Background: A strong Th1 response to HIV infection is considered required for the ultimate control of HIV disease. Most subjects chronically infected with HIV have an imbalance from a Th1 towards a Th2 response to the viral infection. IL-4 and IL-13 are potent mediators of a Th2 response. A novel biologic agent, the IL-4/13 Trap, blocks IL-4 and IL-13 signaling and the resultant Th2 response, thus favoring a Th1 response that is required for the immune control of HIV disease. The IL-4/13 Trap is a disulfide-linked homo-dimeric protein of the extracellular domains from human IL-4Ra and IL-13Ra1receptors fused, in-line, with the Fc domain of human IgG.

Methods: K_d values for Interleukins were determined by biacore. Trap-blocking of receptor signaling, in vitro, was determined using a human eurythroleukemia cell line, engineered with IL-4 and IL-13 receptors, that proliferated in response to the cytokines. Mouse IgE levels were measured by ELISA. Serum Trap levels in pharmacokinetic (PK) analysis were measured by ELISA and PK parameters were determined by WinNonLin.

Results: The Trap binds IL-4 and IL-13 with K_d values of 20 and 4 pM, respectively. The Trap also blocked receptor signaling from IL-4 and 13, in vitro, with IC₅₀ values of 86 and 17 pM, respectively. IL-4/13 Trap, administered as a subcutaneous injection (3 mg/kg) to cynomolgus monkeys, has excellent pharmacokinetic properties (Cl/F = 3.4 ±0.8 ml/h/kg, Cmax = 17 ±4 mg/ml, and t_1/2 = 29 ±2 h) that may translate into weekly dosing in humans. A murine version of the IL-4/13 Trap markedly reduced the anti-IgD-induced Th2 driven B-cell switch to IgE production in mice, demonstrating a block of this IL-4 driven Th2 response in vivo. The subcutaneous administration of human IL-4/13 Trap to mice blocked the airway hyper-reactivity induced upon the instillation of human IL-13 to mouse lungs, demonstrating IL-13 signal blocking in vivo.

Conclusions: From these results, we propose that the IL-4/13 Trap may be useful for the treatment of HIV in combination with other chemotherapeutic agents in all phases of infection by modulating the immune system to a Th1 response to the virus. The agent may also be useful to enhance the immune response in combination with HIV vaccine therapies. The IL-4/13 Trap is currently in Phase I clinical studies to examine its safety and pharmacokinetic properties.