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Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting

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Abstract
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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MLA
Pannecoucke, Erwin, et al. “Cell-Penetrating Alphabody Protein Scaffolds for Intracellular Drug Targeting.” SCIENCE ADVANCES, vol. 7, no. 13, 2021, doi:10.1126/sciadv.abe1682.
APA
Pannecoucke, E., Van Trimpont, M., Desmet, J., Pieters, T., Reunes, L., Demoen, L., … Savvides, S. (2021). Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting. SCIENCE ADVANCES, 7(13). https://doi.org/10.1126/sciadv.abe1682
Chicago author-date
Pannecoucke, Erwin, Maaike Van Trimpont, Johan Desmet, Tim Pieters, Lindy Reunes, Lisa Demoen, Marnik Vuylsteke, et al. 2021. “Cell-Penetrating Alphabody Protein Scaffolds for Intracellular Drug Targeting.” SCIENCE ADVANCES 7 (13). https://doi.org/10.1126/sciadv.abe1682.
Chicago author-date (all authors)
Pannecoucke, Erwin, Maaike Van Trimpont, Johan Desmet, Tim Pieters, Lindy Reunes, Lisa Demoen, Marnik Vuylsteke, Stefan Loverix, Karen Vandenbroucke, Philippe Alard, Paula Henderikx, Sabrina Deroo, Franky Baatz, Eric Lorent, Sophie Thiolloy, Klaartje Somers, Yvonne McGrath, Pieter Van Vlierberghe, Ignace Lasters, and Savvas Savvides. 2021. “Cell-Penetrating Alphabody Protein Scaffolds for Intracellular Drug Targeting.” SCIENCE ADVANCES 7 (13). doi:10.1126/sciadv.abe1682.
Vancouver
1.
Pannecoucke E, Van Trimpont M, Desmet J, Pieters T, Reunes L, Demoen L, et al. Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting. SCIENCE ADVANCES. 2021;7(13).
IEEE
[1]
E. Pannecoucke et al., “Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting,” SCIENCE ADVANCES, vol. 7, no. 13, 2021.
@article{8704185,
  abstract     = {{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.}},
  articleno    = {{eabe1682}},
  author       = {{Pannecoucke, Erwin and Van Trimpont, Maaike and Desmet, Johan and Pieters, Tim and Reunes, Lindy and Demoen, Lisa and Vuylsteke, Marnik and Loverix, Stefan and Vandenbroucke, Karen and Alard, Philippe and Henderikx, Paula and Deroo, Sabrina and Baatz, Franky and Lorent, Eric and Thiolloy, Sophie and Somers, Klaartje and McGrath, Yvonne and Van Vlierberghe, Pieter and Lasters, Ignace and Savvides, Savvas}},
  issn         = {{2375-2548}},
  journal      = {{SCIENCE ADVANCES}},
  language     = {{eng}},
  number       = {{13}},
  pages        = {{17}},
  title        = {{Cell-penetrating Alphabody protein scaffolds for intracellular drug targeting}},
  url          = {{http://doi.org/10.1126/sciadv.abe1682}},
  volume       = {{7}},
  year         = {{2021}},
}

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