Immunosuppressives

Question 1

What are the three chemical types of immunosuppressives?

Answer 1

1. Glucocorticoids
2. Antibiotics
3. Antibodies and fusion proteins

Question 2

What are the two glucocorticoids we need to know? What are they used for?

Answer 2

• Dexamethasone
• Prednisone
• Treatment of cancers that express the requisite receptors

Question 3

What are the two antibiotic immunosuppresives? What are they used for?

Answer 3

• Cyclosporine
• Tacrolimus
• Used to prevent rejection following bone marrow transplantation

Question 4

What are other antibiotics that function as mTOR inhibitors?

Answer 4

Everlolimus, Temsirolimus

Question 5

What are the five antibodies and fusion proteins? What are they used for?

Answer 5

• Alemtuzumab
• Denileukin Diftitux
• Ibritumomab
• Rituximab
• Tositumomab
• Used for special leukemia and lymphomas because they target unique CDs

Question 6

What is the mechanism of action for glucocorticoids?

Answer 6

• Naturally occurring compound is cortisol
• Interfere with the concentration, distribution and function of leukocytes
• –Inc. neutrophils, dec. T & B lymphocytes, monocytes, eosinophils and basophils
• –End result is decrease in cytokine release, including DECREASES IN IL-2 and TNF-alpha
• Decreases size of lymph nodes and spleen

Question 7

How are glucocorticoids used in cancer chemotherapy?

Answer 7

-Given at higher doses, using a “pulse” regimen (in comparison to their use with inflammatory disease like asthma, arthritis, lupus, etc.)

Question 8

What specific type of cancer are glucocorticoids used for?

Answer 8

Those that express the requisite receptors (e.g. prednisone-sensitive lymphomas)

Question 9

What dosing is given for cancer cells?

Answer 9

Chemotherapy

-High dose, “pulse”

Question 10

What dosing is given to suppress a normal immune system?

Answer 10

Immuno-suppression

-Low dose, continuous

Question 11

What are triggers from cell division and what type of cell division is there for cancer cells and for the normal immune system?

Answer 11

Cancer cells - Unstimulated, Random Cell Division

Normal Immune System - Cell division is triggered by a specific antigen and cell division is synchronized

Question 12

What are immunosuppressive antibiotics used for?

Answer 12

1. Prevent rejection following bone marrow transplant

2. Angiogenesis inhibitors

Question 13

What immunosuppressive antibiotics prevent rejection of bone marrow transplants?

Answer 13

Cyclosporine, Tacrolimus

Question 14

What immunosuppressive antibiotics act as angiogenesis inhibitors?

Answer 14

Everolimus, Temsirolimus

Question 15

What two pathways involved in cell proliferation are these immunosuppressive antibiotics involved in?

Answer 15

1. NFAT-mediated regulation of interleukin synthesis

2. mTOR regulation of cell growth and angiogenesis

Question 16

What is the MOA for immunosuppressive antibiotics?

Answer 16

Interfere with intracellular processes that are key for cell proliferation and cytokine production and release

1. The 1st step in the process that leads to IL-2 mediated cell proliferation is activation of receptor tyrosine kinases (RTKs)
2. Immunosuppressive antibiotics do not interfere with this process; they interfere with one of two intracellular signaling cascades

Question 17

What are the two intracellular signaling cascades immunosuppressive antibiotics interfere with?

Answer 17

• Antirejection

- Anti-angiogeneis and anti-proliferation

Question 18

How does antirejection occur with immunosuppressive antibiotics?

Answer 18

-Binds to cytoplasmic proteins and inhibit calcineurin
–Cyclosporine binds to cyclophilin
–Tacrolimus binds to FK-binding protein
Calcineurin is necessary for activation of NFAT, a T cell specific transcription factor that is involved in the synesis of interleukins by activated T cells –> decreased release of IL-2 –> decreased activation of IL-2 receptor –> decreased cell proliferation

Question 19

How does anti-angiogenesis and anti-proliferation occur with immunosuppressive antibiotics?

Answer 19

• Receptor tyrosine kinases can also increase expression of mTOR, an intracellular signaling molecule that increases cell division, increases bioenergetics and facilitates angiogenesis in many cell types
• EVEROLIMUS and TEMSIROLIMUS also function as mTOR inhibitors

Question 20

What are the 5 antibodies and fusion proteins?

Answer 20

1. Alemtuzumab
2. Denileukin Diftitux
3. Ibritumomab
4. Rituximab
5. Tositumomab

Question 21

What types of antibodies have been designed to selectively recruit the immune system to destroy cancer cells?

Answer 21

• Ones that target CDs (CD 20 in NHL, and CD52 in B-CLL)

- Ones that target cell surface proteins (HER2, VEGF, EGFR) that are overexposed in specific cancers

Question 22

What are general concepts of antibodies and fusion proteins?

Answer 22

• Typically prescribed when traditional chemotherapy has failed or when patient factors (esp. age) prevent the use of cytotoxic drugs
• Goal is to get the immune system to recognize, and kill the cell that is expressing antigen
• –Use immune system to suppress itself

Question 23

What is the Target & Use of Rituximab, Ibritumomab (90Y), and Tositumomab (131I)?

Answer 23

Target - CD20

Use - B cell non-hodgkin lymphoma (NHL)

Question 24

What is the Target & Use of Alemtuzumab?

Answer 24

Target - CD52

Use - B cell chronic lymphocytic leukemia (B-CLL)

Question 25

What is Denileukin Diftitux? How does it work? What is it used for?

Answer 25

- Fusion protein that has diphtheria toxin coupled to IL-2 - --Diptheria toxin catalyzes the ADP-ribosylation of elongation factor-2 --> inhibits protein translation by inactivating EF2 - Goal is to kill cells expressing IL-2 receptors (activated T-lymphocytes, B lymphocytes and macrophages) - Approved for use in cutaneous T-cell lymphoma

Question 26

What resistance has developed against antibodies and fusion proteins?

Answer 26

-Changes in target protein that prevent the antibody from recognizing its antigen

Question 27

What are the pharmacokinetics of antibodies and fusion proteins?

Answer 27

- IV admin. | - Long half-lives - detectable at least 3-6 months after completion of treatment

Question 28

What toxicities are common to all antibodies?

Answer 28

1. Infusion reactions (77% of patients on rituximab) 2. Other hypersensitivity reactions: fever, muscle aches, headaches, rashes, anaphylaxis - Mouse (MO) >> chimeric (XI) > humanized (ZU) for HAMA reaction 3. Infections - esp. reactivation of tuberculosis - -Unknown effects on immunization, carcinogenesis, mutagenesis, impairment of fertility, pregnancy, nursing infants (human IgG is secreted in milk)

Question 29

What toxicities are specific for anti-CD antibodies?

Answer 29

- Cardiac arrhythmias - Tumor lysis syndrome - ALEMTUZUMAB: cough, tightness in chest - Suspicion that radiolabelled antibodies (IBRITUMOMAB, TOSITUMOMAB) may be more likely to cause birth defects (this hasn't been tested!)