Castilho Leda R., Moraes Angela Maria (Ed.) Animal Cell Technology: From Biopharmaceuticals to Gene Therapy
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UDP-N-GNAc UDP-N-acetyl-hexosamine
UMP uridine monophosphate
UTP uridine triphosphate
VO 203 hybridoma cell line
WI-38 Wistar Institute-38; human embryonic lung tissue cell line
Chapter 5
bFGF basic fibroblast growth factor
ECGF endothelial growth factor
ECM extracellular matrix
EGF epidermal growth factor
FDA food and drug administration
FGF fibroblast growth factor
IGF-1 insulin-like growth factor-1
IGF-2 insulin-like growth factor-2
IL-1 interleukin-1
IL-6 interleukin-6
NGF nerve growth factor
PDGF platelet-derived growth factor
PW purified water
TGF transforming growth factor
WFI water for injection
Chapter 6
AGE advanced glycation end products
BHK baby hamster kidney cell line
CHO Chinese hamster ovary cell line
DO dissolved oxygen
ER endoplasmic reticulum
FVIII blood coagulation factor eight
FX blood coagulation factor ten
G2 digalactosylated glycans
Gla gamma-carboxyglutamic acid
GlcNAc N-acetyl glucosamine
HEK human embryonic kidney cells
HIF hypoxia-inducible factor
IgG immunoglobulin
OST oligosaccharyltransferase enzyme
t-PA tissue-type plasminogen activator
Xyl xylose
Chapter 7
14-3-3 cytosolic protein that binds to phosphorylated Bad, inactivating it
A-1 anti-apoptotic member of Bcl-2 family
AIF apoptosis-inducing factor
Akt serine/threonine kinase
ALG-2 apoptosis-linked gene-2
xx Animal Cell Technology
ANT adenine nucleotide translocator
AO acridine orange
Apaf-1 apoptosis protease activating factor-1
Apo-I apoptosis antigen-I (also known as Fas and CD95, a member of the TNF
receptor family)
ATP adenosine triphosphate
Bad Bcl-X
L
/Bcl-2 associated death promoter, pro-apoptotic member of Bcl-2
family
Bak Bcl-2 antagonist/killer, pro-apoptotic member of Bcl-2 family
Bax Bcl-2 associated x protein, pro-apoptotic member of Bcl-2 family
Bcl-2 B-cell lymphoma 2, anti-apoptotic member of Bcl-2 family
Bcl-w anti-apoptotic member of Bcl-2 family
Bcl-X
L
long form of Bcl-X, anti-apoptotic member of Bcl-2 family
Bcl-X
S
short form of Bcl-X, pro-apoptotic member of Bcl-2 family
BH1 Bcl-2 homolog domain 1
BH2 Bcl-2 homolog domain 2
BH3 Bcl-2 homolog domain 3
BH4 Bcl-2 homolog domain 4
BHK baby hamster kidney cell line
BHRF1 Epstein-Barr virus Bcl-2 homolog
Bid BH-3 interacting domain death agonist, pro-apoptotic member of Bcl-2
family
Bik Bcl-2 interacting killer, pro-apoptotic member of Bcl-2 family
Bim Bcl-2 interacting mediator of cell death, pro-apoptotic member of Bcl-2
family
BIR baculovirus IAP repeat
Bmf Bcl-2 modifying factor, pro-apoptotic member of Bcl-2 family
Boo Bcl-2 homolog of ovary, anti-apoptotic member of Bcl-2 family
CAD caspase-activated DNAse
CARD caspase recruitment domain
CDK cyclin dependent kinase
CHO Chinese hamster ovary cell line
CHOP C/EBP-homologous protein
cIAP1 cellular inhibitor of apoptosis protein 1
cIAP2 cellular inhibitor of apoptosis protein 2
c-jun cellular homolog of v-Jun avian sarcoma virus 17 oncogene
c-myc cellular homolog of the oncogene v-myc of avian myelocytomatosis virus
strain 29
CO
2
carbon dioxide
COS simian fibroblasts (CV-1 cells) transformed by SV40, deficient in the
