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Introduction to High-Concentration Proteins

  • Wei Wang
  • Arun Alphonse Ignatius
  • Satoshi Ohtake
  • Teng-Chieh Yang
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 38)

Abstract

Monoclonal antibodies (mAbs) have become a major class in protein therapeutics. Many mAbs require development at high concentrations, due to the high dose required for efficacy and patient-preferred self-administration through subcutaneous injection, which is oftentimes limited by dosing volume. Development of high-concentration protein products, however, has been associated with two major challenges—high solution viscosity and enhanced aggregation tendency. These challenges and the relevant strategies to overcome them are discussed herein, and future directions in the development of high-concentration products are proposed.

Keywords

Formulation Viscosity Aggregation Stability Administration 

References

  1. 1.
    Allmendinger A, Fischer S, Huwyler B, Mahler HC, Schwarb E, Zarraga IE, Mueller R. Rheological characterization and injection forces of concentrated protein formulations: an alternative predictive model for non-Newtonian solutions. Eur J Pharm Biopharm. 2014;87(2):318–28.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    America, PRAMO. “Biologics 2013 Report”; 2013.Google Scholar
  3. 3.
    Amidi M, Romeijn SG, Borchard G, Junginger HE, Hennink WE, Jiskoot W. Preparation and characterization of protein-loaded N-trimethyl chitosan nanoparticles as nasal delivery system. J Control Release. 2006;111(1–2):107–16.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Arvinte T, Palais C, Green-Trexler E, Gregory S, Mach H, Narasimhan C, Shameem M. Aggregation of biopharmaceuticals in human plasma and human serum: implications for drug research and development. MAbs. 2013;5(3):491–500.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Ayensu I, Mitchell JC, Boateng JS. In vitro characterisation of chitosan based xerogels for potential buccal delivery of proteins. Carbohydr Polym. 2012;89(3):935–41.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Bajaj H, Sharma VK, Badkar A, Zeng D, Nema S, Kalonia DS. Protein structural conformation and not second virial coefficient relates to long-term irreversible aggregation of a monoclonal antibody and ovalbumin in solution. Pharm Res. 2006;23(6):1382–94.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Bee JS, Stevenson JL, Mehta B, Svitel J, Pollastrini J, Platz R, Freund E, Carpenter JF, Randolph TW. Response of a concentrated monoclonal antibody formulation to high shear. Biotechnol Bioeng. 2009;103(5):936–43.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Bethea D, Wu SJ, Luo J, Hyun L, Lacy ER, Teplyakov A, Jacobs SA, O’Neil KT, Gilliland GL, Feng Y. Mechanisms of self-association of a human monoclonal antibody CNTO607. Protein Eng Des Sel. 2012;25(10):531–7.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Binabaji E, Rao S, Zydney AL. The osmotic pressure of highly concentrated monoclonal antibody solutions: effect of solution conditions. Biotechnol Bioeng. 2014;111(3):529–36.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Bivas-Benita M, Lin MY, Bal SM, van Meijgaarden KE, Franken KL, Friggen AH, Junginger HE, Borchard G, Klein MR, Ottenhoff TH. Pulmonary delivery of DNA encoding Mycobacterium tuberculosis latency antigen Rv1733c associated to PLGA-PEI nanoparticles enhances T cell responses in a DNA prime/protein boost vaccination regimen in mice. Vaccine. 2009;27(30):4010–7.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Bookbinder LH, Kundu A, Frost GI. (2010) Soluble hyaluronidase glycoprotein (shasegp), process for preparing the same, uses and pharmaceutical compositions comprising thereof; 2010.Google Scholar
  12. 12.
    Borwankar AU, Dinin AK, Laber JR, Twu A, Wilson BK, Maynard JA, Truskett TM, Johnston KP. Tunable equilibrium nanocluster dispersions at high protein concentrations. Soft Matter. 2013;9(6):1766–71.CrossRefGoogle Scholar
  13. 13.
