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Production of a novel type of recombinant IL-2 immunocytokine
Bednaříková, Kristýna ; Vaněk, Ondřej (advisor) ; Černá, Věra (referee)
Interleukin 2 is a glycoprotein that in humans consists of 133 amino acids and is produced by helper T cells to amplify immune responses. IL-2 has many immunostimulatory and immunoregulatory functions and has been shown to activate the cytotoxic function of natural killer cells, T lymphocytes and monocytes, and to promote cytotoxicity of these effector cells. In therapy, when given in higher doses, IL-2 stimulates effector lymphocytes and defends the body against pathogens and cancer cells. When IL-2 is administered in lower doses, it stimulates T regulatory cells that inhibit the immune response, thus maintaining autotolerance. While studies to date have shown that IL-2 is effective in the treatment of malignancies, considerable toxicity has also been observed. In recent years, studies have been published showing that when IL-2 is covalently bound through an oligopeptide linker to antiIL-2 monoclonal antibodies, there is an increase in its biological activity in vivo. Also, this antibody may sterically hinder binding to certain subunits of IL-2 receptor and thus contribute to the selective activation and expansion of natural killer cells and T effector cells, whereas regulatory T cells are not stimulated. The length of the peptide linker plays a key role in the association of the IL-2 with the anti-IL-2...
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Biological activity of IL-2/anti-IL-2 mAb immunocomplexes in vivo and their terapeutical potential
Hnilicová, Šárka ; Kovář, Marek (advisor) ; Grobárová, Valéria (referee)
IL-2 belongs to the family of c cytokines (IL-2, 4, 7, 9, 15, and 21) which are key regulators of lymphocyte homeostasis and function. They have the potential to promote lymphocyte proliferation and survival and thus overall enhance dominantly adaptive immune response. IL-2 is an autocrine/paracrine soluble factor produced mainly by activated T cells. Interestingly, the in vivo biological activity of IL-2 can be dramatically increased through complexing with certain anti-IL-2 mAbs and such IL-2/anti-IL-2 mAbs immunocomplexes selectively stimulate proliferation of distinct population of immune cells, depending on the clone of anti-IL-2 mAb used. IL-2/S4B6 mAb immunocomplexes are highly stimulatory for CD122high populations (memory CD8+ T and NK cells) and intermediately also for CD25+ populations (Treg and activated T cells), while IL-2/JES6-1 mAb immunocomplexes enormously expand solely CD25+ cells. Thus, IL-2 immunocomplexes possess a broad spectrum of potential therapeutic applications like tumor immunotherapy, vaccination, autoimmune diseases or transplantology.
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