Skip to main content

Advertisement

Log in

Stability of Protein Pharmaceuticals: An Update

  • Expert Review
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

In 1989, Manning, Patel, and Borchardt wrote a review of protein stability (Manning et al., Pharm. Res. 6:903–918, 1989), which has been widely referenced ever since. At the time, recombinant protein therapy was still in its infancy. This review summarizes the advances that have been made since then regarding protein stabilization and formulation. In addition to a discussion of the current understanding of chemical and physical instability, sections are included on stabilization in aqueous solution and the dried state, the use of chemical modification and mutagenesis to improve stability, and the interrelationship between chemical and physical instability.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

REFERENCES

  1. Manning MC, Patel K, Borchardt RT. Stability of protein pharmaceuticals. Pharm Res. 1989;6:903–18.

    CAS  PubMed  Google Scholar 

  2. Doyle HA, Gee RJ, Mamula MJ. Altered immunogenicity of isoaspartate containing proteins. Autoimmunity. 2007;40:131–7.

    CAS  PubMed  Google Scholar 

  3. Lewis UJ, Cheever EV, Hopkins WC. Kinetic study of the deamidation of growth hormone and prolactin. Biochim Biophys Acta. 1970;214:498–508.

    CAS  PubMed  Google Scholar 

  4. Becker GW, Tackitt PM, Bromer WW, Lefeber DS, Riggin RM. Isolation and characterization of a sulfoxide and a desamido derivative of biosynthetic human growth-hormone. Biotechnol Appl Biochem. 1988;10:326–37.

    CAS  PubMed  Google Scholar 

  5. Fisher BV, Porter PB. Stability of bovine insulin. J Pharm Pharmacol. 1981;33:203–6.

    CAS  PubMed  Google Scholar 

  6. Minta JO, Painter RH. Chemical and immunological characterization of the electrophoretic components of the Fc fragment of immunoglobulin G. Immunochemistry. 1972;9:821–32.

    CAS  PubMed  Google Scholar 

  7. Perutz MF, Fogg JH, Fox JA. Mechanism of deamidation of haemoglobin providence Asn. J Mol Biol. 1980;138:669–70.

    CAS  PubMed  Google Scholar 

  8. Robinson AB, Rudd CJ. Deamidation of glutaminyl and asparaginyl residues in peptides and proteins. In: Horcker BL, Stadtman ER, editors. Current topics in cellular regulations, vol. 8. New York: Academic; 1974. p. 247–95.

    Google Scholar 

  9. Wright HT. Nonenzymatic deamidation of asparaginyl and glutaminyl residues in proteins. Crit Rev Biochem Mol Biol. 1991;26:1–52.

    CAS  PubMed  Google Scholar 

  10. Clarke S, Stephenson RC, Lowenson JD. Liability of asparagine and aspartic acid residues in proteins and peptides: spontaneous deamidation and isomerization reactions. In: Ahern TJ, Manning MC, editors. Stability of protein pharmaceuticals, Part A: chemical and physical pathways of protein degradation. New York: Plenum; 1992. p. 1–29.

    Google Scholar 

  11. Wakanar AA, Borchardt RT. Formulation considerations for proteins susceptible to asparagines deamidation and aspartate isomerization. J Pharm Sci. 2006;95:2321–36.

    Google Scholar 

  12. Topp EM, Zhang L, Zhao H, Payne RW, Evans GJ, Manning MC. Chemical instability in peptide and protein pharmaceuticals. In: Jameel F, Hershenson S, editors. Formulation and process development strategies for manufacturing of a biopharmaceutical. New York: Wiley and Sons; 2010. in press.

  13. Aswad DW. Deamidation and isoaspartate formation in peptides and proteins. Boca Raton: CRC Press; 1995.

    Google Scholar 

  14. Robinson NE, Robinson AB. Molecular clocks: deamidation of asparaginyl and glutaminyl residues in peptides and proteins. Cave Junction: Althouse; 2004.

    Google Scholar 

  15. Geiger T, Clarke SJ. Deamidation, isomerization, and racemization at asparaginyl and aspartyl residues in peptides: succinimide-linked reactions that contribute to protein degradation. J Biol Chem. 1987;266:22549–56.

    Google Scholar 

  16. Li B, Borchardt RT, Topp EM, Vander Velde D, Schowen RL. Racemization of an asparagine residue during peptide deamidation. J Am Chem Soc. 2003;125:11486–7.

    CAS  PubMed  Google Scholar 

  17. Dehart MP, Anderson BD. The role of cyclic imide in alternate degradation pathways for asparagine-containing peptides and proteins. J Pharm Sci. 2007;96:2667–85.

    CAS  PubMed  Google Scholar 

  18. Takemoto L, Fujii N, Boyle D. Mechanism of asparagine deamidation during human senile cataractogenesis. Exp Eye Res. 2001;72:559–63.

    CAS  PubMed  Google Scholar 

  19. Scotchler JW, Robinson AB. Deamidation of glutaminyl residues: dependence on pH, temperature, and ionic strength. Anal Biochem. 1974;59:319–22.

    CAS  PubMed  Google Scholar 

  20. Robinson AB, McKerrow JH, Legaz M. Sequence dependent deamidation rates for model peptides of cytochrome-c. Int J Peptide Prot Res. 1974;6:31–5.

    CAS  Google Scholar 

  21. Robinson NE. Protein deamidation. Proc Natl Acad Sci USA. 2002;99:5283–8.

    CAS  PubMed  Google Scholar 

  22. Robinson NE, Robinson AB. Prediction of protein deamidation rates from primary and three-dimensional structure. Proc Natl Acad Sci USA. 2001;98:4367–72.

    CAS  PubMed  Google Scholar 

  23. Robinson NE, Robinson AB. Deamidation of human proteins. Proc Natl Acad Sci USA. 2001;98:12409–13.

    CAS  PubMed  Google Scholar 

  24. Robinson NE, Robinson AB. Prediction of primary structure deamidation rates of asparaginyl and glutaminyl peptides through steric and catalytic effects. J Peptide Res. 2001;63:437–48.

    Google Scholar 

  25. Robinson NE, Robinson ZW, Robison BR, Robinson AL, Robinson JA, Robinson ML, et al. Structure-dependent nonenzymatic deamidation of glutaminyl and asparaginyl pentapeptides. J Peptide Res. 2001;63:426–36.

    Google Scholar 

  26. Chelius D, Rehder DS, Bondarenko PV. Identification and characterization of deamidation sites in the conserved regions of human immunoglobulin gamma antibodies. Anal Chem. 2005;77:6004–11.

    CAS  PubMed  Google Scholar 

  27. Xiao G, Bondarenko PV. Identification and quantification of degradations in the Asp–Asp motifs of a recombinant monoclonal antibody. J Pharm Biomed Anal. 2008;47:23–30.

    CAS  PubMed  Google Scholar 

  28. Li B, Gorman EM, More KD, Williams T, Schowen RL, Topp EM, et al. Effects of acidic N+1 residues on asparagine deamidation rates in solution and in the solid state. J Pharm Sci. 2005;94:666–75.

    CAS  PubMed  Google Scholar 

  29. Tyler-Cross R, Schirch V. Effects of amino acid sequence, buffers, and ionic strength on the rate and mechanism of deamidation of asparagine residues in small peptides. J Biol Chem. 1991;266:22549–56.

    CAS  PubMed  Google Scholar 

  30. Kossiakoff AA. Tertiary structure is a principal determinant to protein deamidation. Science. 1988;240:191–4.

    CAS  PubMed  Google Scholar 

  31. Xie M, Shahrokh Z, Kadkhodayan M, Henzel WJ, Powell MF, Borchardt RT, et al. Asparagine deamidation in recombinant human lymphotoxin: hindrance by three-dimensional structure. J Pharm Sci. 2003;92:869–80.

    CAS  PubMed  Google Scholar 

  32. DeLuna A, Quezada H, Gomez-Puyou A, Gonzalez A. Asparaginyl deamidation in two glutamate dehydrogenase isoenzymes from Saccharomyces cervisiae. Biochem Biophys Res Commun. 2005;328:1083–90.

    CAS  PubMed  Google Scholar 

  33. Stevenson CL, Donland ME, Friedman AR, Borchardt RT. Solution conformation of Leu27 HGRF(1-32)-NH2 and its deamidation products by 2D NMR. Int J Pept Protein Res. 1991;42:24–32.

    Article  Google Scholar 

  34. Kosky AA, Razzaq UO, Treuheit MJ, Brems DN. The effects of α-helix on the stability of Asn residues: deamidation rates in peptides of varying helicity. Protein Sci. 1999;8:2519–23.

    CAS  PubMed  Google Scholar 

  35. Rivers J, McDonald L, Edwards IJ, Beynon RJ. Asparagine deamidation and the role of higher order protein structure. J Proteome Res. 2008;7:921–7.

    CAS  PubMed  Google Scholar 

  36. Xie M, Aube J, Borchardt RT, Morton M, Topp EM, Vander Velde D, et al. Reactivity toward deamidation of asparagine residues in β-turn structures. J Pept Res. 2000;56:165–71.

    CAS  PubMed  Google Scholar 

  37. Krogmeier SL, Reddy DS, Vander Velde D, Lushington GH, Siahaan TJ, Middaugh CR, et al. Deamidation of model β-turn cyclic peptides in the solid state. J Pharm Sci. 2005;94:2616–31.

    CAS  PubMed  Google Scholar 

  38. Huus K, Havelund S, Olsen HB, van de Weert M, Frokjaer S. Chemical and thermal stability of insulin: effects of zinc and ligand binding to the insulin zinc-hexamer. Pharm Res. 2006;23:2611–20.

    CAS  PubMed  Google Scholar 

  39. Liu H, Gaza-Bulesco G, Faldu D, Chumsae C, Sun J. Heterogeneity of monoclonal antibodies. J Pharm Sci. 2008;97:2426–47.

    CAS  PubMed  Google Scholar 

  40. Kroon DJ, Baldwin-Ferro A, Lalan P. Identification of sites of degradation in a therapeutic monoclonal antibody by peptide mapping. Pharm Res. 1992;9:1386–93.

    CAS  PubMed  Google Scholar 

  41. Usami A, Ohtsu A, Takahama S, Fujii T. The effect of pH, hydrogen peroxide and temperature on the stability of human monoclonal antibody. J Pharm Biomed Anal. 1996;14:1133–40.

    CAS  PubMed  Google Scholar 

  42. Perkins M, Theiler R, Lunte S, Jeschke M. Determination of the origin of charge heterogeneity in a murine monoclonal antibody. Pharm Res. 2000;17:1110–7.

    CAS  PubMed  Google Scholar 

  43. Harris RJ, Kabakoff B, Macchi FD, Shen FJ, Kwong M, Andya JD, et al. Identification of multiple sources of charge heterogeneity in a recombinant antibody. J Chromatogr B. 2001;752:233–45.

    CAS  Google Scholar 

  44. Zheng JY, Janis LJ. Influence of pH, buffer species, and storage temperature on physicochemical stability of a humanized monoclonal antibody LA298. Int J Pharm. 2006;308:46–51.

    CAS  PubMed  Google Scholar 

  45. Kameoka D, Ueda T, Imoto T. A method for the detection of asparagine deamidation and aspartate isomerization of proteins by MALDI-TOF-mass spectrometry using endoproteinase Asn–N. J Biochem. 2003;134:129–35.

    CAS  PubMed  Google Scholar 

  46. Zhang W, Czupryn MJ. Analysis of isoaspartate in a recombinant monoclonal antibody and its charge isoforms. J Pharm Biomed Anal. 2003;30:1479–90.

    CAS  PubMed  Google Scholar 

  47. Wang L, Amphlett G, Lambert JM, Blattler W, Zhang W. Structural characterization of a recombinant monoclonal antibody by electrospray time-of-flight mass spectrometry. Pharm Res. 2005;22:1338–49.

    CAS  PubMed  Google Scholar 

  48. Huang L, Lu J, Wroblewski VJ, Beals JM, Riggin RM. In vivo deamidation characterization of monoclonal antibody by LC/MS/MS. Anal Chem. 2005;77:1432–9.

    CAS  PubMed  Google Scholar 

  49. Cournoyer JJ, Lin C, et al. Quantitating the relative abundance of isoaspartyl residues in deamidated proteins by electron capture dissociation. J Am Soc Mass Spectrom. 2007;18:48–56.

    CAS  PubMed  Google Scholar 

  50. Cournoyer JJ, Pittman JL, Ivleva VB, Fallows E, Waskell L, Costello CE, et al. Deamidation: differentiation of aspartyl from isoasparatyl products in peptides by electron capture dissociation. Protein Sci. 2005;14:452–63.

    CAS  PubMed  Google Scholar 

  51. Wang F, Nakouzi A, Alvarez M, Zaragoza O, Angeletti RH, Casadevall A. Structural and functional characterization of glycosylation in an immunoglobulin G1 to Cryptococcus neoformans glucuronoxylomannan. Mol Immunol. 2006;43:987–98.

    CAS  PubMed  Google Scholar 

  52. Li XJ, Cournoyer JJ, Lin C, O’Connor PB. Use of O-18 labels to monitor deamidation during protein and peptide sample processing. J Am Soc Mass Spectrom. 2008;19:855–64.

    CAS  PubMed  Google Scholar 

  53. Lyubaraskaya Y, Houde D, Woodward J, Murphy D, Mhatre R. Analysis of recombinant monoclonal antibody isoforms by electrospray ionization mass spectrometry as a strategy for streamlining characterization of recombinant monoclonal antibody charge heterogeneity. Anal Biochem. 2006;348:24–39.

    Google Scholar 

  54. Srebalus Barnes CA, Lim A. Applications of mass spectrometry for the structural characterization of recombinant protein pharmaceuticals. Mass Spectrom Rev. 2007;26:370–88.

    PubMed  Google Scholar 

  55. Terashima I, Koga A, Nagai H. Identification of deamidation and isomerization on pharmaceutical recombinant anibody using (H2O)-O-18. Anal Biochem. 2007;368:49–60.

    CAS  PubMed  Google Scholar 

  56. Xiao G, Bondarenko PV, Jacob J, Chu GC, Chelius D. O-18 labeling method for identification and quantification of succinimide in proteins. Anal Chem. 2007;79:2714–21.

    CAS  PubMed  Google Scholar 

  57. Huang HZ, Nichols A, Liu D. Direct identification and quantification of aspartyl succinimide in an IgG2 mAb by RapidGest assisted digestion. Anal Chem. 2009;81:1686–92.

    CAS  PubMed  Google Scholar 

  58. Ahrer K, Jungbauer A. Chromatographic and electrophoretic characterization of protein variants. J Chromatogr B. 2006;841:110–22.

    CAS  Google Scholar 

  59. Sanzgiri RD, McKinnon TA, Cooper BT. Intrinsic charge ladders of a monoclonal antibody in hydroxypropylcellulose-coated capillaries. Analyst. 2006;131:1034–43.

    CAS  PubMed  Google Scholar 

  60. Catai JR, Torano JS, Jongen PMJM, de Jong GJ, Somsen GW. Analysis of recombinant human growth hormone by capillary electrophoresis with bilayer-capillaries using UV and MS detection. J Chromatogr B. 2007;852:160–6.

    CAS  Google Scholar 

  61. Vlasak J, Ionescu R. Heterogeneity if monoclonal antibodies revealed by charge-sensitive methods. Curr Pharm Biotechnol. 2008;9:468–81.

    CAS  PubMed  Google Scholar 

  62. Reubsaet JLE, Beijnen JH, Bult A, van Maanen RJ, Marchal JAD, Underberg WJM. Analytical techniques used to study the degradation of proteins and peptides: chemical instability. J Pharm Biomed Anal. 1999;17:955–78.

    Google Scholar 

  63. De Boni S, Overthür C, Hamburger M, Skriba GKE. Analysis of aspartyl peptide degradation products by high performance liquid chromatography and high performance liquid chromatography-mass spectrometry. J Chromatogr A. 2004;1022:92–102.

    Google Scholar 

  64. Liu HJ, Xu B, Ray MK, Shahrokh Z. Peptide mapping with liquid chromatography using a basic mobile phase. J Chromatogr A. 2008;1210:76–83.

    CAS  PubMed  Google Scholar 

  65. Wong HW, Choi SM, Phillips DL, Ma CY. Raman spectroscopic study of deamidated food proteins. Food Chem. 2009;113:363–70.

    CAS  Google Scholar 

  66. Harris RJ, Shire SJ, Winter C. Commercial manufacturing scale formulation and analytical characterization of therapeutic recombinant antibodies. Drug Dev Res. 2004;61:137–54.

    CAS  Google Scholar 

  67. Liu H, Gaza-Bulesco G, Sun J. Characterization of the stability of a fully human monoclonal IgG after prolonged incubation at elevated temperature. J Chromatogr B. 2006;837:35–43.

    CAS  Google Scholar 

  68. Yan B, Valliere-Douglass J, Brady L, Steen S, Han M, Pace D, et al. Analysis of post-translational modifications in recombinant monoclonal antibody IgG1 by reversed-phase liquid chromatography/mass spectrometry. J Chromatogr A. 2007;1164:153–61.

    CAS  PubMed  Google Scholar 

  69. Paranandi MV, Guzzetta AW, Hancock WS, Aswad DW. Deamidation and isoaspartate formation during in vitro aging of recombinant tissue plasminogen. J Biol Chem. 1994;269:243–53.

    CAS  PubMed  Google Scholar 

  70. Zhang W, Czupryn MJ, Boyle Jr PT, Amari J. Characterization of asparagine deamidation and aspartate isomerization in recombinant interleukin-11. Pharm Res. 2002;19:1223–31.

    CAS  PubMed  Google Scholar 

  71. Hepner F, Csaszar E, Roitinger E, Pollak A, Lubec G. Mass spectrometrical analysis of recombinant human growth hormone Norditropin reveals amino acid exchange at M14_V14 rhGH. Proteomics. 2006;6:775–84.

