REFERENCES

Aghamohseni H, Ohadi K, Spearman M, Krahn N, Moo-Young M, Scharer JM, Butler M, Budman HM. 2014. Effects of nutrient levels and average culture pH on the glycosylation pattern of camelid-humanized monoclonal antibody. J. Biotechnol. 186 :98–109.
Averbeck N, Gao XD, Nishimura SI, Dean N. 2008. Alg13p, the catalytic subunit of the endoplasmic reticulum UDP-GlcNAc glycosyltransferase, is a target for proteasomal degradation. Mol. Biol. Cell19 :1815–2348.
Baik JY, Lee MS, An SR, Yoon SK, Joo EJ, Kim YH, Park HW, Lee GM. 2006. Initial transcriptome and proteome analyses of low culture temperature-induced expression in CHO cells producing erythropoietin.Biotechnol. Bioeng. 93 :361–71.
Boswell CA, Tesar DB, Mukhyala K, Theil FP, Fielder PJ, Khawli LA. 2010. Effects of charge on antibody tissue distribution and pharmacokinetics.Bioconjug. Chem. 21 :2153–2163.
Dick Jr. LW, Kim C, Qiu D, Cheng K-C. 2007. Determination of the origin of the N-terminal pyro-glutamate variation in monoclonal antibodies using model peptides. Biotechnol. Bioeng. 97 :544–553.
Du Y, Walsh A, Ehrick R, Xu W, May K, Liu H. 2012. Chromatographic analysis of the acidic and basic species of recombinant monoclonal antibodies. MAbs 4 :578–585.
Gao Y, Ray S, Dai S, Ivanov AR, Abu-Absi NR, Lewis AM, Huang Z, Xing Z, Borys MC, Li ZJ, Karger BL. 2016. Combined metabolomics and proteomics reveals hypoxia as a cause of lower productivity on scale-up to a 5000-liter CHO bioprocess. Biotechnol. J. 11 :1190–1200.
Gazme B, Boachie RT, Tsopmo A, Udenigwe CC. 2019. Occurrence, properties and biological significance of pyroglutamyl peptides derived from different food sources. Food Sci. Hum. Wellness8 :268–274.
Gerlach JQ, Sharma S, Leister KJ, Joshi L. 2012. A Tight-Knit Group: Protein Glycosylation, Endoplasmic Reticulum Stress and the Unfolded Protein Response. In: . Endoplasmic Reticulum Stress Heal. Dis. , pp. 23–39.
Goetze AM, Liu YD, Zhang Z, Shah B, Lee E, Bondarenko P V., Flynn GC. 2011. High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans. Glycobiology21 :949–959.
Hintersteiner B, Lingg N, Zhang P, Woen S, Hoi KM, Stranner S, Wiederkum S, Mutschlechner O, Schuster M, Loibner H, Jungbauer A. 2016. Charge heterogeneity: Basic antibody charge variants with increased binding to Fc receptors. MAbs 8 :1548–1560.
Hong JK, Lakshmanan M, Lee D-Y. 2018. Towards next generation CHO cell line development and engineering by systems approaches. Curr. Opin. Chem. Eng. 22 :1–10.
Hu Z, Tang D, Misaghi S, Jiang G, Yu C, Yim M, Shaw D, Snedecor B, Laird MW, Shen A. 2017. Evaluation of heavy chain C-terminal deletions on productivity and product quality of monoclonal antibodies in Chinese hamster ovary (CHO) cells. Biotechnol. Prog.33 :786–794.
Hu Z, Zhang H, Haley B, Macchi F, Yang F, Misaghi S, Elich J, Yang R, Tang Y, Joly JC, Snedecor BR, Shen A. 2016. Carboxypeptidase D is the only enzyme responsible for antibody C-terminal lysine cleavage in Chinese hamster ovary (CHO) cells. Biotechnol. Bioeng.113 :2100–6.
Ivarsson M, Villiger TK, Morbidelli M, Soos M. 2014. Evaluating the impact of cell culture process parameters on monoclonal antibody N-glycosylation. J. Biotechnol.
Jennewein MF, Alter G. 2017. The Immunoregulatory Roles of Antibody Glycosylation. Trends Immunol. 38 :358–372.
Jiang R, Chen H, Xu S. 2018. pH excursions impact CHO cell culture performance and antibody N-linked glycosylation. Bioprocess Biosyst. Eng. 41 :1731–1741.
Kaufmann H, Mazur X, Fussenegger M, Bailey JE. 1999. Influence of low temperature on productivity, proteome and protein phosphorylation of CHO cells. Biotechnol. Bioeng. 63 :573–82.
Kellokumpu S. 2019. Golgi pH, ion and redox homeostasis: How much do they really matter? Front. Cell Dev. Biol. 7 :93.
Khawli LA, Goswami S, Hutchinson R, Kwong ZW, Yang J, Wang X, Yao Z, Sreedhara A, Cano T, Tesar D, Nijem I, Allison DE, Wong PY, Kao YH, Quan C, Joshi A, Harris RJ, Motchnik P. 2010. Charge variants in IgG1: Isolation, characterization, in vitro binding properties and pharmacokinetics in rats. MAbs 2 :613–24.
Korovila I, Hugo M, Castro JP, Weber D, Höhn A, Grune T, Jung T. 2017. Proteostasis, oxidative stress and aging. Redox Biol.13 :550–567.
Lakshmanan M, Kok YJ, Lee AP, Kyriakopoulos S, Lim HL, Teo G, Poh SL, Tang WQ, Hong J, Tan AH-M, Bi X, Ho YS, Zhang P, Ng SK, Lee D-Y. 2019. Multi-omics profiling of CHO parental hosts reveals cell line-specific variations in bioprocessing traits. Biotechnol. Bioeng.116 .