    Bowen M, Armstrong N, Maa Y-F. Investigating high-concentration monoclonal antibody powder suspension in nonaqueous suspension vehicles for subcutaneous injection. J Pharm Sci. 2012;101(12):4433–43.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Broersen K, Weijers M, de Groot J, Hamer RJ, de Jongh HH. Effect of protein charge on the generation of aggregation-prone conformers. Biomacromolecules. 2007;8(5):1648–56.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Burckbuchler V, Mekhloufi G, Giteau AP, Grossiord JL, Huille S, Agnely F. Rheological and syringeability properties of highly concentrated human polyclonal immunoglobulin solutions. Eur J Pharm Biopharm. 2010;76(3):351–6.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Carpenter JF, Randolph TW, Jiskoot W, Crommelin DJ, Middaugh CR, Winter G, Fan YX, Kirshner S, Verthelyi D, Kozlowski S, Clouse KA, Swann PG, Rosenberg A, Cherney B. Overlooking subvisible particles in therapeutic protein products: gaps that may compromise product quality. J Pharm Sci. 2008.  https://doi.org/10.1002/jps.21530.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Casaz P, Boucher E, Wollacott R, Pierce BG, Rivera R, Sedic M, Ozturk S, Thomas W, Wang Y. Resolving self-association of a therapeutic antibody by formulation optimization and molecular approaches. MAbs. 2014;6:1533–9.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Chaudhri A, Zarraga IE, Kamerzell TJ, Brandt JP, Patapoff TW, Shire SJ, Voth GA. Coarse-grained modeling of the self-association of therapeutic monoclonal antibodies. J Phys Chem B. 2012;116(28):8045–57.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Chaudhri A, Zarraga IE, Yadav S, Patapoff TW, Shire SJ, Voth GA. The role of amino acid sequence in the self-association of therapeutic monoclonal antibodies: insights from coarse-grained modeling. J Phys Chem B. 2013;117(5):1269–79.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Cheng W, Joshi SB, Jain NK, He F, Kerwin BA, Volkin DB, Middaugh CR. Linking the solution viscosity of an IgG2 monoclonal antibody to its structure as a function of pH and temperature. J Pharm Sci. 2013;102(12):4291–304.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Chi EY, Krishnan S, Kendrick BS, Chang BS, Carpenter JF, Randolph TW. Roles of conformational stability and colloidal stability in the aggregation of recombinant human granulocyte colony-stimulating factor. Protein Sci. 2003;12(5):903–13.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Connolly BD, Petry C, Yadav S, Demeule B, Ciaccio N, Moore JM, Shire SJ, Gokarn YR. Weak interactions govern the viscosity of concentrated antibody solutions: high-throughput analysis using the diffusion interaction parameter. Biophys J. 2012;103(1):69–78.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Daugherty AL, Mrsny RJ. Formulation and delivery issues for monoclonal antibody therapeutics. Adv Drug Deliv Rev. 2006;58(5–6):686–706.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    DeLano WL, Ultsch MH, de Vos AM, Wells JA. Convergent solutions to binding at a protein-protein interface. Science. 2000;287(5456):1279–83.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    des Rieux A, Fievez V, Garinot M, Schneider YJ, Preat V. Nanoparticles as potential oral delivery systems of proteins and vaccines: a mechanistic approach. J Control Release. 2006;116(1):1–27.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Rickwood S, DiBiase S. Searching for terra firma in biosimilars and non-original biologics market: insight for the coming decade of change. 2013. http://www.imshealth.com/deployedfiles/imshealth/Global/Content/Healthcare/Life%20Sciences%20Solutions/Generics/IMSH_Biosimilars_WP.pdf, IMS, p. 1–24.
  27. 27.
    du Plessis LH, Kotze AF, Junginger HE. Nasal and rectal delivery of insulin with chitosan and N-trimethyl chitosan chloride. Drug Deliv. 2010;17(6):399–407.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Du W, Klibanov AM. Hydrophobic salts markedly diminish viscosity of concentrated protein solutions. Biotechnol Bioeng. 2011;108(3):632–6.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Elcock AH, McCammon JA. Calculation of weak protein-protein interactions: the pH dependence of the second virial coefficient. Biophys J. 2001;80(2):613–25.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Esfandiary R, Hayes DB, Parupudi A, Casas-Finet J, Bai S, Samra HS, Shah AU, Satish HA. A systematic multitechnique approach for detection and characterization of reversible self-association during formulation development of therapeutic antibodies. J Pharm Sci. 2013;102(1):62–72.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Esfandiary R, Parupudi A, Casas-Finet J, Gadre D, Sathish H. (2014) Mechanism of reversible self-association of a monoclonal antibody: role of electrostatic and hydrophobic interactions. J Pharm Sci; 2014.Google Scholar
  32. 32.
