Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works..
Effective delivery of protein therapeutics to the central nervous system (CNS) has been greatly restricted by the blood-brain barrier (BBB). We describe the development of a BBB transport vehicle (TV) comprising an engineered Fc fragment that exploits receptor-mediated transcytosis for CNS delivery of biotherapeutics by binding a highly expressed brain endothelial cell target. TVs were engineered using directed evolution to bind the apical domain of the human transferrin receptor (hTfR) without the use of amino acid insertions, deletions, or unnatural appendages. A crystal structure of the TV-TfR complex revealed the TV binding site to be away from transferrin and FcRn binding sites, which was further confirmed experimentally in vitro and in vivo. Recombinant expression of TVs fused to anti-β-secretase (BACE1) Fabs yielded antibody transport vehicle (ATV) molecules with native immunoglobulin G (IgG) structure and stability. Peripheral administration of anti-BACE1 ATVs to hTfR-engineered mice and cynomolgus monkeys resulted in substantially improved CNS uptake and sustained pharmacodynamic responses. The TV platform readily accommodates numerous additional configurations, including bispecific antibodies and protein fusions, yielding a highly modular CNS delivery platform.
| Errataetall: |
CommentIn: Nat Rev Drug Discov. 2020 Jul;19(7):444. - PMID 32504057 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Science translational medicine - 12(2020), 545 vom: 27. Mai |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kariolis, Mihalis S [VerfasserIn] |
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| Links: |
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| Themen: |
Amyloid Precursor Protein Secretases |
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| Anmerkungen: |
Date Completed 23.06.2021 Date Revised 05.01.2022 published: Print CommentIn: Nat Rev Drug Discov. 2020 Jul;19(7):444. - PMID 32504057 Citation Status MEDLINE |
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| doi: |
10.1126/scitranslmed.aay1359 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM310432642 |
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| 500 | |a CommentIn: Nat Rev Drug Discov. 2020 Jul;19(7):444. - PMID 32504057 | ||
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| 520 | |a Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. | ||
| 520 | |a Effective delivery of protein therapeutics to the central nervous system (CNS) has been greatly restricted by the blood-brain barrier (BBB). We describe the development of a BBB transport vehicle (TV) comprising an engineered Fc fragment that exploits receptor-mediated transcytosis for CNS delivery of biotherapeutics by binding a highly expressed brain endothelial cell target. TVs were engineered using directed evolution to bind the apical domain of the human transferrin receptor (hTfR) without the use of amino acid insertions, deletions, or unnatural appendages. A crystal structure of the TV-TfR complex revealed the TV binding site to be away from transferrin and FcRn binding sites, which was further confirmed experimentally in vitro and in vivo. Recombinant expression of TVs fused to anti-β-secretase (BACE1) Fabs yielded antibody transport vehicle (ATV) molecules with native immunoglobulin G (IgG) structure and stability. Peripheral administration of anti-BACE1 ATVs to hTfR-engineered mice and cynomolgus monkeys resulted in substantially improved CNS uptake and sustained pharmacodynamic responses. The TV platform readily accommodates numerous additional configurations, including bispecific antibodies and protein fusions, yielding a highly modular CNS delivery platform | ||
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| 700 | 1 | |a Getz, Jennifer A |e verfasserin |4 aut | |
| 700 | 1 | |a Kwan, Wanda |e verfasserin |4 aut | |
| 700 | 1 | |a Mahon, Cathal S |e verfasserin |4 aut | |
| 700 | 1 | |a Tong, Raymond |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Do Jin |e verfasserin |4 aut | |
| 700 | 1 | |a Srivastava, Ankita |e verfasserin |4 aut | |
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| 700 | 1 | |a Giese, Tina |e verfasserin |4 aut | |
| 700 | 1 | |a Assimon, Victoria A |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xiaocheng |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yin |e verfasserin |4 aut | |
| 700 | 1 | |a Solanoy, Hilda |e verfasserin |4 aut | |
| 700 | 1 | |a Jenkins, Katherine |e verfasserin |4 aut | |
| 700 | 1 | |a Sanchez, Pascal E |e verfasserin |4 aut | |
| 700 | 1 | |a Kane, Lesley |e verfasserin |4 aut | |
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| 700 | 1 | |a Calvert, Meredith E K |e verfasserin |4 aut | |
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| 700 | 1 | |a Silverman, Adam P |e verfasserin |4 aut | |
| 700 | 1 | |a Zuchero, Y Joy Yu |e verfasserin |4 aut | |
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