Identification and characterization of an octameric PEG-protein conjugate system for intravitreal long-acting delivery to the back of the eye.

Autor: Shatz W; Protein Chemistry, Genentech Inc., South San Francisco, California, United States of America., Hass PE; Protein Chemistry, Genentech Inc., South San Francisco, California, United States of America., Peer N; Protein Chemistry, Genentech Inc., South San Francisco, California, United States of America., Paluch MT; Protein Chemistry, Genentech Inc., South San Francisco, California, United States of America., Blanchette C; Protein Chemistry, Genentech Inc., South San Francisco, California, United States of America., Han G; Microchemistry, Proteomics and Lipidomics, Genentech Inc., South San Francisco, California, United States of America., Sandoval W; Microchemistry, Proteomics and Lipidomics, Genentech Inc., South San Francisco, California, United States of America., Morando A; Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, California, United States of America., Loyet KM; Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, California, United States of America., Bantseev V; Safety Assessment, Genentech Inc., South San Francisco, California, United States of America., Booler H; Safety Assessment, Genentech Inc., South San Francisco, California, United States of America., Crowell S; Pre-clinical and Translational Pharmacokinetics, Genentech Inc., South San Francisco, California, United States of America., Kamath A; Pre-clinical and Translational Pharmacokinetics, Genentech Inc., South San Francisco, California, United States of America., Scheer JM; Protein Chemistry, Genentech Inc., South San Francisco, California, United States of America., Kelley RF; Drug Delivery, Genentech, South San Francisco, California, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2019 Jun 28; Vol. 14 (6), pp. e0218613. Date of Electronic Publication: 2019 Jun 28 (Print Publication: 2019).
DOI: 10.1371/journal.pone.0218613
Abstrakt: 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.
Competing Interests: The authors have read the journal's policy and have the following competing interests: W.S., P.E.H., N.P., M.T.P., C.B., W.S., A.M., K.M.L., V.B., H.B., S.C., A.K., and R.F.K. are employees of Genentech. G.H. is an employee of BGI Americas, a genome sequencing company. J.M.S. is an employee of Boeringer Ingleheim, a pharmaceutical company. However, G.H. and J.M.S. were employees of Genentech through the completion of the study. There are no patents, products in development or marketed products associated with this research to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.
Databáze: MEDLINE
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