    Fathallah AM, Balu-Iyer SV. Anatomical, physiological, and experimental factors affecting the bioavailability of sc-administered large biotherapeutics. J Pharm Sci. 2015;104(2):301–6.PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Filipe V, Que I, Carpenter JF, Lowik C, Jiskoot W. In vivo fluorescence imaging of IgG1 aggregates after subcutaneous and intravenous injection in mice. Pharm Res. 2014;31(1):216–27.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Fischer H, Polikarpov I, Craievich AF. Average protein density is a molecular-weight-dependent function. Protein Sci. 2004;13(10):2825–8.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Galush WJ, Le LN, Moore JMR. Viscosity behavior of high-concentration protein mixtures. J Pharm Sci. 2012;101(3):1012–20.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Geng SB, Cheung JK, Narasimhan C, Shameem M, Tessier PM. Improving monoclonal antibody selection and engineering using measurements of colloidal protein interactions. J Pharm Sci. 2014;103(11):3356–63.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Glazer WM, Maynard C, Berkman CS. Injection site leakage of depot neuroleptics: intramuscular versus subcutaneous injection. J Clin Psychiatry. 1987;48(6):237–9.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Godfrin PD, Castaneda-Priego R, Liu Y, Wagner NJ. Intermediate range order and structure in colloidal dispersions with competing interactions. J Chem Phys. 2013;139(15):154904.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Grenha A, Remunan-Lopez C, Carvalho EL, Seijo B. Microspheres containing lipid/chitosan nanoparticles complexes for pulmonary delivery of therapeutic proteins. Eur J Pharm Biopharm. 2008;69(1):83–93.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Guo J, Harn N, Robbins A, Dougherty R, Middaugh CR. Stability of helix-rich proteins at high concentrations. Biochemistry. 2006;45(28):8686–96.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Guo Z, Chen A, Nassar R, Helk B, Mueller C, Tang Y, Gupta K, Klibanov A. Structure-activity relationship for hydrophobic salts as viscosity-lowering excipients for concentrated solutions of monoclonal antibodies. Pharm Res. 2012;29(11):3102–9.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Harn N, Allan C, Oliver C, Middaugh CR. Highly concentrated monoclonal antibody solutions: direct analysis of physical structure and thermal stability. J Pharm Sci. 2007;96(3):532–46.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    He F, Woods CE, Litowski JR, Roschen LA, Gadgil HS, Razinkov VI, Kerwin BA. Effect of sugar molecules on the viscosity of high concentration monoclonal antibody solutions. Pharm Res. 2011;28(7):1552–60.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Holm LS, McUmber A, Rasmussen JE, Obiols-Rabasa M, Thulstrup PW, Kasimova MR, Randolph TW, van de Weert M. The effect of protein PEGylation on physical stability in liquid formulation. J Pharm Sci. 2014;103(10):3043–54.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Hou YW, Chan MH, Hsu HR, Liu BR, Chen CP, Chen HH, Lee HJ. Transdermal delivery of proteins mediated by non-covalently associated arginine-rich intracellular delivery peptides. Exp Dermatol. 2007;16(12):999–1006.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
  47. 47.
  48. 48.
  49. 49.
  50. 50.
  51. 51.
  52. 52.
  53. 53.
  54. 54.
  55. 55.
  56. 56.
  57. 57.