Li W, Prabakaran P, Chen W, Zhu Z, Feng Y, Dimitrov DS. 2016. Antibody Aggregation: Insights from Sequence and Structure. Antibodies (Basel, Switzerland) 5 :19.
Liu Z, Valente J, Lin S, Chennamsetty N, Qiu D, Bolgar M. 2019. Cyclization of N-Terminal Glutamic Acid to pyro-Glutamic Acid Impacts Monoclonal Antibody Charge Heterogeneity Despite Its Appearance as a Neutral Transformation. J. Pharm. Sci. 108 :3194–3200.
Malhotra JD, Kaufman RJ. 2007. Endoplasmic Reticulum Stress and Oxidative Stress: A Vicious Cycle or a Double-Edged Sword?Antioxid. Redox Signal. 9 :2277–93.
McIntyre JC, Sleight RG. 1994. Mechanisms of Intracellular Membrane Lipid Transport. In: Hoekstra, D, editor. Curr. Top. Membr.Academic Press, pp. 453–481.
Nakka VP, Prakash-Babu P, Vemuganti R. 2016. Crosstalk Between Endoplasmic Reticulum Stress, Oxidative Stress, and Autophagy: Potential Therapeutic Targets for Acute CNS Injuries. Mol. Neurobiol.53 :532–544.
Nguyen Dang A, Mun M, Rose CM, Ahyow P, Meier A, Sandoval W, Yuk IH. 2019. Interaction of cell culture process parameters for modulating mAb afucosylation. Biotechnol. Bioeng. 116 :831–845.
Onitsuka M, Kawaguchi A, Asano R, Kumagai I, Honda K, Ohtake H, Omasa T. 2014. Glycosylation analysis of an aggregated antibody produced by Chinese hamster ovary cells in bioreactor culture. J. Biosci. Bioeng. 117 :639–44.
Paroutis P, Touret N, Grinstein S. 2004. The pH of the secretory pathway: Measurement, determinants, and regulation. Physiology19 :207–215.
Paul AJ, Handrick R, Ebert S, Hesse F. 2018. Identification of process conditions influencing protein aggregation in Chinese hamster ovary cell culture. Biotechnol. Bioeng. 115 :1173–1185.
Perez-Garmendia R, Gevorkian G. 2013. Pyroglutamate-Modified Amyloid Beta Peptides: Emerging Targets for Alzheimer´s Disease Immunotherapy.Curr. Neuropharmacol. 11 :491–8.
Quijano C, Trujillo M, Castro L, Trostchansky A. 2016. Interplay between oxidant species and energy metabolism. Redox Biol.8 :28–42.
Rao VK, Zavala G, Deb Roy A, Mains RE, Eipper BA. 2019. A pH-sensitive luminal His-cluster promotes interaction of PAM with V-ATPase along the secretory and endocytic pathways of peptidergic cells. J. Cell. Physiol. 234 :8683–8697.
Roberts CJ. 2014. Therapeutic protein aggregation: Mechanisms, design, and control. Trends Biotechnol. 32 :372–380.
Shields RL, Lai J, Keck R, O’Connell LY, Hong K, Gloria Meng Y, Weikert SHA, Presta LG. 2002. Lack of fucose on human IgG1 N-linked oligosaccharide improves binding to human Fc??RIII and antibody-dependent cellular toxicity. J. Biol. Chem.277 :26733–26740.
Sommeregger W, Sissolak B, Kandra K, von Stosch M, Mayer M, Striedner G. 2017. Quality by control: Towards model predictive control of mammalian cell culture bioprocesses. Biotechnol. J. 12 :1–7.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, Mesirov JP. 2005. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA102 :15545–50.
Tossolini I, López-Díaz FJ, Kratje R, Prieto CC. 2018. Characterization of cellular states of CHO-K1 suspension cell culture through cell cycle and RNA-sequencing profiling. J. Biotechnol. 286 :56–67.
Vázquez-Rey M, Lang DA. 2011. Aggregates in monoclonal antibody manufacturing processes. Biotechnol. Bioeng.108 :1494–1508.
Vishwanatha K, Back N, Mains RE, Eipper BA. 2014. A Histidine-rich Linker Region in Peptidylglycine β-cells-Amidating Monooxygenase Has the Properties of a pH Sensor. J. Biol. Chem.289 :12404–12420.
Xie P, Niu H, Chen X, Zhang X, Miao S, Deng X, Liu X, Tan WS, Zhou Y, Fan L. 2016. Elucidating the effects of pH shift on IgG1 monoclonal antibody acidic charge variant levels in Chinese hamster ovary cell cultures. Appl. Microbiol. Biotechnol. 100 :10343–10353.
Yusufi FNK, Lakshmanan M, Ho YS, Loo BLW, Ariyaratne P, Yang Y, Ng SK, Tan TRM, Yeo HC, Lim HL, Ng SW, Hiu AP, Chow CP, Wan C, Chen S, Teo G, Song G, Chin JX, Ruan X, Sung KWK, Hu WS, Yap MGS, Bardor M, Nagarajan N, Lee DY. 2017. Mammalian Systems Biotechnology Reveals Global Cellular Adaptations in a Recombinant CHO Cell Line. Cell Syst.4 :530-542.e6.
Zhou Y, Raju R, Alves C, Gilbert A. 2018. Debottlenecking protein secretion and reducing protein aggregation in the cellular host.Curr. Opin. Biotechnol. 53 :151–157.