Design of human interleukin-4 antagonists inhibiting interleukin-4-dependent and interleukin-13-dependent responses in T-cells and B-cells with high efficiency

Eur J Biochem. 1994 Oct 15;225(2):659-65. doi: 10.1111/j.1432-1033.1994.00659.x.


Human interleukin-4 possesses two distinct sites for receptor activation. A signalling site, comprising residues near the C-terminus on helix D, determines the efficacy of interleukin-4 signal transduction without affecting the binding to the interleukin-4 receptor alpha subunit. A complete antagonist and a series of low-efficacy agonist variants of human interleukin-4 could be generated by introducing combinations of two or three negatively charged aspartic acid residues in this site at positions 121, 124, and 125. One of the double variants, designated [R121D,Y124D]interleukin-4, with replacements of both Arg121 and Tyr124 by aspartic acid residues was completely inactive in all analysed cellular responses. The loss of efficacy in [R121D,Y124D]interleukin-4 is estimated to be larger than 2000-fold. Variant [R121D,Y124D]interleukin-4 was also a perfect antagonist for inhibition of interleukin-13-dependent responses in B-cells and the TF-1 cell line with a Ki value of approximately 100 pM. In addition, inhibition of both interleukin-4-induced and interleukin-13-induced responses could be obtained by monoclonal antibody X2/45 raised against interleukin-4Rex, the extracellular domain of the interleukin-4 receptor alpha subunit. These results indicate that efficient interleukin-4 antagonists can be designed on the basis of a sequential two-step activation model. In addition, the experiments indicate the functional participation of the interleukin-4 receptor alpha subunit in the interleukin-13 receptor system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal
  • B-Lymphocytes / immunology*
  • Drug Design
  • Humans
  • Interleukin-13 / antagonists & inhibitors*
  • Interleukin-13 / immunology
  • Interleukin-13 Receptor alpha1 Subunit
  • Interleukin-4 / antagonists & inhibitors*
  • Interleukin-4 / immunology
  • Lymphocyte Activation / drug effects
  • Mutagenesis, Site-Directed
  • Receptors, IgE / metabolism
  • Receptors, Interleukin / physiology
  • Receptors, Interleukin-13
  • Receptors, Interleukin-4
  • T-Lymphocytes / immunology*


  • Antibodies, Monoclonal
  • IL13RA1 protein, human
  • Interleukin-13
  • Interleukin-13 Receptor alpha1 Subunit
  • Receptors, IgE
  • Receptors, Interleukin
  • Receptors, Interleukin-13
  • Receptors, Interleukin-4
  • Interleukin-4