High-dose monoclonal antibodies via the subcutaneous route: Challenges and technical solutions, an industry perspective

Therapeutic Delivery

Volumn 3, Issue 7, 2012, Pages 889-900

  Narasimhan, Chakravarthy ^a   MacH, Henryk ^a   Shameem, Mohammed ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

MONOCLONAL ANTIBODY;

BIOMEDICAL ENGINEERING; CRYSTALLIZATION; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DESIGN; DRUG HALF LIFE; DRUG INDUSTRY; DRUG MEGADOSE; DRUG TRANSPORT; FREEZE DRYING; HUMAN; NONHUMAN; PARTICLE SIZE; PHASE SEPARATION; PRIORITY JOURNAL; PRODUCT DEVELOPMENT; PROTEIN AGGREGATION; REVIEW; SELF INJECTION; SPRAY DRYING; SUSPENSION;

EID: 84864579215     PISSN: 20415990     EISSN: 20416008     Source Type: Journal    
DOI: 10.4155/tde.12.68     Document Type: Review

References (159)

1. Ansel HCA, Popovich LV, Allen LV. Pharmaceutical Dosage Forms and Drug Delivery Systems (8th Edition). Williams & Wilkins, PA, USA (2004).
2. Brian Meyer MS. Commercial Therapeutic Protein Drug Products. Woodhead Publishing, Oxford, UK, 1-9 (2011).
3. Dani B, Platz R, Tzannis ST. High concentration formulation feasibility of human immunoglubulin G for subcutaneous administration. J. Pharm. Sci. 96(6), 1504-1517 (2007).
4. Rantner M. Roche plans for more convenient-to-use Herceptin® and Rituxan®. Nat. Biotechnol. 28(4), 298 (2010).
5. Montagna M, Montillo M, Avanzini MA et al. Relationship between pharmacokinetic profile of subcutaneously administered alemtuzumab and clinical response in patients with chronic lymphocytic leukemia. Haematologica 96(6), 932-936 (2011).
6. Xu Z, Wang Q, Zhuang Y et al. Subcutaneous bioavailability of golimumab at 3 different injection sites in healthy subjects. J. Clin. Pharmacol. 50(3), 276-284 (2010).
7. Mach H, Gregory S, Mittal S, Lalloo A, Kirchmeier M, Shameem M. Electrostatic interactions of monoclonal antibodies with subcutaneous tissue. Therapeutic Delivery 2(6), 727-736 (2011).
8. Arakawa T. Solvation and properties of proteins. Tanpakushitsu Kakusan Koso 30(2), 103-111 (1985).
9. Shire SJ, Gombotz W, Bechtold-Peters K, Andya J. Current trends in monoclonal antibody development and manufacturing. Excellent review on high concentration formulation development of monoclonal antibodies. Biotechnol. Pharm. Aspects 11, 351 (2010).
10. Shire SJ, Shahrokh Z, Liu J. Challenges in the development of high protein concentration formulations. Current trends in monoclonal antibody development and manufacturing. Biotechnol. Pharm. Aspects 11, 131-147 (2010).
11. Kamerzell TJ, Kanai S, Liu J, Shire SJ, Wang YJ. Increasing IgG concentration modulates the conformational heterogeneity and bonding network that influence solution properties. J. Phys. Chem. B 113(17), 6109-6118 (2009).
12. Kanai S, Liu J, Patapoff TW, Shire SJ. Reversible self-association of a concentrated monoclonal antibody solution mediated by Fab-Fab interaction that impacts solution viscosity. J. Pharm. Sci. 97(10), 4219-4227 (2008).
13. Liu J, Nguyen MDH, Andya JD, Shire SJ. Reversible self-association increases the viscosity of a concentrated monoclonal antibody in aqueous solution. J. Pharm. Sci. 94(9), 1928-1940 (2005).
14. Yadav S, Shire SJ, Kalonia DS. Viscosity analysis of high concentration bovine serum albumin aqueous solutions. Pharm. Res. 28(8), 1973-1983 (2011).
15. Yadav S, Shire SJ, Kalonia DS. Viscosity behavior of high-concentration monoclonal antibody solutions: Correlation with interaction parameter and electroviscous effects. J. Pharm. Sci. 101(3), 998-1011 (2011).
