Antibodies Flashcards
How many therapeutic monoclonal antibodies are on the market in the U.S?
34
Antibodies Have 2 Major Functions
1) Recognize and bind antigen
2) Induce immune responses after binding antigen
Affinity for antigen is determined by the ________ region
Variable
What does the constant region of an antibody bind to?
Specific Fc receptors
All therapeutic antibodies are ______ type
IgG
Monoclonal Antibodies
Monospecific antibodies that are identical because they are produced by one type of immune cell that are all clones of a single parent cell
Types of therapeutic monoclonal antibodies
Human
Murine (mouse)
Chimeric (Human and Mouse)
Humanized (Human > Mouse)
Source for nomenclature of monoclonal antibodies Human: Mouse: Chimeric: Humanized:
Human: u
Mouse: o
Chimeric: xi
Humanized: zu
Administration and absorption of monoclonal antibodies (percent bioavailability)
Subcutaneous: 24-95%
Intramuscular: 24-95%
Intravenous: 100%
Neonatal Fc Receptor for IgG
1) Protects IgG from degradation-prolongs serum half life
2) Transfers passive immunity to fetus
3) Binding IgG1 = IgG2 = IgG4»_space; IgG3
4) Murine IgG does not bind human FcRn
What is Antibody Re-cycling?
Neonatal Fc receptor binds circulating IgG and protects it from inactivation inside the lysosome.
Unbound IgG is degraded in the lysosome
Half life of antibodies
IgG1, IgG2, IgG4: 20-21 days IgG3: 7 days Human: 20-21 days Murine: 12-48 hours Fab: 0.5-21 hours
4 methods of metabolism and elimination of antibodies
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
Mechanisms of action of monoclonal antibodies
Direct Effects
Complement-dependent cytotoxicity (CDC)
Fc receptor mediated effector functions
Antagonism or Neutralization (Direct Effects)
Antibody binds and inactivates a soluble antigen
Antibody acts as a competitive inhibitor of ligand by binding to cellular receptor
Bevacizumab (Avastin)
- Humanized monoclonal IgG1 antibody
- Metastatic Colorectal, Pancreatic, Breast and Prostate Carcinoma
What is its mechanism of action?
Directed against VEGF
Binds and neutralizes VEGF
Blocks VEGF-mediated neovascularization
Anti-angiogenic reducing vascularization of tumors
Cetuximab
- Chimeric monoclonal antibody
- Metastatic colorectal cancer, head and neck cancer
What is it’s mechanism of action?
Binds and inhibits the EGF receptor blocking EGF action
- ADCC and CC
- Inhibits tumor growth
Abciximab - Chimeric Fab fragment of mAB - Acute coronary syndrome - Percutaneous coronary intervention Mechanism of Action?
Glycoprotein IIb/IIIa receptor antagonist
Prevents platelet aggregation
Inhibits fibrinogen, von Willebrand factor binding
Antibody-dependent cellular cytotoxicity (ADCC)
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
Rituximab - Chimeric monoclonal antibody - Lymphoma, leukemia - Rheumatoid arthritis with methotrexate - Renal transplant Mechanism of Action?
Binds to CD20 on B cells and mediates B-cell lysis
Complement-dependent cytotoxicity (CDC)
- Antibody binds cell surface antigen on target cell
- Fc region binds complement protein and activates complement system resulting in cell lysis
Selective delivery of toxins or radionuclides
- 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
Brentuximab Vedotin
- Chimeric IgG1 monoclonal antibody
- Conjugated to antimitotic microtubule toxin-monmethyl auristatin E (MMAE)
Mechanism of action?
Binds to CD30- restricted in normal cells- expressed in Hodgkins lymphoma
Internalized and MMAE released inhibiting cell proliferation
Antibody itself promotes ADCC and CDC
Ibritumomab tiuxetan- 90Y labelled
- Murine IgG1 monoclonal antibody against membrane protein CD20
- Conjugated to tiuxetan that chelates 90Y
Mechanism of action?
- 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
Adverse Effects of monoclonal antibodies
Rituximab - infection with immunosuppression
Abciximab - Risk of bleeding with anti-platelet mAb
Rituximab - Tumor lysis syndrome
Bevacizumab - Slow wound healing
Cetuximab - Skin rash
Immunogenicity - general to drug class
- 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
Potential for Immunogenicity decreases:
As the antibody is closer to 100% human
Cytokine storm
- 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
