Cytokine-Inducing Activity and Antitumor Effect of a Liposome-Incorporated Interferon-γ-Inducing Molecule Derived From OK-432, a Streptococcal Preparation

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Abstract
An interferon-γ (IFN-γ)-inducing molecule (OK-PSA) has been purified from OK-432 by an affinity chromatographic technique performed on cyanogen bromide-activated Sepharose 4B–bound TS-2 monoclonal antibody, which neutralizes IFN-γ–inducing activity of OK-432. OK-PSA has striking anti-tumor activity in vivo and in vitro. In the current study, the liposomes were used to improve the delivery of the agent (OK-PSA) to effector cells and to increase the therapeutic effect. Significantly less OK-PSA encapsulated into liposomes (Lipo-OK-PSA) than OK-PSA alone (1/100 or less of OK-PSA alone) was required to induce IFN-γ, tumor necrosis factor-α (TNF-α), TNF-β, interleukin-1β (IL-1β), natural killer, and lymphokine-activated killer activities by human peripheral blood mononuclear cells and mouse spleen cells. Furthermore, higher levels of these activities were detected in peripheral blood mononuclear cells and mouse spleen cells treated with Lipo-OK-PSA than in those treated with OK-PSA. All of these activities induced by Lipo-OK-PSA were almost completely neutralized by anti–asialo-GM1 antibody and complement (p < 0.001). In in vivo experiments, Lipo-OK-PSA elicited striking anti-tumor activity on syngeneic Meth-A tumor-bearing and colon 26–bearing BALB/c mice and on salivary gland tumor–bearing nude mice far better than did OK-PSA. Furthermore, high levels of natural killer and lymphokine-activated killer activities and a significant increase in the number of cells positive for asialo-GM1, IFN-γ, TNF-α, or IL-1β were detected in the spleen cells derived from the animals given Lipo-OK-PSA compared with those given saline. These findings clearly indicate that OK-PSA plays an important role in the anti-tumor efficiency of OK-432, and that, for the most part, liposome encapsulation of this molecule markedly accelerates its effect mediated by asialo-GM1–positive cells (mainly natural killer cells).

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