    CAS  PubMed  Google Scholar 

  72. Zhan X, Giogianni F, Desiderio DM. Proteomics analysis of growth hormone isoforms in the human pituitary. Proteomics. 2005;5:1228–41.

    CAS  PubMed  Google Scholar 

  73. Moss CX, Matthews SP, Lamont DJ, Watts C. Asparagine deamidation perturbs antigen presentation on class II major histocompatibility complex molecules. J Biol Chem. 2005;280:18498–503.

    CAS  PubMed  Google Scholar 

  74. Zomber G, Reuveny S, Garti N, Shafferman A, Elhanany E. Effects of spontaneous deamidation on the cytotoxic activity of the Bacillus anthracis protective antigen. J Biol Chem. 2005;280:39897–906.

    CAS  PubMed  Google Scholar 

  75. Ribot WJ, Powell BS, Ivins BE, Little SF, Johnson WM, Hoover TA, et al. Comparative vaccine efficacy of different isoforms of recombinant protective antigen against Bacillus anthracis spore challenge in rabbits. Vaccine. 2006;24:3469–76.

    CAS  PubMed  Google Scholar 

  76. Ren D, Ratnaswamy G, Beierle J, Treuheit MJ, Brems DN, Bondarenko PV. Degradation products analysis of an Fc fusion protein using LC/MS methods. Int J Biol Macromol. 2009;44:81–5.

    CAS  PubMed  Google Scholar 

  77. Harris RJ, Wagner KL, Spellman MW. Structural characterization of a recombinant CD4-IgG hybrid molecule. Eur J Biochem. 1990;194:611–20.

    CAS  PubMed  Google Scholar 

  78. Joshi AB, Sawai M, Kearney WR, Kirsch LE. Studies on the mechanism of asparatic acid cleavage and glutamine deamidation in the acidic degradation of glucagon. J Pharm Sci. 2005;94:1912–27.

    CAS  PubMed  Google Scholar 

  79. Gülich S, Linhult M, Ståhl S, Hober S. Engineering streptococcal protein G for increased alkaline stability. Protein Eng. 2002;15:835–42.

    PubMed  Google Scholar 

  80. Wada Y. Advanced analytical methods for hemoglobin variants. J Chromatogr B. 2002;781:291–301.

    CAS  Google Scholar 

  81. Eng M, Ling V, Briggs JA, Souza K, Canova-Davis E, Powell MF, et al. Formulation development and primary degradation pathways for recombinant human nerve growth factor. Anal Chem. 1997;69:4184–90.

    CAS  PubMed  Google Scholar 

  82. Tuong A, Maftouh M, Ponthus C, Whitechurch O, Roitsch C, Picard C. Characterization of the deamidated forms of recombinant hirudin. Biochemistry. 1992;31:8291–9.

    CAS  PubMed  Google Scholar 

  83. Grossenbacher H, Märki W, Coulot M, Müller D, Richter WJ. Characterization of succinimide-type dehydration products of recombinant hirudin variant 1 by electrospray tandem mass spectrometry. Rapid Commun Mass Spectrom. 1993;7:1082–5.

    CAS  PubMed  Google Scholar 

  84. Han M, Guo A, Jockheim C, Zhang Y, Martinez T, Kodama P, et al. Analysis of glycosylated type II interleukin-1 receptor (IL-1R) by imaged capillary isoelectric focusing (i-cIEF). Chromatographia. 2007;66:969–76.

    CAS  Google Scholar 

  85. Clarke S. Propensity for spontaneous succinimide formation from aspartyl and asparaginyl residues in cellular proteins. Int J Pept Protein Res. 1987;30:808–21.

    Article  CAS  PubMed  Google Scholar 

  86. Stratton LP, Kelly RM, Rowe J, Shively JE, Smith DD, Carpenter JF, et al. Controlling deamidation rates in a model peptide: effects of temperature, peptide concentration, and additives. J Pharm Sci. 2001;90:2141–8.

    CAS  PubMed  Google Scholar 

  87. Miroliaei M, Nemat-Gorgani M. Sugars protect native and apo yeast alcohol dehydrogenase against irreversible thermoinactivation. Enzyme Microb Technol. 2001;29:554–9.

    CAS  Google Scholar 

  88. Athmer L, Kindrachuk J, Georges F, Napper S. The influence of protein structure on the products emerging from succinimide hydrolysis. J Biol Chem. 2002;277:30502–7.

    CAS  PubMed  Google Scholar 

  89. Wang W, Martin-Moe S, Pan C, Musza L, Wang YJ. Stabilization of a polypeptide in non-aqueous solvents. Int J Pharm. 2008;351:1–7.

    CAS  PubMed  Google Scholar 

  90. Li R, D-Souza AJ, Laird BB, Schowen RL, Borchardt RT, Topp EM. Effects of solution polarity and viscosity on peptide deamidation. J Pept Res. 2000;56:326–34.

    CAS  PubMed  Google Scholar 

  91. Li R, Hageman MJ, Topp EM. Effect of viscosity on the deamidation rate of a model Asn-hexapeptide. J Pept Res. 2001;59:211–20.

    Google Scholar 

  92. Wakankar AA, Borchardt RT, et al. Aspartate isomerization in the complementarity-determining regions of two closely related monoclonal antibodies. Biochemistry. 2007;46:1534–44.

    CAS  PubMed  Google Scholar 

  93. Wakankar AA, Liu J, Vander Velde D, Wang YJ, Shire SJ, Borchardt RT. The effect of cosolutes on the isomerization of aspartic acid residues and conformational stability in a monoclonal antibody. J Pharm Sci. 2007;96:1708–18.

    CAS  PubMed  Google Scholar 

  94. Girardet J-M, N’negue M-A, Egito AS, Campagna S, Lagrange A, Gaillard J-L. Multiple forms of equine α-lactalbumin: evidence of N-glycosylated and deamidated forms. Int Dairy J. 2004;14:207–17.

    CAS  Google Scholar 

  95. Lai MC, Topp EM. Solid-state chemical stability of proteins and peptides. J Pharm Sci. 1999;88:489–500.

    CAS  PubMed  Google Scholar 

  96. Li B, Schowen RL, Topp EM, Borchardt RT. Effect of N-1 and N-2 residues on peptide deamidation rate in solution and solid state. AAPS J. 2006;8:E166–73. article 20.

    CAS  PubMed  Google Scholar 

  97. Houchin ML, Topp EM. Chemical degradation of peptides and proteins in PLGA: a review of reactions and mechanisms. J Pharm Sci. 2008;97:2395–404.

    CAS  PubMed  Google Scholar 

  98. Joshi AB, Kirsch LE. The estimation of glutaminyl deamidation and aspartyl cleavage rates in glucagon. Int J Pharm. 2004;273:213–9.

    CAS  PubMed  Google Scholar 

  99. Joshi AB, Kirsch LE. The relative rates of glutamine and asparagine deamidation in glucagon fragment 22–29 under acidic conditions. J Pharm Sci. 2002;91:232–2345.

    Google Scholar 

  100. Flaugh SL, Mills IA, King J. Glutamine deamidation destabilizes human γD-crystallin and lowers the kinetic barrier to unfolding. J Biol Chem. 2006;281:30782–93.

    CAS  PubMed  Google Scholar 

  101. Liu HC, Gaza-Bulesco G, Chumsae C. Glutamine deamidation of a recombinant monoclonal antibody. Rapid Commun Mass Spectrom. 2008;22:4081–8.

    CAS  PubMed  Google Scholar 

  102. Feng J, Ferraro E, Tirozzi B. Impact of temperature and pH value on the stability of hGHRH: a MD approach. Math Comput Model. 2005;41:1157–70.

    Google Scholar 

  103. Peters B, Trout BL. Asparagine deamidation: pH-dependent mechanism from density functional theory. Biochemistry. 2006;45:5384–92.

    CAS  PubMed  Google Scholar 

  104. Konuklar FA, Aviyente V, Ruiz Lopez MF. Theoretical study on the alkaline and neutral hydrolysis of succinimide derivatives in deamidation reactions. J Phys Chem A. 2002;106:11205–14.

    CAS  Google Scholar 

  105. Catak S, Monard G, Aviyenta V, et al. Computational study on nonenzymatic peptide bond cleavage at asparagine and aspartic acid. J Phys Chem A. 2008;112:8752–61.

    CAS  PubMed  Google Scholar 

  106. Radkiewicz JL, Zipse H, Clarke S, Houk KN. Neighboring side chain effects on asparaginyl and aspartyl degradation: an ab initio study of the relationship between peptide conformation and backbone NH acidity. J Am Chem Soc. 2001;123:3499–506.

    CAS  PubMed  Google Scholar 

  107. Chu GC, Chelius D, Xiao G, Khor HK, Coulibaly S, Bondarenko PV. Accumulation of succinimide in a recombinant monoclonal antibody in mildly acidic buffers under elevated temperature. Pharm Res. 2007;24:1145–56.

    CAS  PubMed  Google Scholar 

  108. Valliere-Douglass J, Jones L, Shpektor D, Kodama P, Wallace A, Balland A, et al. Separation and characterization of an IgG2 antibody containing a cyclic imide in CRD1 of light chain by hydrophobic interaction chromatography and mass spectrometry. Anal Chem. 2008;80:3168–74.

    CAS  PubMed  Google Scholar 

  109. Cacia J, Keck R, Presta LG, Frenz J. Isomerization of an aspartic acid residue in the complementarity-determining regions of a recombinant antibody to human IgE: identification and effect on binding affinity. Biochemistry. 1996;35:1897–903.

    CAS  PubMed  Google Scholar 

  110. Teshima G, Stults JT, Ling V, Canova-Davis E. Isolation and characterization of a succinimide variant of methionyl human growth hormone. J Biol Chem. 1991;266:13544–7.

    CAS  PubMed  Google Scholar 

  111. Markell D, Hui J, Narhi L, Lau D, LeBel C, Aparisis D, et al. Pharmaceutical significance of the cyclic imide form of recombinant human glial cell line derived neurotrophic factor. Pharm Res. 2001;18:1361–6.

    CAS  PubMed  Google Scholar 

  112. Tomizawa H, Yamada H, Ueda T, Imoto T. Isolation and characterization of 101-succinimide lysozyme that possesses the cyclic imide at Asp101-Gly102. Biochemistry. 1994;33:8770–4.

    CAS  PubMed  Google Scholar 

  113. Oliyai C, Borchardt RT. Chemical pathways of peptide degradation. IV. Pathways, kinetics, and mechanism of degradation of an aspartyl residue in a model hexapeptide. Pharm Res. 1993;10:95–102.

    CAS  PubMed  Google Scholar 

  114. Oliyai C, Borchardt RT. Chemical pathways of peptide degradation. VI. Effect of the primary sequence on the pathways of degradation of aspartyl residues in model hexapeptides. Pharm Res. 1994;11:751–8.

    CAS  PubMed  Google Scholar 

  115. Breen ED, Curley JG, Overcashier DE, Hsu CC, Shire SJ. Effect of moisture on the stability of a lyophilized humanized monoclonal antibody formulation. Pharm Res. 2001;18:1345–53.

    CAS  PubMed  Google Scholar 

  116. Rehder DS, Chelius D, McAuley A, Dillon TM, Xiao G, Crouse-Zeineddini J, et al. Isomerization of a single aspartyl residue of anti-epidermal growth factor receptor immunoglobulin γ2 highlights the role avidity plays in antibody activity. Biochemistry. 2008;47:2518–30.

    CAS  PubMed  Google Scholar 

  117. Dette C, Wätzig H. Separation of r-hirudin from similar substances by capillary electrophoresis. J Chromatogr A. 1995;700:89–94.

    CAS  PubMed  Google Scholar 

  118. Inglis AS. Cleavage at aspartic acid. Methods Enzymol. 1983;91:324–32.

    CAS  PubMed  Google Scholar 

  119. Capasso S, Mazzarella L, Sorrentino G, Balboni G, Kirby AJ. Kinetics and mechanism of the cleavage of the peptide bond next to asparagine. Peptides. 1996;17:1075–7.

    CAS  PubMed  Google Scholar 

  120. Tarelli E, Corran PH. Ammonia cleaves polypeptides at asparagine proline bonds. J Pept Res. 2003;62:245–51.

    CAS  PubMed  Google Scholar 

  121. Kikwai L, Babu RJ, Kanikkannan N, Singh M. Stability and degradation profiles of Spantide II in aqueous solution. Eur J Pharm Sci. 2006;27:158–66.

    CAS  PubMed  Google Scholar 

  122. Jiskoot W, Beuvery EC, de Koning AA, Herron JN, Crommelin DJ. Analytical approaches to the study of monoclonal antibody stability. Pharm Res. 1990;7:1234–41.

    CAS  PubMed  Google Scholar 

  123. Rao PE, Kroon DJ. Orthoclone OKT3. Pharm Biotechnol. 1993;5:135–48.

    CAS  PubMed  Google Scholar 

  124. Alexander AJ, Hughes DE. Monitoring of IgG antibody thermal stability by micellar electrokinetic capillary chromatography and matrix-assisted laser desorption/ionization mass spectrometry. Anal Chem. 1995;67:3626–32.

    CAS  PubMed  Google Scholar 

  125. Paborji M, Pochopin NL, Coppola WP, Bogardus JB. Chemical and physical stability of chimeric L6, a mouse–human monoclonal antibody. Pharm Res. 1994;11:764–71.

    CAS  PubMed  Google Scholar 

  126. Cordoba AJ, Shyong B-J, Breen D, Harris RJ. Non-enzymatic hinge region fragmentation of antibodies in solution. J Chromatogr B. 2005;818:115–21.

    CAS  Google Scholar 

  127. Dillon TM, Bondarenko PV, Ricci MS. Development of an analytical reversed-phase high-performance liquid chromatography-electrospray ionization mass spectrometry method for characterization of recombinant antibodies. J Chromatogr A. 2004;1053:299–305.

    CAS  PubMed  Google Scholar 

  128. Dillon TM, Bondarenko PV, Rehder DS, Pipes GD, Kleeman GR, Ricci MS. Optimization of a reversed-phase high-performance liquid chromatography/mass spectrometry method for characterizing recombinant antibody heterogeneity and stability. J Chromatogr A. 2006;1120:112–20.

    CAS  PubMed  Google Scholar 

  129. Xiang T, Lundell E, Sun Z, Liu H. Structural effect of a recombinant monoclonal antibody on hinge region peptide bond hydrolysis. J Chromatogr B. 2007;858:254–62.

    CAS  Google Scholar 

  130. Gaza-Bulesco G, Liu H. Fragmentation of a recombinant monoclonal antibody at various pH. Pharm Res. 2008;25:1881–90.

    Google Scholar 

  131. Smith MA, Easton M, Everett P, Lewis G, Payne M, Riveros Moreno V, et al. Specific cleavage of immunoglobulin G by copper ions. Int J Pept Protein Res. 1996;48:48–55.

    Article  CAS  PubMed  Google Scholar 

  132. Ouellette D, Alessandri L, Piparia R, Aikhoje A, Chin A, Radziejewski C, et al. Elevated cleavage of human immunoglobulin gamma molecules containing a lambda light chain mediated by iron and histidine. Anal Biochem. 2009;389:107–17.

    CAS  PubMed  Google Scholar 

  133. Ledvina M, Labella FS. Fluorescent substances in protein hydrolyzates I. Acid “Hydrolyzates” of individual amino acids. Anal Biochem. 1970;36:174–81.

    CAS  PubMed  Google Scholar 

  134. Xing DKL, Crane DT, Bolgiano B, Corbel MJ, Jones C, Sesardic D. Physicochemical and immunological studies on the stability of free and microsphere-encapsulated tetanus toxoid in vitro. Vaccine. 1996;14:1205–13.

    CAS  PubMed  Google Scholar 

  135. Luykx DMAM, Casteleijn MG, Jiskoot W, Westdijk J, Jongen PMJM. Physicochemical studies on the stability of influenza haemagglutinin in vaccine bulk material. Eur J Pharm Sci. 2004;23:65–75.

    CAS  PubMed  Google Scholar 

  136. Fujii N, Muraoka S, Satoh K, Hori H, Harada K. Racemization of aspartic acids at specific sites in alpha-a-crystallin from aged human lens. Biomed Res Tokyo. 1991;12:315–21.

    CAS  Google Scholar 

  137. Fujii N, Momose Y, Ishii N, Takita M, Akaboshi M, Kodama M. The mechanisms of simultaneous stereoinversion, racemization, and isomerization at specific aspartyl residues of aged lens proteins. Mech Ageing Dev. 1997;107:347–58.

    Google Scholar 

  138. Shapira R, Wilkinson KD, Shapira G. Racemization of individual aspartate residues in human myelin basic protein. J Neurochem. 1988;50:649–54.

    CAS  PubMed  Google Scholar 

  139. Ueno AK, Ueda T, Sakai K, Hamasaki N, Okamoto M, Imoto T. Evidence for a novel racemization process of an asparaginyl residue in mouse lysozyme under physiological conditions. Cell Mol Life Sci. 2005;62:199–205.

    CAS  PubMed  Google Scholar 

  140. McCudden CR, Kraus VB. Biochemistry of amino acid racemization and clinical application to musculoskeletal disease. Clin Biochem. 2006;39:1112–30.

    CAS  PubMed  Google Scholar 

  141. Volkin DB, Klibanov AM. Thermal destruction processes in proteins involving cystine residues. J Biol Chem. 1987;262:2945–50.

    CAS  PubMed  Google Scholar 

  142. Chang BS, Kendrick BS, Carpenter JF. Surface-induced denaturation of proteins during freezing and its inhibition by surfactants. J Pharm Sci. 1996;85:1325–30.

