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PCEUT 533 > Final - Amanda > Flashcards

Final - Amanda Flashcards

1
Q

naming convention of antibodies.

A

-zu- humanized. -u- human.

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2
Q

degree and type of sugar attachment

A

any proteins made in E .coli or bacteria are not glycosylated. In yeast any post-translational modifications are different from human cell (CHO) post-translational modifications (similar or identical to endogenous human).

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3
Q

Epogen vs. Eprex.

A

Similar products recombinant Epoetin-alpha, made from the same master stock but with different manufacturing. One caused immune response to endogenous erythropoietin as well as the recombinant drug. Product is dependent on processing/manufacturing even if from the same master stock.

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4
Q

Physiological properties and disposition of antibodies in humans….

A

IgG is antibody platform used in drug development because it has the longest half-life, 21 days, and is very stable and can circulate in the body for a long time

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5
Q

General structure of antibody molecule.

A

Fc region binds to the FcRN receptor. Fab is variable fragment that can be changed and binds to stuff.

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6
Q

mechanisms of antibody functions

A

Antibody IgG mediated biological functions include receptor binding or neutralizing. Neutralizing antibodies bind to and knock out the target protein whereas binding just binds to the target and the target can still retain function.

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7
Q

Enbrel

A

Enbrel is a TNF-alpha-receptor-Fc fusion protein. Binding of TNF-alpha to the Fc region of the antibody increases circulation times. Exploit FcRN to increase exposure

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8
Q

ADCC

A

Example is OKT3 (immunosuppressant drug) IgG Mab which binds to the CD3+ target cell through Fab region and then to the Fc-gamma receptor on T cells through Fc region of IgG antibody. Endocytosis through endo-lysosome pathway causes death/degradation of CD3+ cell.

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9
Q

Darbepoetin

A

darbepoetin, which is hyperglycosylated, has a longer half life and larger molecular size than epoetin. Athletes who are doping, and using darbepoetin, can be distinguished by the different sizes of the two proteins, based on molecular weight due to the hyperglycosylation.

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10
Q

Epoetin alpha vs. darbepoetin isoforms

A

Epoetin-alpha has a mixture of 9-14 sialated isoforms of human Epoetin whereas darbepoeitin is an engineered hyperglycosylated form of Epoetin (only 1 isoform).

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11
Q

IL-11

A

IL-11 (oprelvekin) can stimulate production of platelets and is therefore a platelet growth factor. Interleukin or cytokine.

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12
Q

Proteins/Peptides for Anticoagulation therapy…..

A

Integrilin (Eptifibatide) and Reopro (Abciximab) block binding of GP IIb/IIIa to halt platelet aggregation and prevent clot formation. Integrilin is a cyclic heptapeptide and Reopro is an antibody derivative.

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13
Q

IFNs in cancer therapy….

A

IFN-alpha-2 is used to induce hairy-cell leukemia to undergo differentiation in cancer therapy. Capillary leaky syndrome appears because of immune response to therapy.

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14
Q

INF treatments

A

IFN alpha (2a or 2b) is used for the treatment of chronic hepatitis C and IFN beta is used for the treatment of multiple sclerosis.

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15
Q

IFN in multiple sclerosis

A

IFN-beta-1a (Avonex, Rebif) and beta-1b (Betaseron) are used for the treatment of multiple sclerosis. Reduce rate of relapse and decreases frequency and severity of MS symptoms.

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16
Q

IL-2 for metastatic renal cell carcinoma….

A

IL-2 mediates (does not directly cause tumor killing) anti-tumor effects through stimulation of LAK cells, which kill cancer cells. Initially have sickness due to capillary leak syndrome, where the immune system is working to kill the cancer cells. Sickness is not due to treatment.

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17
Q

Forteo

A

Forteo (Teriparatide) is used in the treatment of osteoporosis and is a parathyroid hormone derivative.

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18
Q

Streptokinase

A

Streptokinase, which has the same mechanism as Urokinase, doesn’t directly activate plasminogen to plasmin directly. Indirect activation of plasminogen.

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19
Q

DNAse

A

DNAse is used to treat cystic fibrosis through the digestion of DNA polymers in mucus which thins and reduces mucus viscosity.

