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Challenges and Opportunities in Absorption, Distribution, Metabolism, and Excretion Studies of Therapeutic Biologics

  • Review Article
  • Theme: ADME of Therapeutic Proteins
  • Published:
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Abstract

With the advancement of biotechnology in the last two decades, optimized and novel modalities and platforms of biologic moieties have emerged rapidly in drug discovery pipelines. In addition, new technologies for delivering therapeutic biologics (e.g., needle-free devices, nanoparticle complexes), as well as novel approaches for disease treatments (e.g., stem cell therapy, individualized medicine), continue to be developed. While pharmacokinetic studies are routinely carried out for therapeutic biologics, experiments that elucidate underlying mechanisms for clearance and biodistribution or identify key factors that govern absorption, distribution, metabolism, and excretion (ADME) of biologics often are not thoroughly conducted. Realizing the importance of biologics as therapeutic agents, pharmaceutical industry has recently begun to move the research focus from small molecules only to a blended portfolio consisting of both small molecules and biologics. This trend brings many opportunities for scientists working in the drug disposition research field. In anticipation of these opportunities and associated challenges, this review highlights impact of ADME studies on clinical and commercial success of biologics, with a particular focus on emerging applications and technologies and linkage with mechanistic pharmacokinetic/pharmacodynamic modeling and biomarker research.

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References

  1. Nelson AL, Dhimolea E, Reichert JM. Development trends for human monoclonal antibody therapeutics. Nat Rev Drug Discov. 2010;9:767–74. doi:10.1038/nrd3229.

    Article  PubMed  CAS  Google Scholar 

  2. Verdine GL, Hilinski GJ. Stapled peptides for intracellular drug targets. Methods Enzymol. 2012;503:3–33. doi:10.1016/B978-0-12-396962-0.00001-X.

    Article  PubMed  CAS  Google Scholar 

  3. Gillies SD, Lan Y, Brunkhorst B, Wong WK, Li Y, Lo KM. Bi-functional cytokine fusion proteins for gene therapy and antibody-targeted treatment of cancer. Cancer Immunol, immunother: CII. 2002;51:449–60. doi:10.1007/s00262-002-0302-6.

    Article  CAS  Google Scholar 

  4. Nelson AL. Antibody fragments: hope and hype. mAbs. 2010;2:77–83.

    Article  PubMed  Google Scholar 

  5. De Lorenzo C, D'Alessio G. Human anti-ErbB2 immunoagents–immunoRNases and compact antibodies. FEBS J. 2009;276:1527–35. doi:10.1111/j.1742-4658.2009.06896.x.

    Article  PubMed  Google Scholar 

  6. Roovers RC, van Dongen GA, van Bergen en Henegouwen PM. Nanobodies in therapeutic applications. Curr Opin Mol Ther. 2007;9:327–35.

    PubMed  CAS  Google Scholar 

  7. Nickerson-Nutter C, Tchistiakova L, Seth NP, Kasaian M, Sibley B, Olland S, et al. Distinct in vitro binding properties of the anti-CD20 small modular immunopharmaceutical 2LM20-4 result in profound and sustained in vivo potency in cynomolgus monkeys. Rheumatol (Oxford, England). 2011;50:1033–44.

    Article  CAS  Google Scholar 

  8. Younes A, Yasothan U, Kirkpatrick P. Brentuximab vedotin. Nat Rev Drug Discov. 2011;11:19–20. doi:10.1038/nrd3629.

    Article  Google Scholar 

  9. Alley SC, Okeley NM, Senter PD. Antibody-drug conjugates: targeted drug delivery for cancer. Curr Opin Chem Biol. 2010;14:529–37. doi:10.1016/j.cbpa.2010.06.170.

    Article  PubMed  CAS  Google Scholar 

  10. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391:806–11. doi:10.1038/35888.

    Article  PubMed  CAS  Google Scholar 

  11. Bell DA, Hooper AJ, Burnett JR. Mipomersen, an antisense apolipoprotein B synthesis inhibitor. Expert Opin Investig Drugs. 2011;20:265–72. doi:10.1517/13543784.2011.547471.

