{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T22:43:15Z","timestamp":1759963395882,"version":"3.37.3"},"reference-count":18,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T00:00:00Z","timestamp":1683763200000},"content-version":"vor","delay-in-days":40,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Coriell Institute for Medical Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u2014namely, 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\u2014a 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\u2019s disease\u2014HZ0412a 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\u00a0mg\/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.<\/jats:p>","DOI":"10.1093\/abt\/tbad008","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T14:06:02Z","timestamp":1683813962000},"page":"119-126","source":"Crossref","is-referenced-by-count":2,"title":["Characterization of HZ0412a, a novel potent humanized anti-IL-6 receptor antibody that blocks IL-6R binding to gp130"],"prefix":"10.1093","volume":"6","author":[{"given":"Jianzhong","family":"Han","sequence":"first","affiliation":[{"name":"Coriell Institute for Medical Research , Camden, NJ 08103 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Xu","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Biology , National Institute of Diabetes and Digestive and Kidney Diseases, , Bethesda, MD 20892 , USA"},{"name":"National Institutes of Health , National Institute of Diabetes and Digestive and Kidney Diseases, , Bethesda, MD 20892 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian","family":"Wang","sequence":"additional","affiliation":[{"name":"IPHASE Therapeutic Ltd. , Philadelphia, PA 19454 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"IPHASE Therapeutic Ltd. , Philadelphia, PA 19454 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kehe","family":"Du","sequence":"additional","affiliation":[{"name":"IPHASE Therapeutic Ltd. , Philadelphia, PA 19454 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenchen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Medicine, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongjun","family":"Liu","sequence":"additional","affiliation":[{"name":"IPHASE Therapeutic Ltd. , Philadelphia, PA 19454 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pulmonary and Critical Care Medicine, Xuanwu Hospital Capital Medical University , Beijing 100053 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1649-0038","authenticated-orcid":false,"given":"Jian","family":"Huang","sequence":"additional","affiliation":[{"name":"Coriell Institute for Medical Research , Camden, NJ 08103 , USA"},{"name":"Center for Metabolic Disease Research, Temple University Lewis Katz School of Medicine , Philadelphia, PA 19140 , USA"},{"name":"Cooper Medical School of Rowan University , Camden, NJ 08103 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"key":"2023061312390469900_ref1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cyto.2014.05.024","article-title":"Interleukin-6 and its receptors: a highly regulated and dynamic system","volume":"70","author":"Wolf","year":"2014","journal-title":"Cytokine"},{"key":"2023061312390469900_ref2","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/j.immuni.2019.03.026","article-title":"Targeting Interleukin-6 Signaling in clinic","volume":"50","author":"Kang","year":"2019","journal-title":"Immunity"},{"key":"2023061312390469900_ref3","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1080\/22221751.2020.1770129","article-title":"Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors","volume":"9","author":"Han","year":"2020","journal-title":"Emerg Microbes Infect"},{"key":"2023061312390469900_ref4","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1056\/NEJMe2103108","article-title":"Interleukin-6 receptor inhibition in Covid-19 - cooling the inflammatory soup","volume":"384","author":"Rubin","year":"2021","journal-title":"N Engl J Med"},{"key":"2023061312390469900_ref5","first-page":"851","article-title":"Reshaping a human antibody to inhibit the interleukin 6-dependent tumor cell growth","volume":"53","author":"Sato","year":"1993","journal-title":"Cancer Res"},{"key":"2023061312390469900_ref6","doi-asserted-by":"crossref","first-page":"432","DOI":"10.4161\/mabs.1.5.9497","article-title":"Tocilizumab","volume":"1","author":"Venkiteshwaran","year":"2009","journal-title":"MAbs"},{"key":"2023061312390469900_ref7","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1136\/annrheumdis-2016-210310","article-title":"Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial","volume":"76","author":"Burmester","year":"2017","journal-title":"Ann Rheum Dis"},{"key":"2023061312390469900_ref8","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/s41584-020-0419-z","article-title":"Translating IL-6 biology into effective treatments","volume":"16","author":"Choy","year":"2020","journal-title":"Nat Rev Rheumatol"},{"key":"2023061312390469900_ref9","doi-asserted-by":"crossref","first-page":"15460","DOI":"10.18632\/oncotarget.7102","article-title":"Potential therapeutic implications of IL-6\/IL-6R\/gp130-targeting agents in breast cancer","volume":"7","author":"Heo","year":"2016","journal-title":"Oncotarget"},{"key":"2023061312390469900_ref10","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/j.biopha.2018.09.177","article-title":"The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer","volume":"108","author":"Masjedi","year":"2018","journal-title":"Biomed Pharmacother"},{"key":"2023061312390469900_ref11","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2021.816646","article-title":"A novel humanized anti-Interleukin-6 antibody HZ0408b with anti-rheumatoid arthritis therapeutic potential","volume":"12","author":"Liu","year":"2022","journal-title":"Front Immunol"},{"key":"2023061312390469900_ref12","article-title":"Generation of murine monoclonal antibodies by Hybridoma technology","volume":"119","author":"Holzlohner","year":"2017","journal-title":"J Vis Exp"},{"key":"2023061312390469900_ref13","first-page":"1619","article-title":"Humanization of antibodies","volume":"13","author":"Almagro","year":"2008","journal-title":"Front Biosci"},{"key":"2023061312390469900_ref14","doi-asserted-by":"crossref","first-page":"113575","DOI":"10.1016\/j.ab.2020.113575","article-title":"Measuring the affinity of protein-protein interactions on a single-molecule level by mass photometry","volume":"592","author":"Wu","year":"2020","journal-title":"Anal Biochem"},{"key":"2023061312390469900_ref15","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1248\/bpb.31.1159","article-title":"Tocilizumab, a humanized anti-interleukin-6 receptor antibody, ameliorates joint swelling in established monkey collagen-induced arthritis","volume":"31","author":"Uchiyama","year":"2008","journal-title":"Biol Pharm Bull"},{"key":"2023061312390469900_ref16","doi-asserted-by":"crossref","first-page":"774","DOI":"10.4161\/mabs.28612","article-title":"Discovery and characterization of olokizumab: a humanized antibody targeting interleukin-6 and neutralizing gp130-signaling","volume":"6","author":"Shaw","year":"2014","journal-title":"MAbs"},{"key":"2023061312390469900_ref17","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1056\/NEJMoa2201302","article-title":"Olokizumab versus placebo or Adalimumab in rheumatoid arthritis","volume":"387","author":"Smolen","year":"2022","journal-title":"N Engl J Med"},{"key":"2023061312390469900_ref18","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1158\/1078-0432.CCR-14-2291","article-title":"Interleukin-6 as a therapeutic target","volume":"21","author":"Rossi","year":"2015","journal-title":"Clin Cancer Res"}],"container-title":["Antibody Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/abt\/advance-article-pdf\/doi\/10.1093\/abt\/tbad008\/50457885\/tbad008.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/abt\/article-pdf\/6\/2\/119\/50569244\/tbad008.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/abt\/article-pdf\/6\/2\/119\/50569244\/tbad008.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T12:40:17Z","timestamp":1686660017000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/abt\/article\/6\/2\/119\/7160113"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4]]},"references-count":18,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,4,17]]}},"URL":"https:\/\/doi.org\/10.1093\/abt\/tbad008","relation":{},"ISSN":["2516-4236"],"issn-type":[{"type":"electronic","value":"2516-4236"}],"subject":[],"published-other":{"date-parts":[[2023,4]]},"published":{"date-parts":[[2023,4]]}}}