An IL-4/IL-13 dual antagonist reduces lung inflammation, airway hyperresponsiveness, and IgE production in mice

• Published in: American journal of respiratory cell and molecular biology Vol. 49; no. 1; pp. 37 - 46
• Main Authors: Kasaian, Marion T, Marquette, Kimberly, Fish, Susan, DeClercq, Charlene, Agostinelli, Rita, Cook, Timothy A, Brennan, Agnes, Lee, Julie, Fitz, Lori, Brooks, Jonathan, Vugmeyster, Yulia, Williams, Cara M M, Lofquist, Alan, Tchistiakova, Lioudmila
• Format: Journal Article
• Language: English
• Published: United States American Thoracic Society 01.07.2013
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - immunology; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Binding Sites; Bronchial Hyperreactivity - drug therapy; Bronchial Hyperreactivity - immunology; CHO Cells; Cricetinae; Cross-Linking Reagents - chemistry; Ear - physiopathology; Female; Half-Life; Immunoglobulin E - immunology; Interleukin-13 - antagonists & inhibitors; Interleukin-13 Receptor alpha2 Subunit - immunology; Interleukin-13 Receptor alpha2 Subunit - metabolism; Interleukin-4 - antagonists & inhibitors; Mice; Mice, Inbred C57BL; Molecular Conformation; Neutralization Tests; Ovalbumin - adverse effects; Ovalbumin - immunology; Pneumonia - drug therapy; Pneumonia - immunology; Protein Binding; Protein Interaction Domains and Motifs; Single-Chain Antibodies - metabolism
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2012-0500OC

IL-4 and IL-13 comprise promising targets for therapeutic interventions in asthma and other Th2-associated diseases, but agents targeting either IL-4 or IL-13 alone have shown limited efficacy in human clinical studies. Because these cytokines may involve redundant function, dual targeting holds promise for achieving greater efficacy. We describe a bifunctional therapeutic targeting IL-4 and IL-13, developed by a combination of specific binding domains. IL-4-targeted and IL-13-targeted single chain variable fragments were joined in an optimal configuration, using appropriate linker regions on a novel protein scaffold. The bifunctional IL-4/IL-13 antagonist displayed high affinity for both cytokines. It was a potent and efficient neutralizer of both murine IL-4 and murine IL-13 bioactivity in cytokine-responsive Ba/F3 cells, and exhibited a half-life of approximately 4.7 days in mice. In a murine model of ovalbumin-induced ear swelling, the bifunctional molecule blocked both the IL-4/IL-13-dependent early-phase response and the IL-4-dependent late-phase response. In the ovalbumin-induced lung inflammation model, the bifunctional IL-4/IL-13 antagonist reduced the IL-4-dependent rise in serum IgE titers, and reduced IL-13-dependent airway hyperresponsiveness, lung inflammation, mucin gene expression, and serum chitinase responses. Taken together, these findings demonstrate the effective dual blockade of IL-4 and IL-13 with a single agent, which resulted in the modulation of a more extensive range of endpoints than could be achieved by targeting either cytokine alone.