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Lyon, France

Godfrin Y.,ERYtech Pharma | Bax B.E.,University of London
Drugs of the Future | Year: 2012

Therapy using erythrocyte-encapsulated enzyme has the advantage of prolonging the half-life of the enzyme and maintaining therapeutic blood levels, reducing the dose and frequency of therapeutic interventions, and preventing the need for expensive chemical modification. The therapeutic index can be strongly improved, especially by reducing immunogenic reactions, which are often observed in enzyme therapy administered by the conventional route. Two products are presented in this paper: erythrocyte-encapsulated L-asparaginase and erythrocyteencapsulated thymidine phosphorylase. For the first, the native enzyme has been the mainstay in the treatment of lymphoblastic leukemia for decades. Improving the therapeutic index by utilizing this new formulation now offers new possibilities in cancer therapy. The second product is proposed for patients diagnosed with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disorder of nucleotide metabolism caused by mutations in the nuclear TYMP gene (thymidine phosphorylase deficiency). These two approaches illustrate how this new formulation works as an enzyme bioreactor in the treatment of cancer and in enzyme replacement therapy. Copyright © 2012 Prous Science, S.A.U. or its licensors. All rights reserved.

Pouilly S.,CNRS Center for Molecular Biophysics | Bourgeaux V.,CNRS Center for Molecular Biophysics | Bourgeaux V.,ERYtech Pharma | Piller F.,CNRS Center for Molecular Biophysics | Piller V.,CNRS Center for Molecular Biophysics
ACS Chemical Biology | Year: 2012

Changes in glycosylation are correlated to disease and associated with differentiation processes. Experimental tools are needed to investigate the physiological implications of these changes either by labeling of the modified glycans or by blocking their biosynthesis. N-Acetylgalactosamine (GalNAc) is a monosaccharide widely encountered in glycolipids, proteoglycans, and glycoproteins; once taken up by cells it can be converted through a salvage pathway to UDP-GalNAc, which is further used by glycosyltransferases to build glycans. In order to find new reporter molecules able to integrate into cellular glycans, synthetic analogues of GalNAc were prepared and tested as substrates of both enzymes acting sequentially in the GalNAc salvage pathway, galactokinase 2 (GK2) and uridylpyrophosphorylase AGX1. Detailed in vitro assays identified the GalNAc analogues that can be transformed into sugar nucleotides and revealed several bottlenecks in the pathway: a modification on C6 is not tolerated by GK2; AGX1 can use all products of GK2 although with various efficiencies; and all analogues transformed into UDP-GalNAc analogues except those with alterations on C4 are substrates for the polypeptide GalNAc transferase T1. Besides, all analogues that could be incorporated in vitro into O-glycans were also integrated into cellular O-glycans as attested by their detection on the cell surface of CHO-ldlD cells. Altogether our results show that GalNAc analogues can help to better define structural requirements of the donor substrates for the enzymes involved in GalNAc metabolism, and those that are incorporated into cells will prove valuable for the development of novel diagnostic and therapeutic tools. © 2012 American Chemical Society.

ERYtech Pharma | Date: 2015-07-31

Use of erythrocytes containing arginine deirainase for the preparation of a medicinal product for lowering the plasma concentration of arginine in vivo. The use relates in particular to the treatment of arginine-dependent tumors, such as hepatocarcinoma and malignant melanoma, or inhibition of the synthesis of nitric oxide, and the prevention and/or treatment of septic shock.

A method for obtaining a stabilised suspension of red blood cells encapsulating an active ingredient, from resealed RBCs incorporating the active ingredient, the method comprising the incubation of the resealed RBCs in an incubation solution at an osmolality of no less than 280 m Osmol/kg, for a time of 30 minutes or more, the incubation solution being a solution that does not contain an agent which is denaturating for the RBC membrane, the liquid medium is then removed from the incubated suspension and the RBCs obtained are placed in suspension in a solution allowing the injection of the suspension in a patient. The suspensions obtained are particularly characterized by an extracellular haemoglobin level maintained at 0.5 or lower, in particular 0.2 g/dl or lower and/or a haemolysis rate maintained at 2 or less, in particular 1% or less, at 72 h after placing in suspension in a preservation solution and at a temperature of between 2 and 8 C.

A lysis/resealing process for preparing erythrocytes containing active ingredient is provided comprising placing a globular concentrate in suspension in an isotonic solution having a haematocrit level which is equal to or greater than 65%, with refrigeration at 1 to 8 C.; measuring the osmotic fragility based on a sample of erythrocytes from that same globular concentrate, preferably on a sample of the suspension; lysis and internalisation procedure of the active ingredient, inside the same chamber, at a temperature maintained at 1 to 8 C., comprising allowing the erythrocyte suspension having a haematocrit level equal to or greater than 65% and a hypotonic lysis solution which is refrigerated at 1 to 8 C., to circulate in a dialysis cartridge; the lysis parameters being adjusted in accordance with the osmotic fragility previously measured; and resealing in a second chamber at a temperature of from 30 to 40 C. by means of a hypertonic solution.

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