Affibody-derived drug conjugates: Potent cytotoxic molecules for treatment of HER2 over-expressing tumors

Journal of Controlled Release : Official Journal of the Controlled Release Society
Mohamed AltaiTorbjörn Gräslund

Abstract

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 exten...Continue Reading

Citations

Jun 13, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Javad GarousiMohamed Altai
May 20, 2020·Biomolecules·Dobeen Hwang, Christoph Rader
May 13, 2020·International Journal of Molecular Sciences·Anzhelika VorobyevaSergey Deyev
Feb 7, 2021·International Journal of Molecular Sciences·Qiyu LiZhangyong Hong
May 1, 2021·Antibody Therapeutics·Mahendra P Deonarain, Quinn Xue
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kristina WesterlundAmelie Eriksson Karlström
Jul 24, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Shahin AghamiriMojgan Bandehpour
Sep 8, 2021·Cancer Cell International·Reza MahmoudiMohammad Rahmati

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