4.8 Article

Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting

Journal

SCIENCE ADVANCES
Volume 7, Issue 13, Pages -

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abe1682

Keywords

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Funding

  1. Flanders Agency for Innovation and Entrepreneurship (IWT Research and Development grant) [120302]
  2. Hercules Foundation [AUGE-11-029]
  3. Research Foundation Flanders [G0E1516N, G0B4918N]
  4. Stand up to Cancer Program of the Flemish Cancer Society (Belgium)
  5. Ghent University [BOF17-GOA-028]
  6. ERC Starting Grant [639784]
  7. IWT-Flanders (Belgium)
  8. European Research Council (ERC) [639784] Funding Source: European Research Council (ERC)

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This study demonstrates the engineering of the Alphabody scaffold into a cell-penetrating protein antagonist against intracellular cancer target MCL-1, with the addition of an albumin-binding moiety to extend serum half-life. The engineered Alphabody reduced tumor burden in mouse tumor xenografts based on myeloma cell lines, providing a proof of concept for using Alphabodies against intracellular disease mediators.
The therapeutic scope of antibody and nonantibody protein scaffolds is still prohibitively limited against intracellular drug targets. Here, we demonstrate that the Alphabody scaffold can be engineered into a cell-penetrating protein antagonist against induced myeloid leukemia cell differentiation protein MCL-1, an intracellular target in cancer, by grafting the critical B-cell lymphoma 2 homology 3 helix of MCL-1 onto the Alphabody and tagging the scaffold's termini with designed cell-penetration polypeptides. Introduction of an albumin-binding moiety extended the serum half-life of the engineered Alphabody to therapeutically relevant levels, and administration thereof in mouse tumor xenografts based on myeloma cell lines reduced tumor burden. Crystal structures of such a designed Alphabody in complex with MCL-1 and serum albumin provided the structural blueprint of the applied design principles. Collectively, we provide proof of concept for the use of Alphabodies against intracellular disease mediators, which, to date, have remained in the realm of small-molecule therapeutics.

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