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Characterization of HZ0412a, a novel potent humanized anti-IL-6 receptor antibody that blocks IL-6R binding to gp130

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机构: [1]Coriell Institute for Medical Research, Camden, NJ 08103, USA. [2]Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. [3]Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. [4]IPHASE Therapeutic Ltd., Philadelphia, PA 19454, USA. [5]Department of Pulmonary and Critical Care Medicine, Xuanwu Hospital Capital Medical University, Beijing 100053, China. [6]Center for Metabolic Disease Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA. [7]Cooper Medical School of Rowan University, Camden, NJ 08103, USA.
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关键词: antibody interleukin-6 (IL-6) high affinity

摘要:
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.© The Author(s) 2023. Published by Oxford University Press on behalf of Antibody Therapeutics. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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第一作者机构: [1]Coriell Institute for Medical Research, Camden, NJ 08103, USA.
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通讯机构: [1]Coriell Institute for Medical Research, Camden, NJ 08103, USA. [4]IPHASE Therapeutic Ltd., Philadelphia, PA 19454, USA. [5]Department of Pulmonary and Critical Care Medicine, Xuanwu Hospital Capital Medical University, Beijing 100053, China. [6]Center for Metabolic Disease Research, Temple University Lewis Katz School of Medicine, Philadelphia, PA 19140, USA. [7]Cooper Medical School of Rowan University, Camden, NJ 08103, USA. [*1]Coriell Institute for Medical Research, 403 Haddon Avenue, Camden, NJ 08103, USA [*2]Department of Pulmonary and Critical Care Medicine, Xuanwu Hospital Capital Medical University, 45 Changchun St, Xicheng District, Beijing 100053, China [*3]Iphase Pharma Services LLC., 422 Industrial Dr, North Wales, PA, 19454, USA.
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