A deimmunized and pharmacologically optimized Toll-like receptor 5 agonist for therapeutic applications
| Autor: | Craig M. Brackett, Catherine Burkhart, Ilia Toshkov, Andrei L. Osterman, Ivan A. Bespalov, Andrei Purmal, Vadim L. Mett, Andrei V. Gudkov, Lyudmila G. Burdelya, Yakov N. Kogan, Anatoli S. Gleiberman, Ekaterina L. Andrianova, Ivan Molodtsov, Oleg V. Kurnasov |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Agonist medicine.drug_class QH301-705.5 medicine.medical_treatment Medicine (miscellaneous) Article General Biochemistry Genetics and Molecular Biology Epitope Recombinant protein therapy 03 medical and health sciences Applied immunology 0302 clinical medicine Immune system Cancer immunotherapy Cell Line Tumor medicine Humans Biology (General) Toll-like receptor business.industry Immunogenicity Toll-Like Receptor 5 HEK293 Cells 030104 developmental biology TLR5 030220 oncology & carcinogenesis Cancer research Peptides General Agricultural and Biological Sciences business Signal Transduction Entolimod |
| Zdroj: | Communications Biology, Vol 4, Iss 1, Pp 1-14 (2021) Communications Biology |
| ISSN: | 2399-3642 |
| Popis: | 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. Mett et al. describe development of GP532, a substantially deimmunized derivative of Toll-like receptor 5 (TLR5) agonist entolimod. GP532 has mutations eliminating key B- and T-cell epitopes and an inflammasome-activating domain yet remains a potent NF-κB activator with biological effects similar to entolimod. Thus, GP532 is suitable for multi-dose TLR5-targeting therapies and patients with high titers of preexisting flagellin-neutralizing antibodies. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
| Nepřihlášeným uživatelům se plný text nezobrazuje | K zobrazení výsledku je třeba se přihlásit. |