Aggregation and chemical modification of monoclonal antibodies under upstream processing conditions

Pharmaceutical Research

Volumn 30, Issue 5, 2013, Pages 1380-1399

  Dengl, Stefan ^a   Wehmer, Marc ^b   Hesse, Friederike ^a   Lipsmeier, Florian ^a   Popp, Oliver ^a   Lang, Kurt ^a  

^a ROCHE DIAGNOSTICS GMBH   (Germany)

^b TECHNICAL UNIVERSITY OF MUNICH   (Germany)

Author keywords

aggregation; antibodies; deamidation; fermentation; stress models

Indexed keywords

BISPECIFIC ANTIBODY; IMMUNOGLOBULIN G1; IMMUNOGLOBULIN G4; MONOCLONAL ANTIBODY;

ANIMAL CELL; ANTIBODY PRODUCTION; ARTICLE; BIOREACTOR; CELL CULTURE; CHEMICAL COMPOSITION; CONTROLLED STUDY; CULTURE MEDIUM; DIFFERENTIAL SCANNING CALORIMETRY; FEMALE; FERMENTATION; GEL PERMEATION CHROMATOGRAPHY; ION EXCHANGE CHROMATOGRAPHY; LIGHT SCATTERING; MOLECULAR WEIGHT; NONHUMAN; PH; PRIORITY JOURNAL; PROTEIN AGGREGATION; PROTEIN EXPRESSION; PROTEIN MODIFICATION; PROTEIN PURIFICATION; PROTEIN STABILITY; SENSITIVITY ANALYSIS; TURBIDITY;

ANIMALS; ANTIBODIES, MONOCLONAL; BIOREACTORS; CELL CULTURE TECHNIQUES; CHO CELLS; CRICETINAE; FERMENTATION; HUMANS; IMMUNOGLOBULIN G; PROTEIN STABILITY; STRESS, MECHANICAL; TEMPERATURE;

EID: 84876464478     PISSN: 07248741     EISSN: 1573904X     Source Type: Journal    
DOI: 10.1007/s11095-013-0977-8     Document Type: Article

References (54)

1. Carter PJ. Potent antibody therapeutics by design. Nat Rev Immunol. 2006;6:343-57.
2. Schaefer W, Regula JT, Bähner M, Schanzer J, Croasdale R, Dürr H, Gassner C, Georges G, Kettenberger H, Imhof-Jung S, Schwaiger M, Stubenrauch KG, Sustmann C, Thomas M, Scheuer W, Klein C. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. Proc Natl Acad Sci USA. 2011;108(27):11187-92.
3. Cromwell MEM, Hilario E, Jacobson F. Protein aggregation and bioprocessing. AAPS J. 2006;8:E572-9.
4. Vazquez-Rey M, Lang DA. Aggregates in monoclonal antibody manufacturing processes. Biotechnol Bioeng. 2011;108:1494-508.
5. Schroder M, Schafer R, Schafer R, Friedl P. Induction of protein aggregation in an early secretory compartment by elevation of expression level. Biotechnol Bioeng. 2002;78:131-40.
6. Zhang YB, Howitt J, McCorkle S, Lawrence P, Springer K, Freimuth P. Protein aggregation during overexpression limited by peptide extensions with large net negative charge. Protein Expr Purif. 2004;36:207-16.
7. Nakanishi K, Sakiyama T, Imamura K. On the adsorption of proteins on solid surfaces, a common but very complicated phenomenon. J Biosci Bioeng. 2001;91:233-44.
8. Franco R, Daniela G, Fabrizio M, Ilaria G, Detlev H. Influence of osmolarity and pH increase to achieve a reduction of monoclonal antibodies aggregates in a production process. Cytotechnology. 1999;29:11-25.
9. Arosio P, Barolo G, Muller-Spath T, Wu H, Morbidelli M. Aggregation stability of a monoclonal antibody during downstream processing. Pharm Res. 2011;28:1884-94.
10. Biddlecombe JG, Craig AV, Zhang H, Uddin S, Mulot S, Fish BC, Bracewell DG. Determining antibody stability: creation of solid-liquid interfacial effects within a high shear environment. Biotechnol Prog. 2007;23:1218-22.
11. Wang W, Singh S, Zeng DL, King K, Nema S. Antibody structure, instability, and formulation. J Pharm Sci. 2007;96:1-26.
12. Rosenberg AS. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8:E501-7.
13. Vazquez E, Corchero JL, Villaverde A. Post-production protein stability: trouble beyond the cell factory. Microb Cell Fact. 2011;10:10-60.
14. Gomez N, Subramanian J, Ouyang J, Nguyen MD, Hutchinson M, Sharma VK, Lin AA, Yuk IH. Culture temperature modulates aggregation of recombinant antibody in cho cells. Biotechnol Bioeng (2011).
15. Quan C, Alcala E, Petkovska I, Matthews D, Canova-Davis E, Taticek R, Ma S. A study in glycation of a therapeutic recombinant humanized monoclonal antibody: where it is, how it got there, and how it affects charge-based behavior. Anal Biochem. 2008;373:179-91.
16. Li S, Schoneich C, Borchardt RT. Chemical instability of protein pharmaceuticals: mechanisms of oxidation and strategies for stabilization. Biotechnol Bioeng. 1995;48:490-500.
17. Liu H, Gaza-Bulseco G, Faldu D, Chumsae C, Sun J. Heterogeneity of monoclonal antibodies. J Pharm Sci. 2008;97:2426-47.
18. Geiger T, Clarke S. Deamidation, isomerization, and racemization at asparaginyl and aspartyl residues in peptides. Succinimide-linked reactions that contribute to protein degradation. J Biol Chem. 1987;262:785-94.
19. Kim JY, Lee GM. CHO cells in biotechnology for production of recombinant proteins: current state and further potential. Appl Microbiol Biotechnol. 2012;93(3):917-30.
20. Becker E, Florin L, Pfizenmaier K, Kaufmann H. An XBP-1 dependent bottle-neck in production of IgG subtype antibodies in chemically defined serum-free Chinese hamster ovary (CHO) fed-batch processes. J Biotechnol. 2008;135:217-23.
21. Kiese S, Papppenberger A, Friess W, Mahler HC. Shaken, not stirred: mechanical stress testing of an IgG1 antibody. J Pharm Sci. 2008;97:4347-66.
22. Ridgway JB, Presta LG, Carter P. 'Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 1996;9:617-21.
23. Mahler HC, 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.
24. Pace CN, Vajdos F, Fee L, Grimsley G, Gray T. How to measure and predict the molar absorption coefficient of a protein. Protein Sci. 1995;4:2411-23.
25. Maa YF, Hsu CC. Protein denaturation by combined effect of shear and air-liquid interface. Biotechnol Bioeng. 1997;54:503-12.
26. Thomas CR, Geer D. Effects of shear on proteins in solution. Biotechnol Lett. 2011;33:443-56.
27. Ishikawa T, Kobayashi N, Osawa C, Sawa E, Wakamatsu K. Prevention of stirring-induced microparticle formation in monoclonal antibody solutions. Biol Pharm Bull. 2010;33:1043-6.