    Article  PubMed  CAS  Google Scholar 

  12. Keefe AD, Pai S, Ellington A. Aptamers as therapeutics. Nature Rev Drug Discov. 2010;9:537–50. doi:10.1038/nrd3141.

    Article  CAS  Google Scholar 

  13. Kratz F, Elsadek B. Clinical impact of serum proteins on drug delivery. J Control Release. 2012;161:429–45. doi:10.1016/j.jconrel.2011.11.028.

    Google Scholar 

  14. Horton S, Walsh C, Emery P. Certolizumab pegol for the treatment of rheumatoid arthritis. Expert Opin Biol Ther. 2012;12:235–49. doi:10.1517/14712598.2012.645533.

    Article  PubMed  CAS  Google Scholar 

  15. Faggioni R. Protein pharmacokinetics and metabolism. New York: Plenum Press; 1992.

    Google Scholar 

  16. Vugmeyster Y, Szklut P, Wensel D, Ross J, Xu X, Awwad M, et al. Complex pharmacokinetics of a humanized antibody against human amyloid beta peptide, anti-abeta Ab2, in nonclinical species. Pharm Res. 2011;28:1696–706. doi:10.1007/s11095-011-0405-x.

    Article  PubMed  CAS  Google Scholar 

  17. Vugmeyster Y, Xu X, Theil FP, Khawli L, 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.

    Article  PubMed  Google Scholar 

  18. van der Graaf P. Influencing early portfolio decision making using preclinical M&S: how early is early and when is it too late? San Francisco: AAPS National Biotechnology Conference; 2010.

    Google Scholar 

  19. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493–507.

    Article  PubMed  CAS  Google Scholar 

  20. Kuo TT, Aveson VG. Neonatal Fc receptor and IgG-based therapeutics. mAbs. 2011;3:422–30. doi:10.4161/mabs.3.5.16983.

    Article  PubMed  Google Scholar 

  21. Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:715–25. doi:10.1038/nri2155.

    Article  PubMed  CAS  Google Scholar 

  22. Andersen JT, Daba MB, Berntzen G, Michaelsen TE, Sandlie I. Cross-species binding analyses of mouse and human neonatal Fc receptor show dramatic differences in immunoglobulin G and albumin binding. J Biol Chem. 2010;285:4826–36.

    Article  PubMed  Google Scholar 

  23. DeSilva B, Smith W, Weiner R, Kelley M, Smolec J, Lee B, et al. Recommendations for the bioanalytical method validation of ligand-binding assays to support pharmacokinetic assessments of macromolecules. Pharm Res. 2003;20:1885–900.

    Article  PubMed  CAS  Google Scholar 

  24. Lee JW, Kelley M, King LE, Yang J, Salimi-Moosavi H, Tang MT, 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. doi:10.1208/s12248-011-9251-3.

    Article  PubMed  CAS  Google Scholar 

  25. Gorovits B. Antidrug antibody assay validation: industry survey results. AAPS J. 2009;11:133–8. doi:10.1208/s12248-009-9091-6.

    Article  PubMed  CAS  Google Scholar 

  26. Rup B, O'Hara D. Critical ligand binding reagent preparation/selection: when specificity depends on reagents. AAPS J. 2007;9:E148–55. doi:10.1208/aapsj0902016.

    Article  PubMed  CAS  Google Scholar 

  27. Yeo LY, Chang HC, Chan PP, Friend JR. Microfluidic devices for bioapplications. Small. 2011;7:12–48. doi:10.1002/smll.201000946.

    Article  PubMed  CAS  Google Scholar 

  28. Mora JR, Obenauer-Kutner L, Vimal Patel V. Application of the Gyrolab platform to ligand-binding assays: a user's perspective. Bioanalysis. 2010;2:1711–5. doi:10.4155/bio.10.122.

    Article  PubMed  CAS  Google Scholar 

  29. Roman J, Qiu J, Dornadula G, Hamuro L, Bakhtiar R, Verch T. Application of miniaturized immunoassays to discovery pharmacokinetic bioanalysis. J Pharmacol Toxicol Methods. 2011;63:227–35. doi:10.1016/j.vascn.2010.12.002.

