluição (Log10) 2/33
Pré-imune
Fator de Diluição (Log10) Fator de Diluição (Log10)
Figura 3A
Meio Figura 3B
Lisado Celular
Figura 3C Figura 3D Meio de IL-31 Meio de IL-31
Petição 870200083618, de 06/07/2020, pág. 118/147 5/33
Faixa Amostra Filtro de 0,22µM Restos de ligação Lavagem 1 Lavagem 2 Lavagem 3 Eluição Grânulos
Figura 4A Petição 870200083618, de 06/07/2020, pág. 119/147 Células DH82 reagem com misturas por 5 min.
Células DH82 Inoculados por 24h Células DH82 (células monocíticas caninas) Lise de células com lisados coletados para análise de pSTAT3/STAT3 ELISA Privação por 2h total 6/33 Células DH82 Anticorpos diluídos serialmente reativos com IL31 pré-misturados com IL-31 a 4 °C por 1h Anticorpos purificados de soros imunológicos anti-IL31
Figura 4B
Petição 870200083618, de 06/07/2020, pág. 120/147 Amostra em mistura Mistura de Coquetel de Lise Celular de Anticorpos
Adicione lisados à microplaca de ensaio InstantOneTM.
Incube poços por 1 hora enquanto agita a 300 rpm.
Adicione o Coquetel de Anticorpos contendo os Lave a Microplaca com o Tampão de Lavagem anticorpos de captura e detecção ao mircopoço. incluído (1X). 7/33
Adicione o Reagente de Detecção colorimétrico a Interrompa a reação colorimétrica com adição de cada um dos poços testados na microplaca.
Solução de Interrupção.
Leia no leitor de placas a Espere o desenvolvimento (~10-30 min) enquanto 450/650 nm. agita a 300 rpm
Petição 870200083618, de 06/07/2020, pág. 121/147 Figura 5A Figura 5B
Nível de Fosforilação Nível de Fosforilação 8/33
Figura 6A Figura 6B
Petição 870200083618, de 06/07/2020, pág. 122/147 Fosforilação de pSTAT3(y705) Fosforilação de pSTAT3(y705)
% fosforilação % fosforilação 9/33
Figura 7
Fosforilação de pSTAT3(y705)
Petição 870200083618, de 06/07/2020, pág. 123/147 % Fosforilação 10/33
Inibição (IC50) de proteína IL-31 canina recombinante induzida por sinalização de pSTAT
Imunogênio
Figura 8
Petição 870200083618, de 06/07/2020, pág. 124/147 Fator de Diluição (Log10) Fator de Diluição (Log10) Fator de Diluição (Log10) 11/33
Pré-imune Fator de Diluição (Log10) Fator de Diluição (Log10)
Figura 9A
Petição 870200083618, de 06/07/2020, pág. 125/147 Fosforilação de pSTAT3(y705) Fosforilação de pSTAT3(y705)
% Fosforilação % Fosforilação 12/33
Figura 9B
Petição 870200083618, de 06/07/2020, pág. 126/147 Fosforilação de pSTAT3(y705) Fosforilação de pSTAT3(y705) 13/33
% Inibição de Fosforilação % Inibição de Fosforilação
Figura 10A
Petição 870200083618, de 06/07/2020, pág. 127/147 Fosforilação de pSTAT3(y705) Fosforilação de pSTAT3(y705) 14/33
% Fosforilação % Fosforilação
Figura 10B
Petição 870200083618, de 06/07/2020, pág. 128/147 Fosforilação de pSTAT3(y705) Fosforilação de pSTAT3(y705) 15/33
% Inibição de fosforilação % Inibição de fosforilação
Figura 11A
Petição 870200083618, de 06/07/2020, pág. 129/147 Fosforilação de pSTAT3(y705) Fosforilação de pSTAT3(y705) Fosforilação de pSTAT3(y705) 16/33
% Fosforilação % Fosforilação
% Fosforilação
Figura 11B
Petição 870200083618, de 06/07/2020, pág. 130/147 Fosforilação de pSTAT3(y705) Fosforilação de pSTAT3(y705) Fosforilação de pSTAT3(y705) 17/33
% Inibição de fosforilação % Inibição de fosforilação % Inibição de fosforilação
Figura 12
Petição 870200083618, de 06/07/2020, pág. 131/147 Fosforilação de pSTAT3(y705) Fosforilação de pSTAT3(y705) Fosforilação de pSTAT3(y705)
% Fosforilação
% Fosforilação % Fosforilação 18/33
Inibição (IC50) de proteína IL-31 canina recombinante induzida por sinalização de pSTAT
Imunogênio
Figura 13 Protocolo de imunização de cão
Petição 870200083618, de 06/07/2020, pág. 132/147 Vacinação Sangramento Pré-imune
Dia
Dose de imunogênio: Prime: 100 µg/dose.
Boost: 100 µg/dose Grupo Imunogênio SEQ ID NO: Adjuvante No. por grupo 19/33
Figura 14
Titulação
Fator de Diluição Figura 15
Fator de Diluição
Fator de Diluição Figura 16
Fator de Diluição
Grupo 3
Dosagem Grupo 2 Figura 17A
Dosagem Dosagem Grupo 1
% Fosforilação de STAT3
Grupo 3
Dosagem Figura 17B
Dosagem Grupo 2
Dosagem Grupo 1
% Inibição de Fosforilação
Figura 18B
% Inibição de Fosforilação Figura 18A
% Fosforilação de STAT3
Petição 870200083618, de 06/07/2020, pág. 138/147 Figura 19A
Inibição de IL-31 canina induzida por sinalização de pSTAT em monócitos DH82 caninos por IgGs purificadas de soros imunológicos de cobaias de 6 e 15 WPI respectivamente
Vacinação 25/33
Sangramento Pré-imune
Semana
Dose de imunogênio: Prime: 400 µg/dose.
Boost: 100 µg/dose
Figura 19B Figura 19C
Petição 870200083618, de 06/07/2020, pág. 139/147 e e 26/33
% Fosforilação de pSTAT3 % Inibição de Fosforilação de pSTAT3(y705) * Cytopoint apenas mostrou as respostas a 0 e 100 µg/mL
Semana
Imunogênio
Titulações ELISA (Log10) Figura 20B Figura 20A
Figura 21
Concentração de IgG (µg/mL)
Concentração de IgG (µg/mL) Figura 22
Concentração de IgG (µg/mL) Figura 23
Expressão relativa de IL-20
Formulação Imunogênio Figura 24A
Figura 24B
Petição 870200083618, de 06/07/2020, pág. 145/147 Figura 25A
Concentração de IgG (µg/mL) 32/33
Imunogênio Formulação
Figura 25B
Figura 26
Concentração de IgG (µg/mL)
Expressão relativa de IL-20
\
4 $ 2 5 % : % 2 / 7 82/ 9 52 5 0 )4 $ # : 5 % 0 5 % 1 5 % )
Este anexo apresenta o código de controle da listagem de sequências biológicas.
Código de Controle Campo 1 9917F28DAC25AE1D Campo 2 A69EA9FD4996858A Outras Informações: - Nome do Arquivo: LISTAGEM DE SEQUÊNCIA JTD TRD-P247535.TXT - Data de Geração do Código: 06/07/2020 - Hora de Geração do Código: 10:16:49 - Código de Controle: - Campo 1: 9917F28DAC25AE1D - Campo 2: A69EA9FD4996858A
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