Development of novel ultra-sensitive IL-11 target engagement assays to support mechanistic PK/PD modeling for an anti-IL-11 antibody therapeutic

References

• Fernando K, Menon S, Jansen K, Naik P, Nucci G, Roberts J, Wu SS, Dolsten M. Achieving end-to-end success in the clinic: pfizer’s learnings on R&D productivity. Drug Discov Today. 2022;27(3):697–13. doi:10.1016/j.drudis.2021.12.010.
   PubMed Web of Science ®Google Scholar
• Peters SA, Petersson C, Blaukat A, Halle J-P, Dolgos H. Prediction of active human dose: learnings from 20 years of Merck KGaA experience, illustrated by case studies. Drug Discov Today. 2020;25(5):909–19. doi:10.1016/j.drudis.2020.01.002.
   PubMed Web of Science ®Google Scholar
• Lee JW, Kelley M, King LE, Yang J, Salimi-Moosavi H, Tang MT, J-F L, Kamerud J, Ahene A, Myler H, et al. Bioanalytical approaches to quantify “total” and “free” therapeutic antibodies and their targets. Technical Challenges and PK/PD Applications over the Course of Drug Development. Aaps J. 2011;13:99–110.
   PubMed Web of Science ®Google Scholar
• Zheng S, McIntosh T, Wang W. Utility of free and total target measurements as target engagement and efficacy biomarkers in biotherapeutic development—Opportunities and challenges. J Clin Pharmacol. 2015;55(S3):S75–84. doi:10.1002/jcph.357.
   PubMedGoogle Scholar
• Wang W, Wang X, Doddareddy R, Fink D, McIntosh T, Davis HM, Zhou H. Mechanistic pharmacokinetic/target engagement/pharmacodynamic (PK/TE/PD) modeling in deciphering interplay between a monoclonal antibody and its soluble target in cynomolgus monkeys. Aaps J. 2014;16(1):129–39. doi:10.1208/s12248-013-9545-8.
   PubMed Web of Science ®Google Scholar
• Lee JW, Salimi-Moosavi H. Bioanalysis of target biomarker and PK/PD relevancy during the development of biotherapeutics. Bioanalysis. 2012;4(20):2513–23. doi:10.4155/bio.12.220.
   PubMed Web of Science ®Google Scholar
• Schafer S, Viswanathan S, Widjaja AA, Lim -W-W, Moreno-Moral A, DeLaughter DM, Ng B, Patone G, Chow K, Khin E, et al. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature. 2017;552(7683):110–15. doi:10.1038/nature24676.
   PubMed Web of Science ®Google Scholar
• Widjaja AA, Singh BK, Adami E, Viswanathan S, Dong J, D’Agostino GA, Ng B, Lim WW, Tan J, Paleja BS, et al. Inhibiting interleukin 11 signaling reduces hepatocyte death and liver fibrosis, inflammation, and steatosis in mouse models of nonalcoholic steatohepatitis. Gastroenterology. 2019;157(3):777–792.e14. doi:10.1053/j.gastro.2019.05.002.
   PubMed Web of Science ®Google Scholar
• Ng B, Dong J, D’Agostino G, Viswanathan S, Widjaja AA, Lim -W-W, Nsj K, Tan J, Chothani SP, Huang B, et al. Interleukin-11 is a therapeutic target in idiopathic pulmonary fibrosis. Sci Transl Med. 2019;11(511). doi:10.1126/scitranslmed.aaw123.
   Web of Science ®Google Scholar
• Elshabrawy HA, Volin MV, Essani AB, Chen Z, McInnes IB, Raemdonck KV, Palasiewicz K, Arami S, Gonzalez M, Ashour HM, et al. IL-11 facilitates a novel connection between RA joint fibroblasts and endothelial cells. Angiogenesis. 2018;21(2):215–28. doi:10.1007/s10456-017-9589-y.
   PubMed Web of Science ®Google Scholar
• Trontzas P, KamperR EF, Potamianou A, Kyriazis NC, Kritikos H, Stavridis J. Comparative study of serum and synovial fluid interleukin-11 levels in patients with various arthritides. Clin Biochem. 1998;31(8):673–79. doi:10.1016/S0009-9120(98)00062-9.
   PubMed Web of Science ®Google Scholar
• Cremer M, Schulze H, Linthorst G, Folman CC, Wehnert S, Strauß G, von Dem BA, Welte K, Ballmaier M. Serum levels of thrombopoietin, IL-11, and IL-6 in pediatric thrombocytopenias. Ann Hematol. 1999;78(9):401–07. doi:10.1007/s002770050538.
   PubMed Web of Science ®Google Scholar
• Fischer SK, Joyce A, Spengler M, Yang T-Y, Zhuang Y, Fjording MS, Mikulskis A. Emerging technologies to increase ligand binding assay sensitivity. Aaps J. 2015;17(1):93–101. doi:10.1208/s12248-014-9682-8.
   PubMed Web of Science ®Google Scholar
• Goodman J, Agoram B. Analytical assay platforms for soluble target engagement biomarkers: old favorites and emerging technologies. Bioanalysis. 2013;5(23):2919–31. doi:10.4155/bio.13.262.
