PMID- 29280480
OWN - NLM
STAT- MEDLINE
DCOM- 20190604
LR  - 20190604
IS  - 1097-0290 (Electronic)
IS  - 0006-3592 (Linking)
VI  - 115
IP  - 5
DP  - 2018 May
TI  - Identification of process conditions influencing protein aggregation in Chinese 
      hamster ovary cell culture.
PG  - 1173-1185
LID - 10.1002/bit.26534 [doi]
AB  - Protein aggregation of monoclonal antibodies (mAbs) is a common phenomenon 
      associated with the production of these biopharmaceuticals. These aggregates can 
      lead to adverse side effects in patients upon administration, thus expensive 
      downstream processing steps to remove the higher molecular weight species are 
      inevitable. A preferable approach is to reduce the level of aggregation during 
      bioprocessing by a careful adjustment of critical process parameters. Recently, 
      new analytical methods enabled characterization of mAb aggregation during 
      bioprocessing of mammalian cells. Furthermore, rapid and efficient bioprocess 
      optimization has been performed using design of experiments (DoE) strategies. In 
      this work, we describe a DoE-based approach for the analysis of process 
      parameters and cell culture additives influencing protein aggregation in Chinese 
      hamster ovary (CHO) cell cultures. Important bioprocess variables influencing the 
      aggregation of mAb and host cell proteins were identified in initial screening 
      experiments. Response surface modeling was further applied in order to find 
      optimal conditions for the reduction of protein aggregation during cell culture. 
      It turned out that a temperature-shift to 31  degrees C, osmolality above 420 mOsm/kg, 
      agitation at 100 rpm and 0.04% (w/v) antifoam significantly reduced the level of 
      aggregates without substantial detrimental effects on cell culture performance in 
      our model system. Finally, the aggregation reducing conditions were verified and 
      applied to another production system using a different bioprocess medium and 
      another CHO cell line producing another mAb. Our results show that protein 
      aggregation can be controlled during cell culture and helps to improve 
      bioprocessing of mAbs, by giving insights into the protein aggregation at its 
      origin in mammalian cell culture.
CI  - (c) 2017 Wiley Periodicals, Inc.
FAU - Paul, Albert J
AU  - Paul AJ
AUID- ORCID: 0000-0003-3684-7329
AD  - Institute of Applied Biotechnology, Biberach University of Applied Sciences, 
      Biberach, Germany.
FAU - Handrick, Rene
AU  - Handrick R
AD  - Institute of Applied Biotechnology, Biberach University of Applied Sciences, 
      Biberach, Germany.
FAU - Ebert, Sybille
AU  - Ebert S
AD  - Institute of Applied Biotechnology, Biberach University of Applied Sciences, 
      Biberach, Germany.
FAU - Hesse, Friedemann
AU  - Hesse F
AD  - Institute of Applied Biotechnology, Biberach University of Applied Sciences, 
      Biberach, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180122
PL  - United States
TA  - Biotechnol Bioeng
JT  - Biotechnology and bioengineering
JID - 7502021
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Culture Media)
RN  - 0 (Protein Aggregates)
RN  - 0 (Recombinant Proteins)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/chemistry/metabolism
MH  - CHO Cells
MH  - Cell Culture Techniques/*methods
MH  - Cricetulus
MH  - Culture Media/chemistry
MH  - Humans
MH  - *Protein Aggregates
MH  - *Protein Denaturation
MH  - *Protein Multimerization
MH  - Recombinant Proteins/*chemistry/*metabolism
MH  - Temperature
OTO - NOTNLM
OT  - CHO cells
OT  - bioprocess engineering
OT  - monoclonal antibodies
OT  - protein aggregation
EDAT- 2017/12/28 06:00
MHDA- 2019/06/05 06:00
CRDT- 2017/12/28 06:00
PHST- 2017/07/26 00:00 [received]
PHST- 2017/11/16 00:00 [revised]
PHST- 2017/12/20 00:00 [accepted]
PHST- 2017/12/28 06:00 [pubmed]
PHST- 2019/06/05 06:00 [medline]
PHST- 2017/12/28 06:00 [entrez]
AID - 10.1002/bit.26534 [doi]
PST - ppublish
SO  - Biotechnol Bioeng. 2018 May;115(5):1173-1185. doi: 10.1002/bit.26534. Epub 2018 
      Jan 22.