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,...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2019-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0218613 |
| _version_ | 1818825632661897216 |
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| author | Whitney Shatz Philip E Hass Nikhil Peer Maciej T Paluch Craig Blanchette Guanghui Han Wendy Sandoval Ashley Morando Kelly M Loyet Vladimir Bantseev Helen Booler Susan Crowell Amrita Kamath Justin M Scheer Robert F Kelley |
| author_facet | Whitney Shatz Philip E Hass Nikhil Peer Maciej T Paluch Craig Blanchette Guanghui Han Wendy Sandoval Ashley Morando Kelly M Loyet Vladimir Bantseev Helen Booler Susan Crowell Amrita Kamath Justin M Scheer Robert F Kelley |
| author_sort | Whitney Shatz |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-19T00:14:51Z |
| format | Article |
| id | doaj.art-82a56a7b258c43e885de3b136fc2e95b |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-19T00:14:51Z |
| publishDate | 2019-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-82a56a7b258c43e885de3b136fc2e95b2022-12-21T20:45:52ZengPublic Library of Science (PLoS)PLoS ONE1932-62032019-01-01146e021861310.1371/journal.pone.0218613Identification and characterization of an octameric PEG-protein conjugate system for intravitreal long-acting delivery to the back of the eye.Whitney ShatzPhilip E HassNikhil PeerMaciej T PaluchCraig BlanchetteGuanghui HanWendy SandovalAshley MorandoKelly M LoyetVladimir BantseevHelen BoolerSusan CrowellAmrita KamathJustin M ScheerRobert F KelleyInnovative 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.https://doi.org/10.1371/journal.pone.0218613 |
| spellingShingle | Whitney Shatz Philip E Hass Nikhil Peer Maciej T Paluch Craig Blanchette Guanghui Han Wendy Sandoval Ashley Morando Kelly M Loyet Vladimir Bantseev Helen Booler Susan Crowell Amrita Kamath Justin M Scheer Robert F Kelley Identification and characterization of an octameric PEG-protein conjugate system for intravitreal long-acting delivery to the back of the eye. PLoS ONE |
| 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 |
| url | https://doi.org/10.1371/journal.pone.0218613 |
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