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

Abstract

SUMMARYThe type 2 helper T cell (T H 2) 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, T H 2 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 T H 2 cell activation and immunoglobulin E production. Clinical trials are under way to test the clinical efficacy of pascolizumab for asthma.

Analysis of serum cytokine levels in patients with pemphigus vulgaris

“…PV'de yeni sitokin paternlerinin tanımlanmasının potansiyel terapotik seçimlere ışık tutacağı düşünülmektedir 6 . Yapılan çalışmalara bakıldığında Th2 lenfosit alt grubunun hakim olduğu IL-4 yüksekliğiyle seyreden astım gibi alerjik kökenli hastalıklarda monoklonal anti IL-4 antikor tedavisi ve IL-4 reseptör tedavisi ile başarılı sonuçlar elde edildiği gözlenmiştir 37,38 . 11 .…”

Severe Asthma: Moving from Phenotype to Endotype Classification with Updates on Treatment

“…IL-4 inhibition was evaluated by Hart et al using a pascolizumab which is a humanized anti-IL-4 monoclonal antibody [59]. Although the in vivo studies demonstrated a good tolerability of the drug, trials were aborted because pascolizumab did not significantly reduce circulating IgE [60].…”

The role of monoclonal antibodies in the treatment of severe asthma

“…Pascolizumab is a humanized anti-IL-4 mAb that inhibits the binding of IL-4 to its receptor [Hart et al 2002]. IL-4 is a cytokine thought to have a role in the early stages of asthma by its involvement in isotype switching to IgE production, eosinophil chemotaxis, Th2 differentiation, and effector T-cell responses [Pauwels et al 1998;Ricci, 1994].…”