Journal
BIOMEDICINES
Volume 10, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/biomedicines10061293
Keywords
affibody molecule; human epidermal growth factor receptor 3 (HER3); BxPC-3; emtansine; DM1; albumin binding domain; affibody drug conjugate (AffiDC)
Categories
Funding
- Swedish Agency for Innovation VINNOVA [2019/00104]
- Swedish Cancer Society (Cancerfonden) [21 1861 Pj, 2020/181, 20 0893 Pj, 20 0815 PjF, 20 1090 PjF, 190101Pj01H]
- Swedish Research Council (Vetenskapsradet) [2019-00986, 2019-05115]
- Knut and Alice Wallenberg Foundation through the Wallenberg Center for Protein Technology [2019.0341]
- China Scholarship Council (CSC)
- Vinnova [2019-05115] Funding Source: Vinnova
- Swedish Research Council [2019-05115] Funding Source: Swedish Research Council
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This study found that Z(HER3)-ABD-mcDM1 is a highly potent and selective drug conjugate with the ability to specifically target HER3-overexpressing cells.
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 studied a novel drug conjugate, Z(HER3)-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. Z(HER3)-ABD-mcDM1 showed a strong affinity to the extracellular domain of HER3 (K-D 6 nM), and an even stronger affinity (K-D 0.2 nM) to the HER3-overexpressing pancreatic carcinoma cell line, BxPC-3. The drug conjugate showed a potent cytotoxic effect on BxPC-3 cells with an IC50 value of 7 nM. Evaluation of a radiolabeled version, [Tc-99m]Tc-Z(HER3)-ABD-mcDM1, showed a relatively high rate of internalization, with a 27% internalized fraction after 8 h. Further in vivo evaluation showed that it could target BxPC-3 (pancreatic carcinoma) and DU145 (prostate carcinoma) xenografts in mice, with an uptake peaking at 6.3 +/- 0.4% IA/g at 6 h post-injection for the BxPC-3 xenografts. The general biodistribution showed uptake in the liver, lung, salivary gland, stomach, and small intestine, organs known to express murine ErbB3 naturally. The results from the study show that Z(HER3)-ABD-mcDM1 is a highly potent and selective drug conjugate with the ability to specifically target HER3 overexpressing cells. Further pre-clinical and clinical development is discussed.
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