Generation of DAR1 Glycosite‐Specific Antibody‐Drug Conjugates Using DisacLink Technology

The drug-to-antibody ratio (DAR) represents a critical quality attribute for antibody-drug conjugates (ADCs). Conventional site-specific conjugation strategies typically generate ADCs with defined DAR values ranging from 2 to 8. However, for ultrapotent cytotoxic payloads, lower DAR values have been shown to enhance tumor tissue penetration and improve safety profiles. Similarly, in antibody-oligonucleotide conjugates (AOCs), reduced DAR values contribute to optimized pharmacokinetic behavior. Previously, we developed a glycosite-specific ADC construction method, termed DisacLink technology, based on synthetic LacNAc oxazoline derivatives. Building on this platform, we have now designed bis-functionalized drug-linkers that enable the generation of glycosite-specific DAR1 ADCs. This method achieves high conjugation efficiency, demonstrates the applicability to the major human IgG subclasses and commonly used payloads, yielding site-specific conjugates with acceptable homogeneity, favorable thermal and aggregation stability, and potent in vitro and in vivo antitumor activity.