Anthrax Protective Antigen Retargeted with Single‐Chain Variable Fragments Delivers Enzymes to Pancreatic Cancer Cells
The nontoxic, anthrax protective antigen/lethal factor N-terminal domain (PA/LFN ) complex is an effective platform for translocating proteins into the cytosol of cells. Mutant PA (mPA) was recently fused to epidermal growth factor (EGF) to retarget delivery of LFN to cells bearing EGF receptors (EG...
| Main Authors: | , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Wiley
2020
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| Online Access: | https://hdl.handle.net/1721.1/128117 |
| _version_ | 1811084479635128320 |
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| author | Loftis, Alexander Robert Santos, Michael Truex, Nicholas Biancucci, Marco Satchell, Karla J. F. Pentelute, Bradley L. |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Loftis, Alexander Robert Santos, Michael Truex, Nicholas Biancucci, Marco Satchell, Karla J. F. Pentelute, Bradley L. |
| author_sort | Loftis, Alexander Robert |
| collection | MIT |
| description | The nontoxic, anthrax protective antigen/lethal factor N-terminal domain (PA/LFN ) complex is an effective platform for translocating proteins into the cytosol of cells. Mutant PA (mPA) was recently fused to epidermal growth factor (EGF) to retarget delivery of LFN to cells bearing EGF receptors (EGFR), but the requirement for a known cognate ligand limits the applicability of this approach. Here, we render practical protective antigen retargeting to a variety of receptors with mPA single-chain variable fragment (scFv) fusion constructs. Our design enables the targeting of two pancreatic cancer-relevant receptors, EGFR and carcinoembryonic antigen. We demonstrate that fusion to scFvs does not disturb the basic functions of mPA. Moreover, mPA-scFv fusions enable cell-specific delivery of diphtheria toxin catalytic domain and Ras/Rap1-specific endopeptidase to pancreatic cancer cells. Importantly, mPA-scFv fusion-based treatments display potent cell-specific toxicity in vitro, opening fundamentally new routes toward engineered immunotoxins and providing a potential solution to the challenge of targeted protein delivery to the cytosol of cancer cells. |
| first_indexed | 2024-09-23T12:51:27Z |
| format | Article |
| id | mit-1721.1/128117 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T12:51:27Z |
| publishDate | 2020 |
| publisher | Wiley |
| record_format | dspace |
| spelling | mit-1721.1/1281172022-09-28T10:32:19Z Anthrax Protective Antigen Retargeted with Single‐Chain Variable Fragments Delivers Enzymes to Pancreatic Cancer Cells Loftis, Alexander Robert Santos, Michael Truex, Nicholas Biancucci, Marco Satchell, Karla J. F. Pentelute, Bradley L. Massachusetts Institute of Technology. Department of Chemistry Massachusetts Institute of Technology. Department of Chemical Engineering The nontoxic, anthrax protective antigen/lethal factor N-terminal domain (PA/LFN ) complex is an effective platform for translocating proteins into the cytosol of cells. Mutant PA (mPA) was recently fused to epidermal growth factor (EGF) to retarget delivery of LFN to cells bearing EGF receptors (EGFR), but the requirement for a known cognate ligand limits the applicability of this approach. Here, we render practical protective antigen retargeting to a variety of receptors with mPA single-chain variable fragment (scFv) fusion constructs. Our design enables the targeting of two pancreatic cancer-relevant receptors, EGFR and carcinoembryonic antigen. We demonstrate that fusion to scFvs does not disturb the basic functions of mPA. Moreover, mPA-scFv fusions enable cell-specific delivery of diphtheria toxin catalytic domain and Ras/Rap1-specific endopeptidase to pancreatic cancer cells. Importantly, mPA-scFv fusion-based treatments display potent cell-specific toxicity in vitro, opening fundamentally new routes toward engineered immunotoxins and providing a potential solution to the challenge of targeted protein delivery to the cytosol of cancer cells. NSF (Grant CHE-1351807) 2020-10-19T18:59:10Z 2020-10-19T18:59:10Z 2020-06 2020-05 2020-10-06T16:54:25Z Article http://purl.org/eprint/type/JournalArticle 1439-4227 1439-7633 https://hdl.handle.net/1721.1/128117 Loftis, Alexander R. et al. "Anthrax Protective Antigen Retargeted with Single‐Chain Variable Fragments Delivers Enzymes to Pancreatic Cancer Cells." ChemBioChem 21, 19 (June 2020): 2772-2776 en http://dx.doi.org/10.1002/cbic.202000201 ChemBioChem Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Wiley Prof. Pentelute via Ye Li |
| spellingShingle | Loftis, Alexander Robert Santos, Michael Truex, Nicholas Biancucci, Marco Satchell, Karla J. F. Pentelute, Bradley L. Anthrax Protective Antigen Retargeted with Single‐Chain Variable Fragments Delivers Enzymes to Pancreatic Cancer Cells |
| title | Anthrax Protective Antigen Retargeted with Single‐Chain Variable Fragments Delivers Enzymes to Pancreatic Cancer Cells |
| title_full | Anthrax Protective Antigen Retargeted with Single‐Chain Variable Fragments Delivers Enzymes to Pancreatic Cancer Cells |
| title_fullStr | Anthrax Protective Antigen Retargeted with Single‐Chain Variable Fragments Delivers Enzymes to Pancreatic Cancer Cells |
| title_full_unstemmed | Anthrax Protective Antigen Retargeted with Single‐Chain Variable Fragments Delivers Enzymes to Pancreatic Cancer Cells |
| title_short | Anthrax Protective Antigen Retargeted with Single‐Chain Variable Fragments Delivers Enzymes to Pancreatic Cancer Cells |
| title_sort | anthrax protective antigen retargeted with single chain variable fragments delivers enzymes to pancreatic cancer cells |
| url | https://hdl.handle.net/1721.1/128117 |
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