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Recombinant Proteins
Exam 2
52
Pharmacology
Professional
03/05/2013

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Term
advantages to recombinant proteins
Definition
limited natural product sources, cheaper than natural products, AVOIDs immunogenicity, avoids pathogen contamination
Term
advantages over small molecules
Definition
MOA of therapeutic targets are complex and impossible to target with low molecular weight
Term
disadvantages of recombinant DNA
Definition
not evolved to be good drugs, complex production, tend to aggravate and susceptible to proteases in vivo
Term
plasmids for recombination (protein synthesis in E coli)
Definition
must have origin of replication and selection markers and maintained in an episome, also offers easy manipulation and modification
Term
inclusion bodies
Definition
cytoplasmic aggregates of proteins that occur during synthesis within E cli
Term
glycosylation
Definition
post-transLATIONAL modifications that does not occur naturally in E coli
Term
E coli protein synthesis limitations
Definition
proteins that do not require glycosylation (post-translations modification), other PTM do not occur the same as eukaryotic cells (disulfide bonds and proteolysis)
Term
proteolysis
Definition
Post-translational modification in which N-terminus is cleaved off the end of proteins within the endoplasmic reticulum
Term
disulfide bridge
Definition
post-translational modification of secreted proteins that occur within compartments of eukaryotic cells
Term
IL-2 (interleukin-2)
Definition
stimulates growth/differentiation of T cells and NK cells, stimulates AB production in B cells
Term
Proleukin
Definition
IL-2
Term
IFN-beta (Interferon beta)
Definition
affects many cells types, induces antiviral genes, enhances MHC-class I expression
Term
Betaseron
Definition
IFN-beta
Term
EPO (erythropooietin)
Definition
stimulate erythropoeisis (increases RBCs), treats anemia
Term
Procrit
Definition
EPO, erythropoietin
Term
G-CSF (granulocyte colony stimulating factor)
Definition
cytokine promoting hematopoiesis
Term
Neupogen
Definition
G-CSF
Term
non-glycosylated IL-2
Definition
retains full biological activity, however they are less soluble because glycans improve solubility
Term
rhIFN-beta
Definition
made within E coli and CHO cells, glycans improve stability in CHO products
Term
rhEPO
Definition
requires glycosylation for stability and to reduce aggregation, exclusively made in mammalian cells
Term
insulin; overcoming PTM E coli production
Definition
Bchain:C-peptide:Achain, C-peptide cleaved in ER allowing for A and B chain to associate via two disulfide bridges, A and B chains initially produced separately
Term
proteins produced in E coli that form inclusion bodies
Definition
must be solubilized and refolded, modifying cystine residues to produce proper folding is often employed
Term
Proleukin (IL-2); protein stability
Definition
mutate cystine into serine (Cys125ser) to improve stability
Term
cystines within native IL-2
Definition
58, 105, 125, two form disulfide bond and the other remains reduced, presence of reduced cystine encourages aggregation
Term
Betaferon and Betaseron (IFN-beta-Ib)
Definition
first cystine is removed (cys17ser)
Term
saccharomyces cerevisiae
Definition
eukaryote that perform some PTMs like glycosylation, short generation time, easily cultured
Term
'humanized' yeast
Definition
deletion of genes that "hyper-mannosylate" proteins and induction of genes that produce human glycosylation structures
Term
DHFR expressing plasmids
Definition
Chinese hamster ovary commonly used for mammalian cell line protein production
Term
improved CHO cells
Definition
introduced anti-apoptosis genes, introduced chaperones (proteins that facilitate folding)
Term
kerinocyte growth factor (KGF); prevents chemotherapy/ radiation-induced mucositis
Definition
aggregation occurs during storage of proteins after synthesis, REMOVAL of 23-N-Terminal amino acid improve stability
Term
Kepivance
Definition
KGF with removed 23-N-terminal amino acid with improved stability and decreased aggregation
Term
insulin Humalog
Definition
point mutation in B chain to improve therapy (pro28lys, and lys29pro) allowing drug to stay in monomer form resulting in rapid action
Term
insulin Novolog
Definition
point mutation to improve therapy (pro28asp) allowing drug to stay in monomer form resulting in rapid action
Term
Aranesp
Definition
EPO; darbepoetin alpha containing two additional N-linked carbohydrates which increases half life
Term
darbepoetin pros and cons
Definition
3-fold increase in serum in half life however there a 5 fold reduction in receptor binding affinity relative to epoeitin-alpha
Term
difference in rodent glycosylation compared to human
Definition
missing 2,6-linked sialylation and has other different components that ilicit immunogenic reactions
Term
Erbitux (epidermal growth factor receptor)
Definition
induced hypersensitivity reactions, ABs against galactose alpha 1,3 galactose which is present on Fab portion of heavy chain
Term
Infergen
Definition
synthetic isoform of interferon; 'consensus IFN' and corresponding DNA sequenced was synthesized
Term
consensus IFN (infergen)
Definition
potent antiviral activity, NK cell activation and cytokine induction
Term
chimeras
Definition
genetic fusions to Ig Fc or albumin
Term
genetic fusions
Definition
fusion of two proteins or domains of two proteins allows modification of activity
Term
Ig Fc
Definition
fusion that is common and improves stability of proteins
Term
Fc and albumin chimeras
Definition
have long half-life with extraordinary serum concentrations compared with other circulating proteins
Term
FcRn receptor
Definition
chimera, pH-dependent, binding allows recycling of Fc or albumin-bound fusion proteins
Term
albumin-interferon chimera
Definition
IFN, insulin, IL-2 fusion have been attempted and increased half-life but there is some risk of immunogenicity
Term
Tumor necrosis factor
Definition
cytokine with many functions, pyrogen, inflammation and apoptosis inducer, potent chemoattractant for neutrophils
Term
Enbrel
Definition
Fc-TNF receptor chimera
Term
Fc-TNF receptor chimera
Definition
captures TNF before it attaches to immune cells, attaching Fc causes dimerization and results in longer serum half-life
Term
PEG modification
Definition
affects hydrophobicity (improved solubility) and electrostatic interactions, increases protein size, reduced immunogenicity (can) and proteolysis
Term
Neulasta
Definition
PEGylated rhG-CSF
Term
somavert
Definition
PEGylated human growth hormone (HGH receptor antagonist)
Term
PEG-intron/PEGasys
Definition
PEGylated interferon alph (ITN-alpha)
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