Cargando…
CD98hc is a target for brain delivery of biotherapeutics
Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TV(CD98hc))....
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10439950/ https://www.ncbi.nlm.nih.gov/pubmed/37598178 http://dx.doi.org/10.1038/s41467-023-40681-4 |
_version_ | 1785093066177118208 |
---|---|
author | Chew, Kylie S. Wells, Robert C. Moshkforoush, Arash Chan, Darren Lechtenberg, Kendra J. Tran, Hai L. Chow, Johann Kim, Do Jin Robles-Colmenares, Yaneth Srivastava, Devendra B. Tong, Raymond K. Tong, Mabel Xa, Kaitlin Yang, Alexander Zhou, Yinhan Akkapeddi, Padma Annamalai, Lakshman Bajc, Kaja Blanchette, Marie Cherf, Gerald Maxwell Earr, Timothy K. Gill, Audrey Huynh, David Joy, David Knight, Kristen N. Lac, Diana Leung, Amy Wing-Sze Lexa, Katrina W. Liau, Nicholas P. D. Becerra, Isabel Malfavon, Mario McInnes, Joseph Nguyen, Hoang N. Lozano, Edwin I. Pizzo, Michelle E. Roche, Elysia Sacayon, Patricia Calvert, Meredith E. K. Daneman, Richard Dennis, Mark S. Duque, Joseph Gadkar, Kapil Lewcock, Joseph W. Mahon, Cathal S. Meisner, René Solanoy, Hilda Thorne, Robert G. Watts, Ryan J. Zuchero, Y. Joy Yu Kariolis, Mihalis S. |
author_facet | Chew, Kylie S. Wells, Robert C. Moshkforoush, Arash Chan, Darren Lechtenberg, Kendra J. Tran, Hai L. Chow, Johann Kim, Do Jin Robles-Colmenares, Yaneth Srivastava, Devendra B. Tong, Raymond K. Tong, Mabel Xa, Kaitlin Yang, Alexander Zhou, Yinhan Akkapeddi, Padma Annamalai, Lakshman Bajc, Kaja Blanchette, Marie Cherf, Gerald Maxwell Earr, Timothy K. Gill, Audrey Huynh, David Joy, David Knight, Kristen N. Lac, Diana Leung, Amy Wing-Sze Lexa, Katrina W. Liau, Nicholas P. D. Becerra, Isabel Malfavon, Mario McInnes, Joseph Nguyen, Hoang N. Lozano, Edwin I. Pizzo, Michelle E. Roche, Elysia Sacayon, Patricia Calvert, Meredith E. K. Daneman, Richard Dennis, Mark S. Duque, Joseph Gadkar, Kapil Lewcock, Joseph W. Mahon, Cathal S. Meisner, René Solanoy, Hilda Thorne, Robert G. Watts, Ryan J. Zuchero, Y. Joy Yu Kariolis, Mihalis S. |
author_sort | Chew, Kylie S. |
collection | PubMed |
description | Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TV(CD98hc)). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATV(CD98hc)) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATV(CD98hc) demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATV(CD98hc) that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TV(CD98hc) as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms. |
format | Online Article Text |
id | pubmed-10439950 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-104399502023-08-21 CD98hc is a target for brain delivery of biotherapeutics Chew, Kylie S. Wells, Robert C. Moshkforoush, Arash Chan, Darren Lechtenberg, Kendra J. Tran, Hai L. Chow, Johann Kim, Do Jin Robles-Colmenares, Yaneth Srivastava, Devendra B. Tong, Raymond K. Tong, Mabel Xa, Kaitlin Yang, Alexander Zhou, Yinhan Akkapeddi, Padma Annamalai, Lakshman Bajc, Kaja Blanchette, Marie Cherf, Gerald Maxwell Earr, Timothy K. Gill, Audrey Huynh, David Joy, David Knight, Kristen N. Lac, Diana Leung, Amy Wing-Sze Lexa, Katrina W. Liau, Nicholas P. D. Becerra, Isabel Malfavon, Mario McInnes, Joseph Nguyen, Hoang