    Inoue N, Takai E, Arakawa T, Shiraki K. Arginine and lysine reduce the high viscosity of serum albumin solutions, for pharmaceutical injection. J Biosci Bioeng. 2014;117(5):539–43.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Inoue N, Takai E, Arakawa T, Shiraki K. Specific decrease in solution viscosity of antibodies by arginine for therapeutic formulations. Mol Pharm. 2014;11(6):1889–96.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Iqbal M, Lin W, Jabbal-Gill I, Davis SS, Steward MW, Illum L. Nasal delivery of chitosan-DNA plasmid expressing epitopes of respiratory syncytial virus (RSV) induces protective CTL responses in BALB/c mice. Vaccine. 2003;21(13–14):1478–85.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Iwura T, Fukuda J, Yamazaki K, Arisaka F. Conformational stability, reversibility and heat-induced aggregation of alpha-1-acid glycoprotein. J Biochem. 2014;156(6):345–52.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Jimenez M, Rivas G, Minton AP. Quantitative characterization of weak self-association in concentrated solutions of immunoglobulin G via the measurement of sedimentation equilibrium and osmotic pressure. Biochemistry. 2007;46(28):8373–8.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Johnston KP, Maynard JA, Truskett TM, Borwankar AU, Miller MA, Wilson BK, Dinin AK, Khan TA, Kaczorowski KJ. Concentrated dispersions of equilibrium protein nanoclusters that reversibly dissociate into active monomers. ACS Nano. 2012;6(2):1357–69.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Jorgensen JT, Romsing J, Rasmussen M, Moller-Sonnergaard J, Vang L, Musaeus L. Pain assessment of subcutaneous injections. Ann Pharmacother. 1996;30(7–8):729–32.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Kanai S, Liu J, Patapoff TW, Shire SJ. Reversible self-association of a concentrated monoclonal antibody solution mediated by Fab-Fab interaction that impacts solution viscosity. J Pharm Sci. 2008;97(10):4219–27.PubMedCrossRefGoogle Scholar
  65. 65.
    Kijanka G, Prokopowicz M, Schellekens H, Brinks V. Influence of aggregation and route of injection on the biodistribution of mouse serum albumin. PLoS ONE. 2014;9(1):e85281.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Kinnunen HM, Mrsny RJ. Improving the outcomes of biopharmaceutical delivery via the subcutaneous route by understanding the chemical, physical and physiological properties of the subcutaneous injection site. J Control Release. 2014;182:22–32.PubMedCrossRefGoogle Scholar
  67. 67.
    Krulevitch P, Wilk R, O’Connor S, Zhao M, Sieh Z, Savage D. Medical device mechanical pump. Google Patents; 2009.Google Scholar
  68. 68.
    Kwaambwa HM, Goodwin JW, Hughs RW, Reynolds PA. Visocisity, molecular weight and concentration relationships at 298 K of low molecular weight cis-polyisoprene in a good solvent. Colloids Surf, A. 2007;294:14–9.CrossRefGoogle Scholar
  69. 69.
    Laue T. Proximity energies: a framework for understanding concentrated solutions. J Mol Recognit. 2012;25(3):165–73.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Lee H, Kirchmeier M, Mach H. Monoclonal antibody aggregation intermediates visualized by atomic force microscopy. J Pharm Sci. 2011;100:416–23.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Lee WC, Balu S, Cobden D, Joshi AV, Pashos CL. (2006) Medication adherence and the associated health-economic impact among patients with type 2 diabetes mellitus converting to insulin pen therapy: an analysis of third-party managed care claims data. Clin Ther. 2006; 28(10):1712–25; discussion 1710-1711.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Li L, Kumar S, Buck PM, Burns C, Lavoie J, Singh SK, Warne NW, Nichols P, Luksha N, Boardman D. Concentration dependent viscosity of monoclonal antibody solutions: explaining experimental behavior in terms of molecular properties. Pharm Res. 2014;31(11):3161–78.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Lilyestrom WG, Yadav S, Shire SJ, Scherer TM. Monoclonal antibody self-association, cluster formation, and rheology at high concentrations. J Phys Chem B. 2013;117(21):6373–84.