origin of replication region
CrmA cytokine response modifier A
DAPI 49,69-diamidino-2-phenylindole (a fluorescent dye)
dATP deoxy-adenosine triphosphate
DD death domain
DED death effector domain
DFF40 DNA fragmentation factor of 40 kDa
DIABLO direct inhibition of apoptosis protein IAP binding protein with low pI
DISC death inducing signaling complex
DNA deoxyribonucleic acid
Abbreviations and Symbols List xxi
E1B-19kDa adenovirus Bcl-2 homologue
EB ethidium bromide
FADD Fas associated death domain
FAK focal adhesion kinase
Fas cell surface receptor, member of the TNF receptor family that promotes
apoptosis (also known as CD95 and APO-1)
FasL Fas ligand
FITC fluorescein isothiocyanate
G
0
cell cycle Gap 0 phase
G
1
cell cycle Gap 1 phase
G
2
cell cycle Gap 2 phase
GADD153 growth arrest and DNA damage-inducible gene 153
HEK 293 human embryonic kidney cell line
HeLa human cervical adenocarcinoma cell line
HMW-DNA high molar mass DNA
HRK harakiri, pro-apoptotic member of Bcl-2 family
HSP heat shock proteins
IAP inhibitor of apoptosis proteins
ICAD inhibitor of caspase-activated DNAse
IGF-1 insulin-like growth factor 1
JNK c-Jun N-terminal kinase
KSBcl-2 Kaposi’s sarcoma-associated herpesvirus Bcl-2 homolog
LMW-DNA low molar mass DNA
M cell cycle mitosis phase
Mcl-1 myeloid cell leukemia 1, anti-apoptotic member of Bcl-2 family
M-CSF macrophage colony stimulating factor
MEKK1 Map/Erk kinase kinase 1
NBD nucleotide-binding domain
NEC necrotic cell
NFkB nuclear factor of immunoglobulin kappa locus in B cells
NGF nerve growth factor
Noxa pro-apoptotic member of Bcl-2 family
NS0 myeloma cell line
NVA non-viable apoptotic cell
Omi/HtrA2 high temperature requirement protein A2
p15 15 kDa protein, truncated Bid
p53 53 kDa protein, tumor suppressor gene product that promotes apoptosis
and is involved in the cell cycle control
PAK2 p21-activated kinase 2
PARP poly (ADP ribose) polymerase
PLK polo-like kinases
PTP permeability transition pore
Puma p53 upregulated modulator of apoptosis, pro-apoptotic member of Bcl-2
family
RNA ribonucleic acid
S cell cycle synthesis phase
SAPK stress-activated protein kinase
Sf9 insect cell line derived from Spodoptera frugiperda
Smac second mitochondrial activator of caspases
TB/C3 hybridoma cell line
xxii Animal Cell Technology
t
d
doubling time
TNF tumor necrosis factor
TNF-R1 tumor necrosis factor receptor 1
TRADD TNF receptor I associated death domain
TRAF2 TNF receptor associated factor 2
TRAIL-R1 TNF-related apoptosis-inducing ligand receptor 1
TRAIL-R2 TNF-related apoptosis-inducing ligand receptor 2
TUNEL nuclear terminal deoxynucleotidyl transferase-mediated dUTP nick-end-
labeling
UPR unfolded protein response
VA viable apoptotic cell
VDAC voltage-dependent anion channel
VNA viable nonapoptotic cell
WD-40 repeats repeated sequence of approximately 40 amino acids, usually tryptophan
(W) and aspartate (D) residues
x-dUTP deoxyuridine triphosfatase; x ¼ biotin, DIG or fluorescein
XIAP X-linked inhibitor of apoptosis protein, member of IAP family that
inhibits apoptosis
˜łm inner mitochondrial membrane potential
Chapter 8
In the definitions below, M, L and T are basic units of mass, length and time, respectively.
