ENDOGENOUS INTERLEUKIN-6 PRODUCTION IN MULTIPLE-MYELOMA PATIENTS TREATED WITH CHIMERIC MONOCLONAL ANTI-IL6 ANTIBODIES INDICATES THE EXISTENCE OF A POSITIVE FEEDBACK LOOP

In vitro as well as in vivo observations have shown that IL6 plays a k ey role in the pathogenesis of multiple myeloma. Therefore we started a phase I/II dose escalating study with chimeric monoclonal anti-IM an tibodies (cMab) in multiple myeloma (MM) patients resistant to second- line chemotherapy, Here we describe the pharmacological data as well a s a new method for calculating the endogenous IL6 production. The cMab (CLB IL6/8; K-d: 6.25 X 10(-12) M) was given in two cycles of 14 dail y infusions, starting on day 1 and day 28. Daily dose: 5 mg in patient s 1-3, 10 mg in patients 4-6, and 20 mg in patients 7-9 (total dose 14 0, 280, and 560 mg of anti-IL6, respectively). Using the pharmacokinet ic data of free IL6 and the binding characteristics of the cMab, the e ndogenous IL6 production could be calculated from day to day using a o ne-compartment open model. The median half-life time of this antibody was 17.6 d. No human anti-chimeric antibodies were induced. Pre-treatm ent median endogenous IL6 production in the MM patients was 60 mu g/d (range 13.8-230; normal controls < 7 mu g/d). During treatment with an ti-IL6 cMabs, the endogenous IL6 production immediately decreased in a ll patients to below 3 mu g/d and never reached the pre-treatment valu e during the treatment period, except in two patients who developed an active infection, resulting in an IL6 production of 128 and 1,208 mu g/d, respectively. We concluded that in MM patients endogenous IL6 pro duction is 2-30 times higher than in healthy individuals. The anti-IL6 cMab strongly suppress this endogenous IL6 production, probably by bl ocking a positive feed-back loop, but this cMab does not prevent infec tion-induced IL6 production. The chimeric anti-IL6 Mabs have a long ha lf-life time, a low immunogenicity, and are able to block IL6-dependen t processes in vivo.