Advanced Drug Delivery 5 - Antibody-Drug-Conjugates

Question 1

Define Antibody-Drug Conjugates (ADC) for cancer therapy

Answer 1

Drug delivery technology in which mabs are covalently conjugated to cytotoxic agents

Question 2

Rationale for ADC

Answer 2

• Most mabs have little anti tumour activity (exceptions are anti-HER2 and anti-CD20)
• However, they do have specificity to the target

Conjugating mab to the effector molecules:

• The Mab ensures specific targeting
• The effector molecule ensures anticancer effect.

Question 3

Structure of ADC

Answer 3

3 main components:
- mab which acts as carrier and ensures specific targeting
- multiple drug molecules - cytotoxic drug which kills cancer cells
- linker: attaches antibody to drug

Question 4

Considerations of ADC

Answer 4

1. Target expression: tumour specific and target internalisation
2. Linker
3. Conjugation
4. Choice of drug

Question 5

1. Tumour specific

Answer 5

• tumour cells
• cells associated with tumour cells e.g. tumour endothelial cells
• antigens present in tumour microenvironment

Question 6

1. Target internalisation

Answer 6

• Complex between target and ADC gets internalised by cell
• Need to know the internalisation pathway to ensure correct activity of the drug.
• Need to know cellular pharmacokinetics of the complex
• Ensure it is compatible with position of effector drug to ensure ADC system works

Question 7

2. Considerations of linker

Answer 7

• Connects antibody to drug
• Needs to be stable in circulation and released at target
• Ensure appropriate bonds e.g. disulphides, dipeptides, hydrazone linkages

Question 8

4. Considerations of choice of drug

Answer 8

• How many drug molecules
• Drug loading stoichiometry
• Molecular homogeneity

Question 9

4. Number of drug molecules

Answer 9

Too many:
- could interfere with recognition of mab+antigen
- impair binding

Too little:
- Could decrease potency of ADC system

Need to balance both to get good potency without compromising interaction

Question 10

4. Drug loading stoichiometry

Answer 10

Ratio between antibody and drug

Question 11

Molecular homogeneicity

Answer 11

• Should have ADC that are as homogenous as possible
• e.g. if 3 drug molecules, then try having all attached in same point as other AD

Question 12

4. Toxicity considerations: ADC compared to parent drug

Answer 12

• ADC expected to be less toxic than parent drug
• May have similar type of toxicity just to a lesser extent (e.g. lot more needed to produce same toxicity)
• Need to consider potential toxicity coming from other components, not just the drug

Question 13

Brentuximab vedotin

Answer 13

• First ADC approved by FDA
• Used for CD30+ Hodkin’s Lymphoma
• Active drug works by disrupting microtubules

Question 14

Ado-trastuzumab emtansine

Answer 14

• IV administration
• HER2+ metastatic breast cancer
• Trastuzumab: mab that recognises and attaches to HER2 expressed on cancer cells, activating immune response that kills them
• DM1: toxic substance that binds to tubulin in cancer cells, preventing mitosis and thus preventing growth and division of cancer cells