D specific feed rate (T
1
)
D
Per
specific perfusion rate (T
1
)
GLC glucose concentration (M L
3
)
GLC
glucose concentration under substrate limitation (M L
3
)
GLC
thres
threshold glucose concentration (M L
3
)
GLN glutamine concentration (M L
3
)
GLN
glutamine concentration under substrate limitation (M L
3
)
K first order constant for glutamine decomposition (T
1
)
k
d
specific cell death rate (T
1
)
k
d,max
maximum specific cell death rate (T
1
)
k
d,min
minimum specific cell death rate (T
1
)
k
GLC
glucose limitation constant to growth (M L
3
)
k
d
GLC
glucose limitation constant to death (M L
3
)
k
LAC
GLC
glucose limitation constant for lactate synthesis (M L
3
)
k
GLN
glutamine limitation constant to growth (M L
3
)
k
MAb
GLN
glutamine limitation constant for monoclonal synthesis (M L
3
)
k
LAC
GLN
glutamine limitation constant for lactate synthesis (M L
3
)
k
NH
3
GLN
glutamine limitation constant for ammonia synthesis (M L
3
)
k
d
i,GLC
glucose inhibition constant for death (M L
3
)
k
MAb
i,GLC
glucose inhibition constant for monoclonal synthesis (M L
3
)
k
d
i,GLN
glutamine inhibition constant for death (M L
3
)
k
i,LAC
lactate inhibition constant for growth (M L
3
)
k
i,NH
3
ammonia inhibition constant for growth (M L
3
)
Abbreviations and Symbols List xxiii
k
i,NH
þ
4
ammonium inhibition constant for growth (M L
3
)
k
i,P
product inhibition constant for growth (M L
3
)
k
p
i,P
product inhibition constant for product synthesis (M L
3
)
k
i,S
substrate inhibition constant for growth (M L
3
)
k
d
LAC
lactate limitation constant for death (M L
3
)
k
d
NH
3
ammonia limitation constant for death (M L
3
)
k
d
NH
þ
4
ammonium limitation constant for death (M L
3
)
k
S
substrate limitation constant for growth (M L
3
)
k
P
S
substrate limitation constant for product synthesis (M L
3
)
k
S
S
substrate limitation constant for substrate uptake (M L
3
)
LAC lactate concentration (M L
3
)
MAb monoclonal antibody concentration (M L
3
)
m
S
specific substrate uptake rate for maintenance, or maintenance coefficient
(M M
1
T
1
or M Cel
1
T
1
)
NH
3
ammonia concentration (M L
3
)
NH
þ
4
ammonium concentration (M L
3
)
OF objective function
P product concentration (M L
3
)
r
P
product synthesis rate (M L
3
T
1
)
r
S
substrate consumption rate (M L
3
T
1
)
r
X
cell growth rate (M L
3
T
1
or Cel L
3
T
1
)
S substrate concentration (M L
3
)
S
substrate concentration under substrate limitation (M L
3
)
t time (T)
X cell concentration (M L
3
or Cel L
3
)
X
d
dead cell concentration (M L
3
or Cel L
3
)
X
t
total cell concentration (M L
3
or Cel L
3
)
X
V
viable cell concentration (M L
3
or Cel L
3
)
Y
LAC=GLC
glucose-to-lactate yield coefficient (M M
1
)
Y
NH
þ
4
=GLN
glutamine-to-ammonium yield coefficient (M M
1
)
Y
P=S
substrate-to-product yield coefficient (or factor) (M M
1
)
Y
X=S
substrate-to-cells yield coefficient (or factor) (M M
1
or Cel M
1
)
Y
max
X=S
maximum substrate-to-cells yield coefficient (or factor) (M M
1
or
Cel M
1
)
Y
X
V
=GLC
glucose-to-viable cells yield coefficient (M M
1
or Cel M
1
)
Y
X
V
=GLN
glutamine-to-viable cells yield coefficient (M M
1
or Cel M
1
)
Æ constant for growth-associated production (M M
1
or M Cel
1
)
constant for non-growth-associated production (M M
1
T
1
or
M Cel
1
T
1
)
˜i variation of element i in the time interval ˜t(M L
3
or Cel L
3
)
˜t time interval (T)
LAC
specific lactate synthesis rate (M M
1
T
1
or M Cel
1
T
1
)
MAb
specific monoclonal synthesis rate (M M
1
T
1
or M Cel
1
T
1
)
NH3
specific ammonia synthesis rate (M M
1
T
1
or M Cel
1
T
1
)
P
specific product synthesis rate (M M
1
T
1
or M Cel
1
T
1
)
P,max
maximum specific product synthesis rate (M M
1
T
1
or
M Cel
1
T
1
)
xxiv Animal Cell Technology
S
specific substrate consumption rate (M M
1
T
1
or M Cel
1
T
1
)
S
specific substrate uptake rate under substrate limitation conditions
(M M
1
T
1
or M Cel
1
T
1
)
X
specific cell growth rate (T
1
)
X,max
maximum specific cell growth rate (T
1
)
X,min
minimum specific cell growth rate (T
1
)
ap
X
apparent specific growth rate (T
1
)
Other parameters ...b
1
,b
2
,b
3
,C
1
,C
2
,d
0
,d
1
,F
1
,F
2
,h
1
,h
2
,K,k
LAC#
GLC
,k
NH
3
#
GLN
,k9
i,NH
3
,k
MAb9
i,GLC
,
k
d#
LAC
,k
d#
NH
3
,k9
S
,k
S#
S
,k
,P
m
,P9
m
, Æ
0
, Æ
1
, Æ
2
, Æ
3
, Æ
4
,
0
,
1
,
2
,
m
, *, , º, ˜
max
S
, ˜
max
P
.
