The Complete Guide to Linker Selection in Antibody-drug Conjugate Development

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The Complete Guide to Linker Selection in
Antibody-drug Conjugate Development
https//www.creative-biolabs.com/adc/
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Background
An antibody-drug conjugate (ADC) connects a
biologically active small molecule drug to a
monoclonal antibody via a chemical link, and the
monoclonal antibody acts as a carrier to
transport the small molecule drug to the target
cell. The use of cytotoxicity of small molecule
drugs to kill tumor cells is the mechanism of
many chemotherapeutic drugs. However, the
cytotoxicity of small molecule drugs is too
strong to pursue better therapeutic effects. Due
to insufficient selectivity, it is also harmful
to normal cells, which in turn causes damage to
the body. The dose range between the maximum
tolerated dose and the minimum effective dose is
the therapeutic window, which may be scaled down
due to the lack of drug selectivity, bringing
inconvenience to clinical medication.
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Background
The basic requirement for an antibody drug
conjugate linker is stability mainly in the water
environment and in vivo. Such conjugates cannot
be degraded in the systemic circulation to avoid
reduction in efficacy and side reactions. In
addition, the linking group can also be degraded
under certain conditions to complete the drug
release.
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Linker Selection
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Amide bond-type linker groups
This linker group forms an amide bond after the
reaction to finish the antibody conjugation.
Microorganisms use carbohydrate fermentation to
produce a variety of industrial solvents and
chemical raw materials, such as ethanol,
acetone-butanol, butanol-isopropanol,
acetone-ethanol, 2,3-butanediol, and glycerol
fermentation. The amide bond has an advantage
over the relatively simple reaction and stable
conjugation, so that the therapeutic window can
be enlarged to improve the tolerance of the body
to the drug. However, the shortcomings are also
obvious, that is, the conjugate is stable to most
conditions, resulting in a single drug release
mechanism and often relying on lysosome
degradation, and it is difficult to design a
complicated delivery strategy.
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Hydrazine linker groups
Hydrazine is formed after the reaction of drug
conjugation. It can be hydrolyzed under acidic
condition. Since the hydrogen ion concentration
index in the human body circulation is close to
neutral, the conjugate is stable in plasma. The
tumor microenvironment and the strong acidity
inside the tumor cells can help release the drug.
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A disulfide linker
The conjugation of the drug is completed after
the formation of the disulfide linker, and the
disulfide linker is stable under normal
conditions without fracture in the systemic
circulation. Since the reduced glutathione of the
glutathione reduction system in the tumor reaches
1000 times that of the normal cell cytoplasm, it
can be broken in the tumor cells to complete drug
release. In addition, tumor cells also contain
enzymes in the protein disulfide isomerase
family, which can also promote the cleavage of
disulfide linkers. Using this strategy,
controlled cleavage of the conjugate can be
achieved, thereby enabling targeted delivery of
the drug.
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A Short Peptide Linker Group
A polypeptide-based linker group is designed to
maintain conjugate stability in the systemic
circulation, and to allow cytotoxic drugs to be
released under specific enzyme cleavage.
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Conclusion
Antibody drug conjugates are a class of drugs
that are very useful in the treatment of tumors.
In the construction of such conjugates, in
addition to focusing on the small molecule drugs
themselves, the choice of monoclonal antibody
species should also be concerned with the choice
of linking groups. The main idea is to achieve
targeted delivery of the drug through a
reasonable fracture strategy, thereby improving
the therapeutic effect.
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