    Article  PubMed  CAS  Google Scholar 

  30. Ezan E, Dubois M, Becher F. Bioanalysis of recombinant proteins and antibodies by mass spectrometry. Analyst. 2009;134:825–34. doi:10.1039/b819706g.

    Article  PubMed  CAS  Google Scholar 

  31. Li F, Fast D, Michael S. Absolute quantitation of protein therapeutics in biological matrices by enzymatic digestion and LC-MS. Bioanalysis. 2011;3:2459–80. doi:10.4155/bio.11.237.

    Article  PubMed  CAS  Google Scholar 

  32. Domon B, Aebersold R. Mass spectrometry and protein analysis. Science. 2006;312:212–7. doi:10.1126/science.1124619.

    Article  PubMed  CAS  Google Scholar 

  33. Ewles M, Goodwin L. Bioanalytical approaches to analyzing peptides and proteins by LC–MS/MS. Bioanalysis. 2011;3:1379–97. doi:10.4155/bio.11.112.

    Article  PubMed  CAS  Google Scholar 

  34. Cristea IM, Chait BT. Affinity purification of protein complexes. Cold Spring Harbor Laboratory Protocol; 2011.

  35. Schoenherr RM, Zhao L, Whiteaker JR, Feng LC, Li L, Liu L, et al. Automated screening of monoclonal antibodies for SISCAPA assays using a magnetic bead processor and liquid chromatography-selected reaction monitoring-mass spectrometry. J Immunol Methods. 2010;353:49–61. doi:10.1016/j.jim.2009.11.017.

    Article  PubMed  CAS  Google Scholar 

  36. Anderson NL, Anderson NG, Haines LR, Hardie DB, Olafson RW, Pearson TW. Mass spectrometric quantitation of peptides and proteins using stable isotope standards and capture by anti-peptide antibodies (SISCAPA). J Proteome Res. 2004;3:235–44.

    Article  PubMed  CAS  Google Scholar 

  37. Brun V, Dupuis A, Adrait A, Marcellin M, Thomas D, Court M, et al. Isotope-labeled protein standards: toward absolute quantitative proteomics. Molecular & Cell Proteomics: MCP. 2007;6:2139–49. doi:10.1074/mcp.M700163-MCP200.

    Article  CAS  Google Scholar 

  38. Neubert H, Grace C, Rumpel K, James I. Assessing immunogenicity in the presence of excess protein therapeutic using immunoprecipitation and quantitative mass spectrometry. Anal Chem. 2008;80:6907–14. doi:10.1021/ac8005439.

    Article  PubMed  CAS  Google Scholar 

  39. Buxton DB, Antman M, Danthi N, Dilsizian V, Fayad ZA, Garcia MJ, et al. Report of the National Heart, Lung, and Blood Institute working group on the translation of cardiovascular molecular imaging. Circulation. 2011;123:2157–63. doi:10.1161/CIRCULATIONAHA.110.000943.

    Article  PubMed  Google Scholar 

  40. Vasquez KO, Casavant C, Peterson JD. Quantitative whole body biodistribution of fluorescent-labeled agents by non-invasive tomographic imaging. PLos One. 2011;6e20594. doi:10.1371/journal.pone.0020594.

  41. Khalil MM, Tremoleda JL, Bayomy TB, Gsell W. Molecular SPECT imaging: an overview. International J Mol Imaging. 2011;2011:796025. doi:10.1155/2011/796025.

    Google Scholar 

  42. Hillman EM, Amoozegar CB, Wang T, McCaslin AF, Bouchard MB, Mansfield J, et al. In vivo optical imaging and dynamic contrast methods for biomedical research. Philos Trans Series A, Math, Physical, Eng Sci. 2011;369:4620–43. doi:10.1098/rsta.2011.0264.

    Article  Google Scholar 

  43. von Schulthess GK, Schlemmer HP. A look ahead: PET/MR versus PET/CT. Eur J Nucl Med Mol Imaging. 2009;36 Suppl 1:S3–9. doi:10.1007/s00259-008-0940-9.

    Article  Google Scholar 

  44. Vugmeyster Y, DeFranco D, Szklut P, Wang Q, Xu X. Biodistribution of [125I]-labeled therapeutic proteins: application in protein drug development beyond oncology. J Pharm Sci. 2010;99:1028–45. doi:10.1002/jps.21855.

