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Affibody-derived drug conjugates: Potent cytotoxic molecules for treatment of HER2 over-expressing tumors
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.ORCID iD: 0000-0003-1093-8222
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
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2018 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 288, p. 84-95Article in journal (Refereed) Published
Abstract [en]

Patients with HER2-positive tumors often suffer resistance to therapy, warranting development of novel treatment modalities. Affibody molecules are small affinity proteins which can be engineered to bind to desired targets. They have in recent years been found to allow precise targeting of cancer specific molecular signatures such as the HER2 receptor. In this study, we have investigated the potential of an affibody molecule targeting HER2, Z(HER2:2891), conjugated with the cytotoxic maytansine derivate MC-DM1, for targeted cancer therapy. Z(HER2:2891) was expressed as a monomer (Z(HER2:2891)), dimer ((Z(HER2:2891)) 2) and dimer with an albumin binding domain (ABD) for half-life extension ((Z(HER2:2891)) 2-ABD). All proteins had a unique C-terminal cysteine that could be used for efficient and site-specific conjugation with MC-DM1. The resulting affibody drug conjugates were potent cytotoxic molecules for human cells over-expressing HER2, with sub-nanomolar IC50-values similar to trastuzumab emtansine, and did not affect cells with low HER2 expression. A biodistribution study of a radiolabeled version of (Z(HER2:2891))(2)-ABD-MC-DM1, showed that it was taken up by the tumor. The major site of off-target uptake was the kidneys and to some extent the liver. (Z(HER2:2891)) 2-ABD-MC-DM1 was found to have a half-life in circulation of 14 h. The compound was tolerated well by mice at 8.5 mg/kg and was shown to extend survival of mice bearing HER2 over-expressing tumors. The findings in this study show that affibody molecules are a promising class of engineered affinity proteins to specifically deliver small molecular drugs to cancer cells and that such conjugates are potential candidates for clinical evaluation on HER2-overexpressing cancers.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2018. Vol. 288, p. 84-95
Keywords [en]
DM1, Maytansine, Affibody molecule, ADC, HER2
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-367025DOI: 10.1016/j.jconrel.2018.08.040ISI: 000446237700007PubMedID: 30172673OAI: oai:DiVA.org:uu-367025DiVA, id: diva2:1266568
Funder
Swedish Research Council, 2015-02509Swedish Research Council, 2015-02353VINNOVA, 2016-04060Swedish Society for Medical Research (SSMF)Swedish Cancer Society, 14-0298Swedish Cancer Society, 14/474Swedish Cancer Society, 15/350Swedish Cancer Society, 15/746Available from: 2018-11-28 Created: 2018-11-28 Last updated: 2018-11-28Bibliographically approved

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Altai, MohamedMitran, BogdanEdqvist, Per-Henrik DTolmachev, VladimirOrlova, Anna

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