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20
Q

Ceredase

A

Ceredase or Cerezyme (Beta-glucuronidase) for Gaucher’s Disease. Mechanism of drug is is to expose terminal mannose residues of glycosylated enzyme to localize the enzyme to lysosome of macrophages to produce an antibody response. Disease causes accumulation of glucocerebroside in lysosomes and is fatal.

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21
Q

Exubera

A

Exubera, inhaled insulin, approved by FDA but failed on market (and discontinued) due to low sales, bulkiness, and safety concerns. Poor patient compliance though product was clinically effective

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22
Q

Renal clearance processes filtration….

A

Proteins less than 50 kDa are filtered through renal filtration. Antibodies, which are usually larger than 50 kDa, are eliminated elsewhere and not filtered.

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23
Q

glycosylation process

A

Glycosylation is not a chemical process but instead is formed in cells and is a biological process

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24
Q

Nonlinear protein drug clearance….

A

PK parameters that change in nonlinear kinetics include clearance, half-life, concentration at steady state and time to reach steady state. Initial concentration won’t necessarily change, especially in IV dosing.

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25
Q

immunogenicity of protein drugs….

A

Patient specific factors include prior immunogenicity, route of administration, dose, frequency of administration, immunological status and competence of patient, genetic status and status of immune tolerance to endogenous proteins. Product specific factors affecting immunogenicity include product origin, product aggregates, primary molecular structure, glycosylation, impurities with adjuvant activity, and formulation.

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26
Q

Therapeutic index, Window and Range…..

A

Therapeutic index and window are related but not interchangeable. Therapeutic index is the ration of the lethal to the effective dose, where a higher value is better. Range is the range of concentrations associated with effective therapy and is from EC50 to IC50. Window is the plasma concentration required for efficacy, where toxicity is not occurring and is specific to a patient.

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27
Q

Ommaya implantable device….

A

Ommaya implantable device is used for direct access to the brain and it increases the TI for the drug. Doesn’t necessarily take up tumor space but is direct site exposure.

28
Q

sustained release concept.

A

Slide 9 is osmotic pump controls release of drug as fluid draws in squeeze bag releasing drug. Slide 17 fentanyl patch. Fentanyl transdermal patch causes slow drug delivery/sustained release.

29
Q

Approaches to improve TI….

A

Physiological and molecular approaches to improve TI include permeation enhancement, modulation of drug clearance, sustained release, target to site of action, and molecular optimization. Traditional approaches included route, frequency and devices.

30
Q

polymers and liposomes.

A

Examples of biodegradable polymers include PLGA which can act as platform to carry therapeutic proteins. Cytokines, including interleukins 1,2,6 and 7, have been formulated in liposomes.

31
Q

Permeability through Lipid Bilayers….

A

Permeability depends on size, increasing size decreases permeability. For example, proteins are larger than glucose and less permeable, you would essentially have to degrade the liposome to release the drug providing a sustained release system. Membrane permeability from lowest to highest of liposome: cations > anions > glucose > tryptophan > HCO3- > glycerol > sucrose > manitol > indole > H2O.

32
Q

Doxorubicin/Daunorubicin…..

A

Liposome encapsulated doxorubicin prevents cardiac toxicity of drug while increasing efficacy because of reduced drug distribution (targeting to site of action). Drug normally binds to cardiolipin lipid in heart membrane leading to destruction but this is inhibited in liposome which is an added benefit.

33
Q

Modulation of Drug Clearance…. PEGylation

A

adds weight to protein as well as increasing hydrophilicity which shields the protein from RES recognition and phagocytosis. PEG is available in different molecular weights and can add multiple PEG molecules of varying sizes to the protein at multiple sites

34
Q

Directing Toxins to Tumor Cells…..

A

Targeting antibody conjugates to tumor cells improve TI in two mechanisms. First, targeting drug to site of action and also reducing off target effects because the drug is bound to antibody (toxicities). Protective effect (or reducing toxic effects) and increasing efficacy increases TI.

35
Q

immunotoxins/cytokine-toxin.

