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pharmaceutics > Quiz 5 > Flashcards

Quiz 5 Flashcards

1
Q

biotechnology

A

technique which uses living organisms (microorganisms) bacteria, yeast, mammalian in the production of products used to affect human health and human environment

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2
Q

uses of biotech

A

treatment, prevention, diagnostics

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3
Q

size of biotech

A

macromolecules

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4
Q

biotech products

A

proteins, Nucleic acids, monoclonal antibodies, RNA

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5
Q

small molecule medicines vs large molecule medicines

A

small: single chem synthesized, active ingredient, made entirely from chem-synthesized reactions between different compounds, manufactured in a chemical process
large: made from living cells and complex, active ingredients are protiens, antibodies, cytokines, insulin, biologics derived from living organisms, characteristics and properties influenced by the manufacturing process, sensitive to changes in their enviroment and handling (all different final products)

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6
Q

CDER vs CBER

A

both FDA regulated CDER is for small molecule medicines and CBER is for large molecule medicines

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7
Q

first biotech product

A

insluin, 1921, university of toronto, banting/best

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8
Q

insulin then vs now

A

then: isolated from cows and pigs
now: recombinant human insulin
issues with then: animals not all the same, allergies/immune response, containmenents

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9
Q

rDNA

A

used to produce biologics, proteins, mAbs, developed in 1973, used to obtain large amounts of protein higher level of purity and lower cost

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10
Q

PCR

A

polymerase chain reaction, proteins, gene therapy, antisense NAs, large scale production if possible

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11
Q

hybridoma technology

A

antibody production

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12
Q

when was the first rDNA marketed?

A

insulin - 1982 - FDA approved

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13
Q

how to obtain the biotech product / protien

A
  1. isolation of DNA with gene of interest
  2. insertion into plasmid for protein synthesis - rDNA - independent of nucleus
  3. host selection for scale-up
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14
Q

cohen-boyer method

A

1971-EcoRI sed to cut plasmid restriction endonuclease

1972 -insertion of rDNA so foreign DNA will replicate naturally

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15
Q

step 1 cohen boyer method

A

DNA isolation - DNA first cut into smaller lengths with restriction endonucleases which recognize specific sequences of base pairs and cut the DNA at that point. the DNA sequence desired can therefore be removed and isolated.

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16
Q

step 2 cohen boyer method

A

recombinant DNA production - protein production begins when incorporating the DNA of interest into the plasmid DNA, DNA segment mixed with the plasmid DNA and ligase, ligase connects the DNA with plasmid, forms the rDNA

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17
Q

step 3 cohen boyer method

A

host cell selection and protein production - cloning accomplished by inserting the recombinant DNA into a host that replicates easily - bacteria, yeast, mammalian cells, proteins increase in complexity with increasing host complexity

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18
Q

bacterial hosts

A

advantages: replication rate is rapid, cheap used for simple proteins
disadvantages: bacterial debris, pyrogens, antigens, fever causing not in here!

cannot make relevant post-translational modifications
can do glycosylation

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19
Q

recombinant insulin came from

A

E. Coli

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20
Q

humalin

A

rDNA insulin

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21
Q

yeast host cells

A

advantages: protien secretion, growth rate, large-scale production, absence, not pathogenic, post-translational modifications
disadvantages: active proteases can degrade proteins
yeasts are attractive hosts for the production of therapuetic proteins, used to express recombinant proteins to overcome the shortcomings of bacterial expression systems

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22
Q

example of yeast host

A

saccaromyces cerevisiae, leukine is a drug

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23
Q

mammalian host cells

A

some proteins only produced with higher organisms, proteins are difficult to express and need folding complex for function

advantages: folding, post-translational modifications, contamination, more complex proteins
disadvantages: higher cost, more time

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24
Q

example of mammalian host cells

A

chinese hamster ovary cells, aransep is an EPO produced in CHO

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25
Q

immunogenicity of biolgoics

A

anti-body responses (AARS)

anti-drug antibodies (ADAs)

