{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T06:58:42Z","timestamp":1793429922948,"version":"4.5.0"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T00:00:00Z","timestamp":1759968000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"funder":[{"DOI":"10.13039\/501100010679","name":"Pasteur Institute of Iran","doi-asserted-by":"publisher","award":["1226"],"award-info":[{"award-number":["1226"]}],"id":[{"id":"10.13039\/501100010679","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Appl Microbiol Biotechnol"],"DOI":"10.1007\/s00253-025-13596-x","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T08:43:11Z","timestamp":1759999391000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A novel bispecific antibody targeting TNF-\u03b1 and IL-6 receptor as a potent immunotherapeutic agent for inflammation"],"prefix":"10.1007","volume":"109","author":[{"given":"Mansooreh","family":"Heravi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shadi","family":"Damough","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ladan","family":"Mafakher","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeganeh","family":"Talebkhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Nematollahi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Ghazizadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soheila","family":"Ajdari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,9]]},"reference":[{"key":"13596_CR1","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","volume":"1","author":"MJ Abraham","year":"2015","unstructured":"Abraham MJ, Murtola T, Schulz R, P\u00e1ll S, Smith JC, Hess B, Lindahl E (2015) GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1:19\u201325. https:\/\/doi.org\/10.1016\/j.softx.2015.06.001","journal-title":"SoftwareX"},{"issue":"11","key":"13596_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.arabjc.2023.105200","volume":"16","author":"RM Aldossari","year":"2023","unstructured":"Aldossari RM, Ali A, Rashid S, Rehman MU, Ahmad SB, Malla BA (2023) Insights on in-silico approaches for identifying potential bioactive inhibitors for TNF-\u03b1 and IL-6 proteins associated with rheumatoid arthritis. Arab J Chem 16(11):105200. https:\/\/doi.org\/10.1016\/j.arabjc.2023.105200","journal-title":"Arab J Chem"},{"issue":"12","key":"13596_CR3","doi-asserted-by":"publisher","first-page":"1734","DOI":"10.18553\/jmcp.2021.21120","volume":"27","author":"C Arnell","year":"2021","unstructured":"Arnell C, Bergman M, Basu D, Kenney JT, Withers JB, Logan J, Harashima JL, Connolly-Strong E (2021) Guided therapy selection in rheumatoid arthritis using a molecular signature response classifier: an assessment of budget impact and clinical utility. J Manag Care Spec Pharm 27(12):1734\u20131742. https:\/\/doi.org\/10.18553\/jmcp.2021.21120","journal-title":"J Manag Care Spec Pharm"},{"key":"13596_CR4","doi-asserted-by":"publisher","unstructured":"Astuti A, Mutiara A (2009) Performance analysis on molecular dynamics simulation of protein using GROMACS. arXiv:0912.0893. https:\/\/doi.org\/10.48550\/arXiv.0912.0893","DOI":"10.48550\/arXiv.0912.0893"},{"issue":"1","key":"13596_CR5","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1111\/j.0105-2896.2009.00859.x","volume":"233","author":"B Bartok","year":"2010","unstructured":"Bartok B, Firestein GS (2010) Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 233(1):233\u2013255. https:\/\/doi.org\/10.1111\/j.0105-2896.2009.00859.x","journal-title":"Immunol Rev"},{"issue":"1\u20132","key":"13596_CR6","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/0022-1759(87)90187-6","volume":"100","author":"JD Beatty","year":"1987","unstructured":"Beatty JD, Beatty BG, Vlahos WG (1987) Measurement of monoclonal antibody affinity by non-competitive enzyme immunoassay. J Immunol Methods 