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Ladies and gentlemen, dear colleagues.
My name is Hans-Georg Lerchen.
I'm Chief Scientist in the Medicine and Chemistry Department in the Pharmaceutical
R&D organization, Bayer AG.
Today, I would like to invite you to
a journey into the world of antibody drug conjugates,
an exciting hot topic in oncology research and development.
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Antibody drug conjugates are biologics which are composed of three modules:
a monoclonal antibody (left-hand side);
a toxophore (right-hand side);
and the linker in between.
The design of antibody drug conjugates follows the vision of magic bullets
which Paul Ehrlich formulated about 120 years ago.
He envisioned that it would be possible to directly
deliver a drug to the target cell without harming the body.
Up to the present day, this vision remains a big challenge.
Today we talk about the 'therapeutic window' between the minimal dose required for
activity and the highest dose which can be
administered without causing unacceptable side effects.
To increase the therapeutic window,
the ADC design follows the goal to combine
tumor specificity of a monoclonal antibody-targeting moiety
with the high potency of a toxophore moiety, to kill tumor cells.
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With the approval of Main Bayer, nine antibody drug conjugates and more than 80
which are in clinical trials,
the ADC landscape has evolved rapidly during the last decade.
However, in parallel to these success stories,
disappointing results in clinical trials also led
to a large number of discontinuations of ADC programs,
mainly due to the occurrence of
dose-limiting toxicities before an efficacious dose was reached.
The ADC mode of action is well understood,
and shown on this cartoon.
The antibody which is stably modified with toxophore moieties, as
symbolized by the Ys with the red pellets, binds to its antigen on the cell surface.
This antigen has been selected for high expression on the surface of tumor cells,
and low (or no) expression on healthy tissues.
Upon binding, the ADC is internalized and
intracellularly trafficked to the lysosomal compartment.
Here the ADC is cleaved and the active metabolite
(shown in the red circle) is released.
After its release from the antibody,
it has to leave the lysosome
and find its intracellular target.
Target inhibition finally leads to apoptosis.
The focus of my talk today is how ADC cleavage and
the physico-chemical properties of the active metabolite
may contribute to an increased therapeutic window of the ADC.