    PubMed  CAS  Google Scholar 

  45. Katsila T, Siskos AP, Tamvakopoulos C. Peptide and protein drugs: the study of their metabolism and catabolism by mass spectrometry. Mass Spectrom Rev. 2012;31:110–33. doi:10.1002/mas.20340.

    Article  PubMed  CAS  Google Scholar 

  46. Reid GE, Stephenson Jr JL, McLuckey SA. Tandem mass spectrometry of ribonuclease A and B: N-linked glycosylation site analysis of whole protein ions. Anal Chem. 2002;74:577–83.

    Article  PubMed  CAS  Google Scholar 

  47. Chen CH. Review of a current role of mass spectrometry for proteome research. Anal Chim Acta. 2008;624:16–36. doi:10.1016/j.aca.2008.06.017.

    Article  PubMed  CAS  Google Scholar 

  48. Wu S, Lourette NM, Tolic N, Zhao R, Robinson EW, Tolmachev AV, et al. An integrated top-down and bottom-up strategy for broadly characterizing protein isoforms and modifications. J Proteome Res. 2009;8:1347–57. doi:10.1021/pr800720d.

    Article  PubMed  CAS  Google Scholar 

  49. Hunt DF, Yates 3rd JR, Shabanowitz J, Winston S, Hauer CR. Protein sequencing by tandem mass spectrometry. Proc Natl Acad Sci U S A. 1986;83:6233–7.

    Article  PubMed  CAS  Google Scholar 

  50. Powers R. Advances in nuclear magnetic resonance for drug discovery. Expert Opin Drug Discov. 2009;4:1077–98. doi:10.1517/17460440903232623.

    Article  PubMed  CAS  Google Scholar 

  51. Lin JH. Pharmacokinetics of biotech drugs: peptides, proteins and monoclonal antibodies. Curr Drug Metabol. 2009;10:661–91.

    Article  CAS  Google Scholar 

  52. Kuo TT, Baker K, Yoshida M, Qiao SW, Aveson VG, Lencer WI, et al. Neonatal Fc receptor: from immunity to therapeutics. J Clin Immunol. 2010;30:777–89. doi:10.1007/s10875-010-9468-4.

    Article  PubMed  CAS  Google Scholar 

  53. Yeung YA, Leabman MK, Marvin JS, Qiu J, Adams CW, Lien S, et al. Engineering human IgG1 affinity to human neonatal Fc receptor: impact of affinity improvement on pharmacokinetics in primates. J Immunol. 2009;182:7663–71. doi:10.4049/jimmunol.0804182.

    Article  PubMed  CAS  Google Scholar 

  54. Wang W, Lu P, Fang Y, Hamuro L, Pittman T, Carr B, et al. Monoclonal antibodies with identical Fc sequences can bind to FcRn differentially with pharmacokinetic consequences. Drug Metabol Dispos: Biol Fate Chem. 2011;39:1469–77. doi:10.1124/dmd.111.039453.

    Article  CAS  Google Scholar 

  55. Thurber GM, Schmidt MM, Wittrup KD. Factors determining antibody distribution in tumors. Trends Pharmacol Sci. 2008;29:57–61. doi:10.1016/j.tips.2007.11.004.

    PubMed  CAS  Google Scholar 

  56. Wittrup KD, Thurber GM, Schmidt MM, Rhoden JJ. Practical theoretic guidance for the design of tumor-targeting agents. Methods Enzymol. 2012;503:255–68. doi:10.1016/B978-0-12-396962-0.00010-0.

    Article  PubMed  CAS  Google Scholar 

  57. Ponce R, Abad L, Amaravadi L, Gelzleichter T, Gore E, Green J, et al. Immunogenicity of biologically-derived therapeutics: assessment and interpretation of nonclinical safety studies. Regulatory Toxicol Pharmacol: RTP. 2009;54:164–82. doi:10.1016/j.yrtph.2009.03.012.

    Article  CAS  Google Scholar 

  58. De Groot AS, McMurry J, Moise L. Prediction of immunogenicity: in silico paradigms, ex vivo and in vivo correlates. Curr Opin Pharmacol. 2008;8:620–6. doi:10.1016/j.coph.2008.08.002.