16. Salinas BA, Sathish HA, Bishop SM, Harn N, Carpenter JF, Randolph TW. Understanding and modulating opalescence and viscosity in a monoclonal antibody formulation. J. Pharm. Sci. 99(1), 82-93 (2009).
17. Saluja A, Kalonia DS. Measurement of fluid viscosity at microtiter volumes using quuartz impedance analysis. AAPS PharmSciTech 5(3), 47 (2004).
18. Yadav S, Liu J, Shire SJ, Kalonia DS. Specific interactions in high concentration antibody solutions resulting in high viscosity. J. Pharm. Sci. 99(3), 1152-1168 (2010).
19. Minton AP. The influence of macromolecular crowding and macromolecular confinement on biochemical reactions in physiological media. J. Biol. Chem. 276(14), 10577-10580 (2001).
20. Minton AP 2000. Implications of macromolecular crowding for protein assembly. Curr. Opin. Struct. Biol. 10(1), 34-39 (2000).
21. Nishi H, Miyajima M, Nakagami H, Noda M, Uchiyama S, Fukui K. Phase separation of an IgG1 antibody solution under a low ionic strength condition. Pharm. Res. 27(7), 1348-1360 (2010).
22. Scherer TM, Liu J, Shire SJ, Minton AP. Intermolecular interactions of IgG1 monoclonal antibodies at high concentrations characterized by light scattering. J. Phys. Chem. B 114(40), 12948-12957 (2010).
23. Yadav S, Sreedhara A, Kanai S et al. Establishing a link between amino acid sequences and self-associating and viscoelastic behavior of two closely related monoclonal antibodies. Pharm. Res. 28(7), 1750-1764 (2011).
24. Printz M, Kalonia DS, Friess W. Individual second virial coefficient determination of monomer and oligomers in heat-stressed protein samples using size-exclusion chromatography-light scattering. J. Pharm. Sci. 101(1), 363-372 (2012).
25. Mach H, Arvinte T. Addressing new analytical challenges in protein formulation development. Eur. J. Pharm. Biopharm. 78(2), 196-207 (2011).
26. Gokarn YR, Fesinmeyer RM, Saluja A, Razinkov V, Chase SF, Laue TM, Brems DN. Effective charge measurements reveal selective and preferential accumulation of anions, but not cations, at the protein surface in dilute salt solutions. Protein Sci. 20(3), 580-587 (2011).
27. Zimmer H. Viscosity and viscosity measurements. Allgem. Osterr. Chem. Tech. Ztg 50, 47-50 (1932).
28. Monkos K. Viscometric study of human, bovine, equine and ovine hemoglobin in aqueous solution. Int. J. Biol. Macromol. 16(1), 31-35 (1994).
29. Monkos K. Studies of protein solution conformations using viscometric measurements. Methods Protein Struct. Stab. Anal. (Pt C), 355-387 (2007).
30. Monkos K. Concentration and temperature dependence of viscosity in lysozyme aqueous solutions. Biochim. Biophys. Acta Protein Struct. Mol. Enzymol. 1339(2), 304-310 (1997).
31. Monkos K, Monkos J, Turczynski B. Analysis of relations between viscosity and concentration of macromolecules based on viscosity measurements of human and bovine albumin and g-globulin aqueous solutions. Postepy. Fiz Med. J. 23(4), 215-222 (1988).
32. Yadav S, Shire SJ, Kalonia DS. Factors affecting the viscosity in high concentration solutions of different monoclonal antibodies. J. Pharm. Sci. 99(12), 4812-4829 (2010).
33. He F, Becker GW, Litowski JR, Narhi LO, Brems DN, Razinkov VI. High-throughput dynamic light scattering method for measuring viscosity of concentrated protein solutions. Anal. Biochem. 399(1), 141-143 (2010)
34. Ansel HCA, Popovich LV, Allen LV. Pharmaceutical Dosage Forms and Drug Delivery Systems (8th Edition). Williams & Wilkins, PA, USA (2004).
35. Brian Meyer MS. Commercial Therapeutic Protein Drug Products. Woodhead Publishing, Oxford, UK, 1-9 (2011).
36. Dani B, Platz R, Tzannis ST. High concentration formulation feasibility of human immunoglubulin G for subcutaneous administration. J. Pharm. Sci. 96(6), 1504-1517 (2007).