   PubMed Web of Science ®Google Scholar
• Breen EC, Reynolds SM, Cox C, Jacobson LP, Magpantay L, Mulder CB, Dibben O, Margolick JB, Bream JH, Sambrano E, et al. Multisite comparison of high-sensitivity multiplex cytokine assays. Clin Vaccine Immunol. 2011;18(8):1229–42. doi:10.1128/CVI.05032-11.
   PubMedGoogle Scholar
• Yeung D, Ciotti S, Purushothama S, Gharakhani E, Kuesters G, Schlain B, Shen C, Donaldson D, Mikulskis A. Evaluation of highly sensitive immunoassay technologies for quantitative measurements of sub-pg/mL levels of cytokines in human serum. J Immunol Methods. 2016;437:53–63. doi:10.1016/j.jim.2016.08.003.
   PubMed Web of Science ®Google Scholar
• Patel P, Kuzmanov U, Mital S. Avoiding false discovery in biomarker research. Bmc Biochem. 2016;17(1):17. doi:10.1186/s12858-016-0073-x.
   PubMedGoogle Scholar
• Gutiérrez OM, Sun CC, Chen W, Babitt JL, Lin HY. Statement of concern about a commercial assay used to measure soluble hemojuvelin in humans. Am J Nephrol. 2012;36(4):332–33. doi:10.1159/000342519.
   PubMed Web of Science ®Google Scholar
• Putoczki TL, Ernst M. IL-11 signaling as a therapeutic target for cancer. Immunotherapy. 2015;7(4):441–53. doi:10.2217/imt.15.17.
   PubMed Web of Science ®Google Scholar
• Aoyama K, Uchida T, Takanuki F, Usui T, Watanabe T, Higuchi S, Toyoki T, Mizoguchi H. Pharmacokinetics of recombinant human interleukin‐11 (rhIL‐11) in healthy male subjects. Brit J Clin Pharmaco. 1997;43(6):571–78. doi:10.1046/j.1365-2125.1997.00605.x.
   PubMed Web of Science ®Google Scholar
• Ma S, Ho S-H, Ma S, Li Y, Li K, Tang X, Zhao G-R, Xu S. The pharmacokinetic and pharmacodynamic properties of site-specific pegylated genetically modified recombinant human interleukin-11 in normal and thrombocytopenic monkeys. Eur J Pharm Biopharm. 2017;119:185–91. doi:10.1016/j.ejpb.2017.05.013.
   PubMed Web of Science ®Google Scholar
• Dimitriadis E, Stoikos C, Tan Y-L, Salamonsen LA. Interleukin 11 signaling components signal transducer and activator of transcription 3 (STAT3) and suppressor of cytokine signaling 3 (SOCS3) regulate human endometrial stromal cell differentiation. Endocrinology. 2006;147(8):3809–17. doi:10.1210/en.2006-0264.
   PubMed Web of Science ®Google Scholar
• Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(10):633–59. doi:10.2165/11535960-000000000-00000.
   PubMed Web of Science ®Google Scholar
• Betts A, Keunecke A, van STJ, van der GPH, Avery LB, Jones H, Berkhout J. Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: a comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach. Mabs. 2018;10(5):751–64. doi:10.1080/19420862.2018.1462429.
   PubMed Web of Science ®Google Scholar
• Kagan L. Pharmacokinetic modeling of the subcutaneous absorption of therapeutic proteins. Drug Metab Dispos. 2014;42(11):1890–905. doi:10.1124/dmd.114.059121.
   PubMedGoogle Scholar
• Davies B, Morris T. Physiological parameters in laboratory animals and humans. Pharmaceut Res. 1993;10(7):1093–95. doi:10.1023/A:1018943613122.
   PubMed Web of Science ®Google Scholar
• Chimalakonda AP, Yadav R, Marathe P. Factors influencing magnitude and duration of target inhibition following antibody therapy: implications in drug discovery and development. Aaps J. 2013;15(3):717–27. doi:10.1208/s12248-013-9477-3.
   PubMed Web of Science ®Google Scholar
• Tang C, Prueksaritanont T. Theoretical analysis of interplay of therapeutic protein drug and circulating soluble target: temporal profiles of ‘free’ and ‘total. Drug and Target Pharmaceut Res. 2011;28(10):2447. doi:10.1007/s11095-011-0471-0.
   Google Scholar
• Wang W, Wang E, Balthasar J. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–58. doi:10.1038/clpt.2008.170.
   PubMed Web of Science ®Google Scholar
• Joyce AP, Wang M, Lawrence-Henderson R, Filliettaz C, Leung SS, Xu X, O’Hara DMOM. One pharmacokinetic profile: quantitative whole blood serial sampling for biotherapeutics. Pharmaceut Res. 2014;31(7):1823–33. doi:10.1007/s11095-013-1286-y.
   PubMed Web of Science ®Google Scholar
• Adami E, Viswanathan S, Widjaja AA, Ng B, Chothani S, Zhihao N, Tan J, Lio PM, George BL, Altunoglu U, et al. IL11 is elevated in systemic sclerosis and IL11-dependent ERK signalling underlies TGFβ-mediated activation of dermal fibroblasts. Rheumatology Oxf Engl. 2021;60(12):5820–26. doi:10.1093/rheumatology/keab168.
   PubMed Web of Science ®Google Scholar