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

Developers

Geoffrey M Lynn, Richard Laga, Patricia A Darrah, Leonard W Seymour, Robert A Seder, etc.

Description of the technology

The efficacy of vaccine adjuvants such as Toll-like receptor agonists (TLRa) can be improved through development of formulation and delivery system. The developers attached small molecule TLR-7/8a to polymer scaffolds and received a complex polymer-TLR-7/8a. Then they 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 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. The authors 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. These findings provide a chemical and structural basis for optimizing adjuvant design to elicit broad-based antibody and T cell responses with protein antigens.

Practical application

Polymer carriers of TLRa, such as those, used in this technology, represent a diverse and versatile class of adjuvant that can be systematically tuned to achieve the optimal magnitude, quality and spatiotemporal characteristics of innate immune activity required for eliciting antibody and T cell immunity. These polymer carriers and adjuvants, produced with their use, can be applicable and important for applications in preventive and therapeutic vaccines for infections and tumors.

Laboratories

• Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, (USA)
• Department of Oncology, University of Oxford (UK)
• Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Prague (Czech Republic)
• Imaging Probe Development Center, National Heart, Lung, and Blood Institute, NIH, Rockville USA)

Links

Publications

• Lynn G.M., et al. «In vivo characterization of the physicochemical properties of polymer-linked TLR agonists that enhance vaccine immunogenicity." 33.11 Nat Biotechnol., (2015): 1201−1210.
• Seder, R.A., Darrah, P.A. & Roederer, M. «T-cell quality in memory and protection: implications for vaccine design." 8 Nat. Rev. Immunol., (2008): 247–258.
• Seymour, L.W. et al. «Hepatic drug targeting: phase I evaluation of polymer-bound doxorubicin." 20 J. Clin. Oncol., (2002): 1668–1676.
• Seymour, L.W., Duncan, R., Strohalm, J. & Kopecek, J. «Effect of molecular weight (Mbarw) of N-(2-hydroxypropyl)methacrylamide copolymers on body distribution and rate of excretion after subcutaneous, intraperitoneal, and intravenous administration to rats." 21 J. Biomed. Mater. Res., (1987): 1341–135.