BR112012026003A2 - estrutura multimérica específica trail r2, seu uso, molécula de ácido nucleico que a codifica, bem como composição - Google Patents

estrutura multimérica específica trail r2, seu uso, molécula de ácido nucleico que a codifica, bem como composição Download PDF

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BR112012026003A2
BR112012026003A2 BR112012026003-0A BR112012026003A BR112012026003A2 BR 112012026003 A2 BR112012026003 A2 BR 112012026003A2 BR 112012026003 A BR112012026003 A BR 112012026003A BR 112012026003 A2 BR112012026003 A2 BR 112012026003A2
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multimeric structure
trail
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Manuel Baca
Thomas Thirsted
Jeffrey Swers
David Tice
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Medimmune, Llc
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Abstract

  ESTRUTURA MULTIMÉRICA RECOMBINANTE ESPECÍFICA TRAIL R2, SEU USO, MOLÉCULA DE ÁCIDO NUCLEICO QUE A CODIFICA, BEM COMO COMPOSIÇÃO. A presente invenção refere-se a estruturas multiméricas a base de domínio Tenascina-3 FnIII que especificamente se ligam ao receptor TRAIL 2 (TRAIL R2), um receptor de membrana de célula envolvido na apoptose. A invenção ainda refere-se a variantes projetadas com afinidade aumentada para o alvo, aumenta a estabilidade e imunogenicidade reduzida. Além disso, a presente invenção refere-se a estruturas multivalentes projetadas como agentes profiláticos, de diagnóstico ou terapêuticos e seus usos contra doenças causadas por células que expressam TRAIL R2, em particular a um uso terapêutico contra câncer.

Description

Relatório Descritivo da Patente de Invenção para "ESTRUTURA MULTIMÉRICA RECOMBINANTE ESPECÍFICA TRAIL R2, SEU USO, MOLÉCULA DE ÁCIDO NUCLEICO QUE A CODIFICA, BEM COMO COMPOSIÇÃO". 5 ANTECEDENTE DA INVENÇÃO Referência à Listagem de Sequências Este pedido incorpora por referência uma Listagem de Sequên- cias submetida com este pedido através de arquivo de texto EFS-Web intitu- lado “2943.011PC02_sequence_listing.txt” criado em 12 de abril de 2011 e tendo um tamanho de 211 kilobytes.
Campo da invenção A presente invenção refere-se em geral ao campo de mimé- ticos de anticorpos, especificamente a estruturas multiméricas basea- das no domínio de fibronectina tipo III (Fn3) útil, por exemplo, para a geração de produtos contendo novas características de ligação.
Em particular, a invenção refere-se a estruturas multiméricas específicas de TRAIL R2 derivada de terceiro domínio de FnIII de Tenascina C hu- mana e seus usos para detecção de receptor TRAIL R2 e modulação de função mediada por TRAIL R2-como tratamento de câncer e outros distúrbios.
Técnica Anterior Biomoléculas capazes de ligação específica a um epítopo alvo desejado são de grande importância como terapêutico, pesquisa, e ferra- mentas de diagnóstico médico.
Um exemplo bem conhecido desta classe de moléculas é o anticorpo.
Anticorpos podem ser selecionados que se li- gam especificamente e com afinidade a quase qualquer epítopo estrutural.
No entanto, os anticorpos clássicos são moléculas heterotretaméricas es- truturalmente complexas que são difíceis de expressarem em sistemas eu- carióticos simples.
Como resultado, a maior parte dos anticorpos é produ- zida usando sistemas de expressão de células mamíferas complexas e ca- ros.
As proteínas contendo estruturas tridimensionais relativa-
mente definidas, comumente referidas como estruturas de proteínas, podem ser usadas como reagentes para o desenho de produtos projeta- dos.
Uma área particular em que sitas estruturas são úteis é o campo de desenho de mimético de anticorpo.
Miméticos de anticorpos, ou seja, 5 terapêuticos de proteínas não anticorpos pequenas, capitalizam as van- tagens de anticorpos e fragmentos de anticorpos, como ligação de alta afinidade de alvos e baixa imunogenicidade e toxicidade, enquanto evi- tando algumas deficiências, como a tendência para fragmentos de anti- corpos para agregar e ser menos estável do que IgGs de comprimento total.
Estas desvantagens podem ser direcionadas usando frag- mentos de anticorpo pela remoção de partes da dobra nativa do anti- corpo.
No entanto, isto geralmente causa agregação quando resíduos de aminoácidos que poderiam normalmente ser ocultado em um ambi- ente hidrofóbico como uma interface entre domínio variável e constante ficam expostos ao solvente.
Um exemplo de mimético de anticorpo ba- seado na estrutura é baseado na estrutura de uma molécula de fibro- nectina de tipo III (FnIII), um domínio encontrado amplamente através de fila e classes de proteína, como em sangue de mamíferos e proteí- nas estruturais.
TRAIL (ligador indutor de apoptose relacionado a fator de necro- se tumoral, ainda referenciado na literatura como Apo2L e TNFSF10) perten- ce a superfamília de fator de necrose tumoral (TNF) e foi identificado como um ativador de morte celular programada, ou apoptose, em células tumorais.
Ambas formas ligada a membrana e solúvel de TRAIL são capazes de dis- parar a apoptose através da interação com receptores TRAIL localizados nas células alvo.
Em humanos, cinco receptores foram identificados por ter atividade de ligação para TRAIL.
Na ligação de TRAIL a TRAIL R1 ou TRAIL R2, a morte celular relacionara a caspase é disparada.
À luz desta atividade de morte celular, abordagens terapêuticas a base de TRAIL estão sendo buscadas.
Várias abordagens terapêuticas baseadas em TRAIL ou TRAIL