    CAS  PubMed  Google Scholar 

  143. Costantino HR, Langer R, Klibanov AM. Solid-phase aggregation of proteins under pharmaceutically relevant conditions. J Pharm Sci. 1994;83:1662–9.

    CAS  PubMed  Google Scholar 

  144. Cohen SL, Price C, Vlasak J. β-Elimination and peptide bond hydrolysis: two distinct mechanisms of human IgG1 hinge fragmentation upon storage. J Am Chem Soc. 2007;129:6976–7.

    CAS  PubMed  Google Scholar 

  145. Battersby JE, Hancock WS, Canovadavis E, Oeswein J, O’Connor B. Diketopiperazine formation and N-terminal degradation in recombinant human growth-hormone. Int J Pept Protein Res. 1994;44:215–22.

    CAS  PubMed  Google Scholar 

  146. Fisher P. Diketopiperazines in peptide and combinatorial chemistry. J Pept Sci. 2003;9:9–35.

    Google Scholar 

  147. Marsden BJ, Nguyen TMD, Schiller PW. Spontaneous degradation via diketopiperazine formation of peptides containing a tetrahydroisoquinoline-3-carboxylic acid residue in the 2-position of the peptide sequence. Int J Pept Protein Res. 1993;41:313–6.

    Article  CAS  PubMed  Google Scholar 

  148. Sepetov NF, Krymsky MA, Ovchinnikov MV, Bespalova ZD, Isakova OL, Soucek M, et al. Rearrangement, racemization and decomposition of peptides in aqueous solution. Peptide Res. 1991;4:308–13.

    CAS  Google Scholar 

  149. Capasso S, Vergara A, Mazzarella L. Mechanism of 2, 5-dioxopiperazine formation. J Am Chem Soc. 1998;120:1990–5.

    CAS  Google Scholar 

  150. Capasso S, Sica F, Mazzarella L, Balboni G, Guerrini R, Salvadori S. Acid catalysis in the formation of dioxopiperazines from peptides containing tetrahydroisoquinoline-3-carboxylic acid at position-2. Int J Pept Protein Res. 1995;45:567–73.

    Article  CAS  PubMed  Google Scholar 

  151. Capasso S, Mazzarella L. Solvent effects on diketopiperazine formation from N-terminal peptide residues. J Chem Soc Perkin Trans. 1999;2(2):329–32.

    Google Scholar 

  152. Kertscher U, Bienert M, Krause E, Sepetov NF, Mehlis B. Spontaneous chemical degradation of substance P in the solid-phase and in solution. Int J Pept Protein Res. 1993;41:207–11.

    Article  CAS  PubMed  Google Scholar 

  153. Goolcharran C., Khossravi M., and Borchardt R.T. Chemical pathways of peptide and protein degradation. In: Frokjaer S, Hovgaard L, editors. Pharmaceutical formulation development of peptides and proteins. New York: CRC Press; 2000;70–88.

  154. Messer M. Enzymatic cyclization of L-glutamine and L-glutaminyl peptides. Nature. 1963;197:1299+.

    CAS  PubMed  Google Scholar 

  155. Blomback B. Derivatives of glutamine in peptides. Methods Enzymol. 1967;11:398–411.

    CAS  Google Scholar 

  156. Abraham GN, Podell DN. Pyroglutamic acid. Mol Cell Biochem. 1981;38:181–90.

    CAS  PubMed  Google Scholar 

  157. Lewis DA, Guzzetta AW, Hancock WS, Costello M. Characterization of humanized anti-TAC, an antibody directed against the interleukin 2 receptor, using electrospray ionization mass spectrometry by direct infusion, LC/MS, and MS/MS. Anal Chem. 1994;66:585–95.

    CAS  PubMed  Google Scholar 

  158. Werner WE, Wu S, Mulkerrin M. The removal of pyroglutamic acid from monoclonal antibodies without denaturation of the protein chains. Anal Biochem. 2005;342:120–5.

    CAS  PubMed  Google Scholar 

  159. Wang L, Amphlett G, Blatter WA, Lambert JM, Zhang W. Structural characterization of the maytansinoid-monoclonal antibody immunoconjugate, huN901-DM1, by mass spectrometry. Protein Sci. 2005;14:2436–46.

    CAS  PubMed  Google Scholar 

  160. Chelius D, Jing K, Lueras A, Rehder DS, Dillion TM, Vizel A, et al. Formation of pyroglutamic acid from N-terminal glutamic acid in immunoglobulin gamma antibodies. Anal Chem. 2006;78:2370–6.

    CAS  PubMed  Google Scholar 

  161. Rehder DS, Dillion TM, Pipes GD, Bondarenko PV. Reversed-phase liquid chromatography/mass spectrometry analysis of reduced monoclonal antibodies in pharmaceutics. J Chromatogr A. 2006;1102:164–75.

    CAS  PubMed  Google Scholar 

  162. Yu L, Vizel A, Huff MB, Young M, Remmele Jr RL, He B. Investigation of N-terminal glutamate cyclization of recombinant monoclonal antibody in formulation development. J Pharm Biomed Anal. 2006;42:455–63.

    CAS  PubMed  Google Scholar 

  163. Saito S, Yano K, Sharma S, McMahon HE, Shimasaki S. Characterization of the post-translational modification of recombinant human BMP-15 mature protein. Protein Sci. 2008;17:362–70.

    CAS  PubMed  Google Scholar 

  164. Dick LW, Kim C, Qiu DF, Cheng KC. Determination of the origin of the N-terminal pyro-glutamate variation in monoclonal antibodies using model peptides. Biotechnol Bioeng. 2007;97:544–53.

    CAS  PubMed  Google Scholar 

  165. Busby Jr WH, Quackenbush GE, Humm J, Youngblood WW, Kizer JS. An enzyme(s) that converts glutaminyl-peptides into pyroglutamyl-peptides. Presence in pituitary, brain, adrenal medulla, and lymphocytes. J Biol Chem. 1987;262:8532–6.

    CAS  PubMed  Google Scholar 

  166. Quan CP, Wu S, Dasovich N, Hsu C, Patapoff T, Canova-Davis E. Susceptability of rhDNase 1 to glycation in the dry powder state. Anal Chem. 1999;71:4445–54.

    CAS  PubMed  Google Scholar 

  167. Beisswenger PJ, Szwergold BS, Yeo KT. Glycated proteins in diabetes. Clin Lab Med. 2001;21:53+.

    CAS  PubMed  Google Scholar 

  168. Quan C, Alcala E, Petkovska I, Matthews D, Canova-Davis E, Taticek R, et al. A study in glycation of a therapeutic recombinant humanized monoclonal antibody: where it is, how it got there, and how it affects change-based behavior. Anal Biochem. 2008;373:179–91.

    CAS  PubMed  Google Scholar 

  169. Kennedy DM, Skillen AW, Self CH. Glycation of monoclonal antibodies impairs their ability to bind antigen. Clin Exp Immunol. 1994;98:245–51.

    Article  CAS  PubMed  Google Scholar 

  170. Li S, Patapoff TW, Overcashier D, Hsu C, Nguyen T-H, Borchardt RT. Effects of reducing sugars on the chemical stability of human relaxin in the lyophilized state. J Pharm Sci. 1996;85:873–7.

    CAS  PubMed  Google Scholar 

  171. Smales CM, Pepper DS, James DC. Protein modifications during antiviral heat bioprocessing and subsequent storage. Biotechnol Prog. 2001;17:974–8.

    CAS  PubMed  Google Scholar 

  172. Smales CM, Pepper DS, James DC. Mechanisms of protein modification during model anti-viral heat-treatment bioprocessing of beta-lactoglobulin variant A in the presence of sucrose. Biotechnol Appl Biochem. 2000;32:109–19.

    CAS  PubMed  Google Scholar 

  173. Fischer S, Hoernschemeyer J, Mahler H-C. Glycation during storage and administration of monoclonal antibody formulations. Eur J Pharm Biopharm. 2008;70:42–50.

    CAS  PubMed  Google Scholar 

  174. Hawe A, Friess W. Development of HSA-free formulations for a hydrophobic cytokine with improved stability. Eur J Pharm Biopharm. 2008;68:169–82.

    CAS  PubMed  Google Scholar 

  175. Gadgil HS, Bondarenko PV, Pipes G, Rehder D, McAuley A, Perico N, et al. The LC/MS analysis of glycation of IgG molecules in sucrose containing formulations. J Pharm Sci. 2007;96:2607–21.

    CAS  PubMed  Google Scholar 

  176. O’Brien J. Stability of trehalose, sucrose and glucose to nonenzymatic browning in model systems. J Food Sci. 1996;61:679–82.

    Google Scholar 

  177. Zhang B, Yang Y, Yuk I, Pai R, Mckay P, Eigenbrot C, et al. Unveiling a glycation hot spot in a recombinant humanized monoclonal antibody. Anal Chem. 2008;80:2379–90.

    CAS  PubMed  Google Scholar 

  178. Brady LJ, Martinez T, Balland A. Characterization of nonenzymatic glycation on a monoclonal antibody. Anal Chem. 2007;79:9403–13.

    CAS  PubMed  Google Scholar 

  179. Gil H, Salcedo D, Romero R. Effect of phosphate buffer on the kinetics of glycation of proteins. J Phys Org Chem. 2005;18:183–6.

    CAS  Google Scholar 

  180. Stadtman ER. Oxidation of free amino acids and amino acid residues in proteins by radiolysis and by metal-catalyzed reactions. Ann Rev Biochem. 1993;62:797–821.

    CAS  PubMed  Google Scholar 

  181. Hovorka SW, Schöneich C. Oxidative degradation of pharmaceuticals: theory, mechanisms and inhibition. J Pharm Sci. 2001;90:253–69.

    CAS  PubMed  Google Scholar 

  182. Hawkins CL, Davies MJ. Generation and propagation of radical reactions on proteins. Biochim Biophys Acta. 2001;1504:196–219.

    CAS  PubMed  Google Scholar 

  183. Li S, Schöneich C, Borchardt RT. Chemical instability of protein pharmaceuticals: mechanisms of oxidation and strategies for stabilization. Biotechnol Bioeng. 1995;48:490–500.

    CAS  PubMed  Google Scholar 

  184. Davies MJ. The oxidative environment and protein damage. Biochim Biophys Acta. 2005;1703:93–109.

    CAS  PubMed  Google Scholar 

  185. Kerwin BA, Remmele Jr RL. Protect from light: photodegradation and protein biologics. J Pharm Sci. 2007;96:1468–79.

    CAS  PubMed  Google Scholar 

  186. Chumsae C, Gaza-Bulseco G, Sun J, Liu H. Comparison of methionine oxidation in thermal stability and chemically stressed samples of a fully human monoclonal antibody. J Chromatogr B. 2007;850:285–94.

    CAS  Google Scholar 

  187. Bertolotti-Ciarlet A, Wang W, Lownes R, Pristatsky P, Fang Y, McKelvey T, et al. Impact of methionine oxidation on the binding of human IgG1 to FcRn and Fcy receptors. Mol Immunol. 2009;46:1878–82.

    CAS  PubMed  Google Scholar 

  188. Pogocki D, Ghezzo-Schoneich E, Schoneich C. Conformational flexibility controls proton transfer between the methionine hydroxy sulfuranyl radical and the N-terminal amino group in Thr-(X)n-Met peptides. J Phys Chem B. 2001;105:1250–9.

    CAS  Google Scholar 

  189. Neuzil J, Gebicki JM, Stocker R. Radical-induced chain oxidation of proteins and its inhibition by chain-breaking antioxidants. Biochem J. 1993;293:601–6.

    CAS  PubMed  Google Scholar 

  190. Mach H, Burke CJ, Sanyal G, Tsai PK, Volkin DB, Middaugh CR. Origin of the photosensitivity of a monoclonal immunoglobulin-G. ACS Symp Ser. 1994;567:72–84.

    CAS  Google Scholar 

  191. Chu J-W, Yin J, Brooks BR, Wang DIC, Ricci MS, Brems DN, et al. A comprehensive picture of non-site specific oxidation of methionine residues by peroxides in protein pharmaceuticals. J Pharm Sci. 2004;93:3096–102.

    CAS  PubMed  Google Scholar 

  192. Qi P, Volkin DB, Zhao H, Nedved ML, Hughes R, Bass R, et al. Characterization of the photodegradation of a human IgG1 monoclonal antibody formulated as a high-concentration liquid dosage form. J Pharm Sci. 2009;98:3117–30.

    CAS  PubMed  Google Scholar 

  193. Roy S, Mason BD, Schöneich CS, Carpenter JF, Boone TC, Kerwin BA. Light-induced aggregation of type 1 soluble tumor necrosis factor receptor. J Pharm Sci. 2009;98:3182–99.

    CAS  PubMed  Google Scholar 

  194. Amels P, Elias H, Wannowius K-J. Kinetics and mechanism of the oxidation of dimethyl sulfide by hydroperoxides in aqueous medium. Study on the potential contribution of liquid-phase oxidation of dimethyl sulfide in the atmosphere. J Chem Soc Faraday Trans. 1997;93:2537–44.

    CAS  Google Scholar 

  195. Ciorba MA, Heinemann SH, Weissbach H, Brot N, Hoshi T. Modulation of potassium channel function by methionine oxidation and reduction. Proc Natl Acad Sci USA. 1997;94:9932–7.

    CAS  PubMed  Google Scholar 

  196. Schenck HL, Dado GP, Gellman SH. Redox-triggered secondary structure changes in the aggregated states of a designed methionine-rich peptide. J Am Chem Soc. 1996;118:12487–94.

    CAS  Google Scholar 

  197. Chu J-W, Yin J, Wang DIC, Trout BL. Molecular dynamics simulations and oxidation rates of methionine residues of granulocyte colony-stimulating factor at different pH values. Biochemistry. 2004;43:1019–29.

    CAS  PubMed  Google Scholar 

  198. Fransson J, Florin-Robertsson E, Axelsson K, Nyhlen C. Oxidation of human insulin-like growth factor 1 in formulation studies: kinetics of methionine oxidation in aqueous solution and in solid state. Pharm Res. 1996;13:1252–7.

    CAS  PubMed  Google Scholar 

  199. Nguyen TH. Oxidation degradation of protein pharmaceuticals. ACS Symp Ser. 1994;567:59–71.

    CAS  Google Scholar 

  200. Yokota H, Saito H, Masuoka K, Kaniwa H, Shibanuma T. Reversed phase HPLC of Met58 oxidized rhIL-11: oxidation enhanced by plastic tubes. J Pharm Biomed Anal. 2000;24:317–24.

    CAS  PubMed  Google Scholar 

  201. Teh L-C, Murphy LJ, Huq NL, Surus AS, Friesen HG, Lazarus L, et al. Methionine oxidation in human growth hormone and human chorionic somatomammotropin. Effects on receptor binding and biological activities. J Biol Chem. 1987;262:6472–7.

    CAS  PubMed  Google Scholar 

  202. Pan H, Chen K, Chu L, Kinderman F, Apostol I, Huang G. Methionine oxidation in human IgG2 Fc decreases binding affinities to protein A and FcRn. Protein Sci. 2009;18:424–33.

    CAS  PubMed  Google Scholar 

  203. Griffiths SW, Cooney CL. Relationship between protein structure and methionine oxidation in recombinant human α1-antitrypsin. Biochemistry. 2002;41:6245–52.

    CAS  PubMed  Google Scholar 

  204. Lu HS, Fausset PR, Narhi LO, Horan T, Shinagawa K, Shimamoto G, et al. Chemical modification and site-directed mutagenesis of methionine residues in recombinant human granulocyte colony-stimulating factor: effect on stability and biological activity. Arch Biochem Biophys. 1999;362:1–9.

    CAS  PubMed  Google Scholar 

  205. Duenas ET, Keck R, DeVos A, Jones AJS, Cleland JL. Comparison between light induced and chemically induced oxidation of rhVEGF. Pharm Res. 2001;18:1455–60.

    CAS  PubMed  Google Scholar 

  206. Payne RW, Manning MC. Peptide formulation: challeges and strategies. Innov Pharm Technol. 2009;28:64–8.

    CAS  Google Scholar 

  207. Kim YH, Berry AH, Spencer DS, Stites WE. Comparing the effect on protein stability of methionine oxidation versus mutagenesis: steps toward engineering oxidative resistance in proteins. Protein Eng. 2001;14:343–7.

    CAS  PubMed  Google Scholar 

  208. Pan B, Abel J, Ricci MS, Brems DN, Wang DIC, Trout BL. Comparative oxidation studies of methionine reflect a structural effect on chemical kinetics in rhG-CSF. Biochemistry. 2006;45:15430–43.

    CAS  PubMed  Google Scholar 

  209. Thirumangalathu R, Krishnan S, Bondarenko P, Speed-Ricci M, Randolph TW, Carpenter JF, et al. Oxidation of methionine residues in recombinant human interleukin-1 receptor antagonist: implications of conformational stability on protein oxidation kinetics. Biochemistry. 2007;46:6213–24.

    CAS  PubMed  Google Scholar 

  210. Liu D, Ren D, Huang H, Dankberg J, Rosenfeld R, Cocco MJ, et al. Structure and stability changes of human IgG1 Fc as a consequence of methionine oxidation. Biochemistry. 2008;47:5088–100.

    CAS  PubMed  Google Scholar 

  211. Hovorka SW, Hong J, Cleland JL, Schöneich C. Metal-catalyzed oxidation of human growth hormone: modulation by solvent-induced changes of protein conformation. J Pharm Sci. 2001;90:58–69.

    CAS  PubMed  Google Scholar 

  212. Uchida K. Histidine and lysine as targets of oxidative modification. Amino Acids. 2003;25:249–57.

    CAS  PubMed  Google Scholar 

  213. Agon VV, Bubb WA, Wright A, Hawkins CL, Davies MJ. Sensitizer-mediated photooxidation of histidine residues: evidence for the formation of reactive side-chain peroxides. Free Radic Biol Med. 2006;40:698–710.

