Immunogenicity of protein aggregates - Concerns and realities

International Journal of Pharmaceutics

Volumn 431, Issue 1-2, 2012, Pages 1-11

  Wang, Wei ^a   Singh, Satish K ^a   Li, Ning ^a   Toler, Maria R ^a   King, Kevin R ^a   Nema, Sandeep ^a  

^a PFIZER INC   (United States)

Author keywords

Adjuvant; Aggregation; Particulates; Subvisible; Vaccine

Indexed keywords

ADJUVANT; ALBINTERFERON ALPHA2B; ANTIGEN; BETA1A INTERFERON; BOVINE IMMUNOGLOBULIN; CREATINE KINASE MM; GLYCOPROTEIN GP 120; GRANULOCYTE COLONY STIMULATING FACTOR; HEPATITIS B ANTIGEN; HUMAN GROWTH HORMONE; HUMAN IMMUNOGLOBULIN; IMMUNOGLOBULIN G; INTERLEUKIN 2; RECOMBINANT ALPHA2 INTERFERON; RECOMBINANT ALPHA2B INTERFERON; RECOMBINANT BLOOD CLOTTING FACTOR 8; RECOMBINANT ERYTHROPOIETIN;

ACIDITY; ANTIBODY PRODUCTION; ANTIBODY RESPONSE; ANTIBODY TITER; ANTIGEN BINDING; BINDING AFFINITY; COMPUTER MODEL; CYTOKINE RELEASE; DRUG DEVELOPMENT; HUMAN; HUMORAL IMMUNITY; IMMUNOCOMPETENT CELL; IMMUNOGENICITY; INFLAMMATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN BINDING; PROTEIN INTERACTION; PROTEIN MODIFICATION; PROTEIN PURIFICATION; PROTEIN STABILITY; PROTEIN STRUCTURE; REPEATED DRUG DOSE; REVIEW; T LYMPHOCYTE ACTIVATION; TREATMENT DURATION;

ANIMALS; ANTIGENS; HUMANS; PROTEIN CONFORMATION; PROTEIN STABILITY; PROTEINS; VACCINES;

EID: 84861337214     PISSN: 03785173     EISSN: 18733476     Source Type: Journal    
DOI: 10.1016/j.ijpharm.2012.04.040     Document Type: Review

References (177)

1. M. Agarkhed Challenges Beyond Stable Formulation Development - Issues Related to in-use Stability 2011 IBC's Formulation Strategies for Protein Therapeutics Long Beach, CA
2. F. Aline, and D. Brand Dendritic cells loaded with HIV-1 p24 proteins adsorbed on surfactant-free anionic PLA nanoparticles induce enhanced cellular immune responses against HIV-1 after vaccination Vaccine 27 2009 5284 5291
3. M.E. Allison, and D.T. Fearon Enhanced immunogenicity of aldehyde-bearing antigens: a possible link between innate and adaptive immunity Eur. J. Immunol. 30 2000 2881 2887
4. S. Babiuk, and D.M. Skowronski Aggregate content influences the Th1/Th2 immune response to influenza vaccine: evidence from a mouse model J. Med. Virol. 72 2004 138 142
5. M.P. Baker, and F.J. Carr Pre-clinical considerations in the assessment of immunogenicity for protein therapeutics Curr. Drug Saf. 5 2010 308 313
6. M.P. Baker, and H.M. Reynolds Immunogenicity of protein therapeutics: The key causes, consequences and challenges Self Nonself 1 2010 314 322
7. S. Barker Immunogenicity of biotherapeutics: a need for consensus on flexibility of approach Curr. Drug Saf. 5 2010 272 274
8. B.S. Barrett, and A.P. Markham Formulation and immunogenicity studies of type III secretion system needle antigens as vaccine candidates J. Pharm. Sci. 99 2010 4488 4496
9. A. Basalp, and Z. Mustafaeva Immunogenic Cu2+-induced biopolymer systems comprising a steroid hormone, protein antigen, and synthetic polyelectrolytes Hybrid Hybridomics 21 2002 45 51
10. A. Basu, and K. Yang Structure-function engineering of interferon-beta-1b for improving stability, solubility, potency, immunogenicity, and pharmacokinetic properties by site-selective mono-PEGylation Bioconjug. Chem. 17 2006 618 630
11. C.E. Biro, and G. Garcia The antigenicity of aggregated and aggregate-free human gamma-globulin for rabbits Immunology 8 1965 411 419
12. B. Bonnotte, and M. Gough Intradermal injection, as opposed to subcutaneous injection, enhances immunogenicity and suppresses tumorigenicity of tumor cells Cancer Res. 63 2003 2145 2149
