Triggered Drug Release from an Antibody-Drug Conjugate Using Fast "Click-to-Release" Chemistry in Mice.
The use of a bioorthogonal reaction for the selective cleavage of tumor-bound antibody-drug conjugates (ADCs) would represent a powerful new tool for ADC therapy, as it would not rely on the currently used intracellular biological activation mechanisms, thereby expanding the scope to noninternalizing cancer targets. Here we report that the recently developed inverse-electron-demand Diels-Alder pyridazine elimination reaction can provoke rapid and self-immolative release of doxorubicin from an ADC in vitro and in tumor-bearing mice.
Tagworks Pharmaceuticals , High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
Raffaella
R
Rossin
Tagworks Pharmaceuticals , High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
Sander M J
SM
van Duijnhoven
Syncom , Kadijk 3, 9747 AT Groningen, The Netherlands.
Wolter
W
Ten Hoeve
SyMO-Chem , Het Kranenveld 14, 5612 AZ Eindhoven, The Netherlands.
Henk M
HM
Janssen
SyMO-Chem , Het Kranenveld 14, 5612 AZ Eindhoven, The Netherlands.
Laurens H J
LH
Kleijn
SyMO-Chem , Het Kranenveld 14, 5612 AZ Eindhoven, The Netherlands.
Freek J M
FJ
Hoeben
SyMO-Chem , Het Kranenveld 14, 5612 AZ Eindhoven, The Netherlands.
Ron M
RM
Versteegen
Tagworks Pharmaceuticals , High Tech Campus 11, 5656 AE Eindhoven, The Netherlands.
Marc S
MS
Robillard
D000818:Animals; D045744:Cell Line, Tumor; D057930:Click Chemistry; D004317:Doxorubicin / Q000737:chemistry; D065546:Drug Liberation; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000097:blood / Q000737:chemistry* / Q000493:pharmacokinetics; D007700:Kinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D011724:Pyridazines / Q000737:chemistry
D018796:Immunoconjugates; D011724:Pyridazines; C062482:pyridazine; D004317:Doxorubicin