Cutting edge: mechanism of enhancement of in vivo cytokine effects by anti-cytokine monoclonal antibodies.
Inhibitory anti-cytokine mAbs are used to treat cytokine-mediated disorders. Recently, however, S4B6, an anti-IL-2 mAb that blocks IL-2 binding to IL-2Ralpha, a receptor component that enhances affinity but is not required for signaling, was shown to enhance IL-2 agonist effects in vivo. We evaluated how S4B6 enhances IL-2 effects and whether a similar mechanism allows mAbs to IL-4 to enhance IL-4 effects. Induction of T cell proliferation by IL-2/S4B6 complexes did not require complex dissociation and was IL-2Ralpha independent. S4B6 increased IL-2 agonist effects by increasing in vivo half-life, not by focusing IL-2 onto cells through Fc receptors. In contrast to IL-2/S4B6 complexes, anti-IL-4 mAb enhancement of in vivo IL-4 effects required IL-4/anti-IL-4 mAb complex dissociation. Thus, agonist effects observed with high doses of anti-IL-2 mAb are most likely only applicable for mAbs that maintain cytokine half-life without blocking binding to receptor signaling components.
Phelan
James D
JD
Immunobiology Graduate Program, University of Cincinnati College of Medicine, and Division of Immunobiology, Children's Hospital Medical Research Foundation, Cincinnati, OH 45267, USA.
Orekov
Tatyana
T
Finkelman
Fred D
FD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D016207:Cytokines / Q000037:antagonists & inhibitors*; D005260:Female; D006207:Half-Life; D007376:Interleukin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000819:agonists*; D015847:Interleukin-4 / Q000037:antagonists & inhibitors; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D000911:Antibodies, Monoclonal; D016207:Cytokines; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015847:Interleukin-4