37. Rantner M. Roche plans for more convenient-to-use Herceptin® and Rituxan®. Nat. Biotechnol. 28(4), 298 (2010).
38. Montagna M, Montillo M, Avanzini MA et al. Relationship between pharmacokinetic profile of subcutaneously administered alemtuzumab and clinical response in patients with chronic lymphocytic leukemia. Haematologica 96(6), 932-936 (2011).
39. Xu Z, Wang Q, Zhuang Y et al. Subcutaneous bioavailability of golimumab at 3 different injection sites in healthy subjects. J. Clin. Pharmacol. 50(3), 276-284 (2010).
40. Mach H, Gregory S, Mittal S, Lalloo A, Kirchmeier M, Shameem M. Electrostatic interactions of monoclonal antibodies with subcutaneous tissue. Therapeutic Delivery 2(6), 727-736 (2011).
41. Arakawa T. Solvation and properties of proteins. Tanpakushitsu Kakusan Koso 30(2), 103-111 (1985).
42. Shire SJ, Gombotz W, Bechtold-Peters K, Andya J. Current trends in monoclonal antibody development and manufacturing. Excellent review on high concentration formulation development of monoclonal antibodies. Biotechnol. Pharm. Aspects 11, 351 (2010).
43. Shire SJ, Shahrokh Z, Liu J. Challenges in the development of high protein concentration formulations. Current trends in monoclonal antibody development and manufacturing. Biotechnol. Pharm. Aspects 11, 131-147 (2010).
44. Kamerzell TJ, Kanai S, Liu J, Shire SJ, Wang YJ. Increasing IgG concentration modulates the conformational heterogeneity and bonding network that influence solution properties. J. Phys. Chem. B 113(17), 6109-6118 (2009).
45. Kanai S, Liu J, Patapoff TW, Shire SJ. Reversible self-association of a concentrated monoclonal antibody solution mediated by Fab-Fab interaction that impacts solution viscosity. J. Pharm. Sci. 97(10), 4219-4227 (2008).
46. Liu J, Nguyen MDH, Andya JD, Shire SJ. Reversible self-association increases the viscosity of a concentrated monoclonal antibody in aqueous solution. J. Pharm. Sci. 94(9), 1928-1940 (2005).
47. Yadav S, Shire SJ, Kalonia DS. Viscosity analysis of high concentration bovine serum albumin aqueous solutions. Pharm. Res. 28(8), 1973-1983 (2011).
48. Yadav S, Shire SJ, Kalonia DS. Viscosity behavior of high-concentration monoclonal antibody solutions: Correlation with interaction parameter and electroviscous effects. J. Pharm. Sci. 101(3), 998-1011 (2011).
49. Salinas BA, Sathish HA, Bishop SM, Harn N, Carpenter JF, Randolph TW. Understanding and modulating opalescence and viscosity in a monoclonal antibody formulation. J. Pharm. Sci. 99(1), 82-93 (2009).
50. Saluja A, Kalonia DS. Measurement of fluid viscosity at microtiter volumes using quuartz impedance analysis. AAPS PharmSciTech 5(3), 47 (2004).
51. Yadav S, Liu J, Shire SJ, Kalonia DS. Specific interactions in high concentration antibody solutions resulting in high viscosity. J. Pharm. Sci. 99(3), 1152-1168 (2010).
52. Minton AP. The influence of macromolecular crowding and macromolecular confinement on biochemical reactions in physiological media. J. Biol. Chem. 276(14), 10577-10580 (2001).
53. Minton AP 2000. Implications of macromolecular crowding for protein assembly. Curr. Opin. Struct. Biol. 10(1), 34-39 (2000).
54. Nishi H, Miyajima M, Nakagami H, Noda M, Uchiyama S, Fukui K. Phase separation of an IgG1 antibody solution under a low ionic strength condition. Pharm. Res. 27(7), 1348-1360 (2010).
55. Scherer TM, Liu J, Shire SJ, Minton AP. Intermolecular interactions of IgG1 monoclonal antibodies at high concentrations characterized by light scattering. J. Phys. Chem. B 114(40), 12948-12957 (2010).
56. Yadav S, Sreedhara A, Kanai S et al. Establishing a link between amino acid sequences and self-associating and viscoelastic behavior of two closely related monoclonal antibodies. Pharm. Res. 28(7), 1750-1764 (2011).
