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.