Anti-IL-6 receptor antibody increases blood IL-6 level via the blockade of IL-6 clearance, but not via the induction of IL-6 production.
We explored the mechanism for the increase of blood IL-6 level after anti-IL-6 receptor (IL-6R) antibody injection. First, we examined whether anti-IL-6R antibody stimulates IL-6 production. Single injection of tocilizumab (anti-IL-6R antibody) in monkeys with collagen-induced arthritis (CIA) caused a marked increase in blood IL-6 and IL-6R levels, but did not increase IL-6 mRNA and IL-6R mRNA expression in liver, spleen, lymph nodes, synovium or whole blood 1, 3 and 7 days later. This suggests that tocilizumab did not induce IL-6 and IL-6R production. Second, we investigated whether anti-IL-6R antibody releases IL-6 from IL-6 complexes in the blood. When plasma from CIA monkeys was incubated with tocilizumab, the IL-6 concentration was not affected. Finally, we studied whether anti-IL-6R antibody affects the clearance of IL-6 from the blood. When MR16-1 (anti-mouse IL-6R antibody) was injected into IL-6-deficient mice continuously infused with human IL-6, blood human IL-6 levels significantly increased. These results suggest that the elevation of blood IL-6 after the administration of anti-IL-6R antibody is the result of inhibition of the clearance of IL-6 due to IL-6R blockade, and that it is not the result of induction of IL-6 production or release of IL-6 from complexes.
Uchiyama
Yasushi
Y
Product Research Department, Chugai Pharmaceutical Co. Ltd., Japan.
Yoshida
Hiroto
H
Koike
Nobuo
N
Hayakawa
Naohiko
N
Sugita
Atsuko
A
Nishimura
Takashi
T
Mihara
Masahiko
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism; D002097:C-Reactive Protein / Q000032:analysis; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000097:blood* / Q000172:deficiency / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D012333:RNA, Messenger / Q000276:immunology* / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000097:blood*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015850:Interleukin-6; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D002097:C-Reactive Protein; C502936:tocilizumab