57. Printz M, Kalonia DS, Friess W. Individual second virial coefficient determination of monomer and oligomers in heat-stressed protein samples using size-exclusion chromatography-light scattering. J. Pharm. Sci. 101(1), 363-372 (2012).
58. Mach H, Arvinte T. Addressing new analytical challenges in protein formulation development. Eur. J. Pharm. Biopharm. 78(2), 196-207 (2011).
59. Gokarn YR, Fesinmeyer RM, Saluja A, Razinkov V, Chase SF, Laue TM, Brems DN. Effective charge measurements reveal selective and preferential accumulation of anions, but not cations, at the protein surface in dilute salt solutions. Protein Sci. 20(3), 580-587 (2011).
60. Zimmer H. Viscosity and viscosity measurements. Allgem. Osterr. Chem. Tech. Ztg 50, 47-50 (1932).
61. Monkos K. Viscometric study of human, bovine, equine and ovine hemoglobin in aqueous solution. Int. J. Biol. Macromol. 16(1), 31-35 (1994).
62. Monkos K. Studies of protein solution conformations using viscometric measurements. Methods Protein Struct. Stab. Anal. (Pt C), 355-387 (2007).
63. Monkos K. Concentration and temperature dependence of viscosity in lysozyme aqueous solutions. Biochim. Biophys. Acta Protein Struct. Mol. Enzymol. 1339(2), 304-310 (1997).
64. Monkos K, Monkos J, Turczynski B. Analysis of relations between viscosity and concentration of macromolecules based on viscosity measurements of human and bovine albumin and g-globulin aqueous solutions. Postepy. Fiz Med. J. 23(4), 215-222 (1988).
65. Yadav S, Shire SJ, Kalonia DS. Factors affecting the viscosity in high concentration solutions of different monoclonal antibodies. J. Pharm. Sci. 99(12), 4812-4829 (2010).
66. He F, Becker GW, Litowski JR, Narhi LO, Brems DN, Razinkov VI. High-throughput dynamic light scattering method for measuring viscosity of concentrated protein solutions. Anal. Biochem. 399(1), 141-143 (2010
67. Smoluchowski M. Molecular kinetic theory of opalescence of gases in their critical region and some allied phenomena. Annalen der Physik 25, 205-226 (1908).
68. Einstein A. Theory of opalescence of homogenous fluids mixtures in the neighbourhood of critical state. Annalen der Physik 33, 1275-1298 (1910).
69. Wang N, Hu B, Ionescu R et al. Opalescence of an IgG1 monoclonal antibody formulation is mediated by ionic strength and excipients. BioPharm Int. 22(4), 36-47 (2009).
70. Woods JM, Nesta D. Formulation effects on opalescence of a high-concentration MAb. BioProcess Int. 8(9), 48-59 (2010).
71. Sukumar M, Doyle BL, Combs JL, Pekar AH. Opalescent appearance of an IgG1 antibody at high concentrations and its relationship to noncovalent association. Pharm. Res. 21(7), 1087-1093 (2004).
72. Meyer BK, Shameem M, Mohammed H. Properties of protein formulations. In: Therapeutic Protein Drug Products: Practical Approaches in the Laboratory, Manufacturing, and the Clinic. Meyer BK (Ed.). Biohealthcare Publishing Oxford, UK (2011).
73. Chen S, Lau H, Brodsky Y, Kleemann GR, Latypov RF. The use of native cation-exchange chromatography to study aggregation and phase separation of monoclonal antibodies. Protein Sci. 19(6), 1191-1204 (2010).
74. Mason BD, Zhang L, Remmele RL, Zhang J. Opalescence of an IgG2 monoclonal antibody solution as it relates to liquid-liquid phase separation. J. Pharm. Sci. 100(11), 4587-4596 (2011).
75. Lewus RA, Darcy PA, Lenhoff AM, Sandler SI. Interactions and phase behavior of a monoclonal antibody. Biotechnol. Prog. 27(1), 280-289 (2011).
76. Mason BD, Zhang-van Enk J, Zhang L, Remmele RL Jr, Zhang J. Liquid-liquid phase separation of a monoclonal antibody and nonmonotonic influence of hofmeister anions. Biophys. J. 99(11), 3792-3800 (2010).
77. Oelmeier SA, Dismer F, Hubbuch J. Application of an aqueous two-phase systems high-throughput screening method to evaluate mAb HCP separation. Biotechnol. Bioeng. 108(1), 69-81 (2010).
