Therapeutic Proteins Flashcards
Why are antibodies receiving attention as “personalized therapies”?
- Their specificity
2. Large number of potential targets
What do therapeutic cytokines do?
Stimulate the immune system
What do MABs do?
- Can stimulate/inhibit the immune system
2. Can block receptors
What is NOT a characteristic of therapeutic proteins?
Oral bioavailability - these proteins are broken down in the stomach
What are characteristics of therapeutic proteins?
- Generation of neutralizing antibodies
- Lack of receptor specificity
- Short duration of action
What therapeutic proteins have very short and very long half lives?
Cytokines-Extremely short half-life! (acts in minutes, acts in limited space in body)
Monoclonal Antibodies - extremely long half life - remain in the body for a long time!
What drug has an extremely short half life?
Tumor necrosis factor
- usually injected in body right near tumor because it degrades so fast (within minutes!)
- shorter than -mab, and drug with Peg added
What does PEG do when you add it to a drug?
It stops the body from degrading it so well/so fast.
Is a human antibody always a better option than a humanized or chimeric antibody?
NO!
- Specificity of Ab can vary
- Is killing cells (recruiting immune system) the goal?
- If stimulating the immune system is your goal, then a chimeric antibody would be better
What must the names of monoclonal antibodies end with?
-MAB
What is the difference between human and humanized antibodies?
Humanized - still has 5% mouse protein in CDR region
Human - 100% human protein
What does a drug with Tu in the middle target?
Tumor
What does a drug with Ci in the middle target?
Circulatory system
What does a drug with Li in the middle target?
Immune system
What source does a drug with Xi in the middle-end come from?
Chimeric
What source does a drug with zu in the middle-end come from?
Humanized
What sourse does a drug with o in the middle come from?
Mouse
What source does a drug with u in the middle come from?
Human
What is the side effect severity of sources from least to most severe?
Human
What would you expect to see as a side effect of antibody treatment?
- Type III hypersensitivity reactions
- HAMA response
- Serum sickness
- Infusion reaction
- Cytokine release syndrome
You are planning to treat a patient who has irritable bowel disease with infliximab. What test should you perform first?
Mantoux test - need to screen before these drugs are given because they can “reactivate” latent/dormant infections - (similar to a hypersensitivity reaction!)
What are the three erythroid growth factors?
- Darbepoietin
- Erythropoietin
- M-PEG-EPOETIN
What are the three classes of hematopoietic agents we need to know? What are they often used for?
- Erythroid Growth Factors
- Myeloid Growth Factors
- Megakaryocytic Growth Factors
- Supportive agents given in lots of different type of cancer
What are the three Myeloid growth factors you need to know?
- Filgrastim (G-CSF)
- Pegfilgrastem
- Sargramostem (GM-CSF)
What are the two Megakaryocyte Growth Factors you need to know?
- Interleukin-11
2. Romiplostim
What types of growth factors cause more side effects/problems?
Those that act earlier in the process (higher in the differentiation tree!)
Where is the site of action for erythropoietin?
Between the erythroid progenitor and the erythrocyte
Where is the site of action for filgramostim (G-CSF)?
Between Granulocyte-monocyte progenitor and neutrophils
What is the site of action for Interleukin-11?
Between the common myeloid progenitor and megakaryocyte
What is the site of action for sargramostim?
- Between the common myeloid progenitor and all myeloid cells (erythroid, megakaryocytic, basophil, eosinophil, granulocyte-monocyte progenitors)
- Between Granulocyte-monocyte progenitor and neutrophils & monocytes
What are two side effects that are not specific to one growth factor but applies to many?
- General malaise
2. Allergic reactions
What is the specific, serious side effect associated with Erythropoietin?
Hypertension & Thrombosis
What is the specific, serious side effect associated with Filgramostim?
Splenic rupture, Bone pain
What is the specific, serious side effect associated with Interleukin-11?
Atrial fibrillation
What are the specific, serious side effects associated with Sargramostim?
Capillary leak syndrome and bone pain (worse than filgramostim!)
What is the major advantage and drawback of monoclonal antibodies?
Advantage: long half-life
Drawback: Hypersensitivity reactions, in particular human anatomies antibody (“HAMA”) reactions
What are the two major disadvantages to cytokine therapy?
