8,035
Views
42
CrossRef citations to date
0
Altmetric
Report

An in vitro FcRn- dependent transcytosis assay as a screening tool for predictive assessment of nonspecific clearance of antibody therapeutics in humans

ORCID Icon, , ORCID Icon, ORCID Icon, ORCID Icon, , , , , , , , , , , , & ORCID Icon show all
Pages 942-955 | Received 20 Oct 2018, Accepted 08 Mar 2019, Published online: 29 Apr 2019

References

  • Deng R, Loyet KM, Lien S, Iyer S, DeForge LE, Theil F-P, Lowman HB, Fielder PJ, Prabhu S. Pharmacokinetics of humanized monoclonal anti-tumor necrosis factor-{alpha} antibody and its neonatal Fc receptor variants in mice and cynomolgus monkeys. Drug Metab Dispos. 2010;38:600–05. doi:10.1124/dmd.109.031310. PMID:20071453.
  • Kamath AV. Translational pharmacokinetics and pharmacodynamics of monoclonal antibodies. Drug Discov Today Technol. 2016;21–22:75–83. doi:10.1016/j.ddtec.2016.09.004.
  • Igawa T, Tsunoda H, Tachibana T, Maeda A, Mimoto F, Moriyama C, Nanami M, Sekimori Y, Nabuchi Y, Aso Y, et al. Reduced elimination of IgG antibodies by engineering the variable region. Protein Eng Des Sel. 2010;23:385–92. doi:10.1093/protein/gzq009. PMID:20159773.
  • Bumbaca Yadav D, Sharma VK, Boswell CA, Hotzel I, Tesar D, Shang Y, Ying Y, Fischer SK, Grogan JL, Chiang EY, et al. Evaluating the use of antibody variable region (Fv) charge as a risk assessment tool for predicting typical cynomolgus monkey pharmacokinetics. J Biol Chem. 2015;290:29732–41. doi:10.1074/jbc.M115.692434. PMID:26491012.
  • Datta-Mannan A, Thangaraju A, Leung D, Tang Y, Witcher DR, Lu J, Wroblewski VJ. Balancing charge in the complementarity-determining regions of humanized mAbs without affecting pI reduces non-specific binding and improves the pharmacokinetics. MAbs. 2015;7:483–93. doi:10.1080/19420862.2015.1016696. PMID:25695748.
  • Sharma VK, Patapoff TW, Kabakoff B, Pai S, Hilario E, Zhang B, Li C, Borisov O, Kelley RF, Chorny I, et al. In silico selection of therapeutic antibodies for development: viscosity, clearance, and chemical stability. Proc Natl Acad Sci U S A. 2014;111:18601–06. doi:10.1073/pnas.1421779112. PMID:25512516.
  • Hotzel I, Theil FP, Bernstein LJ, Prabhu S, Deng R, Quintana L, Lutman J, Sibia R, Chan P, Bumbaca D, et al. A strategy for risk mitigation of antibodies with fast clearance. MAbs. 2012;4:753–60. doi:10.4161/mabs.22189. PMID:23778268.
  • Bumbaca D, Wong A, Drake E, Reyes AE 2nd, Lin BC, Stephan J-P, Desnoyers L, Shen B-Q, Dennis MS. Highly specific off-target binding identified and eliminated during the humanization of an antibody against FGF receptor 4. MAbs. 2011;3:376–86. PMID:21540647.
  • Stefanich EG, Ren S, Danilenko DM, Lim A, Song A, Iyer S, Fielder PJ. Evidence for an asialoglycoprotein receptor on nonparenchymal cells for O-linked glycoproteins. J Pharmacol Exp Ther. 2008;327:308–15. doi:10.1124/jpet.108.142232. PMID:18728239.
  • Yu M, Brown D, Reed C, Chung S, Lutman J, Stefanich E, Wong A, Stephan J-P, Bayer R. Production, characterization, and pharmacokinetic properties of antibodies with N-linked mannose-5 glycans. MAbs. 2012;4:475–87. doi:10.4161/mabs.20737. PMID:22699308.
  • Mortensen DL, Prabhu S, Stefanich EG, Kadkhodayan-Fischer S, Gelzleichter TR, Baker D, Jiang J, Wallace K, Iyer S, Fielder PJ, et al. Effect of antigen binding affinity and effector function on the pharmacokinetics and pharmacodynamics of anti-IgE monoclonal antibodies. MAbs. 2012;4:724–31. doi:10.4161/mabs.22216. PMID:23778267.
  • Chirmule N, Jawa V, Meibohm B. Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. Aaps J. 2012;14:296–302. doi:10.1208/s12248-012-9340-y. PMID:22407289.