N. Lozano, Edwin I. Pizzo, Michelle E. Roche, Elysia Sacayon, Patricia Calvert, Meredith E. K. Daneman, Richard Dennis, Mark S. Duque, Joseph Gadkar, Kapil Lewcock, Joseph W. Mahon, Cathal S. Meisner, René Solanoy, Hilda Thorne, Robert G. Watts, Ryan J. Zuchero, Y. Joy Yu Kariolis, Mihalis S. Nat Commun Article Brain exposure of systemically administered biotherapeutics is highly restricted by the blood-brain barrier (BBB). Here, we report the engineering and characterization of a BBB transport vehicle targeting the CD98 heavy chain (CD98hc or SLC3A2) of heterodimeric amino acid transporters (TV(CD98hc)). The pharmacokinetic and biodistribution properties of a CD98hc antibody transport vehicle (ATV(CD98hc)) are assessed in humanized CD98hc knock-in mice and cynomolgus monkeys. Compared to most existing BBB platforms targeting the transferrin receptor, peripherally administered ATV(CD98hc) demonstrates differentiated brain delivery with markedly slower and more prolonged kinetic properties. Specific biodistribution profiles within the brain parenchyma can be modulated by introducing Fc mutations on ATV(CD98hc) that impact FcγR engagement, changing the valency of CD98hc binding, and by altering the extent of target engagement with Fabs. Our study establishes TV(CD98hc) as a modular brain delivery platform with favorable kinetic, biodistribution, and safety properties distinct from previously reported BBB platforms. Nature Publishing Group UK 2023-08-19 /pmc/articles/PMC10439950/ /pubmed/37598178 http://dx.doi.org/10.1038/s41467-023-40681-4 Text en © The Author(s) 2023, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Chew, Kylie S. Wells, Robert C. Moshkforoush, Arash Chan, Darren Lechtenberg, Kendra J. Tran, Hai L. Chow, Johann Kim, Do Jin Robles-Colmenares, Yaneth Srivastava, Devendra B. Tong, Raymond K. Tong, Mabel Xa, Kaitlin Yang, Alexander Zhou, Yinhan Akkapeddi, Padma Annamalai, Lakshman Bajc, Kaja Blanchette, Marie Cherf, Gerald Maxwell Earr, Timothy K. Gill, Audrey Huynh, David Joy, David Knight, Kristen N. Lac, Diana Leung, Amy Wing-Sze Lexa, Katrina W. Liau, Nicholas P. D. Becerra, Isabel Malfavon, Mario McInnes, Joseph Nguyen, Hoang N. Lozano, Edwin I. Pizzo, Michelle E. Roche, Elysia Sacayon, Patricia Calvert, Meredith E. K. Daneman, Richard Dennis, Mark S. Duque, Joseph Gadkar, Kapil Lewcock, Joseph W. Mahon, Cathal S. Meisner, René Solanoy, Hilda Thorne, Robert G. Watts, Ryan J. Zuchero, Y. Joy Yu Kariolis, Mihalis S. CD98hc is a target for brain delivery of biotherapeutics |
title | CD98hc is a target for brain delivery of biotherapeutics |
title_full | CD98hc is a target for brain delivery of biotherapeutics |
title_fullStr | CD98hc is a target for brain delivery of biotherapeutics |
title_full_unstemmed | CD98hc is a target for brain delivery of biotherapeutics |
title_short | CD98hc is a target for brain delivery of biotherapeutics |
title_sort | cd98hc is a target for brain delivery of biotherapeutics |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10439950/ https://www.ncbi.nlm.nih.gov/pubmed/37598178 http://dx.doi.org/10.1038/s41467-023-40681-4 |