Claims (11)

REIVINDICAÇÕES
1. Estrutura multimérica recombinante específica TRAIL R2, ca- racterizada pelo fato de que compreende pelo menos duas estruturas de monômeros Tn3, em que 5 (a) cada estrutura de monômero Tn3 compreende sete fitas beta designadas A, B, C, D, E, F, e G e seis regiões de alça designadas AB, BC, CD, DE, EF, e FG, (b) as estruturas de monômero Tn3 são conectadas em tandem, e (c) a estrutura multimérica recombinante especificamente se liga a TRAIL R2, em que pelo menos duas estruturas de monômero Tn3 compre- endem a sequência de aminoácido: I- EV(XAB)nALITW(XBC)nCELX1YGI(XCD)nTTIX2L(XDE)nYSI(XEF)nYEVSLIC(XFG)n KX3TFTT em que XAB, XBC, XCD, XDE, XEF, e XFG representam os resíduos de aminoácidos presentes nas alças AB, BC, CD, DE, EF, e FG, respec- tivamente, em que X1 representa resíduo de aminoácido A ou T, em que X2 representa resíduo de aminoácido D ou G, em que X3 representa aminoá- cido E ou G, e em que o comprimento da alça n é um número inteiro entre 2 e 26.
2. Estrutura multimérica de acordo com a reivindicação 1, carac- terizada pelo fato de que a alça AB compreende a SEQ ID NO: 35, a alça CD compreende a SEQ ID NO: 37, e a alça EF compreende a SEQ ID NO:
39.
3. Estrutura multimérica de acordo com a reivindicação 1, carac- terizada pelo fato de que a alça BC compreende uma sequência selecionada do grupo que consiste em: SEQ ID NOs: 97, 98, ou 168.
4. Estrutura multimérica de acordo com a reivindicação 1, carac- terizada pelo fato de que a alça DE compreende uma sequência selecionada do grupo que consiste em: SEQ ID NOs: 102, 103, e 179.
5. Estrutura multimérica de acordo com a reivindicação 1, carac- terizada pelo fato de que a alça FG compreende uma sequência selecionada do grupo que consiste em: SEQ ID NOs: 106, 108, 109, 169, e 170.
6. Estrutura multimérica de acordo com a reivindicação 1, carac- 5 terizada pelo fato de que a alça BC compreende a SEQ ID NO: 97, a alça DE compreende a SEQ ID NO: 179, e a alça FG compreende a SEQ ID NO:
170.
7. Estrutura multimérica de acordo com a reivindicação 1, carac- terizada pelo fato de que a estrutura compreende a SEQ ID NO: 204.
8. Molécula de ácido nucleico isolada, caracterizada pelo fato de que codifica a estrutura multimérica, como definida na reivindicação 1.
9. Composição, caracterizada pelo fato de que compreende a estrutura multimérica recombinante, como definida na reivindicação 1, em um excipiente farmaceuticamente aceitável.
10. Uso de uma estrutura multimérica recombinante, como defi- nida em qualquer uma das reivindicações 1 a 7, caracterizado pelo fato de ser para preparar uma composição para prevenir, tratar, amenizar, ou con- trolar câncer; para diagnosticar ou imagear a doença em um paciente.
11. Invenção, em quaisquer formas de suas concretizações ou em qualquer categoria aplicável de reivindicação, por exemplo, de produto ou de processo ou uso englobadas pela matéria inicialmente descrita, reve- lada ou ilustrada no pedido de patente.
BR112012026003-0A 2010-04-13 2011-04-12 Estrutura multimérica recombinante específica trail r2, seu uso, bem como composição BR112012026003B1 (pt)

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US32370810P 2010-04-13 2010-04-13
US61/323,708 2010-04-13
PCT/US2011/032188 WO2011130328A1 (en) 2010-04-13 2011-04-12 Trail r2-specific multimeric scaffolds

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BR112012026003A2 true BR112012026003A2 (pt) 2020-09-01
BR112012026003B1 BR112012026003B1 (pt) 2022-03-15

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