title: An IL-4/IL-13 dual antagonist reduces lung inflammation, airway hyperresponsiveness, and IgE production in mice.
abstract: 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.
authors: Department of Immunoscience, Pfizer, Cambridge, MA 02140, USA. marion.kasaian@pfizer.com
authors: Marion T
authors: MT
authors: Kasaian
authors: Kimberly
authors: K
authors: Marquette
authors: Susan
authors: S
authors: Fish
authors: Charlene
authors: C
authors: DeClercq
authors: Rita
authors: R
authors: Agostinelli
authors: Timothy A
authors: TA
authors: Cook
authors: Agnes
authors: A
authors: Brennan
authors: Julie
authors: J
authors: Lee
authors: Lori
authors: L
authors: Fitz
authors: Jonathan
authors: J
authors: Brooks
authors: Yulia
authors: Y
authors: Vugmeyster
authors: Cara M M
authors: CM
authors: Williams
authors: Alan
authors: A
authors: Lofquist
authors: Lioudmila
authors: L
authors: Tchistiakova
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology / Q000494:pharmacology*; D001665:Binding Sites; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000276:immunology; D016466:CHO Cells; D006224:Cricetinae; D003432:Cross-Linking Reagents / Q000737:chemistry; D004423:Ear / Q000503:physiopathology; D005260:Female; D006207:Half-Life; D007073:Immunoglobulin E / Q000276:immunology*; D018793:Interleukin-13 / Q000037:antagonists & inhibitors*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D008968:Molecular Conformation; D009500:Neutralization Tests; D010047:Ovalbumin / Q000009:adverse effects / Q000276:immunology; D011014:Pneumonia / Q000188:drug therapy* / Q000276:immunology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D057127:Single-Chain Antibodies / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003432:Cross-Linking Reagents; D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D057127:Single-Chain Antibodies; D015847:Interleukin-4; D007073:Immunoglobulin E; D010047:Ovalbumin