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IHO Week 2 > Therapeutic Proteins - Fitz > Flashcards

Therapeutic Proteins - Fitz Flashcards

1
Q

What can stimulate the immune system?

A

Cytokines

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2
Q

Monoclonal Antibodies can act in 3 ways…

A

1) Stimulate the immune system
2) Inhibit the immune system
3) Non-competitive antagonist that block receptors permanently

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3
Q

Define Fusion Proteins

A

Joining of 2 or more proteins together in a novel way

Done through recombinant DNA technology

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4
Q

Why are antibodies receiving considerable attention as “personalized” therapies?

A

Their specificity and large number of potential targets

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5
Q

What are four problems with using native peptides as therapeutic proteins?

A

1) Lack of oral bioavailability
2) Lack of receptor specificity/selectivity
3) Generation of neutralizing antibodies
4) Short duration of action (due to degradation and renal clearance)

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6
Q

What are three modifications of therapeutic proteins that improve efficacy and overcome the limitations of native peptides?

A

PEGylation
significantly increases half-life
“masks” the drug from the host’s immune system
decreased immunogenicity and antigenicity
Peptibodies
use structure of antibodies as a scaffold to build proteins that interact with a receptor without activating the immune system
Radiolabelled tags
increase the cell kill induced by antineoplastic antibodies
allow visualization of the extent of malignancies

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7
Q

What are 5 advantages of antibody therapy?

A

1) Specificity (increases therapeutic index)
2) Large number of potential targets (every single epitope)
3) Long-term benefits to short-term therapy
4) Diagnostic reagents (check for cell response)
5) Define disease processes

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8
Q

What are 4 characteristics of an ideal therapeutic antibody (MAB)?

A

1) High degree of affinity and specificity
2) Adequate recruitment of effector functions (goal to recruit immune system)
3) Long half-life
4) Reduced systemic immunogenicity (fewer side effects)

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9
Q

What are chimeric antibodies?

A

30-35% mouse (have most side effects)

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10
Q

What are humanized antibodies?

A

Only complementarity-determining regions (CDRs) come from mouse (10%), the rest of the antibody is human (less side effects)

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11
Q

When might fully human antibodies not be as effective as humanized or chimeric version antibodies?

A

When the purpose of the antibody is to stimulate the immune system (kill cancer cells), because even a small amount of mouse protein evokes an immune response.

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12
Q

What type of therapeutic antibody is most likely to produce the HAMA response?

A

Chimeric

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13
Q

How are therapeutic antibodies administered and why?

A

IV - long half life (3-6+months)

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14
Q

What are five types of common side effects to MAB treatments?

A 
Type III Hypersensitivity
HAMA Response
Serum Sickness
Infusion Reaction
Cytokine Release Syndrome
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15
Q

What are the two general strategies in the design of MABs and fusion proteins?

A
  1. Inhibit protein function

2. Recruit immune system to attack and destroy cells that are selectively expressing a particular protein

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16
Q

What are three common themes for multiple antibodies?

A

Same target may be active in different diseases (same drug may be used, ie: VEGF in colon cancer and macular degeneration)
Different antibodies (humanized vs. chimeric) may be used against the same target
Cytotoxic agents can be used to increased efficacy

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17
Q

What do cytokine interactions with target cells often result in?

A

Cascade effects (release of endogenous cytokines)

18
Q

What are the two major disadvantages of cytokine therapy?

A

Extremely short half-lives

Complicated nature of biological response

19
Q

What are common side effects of cytokine therapy?

A 
anorexia
    fever
    flu-like symptoms
    fatigue
    general malaise
20
Q

What are unique/life-threatening side effects of IL-2?

A 
Thrombocytopenia
    Shock
    Respiratory distress
    Coma
    FATAL HYPOTENSION
21
Q

What is the most important (but not sole) regulator of proliferation of committed red blood cell progenitors that is a member of the JAK/STAT superfamily and is produced in the kidneys?

A

Erythropoietin

22
Q

What are unique/life-threatening side effects of IL-2 cytokine therapy?

A 
Thrombocytopenia
 Shock
 Respiratory distress
 Coma
 FATAL HYPOTENSION
23
Q

What are the three erythroid growth factors that we need to know?

A

1) Erythropoietin
2) Darbepoetin
3) MPEG-Epoetin

24
Q

What is the half-life of Erythropoietin?

A

Relatively short: IV administration 3-4x per week

DARB - given weekly, MPEG-EPO - given biweekly

25
Q

What are the two main therapeutic uses of Erythroid growth factors?

A

***Anemia
chronic kidney disease (will need iron/folate supplementation)
primary bone marrow disorders & secondary anemias
high-risk surgery
anticipating significant blood loss

26
Q

In what two situations should you NOT GIVE therapeutic erythroid growth factors?

A

Athletes (banned by olympic committee)

Patients with anemia due to cancer chemotherapy (should not give MPEG-Epoetin mainly)

27
Q

What are the possible side effects of therapeutic erythroid growth factors?

A

Thrombosis (life-threatening)
Hypertension (serious, common)
Increased tumor growth (rare)
Allergic reaction (rare)

28
Q

What are the three myeloid growth factors we need to know?

A

Filgrastim (G-CSF)
Pegfilgrastim
Sagramostim (GM-CSF)

29
Q

What cells does Filgrastim (G-CSF) regulate the production of?

A

Neutrophils

30
Q

What cells do Sagramostim (GM-CSF) stimulate?

A

Myelopoiesis (GM-CSF):

  • Neutrophils
  • Monocytes
31
Q

What are the therapeutic uses of myeloid growth factors?

A 
Cancer chemotherapy-induced neutropenia
    Congenital neutropenia
    Cyclic neutropenia
    Myelodysplasia
    Aplastic anemia
32
Q

What are the possible side effects of Filgrastim/Pegfilgrastim?

A 
Mild-moderate bone pain (common)
    Allergic reactions (rare)
    Splenic rupture (rare)
33
Q

What are the possible side effects of Sargramostim?

A

Capillary leak syndrome (common, serious)
Moderate-severe bone pain (common)
Fever, malaise, arthralgia/myalgia (common)
Allergic reaction (rare)

34
Q

What are the two therapeutic megakaryocyte growth factors we need to know?

A

1) Interleukin 11

2) Romiplostim

35
Q

What cell does Interleukin 11 increase the production of?

A

Platelets

36
Q

What is so unique about the nonimmunogenic peptide agonist of the thrombopoietin receptor, Romiplostim?

A

It is the first approved “peptibody”.

37
Q

What is the half-life of Romiplostim?

A

3-4 days

(longer in pts with thrombocytopenia)

(shorter in pts whose platelet counts have recovered)

38
Q

What are the potential side effects of therapeutic Interleukin 11?

A

Atrial fibrillation (common, serious)
Hypokalemia (rare)
Fatigue, headache, dizziness, dyspnea, anemia, mild-moderate edema (common)
DOES NOT CAUSE FEVER!

39
Q

What are the potential side effects of Romiplostim?

A

Mild headache on the day of administration

Otherwise well tolerated

40
Q

Why is Thrombopoietin not used as a therapeutic megakaryocyte growth factor?

A

Caused production of autoantibodies.

IHO Week 2 (13 decks)

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