    CAS  PubMed  Google Scholar 

  214. Li S, Nguyen TH, Schöneich C, Borchardt RT. Aggregation and precipitation of human relaxin induced by metal-catalyzed oxidation. Biochemistry. 1995;34:5762–72.

    CAS  PubMed  Google Scholar 

  215. Sadineni V, Galeva NA, Schöneich C. Characterization of the metal-binding site of human prolactin by site-specific metal-catalyzed oxidation. Anal Biochem. 2006;358:208–15.

    CAS  PubMed  Google Scholar 

  216. Zhao F, Ghezzo-Schöneich E, Aced GI, Hong J, Milby T, Schöneich C. Metal-catalyzed oxidation of histidine in human growth hormone. Mechanism, isotope effects, and inhibition by a mild denaturing alcohol. J Biol Chem. 1997;272:9019–29.

    CAS  PubMed  Google Scholar 

  217. Manzanares D, Rodriguez-Capote K, Liu S, Haines T, Ramos Y, Zhao L, et al. Modification of tryptophan and methionine residues is implicated in the oxidative inactivation of surfactant protein B. Biochemistry. 2007;46:5604–15.

    CAS  PubMed  Google Scholar 

  218. Yang J, Wang S, Liu J, Raghani A. Determination of tryptophan oxidation of monoclonal antibody by reversed phase high performance liquid chromatography. J Chromatogr A. 2007;1156:174–82.

    CAS  PubMed  Google Scholar 

  219. Dalsgaard TK, Otzen D, Nielsen JH, Larsen LB. Changes in structures of milk proteins upon photo-oxidation. J Agric Food Chem. 2007;55:10968–76.

    CAS  PubMed  Google Scholar 

  220. Wei Z, Feng J, Lin H-Y, Mullapudi S, Bishop E, Tous GI, et al. Identification of a single tryptophan residue as critical for binding activity in a humanized monoclonal antibody against respiratory syncytial virus. Anal Chem. 2007;79:2797–805.

    CAS  PubMed  Google Scholar 

  221. Lorenz CM, Wolk BM, Quan CP, Alcala EW, Eng M, McDonald DJ, et al. The effect of low intensity ultraviolet-C light on monoclonal antibodies. Biotechnol Prog. 2009;25:476–82.

    CAS  PubMed  Google Scholar 

  222. Kim H-H, Lee YM, Suh J-K, Song NW. Photodegradation mechanism and reaction kinetics of recombinant human interferon-alpha 2a. Photochem Photobio Sci. 2007;6:171–80.

    CAS  Google Scholar 

  223. Vanhooren A, Devreese B, Vanhee K, Van Beeumen J, Hanssens I. Photoexcitation of tryptophan groups induces reduction of two disulfide bonds in goat α-lactalbumin. Biochemistry. 2002;41:11035–43.

    CAS  PubMed  Google Scholar 

  224. Mozziconacci O, Sharov V, Williams TD, Kerwin BA, Schöneich C. Peptide cysteine thiyl radicals abstract hydrogen atoms from surrounding amino acids: the photolysis of a cystine containing model peptide. J Phys Chem B. 2008;112:9250–7.

    CAS  PubMed  Google Scholar 

  225. Miller BL, Hageman MJ, Thamann TJ, Barron LB, Schöneich C. Solid state photodegradation of bovine somatotropin (bovine growth hormone): evidence for tryptophan-mediated photooxidation of disulfide bonds. J Pharm Sci. 2003;92:1698–709.

    CAS  PubMed  Google Scholar 

  226. Permyakov EA, Permyakov SE, Deikus GY, Morozova-Roche LA, Grishchenko VM, Kalinchenko LP, et al. Ultraviolet illumination-induced reduction of α-lactalbumin disulfide bridges. Proteins. 2003;51:498–503.

    CAS  PubMed  Google Scholar 

  227. Wu L-Z, Sheng Y-B, Xie J-B. Photoexcitation of tryptophan groups induced reduction of disulfide bonds in hen egg white lysozyme. J Mol Struct. 2008;882:101–6.

    CAS  Google Scholar 

  228. Lam XM, Yang JY, Cleland JL. Antioxidants for prevention of methionine oxidation in recombinant monoclonal antibody HER2. J Pharm Sci. 1997;86:1250–5.

    CAS  PubMed  Google Scholar 

  229. Turrell L, Botti H, Carballal S, Ferrer-Sueta G, Souza JM, Duran R, et al. Reactivity of sulfenic acid in human serum albumin. Biochemistry. 2008;47:358–67.

    Google Scholar 

  230. Schöneich C. Mechanisms of protein damage induced by cysteine thiyl radical formation. Chem Res Toxicol. 2008;21:1175–9.

    PubMed  Google Scholar 

  231. Kerwin BA, Akers MJ, Apostol I, Moore-Einsel C, Etter JE, Hess E, et al. Acute and long-term stability studies of deoxy hemoglobin and characterization of ascorbate-induced modifications. J Pharm Sci. 1999;88:79–88.

    CAS  PubMed  Google Scholar 

  232. DePaz RA, Barnett CC, Dale DA, Carpenter JF, Gaertner AL, Randolph TW. The excluding effects of sucrose on a protein chemical degradation pathway: methionine oxidation in subtilisin. Arch Biochem Biophys. 2000;384:123–32.

    CAS  PubMed  Google Scholar 

  233. Joo H-S, Koo Y-M, Choi J-W, Chang C-S. Stabilization method of an alkaline protease from inactivation by heat. SDS and hydrogen peroxide. Enzyme Microb Technol. 2005;36:766–72.

    CAS  Google Scholar 

  234. Soenderkaer S, Carpenter JF, van de Weert M, Hansen LL, Flink J, Frokjaer S. Effects of sucrose on rFVIIa aggregation and methionine oxidation. Eur J Pharm Sci. 2004;21:597–606.

    CAS  PubMed  Google Scholar 

  235. McCord JM, Fridovich I. The utility of superoxide dismutase in studying free radical reactions. I. Radicals generated by the interaction of sulfite, dimethyl sulfoxide, and oxygen. J Biol Chem. 1969;244:6056–63.

    CAS  PubMed  Google Scholar 

  236. Umemura S, Yumita N, Nishigaki R, Umemura K. Mechanism of cell damage by ultrasound in combination with hematoporphyrin. Jpn J Cancer Res. 1990;81:962–6.

    CAS  PubMed  Google Scholar 

  237. Li S, Patapoff TW, Nguyen TH, Borchardt RT. Inhibitory effect of sugars and polyols on the metal-catalyzed oxidation of human relaxin. J Pharm Sci. 1996;85:868–72.

    CAS  PubMed  Google Scholar 

  238. Knepp VM, Whatley JL, Muchnik A, Calderwood TS. Identification of antioxidants for prevention of peroxide-mediated oxidation of recombinant human ciliary neurotrophic factor and recombinant human nerve growth factor. PDA J Pharm Sci Technol. 1996;50:163–71.

    CAS  PubMed  Google Scholar 

  239. Yin J, Chu J-W, Ricci MS, Brems DN, Wang DIC, Trout BL. Effects of antioxidants on the hydrogen peroxide-mediated oxidation of methionine residues in granulocyte colony-stimulating factor and human parathyroid hormone fragment 13–34. Pharm Res. 2004;21:2377–83.

    CAS  PubMed  Google Scholar 

  240. Anraku M, Kouno Y, Kai T, Tsurusaki Y, Yamasaki K, Otagiri M. The role of N-acetyl-methioninate as a new stabilizer for albumin products. Int J Pharm. 2007;329:19–24.

    CAS  PubMed  Google Scholar 

  241. Anraku M, Tsurusaki Y, Watanabe H, Maruyama T, Kragh-Hansen U, Otagiri M. Stabilizing mechanisms in commercial albumin preparations: octanoate and N-acetyl-L-tryptophanate protect human serum albumin against heat and oxidative stress. Biochim Biophys Acta. 2004;1702:9–17.

    CAS  PubMed  Google Scholar 

  242. Ruiz L, Reyes N, Duany L, Franco A, Aroche K, Rando EH. Long-term stabilization of recombinant human interferon α 2b in aqueous solution without serum albumin. Int J Pharm. 2003;264:57–72.

    CAS  PubMed  Google Scholar 

  243. Andersson MM, Breccia JD, Hatti-Kaul R. Stabilizing effect of chemical additives against oxidation of lactate dehydrogenase. Biotechnol Appl Biochem. 2000;32:145–53.

    CAS  PubMed  Google Scholar 

  244. Hong J, Lee E, Carter JC, Masse JA, Oksanen DA. Antioxidant-accelerated oxidative degradation: a case study of transition metal ion catalyzed oxidation in formulation. Pharm Dev Technol. 2004;9:171–9.

    CAS  PubMed  Google Scholar 

  245. Waterman KC, Adami RC, Alsante KM, Hong J, Landis MS, Lombardo F, et al. Stabilization of pharmaceuticals to oxidative degradation. Pharm Dev Technol. 2002;7:1–32.

    CAS  PubMed  Google Scholar 

  246. Bridgewater JD, Vachet RW. Metal-catalyzed oxidation reactions and mass spectrometry: the roles of ascorbate and different oxidizing agents in determining Cu-protein-binding sites. Anal Biochem. 2005;341:122–30.

    CAS  PubMed  Google Scholar 

  247. Hora MS, Rana RK, Wilcox CL, Katre NV, Hirtzer P, Wolfe SN, et al. Development of a lyophilized formulation of interleukin-2. Dev Biol Stand. 1992;74:295–306.

    CAS  PubMed  Google Scholar 

  248. Ha E, Wang W, Wang YJ. Peroxide formation in polysorbate 80 and protein stability. J Pharm Sci. 2002;91:2252–64.

    CAS  PubMed  Google Scholar 

  249. Wang W, Wang YJ, Wang DQ. Dual effects of Tween 80 on protein stability. Int J Pharm. 2008;347:31–8.

    CAS  PubMed  Google Scholar 

  250. Johnson DM, Taylor WF. Degradation of fenprostalene in polyethylene glycol 400 solution. J Pharm Sci. 1984;73:1414–7.

    CAS  PubMed  Google Scholar 

  251. Kumar V, Kalonia DS. Removal of peroxides in polyethylene glycols by vacuum drying: implications in the stability of biotech and pharmaceutical formulations. AAPS PharmSciTech 2006;7(3):E47–53.

    Google Scholar 

  252. Wasylaschuk WR, Harmon PA, Wagner G, Harman AB, Templeton AC, Xu H, et al. Evaluation of hydroperoxides in common pharmaceutical excipients. J Pharm Sci. 2007;96:106–16.

    CAS  PubMed  Google Scholar 

  253. Guo A, Han M, Martinez T, Ketchem RR, Novick S, Jochheim C, et al. Electrophoretic evidence for the presence of structural isoforms specific for the IgG2 isotype. Electrophoresis. 2008;29:2550–6.

    CAS  PubMed  Google Scholar 

  254. Martinez T, Guo A, Allen MJ, Han M, Pace D, Jones J, et al. Disulfide connectivity of human immunoglobulin G2 structural isoforms. Biochemistry. 2008;47:7496–508.

    CAS  PubMed  Google Scholar 

  255. Wypych J, Li M, Guo A, Zhang Z, Martinez T, Allen MJ, et al. Human IgG2 antibodies display disulfide-mediated structural isoforms. J Biol Chem. 2008;283:16194–205.

    CAS  PubMed  Google Scholar 

  256. Dillon TM, Ricci MS, Vezina C, Flynn GC, Liu YD, Rehder DS, et al. Structural and functional characterization of disulfide isoforms of the human IgG2 subclass. J Biol Chem. 2008;283:16206–15.

    CAS  PubMed  Google Scholar 

  257. Allen MJ, Guo A, Martinez T, Han M, Flynn GC, Wypych J, et al. Interchain disulfide bonding in human IgG2 antibodies probed by site-directed mutagenesis. Biochemistry. 2009;48:3755–66.

    CAS  PubMed  Google Scholar 

  258. Hilser VJ, Dowdy D, Oas TG, Freire E. The structural distribution of cooperative interactions in proteins: analysis of the native state ensemble. Proc Natl Acad Sci USA. 1998;95:9903–8.

    CAS  PubMed  Google Scholar 

  259. Nahri LO, Philo JS, Sun B, Chang BS, Arakawa T. Reversibility of heat-induced denaturation of the recombinant human megakaryocyte growth and development factor. Pharm Res. 1999;16:799–807.

    Google Scholar 

  260. Remmele Jr RL, Nightlinger NS, Srinivasan S, Gombotz WR. Interleukin-1 receptor (IL-1R) liquid formulation development using differential scanning calorimetry. Pharm Res. 1998;15:200–8.

    CAS  PubMed  Google Scholar 

  261. Remmele Jr RL, Bhat SD, Phan DH, Gombotz WR. Minimization of recombinant human Flt3 ligand aggregation at the Tm plateau: a matter of thermal reversibility. Biochemistry. 1999;38:5241–7.

    CAS  PubMed  Google Scholar 

  262. Sanchez-Ruiz JM, Lopez-Lacomba JL, Cortijo M, Mateo PL. Differential scanning calorimetry of the irreversible thermal denaturation of thermolysin. Biochemistry. 1988;27:1648–52.

    CAS  PubMed  Google Scholar 

  263. Cao X, Li J, Yang X, Duan Y, Liu Y, Wang C. Nonisothermal kinetic analysis of the effect of protein concentration on BSA aggregation at high concentration by DSC. Thermochim Acta. 2008;467:99–106.

    CAS  Google Scholar 

  264. Remmele Jr RL, Enk JZ, Dharmavaram V, Balaban D, Durst M, Shoshitaishvili A, et al. Scan-rate-dependent melting transitions of interleukin-1 receptor (Type II): elucidation of meaningful thermodynamic and kinetic parameters of aggregation acquired from DSC simulations. J Am Chem Soc. 2005;127:8328–39.

    CAS  PubMed  Google Scholar 

  265. Shikama K, Yamazaki T. Denaturation of catalase by freezing and thawing. Nature. 1961;190:83–4.

    CAS  Google Scholar 

  266. Privalov PL. Cold denaturation of proteins. Crit Rev Biochem Mol Biol. 1990;25:281–305.

    CAS  PubMed  Google Scholar 

  267. Pace CN. Conformational stability of globular proteins. Trends Biochem Sci. 1990;15:14–7.

    CAS  PubMed  Google Scholar 

  268. Pace CN. Measuring and increasing protein stability. Trends Biotechnol. 1990;8:93–8.

    CAS  PubMed  Google Scholar 

  269. Pace CN, Shaw KL. Linear extrapolation method of analyzing solvent denaturation curves. Proteins. 2000;41 Suppl 4:1–7.

    Google Scholar 

  270. Ramprakash T, Doseeva V, Galkin A, Krajewski W, Muthukumar L, Pullalarevu S, et al. Comparison of the chemical and thermal denaturation of proteins by a two-state transitional model. Anal Biochem. 2008;374:221–30.

    CAS  PubMed  Google Scholar 

  271. Rocco AG, Mollica L, Ricchiuto P, Baptista AM, Gianazza E, Eberini I. Characterization of the protein unfolding processes induced by urea and temperature. Biophys J. 2008;94:2241–51.

    CAS  PubMed  Google Scholar 

  272. Sinha A, Yadav S, Ahmad R, Ahmad F. A possible origin of differences between calorimetric and equilibrium estimates of stability parameters of proteins. Biochem J. 2000;345:711–7.

    CAS  PubMed  Google Scholar 

  273. Almarza J, Rincon L, Bahsas A, Brito F. Molecular mechanism for the denaturation of proteins by urea. Biochemistry. 2009;48:7608–13.

    CAS  PubMed  Google Scholar 

  274. O’Brien EP, Brooks BR, Thirumalai D. Molecular origin of constant m-values, denatured state collapse, and residue-dependent transition midpoints in globular proteins. Biochemistry. 2009;48:3743–54.

    PubMed  Google Scholar 

  275. Stumpe MC, Grubmuller H. Urea impedes the hydrophobic collapse of partially unfolded proteins. Biophys J. 2009;96:3744–52.

    CAS  PubMed  Google Scholar 

  276. Lim WK, Rosgen J, Englander SW. Urea, but not guanidinium, destabilizes proteins by forming hydrogen bonds to the peptide group. Proc Natl Acad Sci USA. 2009;106:2595–600.

    CAS  PubMed  Google Scholar 

  277. Marti DN. Apparent pKa shifts of titratable residues at high denaturant concentration and the impact on protein stability. Biophys Chemist. 2005;118:88–92.

    CAS  Google Scholar 

  278. Gross M, Jaenicke R. Proteins under pressure. Eur J Biochem. 1994;221:617–30.

    CAS  PubMed  Google Scholar 

  279. Royer CA. Revisiting volume changes in pressure-induced protein unfolding. Biochim Biophys Acta. 2002;1595:201–9.

    CAS  PubMed  Google Scholar 

  280. Harano Y, Yoshidome T, Kinoshita M. Molecular mechanism of pressure denaturation of proteins. J Chem Phys. 2008;129:1–9.

    Google Scholar 

  281. Krywka C, Sternemann C, Paulus M, Tolan M, Royer C, Winter R. Effect of osmolytes on pressure-induced unfolding of proteins: a high-pressure SAXS study. ChemPhysChem. 2008;9:2809–15.

    CAS  PubMed  Google Scholar 

  282. Webb JN, Webb SD, Cleland JL, Carpenter JF, Randolph TW. Partial molar volume, surface area, and hydration changes for equilibrium unfolding and formation of aggregation transition and cosolute studies on recombinant human IFN-γ. Proc Natl Acad Sci USA. 2001;98:7259–64.