  • Dall‘Acqua WF, Kiener PA, Wu H. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J Biol Chem. 2006;281:23514–24. doi:10.1074/jbc.M604292200. PMID:16793771.
  • Suzuki T, Ishii-Watabe A, Tada M, Kobayashi T, Kanayasu-Toyoda T, Kawanishi T, Yamaguchi T. Importance of neonatal FcR in regulating the serum half-life of therapeutic proteins containing the Fc domain of human IgG1: a comparative study of the affinity of monoclonal antibodies and Fc-fusion proteins to human neonatal FcR. J Immunol. 2010;184:1968–76. doi:10.4049/jimmunol.0903296. PMID:20083659.
  • Gurbaxani B, Dostalek M, Gardner I. Are endosomal trafficking parameters better targets for improving mAb pharmacokinetics than FcRn binding affinity? Mol Immunol. 2013;56(4):660–74. doi:10.1016/j.molimm.2013.05.008.
  • Pyzik M, Rath T, Lencer WI, Baker K, Blumberg RS. FcRn: the architect behind the immune and nonimmune functions of IgG and albumin. J Immunol. 2015;194:4595–603. doi:10.4049/jimmunol.1403014. PMID:25934922.
  • Ward ES, Devanaboyina SC, Ober RJ. Targeting FcRn for the modulation of antibody dynamics. Mol Immunol. 2015;67:131–41. doi:10.1016/j.molimm.2015.02.007. PMID:25766596.
  • Ghetie V, Ward ES. Transcytosis and catabolism of antibody. Immunol Res. 2002;25:97–113. doi:10.1385/IR:25:2:097.
  • Dickinson BL, Badizadegan K, Wu Z, Ahouse JC, Zhu X, Simister NE, Blumberg RS, Lencer WI. Bidirectional FcRn-dependent IgG transport in a polarized human intestinal epithelial cell line. J Clin Invest. 1999;104(7):903–11. doi:10.1172/JCI6968.
  • Tzaban S, Massol RH, Yen E, Hamman W, Frank SR, Lapierre LA, Hansen SH, Goldenring JR, Blumberg RS, Lencer WI. The recycling and transcytotic pathways for IgG transport by FcRn are distinct and display an inherent polarity. J Cell Biol. 2009;185(4):673–84. doi:10.1083/jcb.200809122.
  • Avery LB, Wang M, Kavosi MS, Joyce A, Kurz JC, Fan -Y-Y, Dowty ME, Zhang M, Zhang Y, Cheng A, et al. Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies. MAbs. 2016;8:1064–78. doi:10.1080/19420862.2016.1193660. PMID:27232760.
  • Vugmeyster Y, Xu X, Theil F-P, Khawli LA, Leach MW. Pharmacokinetics and toxicology of therapeutic proteins: advances and challenges. World J Biol Chem. 2012;3:73–92. doi:10.4331/wjbc.v3.i4.73. PMID:22558487.
  • Deng R, Iyer S, Theil F-P, Mortensen DL, Fielder PJ, Prabhu S. Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: what have we learned? MAbs. 2011;3:61–66. PMID:20962582.
  • Wang J, Iyer S, Fielder PJ, Davis JD, Deng R. Projecting human pharmacokinetics of monoclonal antibodies from nonclinical data: comparative evaluation of prediction approaches in early drug development. Biopharm Drug Dispos. 2016;37:51–65. doi:10.1002/bdd.1952. PMID:25869767.
  • Sampei Z, Igawa T, Soeda T, Okuyama-Nishida Y, Moriyama C, Wakabayashi T, Tanaka E, Muto A, Kojima T, Kitazawa T, et al. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactoractivity. PLoS One. 2013;8(2):e57479. PMID:23468998. doi:10.1371/journal.pone.0057479.
  • Schlothauer T, Rueger P, Stracke JO, Hertenberger H, Fingas F, Kling L, Emrich T, Drabner G, Seeber S, Auer J, et al. Analytical FcRn affinity chromatography for functional characterization of monoclonal antibodies. MAbs. 2013;5:576–86. doi:10.4161/mabs.24981. PMID:23765230.
  • Souders CA, Nelson SC, Wang Y, Crowley AR, Klempner MS, Thomas W Jr. A novel in vitro assay to predict neonatal Fc receptor-mediated human IgG half-life. MAbs. 2015;7:912–21. doi:10.1080/19420862.2015.1054585. PMID:26018774.
  • Praetor A, Ellinger I, Hunziker W. Intracellular traffic of the MHC class I-like IgG Fc receptor, FcRn, expressed in epithelial MDCK cells. J Cell Sci. 1999;112:2291–99.
  • Claypool SM, Dickinson BL, Yoshida M, Lencer WI, Blumberg RS. Functional reconstitution of human FcRn in Madin-Darby canine kidney cells requires co-expressed human beta 2-microglobulin. J Biol Chem. 2002;277:28038–50. doi:10.1074/jbc.M202367200.
