Targeting tumor cells overexpressing the human epidermal growth factor receptor 3 with potent drug conjugates based on affibody molecules

Increasing evidence suggests that therapy targeting the human epidermal growth factor receptor 3 (HER3) could be a viable route for targeted cancer therapy. Here, we have studied a novel drug conjugate, ZHER3-ABD-mcDM1, consisting of a HER3-targeting affibody molecule, coupled to the cytotoxic tubulin polymerization inhibitor DM1, and an albumin- binding domain for in vivo half-life extension. ZHER3-ABD-mcDM1 showed strong affinity to the extracellular domain of HER3 (KD 6 nM), and an even stronger affinity (KD 0.2 nM) to the HER3-overexpressing pancreatic cancer cell line, BxPC3. The drug conjugate showed a potent cytotoxic effect on BxPC3 cells with an IC50 value of 7 nM. Further in vitro evaluation of a radiolabeled version [99mTc]Tc-ZHER3-ABD-mcDM1, showed that it had a relatively high rate of internalization into HER3-expressing BxPC-3 as well as DU145 (prostate cancer) cells, with a 27% internalized fraction after 8 h. Further in vivo evaluation showed that it could specifically target BxPC-3 and DU145-derived xenografts in mice, with an uptake peaking at 6.3 ± 0.4 %ID/g at 6 h post-injection for the BxPC-3-derived xenografts. The general biodistribution showed uptake in liver, lung, salivary gland, stomach, and small intestine, organs known to express HER3 naturally. The results from the study show that ZHER3-ABD- mcDM1 is a highly potent and specific drug conjugate, that may be further developed towards HER3-targeted cancer therapy.
QC 20220225