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Lin YH, Liang HF, Chung CK, Chen MC, Sung HW. Physically crosslinked alginate/N, O-carboxymethyl chitosan hydrogels with calcium for oral delivery of protein drugs. Biomaterials. 2005;26(14):2105–13.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Liu J, Nguyen MD, Andya JD, Shire SJ. Reversible self-association increases the viscosity of a concentrated monoclonal antibody in aqueous solution. J Pharm Sci. 2005;94(9):1928–40.PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Mahler H-C, Friess W, Grauschopf U, Kiese S. Protein aggregation: pathways, induction factors and analysis. J Pharm Sci. 2009;98(9):2909–34.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    McAllister DV, Wang PM, Davis SP, Park JH, Canatella PJ, Allen MG, Prausnitz MR. Microfabricated needles for transdermal delivery of macromolecules and nanoparticles: fabrication methods and transport studies. Proc Natl Acad Sci USA. 2003;100(24):13755–60.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Miller MA, Engstrom JD, Ludher BS, Johnston KP. Low viscosity highly concentrated injectable nonaqueous suspensions of lysozyme microparticles. Langmuir. 2010;26(2):1067–74.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Minton AP. Macromolecular crowding. Curr Biol. 2006;16(8):R269–71.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Moeller EH, Jorgensen L. Alternative routes of administration for systemic delivery of protein pharmaceuticals. Drug Discov Today Technol. 2008;5(2–3):e89–94.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Morishita M, Barichello JM, Takayama K, Chiba Y, Tokiwa S, Nagai T. Pluronic F-127 gels incorporating highly purified unsaturated fatty acids for buccal delivery of insulin. Int J Pharm. 2001;212(2):289–93.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Neal BL, Asthagiri D, Lenhoff AM. Molecular origins of osmotic second virial coefficients of proteins. Biophys J. 1998;75(5):2469–77.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Neergaard MS, Kalonia DS, Parshad H, Nielsen AD, Moller EH, van de Weert M. Viscosity of high concentration protein formulations of monoclonal antibodies of the IgG1 and IgG4 subclass—prediction of viscosity through protein-protein interaction measurements. Eur J Pharm Sci. 2013;49(3):400–10.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Nezlin R. Interactions between immunoglobulin G molecules. Immunol Lett. 2010;132(1–2):1–5.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Nishi H, Miyajima M, Nakagami H, Noda M, Uchiyama S, Fukui K. Phase separation of an IgG1 antibody solution under a low ionic strength condition. Pharm Res. 2010;27(7):1348–60.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Nishi H, Miyajima M, Wakiyama N, Kubota K, Hasegawa J, Uchiyama S, Fukui K. Fc domain mediated self-association of an IgG1 monoclonal antibody under a low ionic strength condition. J Biosci Bioeng. 2011;112(4):326–32.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Pan Y, Cheng R-S. A novel interpretation of concentration dependence of viscosity of dilute polymer solution. Chin J Polym Sci. 2000;18:57–67.Google Scholar
  88. 88.
    Pathak JA, Sologuren RR, Narwal R. Do clustering monoclonal antibody solutions really have a concentration dependence of viscosity? Biophys J. 2013;104:913–23.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Patton JS, Foster L, Platz RM. (1999) Methods and compositions for pulmonary delivery of insulin. Google Patents; 1999.Google Scholar
  90. 90.
    Pavlou AK, Belsey MJ. The therapeutic antibodies market to 2008. Eur J Pharm Biopharm. 2005;59(3):389–96.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Perchiacca JM, Lee CC, Tessier PM. Optimal charged mutations in the complementarity-determining regions that prevent domain antibody aggregation are dependent on the antibody scaffold. Protein Eng Des Sel. 2014;27(2):29–39.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Pharma, E. World Preview 2013, Outlook to 2018; 2013.Google Scholar
  93. 93.
