Fig. 1: Chemical structure and catabolism. | Nature Communications

Fig. 1: Chemical structure and catabolism.

From: Site-specific ligase-dependent conjugation with ring-opening linker improves safety and stability of HER2-targeting ADCs

Fig. 1: Chemical structure and catabolism.

A Application of the thiosuccinimide structure in the antibody-drug conjugate Kadcyla® (trastuzumab-emtansine, T-DM1). While lysine residues-based conjugation is applied for T-DM1, Michael-addition reaction between sulfhydryl and maleimide remains used in the second conjugation reaction, which also produces thiosuccinimide structure fragments. B Design, production, and catabolism pathway of GQ1001. GQ1001 is designed with a stable thiosuccinimide ring-opening linker site-specifically linking DM1 to HER2 antibody via streamlined ligase-dependent conjugation (LDC) sorting, which avoids the presence of the thiosuccinimide structure in the final antibody-drug conjugate (ADC). The linker-payload P31-DM1-α is site-specifically conjugated to the C-terminal of the HER2 antibody using the robust LDC platform to generate a next generation ADC, the highly stable, homogenous GQ1001. When administrated, GQ1001 is highly stable in circulation, and is delivered to the target tumor in a highly specific manner. Then it is internalized into the tumor cells, undergoes trafficking into the lysosome for degradation, and releases the active metabolites, mainly K’-MCC’-DM1, thereby killing tumor cells. mAb, monoclonal antibody; DAR, drug-to-antibody ratio. C Design of T-DXd (left) and GQ1005 (right).

Back to article page