Chapter 9
The units defined for the variables listed below are given in the MLT unit system, except in
cases where cell concentration (given as cell number) is involved. M represents mass, L
length and T time.
a interfacial gas-liquid area per volume of bioreactor (L
2
L
-3
)
CHO Chinese hamster ovary cell line
D dilution rate (T
-1
)
D
wash-out
dilution rate at wash-out conditions (T
-1
)
DO* equilibrium dissolved oxygen concentration (M L
-3
)
DO dissolved oxygen concentration (M L
-3
)
ECS extracapillary space
ICS intracapillary space
F bioreactor volumetric feed flow rate (L
3
T
-1
)
H
O2
Henry’s constant (T
2
L
-2
)
k
L
global oxygen transfer coefficient (L
3
L
-2
T
-1
)
k
L
a volumetric oxygen transfer coefficient (T
-1
)
NS0 myeloma cell line
P product concentration (M L
-3
)
P
A
annual production obtained in a bioreactor (M)
P
acc
amount of product accumulated throughout a bioreactor run (M)
P
O2
partial oxygen pressure (M L
-1
T
-2
)
P
V
volumetric productivity of a bioreactor (M L
-3
T
-1
)
q
O2
specific oxygen consumption rate (M cells
-1
T
-1
)
q
P
specific product formation rate (M cells
-1
T
-1
)
q
S
specific substrate consumption rate (M cells
-1
T
-1
)
r
GLC
glucose consumption rate (M T
-1
)
r
O2
oxygen consumption rate (M T
-1
)
S substrate concentration (M L
-3
)
S
A
substrate concentration in the bioreactor feed (M L
-3
)
t culture time (T)
t
growth
time needed for cells to grow up to the concentration desired for the
process (T)
t
work
number of working days per year (T)
t
prep
time required for the preparation of the bioreactor (includes cleaning and
sterilization) (T)
t
proc
process time (T)
t
prod
duration of the production phase (T)
Abbreviations and Symbols List xxv
V bioreactor working volume (L
3
)
X
V,PERFUSATE
viable cell concentration in the perfusate stream (cel T
-1
)
Xv viable cell concentration (cells L
-3
)
Æ cell passage factor in perfusion processes ( – )
turbulence eddy dissipation (L
2
T
-3
)
º Kolmogorov eddy length (microscale of turbulence) (L)
specific growth rate (T
-1
)
MAX
maximum specific growth rate (T
-1
)
kinematic viscosity (L
2
T
-1
)
Chapter 10
C concentration of dissolved oxygen
C
S
concentration of dissolved oxygen in equilibrium with the gas phase
FACS fluorescence activated cell sorter
FIA flow injection analysis
k
L
a volumetric oxygen transfer coefficient
pCO
2
partial pressure of dissolved carbon dioxide gas
P-I-D proportional-integral-derivative controller
Q
O2
specific respiration rate
Chapter 11
In the definitions below, M, L, and T are basic units of mass, length, and time, respectively.
A
min
minimum settling area (L
2
)
b force field intensity (L T
-2
)
c
v
volumetric concentration (dimensionless)
d particle (or cell) diameter (L)
d
50
cut size (L)
d’
50
reduced cut size (L)
D perfusion rate (T
-1
)
E total separation efficiency (dimensionless)
E’ reduced total separation efficiency (dimensionless)
g acceleration of gravity (L T
-2
)
G grade efficiency (dimensionless)
G’ reduced grade efficiency (dimensionless)
Q feed flow rate (L
3
T
-1
)
Q
C
concentrated stream (underflow) flow rate (L
3
T
-1
)
Q
D
diluted stream (overflow) flow rate (L
3
T
-1
)
r radial position of the particle (L)
R centrifuge radius (L)
R
f
flow ratio (dimensionless)
u ascending velocity of the liquid in the settler (L T
-1
)
V bioreactor volume (L
3
)
v
t
terminal velocity of the particle at low concentrations (L T
-1
)
v
tc
terminal velocity of the particle at a concentration c
v
(L T
-1
)
x particle size frequency in the feed suspension (dimensionless)
X cell concentration, in number, in the feed suspension (L
-3
)
X
C
cell concentration, in number, in the concentrated suspension (L
-3
)
xxvi Animal Cell Technology
X
D
cell concentration, in number, in the diluted suspension (L
-3
)
X
d
concentration of cells with diameter d, in number, in the feed suspension
(L
-3
)
X
dC
concentration of cells with diameter d, in number, in the concentrated
suspension (L
-3
)
X
dD
concentration of cells with diameter d, in number, in the diluted
suspension (L
-3
)
y cumulative particle size distribution (undersize) of the feed suspension
(dimensionless)
y
C
