Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti‐interleukin‐4 antibody with therapeutic potential in asthma

Summary The type 2 helper T cell (TH2) cytokine interleukin (IL)‐4 is thought to play a central role in the early stages of asthma. In an effort to develop an antibody treatment for asthma that neutralizes the effects of IL‐4, a murine monoclonal antibody, 3B9, was generated with specificity for human IL‐4. In vitro studies demonstrated that 3B9 inhibited IL‐4‐dependent events including IL‐5 synthesis, TH2 cell activation and up‐regulation of immunoglobulin E expression. 3B9 was then humanized (pascolizumab, SB 240683) to reduce immunogenicity in humans. SB 240683 demonstrated species specificity for both monkey and human IL‐4 with no reactivity to mouse, rat, cow, goat or horse IL‐4. Pascolizumab inhibited the response of human and monkey T cells to monkey IL‐4 and effectively neutralized IL‐4 bioactivity when tested against several IL‐4‐responsive human cell lines. Affinity studies demonstrated rapid IL‐4 binding by pascolizumab with a slow dissociation rate. In vivo pharmacokinetic and chronic safety testing in cynomolgus monkeys demonstrated that pascolizumab was well tolerated, and no adverse clinical responses occurred after up to 9 months of treatment. Three monkeys developed an anti‐idiotypic response that resulted in rapid pascolizumab clearance. However, in the chronic dosing study the antibody response was transient and not associated with clinical events. In conclusion, pascolizumab is a humanized anti‐IL‐4 monoclonal antibody that can inhibit upstream and downstream events associated with asthma, including TH2 cell activation and immunoglobulin E production. Clinical trials are under way to test the clinical efficacy of pascolizumab for asthma.