Current ADC Linker Chemistry

The list of ADCs in the clinic continues to grow, bolstered by the success of first two marketed ADCs: ADCETRIS® and Kadcyla®. Currently, there are 40 ADCs in various phases of clinical development. However, only 34 of these have published their structures. Of the 34 disclosed structures, 24 of them...

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Bibliographic Details
Published in:Pharmaceutical research 2015-11, Vol.32 (11), p.3526-3540
Main Authors: Jain, Nareshkumar, Smith, Sean W., Ghone, Sanjeevani, Tomczuk, Bruce
Format: Article
Language:English
Subjects:
Antibodies, Monoclonal - chemistry
Biochemistry
Biomedical and Life Sciences
Biomedical Engineering and Bioengineering
Biomedicine
Cysteine - chemistry
Expert Review
Immunoconjugates - chemistry
Immunoglobulins
Lysine - chemistry
Medical Law
Pharmaceutical Preparations - chemistry
Pharmacology/Toxicology
Pharmacy
Protein Engineering - methods
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Summary:The list of ADCs in the clinic continues to grow, bolstered by the success of first two marketed ADCs: ADCETRIS® and Kadcyla®. Currently, there are 40 ADCs in various phases of clinical development. However, only 34 of these have published their structures. Of the 34 disclosed structures, 24 of them use a linkage to the thiol of cysteines on the monoclonal antibody. The remaining 10 candidates utilize chemistry to surface lysines of the antibody. Due to the inherent heterogeneity of conjugation to the multiple lysines or cysteines found in mAbs, significant research efforts are now being directed toward the production of discrete, homogeneous ADC products, via site-specific conjugation. These site-specific conjugations may involve genetic engineering of the mAb to introduce discrete, available cysteines or non-natural amino acids with an orthogonally-reactive functional group handle such as an aldehyde, ketone, azido, or alkynyl tag. These site-specific approaches not only increase the homogeneity of ADCs but also enable novel bio-orthogonal chemistries that utilize reactive moieties other than thiol or amine. This broadens the diversity of linkers that can be utilized which will lead to better linker design in future generations of ADCs.
ISSN:0724-8741
1573-904X
DOI:10.1007/s11095-015-1657-7