A

general concept is bacterial toxins protect bacteria that make them they will cause an immune response in a human but with small molecules less than 1000 da normally don’t cause immune reaction. toxins can be 10 AA peptides and maybe could be about same size as small molecules and they do cause an immune reaction. One more point. can make from synthetic chemistry because small enough or you can isolate bacteria and make biologically through recombinant host cells. Just know can use synthetic or recombinant.

36
Q

Tumor specific vs tumor associated:

A

specific antigen is only on tumor cells and doesn’t exist in nature because there is always a really low level that will bind to normal cells. Use the term tumor-associated. Example is CD20 antigen which is highly expressed in malignant lymphocytes and is expressed with low levels in normal cells. Tumor-associated. Rituxan (Rituximab) and Zevalin (Ibritumomab) are targeted to CD20 antigens which are expressed at a higher frequency in transformed B-cell non-Hodgkins Lymphoma (NHL).

37
Q

NESP….

A

Hyperglycosylated epoetin (darbepoetin alpha termed novel erythropoieses stimulating protein - NESP) which has a modified terminal sialic cap to reduce protein clearance from blood by RES and liver and thus increase half life. Lower frequency of dosing.

38
Q

Macugen-Aptamer to inhibit VEGF……

A

Pegaptanib, which is an aptamer that is pegylated (oligonucleotide). Pegylated nucleotide that blocks VEGF binding to suppress macular degeneration.

39
Q

definition of systems approach to drug delivery.

A

improved therapeutic index. accounts for drug targets, biopharmaceutical characteristics and pharmacokinetic profiles. accounts for human physiological interactions. These strategies that are now considered in the context of… control release, permeation enhancement, modulation of drug clearance, targeting to the site of action as well as molecular optimization.

40
Q

gamma radioactive decay

A

is the most useful for medical imaging.

41
Q

calculating radioactive decay….

A

Radioactive decay is a first order process with decay constant, lamba, ln2/half life. Decay depends on time.

42
Q

Tc99m MDP (methylenediphosphonate).

A

Areas of increased osteoblastic activity have increased uptake and. Useful in detection of bony metastasis, fractures and infection

43
Q

Tc99m sestamibi

A

is used in cardiac imaging

44
Q

Tc99m macro aggregated albumin

A

used to assess pulmonary perfusion and to rule out pulmonary embolism

45
Q

iodine 131

A

is targeted to thyroid glands and indicated for thyroid cancer.

46
Q

yttrium-90

A

indicated for liver cancer and is localized in tumor tissue.

47
Q

fluorine-18.

A

18 FDG is a positron emitter used in PET for diagnostic and cancer staging. has a110 minute half-life and is used as a molecular imaging agent.

48
Q

conventional adjuvants….

A

oil-water emulsions don’t help vaccines cross skin or mucosa more effectively. Example is Freund’s incomplete adjuvant.

49
Q

different adjuvants can result in different outcomes.

A

complete Freund’s adjuvant creates paralysis after developing EAE (Experimental Autoimmune Encephalomyelitis). Freund’s incomplete adjuvant doesn’t have paralysis. Adjuvants can drastically affect outcomes.

50
Q

Function and mechanism of adjuvants…..

A

Adjuvants prolong antigen exposure through depot effect, mimic innate immunity resulting from natural infection (mimics normal response), increase magnitude of response, reduce dose or frequency needed to achieve optimum response (dose-sparing)

51
Q

innate vs autoimmune response.

A

know the difference between. Innate response is responsible for invading pathogens whereas an autoimmune response is the defensive attack against endogenous “pathogens” that normally aren’t supposed to be pathogens.

52
Q

pattern recognition receptors…

A

Two types of PRR: soluble receptors (complement pathway) and membrane-bound (toll-like receptors). TLR’s are receptors in the innate immune system that recognize pathogen-associated molecular patterns (PAMP) They release cytokine but are not directly involved in immune cells and are not function as chemotaxis molecules. Examples include TLR4 which interacts with LPS on gram-negative bacterial cell walls, TLR9 recognizes DNA and TLR2 recognizes peptidoglycan from gram-positive bacteria. Complement activation is through C3 which activates the pathway and causes cell lysis.

53
Q

exogenous vs endogenous pathways….

A

Exogenously delivered antigens stimulate antibody response through B cells, whereas endogenously delivered antigens stimulate cytotoxic T cell response through MHC I and TH-1 cells.