    Article  PubMed  Google Scholar 

  59. Stas P, Lasters I. Strategies for preclinical immunogenicity assessment of protein therapeutics. IDrugs: Investig Drugs J. 2009;12:169–73.

    CAS  Google Scholar 

  60. Brinks V, Jiskoot W, Schellekens H. Immunogenicity of therapeutic proteins: the use of animal models. Pharm Res. 2011;28:2379–85. doi:10.1007/s11095-011-0523-5.

    Article  PubMed  CAS  Google Scholar 

  61. Kumar S, Singh SK, Wang XL, Rup B, Gill D. Coupling of aggregation and immunogenicity in biotherapeutics: T- and B-cell immune epitopes may contain aggregation-prone regions. Pharm Res. 2011;28:949–61. doi:10.1007/s11095-011-0414-9.

    Article  PubMed  CAS  Google Scholar 

  62. Vita R, Zarebski L, Greenbaum JA, Emami H, Hoof I, Salimi N, et al. The immune epitope database 2.0. Nucleic Acids Res. 2010;38(Database issue):D854–62. doi:10.1093/nar/gkp1004.

    Article  PubMed  CAS  Google Scholar 

  63. Gorovits B. Immunogenicity: prediction, detection and effective assay development. Bioanalysis. 2010;2:1539–45. doi:10.4155/bio.10.121.

    Article  PubMed  CAS  Google Scholar 

  64. Koren E, De Groot AS, Jawa V, Beck KD, Boone T, Rivera D, et al. Clinical validation of the "in silico" prediction of immunogenicity of a human recombinant therapeutic protein. Clin Immunol. 2007;124:26–32. doi:10.1016/j.clim.2007.03.544.

    Article  PubMed  CAS  Google Scholar 

  65. Hernandez-Fuentes MP, Salama A. In vitro assays for immune monitoring in transplantation. Methods Mol Biol. 2006;333:269–90.

    PubMed  CAS  Google Scholar 

  66. Wullner D, Zhou L, Bramhall E, Kuck A, Goletz TJ, Swanson S, et al. Considerations for optimization and validation of an in vitro PBMC derived T cell assay for immunogenicity prediction of biotherapeutics. Clin Immunol. 2010;137:5–14. doi:10.1016/j.clim.2010.06.018.

    Article  PubMed  CAS  Google Scholar 

  67. Cohen T, Moise L, Ardito M, Martin W, De Groot AS. A method for individualizing the prediction of immunogenicity of protein vaccines and biologic therapeutics: individualized T cell epitope measure (iTEM). J Biomed Biotechnol. 2010. doi:10.1155/2010/961752.

  68. Frank R, Hargreaves R. Clinical biomarkers in drug discovery and development. Nature Rev Drug Discov. 2003;2:566–80. doi:10.1038/nrd1130.

    Article  CAS  Google Scholar 

  69. Taube SE, Clark GM, Dancey JE, McShane LM, Sigman CC, Gutman SI. A perspective on challenges and issues in biomarker development and drug and biomarker codevelopment. J Natl Cancer Inst. 2009;101:1453–63. doi:10.1093/jnci/djp334.

    Article  PubMed  Google Scholar 

  70. Lee JW. Method validation and application of protein biomarkers: basic similarities and differences from biotherapeutics. Bioanalysis. 2009;1:1461–74. doi:10.4155/Bio.09.130.

    Article  PubMed  CAS  Google Scholar 

  71. Huttenhain R, Malmstrom J, Picotti P, Aebersold R. Perspectives of targeted mass spectrometry for protein biomarker verification. Curr Opin Chem Biol. 2009;13:518–25. doi:10.1016/j.cbpa.2009.09.014.

    Article  PubMed  Google Scholar 

  72. Caprioli RM, Farmer TB, Gile J. Molecular imaging of biological samples: localization of peptides and proteins using MALDI-TOF MS. Anal Chem. 1997;69:4751–60.

    Article  PubMed  CAS  Google Scholar 

  73. Seeley EH, Schwamborn K, Caprioli RM. Imaging of intact tissue sections: moving beyond the microscope. J Biol Chem. 2011;286:25459–66. doi:10.1074/jbc.R111.225854.

