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Biotherapeutics > ADCs > Flashcards

ADCs Flashcards

1
Q

What is the function of antigens?

A

Recognition of target cancer cells

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2
Q

What is the function of the antibody?

A

Guidance system for cytotoxic drugs

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3
Q

What is the function of the linker?

A

Bridge between Ab & drugs & controls release of drugs inside cancer cells

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4
Q

What is the function of the cytotoxic drug?

A

warhead for destroying cancer cells

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5
Q

Why is IgG being rich in lysine good?

A

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

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6
Q

What range must the KED be in and why?

A

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

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7
Q

What does the Fc portion support?

A

bioconjugation

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8
Q

What are 2 possible risks with ADCs?

A

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)

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9
Q

What are ADCs?

A

Effective cancer therapy used in stage 4 severe cancers

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10
Q

What are 5 ADC formats?

A

Bispecific ADCs
Probody-drug conjugates
immune stimulating ADCs
Protein-degrader ADCs
Dual-drug ADcs

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11
Q

Whats an example of a approved ADC?

A

Trastuzumab emtansine (HER2)
Gemtuzumab ozogamicin (CD33 AML)

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12
Q

What does DAR stand for?

A

Drug antibody ratio

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13
Q

What are 5 characteristics of the Ab (human IgG1)

A

high tumour specificty
long circulation life
rapid internalization
with or w/o immune activation
minimal immunogenicity

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14
Q

What are 4 characteristics of the payload?

A

Highly toxic compound
Various MoA - microtubule inhibition & DNA damage
Bystander effect if hydrophobic
Optimal DAR

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15
Q

What are 4 characteristics of the linker & conjugation chemistries?

A

Link MAB & payload
Homogeneity
Non-cleavable or cleavable
Affects physiochemical properties, stability in circulation & potency

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16
Q

What are 2 major classes of linkers?

A

Non-cleavable
Cleavable

17
Q

What is the amine aa?

A

NH

18
Q

What are 6 payloads>

A

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

19
Q

Where in the cell does protease degrade drug?

A

Lysosome

20
Q

What are 3 parts of the novel ADC for HER-2?

A

Maytansinoid - chemical
MCC - hetero bifunctional linker
Trastuzumab (Ab)

21
Q

How was the potential of maytansine improved?

A

Improving therapeutic index by attaching it to a Ab (trastuzumab) with a linker –> DM1 development

22
Q

What type of agent is DM1?

A

antimicrotubule agent
Receptor recycling

23
Q

How is DM1 conjugated to trastuzumab?

A

heterobifunctional N-maleimidomethyl SMCC in 2 step process

24
Q

How did T-DM1 perform in clinical trials?

A

ORR - 6/24 (25%)
CBR - 11/15
at a 3.6mg/kg dose

25
Q

How long was overall survival extended with kadcyla?

A

6 months

26
Q

In the catherine trial what % of Pts were disease free after 3 yrs?

A

88.3% in T-DM1
77% in trastuzumab group

27
Q

Why is trastuzumab D better than TDM1

A

Trastuzumab D has a cleavable linker –> highly hydrophobic -> can be fully released from conjugate and move out of cell to kill others

28
Q

What is HER2 low cancer?

A

HER2 low has low HER2 R amplification and expression

29
Q

What were the results of the DESTINY trial?

A

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

30
Q

What is a positive with cleavable linkers?

A

only need some as drug is cleaved -> highly toxic and highly hydrophobic -> kills cells and neighbouring cells

31
Q
A

Biotherapeutics (9 decks)

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