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2015 ; 32
(11
): 3526-40
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Current ADC Linker Chemistry
#MMPMID25759187
Jain N
; Smith SW
; Ghone S
; Tomczuk B
Pharm Res
2015[Nov]; 32
(11
): 3526-40
PMID25759187
show ga
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.
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