- Extremely short half-lives of drugs
2. Complicated nature of the biological response invoked by cytokines
What is a dose-limiting complication of many antineoplastic drugs?
Bone marrow suppression
What has been developed to combat bone marrow suppression?
Recombinant forms of several colony stimulating factors
What are fusion proteins?
- Joining of two or more proteins together in a novel way
- Can see naturally occurring Fps
e. g. Chronic myeloid leukemia (BCR-ABL)
What is the problem with using native/naturally occurring peptides as therapeutic proteins?
- Lack of receptor specificity (can use it to target many things, not just one)
- Lack of oral bioavailability (must inject)
- generation of antibodies against the protein
- Short duration of action –> degraded/cleared
How can we solve the problem of degradation/elimination when using naturally occurring therapeutic proteins?
- Add a PEG (polyethylene glycol) –> Long half life & “masks” protein from immune system
- Use antibody structure as scaffold w/no immune recruitment –> High t1/2 (half life)
What is the advantages of using Monoclonal antibody therapy?
- Specificity (“magic bullet”)
- Large # of potential targets
- Potential for long term benefit with short term treatment (if Abs stay & become incorporated into the immune system)
- Diagnostics - can use Abs to screen tissue - can tell if cancer is expressing protein Abs will respond to
- Define disease process –> can help you tell what subtype of disease the patient has
What are the approved PEG’d Drugs?
L-asparaginase PEG-liposome containing doxorubicin Interferon alpha Methoxy polyethylene Glycol epoetin Pegfilgrastim
What are characteristics of an ideal therapeutic antibody?
- High affinity & target specificity
- If goal is to recruit immune system, must have adequate recruitment of effectors
- long t1/2 - don’t want immune system to target your Ab
- Few side effects
What route of administration should be used for monoclonal antibodies and fusion proteins?
- Give IV
- Has long t1/2
What are common side effects of monoclonal Abs and fusion proteins?
- Hypersensitivity Rxn: fever, headache, anaphylaxis
- HAMA hypersensitivity + kidney –> serum sickness (human response hypersensitivity to human antimouse antibody)
- Infusion reactions/cytokine release syndrome: chills, fever, arthralgia, diarrhea, vomiting, hypotension, respiratory distress
- Infection: esp. when goal is to suppress immune systems => reactivation of TB (esp. anti-TNFalpha agents)
- ??? Immunizations, carcinogenesis, fertility, pregnancy –> birth defects?? => anti-TNFalpha [thalidomide]
What is the general nomenclature for naming monoclonal Abs?
[Drug company] + [Target] + [Source] + [MAB]
What are the common source identifiers for u, o, xi and zu?
u - human
o - mouse
xi - chimeric
zu - humanized
What are the general diseases or targets for the drugs that contain vir, bac, lim, les, cir?
vir - viral bac - bacterial lim - immune les - infectious lesions cir - cardiovascular
What are the general target abbreviations for drugs that contain col, mel, mar, got, gov, pr(o), tum?
col - colon mel - melanoma mar - mammary got - testis gov - ovary pr(o) - prostate tum - misc
What do fusion proteins end with?
-cept
What are two design strategies for monoclonal Abs?
- Inhibition fo protein fxn
2. Recruit immune system to attack cell
What are three themes for monoclonal Abs?
- Same target –> multiple diseases (e.g. VEGF can be used for colon cancer and macular degeneration)
- Different Abs –> same target (diff. drug company)
- Couple cytotoxic agents to Inc. effectiveness
What are the two main “pitfalls” of using cytokine therapies?
- Extremely short half lives (minutes)
- hard to maintain therapeutic [ ]
- either give SC (subcutaneous) or IA (inter arterial) - Extremely potent –> compliment cascades –> release other cytokines –> unpredictable/undesirable side effects
What are some common side effects of cytokine use?
- Anorexia, fever, flu-like symptoms, fatigue
- GENERAL MALAISE
- Can have unique, life threatening side effects: IL-2: diarrhea, thrombocytopenia, shock, respiratory distress, coma
- FATAL HYPOTENSION
What are hematopoietic agents (colony stimulating factors) used in conjunction with?
Chemotherapy!