78. Cromwell MEM, Carpenter JF, Scherer T, Randolph TW. Opalescence in antibody formulations is a solution critical phenomenon. Presented at: 236th ACS National Meeting. PA, USA, 17-21 August 2008 (Abstract BIOT-029).
79. Carpenter JF, Randolph TW, Jiskoot W et al. Overlooking subvisible particles in therapeutic protein products: gaps that may compromise product quality. J. Pharm. Sci. 98(4), 1201-1205 (2009).
80. Singh SK, Afonina N, Awwad M et al. An industry perspective on the monitoring of subvisible particles as a quality attribute for protein therapeutics. J. Pharm. Sci. 99(8), 3302-3321 (2010).
81. Gabrielson JP, Brader ML, Pekar AH et al . Quantitation of aggregate levels in a recombinant humanized monoclonal antibody formulation by size-exclusion chromatography, asymmetrical flow field flow fractionation, and sedimentation velocity. J. Pharm. Sci. 96(2), 268-279 (2006).
82. Clodfelter DK, Nussbaum MA, Reilly J. Comparison of free solution capillary electrophoresis and size exclusion chromatography for quantitating non-covalent aggregation of an acylated peptide. J. Pharm. Biomed. Anal. 19(5), 763-775 (1999).
83. Riggin RM, Shaar CJ, Dorulla GK, Lefeber DS, Miner DJ. High-performance size-exclusion chromatographic determination of the potency of biosynthetic human growth hormone products. J. Chromatogr. 435(2), 307-318 (1988).
84. Laue TM, Stafford WF III. Modern applications of analytical ultracentrifugation. Annu. Rev. Biophys. Biomol. Struct. 28, 75-100 (1999).
85. Schuck P. Size-distribution analysis of macromolecules by sedimentation velocity ultracentrifugation and Lamm equation modeling. Biophys. J. 78(3), 1606-1619 (2000).
86. Philo JS. A critical review of methods for size characterization of non-particulate protein aggregates. Curr. Pharm. Biotechnol. 10(4), 359-372 (2009).
87. Arakawa T, Ejima D, Li T, Philo JS. The critical role of mobile phase composition in size exclusion chromatography of protein pharmaceuticals. J. Pharm. Sci. 99(4), 1674-1692 (2010).
88. Philo JS. Is any measurement method optimal for all aggregate sizes and types? AAPS J. 8(3), E564-E571 (2006).
89. Huang C-T, Sharma D, Oma P, Krishnamurthy R. Quantitation of protein particles in parenteral solutions using micro-flow imaging. J. Pharm. Sci. 98(9), 3058-3071 (2009).
90. Wuchner K, Buechler J, Spycher R, Dalmonte P, Volkin DB. Development of a microflow digital imaging assay to characterize protein particulates during storage of a high concentration IgG1 monoclonal antibody formulation. J. Pharm. Sci. 99(8), 3343-3361 (2010).
91. Sharma DK, Oma P, Pollo MJ, Sukumar M. Quantification and characterization of subvisible proteinacious particles in opalescent mAb formulations using micro-flow imaging. J. Pharm. Sci. 99, 2628-2642 (2010).
92. Filipe V, Hawe A, Jiskoot W. Critical evaluation of nanoparticle tracking analysis (NTA) by nanosight for the measurement of nanoparticles and protein aggregates. Pharm. Res. 27(5), 796-810 (2010).
93. Griffiths D, Hole P, Smith J, Carr B. Characterization of nanoparticle dispersions by size and scattering intensity simultaneously. Nanotech. Conf. Expo. 1, 414-416 (2009).
94. Demeule B, Gurny R, Arvinte T. Detection and characterization of protein aggregates by fluorescence microscopy. Int. J. Pharm. 329(1-2), 37-45 (2007).
95. He F, Hogan S, Latypov RF, Narhi LO, Razinkov VI. High throughput thermostability screening of monoclonal antibody formulations. J. Pharm. Sci. 99(4), 1707-1720 (2010).
96. Mach H, Bhambhani A, Meyer BK et al. The use of flow cytometry for the detection of therapeutic protein aggregates. J. Pharm. Sci. 100(5), 1671-1678 (2011).
