Chimaeric anti-interleukin 6 monoclonal antibodies in the treatment of advanced 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 chimaeric monoclonal anti-IL6 antibodies (cMab) in MM patients resistant to second-line chemotherapy. 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, repectively, with a daily dose of 5 mg in patients 1-3, 10 mg in patients 4-6, 20 mg in patients 7-9 and 40mg in patients 10-12 (total dose 140 mg, 280mg, 560 mg and 1120 mg of anti-IL6, respectively). 11/12 patients had elevated pretreatment IL6 levels. Except for transient thrombocytopenia in two patients there was no toxicity. There were no changes in haemoglobin levels, granulocyte count, liver enzymes or renal function. No human anti-chimaeric antibodies were induced. This was also reflected in a long half-life time of the cMab (median 17.8 d), resulting in accumulation of the anti-IL6 cMab and high levels of circulating IL6. However, this was in the form of biologically inactive IL6/cMab complexes and did not result in acceleration of the disease. 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 criteria. We conclude that this chimaeric anti-IL6 Mab has a low toxicity, low immunogenicity and a long T1/2. A dose of 40 mg/d for 14 d can safely be used in future phase II studies.
van Zaanen
H C
HC
Department of Haematology, Academic Medical Centre, Amsterdam, The Netherlands.
Lokhorst
H M
HM
Aarden
L A
LA
Rensink
H J
HJ
Warnaar
S O
SO
van der Lelie
J
J
van Oers
M H
MH
D000368:Aged; D000380:Agranulocytosis / Q000209:etiology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D002097:C-Reactive Protein / Q000032:analysis; D064211:Connectin; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D006207:Half-Life; D006801:Humans; D015850:Interleukin-6 / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000097:blood / Q000628:therapy*; D009124:Muscle Proteins; D009194:Myeloma Proteins / Q000032:analysis; D011993:Recombinant Fusion Proteins; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000209:etiology; D016896:Treatment Outcome; D001613:beta 2-Microglobulin / Q000032:analysis
D000911:Antibodies, Monoclonal; D064211:Connectin; D015850:Interleukin-6; D009124:Muscle Proteins; D009194:Myeloma Proteins; D011993:Recombinant Fusion Proteins; D001613:beta 2-Microglobulin; C085016:multiple myeloma M-proteins; D002097:C-Reactive Protein