Tandem-Cleavage Linkers Improve the In Vivo Stability and Tolerability of Antibody-Drug Conjugates was written by Chuprakov, Stepan;Ogunkoya, Ayodele O.;Barfield, Robyn M.;Bauzon, Maxine;Hickle, Colin;Kim, Yun Cheol;Yeo, Dominick;Zhang, Fangjiu;Rabuka, David;Drake, Penelope M.. And the article was included in Bioconjugate Chemistry in 2021.Category: triazoles The following contents are mentioned in the article:
Although peptide motifs represent the majority of cleavable linkers used in clin.-stage antibody-drug conjugates (ADCs), the sequences are often sensitive to cleavage by extracellular enzymes, such as elastase, which leads to systemic release of the cytotoxic payload. This action reduces the therapeutic index by causing off-target toxicities that can be dose-limiting. For example, a common side-effect of ADCs made using peptide-cleavable linkers is myelosuppression, including neutropenia. Only a few reports describe methods for optimizing peptide linkers to maintain efficient and potent tumor payload delivery while enhancing circulating stability. Herein, the authors address these critical limitations through the development of a tandem-cleavage linker strategy, where two sequential enzymic cleavage events mediate payload release. The authors prepared dipeptides that are protected from degradation in the circulation by a sterically encumbering glucuronide moiety. Upon ADC internalization and lysosomal degradation, the monosaccharide is removed and the exposed dipeptide is degraded, which liberates the attached payload inside the target cell. The authors used CD79b-targeted monomethyl auristatin E (MMAE) conjugates as the model system and compared the stability, efficacy, and tolerability of ADCs made with tandem-cleavage linkers to ADCs made using standard technol. with the vedotin linker. The results, where rat studies showed dramatically improved tolerability in the hematopoietic compartment, highlight the role that linker stability plays in efficacy and tolerability and also offer a means of improving an ADC’s therapeutic index for improved patient outcomes. This study involved multiple reactions and reactants, such as ((3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (cas: 156311-83-0Category: triazoles).
((3H-[1,2,3]Triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (cas: 156311-83-0) belongs to triazole derivatives. Among the nitrogen-containing heterocyclic compounds, triazoles emerge with superior pharmacological applications. The presence of the three nitrogen atoms in triazole structures afforded opportunities for a plethora of structural modification with the generation of novel therapeutically potential agents, which is different from other heterocyclic compounds.Category: triazoles
Referemce:
1,2,3-Triazole – Wikipedia,
Triazoles – an overview | ScienceDirect Topics