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Affibody-derived drug conjugates: Potent cytotoxic molecules for treatment of HER2 over-expressing tumors
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science.
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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, ZHER2:2891, conjugated with the cytotoxic maytansine derivate MC-DM1, for targeted cancer therapy. ZHER2:2891 was expressed as a monomer (ZHER2:2891), dimer ((ZHER2:2891)2) and dimer with an albumin binding domain (ABD) for half-life extension ((ZHER2:2891)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 (ZHER2:2891)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. (ZHER2:2891)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 B.V. , 2018. Vol. 288, p. 84-95
Keywords [en]
ADC, Affibody molecule, DM1, HER2, Maytansine, Amino acids, Diseases, Mammals, Molecules, Monoclonal antibodies, Patient treatment, Tumors, Affibody molecules, Clinical evaluation, Molecular signatures, Targeted cancer therapy, Terminal cysteine, Treatment modality, Dimers, (z human epidermal growth factor receptor 2 2891) 2 albumin binding domain iaa conjugate, (z human epidermal growth factor receptor 2 2891) 2 albumin binding domain mc dm1 conjugate, (z human epidermal growth factor receptor 2 2891) 2 mc dm1 conjugate, (z human epidermal growth factor receptor 2 2891) mc dm1 conjugate, (z taq) 2 albumin binding domain mc dm1 conjugate, cysteine, cytotoxic agent, dimer, epidermal growth factor receptor 2, epidermal growth factor receptor kinase inhibitor, monomer, serum albumin, technetium 99m, trastuzumab emtansine, unclassified drug, albumin binding domain, animal experiment, animal model, animal tissue, Article, AU565 cell line, binding affinity, cancer survival, carboxy terminal sequence, controlled study, drug conjugation, drug cytotoxicity, drug dose comparison, drug efficacy, drug half life, drug potency, drug specificity, drug targeting, drug tolerability, female, human, human tissue, IC50, in vitro study, isotope labeling, kidney tissue, liver tissue, MCF-7 cell line, molecularly targeted therapy, mouse, nonhuman, ovary carcinoma, priority journal, protein expression, protein structure, SK-BR-3 cell line, SK-OV-3 cell line, tissue distribution
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-236627DOI: 10.1016/j.jconrel.2018.08.040ISI: 000446237700007Scopus ID: 2-s2.0-85053511226OAI: oai:DiVA.org:kth-236627DiVA, id: diva2:1263076
Funder
Swedish Cancer Society, 14-0298; 14/474; 15/350; 15/746Swedish Research Council, 2015-02509; 2015-02353VINNOVA, 2015-02509; 2015-02353Swedish Society for Medical Research (SSMF)
Note

Export Date: 22 October 2018; Article; CODEN: JCREE; Correspondence Address: Gräslund, T.; Department of Protein Sciecne, KTH Royal Institute of Technology, Roslagstullsbacken 21, Sweden; email: torbjorn@kth.se; Funding details: 14/474, Cancerfonden; Funding details: 14-0298, Cancerfonden; Funding details: 15/746, Cancerfonden; Funding details: 15/350, Cancerfonden; Funding details: SSMF, Svenska Sällskapet för Medicinsk Forskning; Funding details: 2016-04060; Funding details: 2015-02353, VR, Vetenskapsrådet; Funding details: 2015-02509, VR, Vetenskapsrådet; Funding text: This work was supported by The Swedish Cancer Society (Cancerfonden), grants 14-0298, 14/474, 15/350, 15/746 , the Swedish Research Council ; grants 2015-02509 and 2015-02353 , and the Swedish Agency for Innovation VINNOVA (grant 2016-04060 . Mohamed Altai's research activities are kindly supported by the Swedish Society for Medical Research (SSMF). Appendix A. QC 20181114

Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2018-11-14Bibliographically approved

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