Therapeutic Proteins - Fitz Flashcards
Why are antibodies receiving considerable attention as “personalized” therapies?
Because of their specificity and the large number of potential targets.
What are fusion proteins?
- Joining of two or more proteins together in a novel way
- Naturally occurring (Bcr-Abl)
- Done through recombinant DNA technology
What are four problems with using native peptides as therapeutic proteins?
- Lack of receptor specificity/selectivity
- Lack of oral bioavailability
- Generation of neutralizing antibodies
- Short duration of action due to:
- degradation
- 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 five advantages of antibody therapy?
- Specificity (“magic bullet”)
- increased therapeutic index
- Large number of potential targets
- every epitope = potential therapeutic drug
- Long-term benefit to short-term therapy
- Diagnostic reagents - can test to see whether cells will respond before administering the drug
- Define disease process
- e.g. identify cancer metastases using radiolabels
What are four characteristics of an ideal therapeutic antibody (MAB)?
- High degree of affinity and specificity
- Adequate recruitment of effector functions
- if goal is to recruit immune system
- Long half-life
- Reduced systemic immunogenicity (few side effects)
What are chimeric antibodies?
- Fv = mouse
- Fc = human
- 30%-35% mouse
- Most side effects of all MABs
What are humanised antibodies?
- Only complementarity-determining regions (CDRs) = mouse
- Rest of antibody = human
- 10% mouse
- Less side effects compared to chimeric antibodies.
When might fully human antibodies not be as effective as humanised or chimeric version antibodies?
When the purpose of the antibody is to stimulate the immune system (e.g. kill cancer cells).
-since even small amounts of mouse protein evoke an immune response
What type of therapeutic antibody is the most likely to produce the HAMA response?
Chimeric
- older antibodies
- tend to produce more side effects
How are therapeutic antibodies administered? Why?
- Given IV
- Extremely long half-lives (3-6+ months)
What are five types of common side effects to MAB treatments?
- Immediate Response/Hypersensitivity
- fever, headache, anaphylaxis
- Type III Hypersensitivity Reactions
- HAMA (human anti-mouse antibody) = hypersensitivity → kidney damage → serum sickness
- Cytokine release syndrome (“cytokine storm”)
- shaking chills, fever, arthralgia, diarrhea, vomiting, hypotension, and respiratory distress
- Infections
- especially when antibodies suppress immune system (reactivation of TB)
- Unknown effects
- immunization, carcinogensis, fertility, pregnancy, breast feeding (anti-TNFalpha = Thalidomide)
What are the two general strategies in the design of MABs and fusion proteins?
- Inhibit protein function
- 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 to treat different diseases (e.g. VEGF in colon cancer & macular degeneration)
- Different antibodies (humanized vs. chimeric) may be used against the same target
- due to many different drug companies
- Cytotoxic agents can be used to increase efficacy
What do cytokine interactions with target cells often result in?
Cascade effects
(cause release of other endogenous cytokines)
What are the two major disadvantages of cytokine therapy?
- Extremely short half-lives
- Complicated nature of the biological response (potent biological modifiers)
What are common side effects of cytokine therapy?
- anorexia
- fever
- flu-like symptoms
- fatigue
- general malaise
What are unique/life-threatening side effects of IL-2 cytokine therapy?
- Thrombocytopenia
- Shock
- Respiratory distress
- Coma
- FATAL HYPOTENSION
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?
Erythropoietin
What are the three erythroid growth factors that we need to know?
- Erythropoietin
- Darbepoetin
- 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)