13. A. Braun, and L. Kwee Protein aggregates seem to play a key role among the parameters influencing the antigenicity of interferon alpha (IFN-alpha) in normal and transgenic mice Pharm. Res. 14 1997 1472 1478
14. V. Brinks, and W. Jiskoot Immunogenicity of therapeutic proteins: the use of animal models Pharm. Res. 28 2011 2379 2385
15. C.J. Bryson, and T.D. Jones Prediction of immunogenicity of therapeutic proteins: validity of computational tools BioDrugs 24 2010 1 8
16. T. Buskas, and Y. Li The immunogenicity of the tumor-associated antigen Lewis(y) may be suppressed by a bifunctional cross-linker required for coupling to a carrier protein Chemistry 10 2004 3517 3524
17. I.C. Buttel, and P. Chamberlain Taking immunogenicity assessment of therapeutic proteins to the next level Biologicals 39 2011 100 109
18. M. Calamai, and C. Canale Reversal of protein aggregation provides evidence for multiple aggregated States J. Mol. Biol. 346 2005 603 616
19. L. Calderon, and E. Facenda Modulation of the specific allergic response by mite allergens encapsulated into liposomes Vaccine 24 2006 S2-38-39
20. W. Caparros-Wanderley, and B. Clark Effect of dose and long-term storage on the immunogenicity of murine polyomavirus VP1 virus-like particles Vaccine 22 2004 352 361
21. J.F. Carpenter, and T.W. Randolph Overlooking subvisible particles in therapeutic protein products: gaps that may compromise product quality J. Pharm. Sci. 98 2009 1201 1205
22. V. Cernysiov, and N. Gerasimcik Regulation of T-cell-independent and T-cell-dependent antibody production by circadian rhythm and melatonin Int. Immunol. 22 2010 25 34
23. B. Chen, and R. Bautista Influence of histidine on the stability and physical properties of a fully human antibody in aqueous and solid forms Pharm. Res. 20 2003 1952 1960
24. B.L. Chen, and T. Arakawa Aggregation pathway of recombinant human keratinocyte growth factor and its stabilization Pharm. Res. 11 1994 1581 1587
25. E.Y. Chi, and B.S. Kendrick Population balance modeling of aggregation kinetics of recombinant human interleukin-1 receptor antagonist J. Pharm. Sci. 94 2005 2735 2748
26. E.Y. Chi, and S. Krishnan Roles of conformational stability and colloidal stability in the aggregation of recombinant human granulocyte colony-stimulating factor Protein Sci. 12 2003 903 913
27. E.Y. Chi, and J. Weickmann Heterogeneous nucleation-controlled particulate formation of recombinant human platelet-activating factor acetylhydrolase in pharmaceutical formulation J. Pharm. Sci. 94 2005 256 274
28. M.Y. Chia, and S.H. Hsiao The immunogenicity of DNA constructs co-expressing GP5 and M proteins of porcine reproductive and respiratory syndrome virus conjugated by GPGP linker in pigs Vet. Microbiol. 146 2010 189 199
29. S.S. Chiu, and K.H. Chan Immunogenicity and safety of intradermal versus intramuscular route of influenza immunization in infants less than 6 months of age: a randomized controlled trial Vaccine 27 2009 4834 4839
30. D.K. Chou, and R. Krishnamurthy Effects of Tween 20 and Tween 80 on the stability of Albutropin during agitation J. Pharm. Sci. 94 2005 1368 1381
31. C.L. Christian Studies of aggregated gamma-globulin. II. Effect in vivo J. Immunol. 84 1960 117 121
32. H.N. Claman Tolerance to a protein antigen in adult mice and the effect of nonspecific factors J. Immunol. 91 1963 833 839
33. Cohen, T.,Moise, L., et al., 2010. A method for individualizing the prediction of immunogenicity of protein vaccines and biologic therapeutics: individualized T cell epitope measure (iTEM). J. Biomed. Biotechnol.
