Therapeutic Proteins - Fitz Flashcards
What can stimulate the immune system?
Cytokines
Monoclonal Antibodies can act in 3 ways…
1) Stimulate the immune system
2) Inhibit the immune system
3) Non-competitive antagonist that block receptors permanently
Define Fusion Proteins
Joining of 2 or more proteins together in a novel way
Done through recombinant DNA technology
Why are antibodies receiving considerable attention as “personalized” therapies?
Their specificity and large number of potential targets
What are four problems with using native peptides as therapeutic proteins?
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)
What are three modifications of therapeutic proteins that improve efficacy and overcome the limitations of native peptides?
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
What are 5 advantages of antibody therapy?
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
What are 4 characteristics of an ideal therapeutic antibody (MAB)?
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)
What are chimeric antibodies?
30-35% mouse (have most side effects)
What are humanized antibodies?
Only complementarity-determining regions (CDRs) come from mouse (10%), the rest of the antibody is human (less side effects)
When might fully human antibodies not be as effective as humanized or chimeric version antibodies?
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.
What type of therapeutic antibody is most likely to produce the HAMA response?
Chimeric
How are therapeutic antibodies administered and why?
IV - long half life (3-6+months)
What are five types of common side effects to MAB treatments?
Type III Hypersensitivity HAMA Response Serum Sickness Infusion Reaction Cytokine Release Syndrome
What are the two general strategies in the design of MABs and fusion proteins?
- Inhibit protein function
2. Recruit immune system to attack and destroy cells that are selectively expressing a particular protein
What are three common themes for multiple antibodies?
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
What do cytokine interactions with target cells often result in?
Cascade effects (release of endogenous cytokines)
What are the two major disadvantages of cytokine therapy?
Extremely short half-lives
Complicated nature of biological response
What are common side effects of cytokine therapy?
anorexia
fever
flu-like symptoms
fatigue
general malaiseWhat are unique/life-threatening side effects of IL-2?
Thrombocytopenia
Shock
Respiratory distress
Coma
FATAL HYPOTENSIONWhat 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?
Erythropoietin
What are unique/life-threatening side effects of IL-2 cytokine therapy?
Thrombocytopenia Shock Respiratory distress Coma FATAL HYPOTENSION
What are the three erythroid growth factors that we need to know?
1) Erythropoietin
2) Darbepoetin
3) MPEG-Epoetin
What is the half-life of Erythropoietin?
Relatively short: IV administration 3-4x per week
DARB - given weekly, MPEG-EPO - given biweekly
What are the two main therapeutic uses of Erythroid growth factors?
***Anemia
chronic kidney disease (will need iron/folate supplementation)
primary bone marrow disorders & secondary anemias
high-risk surgery
anticipating significant blood loss
In what two situations should you NOT GIVE therapeutic erythroid growth factors?
Athletes (banned by olympic committee)
Patients with anemia due to cancer chemotherapy (should not give MPEG-Epoetin mainly)
What are the possible side effects of therapeutic erythroid growth factors?
Thrombosis (life-threatening)
Hypertension (serious, common)
Increased tumor growth (rare)
Allergic reaction (rare)
What are the three myeloid growth factors we need to know?
Filgrastim (G-CSF)
Pegfilgrastim
Sagramostim (GM-CSF)
What cells does Filgrastim (G-CSF) regulate the production of?
Neutrophils
What cells do Sagramostim (GM-CSF) stimulate?
Myelopoiesis (GM-CSF):
- Neutrophils
- Monocytes
What are the therapeutic uses of myeloid growth factors?
Cancer chemotherapy-induced neutropenia
Congenital neutropenia
Cyclic neutropenia
Myelodysplasia
Aplastic anemiaWhat are the possible side effects of Filgrastim/Pegfilgrastim?
Mild-moderate bone pain (common)
Allergic reactions (rare)
Splenic rupture (rare)What are the possible side effects of Sargramostim?
Capillary leak syndrome (common, serious)
Moderate-severe bone pain (common)
Fever, malaise, arthralgia/myalgia (common)
Allergic reaction (rare)
What are the two therapeutic megakaryocyte growth factors we need to know?
1) Interleukin 11
2) Romiplostim
What cell does Interleukin 11 increase the production of?
Platelets
What is so unique about the nonimmunogenic peptide agonist of the thrombopoietin receptor, Romiplostim?
It is the first approved “peptibody”.
What is the half-life of Romiplostim?
3-4 days
(longer in pts with thrombocytopenia)
(shorter in pts whose platelet counts have recovered)
What are the potential side effects of therapeutic Interleukin 11?
Atrial fibrillation (common, serious)
Hypokalemia (rare)
Fatigue, headache, dizziness, dyspnea, anemia, mild-moderate edema (common)
DOES NOT CAUSE FEVER!
What are the potential side effects of Romiplostim?
Mild headache on the day of administration
Otherwise well tolerated
Why is Thrombopoietin not used as a therapeutic megakaryocyte growth factor?
Caused production of autoantibodies.
