ADCs Flashcards
What is the function of antigens?
Recognition of target cancer cells
What is the function of the antibody?
Guidance system for cytotoxic drugs
What is the function of the linker?
Bridge between Ab & drugs & controls release of drugs inside cancer cells
What is the function of the cytotoxic drug?
warhead for destroying cancer cells
Why is IgG being rich in lysine good?
rich in lyseine - mutate in specific lyseine or take advantage of lyseins already there - amine side chains means we can attach a carboxyl group - can now connect chemical to Ab
What range must the KED be in and why?
picomotor range (mols/second 10^-9) - picomolar Ab - can use a less of dose as the speed it lets go of its target is so slow
What does the Fc portion support?
bioconjugation
What are 2 possible risks with ADCs?
If target antigen site is not as selective –> problem
If we attach chemotherapy to Ab - needs to reach tumour and & not be released anywhere else (linker has to be strong)
What are ADCs?
Effective cancer therapy used in stage 4 severe cancers
What are 5 ADC formats?
Bispecific ADCs
Probody-drug conjugates
immune stimulating ADCs
Protein-degrader ADCs
Dual-drug ADcs
Whats an example of a approved ADC?
Trastuzumab emtansine (HER2)
Gemtuzumab ozogamicin (CD33 AML)
What does DAR stand for?
Drug antibody ratio
What are 5 characteristics of the Ab (human IgG1)
high tumour specificty
long circulation life
rapid internalization
with or w/o immune activation
minimal immunogenicity
What are 4 characteristics of the payload?
Highly toxic compound
Various MoA - microtubule inhibition & DNA damage
Bystander effect if hydrophobic
Optimal DAR
What are 4 characteristics of the linker & conjugation chemistries?
Link MAB & payload
Homogeneity
Non-cleavable or cleavable
Affects physiochemical properties, stability in circulation & potency
What are 2 major classes of linkers?
Non-cleavable
Cleavable
What is the amine aa?
NH
What are 6 payloads>
Anti-mitotic agents - monomethy; auristatin E, MMAF & maytansine derivatives (DM1 & DM4)
DNA-damaging agents - caliheamicins & PBDs, topoisomerase I inhibitors (SN-38)
Tubulysins
Duocarmycins
PNU-159682
Amanitin
Where in the cell does protease degrade drug?
Lysosome
What are 3 parts of the novel ADC for HER-2?
Maytansinoid - chemical
MCC - hetero bifunctional linker
Trastuzumab (Ab)
How was the potential of maytansine improved?
Improving therapeutic index by attaching it to a Ab (trastuzumab) with a linker –> DM1 development
What type of agent is DM1?
antimicrotubule agent
Receptor recycling
How is DM1 conjugated to trastuzumab?
heterobifunctional N-maleimidomethyl SMCC in 2 step process
How did T-DM1 perform in clinical trials?
ORR - 6/24 (25%)
CBR - 11/15
at a 3.6mg/kg dose
How long was overall survival extended with kadcyla?
6 months
In the catherine trial what % of Pts were disease free after 3 yrs?
88.3% in T-DM1
77% in trastuzumab group
Why is trastuzumab D better than TDM1
Trastuzumab D has a cleavable linker –> highly hydrophobic -> can be fully released from conjugate and move out of cell to kill others
What is HER2 low cancer?
HER2 low has low HER2 R amplification and expression
What were the results of the DESTINY trial?
HER2 low had 10.1 progression free survival
Overall survival was 23.9 mths in HER2 low
Overall survival 17.5 mths in physicians choice
What is a positive with cleavable linkers?
only need some as drug is cleaved -> highly toxic and highly hydrophobic -> kills cells and neighbouring cells