34. L. Curatolo, and B. Valsasina Recombinant human IL-2 is cytotoxic to oligodendrocytes after in vitro self aggregation Cytokine 9 1997 734 739
35. T. Defrance, and M. Taillardet T cell-independent B cell memory Curr. Opin. Immunol. 23 2011 330 336
36. J. den Engelsman, and P. Garidel Strategies for the assessment of protein aggregates in pharmaceutical biotech product development Pharm. Res. 28 2011 920 933
37. J. Denis, and N. Majeau Immunogenicity of papaya mosaic virus-like particles fused to a hepatitis C virus epitope: Evidence for the critical function of multimerization Virology 363 2007 59 68
38. H.M. Dintzis, and R.Z. Dintzis Molecular determinants of immunogenicity: the immunon model of immune response Proc. Natl. Acad. Sci. U.S.A. 73 1976 3671 3675
39. D. Ejima, and R. Yumioka Arginine as an effective additive in gel permeation chromatography J. Chromatogr. A 1094 2005 49 55
40. R.K. Evans, and D.M. Zhu Characterization and biological evaluation of a microparticle adjuvant formulation for plasmid DNA vaccines J. Pharm. Sci. 93 2004 1924 1939
41. R. Fagnani, and M.S. Hagan Reduction of immunogenicity by covalent modification of murine and rabbit immunoglobulins with oxidized dextrans of low molecular weight Cancer Res. 50 1990 3638 3645
42. C. Ferri, and A.L. Zignego Cryoglobulins J. Clin. Pathol. 55 2002 4 13
43. T. Fifis, and A. Gamvrellis Size-dependent immunogenicity: therapeutic and protective properties of nano-vaccines against tumors J. Immunol. 173 2004 3148 3154
44. V. Filipe, and R. Poole Fluorescence single particle tracking for the characterization of submicron protein aggregates in biological fluids and complex formulations Pharm. Res. 28 2011 1112 1120
45. D.R. Flower Advances in predicting and manipulating the immunogenicity of biotherapeutics and vaccines BioDrugs 23 2009 231 240
46. A.H. Fradkin, and J.F. Carpenter Immunogenicity of aggregates of recombinant human growth hormone in mouse models J. Pharm. Sci. 98 2009 3247 3264
47. A.H. Fradkin, and J.F. Carpenter Glass particles as an adjuvant: a model for adverse immunogenicity of therapeutic proteins J. Pharm. Sci. 2011
48. A.H. Fradkin, and J.F. Carpenter Glass particles as an adjuvant: a model for adverse immunogenicity of therapeutic proteins J. Pharm. Sci. 100 2011 4953 4964
49. C.N. Gamble The role of soluble aggregates in the primary immune response of mice to human gamma globulin Int. Arch. Allergy Appl. Immunol. 30 1966 446 455
50. M.F. Gebbink, and B. Bouma Physiological responses to protein aggregates: fibrinolysis, coagulation and inflammation (new roles for old factors) FEBS Lett. 583 2009 2691 2699
51. T.J. Giezen, and A.K. Mantel-Teeuwisse Safety-related regulatory actions for biologicals approved in the United States and the European Union JAMA 300 2008 1887 1896
52. G. Giovannoni, and O. Barbarash Immunogenicity and tolerability of an investigational formulation of interferon-beta1a: 24- and 48-week interim analyses of a 2-year, single-arm, historically controlled, phase IIIb study in adults with multiple sclerosis Clin. Therap. 29 2007 1128 1145
53. S.E. Grossberg, and J. Oger Frequency and magnitude of interferon β neutralizing antibodies in the evaluation of interferon β immunogenicity in patients with multiple sclerosis J. Interf. Cytokine Res. 31 2011 337 344
54. L.C. Gu, and E.A. Erdos Stability of interleukin 1 beta (IL-1 beta) in aqueous solution: analytical methods, kinetics, products, and solution formulation implications Pharm. Res. 8 1991 485 490
55. J. Hartikka, and V. Bozoukova Vaxfectin®, a cationic lipid-based adjuvant for protein-based influenza vaccines Vaccine 27 2009 6399 6403
56. F. He, and D.H. Phan Detection of IgG aggregation by a high throughput method based on extrinsic fluorescence J. Pharm. Sci. 99 2010 2598 2608
57. S. Hermeling, and L. Aranha Structural characterization and immunogenicity in wild-type and immune tolerant mice of degraded recombinant human interferon alpha2b Pharm. Res. 22 2005 1997 2006
58. S. Hermeling, and D.J. Crommelin Structure-immunogenicity relationships of therapeutic proteins Pharm. Res. 21 2004 897 903