54
Q

Different routes of immunization

A

will illicit different immune responses in mucosa, therefore it is not possible to do a single route of vaccination to get a response in all tissues. For example, the oral route primarily develops an immune response in the sex glands and the intestine.

55
Q

key concepts in vaccine delivery….

A

Vaccines aren’t just prophylactic but can also be used as therapy after infection. Example is cancer immunotherapy.

56
Q

herd immunity concept.

A

be able to explain to patient. example is influenza vaccine. more people vaccinated means people who don’t get vaccinated are also protected. provide an example. Essay probably.

57
Q

Gardasil

A

only vaccinates against types 16 and 18 which are associated with 70% of cervical cancer. It does not prevent infection by other HPV types nor does it prevent precancerous lesions caused by other HPV infections. It also does not reduce the rate of genital lesions and progression to precancerous lesions in individuals already infected with type 16 or 18 or any other type.

58
Q

HPV infects both sexes and all ages.

A

Three reasons to vaccinate males also include: males can transmit disease to others, HPV causes 70% of precancerous lesions of the penis, and the incident rate of anal cancer increases 17X in HIV-neg MSM and about 70% of anal cancer is associated with type 16/18

59
Q

obstacles to treating cancer with vaccines.

A

The three ways tumor cells have to evade the immune system are down-regulation of MHC molecules on antigen-presenting cells, induction of functional anergy (unresponsiveness) and sequestration. Also, most tumor-associated antigens are self-antigens, which are normally not recognized by the immune system (immune tolerance).

60
Q

Dendritic cells

A

exist in all of our tissues and are potent antigen-presenting cells (APC). They present antigen molecules to T cells which are involved in antibody production and B cell maturation.

61
Q

Approach to break tolerance to self-antigen.

A

Self-antigen is poorly recognized by one’s own T cell receptor. Altered or chemically engineered peptides result in a better fit with TcR and stronger T cell activation/immune response. Highly activated T cells can now kill tumor cells despite weak recognition.

62
Q

CAR receptors….

A

CAR receptors are chimeric antigen receptors and are expressed by T cells to target CD19+ tumor cells and to activate cytolytic activities to destroy tumor cells. The three components are T-cell activation domain (transmits activation signal to T cell after correct antigen binds), co-stimulatory domain (spans the membrane of the activated T cell and stabilizes the receptor) and the antibody-derived recognition moiety (binds the antigen).

63
Q

definition of gene therapy.

A

Gene therapy is an approach to treating disease by either modifying the expressions of an individual’s genes or correction of abnormal genes. You can increase expression, decrease expression or correct mutated disease.

64
Q

monogenic diseases…..

A

Genetic diseases in which one mutation forms a defective gene causing the pathology of the disease. Examples include cystic fibrosis, familial hypercholesterolemia and SCID-X1 (Human severe combined immunodeficiency). Gene therapy for SCID included using complementary DNA with a defective gamma-c retrovirus-derived vector and ex vivo infection of CD34+. This gene therapy was effective with full correction of disease phenotype.

65
Q

insertional mutagenesis….

A

Insertional mutagenesis is when the RNA is inserted upstream of the LMO-2 cell and not opposite. Example of an adverse effect was with successful gene therapy for SCID-X1 with insertion of DNA, which resulted in development of leukemia. A positive effect of insertional mutagenesis is in the treatment of X-linked chronic granulomatous disease, where a functional neutrophil is selected for and insertional mutagenesis allows the cell to proliferate and achieve replacement of defective neutrophil population. Clinically beneficial with sustained correction of the disease.

66
Q

anti-retroviral therapy….

A

The reason combination anti-retroviral therapy is not effective or a cure is because of HIV’s latent stage where it maintains low levels of replication. It is also harder for therapeutics to reach the site of latent infection, which is normally in the brain or lymphatic system. During the latent stage, HIB is normally unrecognizable.

67
Q

General theory of personalized medicine is

A

that genetics, age, sex, race can predict the therapeutic outcome and drug untoward effect for a patient. Personalized medicine would use predictive phenotype or genotype for each patient to tailor and optimize a therapy plan for each individual patient. Note that this doesn’t just have to be genetics.

PCEUT 533 (2 decks)

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