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Identification and characterization of an octameric PEG-protein conjugate system for intravitreal long-acting delivery to the back of the eye
Innovative protein engineering and chemical conjugation technologies have yielded an impressive number of drug candidates in clinical development including >80 antibody drug conjugates, >60 bispecific antibodies, >35 Fc-fusion proteins and >10 immuno-cytokines. Despite these innovations,...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599134/ https://www.ncbi.nlm.nih.gov/pubmed/31251757 http://dx.doi.org/10.1371/journal.pone.0218613 |
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author | Shatz, Whitney Hass, Philip E. Peer, Nikhil Paluch, Maciej T. Blanchette, Craig Han, Guanghui Sandoval, Wendy Morando, Ashley Loyet, Kelly M. Bantseev, Vladimir Booler, Helen Crowell, Susan Kamath, Amrita Scheer, Justin M. Kelley, Robert F. |
author_facet | Shatz, Whitney Hass, Philip E. Peer, Nikhil Paluch, Maciej T. Blanchette, Craig Han, Guanghui Sandoval, Wendy Morando, Ashley Loyet, Kelly M. Bantseev, Vladimir Booler, Helen Crowell, Susan Kamath, Amrita Scheer, Justin M. Kelley, Robert F. |
author_sort | Shatz, Whitney |
collection | PubMed |
description | Innovative protein engineering and chemical conjugation technologies have yielded an impressive number of drug candidates in clinical development including >80 antibody drug conjugates, >60 bispecific antibodies, >35 Fc-fusion proteins and >10 immuno-cytokines. Despite these innovations, technological advances are needed to address unmet medical needs with new pharmacological mechanisms. Age-related eye diseases are among the most common causes of blindness and poor vision in the world. Many such diseases affect the back of the eye, where the inaccessibility of the site of action necessitates therapeutic delivery via intravitreal (IVT) injection. Treatments administered via this route typically have vitreal half-lives <10 days in humans, requiring frequent administration. Since IVT injection is burdensome to patients, there exists a strong need to develop therapeutics with prolonged residence time in the eye. We report here a strategy to increase retention of a therapeutic fragment antibody (Fab) in the eye, using an anti-complement factor D Fab previously optimized for ocular delivery. Polyethylene glycol structures, varying in length, geometry and degree of branching, were coupled to the Fab via maleimide-activated termini. A screening strategy was developed to allow for key determinants of ocular half-life to be measured in vitro. After compound selection, a scalable process was established to enable tolerability and pharmacokinetic studies in cynomolgus monkeys, demonstrating an increase in vitreal half-life with no associated adverse events. Further, we show that the technique for compound selection, analytical characterization, and scalable production is general for a range of antibody fragments. The application of the technology has broad impact in across many therapeutic areas with the first major advancement in the treatment of an important ocular disease. |
format | Online Article Text |
id | pubmed-6599134 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-65991342019-07-12 Identification and characterization of an octameric PEG-protein conjugate system for intravitreal long-acting delivery to the back of the eye Shatz, Whitney Hass, Philip E. Peer, Nikhil Paluch, Maciej T. Blanchette, Craig Han, Guanghui Sandoval, Wendy Morando, Ashley Loyet, Kelly M. Bantseev, Vladimir Booler, Helen Crowell, Susan Kamath, Amrita Scheer, Justin M. Kelley, Robert F. PLoS One Research Article Innovative protein engineering and chemical conjugation technologies have yielded an impressive number of drug candidates in clinical development including >80 antibody drug conjugates, >60 bispecific antibodies, >35 Fc-fusion proteins and >10 immuno-cytokines. Despite these innovations, technological advances are needed to address unmet medical needs with new pharmacological mechanisms. Age-related eye diseases are among the most common causes of blindness and poor vision in the world. Many such diseases affect the back of the eye, where the inaccessibility of the site of action necessitates therapeutic delivery via intravitreal (IVT) injection. Treatments administered via this route typically have vitreal half-lives <10 days in humans, requiring frequent administration. Since IVT injection is burdensome to patients, there exists a strong need to develop therapeutics with prolonged residence time in the eye. We report here a strategy to increase retention of a therapeutic fragment antibody (Fab) in the eye, using an anti-complement factor D Fab previously optimized for ocular delivery. Polyethylene glycol structures, varying in length, geometry and degree of branching, were coupled to the Fab via maleimide-activated termini. A screening strategy was developed to allow for key determinants of ocular half-life to be measured in vitro. After compound selection, a scalable process was established to enable tolerability and pharmacokinetic studies in cynomolgus monkeys, demonstrating an increase in vitreal half-life with no associated adverse events. Further, we show that the technique for compound selection, analytical characterization, and scalable production is general for a range of antibody fragments. The application of the technology has broad impact in across many therapeutic areas with the first major advancement in the treatment of an important ocular disease. Public Library of Science 2019-06-28 /pmc/articles/PMC6599134/ /pubmed/31251757 http://dx.doi.org/10.1371/journal.pone.0218613 Text en © 2019 Shatz et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Shatz, Whitney Hass, Philip E. Peer, Nikhil Paluch, Maciej T. Blanchette, Craig Han, Guanghui Sandoval, Wendy Morando, Ashley Loyet, Kelly M. Bantseev, Vladimir Booler, Helen Crowell, Susan Kamath, Amrita Scheer, Justin M. Kelley, Robert F. Identification and characterization of an octameric PEG-protein conjugate system for intravitreal long-acting delivery to the back of the eye |
title | Identification and characterization of an octameric PEG-protein conjugate system for intravitreal long-acting delivery to the back of the eye |
title_full | Identification and characterization of an octameric PEG-protein conjugate system for intravitreal long-acting delivery to the back of the eye |
title_fullStr | Identification and characterization of an octameric PEG-protein conjugate system for intravitreal long-acting delivery to the back of the eye |
title_full_unstemmed | Identification and characterization of an octameric PEG-protein conjugate system for intravitreal long-acting delivery to the back of the eye |
title_short | Identification and characterization of an octameric PEG-protein conjugate system for intravitreal long-acting delivery to the back of the eye |
title_sort | identification and characterization of an octameric peg-protein conjugate system for intravitreal long-acting delivery to the back of the eye |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599134/ https://www.ncbi.nlm.nih.gov/pubmed/31251757 http://dx.doi.org/10.1371/journal.pone.0218613 |
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