ADC targeting both HER2 and Sort1 How would the heterogeneous cancers in humans respond to this bi specific drug targeting two receptors? The pharmaceutics and pharmacodynamics...
"SORT1 is overexpressed in several types of tumor cells, such as breast, colorectal and ovarian cancer cells [25,27,28]. Its overexpression has been associated with increased cancer cell proliferation, migration and invasion [28,29]. SORT1 plays a crucial role in vasculogenic mimicry formation, which was inhibited by a SORT1-targeted peptide–drug conjugate (TH1902) [29]. Furthermore, TH1902 exerted potent antitumor activity in MDA-MB-231 and HCC-70 murine xenograft models [30], which suggested that SORT1-targeted ADC would also functionate in SORT1-positive tumors. We also found that HER2 and SORT1 were co-expressed on many cancer cells, particularly breast cancer cells. In this study, we developed a BsAb (bsSORT1×HER2) that can facilitate faster internalization and more lysosomal HER2 degradation than trastuzumab. In addition, we showed that bsSORT1×HER2 ADC possessed better antitumor activity than the DS8201a biosimilar in MDA-MB-231 xenograft mice models. Our results suggest that HER2-targeted bsADCs with faster internalization by binding SORT1 may be a promising approach to enhance the antitumor activity in HER2-low-expression tumors."
IJMS | Free Full-Text | Generation of a Novel SORT1×HER2 Bispecific Antibody–Drug Conjugate Targeting HER2-Low-Expression Tumor