    Rao SV, Shao J. Self-nanoemulsifying drug delivery systems (SNEDDS) for oral delivery of protein drugs: I. Formulation development. Int J Pharm. 2008;362(1–2):2–9.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Rathore N, Pranay P, Bernacki J, Eu B, Ji W, Walls E. Characterization of protein rheology and delivery forces for combination products. J Pharm Sci. 2012;101(12):4472–80.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8(3):E501–7.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Roux KH, Tankersley DL. A view of the human idiotypic repertoire. Electron microscopic and immunologic analyses of spontaneous idiotype-anti-idiotype dimers in pooled human IgG. J Immunol. 1990;144(4):1387–95.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Rubio-Hernandez FJ, Carrique F, Ruiz-Reina E. The primary electroviscous effect in colloidal suspensions. Adv Colloid Interface Sci. 2004;107(1):51–60.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Saito S, Hasegawa J, Kobayashi N, Kishi N, Uchiyama S, Fukui K. Behavior of monoclonal antibodies: relation between the second virial coefficient (B (2)) at low concentrations and aggregation propensity and viscosity at high concentrations. Pharm Res. 2012;29(2):397–410.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Salinas BA, Sathish HA, Bishop SM, Harn N, Carpenter JF, Randolph TW. Understanding and modulating opalescence and viscosity in a monoclonal antibody formulation. J Pharm Sci. 2010;99(1):82–93.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Saluja A, Fesinmeyer RM, Hogan S, Brems DN, Gokarn YR. Diffusion and sedimentation interaction parameters for measuring the second virial coefficient and their utility as predictors of protein aggregation. Biophys J. 2010;99(8):2657–65.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Saluja A, Kalonia DS. Nature and consequences of protein-protein interactions in high protein concentration solutions. Int J Pharm. 2008;358(1–2):1–15.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Schaepelynck P, Darmon P, Molines L, Jannot-Lamotte MF, Treglia C, Raccah D. Advances in pump technology: insulin patch pumps, combined pumps and glucose sensors, and implanted pumps. Diabetes Metab. 2011;37(Suppl 4):S85–93.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Scherer TM, Liu J, Shire SJ, Minton AP. Intermolecular interactions of IgG1 monoclonal antibodies at high concentrations characterized by light scattering. J Phys Chem B. 2010;114(40):12948–57.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Shieu W, Torhan SA, Chan E, Hubbard A, Gikanga B, Stauch OB, Maa YF. Filling of high-concentration monoclonal antibody formulations into pre-filled syringes: filling parameter investigation and optimization. PDA J Pharm Sci Technol. 2014;68(2):153–63.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Shire SJ, Shahrokh Z, Liu J. Challenges in the development of high protein concentration formulations. J Pharm Sci. 2004;93(6):1390–402.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Singh SN, Yadav S, Shire SJ, Kalonia DS. Dipole-dipole interaction in antibody solutions: correlation with viscosity behavior at high concentration. Pharm Res. 2014;31:2549–58.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Song C, Wang P, Makse HA. A phase diagram for jammed matter. Nature. 2008;453(7195):629–32.PubMedCrossRefPubMedCentralGoogle Scholar
  108. 108.
    Srinivasan C, Weight AK, Bussemer T, Klibanov AM. Non-aqueous suspensions of antibodies are much less viscous than equally concentrated aqueous solutions. Pharm Res. 2013;30(7):1749–57.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Stradner A, Sedgwick H, Cardinaux F, Poon WC, Egelhaaf SU, Schurtenberger P. Equilibrium cluster formation in concentrated protein solutions and colloids. Nature. 2004;432(7016):492–5.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Sule SV, Cheung JK, Antochshuk V, Bhalla AS, Narasimhan C, Blaisdell S, Shameem M, Tessier PM. Solution pH that minimizes self-association of three monoclonal antibodies is strongly dependent on ionic strength. Mol Pharm. 2012;9(4):744–51.PubMedCrossRefPubMedCentralGoogle Scholar
  111. 111.
    Sule SV, Sukumar M, Weiss WF, Marcelino-Cruz AM, Sample T, Tessier PM. High-throughput analysis of concentration-dependent antibody self-association. Biophys J. 2011;101(7):1749–57.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Tice TR, Gilley RM, Eldridge JH, Staas JK. (1998) Method for oral or rectal delivery of microencapsulated vaccines and compositions therefor. Google Patents; 1998.Google Scholar
  113. 113.