100(1\u20132):173\u2013179. https:\/\/doi.org\/10.1016\/0022-1759(87)90187-6","journal-title":"J Immunol Methods"},{"issue":"18","key":"13596_CR7","doi-asserted-by":"publisher","first-page":"4691","DOI":"10.1093\/bioinformatics\/btaa578","volume":"36","author":"BK Bhandari","year":"2020","unstructured":"Bhandari BK, Gardner PP, Lim CS (2020) Solubility-weighted index: fast and accurate prediction of protein solubility. Bioinformatics 36(18):4691\u20134698. https:\/\/doi.org\/10.1093\/bioinformatics\/btaa578","journal-title":"Bioinformatics"},{"issue":"10","key":"13596_CR8","doi-asserted-by":"publisher","first-page":"e594","DOI":"10.1016\/s2665-9913(23)00211-4","volume":"5","author":"RJ Black","year":"2023","unstructured":"Black RJ, Cross M, Haile LM, Culbreth GT, Steinmetz JD, Hagins H, Kopec JA, Brooks PM, Woolf AD, Ong KL, Kopansky-Giles DR (2023) Global, regional, and national burden of rheumatoid arthritis, 1990\u20132020, and projections to 2050: a systematic analysis of the Global burden of disease study 2021. Lancet Rheumatol 5(10):e594\u2013e610. https:\/\/doi.org\/10.1016\/s2665-9913(23)00211-4","journal-title":"Lancet Rheumatol"},{"key":"13596_CR9","doi-asserted-by":"publisher","first-page":"1191","DOI":"10.1093\/rheumatology\/kem091","volume":"46","author":"S Bombardieri","year":"2007","unstructured":"Bombardieri S, Ruiz A, Fardellone P, Geusens P, McKenna F, Unnebrink K, Oezer U, Kary S, Kupper H, Burmester G (2007) Effectiveness of adalimumab for rheumatoid arthritis in patients with a history of TNF-antagonist therapy in clinical practice. Rheumatology (Oxford) 46:1191\u20131199. https:\/\/doi.org\/10.1093\/rheumatology\/kem091","journal-title":"Rheumatology (Oxford)"},{"key":"13596_CR10","doi-asserted-by":"publisher","first-page":"182","DOI":"10.1080\/19420862.2016.1268307","volume":"9","author":"U Brinkmann","year":"2017","unstructured":"Brinkmann U, Kontermann RE (2017) The making of bispecific antibodies. Mabs 9:182\u2013212. https:\/\/doi.org\/10.1080\/19420862.2016.1268307","journal-title":"Mabs"},{"issue":"2","key":"13596_CR11","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1016\/j.cyto.2015.08.260","volume":"76","author":"E Brzustewicz","year":"2015","unstructured":"Brzustewicz E, Bryl E (2015) The role of cytokines in the pathogenesis of rheumatoid arthritis\u2013practical and potential application of cytokines as biomarkers and targets of personalized therapy. Cytokine 76(2):527\u2013536. https:\/\/doi.org\/10.1016\/j.cyto.2015.08.260","journal-title":"Cytokine"},{"issue":"10086","key":"13596_CR12","doi-asserted-by":"publisher","first-page":"2338","DOI":"10.1016\/S0140-6736(17)31491-5","volume":"389","author":"GR Burmester","year":"2017","unstructured":"Burmester GR, Pope JE (2017) Novel treatment strategies in rheumatoid arthritis. Lancet 389(10086):2338\u20132348. https:\/\/doi.org\/10.1016\/S0140-6736(17)31491-5","journal-title":"Lancet"},{"issue":"3","key":"13596_CR13","doi-asserted-by":"publisher","first-page":"594","DOI":"10.1080\/21645515.2018.1540828","volume":"15","author":"R Burt","year":"2019","unstructured":"Burt R, Warcel D, Fielding AK (2019) Blinatumomab, a bispecific B-cell and T-cell engaging antibody, in the treatment of B-cell malignancies. Hum Vaccin Immunother 15(3):594\u2013602. https:\/\/doi.org\/10.1080\/21645515.2018.1540828","journal-title":"Hum Vaccin Immunother"},{"key":"13596_CR14","doi-asserted-by":"publisher","first-page":"5958429","DOI":"10.1155\/2017\/5958429","volume":"1","author":"SS Chung","year":"2017","unstructured":"Chung SS, Wu Y, Okobi Q, Adekoya D, Atefi M, Clarke O, Dutta P (2017) Vadgama JV (2017) Proinflammatory cytokines IL-6 and TNF-\u03b1 increased telomerase activity through NF-\u03baB\/STAT1\/STAT3 activation, and withaferin a inhibited the signaling in colorectal cancer cells. Mediators Inflamm 1:5958429. https:\/\/doi.org\/10.1155\/2017\/5958429","journal-title":"Mediators