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IHO Week 2 > Therapeutic Proteins > Flashcards

Therapeutic Proteins Flashcards

1
Q

What does the addition of a polyethylene gylcol moietie do for the half life of a therapeutic protein

A

it increases half-life and masks the drug from the immune system, resultin gin decreased immunogenicity and antigenicity

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2
Q

What sort of tag can you add to increase the cell kill induced by antineoplastic antibodies and to allow visualization of the extent of malignancy?

A

radiolabelled tags

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3
Q

Why are peptibodies special?

A

they are the newest modification - they will interact with a receptor, but will not activate the immune system

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4
Q

What are some issues with using native peptides?

A
  1. lack of receptor specificity
  2. lack of oral bioavailability
  3. generation of neutralizing antibodies
  4. short during of action due to - degradation and renal clearance
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5
Q

What are the five advantaes of antibody therapy?

A
  1. specificity
  2. number of potential targets - so many targets = so many drugs options
  3. long term benefit to short term therapy
  4. diagnostic reagents - can be used tot est to see if cells will respond before administering the drug
  5. definition of disease process - so using radiolavels to ID cancer metastases
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6
Q

What are the 4 characteristics of an ideal therapeutic antibody?

A
  1. high degree of affinity and specificity
  2. adequate recruitment of effector functions
  3. long half life
  4. reduced SYSTEMIC immunogenicity
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7
Q

How are antibody antineoplastics made?

A

They are antibodies grown in cell culture following fusion of mouse plsnic cells with tumor cells grown in cultrue

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8
Q

What is the difference between a humanized and a chimeric antibody

A

the chimeric has all of the Fv from a mouse and only the Fc from a human.
The humanized is mostly human - only the complementarity-determining region is from a mouse

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9
Q

If the goal is to label a tumor cell and recruit the immune system to kill it, which would be better - a mouse or a human antibody?

A

mouse - because it will be more likely to recruit a more severe immune response

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10
Q

How are antibodies administered?

A

always IV - they’re proteins, so they’ll be broken down in the gut

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11
Q

For the antibodies, is the half life generally long or short?

A

extremely long

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12
Q

What are the two types of infusion reactions you can get with antibodies?

A

Type 1 and Type 3 hypersensitivity reactions

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13
Q

What are the timing considerations for whether someone has a type 1 or a type 3 HS?

A

type 1 occurs within seconds to minutes, type 3 takes a lot longer - lik 7-10 days.

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14
Q

Of the two HS reactions, which gets better and which gets worse with repeat aadministration?

A

Type 1 gets worse with repeat administration, Type 3 tends to improve

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15
Q

What is the serum sickness (type 3 HS) that can occur with antibody use, especially with mouse or chimeric antibody use?

A

Human anti-mouse antibody (HAMA) - you get a severe reaction that results in kidney damage

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16
Q

What is cytokine release syndrome and why does it occur?

A

One of the things antibody treatments do it increase release of cytokines. If this goes overboard, you get this syndrome - you basically feel like crap.

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17
Q

Why do you always do a skin mantoux test before putting someone on an antibody treatment?

A

Some antibodies decrease immune function (and are often given with other immunosuppressive agents), so reactivation of TB is a possibility

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18
Q

For nomenclature, what do all the antibody treatments end in?

A

-mab

19
Q

What are the source identifiers for nomenclature?

A 
u =  human
o = mouse
xi = chimeric
zu = humanized
20
Q

What are the general disease/target identifiers for nomenclature?

A 
vir = viral
bac = bacterial
lim = immune
les = infectious lesions
cir = cardiovascular
21
Q

What are the tumour target identifiers for nomenclature?

A 
col = colon
mel = melanoma
mar = mammary
got = testis
gov = ovary
pro = prostate
tum = miscellanceous - like leukemias
22
Q

In general, what are the two strategies employed int he design of MABs and fusion proteins?

A

1 inhibit the receptor to suppress normal function (so like any other drug)
2. Recruit the immune system to attack and destroy cells that are selectively expressing a particular protein

23
Q

What are the three potential arms of control for the cytokine drugs?

