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Targeting Tumor Cells Overexpressing the Human Epidermal Growth Factor Receptor 3 with Potent Drug Conjugates Based on Affibody Molecules

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Journal Biomedicines
Date 2022 Jun 24
PMID 35740315
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Abstract

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-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-ABD-mcDM1 showed a strong affinity to the extracellular domain of HER3 (K 6 nM), and an even stronger affinity (K 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 IC value of 7 nM. Evaluation of a radiolabeled version, [Tc]Tc-Z-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-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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References
1.
Zahavi D, Weiner L . Monoclonal Antibodies in Cancer Therapy. Antibodies (Basel). 2020; 9(3). PMC: 7551545. DOI: 10.3390/antib9030034. View

2.
Hofstrom C, Altai M, Honarvar H, Strand J, Malmberg J, Hosseinimehr S . HAHAHA, HEHEHE, HIHIHI, or HKHKHK: influence of position and composition of histidine containing tags on biodistribution of [(99m)Tc(CO)3](+)-labeled affibody molecules. J Med Chem. 2013; 56(12):4966-74. DOI: 10.1021/jm400218y. View

3.
Wong D, Hurvitz S . Recent advances in the development of anti-HER2 antibodies and antibody-drug conjugates. Ann Transl Med. 2015; 2(12):122. PMC: 4260046. DOI: 10.3978/j.issn.2305-5839.2014.08.13. View

4.
Lipton A, Goodman L, Leitzel K, Cook J, Sperinde J, Haddad M . HER3, p95HER2, and HER2 protein expression levels define multiple subtypes of HER2-positive metastatic breast cancer. Breast Cancer Res Treat. 2013; 141(1):43-53. PMC: 3758835. DOI: 10.1007/s10549-013-2665-0. View

5.
Khongorzul P, Ling C, Ullah Khan F, Ihsan A, Zhang J . Antibody-Drug Conjugates: A Comprehensive Review. Mol Cancer Res. 2019; 18(1):3-19. DOI: 10.1158/1541-7786.MCR-19-0582. View