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Screening and Identification of Antibodies with Cross-binding Activity to Human and Mouse IL-1R3 |
QIN Hui1,2,YU Xinrui2,3,LIU Jiao1,2,Gulisaina Qiaerxie2,4,CUI Jingmin2,4,WANG Xi2,DU Peng2,*(),ZHOU Chunyang1,*() |
1 School of Pharmacy, North Sichuan Medical College, Institute of Pharmaceutical Research,North Sichuan Medical College, Nanchong 637000, China 2 Institute of Biotechnology, Academy of Military Medical Science, Academy of Military Science, Beijing 100071, China 3 School of Basic Medical Sciences and Life Sciences, Hainan Medical University, Haikou 571158, China 4 School of Medical Instrumentation, Shenyang Pharmaceutical University, Benxi 117004, China |
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Abstract Objective: Interleukin-1 receptor accessory protein (IL-1R3) is a potential new target for inflammation regulation. The aim of this study is to obtain anti-IL-1R3 antibodies with cross-binding activity to human and mouse IL-1R3 and to lay the foundation for the new drug development and pharmacodynamic mechanism research of a novel inflammation intervention strategy. Methods: Based on the sequence and structure alignment of human and mouse IL-1R3, a phage-displayed human single-chain (scFv) antibody library was challenged by alternately coating immune-tubes with human or mouse IL-1R3. The variable region genes of the resulting antibodies were cloned into eukaryotic expression vectors to prepare antibodies. The binding activities of the candidate antibodies were determined by ELISA and SPR and their functional activities were evaluated by cell assay. A strategy of re-pairing the light and heavy chains of these antibodies was then followed to obtain new antibodies with improved properties. Results: Five antibodies with cross-binding activity to human and mouse IL-1R3 were identified, four of which showed comparable affinity to both human and mouse IL-1R3, approximately 10-7 mol/L. Two candidate antibodies with favorable solubility effectively blocked IL-1R3-mediated activities in the ex vivo functional assay. A new antibody with re-paired light and heavy chains showed improved binding activity and apparently increased solubility. Conclusions: By introducing antibodies AET1907 and 4H6L with comparable human-mouse IL-1R3 cross-binding activity, this study has laid the groundwork for further investigation.
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Received: 25 May 2023
Published: 03 April 2024
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[1] |
Medzhitov R. The spectrum of inflammatory responses. Science, 2021, 374(6571): 1070-1075.
doi: 10.1126/science.abi5200
pmid: 34822279
|
|
|
[2] |
Fajgenbaum D C, June C H. Cytokine storm. The New England Journal of Medicine, 2020, 383(23): 2255-2273.
doi: 10.1056/NEJMra2026131
pmid: 33264547
|
|
|
[3] |
Mantovani A, Garlanda C. Humoral innate immunity and acute-phase proteins. The New England Journal of Medicine, 2023, 388(5): 439-452.
doi: 10.1056/NEJMra2206346
pmid: 36724330
|
|
|
[4] |
Palomo J, Dietrich D, Martin P, et al. The interleukin (IL)-1 cytokine family: balance between agonists and antagonists in inflammatory diseases. Cytokine, 2015, 76(1): 25-37.
doi: 10.1016/j.cyto.2015.06.017
|
|
|
[5] |
Mantovani A, Dinarello C A, Molgora M, et al. Interleukin-1 and related cytokines in the regulation of inflammation and immunity. Immunity, 2019, 50(4): 778-795.
doi: S1074-7613(19)30129-3
pmid: 30995499
|
|
|
[6] |
Barkas F, Christaki E, Liberopoulos E, et al. Anakinra in COVID-19: a step closer to the cure. European Journal of Internal Medicine, 2022, 96: 113-114.
doi: 10.1016/j.ejim.2021.11.005
|
|
|
[7] |
Makaremi S, Asgarzadeh A, Kianfar H, et al. The role of IL-1 family of cytokines and receptors in pathogenesis of COVID-19. Inflammation Research, 2022, 71(7): 923-947.
doi: 10.1007/s00011-022-01596-w
|
|
|
[8] |
Angus D C, van der Poll T. Severe sepsis and septic shock. New England Journal of Medicine, 2013, 369(9): 840-851.
