Immunogenicity of glycans on biotherapeutic drugs produced in plant expression systems—The taliglucerase alfa story

Abstract

Plants are a promising alternative for the production of biotherapeutics. Manufacturing in-planta adds plant specific glycans. To understand immunogenic potential of these glycans, we developed a validated method to detect plant specific glycan antibodies in human serum. Using this assay, low prevalence of pre-existing anti-plant glycan antibodies was found in healthy humans (13.5%) and in glucocerebrosidase-deficient Gaucher disease (GD) patients (5%). A low incidence (9% in naïve patient and none in treatment experienced patients) of induced anti-plant glycan antibodies was observed in GD patients after up to 30 months replacement therapy treatment with taliglucerase alfa, a version of human glucocerebrosidase produced in plant cells. Detailed evaluation of clinical safety and efficacy endpoints indicated that anti-plant glycan antibodies did not affect the safety or efficacy of taliglucerase alfa in patients. This study shows the benefit of using large scale human trials to evaluate the immunogenicity risk of plant derived glycans, and indicates no apparent risk related to anti-plant glycan antibodies.

Expression of Single Chain Variable Fragment (scFv) Molecules in Plants: A Comprehensive Update

“…The results indicated that 8/63 patients developed anti-plant-glycan antibodies. The detailed study of various disease parameters showed that the treatment was as efficient as of any other enzyme replacement therapies used, and the safety indicators were well within limits [17]. This observation substantiated the results obtained by Landry and co-workers on the use of a plant-based H5N1 vaccine.…”

“…The differences in the posttranslational modifications between mammalian cells and the plant cells were a serious concern in using plants for the recombinant antibody expression. Genetic manipulations leading to the mammalian-like post-translational modifications in the model plant systems resulted in the biosynthesis of antibodies equivalent to mammalian products [16][17][18]. Even though biologically active mAbs can be expressed successfully in plants, a more feasible approach would be the expression of antibody fragments.…”

Human protein paucimannosylation: cues from the eukaryotic kingdoms

“…This proposition should be viewed in the light that plant PMPs carry potentially immunogenic and allergenic glycoepitopes foreign to the mammalian immune system including those modified with α1,3‐fucosylation and β1,2‐xylosylation as indicated by reports of mammalian allo‐antibodies recognising Fuc/Xyl glycoepitopes (Bardor et al ., ; van Ree et al ., ; Wang et al ., ). However, it is clear that the association(s) between PMGs and food allergy and the underlying molecular mechanism(s) still require experimental support and validation (Shaaltiel & Tekoah, ; Rup et al ., ).…”

CRISPR/Cas9‐mediated knockout of six glycosyltransferase genes in Nicotiana benthamiana for the production of recombinant proteins lacking β‐1,2‐xylose and core α‐1,3‐fucose

“…plant N‐glycans lack sialic acid and core α‐1,6‐fucose residues, but β‐1,2‐xylose and core α‐1,3‐fucose are present (Lerouge et al ., ). The potential immunogenicity of the plant‐specific N‐glycans has been discussed extensively in the context of molecular farming (Bardor et al ., ; Gomord et al ., ; Shaaltiel and Tekoah, ), and although there are no conclusive data questioning the safety of plant‐made pharmaceuticals (Gomord et al ., ; Rup et al ., ; Santos et al ., ; Tekoah et al ., ; Ward et al ., ), their elimination is desirable to produce glycoproteins lacking non‐human epitopes.…”