Boosting Antitumor Drug Efficacy with Chemically Engineered Multidomain Proteins. Issue 8 (14th June 2018)

• Record Type: Journal Article
• Authors: Kuan, Seah Ling; Fischer, Stephan; Hafner, Susanne; Wang, Tao; Syrovets, Tatiana; Liu, Weina; Tokura, Yu; Ng, David Yuen Wah; Riegger, Andreas; Förtsch, Christina; Jäger, Daniela; Barth, Thomas F. E.; Simmet, Thomas; Barth, Holger; Weil, Tanja
• Is Part Of: Advanced science. Volume 5:Issue 8(2018)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2018-06-14
• Subjects: chemically engineered proteins -- combination oncotherapy -- supramolecular fusion proteins -- targeted delivery; Science -- Periodicals; 505
• DOI: 10.1002/advs.201701036
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: A facile chemical approach integrating supramolecular chemistry, site‐selective protein chemistry, and molecular biology is described to engineer synthetic multidomain protein therapeutics that sensitize cancer cells selectively to significantly enhance antitumor efficacy of existing chemotherapeutics. The desired bioactive entities are assembled via supramolecular interactions at the nanoscale into structurally ordered multiprotein complexes comprising a) multiple copies of the chemically modified cyclic peptide hormone somatostatin for selective targeting and internalization into human A549 lung cancer cells expressing SST‐2 receptors and b) a new cysteine mutant of the C3bot1 (C3) enzyme from Clostridium botulinum, a Rho protein inhibitor that affects and influences intracellular Rho‐mediated processes like endothelial cell migration and blood vessel formation. The multidomain protein complex, SST3‐Avi‐C3, retargets C3 enzyme into non‐small cell lung A549 cancer cells and exhibits exceptional tumor inhibition at a concentration ≈100‐fold lower than the clinically approved antibody bevacizumab (Avastin) in vivo. Notably, SST3‐Avi‐C3 increases tumor sensitivity to a conventional chemotherapeutic (doxorubicin) in vivo. These findings show that the integrated approach holds vast promise to expand the current repertoire of multidomain protein complexes and can pave the way to important new developments in the area of targeted and combination cancer therapy. Abstract : A highly potent multidomain protein therapeutic is engineered through an integrative synthetic platform. The chemically engineered protein exhibits cell‐type selective uptake, selective inhibition of a hallmark protein target molecule in cancer cells, and pH‐induced release into the cytosol of tumor cells, to achieve high antitumor potency and even exceeds the therapeutic efficacy of an existing antibody treatment.