cumulative particle size distribution (undersize) of the concentrated
suspension (dimensionless)
y
D
cumulative particle size distribution (undersize) of the diluted suspension
(dimensionless)
z cumulative particle size distribution (oversize) of the feed suspension
(dimensionless)
specific cell growth rate (T
-1
)
ap
apparent specific cell growth rate (T
-1
)
L
liquid viscosity (M L
-1
T
-1
)
r density of the liquid (M L
-3
)
rs density of the particles or cells (M L
-3
)
ø angular velocity (T
-1
)
Chapter 12
AE Aminoethyl
C Carboxy
C1 Methyl
C8 Octyl
C18 Octyldecyl
CM Carboxymethyl
DEAE Diethylaminoethyl
DS-2 Drosophila melanogaster schneider-2
DTE 1,4-dithioerythritol
DTT 1,4-dithiothreitol
EBA expanded bed adsorption
EDTA ethylenediaminetetraacetic acid
H height of the expanded bed
H
0
height of the packed bed
HBsAg hepatitis B virus surface antigen
HIC hydrophobic interaction chromatography
K partitioning coefficient
K
A
association constant
K
av
alternative distribution coefficient
K
d
distribution coefficient
K
D
dissociation constant
L Ligand
MWCO molecular weight cut-off
P Protein
PEG polyethylene glycol
pI isoelectric point
Abbreviations and Symbols List xx vii
PL reversible complex ptotein-ligand
PVC poly vinyl chloride
Q quaternary amine
RPC reverse phase chromatography
S Sulfonate
SM Sulfomethyl
SP Sulfopropyl
SDS sodium dodecyl sulphate
SDS-PAGE sodium dodecyl sulphate – polyacrylamide gel electrophoresis
TEAE Triethylaminoethyl
TAM Trimethylaminomethyl
V
e
elution volume
V
o
interstitial volume of the porous matrix
V
s
total solvent volume within the pores
V
t
total column volume
x solute concentration in the original solution
y solute concentration in the extract
Chapter 13
CPE Cytopathic effect
DNA Deoxyribonucleic acid
GMP Good manufacturing practise
Had hemadsorption
HPCE High performance capillary electrophoresis
HPLC High performance liquid chromatograpy
HPSEC High-performance size-exclusion chromatography
IEF Isoelectric focusing
mAbs Monoclonal antibodies
MCB Master cell bank
mRNA Messenger RNA
PCR Polymerase chain reaction
pI Isoelectric point
PMA Production of monoclonal antibodies
PVDF Polyvinylidene fluoride
rDNA Recombinant DNA
RNA Ribonucleic acid
SDS sodium dodecyl sulphate
SDS-PAGE sodium dodecyl sulphate – polyacrylamide gel electrophoresis
UV Ultra violet
WCB Working cell bank
WHO World Health Organization
Chapter 14
ANVISA Ageˆncia Nacional de Vigilaˆncia Sanita´ria (Brazilian National Agency for
Sanitary Vigilance)
BL biosafety level
BLA Biologics License Application
xxviii Animal Cell Technology
BSE bovine spongiform encephalopathy
CBER Center for Biologics Evaluation and Research
CDER Center for Drug Evaluation and Research
cGMP current good manufacturing practices
CHO Chinese hamster ovary cell line
CNS Conselho Nacional de Sau´ de (Brazilian National Health Council)
CPMP Committee for Proprietary Medicinal Products
CTNBio Comissa
˜
oTe´cnica Nacional de Biosseguranc¸a (Brazilian National
Biosafety Technical Commission)
EC European Commission
EMEA European Medicines Agency
FDA Food and Drug Administration
GCP good clinical practices
GMO genetically modified organisms
HAP hamster antibody production
HEPA high efficiency particulate air
HIV human immunodeficiency virus
HTLV human T-Cell leukemia virus
ICH International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use
LSBL large-scale biosafety level
MAP mouse antibody production
MCB master cell bank
NDA new drug application
NIH National Institutes of Health
PPC post-production cells
PTC points to consider
QA quality assurance
QC quality control
RAP rat antibody production
WCB working cell bank
WCP well-characterized product
WHO World Health Organization
Chapter 15
ADR alternative dispute resolution
AUTM Association of University Technology Managers
EPC European Patent Convention
IDA irnationally recognized depositary authority
IFN-alpha Interferon-alpha
INPI Brazilian National Institute of Industrial Property
mAb Monoclonal antibody
Chapter 16
BLA Biologics License Application
CG chorionic gonadotrophin
CHO Chinese hamster ovary cell line
CSF colony-stimulating factor
Abbreviations and Symbols List xxix