59. S. Hermeling, and H. Schellekens Micelle-associated protein in epoetin formulations: aA risk factor for immunogenicity? Pharm. Res. 20 2003 1903 1907
60. S. Hermeling, and H. Schellekens 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 2006 1084 1096
61. T.P. Hopp Immunogenicity of a synthetic HBsAg peptide: enhancement by conjugation to a fatty acid carrier Mol. Immunol. 21 1984 13 16
62. N.K. Jain, and I. Roy Accelerated stability studies for moisture-induced aggregation of tetanus toxoid Pharm. Res. 28 2011 626 639
63. A. Jegerlehner, and A. Tissot A molecular assembly system that renders antigens of choice highly repetitive for induction of protective B cell responses Vaccine 20 25-26 2002 3104 3112
64. W. Jiskoot, and E.C. Beuvery Analytical approaches to the study of monoclonal antibody stability Pharm. Res. 7 1990 1234 1241
65. J.C. Jones, and E.W. Settles Virus aggregating peptide enhances the cell-mediated response to influenza virus vaccine Vaccine 29 2011 7696 7703
66. M.K. Joubert, and Q. Luo Classification and characterization of therapeutic antibody aggregates J. Biol. Chem. 286 2011 25118 25133
67. A. Kaliyaperumal, and S. Jing Immunogenicity assessment of therapeutic proteins and peptides Curr. Pharm. Biotechnol. 10 2009 352 358
68. J.M. Katz, and X. Lu A nonionic block co-polymer adjuvant (CRL1005) enhances the immunogenicity and protective efficacy of inactivated influenza vaccine in young and aged mice Vaccine 18 2000 2177 2187
69. R. Kayed, and E. Head Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis Science 300 2003 486 489
70. F. Khan, and P.M. Legler Histidine Affinity Tags Affect MSP1(42) Structural Stability and Immunodominance in Mice Biotechnol. J. 2011
71. J. Kittiworakarn, and A. Lecoq HIV-1 Tat raises an adjuvant-free humoral immune response controlled by its core region and its ability to form cysteine-mediated oligomers J. Biol. Chem. 281 2006 3105 3115
72. P. Kivisakk, and G.V. Alm Neutralizing and binding anti-interferon-beta (IFN-beta) antibodies. A comparison between IFN-beta-1a and IFN-beta-1b treatment in multiple sclerosis Eur. J. Neurol. 7 2000 27 34
73. J.D. Knight, and A.D. Miranker Phospholipid catalysis of diabetic amyloid assembly J., Mol. Biol. 341 2004 1175 1187
74. C. Koch, and S.S. Jensen A comparison of the immunogenicity of the native and denatured forms of a protein APMIS 104 1996 115 125
75. H. Koide, and T. Asai T cell-independent B cell response is responsible for ABC phenomenon induced by repeated injection of PEGylated liposomes Int. J. Pharm 392 2010 218 223
76. B.M. Krenn, and A. Egorov Single HA2 mutation increases the infectivity and immunogenicity of a live attenuated H5N1 intranasal influenza vaccine candidate lacking NS1 PLoS One 6 2011 e18577
77. S. Krishnan, and E.Y. Chi Aggregation of granulocyte colony stimulating factor under physiological conditions: characterization and thermodynamic inhibition Biochemistry 41 2002 6422 6431
78. S. Kumar, and S.K. Singh Coupling of aggregation and immunogenicity in biotherapeutics: T- and B-cell immune epitopes may contain aggregation-prone regions Pharm. Res. 28 2011 949 961
79. V. Kunzi, and J.M. Klap Immunogenicity and safety of low dose virosomal adjuvanted influenza vaccine administered intradermally compared to intramuscular full dose administration Vaccine 27 2009 3561 3567
80. R. Lawatscheck, and E. Aleksaite Chimeric polyomavirus-derived virus-like particles: the immunogenicity of an inserted peptide applied without adjuvant to mice depends on its insertion site and its flanking linker sequence Viral Immunol. 20 2007 453 460
81. S.F. Little, and B.E. Ivins Effect of aluminum hydroxide adjuvant and formaldehyde in the formulation of rPA anthrax vaccine Vaccine 25 2007 2771 2777
82. W. Liu, and Z. Peng High epitope density in a single recombinant protein molecule of the extracellular domain of influenza A virus M2 protein significantly enhances protective immunity Vaccine 23 2004 366 371
83. M. Lu, and S.C. Blacklow A trimeric structural domain of the HIV-1 transmembrane glycoprotein Nat. Struct. Biol. 2 1995 1075 1082
84. Q. Luo, and M.K. Joubert Chemical modifications in therapeutic protein aggregates generated under different stress conditions J. Biol. Chem. 286 2011 25134 25144