  • Tesar DB, Tiangco NE, Bjorkman PJ. Ligand valency affects transcytosis, recycling and intracellular trafficking mediated by the neonatal Fc receptor. Traffic. 2006;7:1127–42. PMID:17004319.
  • Sockolosky JT, Tiffany MR, Szoka FC. Engineering neonatal Fc receptor-mediated recycling and transcytosis in recombinant proteins by short terminal peptide extensions. Proc Natl Acad Sci U S A. 2012;109(40):16095–100. doi:10.1073/pnas.1208857109.
  • Ying T, Wang Y, Feng Y, Prabakaran P, Gong R, Wang L, Crowder K, Dimitrov DS. Engineered antibody domains with significantly increased transcytosis and half-life in macaques mediated by FcRn. MAbs. 2015;7(5):922–30. doi:10.1080/19420862.2015.1067353.
  • Jaramillo CAC, Belli S, Cascais A-C, Dudal S, Edelmann MR, Haak M, Brun M-E, Otteneder MB, Ullah M, Funk C, et al. Toward in vitro-to-in vivo translation of monoclonal antibody pharmacokinetics: application of a neonatal Fc receptor-mediated transcytosis assay to understand the interplaying clearance mechanisms. MAbs. 2017;9:781–91. doi:10.1080/19420862.2017.1320008.
  • Chung S, Lin YL, Nguyen V, Kamen L, Zheng K, Vora B, Song A. Development of a label-free FcRn-mediated transcytosis assay for in vitro characterization of FcRn interactions with therapeutic antibodies and Fc-fusion proteins. J Immunol Methods. 2018. doi:10.1016/j.jim.2018.07.004. PMID:30030147.
  • Grevys A, Nilsen J, Sand KMK, Daba MB, Øynebråten I, Bern M, McAdam MB, Foss S, Schlothauer T, Michaelsen TE, et al. A human endothelial cell-based recycling assay for screening of FcRn targeted molecules. Nat Commun. 2018;9(1):621. doi:10.1038/s41467-018-03061-x.
  • Goebl NA, Babbey CM, Datta-Mannan A, Witcher DR, Wroblewski VJ, Dunn KW, Schmid SL. Neonatal Fc receptor mediates internalization of Fc in transfected human endothelial cells. Mol Biol Cell. 2008;9:5490–505. doi:10.1091/mbc.e07-02-0101.
  • Chaudhury C, Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, Anderson CL. The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J Exp Med. 2003;197:315–22. PMID:12566415.
  • Quartino AL, Hillenbach C, Li J, Li H, Wada RD, Visich J, Li C, Heinzmann D, Jin JY, Lum BL. Population pharmacokinetic and exposure-response analysis for trastuzumab administered using a subcutaneous “manual syringe” injection or intravenously in women with HER2-positive early breast cancer. Cancer Chemother Pharmacol. 2016;77:77–88. doi:10.1007/s00280-015-2922-5. PMID:26645407.
  • Quartino AL, Li H, Jin JY, Wada DR, Benyunes MC, McNally V, Viganò L, Nijem I, Lum BL, Garg A. Pharmacokinetic and exposure-response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer. Cancer Chemother Pharmacol. 2017;79:353–61. doi:10.1007/s00280-016-3218-0. PMID:28074265.
  • Ng CM, Joshi A, Dedrick RL, Garovoy MR, Bauer RJ. Pharmacokinetic-pharmacodynamic-efficacy analysis of efalizumab in patients with moderate to severe psoriasis. Pharm Res. 2005;22:1088–100. doi:10.1007/s11095-005-5642-4. PMID:16028009.
  • Klotz U, Teml A, Schwab M. Clinical pharmacokinetics and use of infliximab. Clin Pharmacokinet. 2007;46:645–60. doi:10.2165/00003088-200746080-00002. PMID:17655372.
  • Singer J, Weichselbaumer M, Stockner T, Mechtcheriakova D, Sobanov Y, Bajna E, Wrba F, Horvat R, Thalhammer JG, Willmann M, et al. Comparative oncology: erbB-1 and ErbB-2 homologues in canine cancer are susceptible to cetuximab and trastuzumab targeting. Mol Immunol. 2012;50(4):200–09. doi:10.1016/j.molimm.2012.01.002.
  • Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 2004;5:317–28.
  • Cho HS, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW, Leahy DJ. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature. 2003;421(6924):756–60. doi:10.1038/nature01392.
  • Boswell CA, Tesar DB, Mukhyala K, Theil FP, Fielder PJ, Khawli LA. Effects of charge on antibody tissue distribution and pharmacokinetics. Bioconjug Chem. 2010;21:2153–63. doi:10.1021/bc100261d. PMID:21053952.