    CAS  PubMed  Google Scholar 

  283. Seefeldt MB, Rosendahl MS, Cleland JL, Hesterberg LK. Application of high hydrostatic pressure to dissociate aggregates and refold proteins. Curr Pharm Biotechnol. 2009;10:447–55.

    CAS  PubMed  Google Scholar 

  284. St. John RJ, Carpenter JF, Randolph TW. High pressure fosters protein refolding from aggregates at high concentrations. Proc Natl Acad Sci USA. 1999;96:13029–33.

    PubMed  Google Scholar 

  285. Bell LN, Hageman MJ, Bauer JM. Impact of moisture on thermally induced denaturation and decomposition of lyophilized bovine somatotropin. Biopolymers. 1995;35:201–9.

    CAS  PubMed  Google Scholar 

  286. Zhou P, Labuza TP. Effect of water content on glass transition and protein aggregation of whey protein powders during short-term storage. Food Biophys. 2007;2:108–16.

    Google Scholar 

  287. D’Cruz NM, Bell LN. Thermal unfolding of gelatin in solids as affected by the glass transition. J Food Sci. 2005;70:E64–8.

    Google Scholar 

  288. Pikal MJ, Rigsbee D, Akers MJ. Solid state chemistry of proteins IV. What is the meaning of thermal denaturation in freeze dried proteins? J Pharm Sci. 2009;98:1387–99.

    CAS  PubMed  Google Scholar 

  289. Bellavia G, Cordone L, Cupane A. Calorimetric study of myoglobin embedded in trehalose-water matrixes. J Ther Anal Calorim. 2009;95:699–702.

    CAS  Google Scholar 

  290. Pikal MJ, Rigsbee D, Roy ML. Solid state stability of proteins III: calorimetric (DSC) and spectroscopic (FTIR) characterization of thermal denaturation in freeze dried human growth hormone. J Pharm Sci. 2008;98:5122–31.

    Google Scholar 

  291. Dunker AK, Lawson JD, Brown CJ, Williams RM, Romero P, Oh JS, et al. Intrinsically disordered protein. J Mol Graph Model. 2001;19:26–59.

    CAS  PubMed  Google Scholar 

  292. Uversky VN. Natively unfolded proteins: a point where biology waits for physics. Protein Sci. 2002;11:739–56.

    CAS  PubMed  Google Scholar 

  293. Garza AS, Ahmad N, Kumar R. Role of intrinsically disordered protein regions/domains in transcriptional regulation. Life Sci. 2009;84:189–93.

    CAS  PubMed  Google Scholar 

  294. Fink AL. Protein aggregation: folding aggregates, inclusion bodies and amyloid. Fold Des. 1998;3:R9–R23.

    CAS  PubMed  Google Scholar 

  295. Carpenter JF, Kendrick BS, Chang BS, Manning MC, Randolph TW. Inhibition of stress-induced aggregation of protein therapeutics. Methods Enzymol. 1999;309:236–55.

    CAS  PubMed  Google Scholar 

  296. Chi EY, Krishnan S, Randolph TW, Carpenter JF. Physical stability of proteins in aqueous solution: mechanism and driving forces in nonnative protein aggregation. Pharm Res. 2003;20:1325–36.

    CAS  PubMed  Google Scholar 

  297. Wang W. Protein aggregation and its inhibition in biopharmaceutics. Int J Pharm. 2005;289:1–30.

    CAS  PubMed  Google Scholar 

  298. Philo JS, Arakawa T. Mechanisms of protein aggregation. Curr Pharm Biotechnol. 2009;10:348–51.

    CAS  PubMed  Google Scholar 

  299. Mahler H-C, Friess W, Grauschopf U, Kiese S. Protein aggregation: pathways, induction factors, and analysis. J Pharm Sci. 2009;98:2909–34.

    CAS  PubMed  Google Scholar 

  300. Hermeling S, Crommelin DJA, Schellekens H, Jiskoot W. Structure-immunogenicity relationships of therapeutic proteins. Pharm Res. 2004;21:897–903.

    CAS  PubMed  Google Scholar 

  301. Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8:E501–7.

    Google Scholar 

  302. Patro SY, Freund E, Chang BS. Protein formulation and fill-finish operations. Biotechnol Annu Rev. 2002;8:55–84.

    CAS  PubMed  Google Scholar 

  303. Cromwell MEM, Hilario E, Jacobson F. Protein aggregation and bioprocessing. AAPS J. 2006;8:E572–9.

    Google Scholar 

  304. Tyagi AK, Randolph TW, Dong A, Maloney KM, Hitscherich Jr C, Carpenter JF. IgG particle formation during filling pump operation: a case study of heterogeneous nucleation on stainless steel nanoparticles. J Pharm Sci. 2009;98:94–104.

    CAS  PubMed  Google Scholar 

  305. Manning MC, Evans GJ, Payne RW. Stability during bioprocessing. In: Jameel F, Hershenson S, editors. Formulation and process development strategies for manufacturing of a biopharmaceutical. 2010, in press.

  306. Rathore N, Rajan RS. Current perspectives on stability of protein drug products during formulation, fill and finish operations. Biotechnol Prog. 2008;24:504–14.

    CAS  PubMed  Google Scholar 

  307. Kendrick BS, Chang BS, Arakawa T, Peterson B, Randolph TW, Manning MC, et al. Preferential exclusion of sucrose from recombinant interleukin-1 receptor antagonist: role in restricted conformational mobility and compaction of native state. Proc Natl Acad Sci USA. 1997;94:11917–22.

    CAS  PubMed  Google Scholar 

  308. Kendrick BS, Carpenter JF, Cleland JL, Randolph TW. A transient expansion of the native state precedes aggregation of recombinant human interferon-gamma. Proc Natl Acad Sci USA. 1998;95:14142–6.

    CAS  PubMed  Google Scholar 

  309. Krishnan S, Chi EY, Webb JN, Chang BS, Shan D, Goldenberg M, et al. Aggregation of granulocyte colony stimulating factor under physiological conditions: characterization and thermodynamic inhibition. Biochemistry. 2002;41:6422–31.

    CAS  PubMed  Google Scholar 

  310. Kim YS, Jones LS, Dong AC, Kendrick BS, Chang BS, Manning MC, et al. Effects of sucrose on conformational equilibria and fluctuations within the native-state ensemble of proteins. Protein Sci. 2003;12:1252–61.

    CAS  PubMed  Google Scholar 

  311. Bam NB, Cleland JL, Yang J, Manning MC, Carpenter JF, Kelley RF, et al. Tween protects recombinant human growth hormone against agitation-induced damage via hydrophobic interactions. J Pharm Sci. 1998;87:1554–9.

    CAS  PubMed  Google Scholar 

  312. Tsai PK, Volkin DB, Dabora JM, Thompson KC, Bruner MW, Gress JO, et al. Formulation design of acidic fibroblast growth factor. Pharm Res. 1993;10:649–59.

    CAS  PubMed  Google Scholar 

  313. Lee JC, Timasheff SN. The stabilization of proteins by sucrose. J Biol Chem. 1981;256:7193–201.

    CAS  PubMed  Google Scholar 

  314. Arakawa T, Timasheff SN. Stabilization of protein structure by sugars. Biochemistry. 1982;21:6536–44.

    CAS  PubMed  Google Scholar 

  315. Timasheff SN. Control of protein stability and reactions by weakly interacting cosolvents: the simplicity of the complicated. Adv Protein Chem. 1998;51:355–432.

    CAS  PubMed  Google Scholar 

  316. Ferrone F. Analysis of protein aggregation kinetics. Methods Enzymol. 1999;309:256–74.

    CAS  PubMed  Google Scholar 

  317. Roberts CJ. Non-native protein aggregation kinetics. Biotechnol Bioeng. 2007;98:927–38.

    CAS  PubMed  Google Scholar 

  318. Morris AM, Watzky MA, Finke RG. Protein aggregation kinetics, mechanism, and curve-fitting: a review of the literature. Biochim Biophys Acta. 2009;1794:375–97.

    CAS  PubMed  Google Scholar 

  319. Bernacki JP, Murphy RM. Model discrimination and mechanistic interpretation of kinetic data in protein aggregation studies. Biophys J. 2009;96:2871–87.

    CAS  PubMed  Google Scholar 

  320. Weiss IV WF, Young TM, Roberts CJ. Principles, approaches, and challenges for predicting protein aggregation rates and shelf life. J Pharm Sci. 2009;98:1246–77.

    CAS  PubMed  Google Scholar 

  321. Das T, Nema S. Protein particulate issues in biologics development. Am Pharm Rev. 2008;11(4):52–7.

    CAS  Google Scholar 

  322. Carpenter JF, Randolph TW, Jiskoot W, Crommelin DJA, Middaugh CR, Winter G, et al. Overlooking subvisible particles in therapeutic protein products: gaps that may compromise product quality. J Pharm Sci. 2009;98:1201–5.

    CAS  PubMed  Google Scholar 

  323. Sharma DK, King D, Moore P, Oma P, Thomas D. Glow microscopy for particlulate analysis in parenteral and pharmaceutical fluids. Eur J Parenteral Pharm Sci. 2007;12:97–101.

    Google Scholar 

  324. Huang C-T, Sharma D, Oma P, Krishnamurthy R. Quantitation of protein particles in parenteral solutions using micro-flow imaging. J Pharm Sci. 2009;98:3058–71.

    CAS  PubMed  Google Scholar 

  325. Sharma DK, Oma P, Krishnan S. Silicone microdroplets in protein formulations. Pharm Technol. 2009;33(4):74–9.

    CAS  Google Scholar 

  326. Trevino SR, Scholtz JM, Pace CN. Measuring and increasing protein solubility. J Pharm Sci. 2008;97:4155–66.

    CAS  PubMed  Google Scholar 

  327. Matheus S, Friess W, Schwartz D, Mahler H-C. Liquid high concentration IgG1 antibody formulations by precipitation. J Pharm Sci. 2009;98:3043–57.

    CAS  PubMed  Google Scholar 

  328. Middaugh CR, Volkin DB. Protein solubility. In: Ahern TJ, Manning MC, editors. Stability of protein pharmaceuticals, Part A: chemical and physical pathways of protein degradation, pharmaceutical biotechnology, volume 2. New York: Plenum; 1992. p. 109–34.

    Google Scholar 

  329. Stratton LP, Dong A, Manning MC, Carpenter JF. Drug delivery matrix containing native protein precipitates suspended in a poloxamer gel. J Pharm Sci. 1997;86:1006–12.

    CAS  PubMed  Google Scholar 

  330. Sharma VK, Kalonia DS. Polyethylene glycol-induced precipitation of interferon alpha-2a followed by vacuum drying: development of a novel process for obtaining a dry, stable powder. AAPS PharmSci. 2004;6(1):31–44.

    Google Scholar 

  331. Harn NR, Jeng YN, Kostelc JG, Middaugh CR. Spectroscopic analysis of highly concentrated suspensions of bovine somatotropin in sesame oil. J Pharm Sci. 2005;94:2487–95.

    CAS  PubMed  Google Scholar 

  332. Johnston TP. Adsorption of recombinant human granulocyte colony stimulating factor (rhG-CSF) to polyvinyl chloride, polypropylene, and glass: effect of solvent additives. PDA J Pharm Sci Technol. 1996;50:238–45.

    CAS  PubMed  Google Scholar 

  333. Reyes N, Ruiz L, Aroche K, Geronimo H, Brito O, Hardy E. Stability of Ala125 recombinant human interleukin-2 in solution. J Pharm Pharmacol. 2005;57:31–7.

    CAS  PubMed  Google Scholar 

  334. Doran PM. Loss of secreted antibody from transgenic plant tissue cultures due to surface adsorption. J Biotechnol. 2006;122:39–54.

    CAS  PubMed  Google Scholar 

  335. Mutlu S, Cokeliler D, Mutlu M. Modification of food contacting surfaces by plasma polymerization technique. Part II: static and dynamic adsorption behavior of a model protein “bovine serum albumin” on stainless steel surface. J Food Eng. 2007;78:494–9.

    CAS  Google Scholar 

  336. Damodaran S, Song KB. Kinetics of adsorption of proteins at interfaces: role of protein conformation in diffusional adsorption. Biochim Biophy Acta. 1988;954:253–64.

    CAS  Google Scholar 

  337. Maa Y-F, Hsu CC. Protein denaturation by combined effect of shear and air–liquid interface. Biotechnol Bioeng. 1997;54:503–12.

    CAS  PubMed  Google Scholar 

  338. Jones LS, Bam NB, Randolph TW. Surfactant-stabilized protein formulations: a review of protein-surfactants interactions and novel analytical methodologies. ACS Symp Ser. 1997;567:206–22.

    Google Scholar 

  339. Wang W. Instability, stabilization, and formulation of liquid protein pharmaceuticals. Int J Pharm. 1999;185:129–88.

    CAS  PubMed  Google Scholar 

  340. Colombie S, Gaunand A, Lindet B. Lysozyme inactivation under mechanical stirring: effect of physical and molecular interfaces. Enzyme Microb Technol. 2001;28:820–6.

    CAS  PubMed  Google Scholar 

  341. Maa Y-F, Hsu CC. Effect of high shear on proteins. Biotechnol Bioeng. 1996;51:458–65.

    CAS  PubMed  Google Scholar 

  342. Randolph TW, Jones LS. Surfactant-protein interactions. In: Carpenter JF, Manning MC, editors. Pharmaceutical biotechnology, vol. 13, rational design of stable protein formulations. New York: Plenum; 2002. p. 159–75.

    Google Scholar 

  343. Katakam M, Bell LN, Banga AK. Effect of surfactants on the physical stability of recombinant human growth hormone. J Pharm Sci. 1995;84:713–6.

    CAS  PubMed  Google Scholar 

  344. Vidanovic D, Askrabic JM, Stankovic M, Poprzen V. Effects of nonionic surfactants on the physical stability of immunoglobulin G in aqueous solution during mechanical agitation. Pharmazie. 2003;58:399–404.

    CAS  PubMed  Google Scholar 

  345. Mahler H-C, Muller R, Friess W, Delille A, Matheus S. Induction and analysis of aggregates in a liquid IgG1-antibody formulation. Eur J Pharm Biopharm. 2005;59:407–17.

    CAS  PubMed  Google Scholar 

  346. Biddlecombe JG, Craig AV, Zhang H, Uddin S, Mulot S, Fish BC, et al. Determining antibody stability: creation of solid–liquid interfacial effects within a high shear environment. Biotechnol Prog. 2007;23:1218–22.

    CAS  PubMed  Google Scholar 

  347. Chen V, Kim KJ, Fane AG. Effect of membrane morphology and operation on protein deposition in ultrafiltration membranes. Biotechnol Bioeng. 1995;47:174–80.

    CAS  PubMed  Google Scholar 

  348. Maa Y-F, Hsu CC. Membrane fouling in sterile filtration of recombinant human growth hormone. Biotechnol Bioeng. 1996;50:319–28.

    CAS  PubMed  Google Scholar 

  349. Chi EY, Weickmann J, Carpenter JF, Manning MC, Randolph TW. Heterogeneous nucleation-controlled particulate formation of recombinant human platelet-activating factor acetylhydrolase in pharmaceutical formulation. J Pharm Sci. 2005;94:256–74.

    CAS  PubMed  Google Scholar 

  350. Bee JS, Davis M, Freund E, Carpenter JF, Randolph TW. Aggregation of a monoclonal antibody induced by adsorption to stainless steel. Biotechnol Bioeng. 2010;105:121–9.

    CAS  PubMed  Google Scholar 

  351. Markovic I. Challenges associated with extractable and/or leachable substances in therapeutic biologic protein products. Am Pharm Rev. 2006;9(6):20–7.

    CAS  Google Scholar 

  352. Wen Z-Q, Torraca G, Yee C, Li G. Investigation of contaminants in protein pharmaceuticals in pre-filled syringes by multiple micro-spectroscopies. Am Pharm Rev. 2007;10(5):101–7.

    CAS  Google Scholar 

  353. Bee JS, Nelson SA, Freund E, Carpenter JF, Randolph TW. Precipitation of a monoclonal antibody by soluble tungsten. J Pharm Sci. 2009;98:3290–301.

    CAS  PubMed  Google Scholar 

  354. Jiang Y, Nashed-Samuel Y, Li C, Liu W, Pollastrini J, Mallard D, et al. Tungsten-induced protein aggregation: solution behavior. J Pharm Sci. 2009;98:4695–710.

    CAS  PubMed  Google Scholar 

  355. Chantelau E. Silicone oil contamination of insulin. Diabet Med. 1989;6:278.

    CAS  PubMed  Google Scholar 

  356. Chantelau EA, Berger M. Pollution of insulin with silicone oil, a hazard of disposable plastic syringes. Lancet. 1985;1:1459.

    CAS  PubMed  Google Scholar 

  357. Baldwin RN. Contamination of insulin by silicone oil—a potential hazard of plastic insulin syringes. Diabet Med. 1988;5:789–90.

    CAS  PubMed  Google Scholar 

  358. Jones LS, Kaufmann A, Middaugh CR. Silicone oil induced aggregation of proteins. J Pharm Sci. 2005;94:918–27.

    CAS  PubMed  Google Scholar 

  359. Thirumangulathu R, Krishnan S, Ricci MS, Brems DN, Randolph TW, Carpenter JF. Silicone oil- and agitation-induced aggregation of a monoclonal antibody in aqueous solution. J Pharm Sci. 2009;98:3167–81.

    Google Scholar 

  360. Charman SA, Mason KL, Charman WN. Techniques for assessing the effects of pharmaceutical excipients on the aggregation of porcine growth hormone. Pharm Res. 1993;10:954–62.

    CAS  PubMed  Google Scholar 

  361. Kiese S, Pappenberger A, Friess W, Mahler H-C. Shaken, not stirred: mechanical stress testing of an IgG1 antibody. J Pharm Sci. 2008;97:4347–66.

