Antibodies

Question 1

How many therapeutic monoclonal antibodies are on the market in the U.S?

Answer 1

34

Question 2

Antibodies Have 2 Major Functions

Answer 2

1) Recognize and bind antigen

2) Induce immune responses after binding antigen

Question 3

Affinity for antigen is determined by the ________ region

Answer 3

Variable

Question 4

What does the constant region of an antibody bind to?

Answer 4

Specific Fc receptors

Question 5

All therapeutic antibodies are ______ type

Answer 5

IgG

Question 6

Monoclonal Antibodies

Answer 6

Monospecific antibodies that are identical because they are produced by one type of immune cell that are all clones of a single parent cell

Question 7

Types of therapeutic monoclonal antibodies

Answer 7

Human
Murine (mouse)
Chimeric (Human and Mouse)
Humanized (Human > Mouse)

Question 8

Source for nomenclature of monoclonal antibodies
Human:
Mouse:
Chimeric:
Humanized:

Answer 8

Human: u
Mouse: o
Chimeric: xi
Humanized: zu

Question 9

Administration and absorption of monoclonal antibodies (percent bioavailability)

Answer 9

Subcutaneous: 24-95%
Intramuscular: 24-95%
Intravenous: 100%

Question 10

Neonatal Fc Receptor for IgG

Answer 10

1) Protects IgG from degradation-prolongs serum half life
2) Transfers passive immunity to fetus
3) Binding IgG1 = IgG2 = IgG4&raquo_space; IgG3
4) Murine IgG does not bind human FcRn

Question 11

What is Antibody Re-cycling?

Answer 11

Neonatal Fc receptor binds circulating IgG and protects it from inactivation inside the lysosome.
Unbound IgG is degraded in the lysosome

Question 12

Half life of antibodies

Answer 12

IgG1, IgG2, IgG4: 20-21 days
IgG3: 7 days
Human: 20-21 days
Murine: 12-48 hours
Fab: 0.5-21 hours

Question 13

4 methods of metabolism and elimination of antibodies

Answer 13

1) Catabolism by proteolysis in biological fluids as plasma or extracellular fluid at site of injection
2) Uptake by phagocytosis and catabolism by phagocytic cells
3) Uptake by endocytosis and catabolism by target tissue
4) Renal and biliary elimination unimportant

Question 14

Mechanisms of action of monoclonal antibodies

Answer 14

Direct Effects
Complement-dependent cytotoxicity (CDC)
Fc receptor mediated effector functions

Question 15

Antagonism or Neutralization (Direct Effects)

Answer 15

Antibody binds and inactivates a soluble antigen

Antibody acts as a competitive inhibitor of ligand by binding to cellular receptor

Question 16

Bevacizumab (Avastin)
- Humanized monoclonal IgG1 antibody
- Metastatic Colorectal, Pancreatic, Breast and Prostate Carcinoma
What is its mechanism of action?

Answer 16

Directed against VEGF
Binds and neutralizes VEGF
Blocks VEGF-mediated neovascularization
Anti-angiogenic reducing vascularization of tumors

Question 17

Cetuximab
- Chimeric monoclonal antibody
- Metastatic colorectal cancer, head and neck cancer
What is it’s mechanism of action?

Answer 17

Binds and inhibits the EGF receptor blocking EGF action

• ADCC and CC
• Inhibits tumor growth

Question 18

Abciximab
- Chimeric Fab fragment of mAB
- Acute coronary syndrome
- Percutaneous coronary intervention
Mechanism of Action?

Answer 18

Glycoprotein IIb/IIIa receptor antagonist
Prevents platelet aggregation
Inhibits fibrinogen, von Willebrand factor binding

Question 19

Antibody-dependent cellular cytotoxicity (ADCC)

Answer 19

Antibody binds cell surface antigen on target cell and Fc region binds Fc receptors on NK cell, neutrophil, or macrophage
Lysis or phagocytosis of target cell by immune cell

Question 20

Rituximab
- Chimeric monoclonal antibody 
- Lymphoma, leukemia
- Rheumatoid arthritis with methotrexate
- Renal transplant
Mechanism of Action?

Answer 20

Binds to CD20 on B cells and mediates B-cell lysis

Question 21

Complement-dependent cytotoxicity (CDC)

Answer 21

• Antibody binds cell surface antigen on target cell

- Fc region binds complement protein and activates complement system resulting in cell lysis

Question 22

Selective delivery of toxins or radionuclides

Answer 22

• Antibody conjugated to toxin or radionuclide
• Antibody binds cell surface protein on target cell and internalized by endocytosis
• Toxin or radionuclide released and kills target cell

Question 23

Brentuximab Vedotin
- Chimeric IgG1 monoclonal antibody
- Conjugated to antimitotic microtubule toxin-monmethyl auristatin E (MMAE)
Mechanism of action?

Answer 23

Binds to CD30- restricted in normal cells- expressed in Hodgkins lymphoma
Internalized and MMAE released inhibiting cell proliferation
Antibody itself promotes ADCC and CDC

Question 24

Ibritumomab tiuxetan- 90Y labelled
- Murine IgG1 monoclonal antibody against membrane protein CD20
- Conjugated to tiuxetan that chelates 90Y
Mechanism of action?

Answer 24

• Binds to CD20 on B cells creating local high concentration of 90Y
• Beta particles from 90Y causes target cell death
• Antibody itself promotes ADCC and CDC

Question 25

Adverse Effects of monoclonal antibodies

Answer 25

Rituximab - infection with immunosuppression Abciximab - Risk of bleeding with anti-platelet mAb Rituximab - Tumor lysis syndrome Bevacizumab - Slow wound healing Cetuximab - Skin rash

Question 26

Immunogenicity - general to drug class

Answer 26

- Generation of endogenous antibodies against therapeutic antibody - Related to type, duration, dose and route - Immune complexes affect pharmacokinetics - Neutralizes the effect of therapeutic antibody - Hypersensitivity reaction-localized or systemic

Question 27

Potential for Immunogenicity decreases:

Answer 27

As the antibody is closer to 100% human

Question 28

Cytokine storm

Answer 28

- Antibody triggers release of a variety of cytokines - May occur with first dose or after repeated exposure - Symptoms may be mild or life threatening - Symptoms - headache, fever, myalgia, bronchospasms, hypotension