Endogenous interleukin 6 production in multiple myeloma patients treated with chimeric monoclonal anti-IL6 antibodies indicates the existence of a positive feed-back loop.
In vitro as well as in vivo observations have shown that IL6 plays a key role in the pathogenesis of multiple myeloma. Therefore we started a phase I/II dose escalating study with chimeric monoclonal anti-IL6 antibodies (cMab) in multiple myeloma (MM) patients resistant to second-line chemotherapy. Here we describe the pharmacological data as well as a new method for calculating the endogenous IL6 production. The cMab (CLB IL6/8; Kd: 6.25 x 10(-12) M) was given in two cycles of 14 daily infusions, starting on day 1 and day 28. Daily dose: 5 mg in patients 1-3, 10 mg in patients 4-6, and 20 mg in patients 7-9 (total dose 140, 280, and 560 mg of anti-IL6, respectively). Using the pharmacokinetic data of free IL6 and the binding characteristics of the cMab, the endogenous IL6 production could be calculated from day to day using a one-compartment open model. The median half-life time of this antibody was 17.6 d. No human antichimeric antibodies were induced. Pre-treatment median endogenous IL6 production in the MM patients was 60 micrograms/d (range 13.8-230; normal controls < 7 micrograms/d). During treatment with anti-IL6 cMabs, the endogenous IL6 production immediately decreased in all patients to below 3 micrograms/d and never reached the pre-treatment value during the treatment period, except in two patients who developed an active infection, resulting in an IL6 production of 128 and 1,208 micrograms/d, respectively. We concluded that in MM patients endogenous IL6 production is 2-30 times higher than in healthy individuals. The anti-IL6 cMab strongly suppress this endogenous IL6 production, probably by blocking a positive feed-back loop, but this cMab does not prevent infection-induced IL6 production. The chimeric anti-IL6 Mabs have a long half-life time, a low immunogenicity, and are able to block IL6-dependent processes in vivo.
van Zaanen
H C
HC
Department of Hermatology, Academic Medical Center, Amsterdam, The Netherlands.
Koopmans
R P
RP
Aarden
L A
LA
Rensink
H J
HJ
Stouthard
J M
JM
Warnaar
S O
SO
Lokhorst
H M
HM
van Oers
M H
MH
D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000276:immunology* / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000378:metabolism* / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins