Engineering aggregation resistance in IgG by two independent mechanisms: Lessons from comparison of Pichia pastoris and mammalian cell expression

Journal of Molecular Biology

Volumn 417, Issue 4, 2012, Pages 309-335

  Schaefer, Jonas V ^a   Plückthun, Andreas ^a  

^a UNIVERSITY OF ZURICH   (Switzerland)

Author keywords

antibody engineering; Pichia pastoris; protein aggregation; signal sequence; factor pre pro sequence

Indexed keywords

AMINO ACID; IMMUNOGLOBULIN G; MANNOSE; TETRAPEPTIDE;

AMINO ACID SEQUENCE; AMINO TERMINAL SEQUENCE; ANTIBODY ENGINEERING; ANTIBODY PRODUCTION; ANTIGEN BINDING; ARTICLE; CELL STRAIN HEK293; CHROMATOGRAPHY; CONTROLLED STUDY; DEGLYCOSYLATION; DIFFERENTIAL SCANNING CALORIMETRY; ELECTROSPRAY MASS SPECTROMETRY; FLUORESCENCE SPECTROSCOPY; FLUOROMETRY; FUNGAL CELL; GENE INACTIVATION; GLYCOSYLATION; HUMAN; HUMAN CELL; IMMUNOGLOBULIN AGGREGATE; INCUBATION TEMPERATURE; KNOCKOUT GENE; MAMMAL CELL; NONHUMAN; PH; PICHIA PASTORIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN PROCESSING; PROTEIN STABILITY; PURIFICATION; THERMOSTABILITY;

MAMMALIA; PICHIA; PICHIA PASTORIS;

EID: 84857999918     PISSN: 00222836     EISSN: 10898638     Source Type: Journal    
DOI: 10.1016/j.jmb.2012.01.027     Document Type: Article

References (93)

1. Plückthun, A. & Moroney, S. E. (2005). Modern antibody technology: the impact on drug development. In Modern Biopharmaceuticals (Knäblein, J., ed.), Vol. 3, pp. 1147-1186. Wiley-VCH, Weinheim, Germany.
2. Carter, P. J. (2006). Potent antibody therapeutics by design. Nat. Rev., Immunol. 6, 343-357.
3. Elbakri, A., Nelson, P. N. & Abu Odeh, R. O. (2010). The state of antibody therapy. Hum. Immunol. 71, 1243-1250.
4. Fontoura, P. (2010). Monoclonal antibody therapy in multiple sclerosis: paradigm shifts and emerging challenges. mAbs, 2, 670-681.
5. Demarest, S. J. & Glaser, S. M. (2008). Antibody therapeutics, antibody engineering, and the merits of protein stability. Curr. Opin. Drug Discov. Dev, 11, 675-687.
6. Shire, S. J. (2009). Formulation and manufacturability of biologics. Curr. Opin. Biotechnol. 20, 708-714.
7. Baynes, B. M. & Trout, B. L. (2004). Rational design of solution additives for the prevention of protein aggregation. Biophys. J. 87, 1631-1639. (Pubitemid 39167020)
8. Di Paolo, C., Willuda, J., Kubetzko, S., Lauffer, I., Tschudi, D., Waibel, R. et al. (2003). A recombinant immunotoxin derived from a humanized epithelial cell adhesion molecule-specific single-chain antibody fragment has potent and selective antitumor activity. Clin. Cancer Res. 9, 2837-2848. (Pubitemid 36842130)
9. Braun, A., Kwee, L., Labow, M. A. & Alsenz, J. (1997). Protein aggregates seem to play a key role among the parameters influencing the antigenicity of interferon alpha (IFN-α) in normal and transgenic mice. Pharm. Res. 14, 1472-1478. (Pubitemid 27481082)
10. Hermeling, S., Crommelin, D. J., Schellekens, H. & Jiskoot, W. (2004). Structure-immunogenicity relationships of therapeutic proteins. Pharm. Res. 21, 897-903. (Pubitemid 38870136)
11. Schellekens, H. (2005). Factors influencing the immunogenicity of therapeutic proteins. Nephrol., Dial., Transplant. 20, vi3-vi9.
12. Rosenberg, A. S. (2006). Effects of protein aggregates: an immunologic perspective. AAPS J. 8, E501-E507.
13. Kessler, M., Goldsmith, D. & Schellekens, H. (2006). Immunogenicity of biopharmaceuticals. Nephrol., Dial., Transplant. 21(Suppl. 5), v9-v12. (Pubitemid 44391026)
14. Maas, C., Hermeling, S., Bouma, B., Jiskoot, W. & Gebbink, M. F. (2007). A role for protein misfolding in immunogenicity of biopharmaceuticals. J. Biol. Chem. 282, 2229-2236. (Pubitemid 47076754)
15. Ring, J., Seifert, J., Jesch, F. & Brendel, W. (1977). Anaphylactoid reactions due to non-immune complex serum protein aggregates. Monogr. Allergy, 12, 27-35.
16. Ring, J., Stephan, W. & Brendel, W. (1979). Anaphylactoid reactions to infusions of plasma protein and human serum albumin. Role of aggregated proteins and of stabilizers added during production. Clin. Allergy, 9, 89-97. (Pubitemid 9081614)
17. Farid, S. S. (2006). Established bioprocesses for producing antibodies as a basis for future planning. Adv. Biochem. Eng./Biotechnol. 101, 1-42.
18. Arnold, J. N., Wormald, M. R., Sim, R. B., Rudd, P. M. & Dwek, R. A. (2007). The impact of glycosylation on the biological function and structure of human immunoglobulins. Annu. Rev. Immunol. 25, 21-50. (Pubitemid 46697901)
19. Cregg, J. M., Tolstorukov, I., Kusari, A., Sunga, J., Madden, K. & Chappell, T. (2009). Expression in the yeast Pichia pastoris. Methods Enzymol. 463, 169-189.
20. Cereghino, G. P., Cereghino, J. L., Ilgen, C. & Cregg, J. M. (2002). Production of recombinant proteins in fermenter cultures of the yeast Pichia pastoris. Curr. Opin. Biotechnol. 13, 329-332. (Pubitemid 35254090)
21. Bretthauer, R. K. & Castellino, F. J. (1999). Glycosylation of Pichia pastoris-derived proteins. Biotechnol. Appl. Biochem. 30, 193-200.
22. Montesino, R., Garcia, R., Quintero, O. & Cremata, J. A. (1998). Variation in N-linked oligosaccharide structures on heterologous proteins secreted by the methylotrophic yeast Pichia pastoris. Protein Expression Purif. 14, 197-207. (Pubitemid 28504165)
23. Jacobs, P. P., Geysens, S., Vervecken, W., Contreras, R. & Callewaert, N. (2009). Engineering complex-type N-glycosylation in Pichia pastoris using GlycoSwitch technology. Nat. Protoc. 4, 58-70.
24. Vervecken, W., Callewaert, N., Kaigorodov, V., Geysens, S. & Contreras, R. (2007). Modification of the N-glycosylation pathway to produce homogeneous, human-like glycans using GlycoSwitch plasmids. Methods Mol. Biol. 389, 119-138. (Pubitemid 350189991)
25. Potgieter, T. I., Cukan, M., Drummond, J. E., Houston-Cummings, N. R., Jiang, Y., Li, F. et al. (2009). Production of monoclonal antibodies by glycoengineered Pichia pastoris. J. Biotechnol. 139, 318-325.
26. Li, H., Sethuraman, N., Stadheim, T. A., Zha, D., Prinz, B., Ballew, N. et al. (2006). Optimization of humanized IgGs in glycoengineered Pichia pastoris. Nat. Biotechnol. 24, 210-215. (Pubitemid 43221706)
27. Cregg, J. M., Cereghino, J. L., Shi, J. & Higgins, D. R. (2000). Recombinant protein expression in Pichia pastoris. Mol. Biotechnol. 16, 23-52.
28. Couderc, R. & Baratti, J. (1980). Oxidation of methanol by the yeast, Pichia pastoris. Purification and properties of the alcohol oxidase. Agric. Biol. Chem. 44, 2279-2289.
29. Digan, M. E., Tschopp, J., Grinna, L., Lair, S. V., Craig, W. S., Velicelebi, G. et al. (1988). Secretion of heterologous proteins from the methylotrophic yeast, Pichia pastoris. In Development in Industrial Microbiology (Pierce, G., ed.), Vol. 29, pp. 59-65. Elsevier Science, Amsterdam, The Netherlands.
30. Ridder, R., Schmitz, R., Legay, F. & Gram, H. (1995). Generation of rabbit monoclonal antibody fragments from a combinatorial phage display library and their production in the yeast Pichia pastoris. Biotechnology (N. Y.), 13, 255-260.
31. Nett, J. H. (2009). Production of antibodies in Pichia pastoris. In Therapeutic Monoclonal Antibodies: From Bench to Clinic (An, Z., ed.), pp. 569-584, John Wiley & Sons, Inc., Hoboken, NJ.
32. Takahashi, K., Yuuki, T., Takai, T., Ra, C., Okumura, K., Yokota, T. & Okumura, Y. (2000). Production of humanized Fab fragment against human high affinity IgE receptor in Pichia pastoris. Biosci., Biotechnol., Biochem. 64, 2138-2144.
33. Lange, S., Schmitt, J. & Schmid, R. D. (2001). High-yield expression of the recombinant, atrazine-specific Fab fragment K411B by the methylotrophic yeast Pichia pastoris. J. Immunol. Methods, 255, 103-114. (Pubitemid 32695388)
34. Gach, J. S., Maurer, M., Hahn, R., Gasser, B., Mattanovich, D., Katinger, H. & Kunert, R. (2007). High level expression of a promising anti-idiotypic antibody fragment vaccine against HIV-1 in Pichia pastoris. J. Biotechnol. 128, 735-746. (Pubitemid 46341491)
35. Ogunjimi, A. A., Chandler, J. M., Gooding, C. M., Recinos, A. & Choudary, P. V. (1999). High-level secretory expression of immunologically active intact antibody from the yeast Pichia pastoris. Biotechnol. Lett. 21, 561-567. (Pubitemid 29349167)
36. Ellis, S. B., Brust, P. F., Koutz, P. J., Waters, A. F., Harpold, M. M. & Gingeras, T. R. (1985). Isolation of alcohol oxidase and two other methanol regulatable genes from the yeast Pichia pastoris. Mol. Cell. Biol. 5, 1111-1121. (Pubitemid 15110302)
37. Waterham, H. R., Digan, M. E., Koutz, P. J., Lair, S. V. & Cregg, J. M. (1997). Isolation of the Pichia pastoris glyceraldehyde-3-phosphate dehydrogenase gene and regulation and use of its promoter. Gene, 186, 37-44. (Pubitemid 27084827)
38. Zhang, A. L., Luo, J. X., Zhang, T. Y., Pan, Y. W., Tan, Y. H., Fu, C. Y. & Tu, F. Z. (2009). Recent advances on the GAP promoter derived expression system of Pichia pastoris. Mol. Biol. Rep. 36, 1611-1619.
39. Boer, H., Teeri, T. T. & Koivula, A. (2000). Characterization of Trichoderma reesei cellobiohydrolase Cel7A secreted from Pichia pastoris using two different promoters. Biotechnol. Bioeng. 69, 486-494. (Pubitemid 30629367)
40. Hohenblum, H., Gasser, B., Maurer, M., Borth, N. & Mattanovich, D. (2004). Effects of gene dosage, promoters, and substrates on unfolded protein stress of recombinant Pichia pastoris. Biotechnol. Bioeng. 85, 367-375. (Pubitemid 38186091)
41. Gasser, B., Maurer, M., Gach, J., Kunert, R. & Mattanovich, D. (2006). Engineering of Pichia pastoris for improved production of antibody fragments. Biotechnol. Bioeng. 94, 353-361. (Pubitemid 43799534)
42. H3 domains. Biochemistry, 41, 3628-3636.
43. Knappik, A. & Plückthun, A. (1995). Engineered turns of a recombinant antibody improve its in vivo folding. Protein Eng. 8, 81-89.
44. Nieba, L., Honegger, A., Krebber, C. & Plückthun, A. (1997). Disrupting the hydrophobic patches at the antibody variable/constant domain interface: improved in vivo folding and physical characterization of an engineered scFv fragment. Protein Eng. 10, 435-444. (Pubitemid 27252635)
45. Bode, J., Schlake, T., Iber, M., Schubeler, D., Seibler, J., Snezhkov, E. & Nikolaev, L. (2000). The transgeneticist's toolbox: novel methods for the targeted modification of eukaryotic genomes. Biol. Chem. 381, 801-813.
46. Knappik, A., Ge, L., Honegger, A., Pack, P., Fischer, M., Wellnhofer, G. et al. (2000). Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucleotides. J. Mol. Biol. 296, 57-86.
47. Ewert, S., Honegger, A. & Plückthun, A. (2003). Structure-based improvement of the biophysical properties of immunoglobulin VH domains with a generalizable approach. Biochemistry, 42, 1517-1528. (Pubitemid 36205958)
48. Jefferis, R. (2005). Glycosylation of recombinant antibody therapeutics. Biotechnol. Prog. 21, 11-16.
49. Harris, R. J. (1995). Processing of C-terminal lysine and arginine residues of proteins isolated from mammalian cell culture. J. Chromatogr., A, 705, 129-134.
50. Kaplan, A. P., Hood, L. E., Terry, W. D. & Metzger, H. (1971). Amino terminal sequences of human immunoglobulin heavy chains. Immunochemistry, 8, 801-811.
51. Chelius, D., Jing, K., Lueras, A., Rehder, D. S., Dillon, T. M., Vizel, A. et al. (2006). Formation of pyroglutamic acid from N-terminal glutamic acid in immunoglobulin gamma antibodies. Anal. Chem. 78, 2370-2376.
52. Roberts, G. D., Johnson, W. P., Burman, S., Anumula, K. R. & Carr, S. A. (1995). An integrated strategy for structural characterization of the protein and carbohydrate components of monoclonal antibodies: application to anti-respiratory syncytial virus MAb. Anal. Chem. 67, 3613-3625.
53. Kurjan, J. & Herskowitz, I. (1982). Structure of a yeast pheromone gene (MFα): a putative α-factor precursor contains four tandem copies of mature α-factor. Cell, 30, 933-943. (Pubitemid 13204676)
54. Kozlov, D. G. & Yagudin, T. A. (2008). Antibody fragments may be incorrectly processed in the yeast Pichia pastoris. Biotechnol. Lett. 30, 1661-1663.
55. Emberson, L. M., Trivett, A. J., Blower, P. J. & Nicholls, P. J. (2005). Expression of an anti-CD33 single-chain antibody by Pichia pastoris. J. Immunol. Methods, 305, 135-151. (Pubitemid 41416709)
56. Daly, R. & Hearn, M. T. (2005). Expression of heterologous proteins in Pichia pastoris: a useful experimental tool in protein engineering and production. J. Mol. Recognit. 18, 119-138. (Pubitemid 40328574)
57. Garidel, P., Hegyi, M., Bassarab, S. & Weichel, M. (2008). A rapid, sensitive and economical assessment of monoclonal antibody conformational stability by intrinsic tryptophan fluorescence spectroscopy. Biotechnol. J. 3, 1201-1211.
58. Garber, E. & Demarest, S. J. (2007). A broad range of Fab stabilities within a host of therapeutic IgGs. Biochem. Biophys. Res. Commun. 355, 751-757. (Pubitemid 46343718)
59. Helenius, A. & Aebi, M. (2004). Roles of N-linked glycans in the endoplasmic reticulum. Annu. Rev. Biochem. 73, 1019-1049. (Pubitemid 39050393)
60. Roth, J., Zuber, C., Park, S., Jang, I., Lee, Y., Kysela, K. G. et al. (2010). Protein N-glycosylation, protein folding, and protein quality control. Mol. Cell, 30, 497-506.
61. H2 antibody domain. J. Mol. Biol. 344, 107-118.
62. Feige, M. J., Hendershot, L. M. & Buchner, J. (2010). How antibodies fold. Trends Biochem. Sci. 35, 189-198.
63. Krapp, S., Mimura, Y., Jefferis, R., Huber, R. & Sondermann, P. (2003). Structural analysis of human IgG-Fc glycoforms reveals a correlation between glycosylation and structural integrity. J. Mol. Biol. 325, 979-989. (Pubitemid 36263407)
64. Hulett, M. D., Witort, E., Brinkworth, R. I., McKenzie, I. F. & Hogarth, P. M. (1994). Identification of the IgG binding site of the human low affinity receptor for IgG FcγRII. Enhancement and ablation of binding by site-directed mutagenesis. J. Biol. Chem. 269, 15287-15293.
65. Huber, R., Deisenhofer, J., Colman, P. M., Matsushima, M. & Palm, W. (1976). Crystallographic structure studies of an IgG molecule and an Fc fragment. Nature, 264, 415-420.
66. Sondermann, P., Huber, R., Oosthuizen, V. & Jacob, U. (2000). The 3.2-Å crystal structure of the human IgG1 Fc fragment-FcγRIII complex. Nature, 406, 267-273. (Pubitemid 30604397)
67. Ferrara, C., Stuart, F., Sondermann, P., Brunker, P. & Umana, P. (2006). The carbohydrate at FcγRIIIa Asn-162. An element required for high affinity binding to non-fucosylated IgG glycoforms. J. Biol. Chem. 281, 5032-5036. (Pubitemid 43847767)
68. Ravetch, J. V. & Bolland, S. (2001). IgG Fc receptors. Annu. Rev. Immunol. 19, 275-290. (Pubitemid 32368037)
69. Grinna, L. S. & Tschopp, J. F. (1989). Size distribution and general structural features of N-linked oligosaccharides from the methylotrophic yeast, Pichia pastoris. Yeast, 5, 107-115.
70. Martinet, W., Saelens, X., Deroo, T., Neirynck, S., Contreras, R., Min Jou, W. & Fiers, W. (1997). Protection of mice against a lethal influenza challenge by immunization with yeast-derived recombinant influenza neuraminidase. Eur. J. Biochem. 247, 332-338. (Pubitemid 27319521)
71. Kayser, V., Chennamsetty, N., Voynov, V., Forrer, K., Helk, B. & Trout, B. L. (2011). Glycosylation influences on the aggregation propensity of therapeutic monoclonal antibodies. Biotechnol. J. 6, 38-44.
72. Li, P., Anumanthan, A., Gao, X. G., Ilangovan, K., Suzara, V. V., Duzgunes, N. & Renugopalakrishnan, V. (2007). Expression of recombinant proteins in Pichia pastoris. Appl. Biochem. Biotechnol. 142, 105-124. (Pubitemid 47557234)
73. Cereghino, J. L. & Cregg, J. M. (2000). Heterologous protein expression in the methylotrophic yeast Pichia pastoris. FEMS Microbiol. Rev. 24, 45-66. (Pubitemid 30047114)
74. Brake, A. J., Merryweather, J. P., Coit, D. G., Heberlein, U. A., Masiarz, F. R., Mullenbach, G. T. et al. (1984). Alpha-factor-directed synthesis and secretion of mature foreign proteins in Saccharomyces cerevisiae. Proc. Natl Acad. Sci. USA, 81, 4642-4646. (Pubitemid 14065131)
75. Brocca, S., Schmidt-Dannert, C., Lotti, M., Alberghina, L. & Schmid, R. D. (1998). Design, total synthesis, and functional overexpression of the Candida rugosa lip1 gene coding for a major industrial lipase. Protein Sci. 7, 1415-1422. (Pubitemid 28272910)
