Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
Mais filtros

Base de dados
Ano de publicação
Tipo de documento
Intervalo de ano de publicação
1.
J Biotechnol ; 349: 53-64, 2022 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-35341894

RESUMO

In recent years, acceleration of development timelines has become a major focus within the biopharmaceutical industry to bring innovative therapies faster to patients. However, in order to address a high unmet medical need even faster further acceleration potential has to be identified to transform "speed-to-clinic" concepts into "warp-speed" development programs. Recombinant Chinese hamster ovary (CHO) cell lines are the predominant expression system for monoclonal antibodies (mAbs) and are routinely generated by random transgene integration (RTI) of the genetic information into the host cell genome. This process, however, exhibits considerable challenges such as the requirement for a time-consuming clone screening process to identify a suitable clonally derived manufacturing cell line. Hence, RTI represents an error prone and tedious method leading to long development timelines until availability of Good Manufacturing Practice (GMP)-grade drug substance (DS). Transposase-mediated semi-targeted transgene integration (STI) has been recently identified as a promising alternative to RTI as it allows for a more rapid generation of high-performing and stable production cell lines. In this report, we demonstrate how a STI technology was leveraged to develop a very robust DS manufacturing process based on a stable pool cell line at unprecedented pace. Application of the novel strategy resulted in the manufacturing of GMP-grade DS at 2,000 L scale in less than three months paving the way for a start of Phase I clinical trials only six months after transfection. Finally, using a clonally derived production cell line, which was established from the parental stable pool, we were able to successfully implement a process with an increased mAb titer of up to 5 g per liter at the envisioned commercial scale (12,000 L) within eight months.


Assuntos
Anticorpos Monoclonais , Infecções Sexualmente Transmissíveis , Aceleração , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Infecções Sexualmente Transmissíveis/tratamento farmacológico , Transposases
2.
Biol Chem ; 383(7-8): 1185-91, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12437104

RESUMO

A putative non-substrate like binding mode of (R)-3-amidinophenylalanine derivatives to factor Xa, as derived from modeling experiments based on X-ray analysis of their complexes with trypsin, was used to design a new generation of inhibitors. However, the resulting inhibitory potencies were not at all consistent with the working assumption, although with an adamantyl-ureido derivative of (R)-3-amidinophenylalanine phenetyl amide a highly selective nanomolar inhibition of factor Xa was achieved. The X-ray analysis of the complex of this ligand with factor Xa revealed an unexpected new binding mode, of which the most important feature is the interaction of the C-terminal aryl moiety with a hydrophobic subregion of the S1 subsite, while the adamantyl group occupies the hydrophobic S3/S4 subsites of the enzyme.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores do Fator Xa , Fenilalanina/análogos & derivados , Fenilalanina/síntese química , Sítios de Ligação , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Modelos Moleculares , Fenilalanina/química , Fenilalanina/farmacologia , Ligação Proteica , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA