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Cytokine/anti-cytokine mAb complexes and their biological activity
Hnízdilová, Tereza ; Kovář, Marek (advisor) ; Grobárová, Valéria (referee)
biologická aktivita některých cytokinů může být paradoxně zvýšena tvorbou komplexu některými svými monoklonálními protilátkami (mAb) rozpoznávajícími tento cytokin. Prodloužení poločasu eliminace z 2 mAb komplexy, neboť v použitém klonu mAb dochází k selektivní stimulaci buď CD25 2/S4B6 komplex) buněk. Díky výrazné stimulaci NK buněk a paměťových CD8 lymfocytů a pouze mírné stimulaci Treg buněk by IL nahradit konvenční IL vysoce selektivní stimulací Treg buněk naopak mohly uplatnit při léčbě autoimunitních onemocnění a transplantacích. Potenciálně klinicky využitelné jsou dále IL stimulaci žírných buněk, IL plazmatickými buňkami či IL proliferaci a přežívání T lymfocytů. Imunokomplexy mohou být tvořeny také cytokinem a jeho 15Rα komplexy představují generaci IL onistů, které mohou být díky stimulaci expanze NK buněk a paměťových CD8 T lymfocytů využity jako Klíčová slova 15Rα komplexy
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IL-15/IL-15Rα complexes as IL-15 superagonist
Honzírková, Lucie ; Kovář, Marek (advisor) ; Javorková, Eliška (referee)
Interleukin 15 binds to its hight-afinity receptor IL-15Rα and forms stable IL-15/IL-15Rα complexes. IL-15Rα presents IL-15 in trans to target CD122/CD132 cells, where initiates signal transduction. Interleukin 15 has important role in immune system as it - regulates the homeostatic proliferation of memory CD8+ T cells and it is an essential for function, development and homeostasis of NK and NKT cells. Cell surface-expressed IL-15/IL15Rα complexes can be completely substituted by soluble recombinant IL-15/IL-15Rα-Fc complexes, which have substantially higher biological activity in composition to free IL-15 and behave as IL-15 superagonist. Il-15/IL-15Rα-Fc complexes are thus promising tool for some clinical use, i.e. cancer immune therapy, treatment of HIV or improvement of vaccination.
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Potentiation of the biological activity of IL-2 and IL-15 in vivo
Votavová, Petra ; Kovář, Marek (advisor) ; Reiniš, Milan (referee)
5 Abstract Interleukin-2 possesses strong stimulatory activity for activated T and NK cells and thus it is an attractive molecule for immunotherapy. However, its unfavourable pharmacological properties, extremely short half-life and severe toxicities associated with high-dose IL-2 are the most serious and limiting drawbacks. Moreover, IL-2 has been also implicated in the homeostasis of T regulatory cells where it plays a decisive role as an essential growth factor of these cells. Several different approaches to improve the therapeutic potential of IL-2 have been studied. Recently described IL-2/anti-IL-2 mAb immunocomplexes which show much higher and selective biological activity in contrast with free IL-2 in vivo are probably the most promising of them. In this study, we compared the biological activity of free IL-2 with IL-2/anti-IL-2 mAb immunocomplexes in order to demonstrate their benefits over free IL-2. We also demonstrated that IL-2/anti-IL-2 mAb immunocomplexes possess noticeable antitumor activity in two syngeneic mouse tumor models, namely EL4 T lymphoma and B16F10 melanoma, if administered early in tumor progression. Therefore, we justified potential use of IL-2/anti-IL-2 mAb immunocomplexes in tumor immunotherapy. We covalently conjugated IL-2 to synthetic semitelechelic polymeric carrier based...
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