work_keys_str_mv | AT chewkylies cd98hcisatargetforbraindeliveryofbiotherapeutics AT wellsrobertc cd98hcisatargetforbraindeliveryofbiotherapeutics AT moshkforousharash cd98hcisatargetforbraindeliveryofbiotherapeutics AT chandarren cd98hcisatargetforbraindeliveryofbiotherapeutics AT lechtenbergkendraj cd98hcisatargetforbraindeliveryofbiotherapeutics AT tranhail cd98hcisatargetforbraindeliveryofbiotherapeutics AT chowjohann cd98hcisatargetforbraindeliveryofbiotherapeutics AT kimdojin cd98hcisatargetforbraindeliveryofbiotherapeutics AT roblescolmenaresyaneth cd98hcisatargetforbraindeliveryofbiotherapeutics AT srivastavadevendrab cd98hcisatargetforbraindeliveryofbiotherapeutics AT tongraymondk cd98hcisatargetforbraindeliveryofbiotherapeutics AT tongmabel cd98hcisatargetforbraindeliveryofbiotherapeutics AT xakaitlin cd98hcisatargetforbraindeliveryofbiotherapeutics AT yangalexander cd98hcisatargetforbraindeliveryofbiotherapeutics AT zhouyinhan cd98hcisatargetforbraindeliveryofbiotherapeutics AT akkapeddipadma cd98hcisatargetforbraindeliveryofbiotherapeutics AT annamalailakshman cd98hcisatargetforbraindeliveryofbiotherapeutics AT bajckaja cd98hcisatargetforbraindeliveryofbiotherapeutics AT blanchettemarie cd98hcisatargetforbraindeliveryofbiotherapeutics AT cherfgeraldmaxwell cd98hcisatargetforbraindeliveryofbiotherapeutics AT earrtimothyk cd98hcisatargetforbraindeliveryofbiotherapeutics AT gillaudrey cd98hcisatargetforbraindeliveryofbiotherapeutics AT huynhdavid cd98hcisatargetforbraindeliveryofbiotherapeutics AT joydavid cd98hcisatargetforbraindeliveryofbiotherapeutics AT knightkristenn cd98hcisatargetforbraindeliveryofbiotherapeutics AT lacdiana cd98hcisatargetforbraindeliveryofbiotherapeutics AT leungamywingsze cd98hcisatargetforbraindeliveryofbiotherapeutics AT lexakatrinaw cd98hcisatargetforbraindeliveryofbiotherapeutics AT liaunicholaspd cd98hcisatargetforbraindeliveryofbiotherapeutics AT becerraisabel cd98hcisatargetforbraindeliveryofbiotherapeutics AT malfavonmario cd98hcisatargetforbraindeliveryofbiotherapeutics AT mcinnesjoseph cd98hcisatargetforbraindeliveryofbiotherapeutics AT nguyenhoangn cd98hcisatargetforbraindeliveryofbiotherapeutics AT lozanoedwini cd98hcisatargetforbraindeliveryofbiotherapeutics AT pizzomichellee cd98hcisatargetforbraindeliveryofbiotherapeutics AT rocheelysia cd98hcisatargetforbraindeliveryofbiotherapeutics AT sacayonpatricia cd98hcisatargetforbraindeliveryofbiotherapeutics AT calvertmeredithek cd98hcisatargetforbraindeliveryofbiotherapeutics AT danemanrichard cd98hcisatargetforbraindeliveryofbiotherapeutics AT dennismarks cd98hcisatargetforbraindeliveryofbiotherapeutics AT duquejoseph cd98hcisatargetforbraindeliveryofbiotherapeutics AT gadkarkapil cd98hcisatargetforbraindeliveryofbiotherapeutics AT lewcockjosephw cd98hcisatargetforbraindeliveryofbiotherapeutics AT mahoncathals cd98hcisatargetforbraindeliveryofbiotherapeutics AT meisnerrene cd98hcisatargetforbraindeliveryofbiotherapeutics AT solanoyhilda cd98hcisatargetforbraindeliveryofbiotherapeutics AT thornerobertg cd98hcisatargetforbraindeliveryofbiotherapeutics AT wattsryanj cd98hcisatargetforbraindeliveryofbiotherapeutics AT zucheroyjoyyu cd98hcisatargetforbraindeliveryofbiotherapeutics AT kariolismihaliss cd98hcisatargetforbraindeliveryofbiotherapeutics |