Inflamm"},{"issue":"9","key":"13596_CR15","doi-asserted-by":"publisher","first-page":"1511","DOI":"10.1002\/pro.5560020916","volume":"2","author":"C Colovos","year":"1993","unstructured":"Colovos C, Yeates TO (1993) Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci 2(9):1511\u20131519. https:\/\/doi.org\/10.1002\/pro.5560020916","journal-title":"Protein Sci"},{"issue":"1","key":"13596_CR16","doi-asserted-by":"publisher","first-page":"9265","DOI":"10.1038\/s41598-020-66123-5","volume":"10","author":"H Daub","year":"2020","unstructured":"Daub H, Traxler L, Ismajli F, Groitl B, Itzen A, Rant U (2020) The trimer to monomer transition of Tumor Necrosis Factor-Alpha is a dynamic process that is significantly altered by therapeutic antibodies. Sci Rep 10(1):9265. https:\/\/doi.org\/10.1038\/s41598-020-66123-5","journal-title":"Sci Rep"},{"issue":"27","key":"13596_CR17","doi-asserted-by":"publisher","first-page":"3493","DOI":"10.1038\/onc.2014.286","volume":"34","author":"V De Simone","year":"2015","unstructured":"De Simone V, Franz\u00e8 E, Ronchetti G, Colantoni A, Fantini MC, Di Fusco D, Sica GS, Sileri P, MacDonald TT, Pallone F, Monteleone G, Stolfi C (2015) Th17-type cytokines, IL-6 and TNF-\u03b1 synergistically activate STAT3 and NF-kB to promote colorectal cancer cell growth. Oncogene 34(27):3493\u20133503. https:\/\/doi.org\/10.1038\/onc.2014.286","journal-title":"Oncogene"},{"issue":"8","key":"13596_CR18","doi-asserted-by":"publisher","DOI":"10.3390\/jcm8081237","volume":"8","author":"AA Drosos","year":"2019","unstructured":"Drosos AA, Pelechas E, Voulgari PV (2019) Rheumatoid arthritis treatment. A back to the drawing board project or high expectations for low unmet needs? J Clin Med 8(8):1237. https:\/\/doi.org\/10.3390\/jcm8081237","journal-title":"J Clin Med"},{"key":"13596_CR19","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1007\/s10456-015-9477-2","volume":"18","author":"HA Elshabrawy","year":"2015","unstructured":"Elshabrawy HA, Chen Z, Volin MV, Ravella S, Virupannavar S, Shahrara S (2015) The pathogenic role of angiogenesis in rheumatoid arthritis. Angiogenesis 18:433\u2013448. https:\/\/doi.org\/10.1007\/s10456-015-9477-2","journal-title":"Angiogenesis"},{"issue":"9877","key":"13596_CR20","doi-asserted-by":"publisher","first-page":"1541","DOI":"10.1016\/S0140-6736(13)60250-0","volume":"381","author":"C Gabay","year":"2013","unstructured":"Gabay C, Emery P, Van Vollenhoven R, Dikranian A, Alten R, Pavelka K, Klearman M, Musselman D, Agarwal S, Green J (2013) Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 381(9877):1541\u20131550. https:\/\/doi.org\/10.1016\/S0140-6736(13)60250-0","journal-title":"Lancet"},{"issue":"1","key":"13596_CR21","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1038\/s41413-018-0016-9","volume":"6","author":"Q Guo","year":"2018","unstructured":"Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J (2018) Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res 6(1):15. https:\/\/doi.org\/10.1038\/s41413-018-0016-9","journal-title":"Bone Res"},{"key":"13596_CR22","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/765624","volume":"1","author":"M Hashizume","year":"2011","unstructured":"Hashizume M (2011) Mihara M (2011) The roles of interleukin-6 in the pathogenesis of rheumatoid arthritis. Arthritis 1:765624. https:\/\/doi.org\/10.1155\/2011\/765624","journal-title":"Arthritis"},{"issue":"19","key":"13596_CR23","doi-asserted-by":"publisher","first-page":"3098","DOI":"10.1093\/bioinformatics\/btx345","volume":"33","author":"M Hebditch","year":"2017","unstructured":"Hebditch M, Carballo-Amador MA, Charonis S, Curtis R, Warwicker J (2017) Protein\u2013sol: a web tool for predicting protein solubility from sequence. Bioinformatics 