    CAS  PubMed  Google Scholar 

  362. Arakawa T, Dix DB, Chang BS. The effects of protein stabilizers on aggregation induced by multiple-stresses. Yakugaku Zasshi. 2003;123:957–61.

    CAS  PubMed  Google Scholar 

  363. Wendorf JR, Radke CJ, Blanch HW. Reduced protein adsorption at solid interfaces by sugar excipients. Biotechnol Bioeng. 2004;87:565–73.

    CAS  PubMed  Google Scholar 

  364. Karlsson M, Ekeroth J, Elwing H, Carlsson U. Reduction of irreversible protein adsorption on solid surfaces by protein engineering for increased stability. J Biol Chem. 2005;280:25558–64.

    CAS  PubMed  Google Scholar 

  365. Israelachvili J. Intermolecular & surface forces. 2nd ed. San Diego: Academic; 1992.

    Google Scholar 

  366. Guzey D, McClements DJ, Weiss J. Adsorption kinetics of BSA at air–sugar solution interface as affected by sugar type and concentration. Food Res Int. 2003;36:649–60.

    CAS  Google Scholar 

  367. Antipova AS, Semenova MG. Influence of sucrose on the thermodynamic properties of the 11S globulin of Vicia faba-dextran aqueous solvent system. Food Hydrocoll. 1997;11:415–21.

    CAS  Google Scholar 

  368. Cacace MG, Landau EM, Ramsden JJ. The Hofmeister series: salt and solvent effects on interfacial phenomena. Q Rev Biophys. 1997;30:241–77.

    CAS  PubMed  Google Scholar 

  369. Bommarius AS, Karau A. Deactivation of formate dehydrogenase (FDH) in solution and at gas–liquid interfaces. Biotechnol Prog. 2005;21:1663–72.

    CAS  PubMed  Google Scholar 

  370. Fesinmeyer RM, Hogan S, Saluja A, Brych SR, Kras E, Narhi LO, et al. Effect of ions on agitation- and temperature-induced aggregation reactions of antibodies. Pharm Res. 2009;26:903–13.

    CAS  PubMed  Google Scholar 

  371. Eckhardt BM, Oeswein JQ, Bewley TA. Effect of freezing on aggregation of human growth hormone. Pharm Res. 1991;8:1360–4.

    CAS  PubMed  Google Scholar 

  372. Strambini GB, Gabellieri E. Proteins in frozen solutions: evidence of ice-induced partial unfolding. Biophys J. 1996;70:971–6.

    CAS  PubMed  Google Scholar 

  373. Luthra S, Obert J-P, Kalonia DS, Pikal MJ. Investigation of drying stresses on proteins during lyophilization: differentiation between primary and secondary-drying stresses on lactate dehydrogenase using a humidity controlled mini freeze-dryer. J Pharm Sci. 2007;96:61–70.

    CAS  PubMed  Google Scholar 

  374. Hillgren A, Lindgren J, Alden M. Protection mechanism of Tween 80 during freeze-thawing of a model protein, LDH. Int J Pharm. 2002;237:57–69.

    CAS  PubMed  Google Scholar 

  375. Kerwin BA, Heller MC, Levin SH, Randolph TW. Effects of Tween 80 and sucrose on acute short-term stability and long-term storage at −20°C of a recombinant hemoglobin. J Pharm Sci. 1998;87:1062–8.

    CAS  PubMed  Google Scholar 

  376. Krielgaard L, Jones LS, Randolph TW, Frokjaer S, Flink JM, Manning MC, et al. Effect of tween 20 on freeze-thawing and agitation-induced aggregation of recombinant human factor XIII. J Pharm Sci. 1998;87:1597–603.

    Google Scholar 

  377. Kueltzo LA, Wang W, Randolph TW, Carpenter JF. Effects of solution conditions, processing parameters, and container materials on aggregation of a monoclonal antibody during freeze-thawing. J Pharm Sci. 2008;97:1801–12.

    CAS  PubMed  Google Scholar 

  378. Hawe A, Kasper JC, Friess W, Jiskoot W. Structural properties of monoclonal antibody aggregates induced by freeze-thawing and thermal stress. Eur J Pharm Sci. 2009;38:79–87.

    CAS  PubMed  Google Scholar 

  379. Gombotz WR, Pankey SC, Bouchard LS, Phan DH, MacKenzie AP. Stability, characterization, formulation and delivery system development for transforming growth factor-beta1. In: Pearlman R, Wang YJ, editors. Formulation, characterization, and stability of protein drugs. New York: Plenum; 1996. p. 219–45.

    Google Scholar 

  380. Bam NB, Cleland JL, Randolph TW. Molten globule intermediate of recombinant human growth hormone: stabilization with surfactants. Biotechnol Prog. 1996;12:801–9.

    CAS  PubMed  Google Scholar 

  381. Treuheit MJ, Kosky AA, Brems DN. Inverse relationship of protein concentration and aggregation. Pharm Res. 2002;19:511–6.

    CAS  PubMed  Google Scholar 

  382. Timasheff SN. Solvent stabilization of protein structure. Methods Mol Biol. 1995;40:253–69.

    CAS  PubMed  Google Scholar 

  383. Arakawa T, Timasheff SN. The stabilization of proteins by osmolytes. Biophys J. 1985;47:411–4.

    CAS  PubMed  Google Scholar 

  384. Kita Y, Arakawa T, Lin T-Y, Timasheff SN. Contribution of the surface free energy perturbation to protein-solvent interactions. Biochemistry. 1994;33:15178–89.

    CAS  PubMed  Google Scholar 

  385. Gheibi N, Saboury AA, Haghbeen K, Moosavi-Movahedi AA. The effect of some osmolytes on the activity and stability of mushroom tyrosinase. J Biosci. 2006;31:355–62.

    CAS  PubMed  Google Scholar 

  386. Kar K, Alex B, Kishore N. Thermodynamics of the interactions of calcium chloride with α-chymotrypsin. J Chem Thermodyn. 2002;34:319–36.

    CAS  Google Scholar 

  387. Vrkljan M, Foster TM, Powers ME, Henkin J, Porter WR, Staack H, et al. Thermal stability of low molecular weight urokinase during heat treatment. II. Effect of polymeric additives. Pharm Res. 1994;11:1004–8.

    CAS  PubMed  Google Scholar 

  388. Wyman J. Linked functions and reciprocal effects in hemoglobin—a 2nd look. Adv Protein Chem. 1964;19:223–86.

    CAS  PubMed  Google Scholar 

  389. Tanford C. Extension of the theory of linked functions to incorporate the effects of protein hydration. J Mol Biol. 1969;39:539–44.

    CAS  PubMed  Google Scholar 

  390. Miyawaki O. Hydration state change of proteins upon unfolding in sugar solutions. Biochim Biophys Acta. 2007;1774:928–35.

    CAS  PubMed  Google Scholar 

  391. Miyawaki O. Thermodynamic analysis of protein unfolding in aqueous solutions as a multisite reaction of protein with water and solute molecules. Biophys Chemist. 2009;144:46–52.

    CAS  Google Scholar 

  392. Gokarn YR, Kras E, Nodgaard C, Dharmavaram V, Fesinmeyer RM, Hultgen H, et al. Self-buffering antibody formulations. J Pharm Sci. 2008;97:3051–66.

    CAS  PubMed  Google Scholar 

  393. Ugwu SO, Apte SP. The effect of buffers on protein conformational stability. Pharm Technol. 2004;28:86–108.

    CAS  Google Scholar 

  394. Good NE, Winget GD, Winter W, Connolly TN, Izawa S, Singh RMM. Hydrogen ion buffers for biological research. Biochemistry. 1966;5:467–77.

    CAS  PubMed  Google Scholar 

  395. Mezzasalma TM, Kranz JK, Chan W, Struble GT, Schalk-Hihi C, Deckman IC, et al. Enhancing recombinant protein quality and yield by protein stability profiling. J Biomol Screen. 2007;12:418–28.

    CAS  PubMed  Google Scholar 

  396. Fayos R, Pons M, Millet O. On the origin of the thermostabilization of proteins induced by sodium phosphate. J Am Chem Soc. 2005;127:9690–1.

    CAS  PubMed  Google Scholar 

  397. Kameoka D, Masuzaki E, Ueda T, Imoto T. Effect of buffer species on the unfolding and the aggregation of humanized IgG. J Biochem. 2007;142:383–91.

    CAS  PubMed  Google Scholar 

  398. Chen B, Bautista R, Yu K, Zapata GA, Mulkerrin MG, Chamow SM. Influence of histidine on the stability and physical properties of a fully human antibody in aqueous and solid forms. Pharm Res. 2003;20:1952–60.

    CAS  PubMed  Google Scholar 

  399. Katayama DS, Nayar R, Chou DK, Valente JJ, Cooper J, Henry CS, et al. Effect of buffer species on the thermally induced aggregation of interferon-tau. J Pharm Sci. 2006;95:1212–26.

    CAS  PubMed  Google Scholar 

  400. Arakawa T, Philo JS, Kita Y. Kinetic and thermodynamic analysis of thermal unfolding of recombinant erythropoietin. Biosci Biotechnol Biochem. 2001;65:1321–7.

    CAS  PubMed  Google Scholar 

  401. Ruiz L, Aroche K, Reyes N. Aggregation of recombinant human interferon alpha 2b in solution: technical note. AAPS PharmSciTech. 2006;7:E1–5.

    Google Scholar 

  402. Bottomley SP, Tew DJ. The citrate ion increases the conformational stability of α1-antitrypsin. Biochim Biophys Acta. 2001;1481:11–7.

    Google Scholar 

  403. Raibekas AA, Bures EJ, Siska CC, Kohno T, Latypov RF, Kerwin BA. Anion binding and controlled aggregation of human interleukin-1 receptor antagonist. Biochemistry. 2005;44:9871–9.

    CAS  PubMed  Google Scholar 

  404. Bam NB, Randolph TW, Cleland JL. Stability of protein formulations: investigation of surfactant effects by a novel EPR spectroscopic technique. Pharm Res. 1995;12:2–11.

    CAS  PubMed  Google Scholar 

  405. Chou DK, Krishnamurthy R, Randolph TW, Carpenter JF, Manning MC. Effects of Tween 20 and Tween 80 on the stability of Albutropin during agitation. J Pharm Sci. 2005;94:1368–81.

    CAS  PubMed  Google Scholar 

  406. Garidel P, Hoffmann C, Blume A. A thermodynamic analysis of the binding interaction between polysorbate 20 and 80 with human serum albumins and immunoglobulins: a contribution to understand colloidal protein stabilization. Biophys Chemist. 2009;143:70–8.

    CAS  Google Scholar 

  407. Jones LS, Randolph TW, Kohnert U, Papadimitriou A, Winter G, Hagmann M-L, et al. The effect of including Tween 20 and/or sucrose in the lyophilization and reconstitution medium of a lyophilized antibody. J Pharm Sci. 2001;90:1466–77.

    CAS  PubMed  Google Scholar 

  408. Wang P-L, Udeani GO, Johnston TP. Inhibition of granulocyte colony stimulating factor (G-CSF) adsorption to polyvinyl chloride using a nonionic surfactant. Int J Pharm. 1995;114:177–84.

    CAS  Google Scholar 

  409. Matsuura J, Powers ME, Manning MC, Shefter E. Structure and stability of insulin dissolved in 1-octanol. J Am Chem Soc. 1993;115:1261–4.

    CAS  Google Scholar 

  410. Meyer JD, Matsuura JE, Kendrick BS, Evans ES, Evans GJ, Manning MC. Solution behavior of α-chymotrypsin dissolved in nonpolar solvents via hydrophobic ion pairing. Biopolymers. 1995;35:451–6.

    CAS  Google Scholar 

  411. Moriyama Y, Watanabe E, Kobayashi K, Harano H, Inui E, Takeda K. Secondary structural change of bovine serum albumin in thermal denaturation up to 130o C and protective effect of sodium dodecyl sulfate on the change. J Phys Chem B. 2008;112:16585–9.

    CAS  PubMed  Google Scholar 

  412. Rafikova ER, Panyukov YV, Arutyunyan AM, Yaguzhinsky LS, Drachev VA, Dobrov EN. Low sodium dodecyl sulfate concentrations inhibit tobacco mosaic virus coat protein amorphous aggregation and change the protein stability. Biochemistry (Moscow). 2004;69:1372–8.

    CAS  Google Scholar 

  413. Fan H, Vitharana SN, Chen T, O’Keefe D, Middaugh CR. Effects of pH and polyanions on the thermal stability of fibroblast growth factor 20. Mol Pharmacol. 2007;4:232–40.

    CAS  Google Scholar 

  414. Derrick T, Grillo AO, Vitharana SN, Jones L, Rexroad J, Shah A, et al. Effect of polyanions on the structure and stability of repifermin™ (keratinocyte growth factor-2). J Pharm Sci. 2007;96:761–76.

    CAS  PubMed  Google Scholar 

  415. Giger K, Vanham RP, Seyrek E, Dubin PL. Suppression of insulin aggregation by heparin. Biomacromolecules. 2008;9:2338–44.

    CAS  PubMed  Google Scholar 

  416. Fedunova D, Antalik M. Prevention of thermal induced aggregation of cytochrome c at isoelectric pH values by polyanions. Biotechnol Bioeng. 2006;93:485–93.

    CAS  PubMed  Google Scholar 

  417. Prajapati BG, Patel RP, Patel RB, Patel GN, Patel HR, Patel M. Beefing up bioavailability. PFQ. 2007;9(1):42+.

    Google Scholar 

  418. Rao VM, Stella VJ. When can cyclodextrins be considered for solubilization purposes? J Pharm Sci. 2003;92:927–32.

    CAS  PubMed  Google Scholar 

  419. Otzen DE, Knudsen BR, Aachmann F, Larsen KL, Wimmer R. Structural basis for cyclodextrins’ suppression of human growth hormone aggregation. Protein Sci. 2002;11:1779–87.

    CAS  PubMed  Google Scholar 

  420. Tavornvipas S, Tajiri S, Hirayama F, Arima H, Uekama K. Effects of hydrophilic cyclodextrins on aggregation of recombinant human growth hormone. Pharm Res. 2004;21:2369–76.

    CAS  PubMed  Google Scholar 

  421. Tokihiro K, Irie T, Uekama K. Varying effects of cyclodextrin derivatives on aggregation and thermal behavior of insulin in aqueous solution. Chem Pharm Bull. 1997;45:525–31.

    CAS  PubMed  Google Scholar 

  422. Cooper A. Effect of cyclodextrins on the thermal stability of globular proteins. J Am Chem Soc. 1992;114:9208–9.

    CAS  Google Scholar 

  423. Saboury AA, Atri MS, Sanati MH, Moosavi-Movahedi AA, Haghbeen K. Effects of calcium binding on the structure and stability of human growth hormone. Int J Biol Macromol. 2005;36:305–9.

    CAS  PubMed  Google Scholar 

  424. Saboury AA, Atri MS, Sanati MH, Moosavi-Movahedi AA, Hakimelahi GH, Sadeghi M. A thermodynamic study on the interaction between magnesium ion and human growth hormone. Biopolymers. 2006;81:120–6.

    CAS  PubMed  Google Scholar 

  425. Yang T-H, Cleland JL, Lam X, Meyer JD, Jones LS, Randolph TW, et al. Effect of zinc binding and precipitation on structures of recombinant human growth hormone and nerve growth factor. J Pharm Sci. 2000;89:1480–5.

    CAS  PubMed  Google Scholar 

  426. Chen B, Costantino HR, Liu J, Hsu CC, Shire SJ. Influence of calcium ions on the structure and stability of recombinant human deoxyribonuclease 1 in the aqueous and lyophilized states. J Pharm Sci. 1999;88:477–82.

    CAS  PubMed  Google Scholar 

  427. Pretzer D, Schulteis BS, Smith CD, Vander Velde DG, Mitchell JW, Manning MC. Effect of zinc binding on the structure and stability of fibrolase, a fibrinolytic protein from snake venom. Pharm Res. 1992;9:870–7.

    CAS  PubMed  Google Scholar 

  428. Grillo AO, Edwards K-LT, Kashi RS, Shipley KM, Hu L, Besman MJ, et al. Conformational origin of the aggregation of recombinant human factor VIII. Biochemistry. 2001;40:586–95.

    CAS  PubMed  Google Scholar 

  429. Fu Y, Wu X, Han Q, Liang Y, He Y, Luo Y. Sulfate stabilizes the folding intermediate more than the native structure of endostatin. Arch Biochem Biophys. 2008;471:232–9.

    CAS  PubMed  Google Scholar 

  430. Ramos CHI, Baldwin RL. Sulfate anion stabilization of native ribonuclease A both by anion binding and by the Hofmeister effect. Protein Sci. 2002;11:1771–8.

    CAS  PubMed  Google Scholar 

  431. Moody TP, Kingsbury JS, Durant JA, Wilson TJ, Chase SF, Laue TM. Valence and anion binding of bovine ribonuclease A between pH 6 and 8. Anal Biochem. 2005;336:243–52.

    CAS  PubMed  Google Scholar 

  432. Muzammil S, Kumar Y, Tayyab S. Anion-induced stabilization of human serum albumin prevents the formation of intermediate during urea denaturation. Proteins. 2000;40:29–38.

    CAS  PubMed  Google Scholar 

  433. Shrake A, Frazier D, Schwarz FP. Thermal stabilization of human albumin by medium and short-chain n-alkyl fatty acid anions. Biopolymers. 2006;81:235–48.

    CAS  PubMed  Google Scholar 

  434. Hofmeister F. Zur Lehre von der Wirkung der Salze. II. Arch Exp Pathol Pharmakol. 1888;24:247–60.

    Google Scholar 

  435. Von Hippel PH, Schleich T. Ion effects on the solution structure of biological macromolecules. Acc Chem Res. 1969;2:257–65.

