Advanced Drug Delivery 5 - Antibody-Drug-Conjugates

Question 1

Define 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
Anticancer activity can be conferred by conjugating mab to 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, linker

Question 4

Considerations of the target expression

Answer 4

TUMOUR SPECIFIC: tumour cells, cells associated with tumour cells e.g. tumour endothelial cells, antigens present in tumour microenvironment
TARGET INTERNALISATION: 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 and ensure it is compatible with where the effector drug needs to go to ensure ADC system works

Question 5

Considerations of linker

Answer 5

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

Question 6

Considerations of choice of drug

Answer 6

HOW MUCH DRUG MOLECULES: too many could interfere with recognition of mab+antigen so impair binding, too little could decrease potency of ADC system, need to balance both out to get good potency without compromising interaction
DRUG LOADING STOICHIOMETRY: ratio between antibody and drug
MOLECULAR HOMOGENEITY: 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 ADC)

Question 7

Toxicity considerations: ADC compared to parent drug

Answer 7

Would expect it to be less toxic than parent drug, but 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 8

Brentuximab vedotin

Answer 8

First ADC approved by FDA
Used for CD30+ Hodkin’s Lymphoma
Active drug works by disrupting microtubules
Anti-CD30 is the mab

Question 9

Ado-trastuzumab emtansine

Answer 9

ADC, IV administration, for 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