85. C. Maas, and S. Hermeling A role for protein misfolding in immunogenicity of biopharmaceuticals J. Biol. Chem. 282 2007 2229 2236
86. H. Mach, and T. Arvinte Addressing new analytical challenges in protein formulation development Eur. J. Pharm. Biopharm. 78 2011 196 207
87. H.-C. Mahler, and W. Friess Protein aggregation: Pathways, induction factors and analysis J. Pharm. Sci. 98 2009 2909 2934
88. N. Man, and A.J. Cartwright Treatment of human muscle creatine kinase with glutaraldehyde preferentially increases the immunogenicity of the native conformation and permits production of high-affinity monoclonal antibodies which recognize two distinct surface epitopes J. Immunol. Methods 125 1989 251 259
89. S.S. Martin, and R.R. Bakken Comparison of the immunological responses and efficacy of gamma-irradiated V3526 vaccine formulations against subcutaneous and aerosol challenge with Venezuelan equine encephalitis virus subtype IAB Vaccine 28 2010 1031 1040
90. I.C. Martins, and I. Kuperstein Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice EMBO J. 27 2008 224 233
91. W.V. Moore, and P. Leppert Role of aggregated human growth hormone (hGH) in development of antibodies to hGH J. Clin. Endocrinol. Metab. 51 1980 691 697
92. G.L. Morefield, and D. Jiang Effect of phosphorylation of ovalbumin on adsorption by aluminum-containing adjuvants and elution upon exposure to interstitial fluid Vaccine 23 2005 1502 1506
93. S.A. Moschos, and V.W. Bramwell Comparative immunomodulatory properties of a chitosan-MDP adjuvant combination following intranasal or intramuscular immunisation Vaccine 23 2005 1923 1930
94. R. Mueller, and A. Karle Evaluation of the immuno-stimulatory potential of stopper extractables and leachables by using dendritic cells as readout J. Pharm. Sci. 98 2009 3548 3561
95. M.G. Mulkerrin, and R. Wetzel pH dependence of the reversible and irreversible thermal denaturation of gamma interferons Biochemistry 28 1989 6556 6561
96. M.I. Mustafaev, and A. Norimov Polymer-metal complexes of protein antigens - new highly effective immunogens Biomed. Sci. 1 1990 274 278
97. M.I. Mustafaev, and F. Yucel Cu(2+)-mediated complex formation between polyacrylic acid (PAA) and bovine serum albumin J. Immunol. Methods 197 1996 31 37
98. J.O. Naim, and C.J. van Oss The effect of hydrophilicity-hydrophobicity and solubility on the immunogenicity of some natural and synthetic polymers Immunol. Invest. 21 1992 649 662
99. L.O. Narhi, and Y. Jiang A critical review of analytical methods for subvisible and visible particles Curr. Pharm. Biotechnol. 10 2009 373 381
100. L.O. Narhi, and J. Schmit Classification of protein aggregates J. Pharm. Sci. 2011
101. K.G. Nicholson, and C.I. Thompson Safety and immunogenicity of whole-virus, alum-adjuvanted whole-virus, virosomal, and whole-virus intradermal influenza A/H9N2 vaccine formulations Vaccine 28 2009 171 178
102. K. Oda, and Y. Sato Separation and characterization of adjuvant oligosaccharide oleate ester derived from product mixture of mannitol-oleic acid esterification Vaccine 22 2004 2812 2821
103. T. Ohkuri, and S. Nagatomo A protein's conformational stability is an immunologically dominant factor: evidence that free-energy barriers for protein unfolding limit the immunogenicity of foreign proteins J. Immunol. 185 2010 4199 4205
104. M.O. Oyewumi, and A. Kumar Nano-microparticles as immune adjuvants: correlating particle sizes and the resultant immune responses Expert Rev. Vaccines 9 2010 1095 1107
105. K. Peerlinck, and J. Arnout Factor VIII inhibitors in previously treated haemophilia A patients with a double virus-inactivated plasma derived factor VIII concentrate Thromb. Haemost. 77 1997 80 86
106. A. Peng, and P. Gaitonde Effect of route of administration of human recombinant factor VIII on its immunogenicity in Hemophilia A mice J. Pharm. Sci. 98 2009 4480 4484
107. P. Perini, and A. Facchinetti Interferon-beta (INF-beta) antibodies in interferon-beta1a- and interferon-beta1b-treated multiple sclerosis patients. Prevalence, kinetics, cross-reactivity, and factors enhancing interferon-beta immunogenicity in vivo Eur. Cytokine Netw. 12 2001 56 61
