A deimmunized and pharmacologically optimized Toll-like receptor 5 agonist for therapeutic applications.
Commun Biol
; 4(1): 466, 2021 04 12.
Article
em En
| MEDLINE
| ID: mdl-33846531
ABSTRACT
The Toll-like receptor 5 (TLR5) agonist entolimod, a derivative of Salmonella flagellin, has therapeutic potential for several indications including radioprotection and cancer immunotherapy. However, in Phase 1 human studies, entolimod induced a rapid neutralizing immune response, presumably due to immune memory from prior exposure to flagellated enterobacteria. To enable multi-dose applications, we used structure-guided reengineering to develop a next-generation, substantially deimmunized entolimod variant, GP532. GP532 induces TLR5-dependent NF-κB activation like entolimod but is smaller and has mutations eliminating an inflammasome-activating domain and key B- and T-cell epitopes. GP532 is resistant to human entolimod-neutralizing antibodies and shows reduced de novo immunogenicity. GP532 also has improved bioavailability, a stronger effect on key cytokine biomarkers, and a longer-lasting effect on NF-κB. Like entolimod, GP532 demonstrated potent prophylactic and therapeutic efficacy in mouse models of radiation-induced death and tissue damage. These results establish GP532 as an optimized TLR5 agonist suitable for multi-dose therapies and for patients with high titers of preexisting flagellin-neutralizing antibodies.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
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Transdução de Sinais
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Receptor 5 Toll-Like
Limite:
Humans
Idioma:
En
Revista:
Commun Biol
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos