Dysregulated elevation of interleukin-6 (IL-6) signaling is implicated in the pathogenesis of multiple pathophysiological states, and the functional neutralization of the IL-6 pathway with monoclonal antibodies has been proven an effective therapeutic method in treating various diseases with abnormally enhanced IL-6 signaling, and its clinical indications are expanding. Here, we report that by using the conventional hybridoma technology and humanization mutation method, we develop a novel humanized anti-IL-6 receptor (IL-6R) antibody - namely, HZ0412a. In our study, we found that HZ0412a exhibits higher binding affinity to soluble recombinant human IL-6R than tocilizumab. Importantly, in contrast to tocilizumab - a humanized anti-IL-6R antibody approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis and Castleman's disease - HZ0412a does not significantly affect the binding of IL-6 to IL-6R. Further analysis revealed that HZ0412a prevents IL-6R from binding to gp130 in vitro, while tocilizumab has a minimal effect under the same condition. Using various cell-based assays, we demonstrate that HZ0412a is noninferior to tocilizumab in inhibiting IL-6 signaling. Finally, we showed that HZ0412a is well tolerated in cynomolgus monkeys after a single subcutaneous injection at a dose of 1 or 5 mg/kg. Taken together, our results indicated that HZ0412a targets an epitope on human IL-6R that is different from that of tocilizumab, and the epitope region is essential for the interaction between IL-6R and gp130. This distinctive mode of action plus its high affinity to IL-6R led to the high potency of HZ0412a in suppressing in vitro IL-6 signaling.
CITATION STYLE
Han, J., Liu, X., Xu, Y., Wang, Q., Li, L., Du, K., … Huang, J. (2023). Characterization of HZ0412a, a novel potent humanized anti-IL-6 receptor antibody that blocks IL-6R binding to gp130. Antibody Therapeutics, 6(2), 119–126. https://doi.org/10.1093/abt/tbad008
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