28. Heads JT, Adams R, D'Hooghe LE, Page MJT, Humphreys DP, Popplewell AG, Henry AJ. Relative stabilities of IgG1 and IgG4 Fab domains: influence of the light-heavy interchain disulfide bond architecture. Protein Sci. 2012;21:1315-22.
29. Ionescu RM, Vlasak J, Price C, Kirchmeier M. Contribution of variable domains to the stability of humanized IgG1 monoclonal antibodies. J Pharm Sci. 2008;97:1414-26.
30. Li F, Vijayasankaran N, Shen AY, Kiss R, Amanullah A. Cell culture processes for monoclonal antibody production. MAbs. 2010;2:466-79.
31. 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.
32. Bam NB, Cleland JL, Yang J, Manning MC, Carpenter JF, Kelley RF, Randolph TW. Tween protects recombinant human growth hormone against agitation-induced damage via hydrophobic interactions. J Pharm Sci. 1998;87:1554-9.
33. Bahrami A, Shojaosadati SA, Khalilzadeh R, Mohammadian J, Farahani EV, Masoumian MR. Prevention of human granulocyte colony-stimulating factor protein aggregation in recombinant Pichia pastoris fed-batch fermentation using additives. Biotechnol Appl Biochem. 2009;52:141-8.
34. Chisti Y. Animal-cell damage in sparged bioreactors. Trends Biotechnol. 2000;18:420-32.
35. Clincke MF, Guedon E, Yen FT, Ogier V, Roitel O, Goergen JL. Effect of surfactant pluronic F-68 on CHO cell growth, metabolism, production, and glycosylation of human recombinant IFN-gamma in mild operating conditions. Biotechnol Prog. 2011;27:181-90.
36. Gigout A, Buschmann MD, Jolicoeur M. The fate of Pluronic F-68 in chondrocytes and CHO cells. Biotechnol Bioeng. 2008;100:975-87.
37. Vlasak J, Ionescu R. Heterogeneity of monoclonal antibodies revealed by charge-sensitive methods. Curr Pharm Biotechnol. 2008;9:468-81.
38. 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.
39. Vermeer AW, Norde W. The thermal stability of immunoglobulin: unfolding and aggregation of a multi-domain protein. Biophys J. 2000;78:394-404.
40. Wang W, Nema S, Teagarden D. Protein aggregation-pathways and influencing factors. Int J Pharm. 2010;390:89-99.
41. Schaefer JV, Pluckthun A. Engineering aggregation resistance in IgG by two independent mechanisms: lessons from comparison of Pichia pastoris and mammalian cell expression. J Mol Biol. 2012;417:309-35.
42. King AC, Woods M, Liu W, Lu Z, Gill D, Krebs MR. High-throughput measurement, correlation analysis, and machine-learning predictions for pH and thermal stabilities of Pfizer-generated antibodies. Protein Sci. 2011;20:1546-57.
43. Abbas SA, Sharma VK, Patapoff TW, Kalonia DS. Opposite effects of polyols on antibody aggregation: thermal versus mechanical stresses. Pharm Res. 2012;29:683-94.
44. Cartaya OA. Serum-free cell culture media. United States Patent 4,205,126, 1980.
45. Wang W. Instability, stabilization, and formulation of liquid protein pharmaceuticals. Int J Pharm. 1999;185:129-88.
46. Randolph TW, Jones LS. Surfactant-protein interactions. Pharm Biotechnol. 2002;13:159-75.
47. van der Pol L, Tramper J. Shear sensitivity of animal cells from a culture-medium perspective. Trends Biotechnol. 1998;16:323-8.
48. Manning MC, Chou DK, Murphy BM, Payne RW, Katayama DS. Stability of protein pharmaceuticals: an update. Pharm Res. 2010;27:544-75.
49. Gandhi S, Ren D, Xiao G, Bondarenko P, Sloey C, Ricci MS, Krishnan S. Elucidation of degradants in acidic peak of cation exchange chromatography in an IgG1 monoclonal antibody formed on long-term storage in a liquid formulation. Pharm Res. 2012;29:209-24.
50. Harris RJ, Kabakoff B, Macchi FD, Shen FJ, Kwong M, Andya JD, Shire SJ, Bjork N, Totpal K, Chen AB. Identification of multiple sources of charge heterogeneity in a recombinant antibody. J Chromatogr B Biomed Sci Appl. 2001;752:233-45.
51. Patel K, Borchardt RT. Chemical pathways of peptide degradation. II. Kinetics of deamidation of an asparaginyl residue in a model hexapeptide. Pharm Res. 1990;7:703-11.
52. Kaneko Y, Sato R, Aoyagi H. Changes in the quality of antibodies produced by Chinese hamster ovary cells during the death phase of cell culture. J Biosci Bioeng. 2010;109:281-7.
53. 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.
54. Liu YD, van Enk JZ, Flynn GC. Human antibody Fc deamidation in vivo. Biologicals. 2009;37:313-22.