108. J.S. Philo, and T. Arakawa Mechanisms of protein aggregation Curr. Pharm. Biotechnol. 10 2009 348 351
109. S. Poon, and N.R. Birkett Amyloidogenicity and aggregate cytotoxicity of human glucagon-like peptide-1 (hGLP-1) Protein Pept. Lett. 16 2009 1548 1556
110. S. Porter Human immune response to recombinant human proteins J. Pharm. Sci. 90 2001 1 11
111. C. Prego, and P. Paolicelli Chitosan-based nanoparticles for improving immunization against hepatitis B infection Vaccine 28 2010 2607 2614
112. O. Prummer Treatment-induced antibodies to interleukin-2 Biotherapy 10 1997 15 24
113. P. Puddu, and G.M. Puddu The involvement of circulating microparticles in inflammation, coagulation and cardiovascular diseases Can. J. Cardiol. 26 2010 140 145
114. V.S. Purohit, and S.V. Balasubramanian Interaction of dicaproyl phosphatidylserine with recombinant factor VIII and its impact on immunogenicity AAPS J. 8 2006 E362 E370
115. V.S. Purohit, and C.R. Middaugh Influence of aggregation on immunogenicity of recombinant human Factor VIII in hemophilia A mice J. Pharm. Sci. 95 2006 358 371
116. K. Ramani, and R.D. Miclea Phosphatidylserine containing liposomes reduce immunogenicity of recombinant human factor VIII (rFVIII) in a murine model of hemophilia A J. Pharm. Sci. 97 2008 1386 1398
117. P.A. Ramsland, and W. Farrugia Crystal structures of human antibodies: a detailed and unfinished tapestry of immunoglobulin gene products J. Mol. Recogn. 15 2002 248 259
118. T.W. Randolph, and L.S. Jones Surfactant-protein interactions Pharm. Biotechnol. 13 2002 159 175
119. Z. Rao, and A.S. Belyaev Crystal structure of SIV matrix antigen and implications for virus assembly Nature 378 1995 743 747
120. S.W. Raso, and J. Abel Aggregation of granulocyte-colony stimulating factor in vitro involves a conformationally altered monomeric state Protein Sci. 14 2005 2246 2257
121. M. Reichlin, and A. Nisonoff Immunological activity of cytochrome c. 3. Enhancement of antibody detection and immune response initiation by cytochrome c polymers J. Biol. Chem. 245 1970 947 954
122. J. Richard, and N. Prang The formulation and immunogenicity of therapeutic proteins: Product quality as a key factor IDrugs 13 2010 550 558
123. R.A. Rifkin, and E.T. Maggio n-Dodecyl-beta-D-maltoside inhibits aggregation of human interferon-beta-1b and reduces its immunogenicity J. Neuroimmune Pharmacol. 6 2011 158 162
124. J. Ring, and W. Stephan Anaphylactoid reactions to infusions of plasma protein and human serum albumin. Role of aggregated proteins and of stabilizers added during production Clin. Allergy 9 1979 89 97
125. C.J. Roberts Kinetics of irreversible protein aggregation: analysis of extended lumry-eyring models and implications for predicting protein shelf life J. Phys. Chem. B 107 2003 1194 1207
126. C.J. Roberts, and R.T. Darrington Irreversible aggregation of recombinant bovine granulocyte-colony stimulating factor (bG-CSF) and implications for predicting protein shelf life J. Pharm. Sci. 92 2003 1095 1111
127. A.S. Rosenberg Effects of protein aggregates: an immunologic perspective AAPS J. 8 2006 E501 E507
128. S. Roy, and I. Henderson Effect of pH on stability of recombinant botulinum serotype A vaccine in aqueous solution and during storage of freeze-dried formulations J. Pharm. Sci. 2008 10.1002/jps.21409
129. S. Roy, and D. Katayama Temperature dependence of benzyl alcohol- and 8-anilinonaphthalene-1- sulfonate-induced aggregation of recombinant human interleukin-1 receptor antagonist Biochemistry 45 2006 3898 3911
130. I. Rubio, and A. Bolchi Potent anti-HPV immune responses induced by tandem repeats of the HPV16 L2 (20 - 38) peptide displayed on bacterial thioredoxin Vaccine 27 2009 1949 1956
131. J.S. Rudra, and P.K. Tripathi Immune responses to coiled coil supramolecular biomaterials Biomaterials 31 2010 8475 8483
132. M. Sauerborn, and V. Brinks Immunological mechanism underlying the immune response to recombinant human protein therapeutics Trends Pharmacol. Sci. 31 2010 53 59
133. Schellekens, H., 2002. Immunogenicity of therapeutic proteins: clinical implications and future prospects. Clin. Ther. 24, 1720-1740; discussion 1719.
