Immunosuppressant Drugs -Fitz

Question 1

Glucocoritcoids MOA:

Answer 1

Dexamethasone, Prednisone

-increase cortisol –> decrease T & B cells, monocytes, eosinophils, basophils

–> decreased cytokine release, IL-2 and TNF alpha

+ use on cancers that express the requisite receptor

Question 2

What kind of dose do we give when using Dexamethasone and Prednisone?

Answer 2

Given in higher doses, using a “pulse” regimen (when you compare it to how we dose for inflammatory diseases)

Question 3

Antibiotics used as immunosuppressants?

When do we use these?

Answer 3

Cyclosporine and Tacrolimus

Used to prevent rejection after a bone marrow transplant (Cyclosporine, Tacrolimus)

Question 4

MOA of immunosuppressive antibiotics:

Answer 4

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

Pathway 1: Antirejection: bind to cytoplasmic protein and inhibit calcineurin

Cyclosporine binds to cyclophilin

Tacrolimus binds to FK-binding protein

Question 5

What does calcineurin do?

Answer 5

It is needed for activation of NFAT, a T cell specific transcription factor that is involved in the synthesis of ILs by activated T cells

Block calcineurin –> decreased NFAT –> decrease release of IL-2 —> decreased cell proliferation

Question 6

Antibodies and Fusion Proteins:

Answer 6

• Alemtuzumab
• Denileukin Diftitux
• Ibritumomab
• Rituximab
• Tositumomab

Question 7

What are monoclonal antibodies used for?

What do they target?

Answer 7

• finding molecular targets that distinguish cancer cells from normal –> Devleop antibodies to selectively recruite the immune system to destroy cancer cells
• Target CDs and cell surface proteins that are overexpressed (HER2, VEGF, EGFR)

Question 8

When do we use monoclonal antibodies and what is our goal?

Answer 8

Use when traditional chemotherapy has failed

Use when you can’t use cytotoxic drugs (pt age)

Goal: use immune system to suppress itself! Truck yeah!

Question 9

What drugs target CD20?

Answer 9

Rituximab

Ibritumomab (90Y)

Tositumomab (131I)

*B cell non-Hodgkin’s lymphoma

Question 10

What drugs target CD52?

Answer 10

Alemtuzumab

*B cell chronic lymphocytic leukemia (B-CLL)

Question 11

Denileukin Diftitux: MOA?

Answer 11

Fusion protein that has diptheria toxin coupled to IL-2

Diptheria toxin ends up inhibiting protein translation by inactivating EF2

Goal: kill all cells expressing IL-2 receptors

*use for cutaneous T-Cell lymphoma

Question 12

Denileukin Diftitux

Resistance?

Answer 12

Resistance: Changes in target protein (prevent Ab from recognizing its antigen)

PK: IV administration , Long half-lives

Question 13

Toxicity of all antibodies?

Answer 13

• Infusion Reactions
• Other hypersensitivity reactions: fever, muscle aches, heachaches, rashes, anaphylaxis
  
  • HAMA
• Infections : reactivation of TB

Question 14

Specific Toxicities for anti-CD antibodies

Answer 14

• Cardiac arrhythmias
• Tumor lysis syndrome
• Alemtuzumab: cough, tightness in chest

Ibritumomab, Tositumomab(radiolabelled Abs): maybe they cause birth defects? we don’t really know…. but we are suspisious.