Pascolizumab, also known as SB240683, is a humanized monoclonal antibody direct against interleukin-4 (IL-4). This drug was developed by GlaxoSmithKline as an antiasthmatic for the treatment of asthma. In 2002, in vitro studies showed that pascolizumab could effectively neutralize the bioactivity of IL-4, and the binding of pascolizumab to IL-4 had a slow dissociation rate. Subsequently, a phase II clinical trial was conducted with pascolizumab in patients with simple glucocorticoid asthma. But in 2003, the II phase clinical trial was terminated in the United States.
Interleukin-4 (IL-4), the target molecular of pascolizumab, is an important cytokine in the early stages of asthma. IL-4 is mainly produced by activated T cells and also comes from a variety of cytokines. IL-4 is a cytokine produced by activated T cells monocytes basophils mast cells and eosinophils. IL-4 binds to IL-4Rα on the surface of effector cells to form dimer between IL-4Rα and γc or IL-13 Rα1, and phosphorylated at the tail of intracellular domain. Then a signal transduction complex is assembled in the intracellular domain of the dimer, and downstream intracellular molecules are activated to promote the transcription of the target gene. The main biological signal transduction pathways involved by IL-4 are JAK-STAT pathway, Ras-ERK pathway and PI3K-PKB pathway. IL-4 has multiple biological functions and therapeutic effects on swelling, hypersensitivity, rheumatoid arthritis, hematopoietic stem cell transplantation, pregnancy, aplastic anemia and ischemic heart disease. In allergic asthma, Th2 cells may resist the immunosuppressive effect of Treg by secreting IL-4, which can interact with IL-4R expressed on the Treg cell, and inhibiting the expression of Foxp3 through STAT6 signaling pathway, affecting the occurrence and development of asthma. Studies have shown that IL-4 mediates important pro-inflammatory effects in asthma, such as induction of IgE-like rearrangement, expression of vascular cell adhesion molecule-1(VCAM-1), promoting eosinophil migration and release of cytokines. Pascolizumab is a monoclonal antibody that neutralizes IL-4, to inhibit asthma-related responses such as activation of T (H)-2 cells and production of immunoglobulin E.
Fig.1 Mechanism of Action of Pascolizumab