Effects of tocilizumab on neutrophil function and kinetics

• Published in: European journal of clinical investigation Vol. 47; no. 10; pp. 736 - 745
• Main Authors: Lok, Laurence S. C., Farahi, Neda, Juss, Jatinder K., Loutsios, Chrystalla, Solanki, Chandra K., Peters, Adrien M., Donaldson, Francis, Porter‐Brown, Benjamin, Chilvers, Edwin R.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.10.2017
• Subjects: Adolescent; Adult; Aged; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - pharmacokinetics; Apoptosis; Apoptosis - drug effects; Autografts; Bone marrow; Cell activation; Cell Movement - drug effects; Healthy Volunteers; Humans; Immunosuppressive agents; Indium; Infusions, Intravenous; Interleukin 6; Intravenous administration; Kinetics; Leukocytes; Leukocytes (neutrophilic); Liver; Male; Middle Aged; neutrophil; Neutrophils; Neutrophils - cytology; Neutrophils - drug effects; Neutrophils - physiology; Reference Values; Sensitivity and Specificity; Single-Blind Method; Spleen; tocilizumab; trafficking; Young Adult; tocilizumab; neutrophil; trafficking; Interleukin-6
• ISSN: 0014-2972; 1365-2362
• DOI: 10.1111/eci.12799

Background Decreases in circulating neutrophils (polymorphonuclear leucocytes, PMNs) have been reported in patients treated with the anti‐interleukin‐6 receptor (IL‐6R) antibody tocilizumab (TCZ); the mechanism for this is unclear. We hypothesize that TCZ reduces circulating neutrophils by affecting margination and/or bone marrow trafficking without affecting neutrophil function or apoptosis. Materials and methods Eighteen healthy subjects were randomized to single intravenous dose of TCZ 8 mg/kg (n = 12) or placebo (n = 6) on day 0. On day 4, each subject had autologous indium‐111‐labelled neutrophils re‐injected, and their kinetics quantified with longitudinal profiling in a whole body gamma‐counter. TCZ‐treated subjects were divided into two groups according to the extent of reduction in neutrophil count. Results Mean day 4 neutrophil counts, as % baseline, were 101·9%, 68·3% and 44·2% in the placebo, TCZ‐PMN‐’high’ and TCZ‐PMN‐’low’ groups, respectively (P < 0·001). Following TCZ, neutrophil function, activation and apoptosis ex vivo were all unaffected. In vivo, there were no differences in early blood recovery or margination to liver/spleen and bone marrow; however, later neutrophil re‐distribution to bone marrow was markedly reduced in the TCZ‐PMN‐low group (peak pelvic count as % day 4 count on: day 5, 188% placebo vs. 127% TCZ‐PMN‐low, P < 0·001; day 10, 180% placebo vs. 132% TCZ‐PMN‐low, P < 0·01), with a trend towards higher liver/spleen neutrophil retention. Conclusions We have demonstrated for the first time in humans that IL‐6R blockade affects neutrophil trafficking to the bone marrow without influencing neutrophil functional capacity.