    Article  PubMed  CAS  Google Scholar 

  74. Cazares LH, Troyer DA, Wang B, Drake RR, Semmes OJ. MALDI tissue imaging: from biomarker discovery to clinical applications. Anal Bioanal Chem. 2011;401:17–27. doi:10.1007/s00216-011-5003-6.

    Article  PubMed  CAS  Google Scholar 

  75. McDonnell LA, Corthals GL, Willems SM, van Remoortere A, van Zeijl RJ, Deelder AM. Peptide and protein imaging mass spectrometry in cancer research. Journal of proteomics. 2010;73:1921–44. doi:10.1016/j.jprot.2010.05.007.

    Article  PubMed  CAS  Google Scholar 

  76. Leiser SC, Dunlop J, Bowlby MR, Devilbiss DM. Aligning strategies for using EEG as a surrogate biomarker: a review of preclinical and clinical research. Biochem Pharmacol. 2011;81:1408–21. doi:10.1016/j.bcp.2010.10.002.

    Article  PubMed  CAS  Google Scholar 

  77. Polson AG, Ho WY, Ramakrishnan V. Investigational antibody–drug conjugates for hematological malignancies. Expert Opin Invest Drugs. 2011;20:75–85. doi:10.1517/13543784.2011.539557.

    Article  CAS  Google Scholar 

  78. Herbertson RA, Tebbutt NC, Lee FT, MacFarlane DJ, Chappell B, Micallef N, et al. Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers. Clin Cancer Res. 2009;15:6709–15. doi:10.1158/1078-0432.CCR-09-0536.

    Article  PubMed  CAS  Google Scholar 

  79. Wang MM, Defranco D, Wright K, Quazi S, Spencer-Pierce J, et al. Decreased exposure of Peptide X in Zn formulation after subcutaneous dosing and in vitro metabolism in skin. AAPS J. 2011;13(S1):M1086.

    Google Scholar 

  80. Pardridge WM, Boado RJ. Reengineering biopharmaceuticals for targeted delivery across the blood–brain barrier. Methods Enzymol. 2012;503:269–92. doi:10.1016/B978-0-12-396962-0.00011-2.

    Article  PubMed  CAS  Google Scholar 

  81. Pardridge WM. Biologic TNFalpha-inhibitors that cross the human blood–brain barrier. Bioeng Bugs. 2010;1:231–4. doi:10.4161/bbug.1.4.12105.

    Article  PubMed  Google Scholar 

  82. U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for industry: nonclinical safety evaluation of drug or biologic combinations. 2006. http://www.fda.gov/OHRMS/DOCKETS/98fr/05d-0004-gdl0002.pdf.

  83. Lee JI, Zhang L, Men AY, Kenna LA, Huang SM. CYP-mediated therapeutic protein–drug interactions: clinical findings, proposed mechanisms and regulatory implications. Clin Pharmacokinet. 2010;49:295–310. doi:10.2165/11319980-000000000-00000.

    Article  PubMed  CAS  Google Scholar 

  84. Girish S, Martin SW, Peterson MC, Zhang LK, Zhao H, Balthasar J, et al. AAPS workshop report: strategies to address therapeutic protein–drug interactions during clinical development. AAPS J. 2011;13:405–16. doi:10.1208/s12248-011-9285-6.

    Article  PubMed  CAS  Google Scholar 

  85. Park J-H, Davis S, Yoon Y-K, Prausnitz MR, Allen MG (eds). Micromachined biodegradable microstructures. Proc IEEE Microelectromechanical Systems Conference. 2003; 371–4.

  86. Webb JL, Cullifer Jr RE, Lee D. Market trends of injectable drug delivery systems. J Med Mark. 2011;11:237–43. doi:10.1177/1745790411412241.

    Article  Google Scholar 

  87. Shi J, Votruba AR, Farokhzad OC, Langer R. Nanotechnology in drug delivery and tissue engineering: from discovery to applications. Nano Lett. 2010;10:3223–30. doi:10.1021/nl102184c.