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26
Q

pegylation

A

used to extand half life

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27
Q

filgrastim (neupogen)

A

half life of 3.5 hours, 18,800 Da, requires daily dosing by injection to maintain its effects in the bone marrow

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28
Q

pegfilgrastim (neulasta)

A

half life of 15-18 hours, longer acting form, 20KDa PEG molecules to the N-terminal of filgrastim, once per chemotherapy cycle admin

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29
Q

peglation

A

earliest chem modifications of therapeutic proteins, attachment to PEG, conjugation of proteins to PEG changes the immune response to them
result- proteins get hidden from the immune system like native proteins, forms a shell around protein, hinders circulation time and metabolism

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30
Q

polymerase chaine reaction

A

makes genes, protein, antisense NAs, quick scale up

  1. denaturation
  2. annealing
  3. extension (2 minutes 72 degrees C- only dNTPs
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31
Q

denaturation

A

DNA heated which allows the strands to separate/denature(1 min 94 degrees C)

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32
Q

annealing

A

single-stranded DNA (primers) are added. these bind to complementary sequences of DNA interest, bracket the region to be replicated (45 seconds 54 degrees C)

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33
Q

extension

A

DNA Polymerase is added, DNA heated again. DNA polymerase added, DNA heated again. DNA polymerase starts at primer and synthesizes few DNA complementary to the single strand - developed 1983 - very quick method for replication

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34
Q

post-translational modification

A

often necessary to obtain a functional protein. occurs through- glycosylation, proteolytic cleavage of a pro-peptide bond, disulfide bond formation, protein folding

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35
Q

post-translational modification falls into 2 broad categories

A
  1. those needed to produce a functional protein- glycosylation
  2. produces enhanced pharmacokinetic properties - glycosylation/pegylation
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36
Q

glycosylation

A

most common post-translational modification of proteins - attachement of a polysaccharide chain to a specific AA residue. carbohydrate components may play a variety of critical roles

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37
Q

how do you glycosylate a recombinant protein?

A

easiest system for recombinant protein - E Coli BUT resulting protein not glycosylated (E. Coli lacks an endogenous glycosylation pathway)

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38
Q

conditions unique to biotech products

A
  1. biosimilars and interchangeables
  2. manufacturing
  3. storage
  4. administration
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39
Q

definition of a biosimilar

A

basically a generic form of a biotech product
WHO: similar quality, safety and efficacy to an already licensed biotherapeutic product
USFDA: no meaningful differences, same in safety, purity, and potency
EMA: version of active substance of an authorized original biological medicinal product

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40
Q

Can large molecule medicines be exactly reproduced?

A

no - derived from living cells. can be highly similar to the orginial in terms of safety, purity, and potency and used to treat the same illness. AA sequence is expected to be the same as the reerence product

41
Q

what data needs to be similar to the original biologic

A

analytical, non-clinical, clinical data (characteristics, safety, efficacy) - more expensive and more involvement with patients - require high investment (clinical trials and pot-approval safety monitoring)

42
Q

zarxio

A

first biosimilar approved in the US and added to the FDAs new purple book - march 6th 2015 - biosimilar product of amgens cancer drug neupogen - approved 2015 after launch of purple book 2014

43
Q

herceptin

A

trastuzumab, fourth tratuzumab biosimilar granted FDA approval

44
Q

purple book

A

lists of licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations - adding in a list to describe the degree to which a biosimilar drug is equivalent to the biologic product. launched in anticipation of biosimilar product zarxio

45
Q

manufacturing a biotech

A

rDNA technology
PCR
back in the day - hybridoma technology for MAbs (mouse + protein to secrete antibodies and extract the spleen to get B -lymph - so lymph + mylenoma cells

46
Q

manufacturing process

A

large scale plants - multiple 10,000 L or larger cell cultures bioreactors (fermentation tanks)
intensive development work in cell line, media, bioreactor conditon g/L and cell densities of over 20 million cells/mL in fed-batch processes to be achieved - all biotech products NEED to be sterile with optimal growth condtions (temp, O2/ nutrients/pH)