134. H. Schellekens Immunogenicity of therapeutic proteins Nephrol. Dial. Transplant. 18 2003 1257 1259
135. R. Schirmbeck, and W. Bohm Processing of exogenous heat-aggregated (denatured) and particulate (native) hepatitis B surface antigen for class I-restricted epitope presentation J. Immunol. 155 1995 4676 4684
136. R. Schirmbeck, and K. Melber Selective stimulation of murine cytotoxic T cell and antibody responses by particulate or monomeric hepatitis B virus surface (S) antigen Eur. J. Immunol. 24 1994 1088 1096
137. D.W. Scott, and A.S. De Groot Can we prevent immunogenicity of human protein drugs? Ann. Rheum. Dis. 69 2010 i72 i76
138. P.G. Seferian, and M.L. Martinez Immune stimulating activity of two new chitosan containing adjuvant formulations Vaccine 19 2000 661 668
139. A. Seidl, and O. Hainzl Tungsten-induced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity Pharm. Res. 2011
140. G. Shankar, and E. Shores Scientific and regulatory considerations on the immunogenicity of biologics Trends Biotechnol. 24 2006 274 280
141. M. Shlapobersky, and Q. Wei Vaxfectin®-adjuvanted seasonal influenza protein vaccine: Correlation of systemic and local immunological markers with formulation parameters Vaccine 27 2009 6404 6410
142. S.K. Singh Impact of product-related factors on immunogenicity of biotherapeutics J. Pharm. Sci. 100 2011 354 387
143. S.K. Singh, and N. Afonina An industry perspective on the monitoring of subvisible particles as a quality attribute for protein therapeutics J. Pharm. Sci. 99 2010 3302 3321
144. B. Slutter, and P.C. Soema Conjugation of ovalbumin to trimethyl chitosan improves immunogenicity of the antigen J. Control. Release 143 2010 207 214
145. L. Stertman, and L. Strindelius Starch microparticles as an adjuvant in immunisation: effect of route of administration on the immune response in mice Vaccine 22 2004 2863 2872
146. M. Sukumar, and B.L. Doyle Opalescent appearance of an IgG1 antibody at high concentrations and its relationship to noncovalent association Pharm. Res. 21 2004 1087 1093
147. B. Sulzer, and A.S. Perelson Immunons revisited: binding of multivalent antigens to B cells Mol. Immunol. 34 1997 63 74
148. R. Thirumangalathu, and S. Krishnan Effects of pH, temperature, and sucrose on benzyl alcohol-induced aggregation of recombinant human granulocyte colony stimulating factor J. Pharm. Sci. 95 2006 1480 1497
149. C. Thomas, and V. Gupta Particle size influences the immune response produced by hepatitis B vaccine formulated in inhalable particles Pharm. Res. 27 2010 905 919
150. I. Valdes, and L. Bernardo A novel fusion protein domain III-capsid from dengue-2, in a highly aggregated form, induces a functional immune response and protection in mice Virology 394 2009 249 258
151. A.A. Valiente-Gabioud, and C. Veaute Effect of repetitiveness on the immunogenicity and antigenicity of Trypanosoma cruzi FRA protein Exp. Parasitol. 127 2011 672 679
152. M.M. Van Beers, and F. Gilli Immunogenicity of recombinant human interferon beta interacting with particles of glass, metal, and polystyrene J. Pharm. Sci. 101 2012 187 199
153. M.M. van Beers, and W. Jiskoot On the role of aggregates in the immunogenicity of recombinant human interferon beta in patients with multiple sclerosis J. Interferon Cytokine Res. 30 2010 767 775
154. M.M. van Beers, and M. Sauerborn Aggregated recombinant human interferon Beta induces antibodies but no memory in immune-tolerant transgenic mice Pharm. Res. 27 2010 1812 1824
155. M.M. van Beers, and M. Sauerborn Oxidized and aggregated recombinant human interferon beta is immunogenic in human interferon beta transgenic mice Pharm. Res. 28 2011 2393 2402
