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ORIGINAL RESEARCH article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
Volume 15 - 2024 |
doi: 10.3389/fimmu.2024.1434127
This article is part of the Research Topic The Pivotal Role of Cytokines in Autoimmune Diseases View all 5 articles
Dual blockade of IL-17A and IL-36 pathways via a bispecific antibody exhibits enhanced anti-inflammatory potency
Provisionally accepted- 1 Department of Drug Discovery, Huaota Biopharm, Shanghai, China
- 2 Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Dongyuan, China
- 3 Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, Shanghai, China
Antibody drugs targeting single inflammatory cytokines have revolutionized the treatment of immune-mediated inflammatory diseases. To investigate whether dual targeting interleukin-17 (IL-17) and IL-36 enhances anti-inflammatory activity, bispecific Ab HB0043 was generated by linking the single chain fragment variables (scFVs) from humanized Anti-IL-36R AB (HB0034) to the C-terminus of the heavy chain of anti-IL-17A IgG1 (HB0017) Fc using a flexible peptide linker. HB0043 largely maintained the binding affinities and biological activities of the two parent monoclonal antibodies (mAbs) in vitro. IL-17 and IL-36 cooperated to amplify the expression of pro-inflammatory and pro-fibrotic genes in normal human dermal fibroblasts (NHDF). However, HB0043 more effectively blocked IL-6 and IL-8 production in NHDF stimulated by IL-17A and IL-36 compared to two monoclonal antibodies. In a mouse model of Oxazolone (OXA)-induced atopic dermatitis and Imiquimod (IMQ)-induced skin inflammation, administration of both anti-IL17A mAb HB0017 and anti-mouse IL-36R surrogate antibody HB0034SA showed improved effectiveness in alleviating skin thickening and inflammation based on histological assessment. Further, in cynomolgus monkeys, HB0043 showed no enhanced target-related toxicity compared with the two parental mAbs in vivo and with a moderate increase in production of anti-drug antibodies. Together, dual blockade of IL-17A and IL-36R in the form of a bispecific antibody may have advantages in blocking the overlapping and non-overlapping functions of these two cytokines in skin inflammation that could not optimally be curtailed with single mAbs. In conclusion, as monotherapy may reach therapeutic celling for certain difficult-totreat inflammatory and fibrotic diseases, dual targeting could potentially pave a way to combat these diseases.
Keywords: bispecific antibodies, IL-17A, IL-36, Skin inflammation, Skin fibrosis
Received: 17 May 2024; Accepted: 14 Oct 2024.
Copyright: © 2024 Ma, Zhang, Ren, Feng, Li, Shi, Xu, Wang, Peng, Yan, Jia, Xia, Cui, Chen, Pan, Wang, Yu, Wei, Li, Liu, Xu, Qian, Zhu, Zhan and Liangjing. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Xiangyang Zhu, Department of Drug Discovery, Huaota Biopharm, Shanghai, China
Yifan Zhan, Department of Drug Discovery, Huaota Biopharm, Shanghai, China
Lu Liangjing, Department of Rheumatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Dongyuan, China
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