97. Ludwig DB, Trotter JT, Gabrielson JP, Carpenter JF, Randolph TW. Flow cytometry: A promising technique for the study of silicone oil-induced particulate formation in protein formulations. Anal. Biochem. 410(2), 191-199 (2011).
98. Lee H, Kirchmeier M, Mach H. Monoclonal antibody aggregation intermediates visualized by atomic force microscopy. J. Pharm. Sci. 100(2), 416-423 (2011).
99. Jiskoot W, Randolph TW, Volkin DB et al. Protein instability and immunogenicity: Roadblocks to clinical application of injectable protein delivery systems for sustained release. J. Pharm. Sci. doi:10.1002/jps.23018 (2012) (Epub ahead of print).
100. Mahler H-C, Friess W, Grauschopf U, Kiese S. Protein aggregation: pathways, induction factors and analysis. J. Pharm. Sci. 98(9), 2909-2934 (2009).
101. Zolls S, Tantipolphan R, Wiggenhorn M et al. Particles in therapeutic protein formulations. Part 1: overview of analytical methods. J. Pharm. Sci. 101(3), 914-935 (2012)
102. Weiss WF, Young TM, Roberts CJ. Principles, approaches, and challenges for predicting protein aggregation rates and shelf life. J. Pharm. Sci. 98(4), 1246-1277 (2009).
103. Robinson NE, Robinson AB. Deamidation of human proteins. Proc. Natl Acad. Sci. USA 98(22), 12409-12413 (2001).
104. 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. 18(2), 424-433 (2009).
105. Salinas B, Sathish HA, Carpenter JF, Randolph TW. Buffer-dependent fragmentation of a humanized full-length monoclonal antibody. Presented at: 236th ACS National Meeting. PA, USA, 17-21 August 2008 (Abstract BIOT-032).
106. Andya JD, Liu J, Shire SJ. Analysis of irreversible aggregation, reversible self-association and fragmentation of monoclonal antibodies by analytical ultracentrifugation. Biotechnol. Pharm. Aspects (Current Trends in Monoclonal Antibody Development and Manufacturing), 11, 207-227 (2010).
107. Gaza-Bulseco G, Liu H. Fragmentation of a recombinant monoclonal antibody at various pH. Pharm. Res. 25(8), 1881-1890 (2008).
108. Vlasak J, Price CE, Cohen SL. Fragmentation within human IgG1 hinge region: Two distinct mechanisms, two different outcomes. Presented at: 234th ACS National Meeting. MA, USA, 19-23 August 2007 (Abstract BIOT-134).
109. Li Y, Mach H, Blue JT. High throughput formulation screening for global aggregation behaviors of three monoclonal antibodies. J. Pharm. Sci. 100(6), 2120-2135 (2011).
110. Wang S-L, Lin S-Y, Li M-J, Wei Y-S, Hsieh T-F. Temperature effect on the structural stability, similarity, and reversibility of human serum albumin in different states. Biophys. Chem. 114(2-3), 205-212 (2005).
111. Hawe A, Filipe V, Jiskoot W. Fluorescent molecular rotors as dyes to characterize polysorbate-containing IgG formulations. Pharm. Res. 27(2), 314-326 (2010).
112. Lo M-C AA, Jin G, Cowling R, Bard J, Malamas M, Ellestad G. Evaluation of fluorescence-based thermal shift assays for hit identification in drug discovery. Anal. Biochem. 332(1), 153-159 (2004).
113. He F, Phan DH, Hogan S, Bailey R, Becker GW, Narhi LO, Razinkov VI. Detection of IgG aggregation by a high throughput method based on extrinsic fluorescence. J. Pharm. Sci. 99(6), 2598-2608 (2010).
114. Ericsson UB, Hallberg BM, DeTitta GT, Dekker N, Nordlund P. Thermofluor-based high-throughput stability optimization of proteins for structural studies. Anal. Biochem. 357(2), 289-298 (2006).
115. Chennamsetty N, Voynov V, Kayser V, Helk B, Trout BL. Prediction of aggregation prone regions of therapeutic proteins. J. Chem. B 114(19), 6614-6624 (2010).
116. Lazar GA, Desjarlais JR. Engineering the antibody Fc region for optimal effector function. In: Therapeutic Monoclonal Antibodies: From Bench to Clinic. Johm Wiley & Sons, NY, USA, 349-370 (2009).
