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Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce

Authors :
Timothy C. Nichols
Henry Daniell
Elizabeth P. Merricks
Alexandra Sherman
Bei Zhang
Mattias Häger
George Q. Perrin
Jin Su
Roland W. Herzog
Bo Wiinberg
Robin A. Raymer
Source :
Molecular Therapy. 25(2):512-522
Publication Year :
2017
Publisher :
Elsevier BV, 2017.

Abstract

Anti-drug antibodies in hemophilia patients substantially complicate treatment. Their elimination through immune tolerance induction (ITI) protocols poses enormous costs, and ITI is often ineffective for factor IX (FIX) inhibitors. Moreover, there is no prophylactic ITI protocol to prevent anti-drug antibody (ADA) formation. Using general immune suppression is problematic. To address this urgent unmet medical need, we delivered antigen bioencapsulated in plant cells to hemophilia B dogs. Commercial-scale production of CTB-FIX fusion expressed in lettuce chloroplasts was done in a hydroponic facility. CTB-FIX (∼1 mg/g) in lyophilized cells was stable with proper folding, disulfide bonds, and pentamer assembly after 30-month storage at ambient temperature. Robust suppression of immunoglobulin G (IgG)/inhibitor and IgE formation against intravenous FIX was observed in three of four hemophilia B dogs fed with lyophilized lettuce cells expressing CTB-FIX. No side effects were detected after feeding CTB-FIX-lyophilized plant cells for >300 days. Coagulation times were markedly shortened by intravenous FIX in orally tolerized treated dogs, in contrast to control dogs that formed high-titer antibodies to FIX. Commercial-scale production, stability, prolonged storage of lyophilized cells, and efficacy in tolerance induction in a large, non-rodent model of human disease offer a novel concept for oral tolerance and low-cost production and delivery of biopharmaceuticals.

Details

ISSN :
15250016
Volume :
25
Issue :
2
Database :
OpenAIRE
Journal :
Molecular Therapy
Accession number :
edsair.doi.dedup.....9af9b3c29bd06ce2710db787d05c76fd
Full Text :
https://doi.org/10.1016/j.ymthe.2016.11.009