  • Higel F, Seidl A, Sorgel F, Friess W. N-glycosylation heterogeneity and the influence on structure, function and pharmacokinetics of monoclonal antibodies and Fc fusion proteins. Eur J Pharm Biopharm. 2016;100:94–100. doi:10.1016/j.ejpb.2016.01.005. PMID:26775146.
  • Leabman MK, Meng YG, Kelley RF, DeForge LE, Cowan KJ, Iyer S. Effects of altered FcgammaR binding on antibody pharmacokinetics in cynomolgus monkeys. MAbs. 2013;5:896–903. doi:10.4161/mabs.26436. PMID:24492343.
  • Lee SJ, Evers S, Roeder D, Parlow AF, Risteli J, Risteli L, Lee YC, Feizi T, Langen H, Nussenzweig MC. Mannose receptor-mediated regulation of serum glycoprotein homeostasis. Science. 2002;295:1898–901. doi:10.1126/science.1069540. PMID:11884756.
  • Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and expression. Physiol Rev. 1995;75:591–609. doi:10.1152/physrev.1995.75.3.591. PMID:7624395.
  • Kenanova V, Olafsen T, Crow DM, Sundaresan G, Subbarayan M, Carter NH, Ikle DN, Yazaki PJ, Chatziioannou AF, Gambhir SS, et al. Tailoring the pharmacokinetics and positron emission tomography imaging properties of anti-carcinoembryonic antigen single-chain Fv-Fc antibody fragments. Cancer Res. 2005;65:622–31. PMID:15695407.
  • Wang W, Lu P, Fang Y, Hamuro L, Pittman T, Carr B, Hochman J, Prueksaritanont T. Monoclonal antibodies with identical Fc sequences can bind to FcRn differentially with pharmacokinetic consequences. Drug Metab Dispos. 2011;39:1469–77. doi:10.1124/dmd.111.039453.
  • Hu J, Liu J, Yang D, Lu M, Yin J. Physiological roles of asialoglycoprotein receptors (ASGPRs) variants and recent advances in hepatic-targeted delivery of therapeutic molecules via ASGPRs. Protein Pept Lett. 2014;21:1025–30.
  • Wright A, Sato Y, Okada T, Chang K, Endo T, Morrison S. In vivo trafficking and catabolism of IgG1 antibodies with Fc associated carbohydrates of differing structure. Glycobiology. 2000;10:1347–55.
  • Cianga P, Medesan C, Richardson JA, Ghetie V, Ward ES. Identification and function of neonatal Fc receptor in mammary gland of lactating mice. Eur J Immunol. 1999;29:2515–23. doi:10.1002/(SICI)1521-4141(199908)29:08<2515::AID-IMMU2515>3.0.CO;2-D. PMID:10458766.
  • Antohe F, Radulescu L, Gafencu A, Ghetie V, Simionescu M. Expression of functionally active FcRn and the differentiated bidirectional transport of IgG in human placental endothelial cells. Hum Immunol. 2001;62:93–105. PMID:11182218.
  • Sarav M, Wang Y, Hack BK, Chang A, Jensen M, Bao L, Quigg RJ. Renal FcRn reclaims albumin but facilitates elimination of IgG. J Am Soc Nephrol. 2009;20:1941–52. doi:10.1681/ASN.2008090976. PMID:19661163.
  • Yip V, Palma E, Tesar DB, Mundo EE, Bumbaca D, Torres EK, Reyes NA, Shen BQ, Fielder PJ, Prabhu S, et al. Quantitative cumulative biodistribution of antibodies in mice: effect of modulating binding affinity to the neonatal Fc receptor. MAbs. 2014;6:689–96. doi:10.4161/mabs.28254. PMID:24572100.
  • Kim JH, Lee SR, Li LH, Park HJ, Park JH, Lee KY, Kim M-K, Shin BA, Choi S-Y, Thiel V. High cleavage efficiency of a 2A peptide derived from porcine teschovirus-1 in human cell lines, zebrafish and mice. PLoS One. 2011;6:e18556. doi:10.1371/journal.pone.0018556. PMID:21602908.
  • Li B, Tesar D, Boswell CA, Cahaya HS, Wong A, Zhang J, Meng YG, Eigenbrot C, Pantua H, Diao J, et al. Framework selection can influence pharmacokinetics of a humanized therapeutic antibody through differences in molecule charge. MAbs. 2014;6:1255–64. doi:10.4161/mabs.29809. PMID:25517310.
  • Williams K, Erickson R, Fischer SK. Overcoming disease-specific matrix effect in a clinical pharmacokinetic assay using a microfluidic immunoassay technology. Bioanalysis. 2017;9:1207–16. doi:10.4155/bio-2017-0102. PMID:28766364.