    Uchiyama S. Liquid formulation for antibody drugs. Biochim Biophys Acta. 2014;1844(11):2041–52.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Valente JJ, Fryksdale BG, Dale DA, Gaertner AL, Henry CS. Screening for physical stability of a Pseudomonas amylase using self-interaction chromatography. Anal Biochem. 2006;357(1):35–42.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Valente JJ, Payne RW, Manning MC, Wilson WW, Henry CS. Colloidal behavior of proteins: effects of the second virial coefficient on solubility, crystallization and aggregation of proteins in aqueous solution. Curr Pharm Biotechnol. 2005;6(6):427–36.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Valente JJ, Verma KS, Manning MC, Wilson WW, Henry CS. Second virial coefficient studies of cosolvent-induced protein self-interaction. Biophys J. 2005;89(6):4211–8.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Wang N, Hu B, Ionescu R, Mach H, Sweeney J, Hamm C, Kirchmeier MJ, Meyer BK. Opalescence of an IgG1 monoclonal antibody formulation is mediated by ionic strength and excipients. BioPharm Int. 2009;22(4):36–47.Google Scholar
  118. 118.
    Wang W, Nema S, Teagarden D. Protein aggregation–pathways and influencing factors. Int J Pharm. 2010;390(2):89–99.PubMedCrossRefPubMedCentralGoogle Scholar
  119. 119.
    Wang W, Singh SK, Li N, Toler MR, King KR, Nema S. Immunogenicity of protein aggregates–concerns and realities. Int J Pharm. 2012;431(1–2):1–11.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Warne NW. Development of high concentration protein biopharmaceuticals: The use of platform approaches in formulation development. Eur J Pharm Biopharm. 2011;78:208–12.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Williams AC, Barry BW. Penetration enhancers. Adv Drug Deliv Rev. 2004;56(5):603–18.PubMedCrossRefPubMedCentralGoogle Scholar
  122. 122.
    Woods JM, Nesta D. (2010) Formulation effects on opalescence of a high-concentration MAb. BioProcess Int. 2010; 48–59.Google Scholar
  123. 123.
    Wu SJ, Luo J, O’Neil KT, Kang J, Lacy ER, Canziani G, Baker A, Huang M, Tang QM, Raju TS, Jacobs SA, Teplyakov A, Gilliland GL, Feng Y. Structure-based engineering of a monoclonal antibody for improved solubility. Protein Eng Des Sel. 2010;23(8):643–51.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Yadav S, Shire SJ, Kalonia DS. Factors affecting the viscosity in high concentration solutions of different monoclonal antibodies. J Pharm Sci. 2010;99(12):4812–29.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Yadav S, Shire SJ, Kalonia DS. Viscosity behavior of high-concentration monoclonal antibody solutions: correlation with interaction parameter and electroviscous effects. J Pharm Sci. 2012;101(3):998–1011.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Yang MX, Shenoy B, Disttler M, Patel R, McGrath M, Pechenov S, Margolin AL. Crystalline monoclonal antibodies for subcutaneous delivery. Proc Natl Acad Sci USA. 2003;100(12):6934–9.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Yearley EJ, Godfrin PD, Perevozchikova T, Zhang H, Falus P, Porcar L, Nagao M, Curtis JE, Gawande P, Taing R, Zarraga IE, Wagner NJ, Liu Y. Observation of small cluster formation in concentrated monoclonal antibody solutions and its implications to solution viscosity. Biophys J. 2014;106:1763–70.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Yearley EJ, Zarraga IE, Shire SJ, Scherer TM, Gokarn Y, Wagner NJ, Liu Y. Small-angle neutron scattering characterization of monoclonal antibody conformations and interactions at high concentrations. Biophys J. 2013;105(3):720–31.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Zarraga IE, Taing R, Zarzar J, Luoma J, Hsiung J, Patel A, Lim FJ. High shear rheology and anisotropy in concentrated solutions of monoclonal antibodies. J Pharm Sci. 2013;102(8):2538–49.PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Wei Wang
    • 1
    • 2
    • 3
  • Arun Alphonse Ignatius
    • 1
  • Satoshi Ohtake
    • 4
  • Teng-Chieh Yang
    • 1
    • 3
  1. 1.PfizerChesterfieldUSA
  2. 2.Bayer U.S. LLCBerkeleyUSA
  3. 3.Regeneron PharmaceuticalsTarrytownUSA
  4. 4.BioTherapeutics Pharmaceutical Sciences, Pharmaceutical R&DPfizerChesterfieldUSA

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