Dual blockade of IL-17A and IL-36 pathways via a bispecific antibody exhibits enhanced anti-inflammatory potency
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 chai...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2024-11-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1434127/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846169647836037120 |
|---|---|
| author | Xiaojuan Ma Xiaojuan Ma Shuang Zhang Xiaochen Ren Xiaochen Ren Yujie Feng Hui Li Shi Chen Jingen Xu Yanting Wang Guo-yuan Peng Qingran Yan Huifeng Jia Simin Xia Xiaopei Cui Xiaofang Chen Xianfei Pan Shaojie Wang Haijia Yu Xiaoyue Wei Mingwei Li Bei Liu Jingyue Xu Qiaoxia Qian Xiangyang Zhu Yifan Zhan Liangjing Lu |
| author_facet | Xiaojuan Ma Xiaojuan Ma Shuang Zhang Xiaochen Ren Xiaochen Ren Yujie Feng Hui Li Shi Chen Jingen Xu Yanting Wang Guo-yuan Peng Qingran Yan Huifeng Jia Simin Xia Xiaopei Cui Xiaofang Chen Xianfei Pan Shaojie Wang Haijia Yu Xiaoyue Wei Mingwei Li Bei Liu Jingyue Xu Qiaoxia Qian Xiangyang Zhu Yifan Zhan Liangjing Lu |
| author_sort | Xiaojuan Ma |
| collection | DOAJ |
| description | 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 antibody (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-to-treat inflammatory and fibrotic diseases, dual targeting could potentially pave a way to combat these diseases. |
| format | Article |
| id | doaj-art-e25db7dcba894a3da6c08a51ec9bda6c |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-e25db7dcba894a3da6c08a51ec9bda6c2024-11-12T13:47:33ZengFrontiers Media S.A.Frontiers in Immunology1664-32242024-11-011510.3389/fimmu.2024.14341271434127Dual blockade of IL-17A and IL-36 pathways via a bispecific antibody exhibits enhanced anti-inflammatory potencyXiaojuan Ma0Xiaojuan Ma1Shuang Zhang2Xiaochen Ren3Xiaochen Ren4Yujie Feng5Hui Li6Shi Chen7Jingen Xu8Yanting Wang9Guo-yuan Peng10Qingran Yan11Huifeng Jia12Simin Xia13Xiaopei Cui14Xiaofang Chen15Xianfei Pan16Shaojie Wang17Haijia Yu18Xiaoyue Wei19Mingwei Li20Bei Liu21Jingyue Xu22Qiaoxia Qian23Xiangyang Zhu24Yifan Zhan25Liangjing Lu26Rheumatology, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Pharmacology, School of Pharmacy, Fudan University, Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaRheumatology, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaRheumatology, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaDepartment of Drug Discovery, Shanghai Huaota Biopharmaceutical Co. Ltd., Shanghai, ChinaRheumatology, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, ChinaAntibody 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 antibody (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-to-treat inflammatory and fibrotic diseases, dual targeting could potentially pave a way to combat these diseases.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1434127/fullbispecific antibodyIL-17AIL-36Rskin inflammationskin fibrosis |
| spellingShingle | Xiaojuan Ma Xiaojuan Ma Shuang Zhang Xiaochen Ren Xiaochen Ren Yujie Feng Hui Li Shi Chen Jingen Xu Yanting Wang Guo-yuan Peng Qingran Yan Huifeng Jia Simin Xia Xiaopei Cui Xiaofang Chen Xianfei Pan Shaojie Wang Haijia Yu Xiaoyue Wei Mingwei Li Bei Liu Jingyue Xu Qiaoxia Qian Xiangyang Zhu Yifan Zhan Liangjing Lu Dual blockade of IL-17A and IL-36 pathways via a bispecific antibody exhibits enhanced anti-inflammatory potency Frontiers in Immunology bispecific antibody IL-17A IL-36R skin inflammation skin fibrosis |
| title | Dual blockade of IL-17A and IL-36 pathways via a bispecific antibody exhibits enhanced anti-inflammatory potency |
| title_full | Dual blockade of IL-17A and IL-36 pathways via a bispecific antibody exhibits enhanced anti-inflammatory potency |
| title_fullStr | Dual blockade of IL-17A and IL-36 pathways via a bispecific antibody exhibits enhanced anti-inflammatory potency |
| title_full_unstemmed | Dual blockade of IL-17A and IL-36 pathways via a bispecific antibody exhibits enhanced anti-inflammatory potency |
| title_short | Dual blockade of IL-17A and IL-36 pathways via a bispecific antibody exhibits enhanced anti-inflammatory potency |
| title_sort | dual blockade of il 17a and il 36 pathways via a bispecific antibody exhibits enhanced anti inflammatory potency |
| topic | bispecific antibody IL-17A IL-36R skin inflammation skin fibrosis |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1434127/full |
| work_keys_str_mv | AT xiaojuanma dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT xiaojuanma dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT shuangzhang dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT xiaochenren dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT xiaochenren dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT yujiefeng dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT huili dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT shichen dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT jingenxu dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT yantingwang dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT guoyuanpeng dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT qingranyan dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT huifengjia dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT siminxia dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT xiaopeicui dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT xiaofangchen dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT xianfeipan dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT shaojiewang dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT haijiayu dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT xiaoyuewei dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT mingweili dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT beiliu dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT jingyuexu dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT qiaoxiaqian dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT xiangyangzhu dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT yifanzhan dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency AT liangjinglu dualblockadeofil17aandil36pathwaysviaabispecificantibodyexhibitsenhancedantiinflammatorypotency |