Novel IL-2-Poly(HPMA)Nanoconjugate Based Immunotherapy.
Interleukin-2 (IL-2) possesses a strong stimulatory activity for activated T and NK cells and it is an attractive molecule for immunotherapy. Nevertheless, extremely short half-life and severe toxicities associated with high-dose IL-2 treatment are serious and limiting drawbacks. In order to increase IL-2 half-life in vivo, we covalently conjugated synthetic semitelechelic polymeric carrier based on N-(2-hydroxypropyl)methacrylamide (HPMA) to IL-2. Thus, we synthesized IL-2-poly(HPMA) conjugate containing 2-3 polymer chains per IL-2 molecule in average. Such conjugate has lower biologic activity in comparison to IL-2 in vitro. However, it exerts much higher activity than IL-2 in vivo as shown by expansion of memory CD8+ T, NK, NKT, γδT and Treg cells. Moreover, IL-2-poly(HPMA) extremely effectively potentiates CD8+ T cell peptide-based vaccination. IL-2-poly(HPMA) shows also much longer half-time in circulation than IL-2 (-4 h versus -5 min). Collectively, modification of IL-2 with poly(HPMA) chains dramatically improves its potency and pharmacologic features in vivo, which have implications for immunotherapy. To our knowledge, this is the first proof-of-concept report of the use of polymer/protein modification of IL-2 to obtain more pronounced biological activity.
Petra
P
Votavova
Jakub
J
Tomala
Vladimir
V
Subr
Jiri
J
Strohalm
Karel
K
Ulbrich
Blanka
B
Rihova
Marek
M
Kovar
D000818:Animals; D004058:Diffusion; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D007155:Immunologic Factors / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods; D007376:Interleukin-2 / Q000737:chemistry / Q000276:immunology* / Q000627:therapeutic use*; D008297:Male; D008422:Materials Testing; D008689:Methacrylates / Q000737:chemistry*; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000008:administration & dosage / Q000737:chemistry* / Q000648:ultrastructure; D058726:Nanoconjugates / Q000737:chemistry / Q000627:therapeutic use* / Q000648:ultrastructure; D010316:Particle Size; D013499:Surface Properties
D007155:Immunologic Factors; D007376:Interleukin-2; D008689:Methacrylates; D053769:Nanocapsules; D058726:Nanoconjugates; C032802:hydroxypropyl methacrylate