Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma.
The 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.
Hart
T K
TK
GlaxoSmithKline, King of Prussia, PA, and Protein Design Laboratories, Inc., Fremont, CA, USA. timothy.hart@gsk.com
Blackburn
M N
MN
Brigham-Burke
M
M
Dede
K
K
Al-Mahdi
N
N
Zia-Amirhosseini
P
P
Cook
R M
RM
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D000918:Antibody Specificity; D019540:Area Under Curve; D001249:Asthma / Q000628:therapy*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D000939:Epitopes / Q000276:immunology; D005260:Female; D006041:Goats; D006207:Half-Life; D006736:Horses; D006801:Humans; D007073:Immunoglobulin E / Q000096:biosynthesis; D007167:Immunotherapy; D015847:Interleukin-4 / Q000037:antagonists & inhibitors* / Q000276:immunology; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D009928:Organ Specificity; D012449:Safety; D013154:Spleen / Q000166:cytology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018927:Anti-Asthmatic Agents; D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000939:Epitopes; D015847:Interleukin-4; D007073:Immunoglobulin E