Tuning the Diels–Alder Reaction for Bioconjugation
to Maleimide Drug-Linkers
Posted on 2018-06-22 - 19:13
The thiol–maleimide
linkage is widely used for antibody–drug
conjugate (ADC) production; however, conjugation of maleimide–drugs
could be improved by simplified procedures and reliable conjugate
stability. Here, we report the evaluation of electron-rich and cyclic
dienes that can be appended to antibodies and reacted with maleimide-containing
drugs through the Diels–Alder (DA) reaction. Drug conjugation
is fast and quantitative due to reaction acceleration in water, and
the linkage is more stable in serum than in the corresponding thiol–maleimide
adduct with the same drug. ADCs produced using the DA reaction (DAADCs)
are effective in vitro and in vivo, demonstrating the utility of this
reaction in producing effective biotherapeutics. Given the large number
of commercially available maleimide compounds, this conjugation approach
could be readily applied to the production of a wide range of antibody
(or protein) conjugates.
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St. Amant, Andre
H.; Lemen, Daniel; Florinas, Stelios; Mao, Shenlan; Fazenbaker, Christine; Zhong, Haihong; et al. (2018). Tuning the Diels–Alder Reaction for Bioconjugation
to Maleimide Drug-Linkers. ACS Publications. Collection. https://doi.org/10.1021/acs.bioconjchem.8b00320
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AUTHORS (10)
AS
Andre
H. St. Amant
DL
Daniel Lemen
SF
Stelios Florinas
SM
Shenlan Mao
CF
Christine Fazenbaker
HZ
Haihong Zhong
HW
Herren Wu
CG
Changshou Gao
RC
R. James Christie
JR
Javier Read de Alaniz