CHIMERIC ANTI-INTERLEUKIN-6 MONOCLONAL-ANTIBODIES IN THE TREATMENT OFADVANCED MULTIPLE-MYELOMA - A PHASE-I DOSE-ESCALATING STUDY

Interleukin 6 plays a key role in the pathogenesis of multiple myeloma (MM). Therefore we conducted a phase I dose-escalating study with chi maeric monoclonal anti-IL6 antibodies (cMab) in MM patients resistant to second-line chemotherapy. The cMab (CLB IL6/8; K-d 6.25 x 10(-12) M ) was given in two cycles of 14 daily infusions, starting on day 1 and day 28, respectively, with a daily dose of 5 mg in patients 1-3, 10 m g in patients 4-6, 20 mg in patients 7-9 and 40 mg in patients 10-12 ( total dose 140 mg, 280 mg, 560 mg and 1120 mg of anti-IL6, respectivel y). 11/12 patients had elevated pretreatment IL6 levels. Except for tr ansient thrombocytopenia in two patients there was no toxicity. There were no changes in haemoglobin levels, granulocyte count, liner enzyme s or renal function. No human anti-chimaeric antibodies were induced. This was also reflected in a long half-life time of the cMab (median 1 7.8 d), resulting in accumulation of the anti-IL6 cMab and high levels of circulating IL6. However, this was in the form of biologically ina ctive IL6/cMab complexes and did not result in acceleration of the dis ease. Although C-reactive protein (CRP) levels were decreased to below detection level in 11/12 patients, indicating effective IL6 blocking, none of the patients achieved a response according to the standard cr iteria. We conclude that this chimaeric anti-IL6 Mab has a low toxicit y, low immunogenicity and a long T-1/2. A dose of 40 mg/d for 14 d can safely be used in future phase II studies.