47
Q

storage

A

proteins more fragile than small-molecule drugs
extremes in temp can cause proteins to aggregate or damage 3D conformation - stored at 4 degrees - too much heat will cause denaturation (unfold/break down)

48
Q

lyophilization

A

“freeze dried” converts aqueous solution of a protein into a solid - elimination of water, use a vacuum conditions, protectants to replace lost waste and keep 3D/ tertiary structures in tact

49
Q

reconstitution

A

before use if product was lyophilized - use bacteriostatic water for injection - has a preservative - in newborns use WFI (use each vial only once) - do not use solution of cloudy

50
Q

admin for biotech product - therapy

A

self - admin

RA, MS, psoriasis

51
Q

admin for biotech products - conditions

A

injected in a clinical setting - vaccines, asthma, immune disorders

52
Q

admin for biotech products - chemotherapy

A

under trained medical personnel - cancer, anemia, neutropenia

53
Q

self admin

A

demonstrate reconstitution, perform first injection under supervision, rotating sites to avoid site reactions, safe disposal of needles and syringes, storage instructions/light, do not agitate, roll in palms, regimen compliance

54
Q

top biotech products marketed (biggest to smallest)

A

monoclonal antibodies, synthetic immunomodulators, vaccines, recombinant hormones (insulin, NPH, lantus), purified proteins, recombinant enzymes
$192 billion total value including drugs in development

55
Q

blockbuster product

A

drugs that make a lot of money, $1 billion in sales, 1st of its kind, lead for new drug/biologics category, Humira (IV, SubQ)

56
Q

orphan drug

A

treats a small population of people

ex: cystic fibrosis - manufaturing companies do not want to invest in these disease states

57
Q

how many MAb on market

A

110

58
Q

Hinge

A

helps with flexibility

59
Q

VH

A

variable heavy chain

60
Q

VL

A

variable light chain

61
Q

Fab-Fragment

A

binds the antigen

62
Q

FC fragment

A

crystallizable fragment - helps stay in circulation longer and stabilizes the fragment

63
Q

monoclonal antibodies

A

made of of AA, bone marrow helps to produce antibody (immunoglobin secreted by B cells)
controls immune response to foreign materials, antigen stimulates the antibody production, IGG change variability of the binding sites FV

64
Q

administration of monoclonal antibodies

A

IV, SQ, IM (SQ and IM are fragile)

issues- BA and adverse drug infusion reactions (BC protein )

65
Q

antibodies

A

secreted by the B lymphocytes, body makes polyclonal,

66
Q

monoclonal

A

uniform structure, specific, derived, single clone of cells, specific gene sequence

67
Q

treatment of MAbs

A

targets receptors on cells, very specific, specificity is a disadvantage because market for these drugs can be small, adv: less adverse reactions because so specific

68
Q

Humira

A

adalimumab, RA (anti-inflammatory, MAb, 2002 approved, binds to TNFalpha - anti-TNF alpha, higherst revenue biologic on the market, Abbvie, CHO

69
Q

herecebtin

A

trastumab, 1998, HER-2 overexpressed receptor

70
Q

first Mab approved

A

1986, muromomab, recruits t-cells, binds to CD3 on the t-cells, alled OKT3 or orthoclone, prevented kidney transplant injection

71
Q

how many FDA biologics/biosimilars approve as of 2018

A

100 FDA approved

72
Q

amjevita (adalimumab)

A

2016 FDA first approved generic for humera, amgen, CHO, hard to get same product because it is a protein and it has a 3D structure, may not be the same but it does the same thing

73
Q

MAbs host cells used

A

E-coli, CHO, Mammalian

74
Q

biotechs in mammalian

A

MAbs, biospecific (2places for attachment of antigen), antibody drug conjugates, radio-labelled (isotope lit up), antigen binding fragment (Fab), fusion proteins)