doi: 10.1056/NEJMra1208623
|
|
|
[9] |
Burkovskiy I, Sardinha J, Zhou J, et al. Cytokine release in sepsis. Advances in Bioscience and Biotechnology, 2013, 4(9): 860-865.
doi: 10.4236/abb.2013.49114
|
|
|
[10] |
Heffernan I M, McGeary J E, Chung C S, et al. Unmasking unique immune altering aspects of the microbiome as a tool to correct sepsis-induced immune dysfunction. Surgical Infections, 2021, 22(4): 400-408.
doi: 10.1089/sur.2020.233
|
|
|
[11] |
Yang M, Wang Y W, Zhang Y H, et al. Role of interleukin-33 in Staphylococcus epidermidis-induced septicemia. Frontiers in Immunology, 2020, 11: 534099.
doi: 10.3389/fimmu.2020.534099
|
|
|
[12] |
Nascimento D C, Melo P H, Piñeros A R, et al. IL-33 contributes to sepsis-induced long-term immunosuppression by expanding the regulatory T cell population. Nature Communications, 2017, 8: 14919.
doi: 10.1038/ncomms14919
pmid: 28374774
|
|
|
[13] |
Xu H, Turnquist H R, Hoffman R, et al. Role of the IL-33-ST 2 axis in sepsis. Military Medical Research, 2017, 4: 3.
doi: 10.1186/s40779-017-0115-8
|
|
|
[14] |
Buhl A L, Wenzel J. Interleukin-36 in infectious and inflammatory skin diseases. Frontiers in Immunology, 2019, 10: 1162.
doi: 10.3389/fimmu.2019.01162
|
|
|
[15] |
Nanjo Y, Newstead M W, Aoyagi T, et al. Overlapping roles for interleukin-36 cytokines in protective host defense against murine Legionella pneumophila pneumonia. Infection and Immunity, 2019, 87(1): e00583-e00518.
|
|
|
[16] |
Aoyagi T, Newstead M W, Zeng X Y, et al. Interleukin-36γ and IL-36 receptor signaling mediate impaired host immunity and lung injury in cytotoxic Pseudomonas aeruginosa pulmonary infection: role of prostaglandin E2. PLoS Pathogens, 2017, 13(11): e1006737.
|
|
|
[17] |
Aoyagi T, Newstead M W, Zeng X, et al. IL-36 receptor deletion attenuates lung injury and decreases mortality in murine influenza pneumonia. Mucosal Immunology, 2017, 10(4): 1043-1055.
doi: 10.1038/mi.2016.107
pmid: 27966554
|
|
|
[18] |
Højen J F, Kristensen M L V, McKee A S, et al. IL-1R3 blockade broadly attenuates the functions of six members of the IL-1 family, revealing their contribution to models of disease. Nature Immunology, 2019, 20: 1138-1149.
doi: 10.1038/s41590-019-0467-1
pmid: 31427775
|
|
|
[19] |
Boraschi D, Italiani P, Weil S, et al. The family of the interleukin-1 receptors. Immunological Reviews, 2018, 281(1): 197-232.
doi: 10.1111/imr.12606
pmid: 29248002
|
|
|
[20] |
Jensen L E. Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling. Science Signaling, 2017, 10(492): eaan3589.
|
|
|
[21] |
Fields J K, Kihn K, Birkedal G S, et al. Molecular basis of selective cytokine signaling inhibition by antibodies targeting a shared receptor. Frontiers in Immunology, 2021, 12: 779100.
doi: 10.3389/fimmu.2021.779100
|
|
|
[22] |
Rydberg Millrud C, Deronic A, Grönberg C, et al. Blockade of IL-1α and IL-1β signaling by the anti-IL1RAP antibody nadunolimab (CAN04) mediates synergistic anti-tumor efficacy with chemotherapy. Cancer Immunology, Immunotherapy, 2023, 72(3): 667-678.
doi: 10.1007/s00262-022-03277-3
|
|
|
[23] |
Robbrecht D, Jungels C, Sorensen M M, et al. First-in-human phase 1 dose-escalation study of CAN04, a first-in-class interleukin-1 receptor accessory protein (IL1RAP) antibody in patients with solid tumours. British Journal of Cancer, 2022, 126: 1010-1017.
doi: 10.1038/s41416-021-01657-7
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