33(19):3098\u20133100. https:\/\/doi.org\/10.1093\/bioinformatics\/btx345","journal-title":"Bioinformatics"},{"issue":"1","key":"13596_CR24","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1093\/bioinformatics\/btaa1102","volume":"37","author":"J Hon","year":"2021","unstructured":"Hon J, Marusiak M, Martinek T, Kunka A, Zendulka J, Bednar D, Damborsky J (2021) Soluprot: prediction of soluble protein expression in Escherichia coli. Bioinformatics 37(1):23\u201328. https:\/\/doi.org\/10.1093\/bioinformatics\/btaa1102","journal-title":"Bioinformatics"},{"key":"13596_CR25","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.729513","volume":"8","author":"RV Honorato","year":"2021","unstructured":"Honorato RV, Koukos PI, Jim\u00e9nez-Garc\u00eda B, Tsaregorodtsev A, Verlato M, Giachetti A, Rosato A, Bonvin AM (2021) Structural biology in the clouds: the WeNMR-EOSC ecosystem. Front Mol Biosci 8:729513. https:\/\/doi.org\/10.3389\/fmolb.2021.729513","journal-title":"Front Mol Biosci"},{"key":"13596_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2022.102379","volume":"74","author":"AM Hummer","year":"2022","unstructured":"Hummer AM, Abanades B, Deane CM (2022) Advances in computational structure-based antibody design. Curr Opin Struct Biol 74:102379. https:\/\/doi.org\/10.1016\/j.sbi.2022.102379","journal-title":"Curr Opin Struct Biol"},{"issue":"6","key":"13596_CR27","doi-asserted-by":"publisher","first-page":"1895","DOI":"10.1093\/oxfordjournals.jbchem.a133168","volume":"88","author":"A Ikai","year":"1980","unstructured":"Ikai A (1980) Thermostability and aliphatic index of globular proteins. J Biochem 88(6):1895\u20131898. https:\/\/doi.org\/10.1093\/oxfordjournals.jbchem.a133168","journal-title":"J Biochem"},{"key":"13596_CR28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.853008","volume":"13","author":"C Ishiwatari-Ogata","year":"2022","unstructured":"Ishiwatari-Ogata C, Kyuuma M, Ogata H, Yamakawa M, Iwata K, Ochi M, Hori M, Miyata N, Fujii Y (2022) Ozoralizumab, a humanized anti-TNF\u03b1 NANOBODY\u00ae compound, exhibits efficacy not only at the onset of arthritis in a human TNF transgenic mouse but also during secondary failure of administration of an anti-TNF\u03b1 IgG. Front Immunol 13:853008. https:\/\/doi.org\/10.3389\/fimmu.2022.853008","journal-title":"Front Immunol"},{"issue":"5","key":"13596_CR29","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22052719","volume":"22","author":"D-i Jang","year":"2021","unstructured":"Jang D-i, Lee A-H, Shin H-Y, Song H-R, Park J-H, Kang T-B, Lee S-R, Yang S-H (2021) The role of tumor necrosis factor alpha (TNF-\u03b1) in autoimmune disease and current TNF-\u03b1 inhibitors in therapeutics. Int J Mol Sci 22(5):2719. https:\/\/doi.org\/10.3390\/ijms22052719","journal-title":"Int J Mol Sci"},{"issue":"1","key":"13596_CR30","doi-asserted-by":"publisher","first-page":"20150","DOI":"10.1038\/srep20150","volume":"6","author":"Y Kim","year":"2016","unstructured":"Kim Y, Yi H, Jung H, Rim YA, Park N, Kim J, Jung SM, Park S-H, Park YW, Ju JH (2016) A dual target-directed agent against interleukin-6 receptor and tumor necrosis factor \u03b1 ameliorates experimental arthritis. Sci Rep 6(1):20150. https:\/\/doi.org\/10.1038\/srep20150","journal-title":"Sci Rep"},{"key":"13596_CR31","doi-asserted-by":"publisher","first-page":"182","DOI":"10.4161\/mabs.4.2.19000","volume":"4","author":"R Kontermann","year":"2012","unstructured":"Kontermann R (2012) Dual targeting strategies with bispecific antibodies. Mabs 4:182\u2013197. https:\/\/doi.org\/10.4161\/mabs.4.2.19000","journal-title":"Mabs"},{"issue":"W1","key":"13596_CR32","doi-asserted-by":"publisher","first-page":"W300","DOI":"10.1093\/nar\/gkz321","volume":"47","author":"A Kuriata","year":"2019","unstructured":"Kuriata A, Iglesias V, Pujols J, Kurcinski M, Kmiecik S, Ventura S (2019) Aggrescan3D (A3D) 2.0: prediction and engineering of protein solubility. Nucleic Acids Res 