Multiple‐unit and second transfusions of red cells enzymatically converted from group B to group O: report on the end of phase 1 trials

Lenny, Leslie L.; Hurst, Rosa; Zhu, Alex; Goldstein, Jack; Galbraith, R.A.

doi:10.1046/j.1537-2995.1995.351196110892.x

Cited by 46 publications

(22 citation statements)

References 7 publications

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“…1); however, the low pH preference of the human enzyme [pH Ϸ5 (15)] would most likely prevent its use ex vivo on tissues or organs for any extended period of time without significant cell death. To date, the most useful enzyme for cleaving cell surface Gal␣(1,3)Gal has been coffee bean ␣-galactosidase, which works efficiently ex vivo at physiological pH to cleave galactosyl residues and convert group B to group O erythrocytes (26,27). However, because the Gal␣(1,3)Gal epitope is continually resynthesized and replaced, efforts were directed to determine whether ␣-galactosidase could be constitutively expressed in cells, thereby decreasing the amount of cell surface Gal␣(1,3)Gal.…”

Section: Discussionmentioning

confidence: 99%

Combined transgenic expression of α-galactosidase and α1,2-fucosyltransferase leads to optimal reduction in the major xenoepitope Galα(1,3)Gal

Osman

McKenzie

Ostenried

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

106

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Hyperacute rejection of pig organs by humans involves the interaction of Gal␣(1,3)Gal with antibodies and complement. Strategies to reduce the amount of xenoantigen Gal␣(1,3)Gal were investigated by overexpression of human lysosomal ␣-galactosidase in cultured porcine cells and transgenic mice. The overexpression of human ␣-galactosidase in cultured porcine endothelial cells and COS cells resulted in a 30-fold reduction of cell surface Gal␣(1,3)Gal and a 10-fold reduction in cell reactivity with natural human antibodies. Splenocytes from transgenic mice overexpressing human ␣-galactosidase showed only a 15-25% reduction in binding to natural human anti-Gal␣(1,3)Gal antibodies; however, this decrease was functionally significant as demonstrated by reduced susceptibility to human antibodymediated lysis. However, because there is residual Gal␣(1,3)Gal and degalactosylation results in the exposure of N-acetyllactosamine residues and potential new xenoepitopes, using ␣-galactosidase alone is unlikely to overcome hyperacute rejection. We previously reported that mice overexpressing human ␣1,2-fucosyltransferase as a transgene had Ϸ90% reduced Gal␣(1,3)Gal levels due to masking of the xenoantigen by fucosylation; we evaluated the effect of overexpressing ␣-galactosidase and ␣1,2-fucosyltransferase on Gal␣(1,3)Gal levels. Gal␣(1,3)Gal-positive COS cells expressing ␣1,3-galactosyltransferase, ␣1,2-fucosyltransferase, and ␣-galactosidase showed negligible cell surface staining and were not susceptible to lysis by human serum containing antibody and complement. Thus, ␣1,2-fucosyltransferase and ␣-galactosidase effectively reduced the expression of Gal␣(1,3)Gal on the cell surface and could be used to produce transgenic pigs with negligible levels of cell surface Gal␣(1,3)Gal, thereby having no reactivity with human serum and improving graft survival.

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Section: Discussionmentioning

confidence: 99%

Combined transgenic expression of α-galactosidase and α1,2-fucosyltransferase leads to optimal reduction in the major xenoepitope Galα(1,3)Gal

Osman

McKenzie

Ostenried

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

106

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“…Specific exoglycosidases have been used to convert blood types B and A to type O. Studies by Lenny et al [241–243] have shown that an exoglycosidase from green coffee bean is able convert blood type B to type O at pH 5.5 by removing the relevant terminal sugar. These RBCs appeared to survive normally in all recipients.…”

Section: Choosing Target Binding Sites On Carrier Rbcsmentioning

confidence: 99%

Delivery of Drugs Bound to erythrocytes: New Avenues for an Old Intravascular Carrier

et al. 2015

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For several decades, researchers have used erythrocytes for drug delivery of a wide variety of therapeutics in order to improve their pharmacokinetics, biodistribution, controlled release and pharmacodynamics. Approaches include encapsulation of drugs within erythrocytes, as well as coupling of drugs onto the red cell surface. This review focuses on the latter approach, and examines the delivery of red blood cell (RBC)-surface-bound anti-inflammatory, anti-thrombotic and anti-microbial agents, as well as RBC carriage of nanoparticles. Herein, we discuss the progress that has been made in surface loading approaches, and address in depth the issues relevant to surface loading of RBC, including intrinsic features of erythrocyte membranes, immune considerations, potential surface targets and techniques for the production of affinity ligands.

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“…Despite this, coffee-bean-derived enzyme was successfully used to complete phase I (Lenny et al, 1991(Lenny et al, , 1994(Lenny et al, , 1995 and phase II clinical trials in which B-ECO RBCs were shown to be safe and functional, providing RBC survival and recovery values equal to ABO-compatible control transfusions in patients during a randomized cross-over study (Kruskall et al, 2000).…”

Section: The Eco Process and The Enzymesmentioning

confidence: 99%

“…Clinical phase I studies were conducted using B-ECO RBCs given to group A and O healthy volunteers and the initial small infusions were escalated to full single RBC units (Lenny et al, 1991), multiple units and finally repeated transfusions (Lenny et al, 1994(Lenny et al, , 1995. A successful phase II cross-over clinical trial in patients was reported in 2000 (Kruskall et al, 2000).…”

Section: Clinical Experience With Eco Rbcsmentioning

confidence: 99%

Modifying the red cell surface: towards an ABO‐universal blood supply

Olsson¹,

Clausen²

2007

Br J Haematol

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SummaryEliminating the risk for ABO-incompatible transfusion errors and simplifying logistics by creating a universal blood inventory is a challenging idea. Goldstein and co-workers pioneered the field of enzymatic conversion of blood group A and B red blood cells (RBCs) to O (ECO). Using a-galactosidase from coffee beans to produce B-ECO RBCs, proof of principle for this revolutionary concept was achieved in clinical trials. However, because this enzyme has poor kinetic properties and low pH optimum the process was not economically viable. Conversion of group A RBCs was only achieved with the weak A 2 subgroup with related enzymes having acidic pH optima. More recently, the identification of entirely new families of bacterial exoglycosidases with remarkably improved kinetic properties for cleaving A and B antigens has reinvigorated the field. Enzymatic conversion of groups A, B and AB RBCs with these novel enzymes resulting in ECO RBCs typing as O can now be achieved with low enzyme protein consumption, short incubation times and at neutral pH. Presently, clinical trials evaluating safety and efficacy of ECO RBCs are ongoing. Here, we review the status of the ECO technology, its impact and potential for introduction into clinical component preparation laboratories.

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Multiple‐unit and second transfusions of red cells enzymatically converted from group B to group O: report on the end of phase 1 trials

Abstract: ECO RBCs are safe and efficacious when transfused more than once or in multiple-unit volumes to group O or A subjects, and ECO RBCs prepared with recombinant or native enzyme are equivalent in vivo.

Cited by 46 publications

References 7 publications

Combined transgenic expression of α-galactosidase and α1,2-fucosyltransferase leads to optimal reduction in the major xenoepitope Galα(1,3)Gal

Combined transgenic expression of α-galactosidase and α1,2-fucosyltransferase leads to optimal reduction in the major xenoepitope Galα(1,3)Gal

Delivery of Drugs Bound to erythrocytes: New Avenues for an Old Intravascular Carrier

Modifying the red cell surface: towards an ABO‐universal blood supply

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