A
  1. control immune cell function
  2. control hematopoiesis
  3. antimicrobial and antitumour effects
24
Q

What are the two pitfals of cytokine therapy?

A
  1. short serum half-lives (like minutes)
  2. extremely potent biological modifiers - thus they can invoke complicated cascades that result in unpredictable and undesired effects
25
Q

What side effects are common to all cytokine therapies?

A

anorexia, fever, flu-like symptoms, fatigue and general malaise (so you just feel sick)

26
Q

What are the three hematopoietic agents that work on erythroid growth factors?

A
  1. erythropoietin
  2. darbepoietin
  3. Methoxy Polyethylene glycol epoietin
27
Q

What are the three hematopoietic agents that work as myeloid growth factors?

A
  1. filgrastim (G-CSF) (for neutrophils)
  2. Pegfilgrastim
  3. Sargramostim (GM-CSF) (for neutrophils, eosinophils, basophils and monocytes)
28
Q

What are the two hematopoietic agents that work as megakaryocyte growth factors?

A
  1. interleukin 11

2. rimoplostim

29
Q

Why are the hematopoietic agents so helpful in cancer?

A

Because bone marrow suppression is the dose-limiting complication of many antineoplastic drugs

30
Q

Which is more specific: sagramostim (GM-CSF) or filgrastim (G-CSF)? What side effect is worse in sagramostim then?

A

sagramostim is less specific because it works higher up in the developmental pathway, so it will induce formation of all the granulocytes and th emonocytes whil filgrastim basically just does neutrophils. Because of this, sagramostim causes worse bone pain.

31
Q

How does Darbopoietin differ from erythropoietin?

A

It is more heavily glycosylated, so it has a 2-3 times longer half-life: given weekly instead of 3-4 times per week

32
Q

How is methoxy polyethylene glycol epoietin different from erythropoietin? Shorter or longer half life than darbopoietin?

A

It’s attached to a PEG polymer

has the longest half life of the three - given biweekly or monthly

33
Q

What are the three cases where the erythropoietin drugs are useful?

A
  1. anemia (secondary to chronic kidney disease especially, but also with bone marrow disorders and secondary anemias)
  2. reduce the need for transfusion in high-risk surgical patients
  3. iron overload (hemochromatosis)
34
Q

Which of the erythropoietin drugs shouldn’t be used in patients with anemia secondary to chemotherapy?

A

M-PEG-epoietin - clinical trial found increase in death, not sure why

35
Q

What’s the life-threatening side effect of the erythropoietin drugs?

A

thrombosis

36
Q

what’s the common, serious side effect of the erythropoietin drugs?

A

hypertension

37
Q

What are the two rare, but serious side effects of the erythropoietin drugs?

A
  • faster tumor growth (head and neck cancer0

- allergic reactions

38
Q

In what situations are the myeloid growth factors like filgrastim useful?

A
  1. cancer chemotherpy - induced neutropenia
  2. congenital neutropenis, cuclic neutropenia, myelodysplasia, aplastic anemia

the goal is to avoid infection

39
Q

What are the rare but serious side effects of filgrastim and pegfilgrastim?

A

allergic reactions and splenic rupture

40
Q

What’s the common and serious side effect of sagramostim?

A

capillary leak syndrome - you have peripheral edema, pleual or pericardial effusions

41
Q

WHat do IL-11 and Romiplostim do?

A

they increase platelet production

42
Q

When is romiplostim particularly helpful?

A

It’s a nonimmunogenic peptide agononist of the thrombopoietin receptor, so it’s helpful after the patient develops autoantibodies against thromobpoietin

43
Q

What’s the common and serious side effect of the megakaryocyte growth factors?

A

atrial fibrillation (especially in elderly and kids)

44
Q

What’s the rare and serious side effect of the magakaryocyte growth factors?

A

hypokalemia

IHO Week 2 (13 decks)

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