47(W1):W300\u2013W307. https:\/\/doi.org\/10.1093\/nar\/gkz321","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"13596_CR33","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/0022-2836(82)90515-0","volume":"157","author":"J Kyte","year":"1982","unstructured":"Kyte J, Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein. J Mol Biol 157(1):105\u2013132. https:\/\/doi.org\/10.1016\/0022-2836(82)90515-0","journal-title":"J Mol Biol"},{"issue":"2","key":"13596_CR34","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1107\/S0021889892009944","volume":"26","author":"RA Laskowski","year":"1993","unstructured":"Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Cryst 26(2):283\u2013291. https:\/\/doi.org\/10.1107\/S0021889892009944","journal-title":"J Appl Cryst"},{"key":"13596_CR35","doi-asserted-by":"publisher","unstructured":"Laskowski R, MacArthur M, Thornton J (2012) Chapter 21.4. PROCHECK: validation of protein-structure coordinates, in: Arnold, E., Himmel, D. M., Rossmann, M. G. [Eds], Volume F. Crystallography of biological macromolecules. pp. 684\u2013687. https:\/\/doi.org\/10.1107\/97809553602060000882","DOI":"10.1107\/97809553602060000882"},{"issue":"1","key":"13596_CR36","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1016\/j.intimp.2014.04.018","volume":"21","author":"Q Li","year":"2014","unstructured":"Li Q, Ren G, Xu L, Wang Q, Qi J, Wang W, Zhou B, Han X, Sun C, Wu Q (2014) Therapeutic efficacy of three bispecific antibodies on collagen-induced arthritis mouse model. Int Immunopharmacol 21(1):119\u2013127. https:\/\/doi.org\/10.1016\/j.intimp.2014.04.018","journal-title":"Int Immunopharmacol"},{"issue":"2","key":"13596_CR37","doi-asserted-by":"publisher","first-page":"10821","DOI":"10.1080\/21655979.2021.1967710","volume":"12","author":"X Liao","year":"2021","unstructured":"Liao X, Liang H, Pan J, Zhang Q, Niu J, Xue C, Ni J, Cui D (2021) Preparation and characterization of a fully human monoclonal antibody specific for human tumor necrosis factor alpha. Bioengineered 12(2):10821\u201310834. https:\/\/doi.org\/10.1080\/21655979.2021.1967710","journal-title":"Bioengineered"},{"key":"13596_CR38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jbiotec.2014.06.017","volume":"186","author":"M Liu","year":"2014","unstructured":"Liu M, Xie M, Jiang S, Liu G, Li L, Liu D, Yang X (2014) A novel bispecific antibody targeting tumor necrosis factor \u03b1 and ED-B fibronectin effectively inhibits the progression of established collagen-induce arthritis. J Biotechnol 186:1\u201312. https:\/\/doi.org\/10.1016\/j.jbiotec.2014.06.017","journal-title":"J Biotechnol"},{"key":"13596_CR39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.816646","volume":"12","author":"X Liu","year":"2022","unstructured":"Liu X, Li L, Wang Q, Jiang F, Zhang P, Guo F, Liu H, Huang J (2022) A novel humanized anti-interleukin-6 antibody HZ0408b with anti-rheumatoid arthritis therapeutic potential. Front Immunol 12:816646. https:\/\/doi.org\/10.3389\/fimmu.2021.816646","journal-title":"Front Immunol"},{"issue":"6364","key":"13596_CR40","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/356083a0","volume":"356","author":"R L\u00fcthy","year":"1992","unstructured":"L\u00fcthy R, Bowie JU, Eisenberg D (1992) Assessment of protein models with three-dimensional profiles. Nature 356(6364):83\u201385. https:\/\/doi.org\/10.1038\/356083a0","journal-title":"Nature"},{"key":"13596_CR41","doi-asserted-by":"publisher","first-page":"19","DOI":"10.2147\/OARRR.S17118","volume":"3","author":"M Mihara","year":"2011","unstructured":"Mihara M, Ohsugi Y, Kishimoto T (2011) Tocilizumab, a humanized anti-interleukin-6 receptor antibody, for treatment of rheumatoid arthritis. Open Access Rheumatol 3:19\u201329. https:\/\/doi.org\/10.2147\/OARRR.S17118","journal-title":"Open Access