In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity

0450872 - ÚMCH 2016 RIV US eng J - Článek v odborném periodiku
Lynn, G. M. - Laga, Richard - Darrah, P. A. - Ishizuka, A. S. - Balaci, A. J. - Dulcey, A. E. - Pechar, Michal - Pola, Robert - Gerner, M. Y. - Yamamoto, A. - Buechler, C. R. - Quinn, K. M. - Smelkinson, M. G. - Vanek, O. - Cawood, R. - Hills, T. - Vasalatiy, O. - Kastenmüller, K. - Francica, J. R. - Stutts, L. - Tom, J. K. - Ah Ryu, K. - Esser-Kahn, A. P. - Etrych, Tomáš - Fisher, K. D. - Seymour, L. W. - Seder, R. A.
In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity.
Nature Biotechnology. Roč. 33, č. 11 (2015), s. 1201-1210. ISSN 1087-0156. E-ISSN 1546-1696
Grant CEP: GA MŠMT(CZ) EE2.3.30.0029
Institucionální podpora: RVO:61389013
Klíčová slova: adjuvants * biomedical engineering * drug delivery
Kód oboru RIV: CE - Biochemie
Impakt faktor: 43.113, rok: 2015

The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through formulation and delivery approaches. Here, we attached small molecule TLR-7/8a to polymer scaffolds (polymer–TLR-7/8a) and evaluated how different physicochemical properties of the TLR-7/8a and polymer carrier influenced the location, magnitude and duration of innate immune activation in vivo. Particle formation by polymer–TLR-7/8a was the most important factor for restricting adjuvant distribution and prolonging activity in draining lymph nodes. The improved pharmacokinetic profile by particulate polymer–TLR-7/8a was also associated with reduced morbidity and enhanced vaccine immunogenicity for inducing antibodies and T cell immunity. We extended these findings to the development of a modular approach in which protein antigens are site-specifically linked to temperature-responsive polymer–TLR-7/8a adjuvants that self-assemble into immunogenic particles at physiologic temperatures in vivo. Our findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.
Trvalý link: http://hdl.handle.net/11104/0252994