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Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce.


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.

SUBMITTER: Herzog RW 

PROVIDER: S-EPMC5368425 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Oral Tolerance Induction in Hemophilia B Dogs Fed with Transplastomic Lettuce.

Herzog Roland W RW   Nichols Timothy C TC   Su Jin J   Zhang Bei B   Sherman Alexandra A   Merricks Elizabeth P EP   Raymer Robin R   Perrin George Q GQ   Häger Mattias M   Wiinberg Bo B   Daniell Henry H  

Molecular therapy : the journal of the American Society of Gene Therapy 20170201 2


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. Commerc  ...[more]

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