Rheumatol"},{"issue":"2","key":"13596_CR42","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1080\/14397595.2018.1546357","volume":"29","author":"A Ogata","year":"2019","unstructured":"Ogata A, Kato Y, Higa S, Yoshizaki K (2019) IL-6 inhibitor for the treatment of rheumatoid arthritis: a comprehensive review. Mod Rheumatol 29(2):258\u2013267. https:\/\/doi.org\/10.1080\/14397595.2018.1546357","journal-title":"Mod Rheumatol"},{"issue":"2","key":"13596_CR43","doi-asserted-by":"publisher","first-page":"111","DOI":"10.5114\/reum.2018.75523","volume":"56","author":"M Ostrowska","year":"2018","unstructured":"Ostrowska M, Ma\u015bli\u0144ski W, Prochorec-Sobieszek M, Nieciecki M, Sudo\u0142-Szopi\u0144ska I (2018) Cartilage and bone damage in rheumatoid arthritis. Reumatologia 56(2):111\u2013120. https:\/\/doi.org\/10.5114\/reum.2018.75523","journal-title":"Reumatologia"},{"issue":"12","key":"13596_CR44","doi-asserted-by":"publisher","DOI":"10.1016\/j.autrev.2019.102398","volume":"18","author":"A Rubbert-Roth","year":"2019","unstructured":"Rubbert-Roth A, Szab\u00f3 MZ, Kedves M, Nagy G, Atzeni F, Sarzi-Puttini P (2019) Failure of anti-TNF treatment in patients with rheumatoid arthritis: the pros and cons of the early use of alternative biological agents. Autoimmun Rev 18(12):102398. https:\/\/doi.org\/10.1016\/j.autrev.2019.102398","journal-title":"Autoimmun Rev"},{"issue":"4","key":"13596_CR45","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.cytogfr.2014.07.016","volume":"25","author":"LM Sedger","year":"2014","unstructured":"Sedger LM, McDermott MF (2014) TNF and TNF-receptors: from mediators of cell death and inflammation to therapeutic giants\u2013past, present and future. Cytokine Growth Factor Rev 25(4):453\u2013472. https:\/\/doi.org\/10.1016\/j.cytogfr.2014.07.016","journal-title":"Cytokine Growth Factor Rev"},{"issue":"1","key":"13596_CR46","doi-asserted-by":"publisher","first-page":"8200","DOI":"10.1038\/s41598-017-07800-w","volume":"7","author":"P Sormanni","year":"2017","unstructured":"Sormanni P, Amery L, Ekizoglou S, Vendruscolo M, Popovic B (2017) Rapid and accurate in silico solubility screening of a monoclonal antibody library. Sci Rep 7(1):8200. https:\/\/doi.org\/10.1038\/s41598-017-07800-w","journal-title":"Sci Rep"},{"issue":"5","key":"13596_CR47","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1177\/1759720X10378372","volume":"2","author":"S Srirangan","year":"2010","unstructured":"Srirangan S, Choy EH (2010) The role of interleukin 6 in the pathophysiology of rheumatoid arthritis. Ther Adv Musculoskelet Dis 2(5):247\u2013256. https:\/\/doi.org\/10.1177\/1759720X10378372","journal-title":"Ther Adv Musculoskelet Dis"},{"issue":"10","key":"13596_CR48","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1038\/nrrheum.2009.181","volume":"5","author":"PC Taylor","year":"2009","unstructured":"Taylor PC, Feldmann M (2009) Anti-TNF biologic agents: still the therapy of choice for rheumatoid arthritis. Nat Rev Rheumatol 5(10):578\u2013582. https:\/\/doi.org\/10.1038\/nrrheum.2009.181","journal-title":"Nat Rev Rheumatol"},{"issue":"4","key":"13596_CR49","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1093\/bioinformatics\/btab801","volume":"38","author":"V Thumuluri","year":"2022","unstructured":"Thumuluri V, Martiny H-M, Almagro Armenteros JJ, Salomon J, Nielsen H, Johansen AR (2022) NetSolP: predicting protein solubility in Escherichia coli using language models. Bioinformatics 38(4):941\u2013946. https:\/\/doi.org\/10.1093\/bioinformatics\/btab801","journal-title":"Bioinformatics"},{"key":"13596_CR50","doi-asserted-by":"publisher","first-page":"A375","DOI":"10.1136\/annrheumdis-2013-eular.1149","volume":"72","author":"M Van Roy","year":"2013","unstructured":"Van Roy M, Van de Sompel A, De Smet K, Jacobs J, Denayer T, Ulrichts H, Baumeister J, Holz J-B (2013) FRI0021 Alx-0061, an anti-IL-6R