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Clinically relevant dosing and pharmacokinetics of DNA-encoded antibody therapeutics in a sheep model
DNA-encoded delivery and in vivo expression of antibody therapeutics presents an innovative alternative to conventional protein production and administration, including for cancer treatment. To support clinical translation, we evaluated this approach in 18 40-45 kg sheep, using a clinical-matched in...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9574358/ https://www.ncbi.nlm.nih.gov/pubmed/36263202 http://dx.doi.org/10.3389/fonc.2022.1017612 |
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author | Hollevoet, Kevin Thomas, Debby Compernolle, Griet Vermeire, Giles De Smidt, Elien De Vleeschauwer, Stéphanie Smith, Trevor R. F. Fisher, Paul D. Dewilde, Maarten Geukens, Nick Declerck, Paul |
author_facet | Hollevoet, Kevin Thomas, Debby Compernolle, Griet Vermeire, Giles De Smidt, Elien De Vleeschauwer, Stéphanie Smith, Trevor R. F. Fisher, Paul D. Dewilde, Maarten Geukens, Nick Declerck, Paul |
author_sort | Hollevoet, Kevin |
collection | PubMed |
description | DNA-encoded delivery and in vivo expression of antibody therapeutics presents an innovative alternative to conventional protein production and administration, including for cancer treatment. To support clinical translation, we evaluated this approach in 18 40-45 kg sheep, using a clinical-matched intramuscular electroporation (IM EP) and hyaluronidase-plasmid DNA (pDNA) coformulation setup. Two cohorts of eight sheep received either 1 or 4 mg pDNA encoding an ovine anti-cancer embryonic antigen (CEA) monoclonal antibody (mAb; OVAC). Results showed a dose-response with average maximum serum concentrations of respectively 0.3 and 0.7 µg/ml OVAC, 4-6 weeks after IM EP. OVAC was detected in all 16 sheep throughout the 6-week follow-up, and no anti-OVAC antibodies were observed. Another, more exploratory, cohort of two sheep received a 12 mg pOVAC dose. Both animals displayed a similar dose-dependent mAb increase and expression profile in the first two weeks. However, in one animal, an anti-OVAC antibody response led to loss of mAb detection four weeks after IM EP. In the other animal, no anti-drug antibodies were observed. Serum OVAC concentrations peaked at 4.9 µg/ml 6 weeks after IM EP, after which levels gradually decreased but remained detectable around 0.2 to 0.3 µg/ml throughout a 13-month follow-up. In conclusion, using a delivery protocol that is currently employed in clinical Phase 1 studies of DNA-based antibodies, we achieved robust and prolonged in vivo production of anti-cancer DNA-encoded antibody therapeutics in sheep. The learnings from this large-animal model regarding the impact of pDNA dose and host immune response on the expressed mAb pharmacokinetics can contribute to advancing clinical translation. |
format | Online Article Text |
id | pubmed-9574358 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-95743582022-10-18 Clinically relevant dosing and pharmacokinetics of DNA-encoded antibody therapeutics in a sheep model Hollevoet, Kevin Thomas, Debby Compernolle, Griet Vermeire, Giles De Smidt, Elien De Vleeschauwer, Stéphanie Smith, Trevor R. F. Fisher, Paul D. Dewilde, Maarten Geukens, Nick Declerck, Paul Front Oncol Oncology DNA-encoded delivery and in vivo expression of antibody therapeutics presents an innovative alternative to conventional protein production and administration, including for cancer treatment. To support clinical translation, we evaluated this approach in 18 40-45 kg sheep, using a clinical-matched intramuscular electroporation (IM EP) and hyaluronidase-plasmid DNA (pDNA) coformulation setup. Two cohorts of eight sheep received either 1 or 4 mg pDNA encoding an ovine anti-cancer embryonic antigen (CEA) monoclonal antibody (mAb; OVAC). Results showed a dose-response with average maximum serum concentrations of respectively 0.3 and 0.7 µg/ml OVAC, 4-6 weeks after IM EP. OVAC was detected in all 16 sheep throughout the 6-week follow-up, and no anti-OVAC antibodies were observed. Another, more exploratory, cohort of two sheep received a 12 mg pOVAC dose. Both animals displayed a similar dose-dependent mAb increase and expression profile in the first two weeks. However, in one animal, an anti-OVAC antibody response led to loss of mAb detection four weeks after IM EP. In the other animal, no anti-drug antibodies were observed. Serum OVAC concentrations peaked at 4.9 µg/ml 6 weeks after IM EP, after which levels gradually decreased but remained detectable around 0.2 to 0.3 µg/ml throughout a 13-month follow-up. In conclusion, using a delivery protocol that is currently employed in clinical Phase 1 studies of DNA-based antibodies, we achieved robust and prolonged in vivo production of anti-cancer DNA-encoded antibody therapeutics in sheep. The learnings from this large-animal model regarding the impact of pDNA dose and host immune response on the expressed mAb pharmacokinetics can contribute to advancing clinical translation. Frontiers Media S.A. 2022-10-03 /pmc/articles/PMC9574358/ /pubmed/36263202 http://dx.doi.org/10.3389/fonc.2022.1017612 Text en Copyright © 2022 Hollevoet, Thomas, Compernolle, Vermeire, De Smidt, De Vleeschauwer, Smith, Fisher, Dewilde, Geukens and Declerck https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Hollevoet, Kevin Thomas, Debby Compernolle, Griet Vermeire, Giles De Smidt, Elien De Vleeschauwer, Stéphanie Smith, Trevor R. F. Fisher, Paul D. Dewilde, Maarten Geukens, Nick Declerck, Paul Clinically relevant dosing and pharmacokinetics of DNA-encoded antibody therapeutics in a sheep model |
title | Clinically relevant dosing and pharmacokinetics of DNA-encoded antibody therapeutics in a sheep model |
title_full | Clinically relevant dosing and pharmacokinetics of DNA-encoded antibody therapeutics in a sheep model |
title_fullStr | Clinically relevant dosing and pharmacokinetics of DNA-encoded antibody therapeutics in a sheep model |
title_full_unstemmed | Clinically relevant dosing and pharmacokinetics of DNA-encoded antibody therapeutics in a sheep model |
title_short | Clinically relevant dosing and pharmacokinetics of DNA-encoded antibody therapeutics in a sheep model |
title_sort | clinically relevant dosing and pharmacokinetics of dna-encoded antibody therapeutics in a sheep model |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9574358/ https://www.ncbi.nlm.nih.gov/pubmed/36263202 http://dx.doi.org/10.3389/fonc.2022.1017612 |
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