    Google Scholar 

  436. Melander W, Horvath C. Salt effects on hydrophobic interactions in precipitation and chromatography of proteins: an interpretation of the lyotropic series. Arch Biochem Biophys. 1977;183:200–15.

    CAS  PubMed  Google Scholar 

  437. Broering JM, Bommarius AS. Evaluation of Hofmeister effects on the kinetic stability of proteins. J Phys Chem B. 2005;109:20612–9.

    CAS  PubMed  Google Scholar 

  438. Jones G, Dole M. The viscosity of aqueous solutions of strong electrolytes with special reference to barium chloride. J Am Chem Soc. 1929;51:2950–64.

    CAS  Google Scholar 

  439. Broering JM, Bommarius AS. Cation and strong co-solute effects on protein kinetic stability. Biochem Soc Trans. 2007;35:1602–5.

    CAS  PubMed  Google Scholar 

  440. Collins KD, Washabaugh MW. The Hofmeister effect and the behavior of water at interfaces. Q Rev Biophys. 1985;18:323–422.

    CAS  PubMed  Google Scholar 

  441. Broering JM, Bommarius AS. Kinetic model for salt-induced protein deactivation. J Phys Chem B. 2008;112:12768–75.

    CAS  PubMed  Google Scholar 

  442. Sedlak E, Stagg L, Wittung-Stafshede P. Effect of Hofmeister ions on protein thermal stability: roles of ion hydration and peptide groups? Arch Biochem Biophys. 2008;479:69–73.

    CAS  PubMed  Google Scholar 

  443. Wilson EK. A renaissance for Hofmeister. Chem Eng News. 2007;85(48):47–9.

    Google Scholar 

  444. Hribar B, Southall NT, Vlachy V, Dill KA. How ions affect the structure of water. J Am Chem Soc. 2002;124:12302–11.

    CAS  PubMed  Google Scholar 

  445. Collins KD. Charge density-dependent strength of hydration and biological structure. Biophys J. 1997;72:65–76.

    CAS  PubMed  Google Scholar 

  446. Collins KD. Ions from the Hofmeister series and osmolytes: effects on proteins in solution and in the crystallization process. Methods. 2004;34:300–11.

    CAS  PubMed  Google Scholar 

  447. Omta AW, Kropman MF, Woutersen S, Bakker HJ. Negligible effect of ions on the hydrogen-bond structure in liquid water. Science. 2003;301:347–9.

    CAS  PubMed  Google Scholar 

  448. Batchelor JD, Olteanu A, Tripathy A, Pielak GJ. Impact of protein denaturants and stabilizers on water structure. J Am Chem Soc. 2004;126:1958–61.

    CAS  PubMed  Google Scholar 

  449. Rosenbaum D, Zamora PC, Zukowski CF. Phase behavior of small attractive colloidal particles. Phys Rev Lett. 1996;76:150–3.

    CAS  PubMed  Google Scholar 

  450. Haas C, Drenth J, Wilson WW. Relation between the solubility of proteins in aqueous solutions and the second virial coefficient of the solution. J Phys Chem B. 1999;103:2808–11.

    CAS  Google Scholar 

  451. Neal BL, Asthagiri D, Lenhoff AM. Molecular origins of osmotic second virial coefficients of proteins. Biophys J. 1998;75:2469–77.

    CAS  PubMed  Google Scholar 

  452. Zhang J, Liu XY. Effect of protein–protein interactions on protein aggregation kinetics. J Chem Phys. 2003;119:10972–6.

    CAS  Google Scholar 

  453. Ho JGS, Middelberg APJ, Ramage P, Kocher HP. The likelihood of aggregation during protein renaturation can be assessed using the second virial coefficient. Protein Sci. 2003;12:708–16.

    CAS  PubMed  Google Scholar 

  454. George A, Chiang Y, Guo B, Arabshahi A, Cai Z, Wilson WW. Second virial coefficient as predictor in protein crystal growth. Methods Enzymol. 1997;276:100–10.

    CAS  Google Scholar 

  455. 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;12:903–13.

    CAS  PubMed  Google Scholar 

  456. Carpenter JF, Pikal MJ, Chang BS, Randolph TW. Rational design of stable lyophilized protein formulations: some practical advice. Pharm Res. 1997;14:969–75.

    CAS  PubMed  Google Scholar 

  457. Carpenter JF, Chang BS, Garzon-Rodriguez W, Randolph TW. Rational design of stable lyophilized protein formulations: theory and practice. In: Carpenter JF, Manning MC, editors. Rational design of stable protein formulations: theory and practice, Pharm. Biotechnol., Volume 13. New York: Plenum; 2002. p. 109–33.

    Google Scholar 

  458. Pikal MJ. Freeze-drying of proteins. Part 2: formulation selection. BioPharm Intl. 1990;3:26–30.

    CAS  Google Scholar 

  459. Wang W. Lyophilization and development of solid protein pharmaceuticals. Int J Pharm. 2000;203:1–60.

    CAS  PubMed  Google Scholar 

  460. Tang X, Pikal MJ. Design of freeze-drying processes for pharmaceuticals: practical advice. Pharm Res. 2004;21:191–200.

    CAS  PubMed  Google Scholar 

  461. Patapoff TW, Overcashier DE. The importance of freezing on lyophilization cycle development. BioPharm Intl. 2002;16–21, March.

  462. Sarciaux J-M, Mansour S, Hageman MJ, Nail SL. Effects of buffer composition and processing conditions on aggregation of bovine IgG during freeze-drying. J Pharm Sci. 1999;88:1354–61.

    CAS  PubMed  Google Scholar 

  463. Anchordoquy TJ, Carpenter JF. Polymers protect lactate dehydrogenase during freeze-drying by inhibiting dissociation in the frozen state. Arch Biochem Biophys. 1996;332:231–8.

    CAS  PubMed  Google Scholar 

  464. Pikal-Cleland KA, Cleland JL, Anchordoquy TJ, Carpenter JF. Effect of glycine on pH changes and protein stability during freeze-thawing in phosphate buffer systems. J Pharm Sci. 2002;91:1969–79.

    CAS  PubMed  Google Scholar 

  465. Pikal-Cleland KA, Rodriguez-Hornedo N, Amidon GL, Carpenter JF. Protein denaturation during freezing and thawing in phosphate buffer systems: monomeric and tetrameric β-galactosidase. Arch Biochem Biophys. 2000;384:398–406.

    CAS  PubMed  Google Scholar 

  466. Shalaev EY, Johnson-Elton TD, Chang LQ, Pikal MJ. Thermophysical properties of pharmaceutically compatible buffers at sub-zero temperatures: implications for freeze-drying. Pharm Res. 2002;19:195–201.

    CAS  PubMed  Google Scholar 

  467. Lam XM, Costantino HR, Overcashier DE, Nguyen TH, Hsu CC. Replacing succinate with glycolate buffer improves the stability of lyophilized interferon-γ. Int J Pharm. 1996;142:85–95.

    CAS  Google Scholar 

  468. Lashmar UT, Vanderburgh M, Little SJ. Bulk freeze-thawing of macromolecules. Effects of cryoconcentration on their formulation and stability. Bioprocess Intl. 2007;5:44–54.

    CAS  Google Scholar 

  469. Webb SD, Webb JN, Hughes TG, Sesin DF, Kincaid AC. Freezing biopharmaceuticals using common techniques- and the magnitude of bulk-scale freeze-concentration. BioPharm Intl. 2002;22–34, May.

  470. Carpenter JF, Crowe JH. Modes of stabilization of a protein by organic solutes during desiccation. Cryobiology. 1988;25:459–70.

    CAS  Google Scholar 

  471. Allison SD, Manning MC, Randolph TW, Middleton K, Davis A, Carpenter JF. Optimization of storage stability of lyophilized actin using combinations of disaccharides and dextran. J Pharm Sci. 2000;89:199–214.

    CAS  PubMed  Google Scholar 

  472. Tzannis ST, Prestrelski SJ. Activity-stability considerations of trypsinogen during spray drying: effects of sucrose. J Pharm Sci. 1999;88:351–9.

    CAS  PubMed  Google Scholar 

  473. Prestrelski SJ, Tedeschi N, Arakawa T, Carpenter JF. Dehydration-induced conformational transitions in proteins and their inhibition by stabilizers. Biophys J. 1993;65:661–71.

    CAS  PubMed  Google Scholar 

  474. Prestrelski SJ, Pikal KA, Arakawa T. Optimization of lyophilization conditions for recombinant human interleukin-2 by dried-state conformational analysis using Fourier-transform infrared spectroscopy. Pharm Res. 1995;12:1250–9.

    CAS  PubMed  Google Scholar 

  475. Katayama DS, Kirchhoff CF, Elliott CM, Johnson RE, Borgmeyer J, Thiele BR, et al. Retrospective statistical analysis of lyophilized protein formulations of progenipoietin using PLS: determination of the critical parameters for long-term storage stability. J Pharm Sci. 2004;93:2609–23.

    CAS  PubMed  Google Scholar 

  476. Pikal MJ, Rigsbee D, Roy ML, Galreath D, Kovach KJ, Wang B, et al. Solid state chemistry of proteins: II. The correlation of storage stability of freeze-dried human growth hormone (hGH) with structure and dynamics in the glassy solid. J Pharm Sci. 2008;97:5106–21.

    CAS  PubMed  Google Scholar 

  477. Meyer JD, Nayar R, Manning MC. Impact of bulking agents on the stability of a lyophilized monoclonal antibody. Eur J Pharm Sci. 2009;38:29–38.

    CAS  PubMed  Google Scholar 

  478. Duddu SP, DalMonte PR. Effect of glass transition temperature on the stability of lyophilized formulations containing a chimeric therapeutic monoclonal antibody. Pharm Res. 1997;14:591–5.

    CAS  PubMed  Google Scholar 

  479. Duddu SP, Zhang GZ, DalMonte PR. The relationship between protein aggregation and molecular mobility below the glass transition temperature of lyophilized formulations containing a monoclonal antibody. Pharm Res. 1997;14:596–600.

    CAS  PubMed  Google Scholar 

  480. Davidson P, Sun WQ. Effect of sucrose/raffinose mass ratios on the stability of co-lyophilized protein during storage above the T g. Pharm Res. 2001;18:474–9.

    CAS  PubMed  Google Scholar 

  481. Schebor C, del Pilar Buera M, Chirife J. Glassy state in relation to the thermal inactivation of the enzyme invertase in amorphous dried matrices of trehalose, maltodextrin and PVP. J Food Eng. 1996;30:269–82.

    Google Scholar 

  482. Randolph TW. Phase separation of excipients during lyophilization: effects on protein stability. J Pharm Sci. 1997;86:1198–203.

    CAS  PubMed  Google Scholar 

  483. Cordone L, Cottone G, Giuffrida S, Palazzo S, Venturdi G, Viappiani C. Internal dynamics and protein-matrix coupling in trehalose-coated proteins. Biochim Biophys Acta. 2005;1749:252–81.

    CAS  PubMed  Google Scholar 

  484. Francia F, Dezi M, Mallardi A, Palazzo G, Cordone L, Venturoli G. Protein matrix coupling/uncoupling in “dry” systems of photosynthetic reaction center embedded in trehalose/sucrose: the origin of trehalose peculiarity. J Am Chem Soc. 2008;130:10240–6.

    CAS  PubMed  Google Scholar 

  485. Dranca I, Bhattacharya S, Vyazovkin S, Suryanarayanan R. Implications of global and local mobility in amorphous sucrose and trehalose as determined by differential scanning calorimetry. Pharm Res. 2009;26:1064–72.

    CAS  PubMed  Google Scholar 

  486. Giuffrida S, Cottone G, Cordone L. Role of solvent on protein-matrix coupling in MbCO embedded in water-saccharide systems: a fourier transform infrared spectroscopy study. Biophys J. 2006;91:968–80.

    CAS  PubMed  Google Scholar 

  487. Cottone G. A comparative study of carboxy myoglobin in saccharide-water systems by molecular dynamics simulation. J Phys Chem B. 2007;111:3563–9.

    CAS  PubMed  Google Scholar 

  488. Cicerone MT, Tellington A, Trost L, Sokolov A. The role of glassy dynamics in preservation of biopharmaceuticals. Bioprocess Int. 2003;1:36–47.

    CAS  Google Scholar 

  489. Cicerone MT, Soles CL. Fast dynamics and stabilization of proteins: binary glasses of trehalose and glycerol. Biophys J. 2004;86:3836–46.

    CAS  PubMed  Google Scholar 

  490. Cicerone MT, Soles CL, Chowdhuri Z, Pikal MJ, Chang L. Fast dynamics as a diagnostic for excipients in preservation of dried proteins. Am Pharm Rev. 2005;8:22–7.

    CAS  Google Scholar 

  491. Caliskan G, Mechtani D, Roh JH, Kisliuk A, Sokolov AP, Azzam S, et al. Protein and solvent dynamics: how strongly are they coupled? J Chem Phys. 2004;121:1978–83.

    CAS  PubMed  Google Scholar 

  492. Chang L, Shepherd D, Sun J, Tang X, Pikal MJ. Effect of sorbitol and residual moisture on the stability of lyophilized antibodies: implications for the mechanism of protein stabilization in the solid state. J Pharm Sci. 2005;94:1445–55.

    CAS  PubMed  Google Scholar 

  493. Athamneh AI, Griffin M, Whaley M, Barone JR. Conformational changes and molecular mobility in plasticized proteins. Biomacromolecules. 2008;9:3181–7.

    CAS  PubMed  Google Scholar 

  494. Luthra SA, Hodge IM, Utz M, Pikal MJ. Correlation of annealing with chemical stability in lyophilized pharmaceutical glasses. J Pharm Sci. 2008;97:5240–51.

    CAS  PubMed  Google Scholar 

  495. Luthra SA, Hodge IM, Pikal MJ. Investigation of the impact of annealing on global molecular mobility in glasses: optimization for stabilization of amorphous pharmaceuticals. J Pharm Sci. 2008;97:3865–82.

    CAS  PubMed  Google Scholar 

  496. Randolph TW, Searles JA. Freezing and annealing phenomena in lyophilization: effects upon primary drying rate, morphology, and heterogeneity. Am Pharm Rev. 2002;4:40–6.

    Google Scholar 

  497. Izutsu K, Yoshioka S, Terao T. Decreased protein-stabilizing effects of cryoprotectants due to crystallization. Pharm Res. 1993;10:1232–7.

    CAS  PubMed  Google Scholar 

  498. Izutsu K, Kojima S. Excipient crystallinity and its protein-structure-stabilizing effect during freeze-drying. J Pharm Pharmacol. 2002;54:1033–9.

    CAS  PubMed  Google Scholar 

  499. Garzon-Rodriguez W, Koval RL, Chongprasert S, Krishnan S, Randolph TW, Warne NW, et al. Optimizing storage stability of lyophilized recombinant human interleukin-11 with disaccharide/hydroxyethyl starch mixtures. J Pharm Sci. 2004;93:684–96.

    CAS  PubMed  Google Scholar 

  500. Mattern M, Winter G, Kohnert U, Lee G. Formulation of proteins in vacuum-dried glasses. II. Process and storage stability in sugar-free amino acid systems. Pharm Dev Technol. 1999;4:199–208.

    CAS  PubMed  Google Scholar 

  501. Tian F, Sane S, Rytting JH. Calorimetric investigation of protein/amino acid investigations in the solid state. Int J Pharm. 2006;310:175–86.

    CAS  PubMed  Google Scholar 

  502. Tian F, Middaugh CR, Offerdahl T, Munson E, Sane S, Rytting JH. Spectroscopic evaluation of the stabilization of humanized monoclonal antibodies in amino acid formulations. Int J Pharm. 2007;335:20–31.

    CAS  PubMed  Google Scholar 

  503. Izutsu K, Kadoya S, Yomota C, Kawanishi T, Yonemochi E, Terada K. Freeze-drying of proteins in glass solids formed by basic amino acids and dicarboxylic acids. Chem Pharm Bull. 2009;57:43–8.

    CAS  PubMed  Google Scholar 

  504. Ragoonanan V, Aksan A. Heterogeneity in desiccated solutions: implications for biostabilization. Biophys J. 2008;94:2212–27.

    CAS  PubMed  Google Scholar 

  505. Izutsu K, Fujimaki Y, Kuwabara A, Aoyagi N. Effect of counterions on the physical properties of 1-arginine in frozen solutions and freeze-dried solids. Int J Pharm. 2005;301:161–9.

    CAS  PubMed  Google Scholar 

  506. Kadoya S, Izutsu K, Yonemochi E, Terada K, Yomota C, Kawanishi T. Glass-state amorphous salt solids formed by freeze-drying of amines and hydroxy carboxylic acids: effect of hydrogen-bonding and electrostatic interactions. Chem Pharm Bull. 2008;56:821–6.

    CAS  PubMed  Google Scholar 

  507. Adler M, Lee G. Stability and surface activity of lactate dehydrogenase in spray-dried trehalose. J Pharm Sci. 1999;88:199–208.

    CAS  PubMed  Google Scholar 

  508. Lee G. Spray-drying of proteins. In: Carpenter JF, Manning MC, editors. Rational design of stable protein formulations: theory and practice, Pharm. Biotechnol, Volume 13. New York: Plenum; 2002. p. 135–58.

    Google Scholar 

  509. Ameri M, Maa YF. Spray drying of biopharmaceuticals: stability and process considerations. Drying Technol. 2006;24:763–8.

    CAS  Google Scholar 

  510. Hulse WL, Forbes RT, Bonner ML, Getrost M. Do co-spray dried excipients offer better lysozyme stabilization than single excipients. Eur J Pharm Sci. 2008;33:294–305.

