GlycoConnect
technology can be readily adapted to provide different
drug-to-antibody ratios (DARs) and is currently also evaluated in
various clinical programs, including ADCT-601 (DAR2), MRG004a (DAR4),
and XMT-1660 (DAR6). While antibody-drug conjugates (ADCs) typically
feature a DAR2–8, it has become clear that ADCs with ultrapotent
payloads (e.g., PBD dimers and calicheamicin) can only be administered
to patients at low doses (<0.5 mg/kg), which may compromise effective
biodistribution and may be insufficient to reach target receptor saturation
in the tumor. Here, we show that GlycoConnect technology can be readily
extended to DAR1 ADCs without the need of antibody re-engineering.
We demonstrate that various ultrapotent, cytotoxic payloads are amenable
to this methodology. In a follow-up experiment, HCC-1954 tumor spheroids
were treated with either an AlexaFluor647-labeled DAR1 or DAR2 PBD-based
ADC to study the effect on tumor penetration. Significant improvement
of tumor spheroid penetration was observed for the DAR1 ADC compared
to the DAR2 ADC at an equal payload dose, underlining the potential
of a lower DAR for ADCs bearing ultrapotent payloads.
Indole derivatives
Indole derivatives R 0140An Efficient One-Pot Synthesis of Novel 4-Aryl-1-methyloxindoles. -The intramolecular Pd-catalyzed amidation of substrate (I) followed by in situ Suzuki cross-coupling with boronic acids offers a direct synthesis of the pharmacologically interesting skeleton (III). -(VAN DEN HOOGENBAND*, A.; LANGE, J. H. M.; IWEMA-BAKKER, W. I.; DEN HARTOG, J. A. J.; VAN SCHAIK, J.; FEENSTRA, R. W.; TERPSTRA, J. W.; Tetrahedron Lett. 47 (2006) 26, 4361-4364; Res. Lab., Solvay Pharm., NL-1380 DA Weesp, Neth.; Eng.) -Mais 40-116
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