nanobody\u00ae for therapeutic use in rheumatoid arthritis, demonstrates in vitro a differential biological activity profile as compared to tocilizumab. Ann Rheum Dis 72:A375. https:\/\/doi.org\/10.1136\/annrheumdis-2013-eular.1149","journal-title":"Ann Rheum Dis"},{"issue":"1","key":"13596_CR51","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1046\/j.1365-2443.1997.1020301.x","volume":"2","author":"A Varshavsky","year":"1997","unstructured":"Varshavsky A (1997) The N-end rule pathway of protein degradation. Genes Cells 2(1):13\u201328. https:\/\/doi.org\/10.1046\/j.1365-2443.1997.1020301.x","journal-title":"Genes Cells"},{"issue":"4","key":"13596_CR52","doi-asserted-by":"publisher","first-page":"404","DOI":"10.31138\/mjr.301223.eaf","volume":"34","author":"AI Venetsanopoulou","year":"2023","unstructured":"Venetsanopoulou AI, Alamanos Y, Voulgari PV, Drosos AA (2023) Epidemiology and risk factors for rheumatoid arthritis development. Mediterr J Rheumatol 34(4):404. https:\/\/doi.org\/10.31138\/mjr.301223.eaf","journal-title":"Mediterr J Rheumatol"},{"key":"13596_CR53","doi-asserted-by":"publisher","unstructured":"Walker JM (2005) The proteomics protocols handbook. 1st ed. Humana Totowa, NJ. https:\/\/doi.org\/10.1385\/1592598900","DOI":"10.1385\/1592598900"},{"issue":"2","key":"13596_CR54","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1093\/protein\/8.2.127","volume":"8","author":"AC Wallace","year":"1995","unstructured":"Wallace AC, Laskowski RA, Thornton JM (1995) Ligplot: a program to generate schematic diagrams of protein-ligand interactions. Protein Eng 8(2):127\u2013134. https:\/\/doi.org\/10.1093\/protein\/8.2.127","journal-title":"Protein Eng"},{"issue":"11","key":"13596_CR55","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.4314\/tjpr.v18i11.11","volume":"18","author":"S-Q Wang","year":"2019","unstructured":"Wang S-Q, Shi M, Fang L, Xu S-M, Wang C, Yu Z (2019) Design of dual inhibitors of human TNF-\u03b1 and IL-6 with potentials for the treatment of rheumatoid arthritis. Trop J Pharm Res 18(11):2305\u20132312. https:\/\/doi.org\/10.4314\/tjpr.v18i11.11","journal-title":"Trop J Pharm Res"},{"issue":"supplSuppl-2","key":"13596_CR56","doi-asserted-by":"publisher","first-page":"W407","DOI":"10.1093\/nar\/gkm290","volume":"35","author":"M Wiederstein","year":"2007","unstructured":"Wiederstein M, Sippl MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res 35(supplSuppl-2):W407\u2013W410. https:\/\/doi.org\/10.1093\/nar\/gkm290","journal-title":"Nucleic Acids Res"},{"issue":"13","key":"13596_CR57","doi-asserted-by":"publisher","first-page":"3316","DOI":"10.1093\/nar\/gkg565","volume":"31","author":"L Willard","year":"2003","unstructured":"Willard L, Ranjan A, Zhang H, Monzavi H, Boyko RF, Sykes BD, Wishart DS (2003) VADAR: a web server for quantitative evaluation of protein structure quality. Nucleic Acids Res 31(13):3316\u20133319. https:\/\/doi.org\/10.1093\/nar\/gkg565","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"13596_CR58","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1002\/pro.3330","volume":"27","author":"CJ Williams","year":"2018","unstructured":"Williams CJ, Headd JJ, Moriarty NW, Prisant MG, Videau LL, Deis LN, Verma V, Keedy DA, Hintze BJ, Chen VB (2018) Molprobity: more and better reference data for improved all-atom structure validation. Protein Sci 27(1):293\u2013315. https:\/\/doi.org\/10.1002\/pro.3330","journal-title":"Protein Sci"},{"issue":"1","key":"13596_CR59","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1007\/s12026-021-09173-9","volume":"69","author":"I Wo\u015b","year":"2021","unstructured":"Wo\u015b I, Tabarkiewicz J (2021) Effect of interleukin-6, -17, -21, -22, and -23 and STAT3 on signal transduction pathways and their inhibition in autoimmune arthritis. Immunol Res 69(1):26\u201342. https:\/\/doi.org\/10.1007\/s12026-021-09173-9","journal-title":"Immunol