    CAS  PubMed  Google Scholar 

  511. Maury M, Murphy K, Kumar S, Mauerer A, Lee G. Spray-drying of proteins: effects of sorbitol and trehalose on aggregation and FT-IR amide I spectrum of an immunoglobulin G. Eur J Pharm Biopharm. 2005;59:251–61.

    CAS  PubMed  Google Scholar 

  512. Schüle S, Frieb W, Bechtold-Peters K, Garidel P. Conformational analysis of protein secondary structure during spray-drying of antibody/mannitol formulations. Eur J Pharm Biopharm. 2007;65:1–9.

    PubMed  Google Scholar 

  513. Abdul-Fattah AM, Kalonia DS, Pikal MJ. The challenge of drying method selection for protein pharmaceuticals: product quality implications. J Pharm Sci. 2007;96:1886–916.

    CAS  PubMed  Google Scholar 

  514. Costantino HR, Firouzabadian L, Hogeland K, Wu C, Beganski C, Carrasquillo KG, et al. Protein spray freeze-drying. Effect of atomization conditions on particle size and stability. Pharm Res. 2000;17:1374–82.

    CAS  PubMed  Google Scholar 

  515. Costantino HR, Firouzabadian L, Wu C, Carrasquillo KG, Griebenow K, Zale SE, et al. Protein spray freeze drying. 2. Effect of formulation variables on particle size and stability. J Pharm Sci. 2002;91:388–95.

    CAS  PubMed  Google Scholar 

  516. Yu Z, Rogers TL, Hu J, Johnston KP, Williams III RO. Preparation and characterization of microparticles containing peptide produced by a novel process: spray freezing into liquid. Eur J Pharm Biopharm. 2002;54:221–8.

    CAS  PubMed  Google Scholar 

  517. Yu Z, Garcia AS, Johnston KP, Williams III RO. Spray freezing into liquid nitrogen for highly stable protein nanostructured microparticles. Eur J Pharm Biopharm. 2004;58:529–37.

    CAS  PubMed  Google Scholar 

  518. Yu Z, Johnston KP, Williams III RO. Spray freezing into liquid versus spray-freeze drying: influence of atomization on protein aggregation and biological activity. Eur J Pharm Sci. 2006;27:9–18.

    CAS  PubMed  Google Scholar 

  519. Mattern M, Winter G, Rudolph R, Lee G. Formulation of proteins in vacuum-dried glasses. I: Improved vacuum-drying of sugars using crystallizing amino acids. Eur J Pharm Biopharm. 1997;44:177–85.

    CAS  Google Scholar 

  520. Kumar V, Sharma VK, Kalonia DS. In situ precipitation and vacuum drying of interferon alpha-2a: development of a single-step process for obtaining dry, stable protein formulation. Int J Pharm. 2009;366:88–98.

    CAS  PubMed  Google Scholar 

  521. Abdul-Fattah AM, Lechuga-Ballesteros D, Kalonia DS, Pikal MJ. The impact of drying method and formulation on the physical properties and stability of methionyl human growth hormone in the amorphous solid state. J Pharm Sci. 2008;97:163–84.

    CAS  PubMed  Google Scholar 

  522. Jovanovi N, Bouchard A, Hofland GW, Witkamp G-J, Crommelin DJA, Jiskoot W. Distinct effects of sucrose and trehalose on protein stability during supercritical fluid drying and freeze-drying. Eur J Pharm Sci. 2006;27:336–45.

    Google Scholar 

  523. Jovanovi N, Bouchard A, Hofland GW, Witkamp G-J, Crommelin DJA, Jiskoot W. Stabilization of IgG by supercritical fluid drying: optimization of formulation and process parameters. Eur J Pharm Biopharm. 2008;68:183–90.

    Google Scholar 

  524. Jovanovi N, Bouchard A, Sutter M, Speybroeck MV, Hofland GW, Witkamp G-J, et al. Stable sugar-based protein formulations by supercritical fluid drying. Int J Pharm. 2008;346:102–8.

    Google Scholar 

  525. Todo H, Iida K, Okamoto H, Danjo K. Improvement of insulin absorption from intratracheally administrated dry powder prepared by supercritical carbon dioxide process. J Pharm Sci. 2003;92:2475–86.

    CAS  PubMed  Google Scholar 

  526. Maa Y-F, Prestrelski SJ. Biopharmaceutical powders: particle formation and formulation considerations. Curr Pharm Biotechnol. 2000;1:283–302.

    CAS  PubMed  Google Scholar 

  527. Nosoh Y, Sekiguchi T. Protein stability and stabilization through protein engineering. Chichester: Ellis Horwood; 1991.

    Google Scholar 

  528. Brannigan JA, Wilkinson AJ. Protein engineering 20 years on. Nat Rev Mol Cell Biol. 2002;3:964–70.

    CAS  PubMed  Google Scholar 

  529. Brems DN, Plaisted SM, Havel HA, Tomich CSC. Stabilization of an associated folding intermediate of bovine growth hormone by site-directed mutagenesis. Proc Natl Acad Sci USA. 1988;85:3367–71.

    CAS  PubMed  Google Scholar 

  530. Lehrman SR, Tuls JL, Havel HA, Haskell RJ, Putnam SD, Tomich CS. Site-directed mutagenesis to probe protein folding: evidence that the formation and aggregation of a bovine growth hormone folding intermediate are dissociable processes. Biochemistry. 1991;30:5777–84.

    CAS  PubMed  Google Scholar 

  531. Ricci M, Pallitto M, Narhi L, Boone T, Brems D. Mutational approach to improve physical stability of protein therapeutics susceptible to aggregation. Role of altered conformation in irreversible precipitation. In: Murphy RM, Tsai AM, editors. Misbehaving proteins: protein (Mis)folding, aggregation, and stability. New York: Springer; 2006. p. 331–50.

    Google Scholar 

  532. Fu H, Grimsley GR, Razvi A, Scholtz JM, Pace CN. Increasign protein stability by improving beta-turns. Proteins. 2009;77:491–8.

    CAS  PubMed  Google Scholar 

  533. Desiderio A, Franconi R, Lopez M, Villani ME, Viti F, Chiaraluce R, et al. A semi-synthetic repertoire of intrinsically stable antibody fragments derived from a single-framework scaffold. J Mol Biol. 2001;310:603–15.

    CAS  PubMed  Google Scholar 

  534. Brockmann E-C, Cooper M, Stromsten N, Vehniainen M, Saviranta P. Selecting for antibody scFv fragments with improved stability using phage display with denaturation under reducing conditions. J Immunol Meth. 2005;296:159–70.

    CAS  Google Scholar 

  535. Chennamsetty N, Voynov V, Kayser V, Helk B, Trout BL. Design of therapeutic proteins with enhanced stability. Proc Natl Acad Sci USA. 2009;106:11937–42.

    CAS  PubMed  Google Scholar 

  536. Monsellier E, Bedouelle H. Improving the stability of an antibody variable fragment by a combination of knowledge-based approaches: validation and mechanisms. J Mol Biol. 2006;362:580–93.

    CAS  PubMed  Google Scholar 

  537. Manning MC, Evans GJ, Van Pelt CM, Payne RW. Prediction of aggregation propensity from primary sequence information. In: Jameel F, Hershenson S, editors. Formulation and process development strategies for manufacturing of a biopharmaceutical. 2010, in press.

  538. Sadeghi M, Naderi-Manesh H, Zarrabi M, Ranjbar B. Effective factors in thermostability of thermophilic proteins. Biophys Chemist. 2006;119:256–70.

    CAS  Google Scholar 

  539. Ghosh K, Dill KA. Computing protein stabilities from their chain lengths. Proc Natl Acad Sci USA. 2009;106:10649–54.

    CAS  PubMed  Google Scholar 

  540. De Groot AS, Moise L. Prediction of immunogenicity for therapeutic proteins: state of the art. Curr Opin Drug Disc Dev. 2007;10:332–40.

    Google Scholar 

  541. 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.

    PubMed  Google Scholar 

  542. Shivange AV, Marienhagen J, Mundhada H, Schenk A, Schwaneberg U. Advances in generating functional diversity for directed protein evolution. Curr Opin Chem Biol. 2009;13:19–25.

    CAS  PubMed  Google Scholar 

  543. Dudgeon K, Famm K, Christ D. Sequence determinants of protein aggregation in human VH domains. Protein Eng Des Select. 2009;22:217–20.

    CAS  Google Scholar 

  544. Gribenko AV, Patel MM, Liu J, McCallum SA, Wang C, Makhatadze GI. Rational stabilization of enzymes by computational redesign of surface charge–charge interactions. Proc Natl Acad Sci USA. 2009;106:2601–6.

    CAS  PubMed  Google Scholar 

  545. Dahiyat BI. In silico design for protein stabilization. Curr Opin Biotechnol. 1999;10:387–90.

    CAS  PubMed  Google Scholar 

  546. Reinders J, Sickmann A. Modificomics: posttranslational modifications beyond protein phosphorylation and glycosylation. Biomol Eng. 2007;24:169–77.

    CAS  PubMed  Google Scholar 

  547. Veronese FM, Mero A. The impact of PEGylation on biological therapies. BioDrugs. 2008;22:315–29.

    CAS  PubMed  Google Scholar 

  548. Basu A, Yang K, Wang M, Liu S, Chintala R, Palm T, et al. Structure-function engineering of interferon-β-1b for improving stability, solubility, potentcy, immunogenicity, and pharmacokinetic properties by site-selective mono-PEGylation. Bioconjug Chem. 2006;17:618–30.

    CAS  PubMed  Google Scholar 

  549. Treetharnmathurot B, Ovartlarnporn C, Wungsintaweekul J, Duncan R, Wiwattanapatapee R. Effect of PEG molecular weight and linking chemistry on the biological activity and thermal stability of PEGylated trypsin. Int J Pharm. 2008;357:252–9.

    CAS  PubMed  Google Scholar 

  550. Rodriguez-Martinez JA, Solá RJ, Castillo B, Cintron-Colon HR, Rivera-Rivera I, Barletta G, et al. Stabilization of α-chymotrypsin upon PEGylation correlates with reduced structural dynamics. Biotechnol Bioeng. 2008;101:1142–9.

    CAS  PubMed  Google Scholar 

  551. Nie Y, Zhang X, Wang X, Chen J. Preparation and stability of N-terminal mono-PEGylated recombinant human endostatin. Bioconjug Chem. 2006;17:147–54.

    Google Scholar 

  552. Kim S-H, Lee Y-S, Hwang S-Y, Bae G-W, Nho K, Kang S-W, et al. Effects of PEGylated scFv antibodies against plasmodium vivax duffy binding protein on the biological activity and stability in vitro. J Microbiol Biotechnol. 2007;17:1670–4.

    CAS  PubMed  Google Scholar 

  553. Apweiler R, Hermjakob H, Sharon N. On the frequency of protein glycosylation, as deduced from analysis of the SWISS-PROT database. Biochim Biophys Acta. 1999;1473:4–8.

    CAS  PubMed  Google Scholar 

  554. Solá RJ, Griebenow K. Effects of glycosylation on the stability of protein pharmaceuticals. J Pharm Sci. 2009;98:1223–45.

    PubMed  Google Scholar 

  555. Solá RJ, Griebenow K. Chemical glycosylation: new insights on the interrelation between protein structural mobility, thermodynamic stability, and catalysis. FEBS Lett. 2006;580:1685–90.

    PubMed  Google Scholar 

  556. Solá RJ, Rodriguez-Martinez JA, Griebenow K. Modulation of protein biophysical properties by chemical glycosylation: biochemical insights and biomedical implications. Cell Mol Life Sci. 2007;64:2133–52.

    PubMed  Google Scholar 

  557. Uchida E, Morimoto K, Kawasaki N, Izaki Y, Said AA, Hayakawa T. Effect of active oxygen radicals on protein and carbohydrate moieties of recombinant human erythropoietin. Free Radic Res. 1997;27:311–23.

    CAS  PubMed  Google Scholar 

  558. Pham VT, Ewing E, Kaplan H, Choma C, Hefford MA. Glycation improves the thermostability of trypsin and chymotrypsin. Biotechnol Bioeng. 2008;101:452–9.

    CAS  PubMed  Google Scholar 

  559. Fágáin C. Understanding and increasing protein stability. Biochim Biophys Acta. 1995;1252:1–14.

    PubMed  Google Scholar 

  560. Mozhaev VV, Siknis VA, Melik-Nubarov NS, Galkantaite NZ, Denis GJ, Butkus EP, et al. Protein stabilization via hydrophilization. Eur J Biochem. 1988;173:147–54.

    CAS  PubMed  Google Scholar 

  561. Takata T, Oxford JT, Brandon TR, Lampi KJ. Deamidation alters the structure and decreases the stability of human lens βA3-crystallin. Biochemistry. 2007;46:8861–71.

    CAS  PubMed  Google Scholar 

  562. Takata T, Oxford JT, Demeler B, Lampi KJ. Deamidation destabilizes and triggers aggregation of a lens protein, βA3-crystallin. Protein Sci. 2008;17:1565–75.

    CAS  PubMed  Google Scholar 

  563. Wilmarth PA, Tanner S, Dasari S, Nagella SR, Riviere MA, Bafna V, et al. Age-related changes in human crystallins determined from comparative analysis of post-translational modifications in young and aged lens: does deamidation contribute to crystallin insolubility? J Proteome Res. 2006;5:2554–66.

    CAS  PubMed  Google Scholar 

  564. Silva T, Kirkpatrick A, Brodsky B, Ramshaw JAM. Effect of deamidation on stability for the collagen to gelatin transition. J Agric Food Chem. 2005;53:7802–6.

    CAS  PubMed  Google Scholar 

  565. Harms MJ, Wilmarth PA, Kapfer DM, Steel EA, David LL, Bachinger HP, et al. Laser light-scattering evidence for an altered association of βb1-crystallin deamidated in the connecting peptide. Protein Sci. 2004;13:678–86.

    CAS  PubMed  Google Scholar 

  566. Lampi KJ, Kim YH, Bachinger HP, Boswell BA, Lindner RA, Carver JA, et al. Decreased heat stability and increase chaperone requirement at modified human βB1-crystallin. Mol Vision. 2002;8:359–66.

    CAS  Google Scholar 

  567. Kim YH, Kapfer DM, Boekhorst J, Lubsen NH, Bächinger HP, Shearer TR, et al. Deamidation, but not truncation, decreases the urea stability of a lens structural protein, βB1-crystallin. Biochemistry. 2002;41:14076–84.

    CAS  PubMed  Google Scholar 

  568. Shimizu T, Fukuda H, Murayama S, Izumiyama N, Shirasawa T. Isoaspartate formation at position 23 of amyloid beta peptide enhanced fibril formation and deposited onto senile plaques and vascular amyloids in Alzheimer’s disease. J Neurochem Res. 2002;70:451–61.

    CAS  Google Scholar 

  569. Nilsson MR, Driscoll M, Raleigh DP. Low levels of asparagine deamidation can have a dramatic effect on aggregation of amyloidogenic peptides: implications for the study of amyloid formation. Protein Sci. 2002;11:342–9.

    CAS  PubMed  Google Scholar 

  570. Kad NM, Thomson NH, Smith DP, Smith DA, Radford SE. Beta(2)-microglobulin and its deamidated variant N17D form amyloid fibrils with a range of morphologies in vitro. J Mol Biol. 2001;313:559–71.

    CAS  PubMed  Google Scholar 

  571. Bouma B, Kroon-Batenburg LMJ, Wu YP, Brunjes B, Posthuma G, Kranenburg O, et al. Glycation induces formation of amyloid cross-β structure in albumin. J Biol Chem. 2003;278:41810–9.

    CAS  PubMed  Google Scholar 

  572. Krishnan S, Chi EY, Wood SJ, Kendrick BS, Li C, Garzon-Rodriguez W, et al. Oxidative dimer formation is the critical rate-limiting step for Parkinson’s disease α-synuclein fibrillogenesis. Biochemistry. 2003;42:829–37.

    CAS  PubMed  Google Scholar 

  573. Gaudiano MC, Colone M, Bombelli C, Chistolini P, Valvo L, Diociaiuti M. Early stages of salmon calcitonin aggregation: effect induced by ageing and oxidation processes in water and in the presence of model membranes. Biochim Biophys Acta. 2005;1750:134–45.

    CAS  PubMed  Google Scholar 

  574. Hawkins CL, Davies MJ. The role of aromatic amino acid oxidation, protein unfolding, and aggregation in the lypobromous acid-induced inactivation of trypsin inhibitor and lysozyme. Chem Res Toxicol. 2005;18:1669–77.

    CAS  PubMed  Google Scholar 

  575. Barteri M, Coluzza C, Rotella S. Fractal aggregation of porcine fumarase induced by free radicals. Biochim Biophys Acta. 2007;1774:192–9.

    CAS  PubMed  Google Scholar 

  576. Fisher MT, Stadtman ER. Oxidative modification of Escherichia coli glutamine synthetase—decreases in the thermodynamic stability of protein structure and specific changes in the active site conformation. J Biol Chem. 1992;267:1872–80.

    CAS  PubMed  Google Scholar 

  577. Gao J, Yin DH, Yao YH, Sun HY, Qin ZH, Schoneich C, et al. Loss of conformational stability in calmodulin upon methionine oxidation. Biophys J. 1998;74:1115–34.

    CAS  PubMed  Google Scholar 

Download references

ACKNOWLEDGMENTS

The assistance of Gabe Evans with the reference formatting and proofreading is gratefully appreciated.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mark Cornell Manning.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Manning, M.C., Chou, D.K., Murphy, B.M. et al. Stability of Protein Pharmaceuticals: An Update. Pharm Res 27, 544–575 (2010). https://doi.org/10.1007/s11095-009-0045-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-009-0045-6

KEY WORDS

Navigation