76. Lombardi, A., Bursomanno, S., Lopardo, T., Traini, R., Colombatti, M., Ippoliti, R. et al. (2010). Pichia pastoris as a host for secretion of toxic saporin chimeras. FASEB J. 24, 253-265.
77. Monsalve, R. I., Lu, G. & King, T. P. (1999). Expressions of recombinant venom allergen, antigen 5 of yellowjacket (Vespula vulgaris) and paper wasp (Polistes annularis), in bacteria or yeast. Protein Expression Purif. 16, 410-416. (Pubitemid 29375395)
78. Brake, A. J. (1989). Secretion of heterologous proteins directed by the yeast alpha-factor leader. Biotechnology, 13, 269-280.
79. Piggott, J. R., Watson, M. E., Doel, S. M., Goodey, A. R. & Carter, B. L. (1987). The secretion and post translational modification of interferons from Saccharomyces cerevisiae. Curr. Genet. 12, 561-567.
80. Zsebo, K. M., Lu, H. S., Fieschko, J. C., Goldstein, L., Davis, J., Duker, K. et al. (1986). Protein secretion from Saccharomyces cerevisiae directed by the prepro-α-factor leader region. J. Biol. Chem. 261, 5858-5865. (Pubitemid 17207416)
81. Zhao, H. L., He, Q., Xue, C., Sun, B., Yao, X. Q. & Liu, Z. M. (2009). Secretory expression of glycosylated and aglycosylated mutein of onconase from Pichia pastoris using different secretion signals and their purification and characterization. FEMS Yeast Res. 9, 591-599.
82. Kjeldsen, T., Brandt, J., Andersen, A. S., Egel-Mitani, M., Hach, M., Pettersson, A. F. & Vad, K. (1996). A removable spacer peptide in an α-factor-leader/insulin precursor fusion protein improves processing and concomitant yield of the insulin precursor in Saccharomyces cerevisiae. Gene, 170, 107-112. (Pubitemid 26130804)
83. Bendtsen, J. D., Nielsen, H., von Heijne, G. & Brunak, S. (2004). Improved prediction of signal peptides: SignalP 3.0. J. Mol. Biol. 340, 783-795. (Pubitemid 38829638)
84. Liu, Y. D., Goetze, A. M., Bass, R. B. & Flynn, G. C. (2011). N-terminal glutamate to pyroglutamate conversion in vivo for human IgG2 antibodies. J. Biol. Chem. 286, 11211-11217.
85. Lawrence, M. S., Phillips, K. J. & Liu, D. R. (2007). Supercharging proteins can impart unusual resilience. J. Am. Chem. Soc. 129, 10110-10112. (Pubitemid 47312950)
86. Arbabi-Ghahroudi, M., To, R., Gaudette, N., Hirama, T., Ding, W., MacKenzie, R. & Tanha, J. (2009). Aggregation-resistant VHs selected by in vitro evolution tend to have disulfide-bonded loops and acidic isoelectric points. Protein Eng. Des. Sel. 22, 59-66.
87. Jespers, L., Schon, O., Famm, K. & Winter, G. (2004). Aggregation-resistant domain antibodies selected on phage by heat denaturation. Nat. Biotechnol. 22, 1161-1165. (Pubitemid 39166856)
88. Perchiacca, J. M., Bhattacharya, M. & Tessier, P. M. (2011). Mutational analysis of domain antibodies reveals aggregation hotspots within and near the complementarity determining regions. Proteins, 79, 2637-2647.
89. Vincke, C., Loris, R., Saerens, D., Martinez-Rodriguez, S., Muyldermans, S. & Conrath, K. (2009). General strategy to humanize a camelid single-domain antibody and identification of a universal humanized nanobody scaffold. J. Biol. Chem. 284, 3273-3284.
90. Sambrook, J. & Russell, D. W. (2001). Molecular Cloning: A Laboratory Manual, 3rd edit. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.
91. Laemmli, U. K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 227, 680-685.
92. Werner, W. E., Wu, S. & Mulkerrin, M. (2005). The removal of pyroglutamic acid from monoclonal antibodies without denaturation of the protein chains. Anal. Biochem. 342, 120-125. (Pubitemid 40805635)
93. Wienken, C. J., Baaske, P., Rothbauer, U., Braun, D. & Duhr, S. (2010). Protein-binding assays in biological liquids usingmicroscale thermophoresis. Nat. Commun. 1, 100.