156. N. Van Buren, and D. Rehder Elucidation of two major aggregation pathways in an IgG2 antibody J. Pharm. Sci. 2008 10.1002/jps.21514
157. S. Vilasi, and C. Iannuzzi Effect of trehalose on W7FW14F apomyoglobin and insulin fibrillization: new insight into inhibition activity Biochemistry 47 2008 1789 1796
158. A.P. Villalobos, and S.R. Gunturi Interaction of polysorbate 80 with erythropoietin: a case study in protein-surfactant interactions Pharm. Res. 22 2005 1186 1194
159. Q. Vos, and A. Lees B-cell activation by T-cell-independent type 2 antigens as an integral part of the humoral immune response to pathogenic microorganisms Immunol. Rev. 176 2000 154 170
160. W. Wang, and S. Nema Protein aggregation - pathways and influencing factors Int. J. Pharm. 390 2010 89 99
161. W. Wang, and M. Singh Selection of adjuvants for enhanced vaccine potency World J. Vaccines 1 2011 33 78
162. X. Wang, and T. Uto Poly(gamma-glutamic acid) nanoparticles as an efficient antigen delivery and adjuvant system: potential for an AIDS vaccine J Med Virol 80 1 2008 11 19
163. K.L. Warfield, and N.A. Posten Filovirus-like particles produced in insect cells: immunogenicity and protection in rodents J Infect Dis 196 Suppl 2 2007 S421L 429
164. M.E. Weksler, and G. Bull Immunologic responses of graft recipients to antilymphocyte globulin: effect of prior treatment with aggregate-free gamma globulin J Clin Invest 49 8 1970 1589 1595
165. W.C. Weldon, and B.Z. Wang Enhanced immunogenicity of stabilized trimeric soluble influenza hemagglutinin PLoS One 5 9. 2010
166. J. Wendorf, and J. Chesko A comparison of anionic nanoparticles and microparticles as vaccine delivery systems Hum Vaccin 4 1 2008 44 49
167. P.J. White, and F. Anastasopoulos Generic construction of single component particles that elicit humoural and cellular immune responses without the need for adjuvants Vaccine 26 2008 6824 6831
168. K. Wuchner, and J. Buchler 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 2010 3343 3361
169. S.D. Xiang, and A. Scholzen Pathogen recognition and development of particulate vaccines: does size matter? Methods 40 2006 1 9
170. D. Yang, and M.V. Rogers Immunological analysis of the zinc-binding peptides of surface metalloproteinase (gp63) of Leishmania major Immunology 78 1993 582 585
171. X. Yang, and R. Wyatt Improved elicitation of neutralizing antibodies against primary human immunodeficiency viruses by soluble stabilized envelope glycoprotein trimers J. Virol. 75 2001 1165 1171
172. X. Zhang, and X. Wang Design and immunogenicity assessment of HIV-1 virus-like particles as a candidate vaccine Sci. China Life Sci. 54 2011 1042 1047
173. H. Zhao, and E.K. Tuominen Formation of amyloid fibers triggered by phosphatidylserine-containing membranes Biochemistry 43 2004 10302 10307
174. H.L. Zhao, and C. Xue Elimination of the free sulfhydryl group in the human serum albumin (HSA) moiety of human interferon-alpha2b and HSA fusion protein increases its stability against mechanical and thermal stresses Eur. J. Pharm. Biopharm. 72 2009 405 411
175. S. Zhou, and C. Schoneich Biologics formulation factors affecting metal leachables from stainless steel AAPS Pharm. Sci. Tech. 12 2011 411 421
176. S. Zolls, and R. Tantipolphan Particles in therapeutic protein formulations, Part 1: Overview of analytical methods J. Pharm. Sci. 2011
177. S. Zolls, and R. Tantipolphan Particles in therapeutic protein formulations, Part 1: overview of analytical methods J. Pharm. Sci. 101 2012 914 935