75
Q

biotechs in Ecoli

A

fusion proteins, Fabs

76
Q

latest Mab

A

tecentriq (atezolizumab) FDA approved 2019, genentech, CHO cells bladder and UT cancer, combination therapy with abraxane for metastatic triple negative breast cancerwhich expresses PD-L1

77
Q

mouse MAb

A

mo = mouse

ex: muromomab, high potential for immunogenicity

78
Q

chimeric MAb

A

Xi = 75% human, rest mouse (better acceptance than mouse)

ex: rituximab

79
Q

humanized MAb

A

zu = human, more acceptance than chimeric

ex: trastuzumab

80
Q

human MAb

A

mu, su= fully human

ex: adalimumab, low potential for immunogenicity

81
Q

toxicities with MAb - target related

A
  1. mAb binding specific - HUMIRA - may cause immunosuppression and lead to infection
  2. mAb interactions with the target antigen on tissue other than the intended target- anti EGFR mAb causes skin rash, pruritus, erythema - EGFR target receptor that reflects the wide expression of epideraml growth but also on skin cells
82
Q

toxicities with MAb - modality related

A

target-independent and can occur acutely at the time of injection, or develop through prolonged treatment with the antibody,

acute immune reactions- hypersensitivity reactions, cytokine-release syndrome, infusion-related reactions

fever, nausea, chills, cytokine release,

83
Q

enbrel (etanercept)

A

fusion protein, blockbuster biological product - fusion of extracellular (EC) domain of the TNF - alpha receptor and Fc portion of the IgG1, anti-inflammatory disorders, CHO cells

84
Q

fusion proteins admin

A

pre-filled syringes - SC

85
Q

synthetic immunomodulators

A

cytokines - 20

growth factors - 35

86
Q

growth factors/ colony-stimulating factors

A

ESAs (EPO stimulating agents) (erythrocytes/ leukocytes) and CSF (colony stimulating factors (WBC)), regulates process by which stem cells in bone marrow reproduce/differentiate

87
Q

overall decline in sales of ESA

A

safety concerns and small molecule competition

88
Q

admin of growth factors/colony-stimulating factors

A

IV or SC

89
Q

neutropenia

A

neupogen (fibrostin)

neulasta

90
Q

anemia

A

epoetin alpha, poeitin alpha

91
Q

neupogen

A

colony stimulating factor
filgrastin, not glycosylated, half life 3.5 hours, E-coli host, requires daily dosing by injection to maintain effects on the bone marrow

92
Q

neulasta

A

CSF, pegylation increases size of filgrastim, too large for renal clearance, retains same biological activity, binds to same G-CSF receptor, stimulates proliferation, differentation, activation of neutrophils - same AA as neupogen just addition of PEG, half life 15-18 hours - single dose not cheaper

93
Q

procrit/epogen/epoetin alfa

A

parent biologic, stimulates RBC, half-life 4 to 13 hours, glycosylated protein, mature polypeptide 165 amino acids, mammalian cells - requires glycosylation for biologic activity - CHO host

94
Q

aranesp/ darbepoetin alpha

A

difference is carbs, parent + glycosylation, same AA just diff carbohydrates, half life 27-89 hours, 5 N-linked oligosaccharide chains, no change in tertiary structure/biologic activity
requires glycosylation for biologic activity - CHO host

95
Q

cytokines

A

lymphatic system
soluble mediators or glycoproteins, helps communicate between cells in the immune system, hematological or neurological systems, interferons/ interleukis, avonex IFN-beta, relapsing MS, CHO host cells

96
Q

prophylatic vaccine

A

proteins for future pathogens

97
Q

therapeutic vaccines

A

after the infection has occured

98
Q

recombivax HB

A

hep B (energix-B, recombivax HB), 3 dose schedule, has surface antigen that will stimulate the immune response (antibody production in the body) - S. cerevisiae

99
Q

provenge

A

therapeutic prostate cancer vaccine - personalized therapy- stimulates patients’ immune cells outside the body with PAP and GM-CSF - 93,000

pharmaceutics (8 decks)

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