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Protein engineering to increase the potential of a therapeutic antibody Fab for long-acting delivery to the eye

Tesar, Devin and Luoma, Jacob and Wyatt, Emily A. and Shi, Catherine and Shatz, Whitney and Hass, Philip E. and Mathieu, Mary and Yi, Li and Corn, Jacob E. and Maass, Katie F. and Wang, Kathryn and Dion, Michelle Z. and Andersen, Nisana and Loyet, Kelly M. and van Lookeren Campagne, Menno and Rajagopal, Karthikan and Dickmann, Leslie and Scheer, Justin M. and Kelley, Robert F. (2017) Protein engineering to increase the potential of a therapeutic antibody Fab for long-acting delivery to the eye. mAbs, 9 (8). pp. 1297-1305. ISSN 1942-0862. PMCID PMC5680807. https://resolver.caltech.edu/CaltechAUTHORS:20171212-091558471

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Abstract

To date, ocular antibody therapies for the treatment of retinal diseases rely on injection of the drug into the vitreous chamber of the eye. Given the burden for patients undergoing this procedure, less frequent dosing through the use of long-acting delivery (LAD) technologies is highly desirable. These technologies usually require a highly concentrated formulation and the antibody must be stable against extended exposure to physiological conditions. Here we have increased the potential of a therapeutic antibody antigen-binding fragment (Fab) for LAD by using protein engineering to enhance the chemical and physical stability of the molecule. Structure-guided amino acid substitutions in a negatively charged complementarity determining region (CDR-L1) of an anti-factor D (AFD) Fab resulted in increased chemical stability and solubility. A variant of AFD (AFD.v8), which combines light chain substitutions (VL-D28S:D30E:D31S) with a substitution (VH-D61E) to stabilize a heavy chain isomerization site, retained complement factor D binding and inhibition potency and has properties suitable for LAD. This variant was amenable to high protein concentration (>250 mg/mL), low ionic strength formulation suitable for intravitreal injection. AFD.v8 had acceptable pharmacokinetic (PK) properties upon intravitreal injection in rabbits, and improved stability under both formulation and physiological conditions. Simulations of expected human PK behavior indicated greater exposure with a 25-mg dose enabled by the increased solubility of AFD.v8.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1080/19420862.2017.1372078DOIArticle
http://www.tandfonline.com/doi/full/10.1080/19420862.2017.1372078PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680807/PubMed CentralArticle
ORCID:
AuthorORCID
Yi, Li0000-0002-1994-0284
Scheer, Justin M.0000-0002-4621-2311
Additional Information:© 2017 Devin Tesar, Jacob Luoma, Emily A. Wyatt, Catherine Shi, Whitney Shatz, Philip E. Hass, Mary Mathieu, Li Yi, Jacob E. Corn, Katie F. Maass, Kathryn Wang, Michelle Z. Dion, Nisana Andersen, Kelly M. Loyet, Menno van Lookeren Campagne, Karthikan Rajagopal, Leslie Dickmann, Justin M. Scheer, and Robert F. Kelley. Published with license by Taylor & Francis Group, LLC. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. Received 11 Jul 2017, Accepted 21 Aug 2017, Accepted author version posted online: 30 Aug 2017, Published online: 14 Sep 2017. Disclosure of potential conflicts of interest: All authors are current or former employees of Genentech, Inc., a member of the Roche group, and may own Roche stock or stock options. The authors acknowledge helpful discussions with Atul Dandekar and Thierry Nivaggioli.
Subject Keywords:age-related macular degeneration; isomerization; deamidation; stability; solubility; protein engineering; high concentration formulation; long-acting delivery
Issue or Number:8
PubMed Central ID:PMC5680807
Record Number:CaltechAUTHORS:20171212-091558471
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20171212-091558471
Official Citation:Protein engineering to increase the potential of a therapeutic antibody Fab for long-acting delivery to the eye. Devin Tesar, Jacob Luoma, Emily A. Wyatt, Catherine Shi, Whitney Shatz, Philip E. Hass, Mary Mathieu, Li Yi, Jacob E. Corn, Katie F. Maass, Kathryn Wang, Michelle Z. Dion, Nisana Andersen, Kelly M. Loyet, Menno van Lookeren Campagne, Karthikan Rajagopal, Leslie Dickmann, Justin M. Scheer & Robert F. Kelley. mAbs Vol. 9, Iss. 8, 2017
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:83820
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:12 Dec 2017 18:11
Last Modified:03 Oct 2019 19:11

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