    Article  PubMed  CAS  Google Scholar 

  88. van der Laan JW, Brightwell J, McAnulty P, Ratky J, Stark C. Regulatory acceptability of the minipig in the development of pharmaceuticals, chemicals and other products. J Pharmacol Toxicol Methods. 2010;62:184–95. doi:10.1016/j.vascn.2010.05.005.

    Article  PubMed  Google Scholar 

  89. Roger SD. Biosimilars: current status and future directions. Expert Opin Biol Ther. 2010;10:1011–8. doi:10.1517/14712591003796553.

    Article  PubMed  CAS  Google Scholar 

  90. Dranitsaris G, Amir E, Dorward K. Biosimilars of biological drug therapies: regulatory, clinical and commercial considerations. Drugs. 2011;71:1527–36. doi:10.2165/11593730-000000000-00000.

    Article  PubMed  CAS  Google Scholar 

  91. Minghetti P, Rocco P, Cilurzo F, Del Vecchio L, Locatelli F. The regulatory framework of biosimilars in the European Union. Drug Discov Today. 2012;17:63–70. doi:10.1016/j.drudis.2011.08.001.

    Article  PubMed  Google Scholar 

  92. Woodcock J, Griffin J, Behrman R, Cherney B, Crescenzi T, Fraser B, et al. The FDA's assessment of follow-on protein products: a historical perspective. Nature Rev Drug Discov. 2007;6:437–42. doi:10.1038/nrd2307.

    Article  Google Scholar 

  93. Chirino AJ, Mire-Sluis A. Characterizing biological products and assessing comparability following manufacturing changes. Nat Biotechnol. 2004;22:1383–91. doi:10.1038/nbt1030.

    Article  PubMed  CAS  Google Scholar 

  94. Brambell FW. The transmission of immunity from mother to young and the catabolism of immunoglobulins. Lancet. 1966;2:1087–93.

    Article  PubMed  CAS  Google Scholar 

  95. Redman DR. Prenatal influence on immunocompetence of the neonate. J Anim Sci. 1979;49:258–67.

    PubMed  CAS  Google Scholar 

  96. Kane SV, Acquah LA. Placental transport of immunoglobulins: a clinical review for gastroenterologists who prescribe therapeutic monoclonal antibodies to women during conception and pregnancy. Am J Gastroenterol. 2009;104:228–33. doi:10.1038/ajg.2008.71.

    Article  PubMed  CAS  Google Scholar 

  97. Chaparro M, Gisbert JP. Transplacental transfer of immunosuppressants and biologics used for the treatment of inflammatory bowel disease. Curr Pharm Biotechnol. 2011;12:765–73.

    PubMed  CAS  Google Scholar 

  98. Pentsuk N, van der Laan JW. An interspecies comparison of placental antibody transfer: new insights into developmental toxicity testing of monoclonal antibodies. Birth Defects Res Part B, Dev Reprod Toxicol. 2009;86:328–44. doi:10.1002/bdrb.20201.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors would like to thank Jennifer Spencer-Pierce, David DeFranco, Jianqing Chen, Mengmeng Wang, Kathy Laws, Shakey Quazi, Josef Olzer, Lisa Dyleski, Allison Joyce, Rosemery Lawrence-Henderson, Beth Leary, Mania Kavosi, Chris Shea, Jeremy Wellen, Mauricio Leal, Chengjie Ji, Bonnie Rup, Wenwei Huang, and Krishna Balakrishnan for their contributions to this manuscript. The authors also would like to acknowledge the support and contributions of Andover Comparative Medicine and Protein Formulation Group, Pfizer Inc.

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  1. National Center for Translational Therapeutics, National Institutes of Health, 9800 Medical Center Dr, Rockville, Maryland, 20850, USA

    Xin Xu

  2. Pharmacokinetics, Dynamics and Metabolism, Pfizer, Andover, Massachusetts, 01810, USA

    Yulia Vugmeyster

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Correspondence to Xin Xu.

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Guest Editors: Craig Svensson, Joseph Balthasar, and Frank-Peter Theil

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Xu, X., Vugmeyster, Y. Challenges and Opportunities in Absorption, Distribution, Metabolism, and Excretion Studies of Therapeutic Biologics. AAPS J 14, 781–791 (2012). https://doi.org/10.1208/s12248-012-9388-8

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