07 Therapeutic Antibodies

Question 1

List mechanisms of action of therapeutic antibodies (6)

Answer 1

1. Antagonism/Neutralization of soluble antigen
2. Signaling inhibition
3. ADCC
4. CDC
5. Delivery of drugs/chemo/radiation
6. selective imaging

Question 2

Therapeutic antibodies:

Antagonism/Neutralization of soluble antigen

Answer 2

• antibody binds to soluble antigen, preventing its signaling to a cell
• ex: anti-VEGF antibodies prevent tumor vessel growth

Question 3

Therapeutic antibodies:

Signaling Inhibition

Answer 3

• antibody binds to cell receptors to block signals (like standard drugs)
• Ex: Anti-EGF (epidermal growth factor) antibodies inhibit tumor growth

Question 4

Therapeutic antibodies:

ADCC

Answer 4

• Antibody dependent cellular cytotoxicity
• antibodies recruit NK cells by their Fc region to kill tumor cells
• Ex: Anti-EGF antibodies also recruit NK cells to kill the tumor cells

Question 5

Therapeutic antibodies:

CDC

Answer 5

• complement dependent cytotoxicity
• antibodies induce CDC (including MAC)
• Ex: Lymphoma–antibodies bind to CD20 on B cells, signaling CDC to kill them.

Question 6

Therapeutic antibodies:

Delivery of drugs/chemo/radiation

Answer 6

• Toxins or radionuclides are conjugated to Fc portion
• Delivery relies on endocytosis
• Ex: Lymphoma–B-cell CD20 binding antibodies deliver radionuclides to kill cell

Question 7

Therapeutic antibodies:

Imaging using antibodies

Answer 7

• Radionuclides for radiocontrast imaging

- Ex: prostate cancer imaging

Question 8

All therapeutic antibodies are which type

Answer 8

IgG

Question 9

Types of monoclonal antibodies by animal origin (4)

Answer 9

1. Murine (mouse)
2. Chimeric (mostly human)
3. Humanized (almost all human)
4. Human

Question 10

Pharmacokinetics of therapeutic antibodies:

• administration route
• CNS access?
• half life prolongation
• metabolism/elimination

Answer 10

• parental administration (no oral). subcutaneous/intramuscular: 25-95% bioavailability, so IV is best. This is a drawback.
• No CNS access
• Use of FcRn for IgG prolongs half-life
• Degradation both extra/intracelullar. Antibodies too big for glomerular filtration.

Question 11

FcRn

Answer 11

• neonatal Fc receptor, binds IgG
• Prolongs half-life of IgG antibodies in cells by preventing their degradation during endocytosis, allowing them to be recycled to cell surface.
• mech relies on pH: FcRn binds IgG only at pH<6.5

Question 12

half life of different antibodies

Answer 12

• human IgG 1,2,4: 21 days
• human IgG 3: 7 days (does not bind FcRn)
• murine IgG: 12-48 h (does not bind FcRn)