117. Bee JS, Davis M, Freund E, Carpenter JF, Randolph TW. Aggregation of a monoclonal antibody induced by adsorption to stainless steel. Biotechnol. Bioeng. 105(1), 121-129 (2009).
118. Hanna LS, Pine P, Reuzinsky G, Nigam S, Omstead DR. Removing specific cell culture contaminants in a MAb purification process. BioPharm 4(9), 33-37 (1991).
119. Shukla AA, Hinckley PJ, Gupta P, Yigzaw Y, Hubbard B. Strategies to address aggregation during protein A chromatography. BioProcess Int. 3(5), 36-43 (2005).
120. Tyagi AK, Randolph TW, Dong A, Maloney KM, Hitscherich C Jr, Carpenter JF. IgG particle formation during filling pump operation: A case study of heterogeneous nucleation on stainless steel nanoparticles. J. Pharm. Sci. 98(1), 94-104 (2009).
121. Bee JS, Stevenson JL, Mehta B et al. Response of a concentrated monoclonal antibody formulation to high shear. Biotechnol. Bioeng. 103(5), 936-943 (2009).
122. Macdougall IC. Epoetin-induced pure red cell aplasia: diagnosis and treatment. Curr. Opin. Nephrol. Hypertens. 16(6), 585-588 (2007).
123. Ludwig DB, Carpenter JF, Hamel J-B, Randolph TW. Protein adsorption and excipient effects on kinetic stability of silicone oil emulsions. J. Pharm. Sci. 99(4), 1721-1733 (2010).
124. Bee JS, Nelson SA, Freund E, Carpenter JF, Randolph TW. Precipitation of a monoclonal antibody by soluble tungsten. J. Pharm. Sci. 98(9), 3290-3301 (2009).
125. Schellekens H, Jiskoot W. Erythropoietin-associated PRCA: Still an unsolved mystery. J. Immunotoxicol. 3(3), 123-130 (2006).
126. Chung CH, Mirakhur B, Chan E et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-a-1,3-galactose. N. Engl. J. Med. 358(11), 1109-1117 (2008).
127. Koren E, De Groot AS, Jawa V et al. Clinical validation of the 'in silico' prediction of immunogenicity of a human recombinant therapeutic protein. Clin. Immunol. 124(1), 26-32 (2007).
128. Dintzis HM, Dintzis RZ, Vogelstein B. Molecular determinants of immunogenicity: The immunon model of immune response. Proc. Natl Acad. Sci. USA 73(10), 3671-3675 (1976).
129. Roberts CJ. Non-native protein aggregation kinetics. Biotechnol. Bioeng. 98(5), 927-938 (2007).
130. Rosenberg AS. Effects of protein aggregates: An immunologic perspective. AAPS J. 8(3), E501-E507 (2006).
131. Fradkin AH, Carpenter JF, Randolph TW. Glass particles as an adjuvant: A model for adverse immunogenicity of therapeutic proteins. J. Pharm. Sci. 100(11), 4953-4964 (2011).
132. Scott DW, De Groot AS. Can we prevent immunogenicity of human protein drugs. Ann. Rheum. Dis. 69, 72-76 (2010).
133. Hermeling S, Schellekens H, Maas C et al. Antibody response to aggregated human interferon alpha2b in wild-type and transgenic immune tolerant mice depends on type and level of aggregation. J. Pharm. Sci. 95(5), 1084-1096 (2006).
134. Pisal DS, Kosloski MP, Middaugh CR, Bankert RB, Balu-Iyer SV. Native-like aggregates of factor VIII are immunogenic in von Willebrand factor deficient and hemophilia a mice. J. Pharm. Sci. 101(6), 2055-2065 (2012).
135. Fradkin AH, Carpenter JF, Randolph TW. Immunogenicity of aggregates of recombinant human growth hormone in mouse models. J. Pharm. Sci. 98(9), 3247-3264 (2009).
136. van Beers MMC, Sauerborn M, Gilli F, Brinks V, Schellekens H, Jiskoot W. Aggregated recombinant human interferon beta induces antibodies but no memory in immune-tolerant transgenic mice. Pharm. Res. 27(9), 1812-1824 (2010).
137. Frei PC, Benacerraf B, Thorbecke GJ. Phagocytosis of the antigen, a crucial step in the induction of the primary response. Proc. Natl Acad. Sci. USA 53, 20-23 (1965).
