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A deimmunized and pharmacologically optimized Toll-like receptor 5 agonist for therapeutic applications

2021; Nature Portfolio; Volume: 4; Issue: 1 Linguagem: Inglês

10.1038/s42003-021-01978-6

2399-3642

Vadim Mett, Oleg V. Kurnasov, Ivan A. Bespalov, Ivan Molodtsov, Craig M. Brackett, Lyudmila G. Burdelya, Andrei A. Purmal, Anatoli S. Gleiberman, Ilia Toshkov, Catherine A. Burkhart, Yakov Kogan, Ekaterina L. Andrianova, Andrei V. Gudkov, Andrei L. Osterman,

Cancer, Stress, Anesthesia, and Immune Response

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.