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• The antibody (or fragment) is linked via a stable chemical linker, with a labile bond
to a biologically active cytotoxic (anti-cancer) drug.
• Deals typically also include an undisclosed single-digit percent of sales that is paid to the
licenser for any ADC from the collaboration that makes it to market.
Data taken Zolot et al., (2013)., Nature Reviews Drug Discovery 12, 259-260
– ADC stability (the drug should not be released before the ADC reaches its in vivo target)
– Pharmacokinetics (the drug should not confer an undesired accumulation in a non-
target organ)
– Retention of immunoreactivity
– Efficient release of the active form of the drug at the site of disease
• The antibody should target a well characterised antigen with high expression at
the tumour site and low expression on normal tissue to maximise efficacy.
• Bifunctional linkers with attachment sites for both the antibody and drug are used
to join the two components.
• As low drug loading reduces potency and high drug loading can adversely affect
pharmacokinetics, DAR can significantly affect ADC efficacy.
• Crucially the selected linker must be stable in the circulation to minimise toxicity
but also be cleaved rapidly after the ADC finds its target antigen.
• After binding to the target antigen the ADC receptor complex is internalised and
once inside the cell the drug is released;
– Hydrolysis of the linker
– Enzymatic cleavage of the linker
– Degradation of the antibody
• The average number of drugs that are conjugated to the antibody is the most
important quality attributes of an ADC.
• The DAR determines the amount of “payload” that can be delivered to the tumour
cell.
• The identity and stability of the linker is crucial to the success of an ADC.
• The linker must be stable to allow the ADC to circulate in the bloodstream before
reaching the tumour site without prematurely releasing the free “cytotoxic” drug
and damaging normal tissue.
• The linker should also be labile enough to release the free drug efficiently.
• The free drug is released with the linker attached to an amino acid from the mAb.
• Non-cleavable linker strategies are best applied to payloads that are capable of
exerting their anti-tumour effect despite being chemically modified e.g. Kadcyla
(trastuzumab-MCC-DM1) (Genentech/Immunogen).
– Drugs that target DNA structure, bind the minor groove of DNA causing DNA
double strand cleavage
• Calicheamicin analogs (Mylotarg)
• High potency is crucial because only an estimated 1-2% of the ADC dose will reach
the tumour site, resulting in low intracellular drug concentrations!!!
Antibody Drug Conjugates: An Introduction 18
If the efficiency of each step is 50%, only 1.56% of the administered
dose will reach the intracellular target.
Ref: Teicher B A , and Chari R V Clin Cancer Res 2011;17:6389-6397
Antibody Drug Conjugates: An Introduction 19
Summary: Efficacy of ADC
• A reactive moiety on the linker molecule is joined covalently to the antibody via
an amino acid side chain, commonly the e-amino group of lysine.
• Alternatively in a two-step process the surface lysines on the antibody are first
modified to introduce a reactive group, such as a maleimide and then conjugated
to the drug linker containing a reactive handle (e.g a thiol group), e.g. Kadcyla.
• When lysines are used for conjugation, heterogeneity in overall charge can impact
solubility, stability and pharmacokinetics.