138. Treuheit MJ, Kosky AA, Brems DN. Inverse relationship of protein concentration and aggregation. Pharm. Res. 19(4), 511-516 (2002).
139. Shire SJ, Liu JJ. Development of high protein concentration pharmaceuticals for SC delivery: fitting all the pieces together. Presented at: 239th ACS National Meeting. CA, USA, 21-25 March 2010 (Abstract BIOT-132).
140. Guo J, Harn N, Robbins A, Dougherty R, Middaugh CR. Stability of helix-rich proteins at high concentrations. B.i.
141. Chari R, Jerath K, Badkar AV, Kalonia DS. Long- and short-range electrostatic interactions affect the rheology of highly concentrated antibody solutions. Pharm. Res. 26(12), 2607-2618 (2009).
142. Saluja A, Kalonia DS. Nature and consequences of protein-protein interactions in high protein concentration solutions. Int. J. Pharm. 358(1-2), 1-15 (2008).
143. Vazquez-Rey M, Lang DA. Aggregates in monoclonal antibody manufacturing processes. Biotechnol. Bioeng. 108(7), 1494-1508 (2011).
144. van Reis R, Zydney A. Membrane separations in biotechnology. Curr. Opin. Biotechnol. 12(2), 208-211 (2001).
145. He F, Woods CE, Trilisky E et al. Screening of monoclonal antibody formulations based on high-throughput thermostability and viscosity measurements: design of experiment and statistical analysis. J. Pharm. Sci. 100(4), 1330-1340 (2011).
146. Waldmann TA, Strober W. Metabolism of immunoglobulins. Progr. Allergy 13, 1-110 (1969).
147. Wang W WE, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin. Pharm. Ther. 84, 548-558 (2008).
148. Harvey AJ, Kaestner SA, Sutter DE, Harvey NG, Mikszta JA, Pettis RJ. Microneedle-based intradermal delivery enables rapid lymphatic uptake and distribution of protein drugs. Pharm. Res. 28(1), 107-116 (2010).
149. Skladany MJ, Miller M, Guthermann JS, Ludwig CR. Patch-pump technology to manage type 2 diabetes mellitus: hurdles to market acceptance. J. Diabetes Sci. Technol. 2(6), 1147-1150 (2008).
150. Loscher W. The pharmacokinetics of antiepileptic drugs in rats: Consequences for maintaining effective drug levels during prolonged drug administration in rat models of epilepsy. Epilepsia 48(7), 1245-1258 (2007).
151. Jones R, Mustafa N. A fresh look at continuous subcutaneous insulin infusion. JAAPA 21(3), 36-37, 41-42 (2008).
152. Yang MX, Shenoy B, Disttler M et al. Crystalline monoclonal antibodies for subcutaneous delivery. Proc. Natl Acad. Sci. USA 100(12), 6934-6939 (2003).
153. Basu SK, Govardhan CP, Jung CW, Margolin AL. Protein crystals for the delivery of biopharmaceuticals. Exp. Opin. Biological Ther. 4(3), 301-317 (2004).
154. Bookbinder LH, Hofer A, Haller MF et al. A recombinant human enzyme for enhanced interstitial transport of therapeutics. J. Control. Release 114(2), 230-241 (2006).
155. Keith P. Johnston JA, Maynard et al. Concentrated dispersions of equilibrium protein nanoclusters that reversibly dissociate into active monomers. ACS Nano. 6(2), 1357-1369 (2012).
156. Kuroda Y, Kuroki A, Kikuchi S, Funase T, Nakata M, Izui S. A critical role for sialylation in cryoglobulin activity of murine IgG3 monoclonal antibodies. J. Immunol. 175(2), 1056-1061 (2005).
157. Zhang M, Koskie K, Ross JS, Kayser KJ, Caple MV. Enhancing glycoprotein sialylation by targeted gene silencing in mammalian cells. Biotechnol. Bioeng. 105(6), 1094-1105 (2010).
158. Schuele S, Friess W, Bechtold-Peters K, Garidel P. Conformational analysis of protein secondary structure during spray-drying of antibody/mannitol formulations. Eur. J. Pharm. Biopharm. 65(1), 1-9 (2007).
159. Cortez-Retamozo V, Backmann N, Senter PD et al. Efficient cancer therapy with a nanobody-based conjugate. Cancer Res. 64(8), 2853-2857 (2004).