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General and Virus-Specific Immune Augmentation Strategies
Tuesday, 1:30 - 3:30 pm
Background: Combination therapy with highly active antiretroviral therapy (HAART) and aldesleukin (Proleukin) produces sustained increases in CD4+ T-cell counts and augments the immune system more effectively than HAART alone. However, treatment with aldesleukin is associated with toxicity, which may be due to the eliciting of inflammatory mediator production by cells expressing the intermediate affinity IL-2 receptor (IL2Rbg). BAY 50-4798, an engineered form of IL-2, is a selective agonist for the high affinity receptor (IL2Rabg) and induces the proliferation of activated T cells. BAY 50-4798 has greatly reduced ability to activate cells expressing IL2Rbg and is therefore predicted to have better safety and a greater therapeutic index in humans, compared with aldesleukin. To further characterize the biological effects of BAY 50-4798, we compared the production of cytokines in response to BAY 50-4798 and aldesleukin.
Methods: Peripheral blood mononuclear cells (PBMC) from 16 healthy male donors were stimulated with BAY 50-4798 or aldesleukin at clinically relevant concentrations. Levels of 12 cytokines and 3 chemokines were determined in culture supernatants by Luminex Multiplex ELISA.
Results: Compared with
aldesleukin, BAY 50-4798 induced at least 75% lower levels of endogenous IL-2,
and at least 50% lower levels of pro-inflammatory cytokines such as TNFa,
IL-6, and IFNg.
Decreased IL-2 mRNA was confirmed by quantitative
Conclusions: These findings extend our understanding of the biological action of BAY 50-4798. Our data demonstrate that PBMC stimulation with BAY 50-4798 is associated with reduced levels of both inflammatory cytokines and endogenous IL-2 production compared with aldesleukin, and suggest that BAY 50-4798 may exhibit better safety in humans. BAY 50-4798 is currently being evaluated in a phase 1/2 clinical trial in patients with HIV.
Keywords: BAY 50-4798; Aldesleukin; IL-2