Res"},{"issue":"47","key":"13596_CR60","doi-asserted-by":"publisher","first-page":"81860","DOI":"10.18632\/oncotarget.19899","volume":"8","author":"T Xu","year":"2017","unstructured":"Xu T, Ying T, Wang L, Zhang XD, Wang Y, Kang L, Huang T, Cheng L, Wang L, Zhao Q (2017) A native-like bispecific antibody suppresses the inflammatory cytokine response by simultaneously neutralizing tumor necrosis factor-alpha and interleukin-17A. Oncotarget 8(47):81860. https:\/\/doi.org\/10.18632\/oncotarget.19899","journal-title":"Oncotarget"},{"issue":"23","key":"13596_CR61","doi-asserted-by":"publisher","first-page":"3676","DOI":"10.1093\/bioinformatics\/btw514","volume":"32","author":"LC Xue","year":"2016","unstructured":"Xue LC, Rodrigues JP, Kastritis PL, Bonvin AM, Vangone A (2016) Prodigy: a web server for predicting the binding affinity of protein\u2013protein complexes. Bioinformatics 32(23):3676\u20133678. https:\/\/doi.org\/10.1093\/bioinformatics\/btw514","journal-title":"Bioinformatics"},{"issue":"1","key":"13596_CR62","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1038\/s41392-023-01381-z","volume":"8","author":"Z Yang","year":"2023","unstructured":"Yang Z, Zeng X, Zhao Y, Chen R (2023) AlphaFold2 and its applications in the fields of biology and medicine. Signal Transduct Target Ther 8(1):115. https:\/\/doi.org\/10.1038\/s41392-023-01381-z","journal-title":"Signal Transduct Target Ther"},{"issue":"8","key":"13596_CR63","doi-asserted-by":"publisher","first-page":"e516","DOI":"10.1097\/RHU.0000000000001293","volume":"27","author":"RML Yip","year":"2021","unstructured":"Yip RML, Yim CW (2021) Role of interleukin 6 inhibitors in the management of rheumatoid arthritis. J Clin Rheumatol 27(8):e516\u2013e524. https:\/\/doi.org\/10.1097\/RHU.0000000000001293","journal-title":"J Clin Rheumatol"},{"key":"13596_CR64","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.111240","volume":"126","author":"N Zhang","year":"2024","unstructured":"Zhang N, Zheng N, Luo D, Lin J, Lin D, Lu Y, Lai W, Bian Y, Wang H, Ye J (2024) A novel single domain bispecific antibody targeting VEGF and TNF-\u03b1 ameliorates rheumatoid arthritis. Int Immunopharmacol 126:111240. https:\/\/doi.org\/10.1016\/j.intimp.2023.111240","journal-title":"Int Immunopharmacol"},{"issue":"1","key":"13596_CR65","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1196\/annals.1361.116","volume":"1051","author":"J Zwerina","year":"2005","unstructured":"Zwerina J, Redlich K, Schett G, Smolen JS (2005) Pathogenesis of rheumatoid arthritis: targeting cytokines. Ann N Y Acad Sci 1051(1):716\u2013729. https:\/\/doi.org\/10.1196\/annals.1361.116","journal-title":"Ann N Y Acad Sci"}],"container-title":["Applied Microbiology and Biotechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00253-025-13596-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00253-025-13596-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00253-025-13596-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T12:31:51Z","timestamp":1770294711000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00253-025-13596-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,9]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["13596"],"URL":"https:\/\/doi.org\/10.1007\/s00253-025-13596-x","relation":{},"ISSN":["1432-0614"],"issn-type":[{"value":"1432-0614","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,9]]},"assertion":[{"value":"11 June 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"30 August 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 September 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 October 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This article contains no studies with human participants or animals performed by the authors.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"217"}}