Glycans Derived From Porcine Stomach Mucin Are Effective Inhibitors of Natural Anti-??-Galactosyl Antibodies in Vitro and After Intravenous Infusion in Baboons1

Li, S. F.; Neethling, Francisca A.; Taniguchi, Shigeki; Yeh, Jeunliang; Kobayashi, Takaaki; Ye, Y.; Koren, Eugen; Cummings, Richard D.; Cooper, D. K. C.

doi:10.1097/00007890-199611150-00026

Cited by 20 publications

(7 citation statements)

References 16 publications

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“…The well-established principle of multivalent potentiation of weak carbohydrate-protein interactions [6] should also be operative for anti-carbohydrate antibodies. For this purpose attempts with high molecular weight oligosaccharides from pig-stomach mucins, [7] with serum albumin conjugates, [8] with multivalent arrays on oligo-ethylene glycol scaffolds, [9] and with poly-acryl amide conjugates [10] were made.…”

Section: From Chemical Research To Industrial Applicationsmentioning

confidence: 99%

In vivo Neutralization of Naturally Existing Antibodies against Linear ?(1,3)-Galactosidic Carbohydrate Epitopes by Multivalent Antigen Presentation: A Solution for the First Hurdle of Pig-to-Human Xenotransplantation

Duthaler

Ernst

Fischer

et al. 2010

Chimia

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Pig-to-human xenotransplantation of islet cells or of vascularized organs would offer a welcome treatment alternative for the ever-increasing number of patients with end-stage organ failure who are waiting for a suitable allograph. The main hurdle are preexisting antibodies, most of which are specific for 'Linear-B', carbohydrate epitopes terminated by the unbranched Gal-?(1,3)Gal disaccharide. These antibodies are responsible for the 'hyper-acute rejection' of the xenograft by complement mediated hemorrhage. For depletion of such antibodies we have developed an artificial injectable antigen, a glycopolymer (GAS914) with a charge neutral poly-lysine backbone (degree of polymerization n = 1000) and 25% of its side chains coupled to Linear-B-trisaccharide. With an average molecular weight of 400 to 500 kD, presenting 250 trisaccharide epitopes per molecule, this multivalent array binds anti-?Gal antibodies with at least three orders of magnitude higher avidity on a per-saccharide basis than the monomeric epitope. In vivo experiments with non-human primates documented that rather low doses – 1 to 5 mg/kg of GAS914 injected i.v. – efficiently reduce the load of anti-Linear-B antibodies quickly by at least 80%. This treatment can be repeated without any sensitization to GAS914. Interestingly, although the antibody levels start raising 12 h after injection, they do not reach pretreatment levels. The polymer is degraded and excreted within hours, with a minute fraction remaining in lymphoid tissue of anti-?Gal producing animals only, probably binding to and inhibiting antibody-producing B-cells. The results of pig-to-non-human primate xenotransplantations established GAS914 as a relevant therapeutic option for pig-to-human transplantations as well. The synthesis of GAS914 was successfully scaled up to kg amounts needed for first clinical studies. Key was the use of galactosyl transferases and UDP-galactose for the synthesis of the trisaccharide.

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Section: From Chemical Research To Industrial Applicationsmentioning

confidence: 99%

In vivo Neutralization of Naturally Existing Antibodies against Linear ?(1,3)-Galactosidic Carbohydrate Epitopes by Multivalent Antigen Presentation: A Solution for the First Hurdle of Pig-to-Human Xenotransplantation

Duthaler

Ernst

Fischer

et al. 2010

Chimia

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“…Gal α1,3Gal columns specifically remove antipig activity from human-and baboon serum [16] and are sufficient to prevent HAR in various models [17][18][19]. Intravenous infusion of the αGal antigens in various forms [6,20,21], or peptides mimicking the three-dimensional structure of the αgalactosyl antigens [22] or even induction of anti-idiotypic antibodies [23] were proposed as methods to interfere with antibody binding.…”

Section: Strategies To Deplete Anti-pig Antibodiesmentioning

confidence: 99%

Beyond Antibody-Mediated Rejection: Hyperacute Lung Rejection as a Paradigm for Dysregulated Inflammation

Nguyen¹,

Zwets²,

Schroeder³

et al. 2005

CDTCHD

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The use of animal organs for transplantation in humans is seen as a potential solution to the short supply of human donor organs available for clinical transplantation. However, to develop this therapeutic option as clinical reality will require surmounting formidable obstacles. The primary immunologic barrier to pig-to-human xenotransplantation is hyperacute rejection (HAR), a phenomenon previously characterized as resulting from antibody binding and complement activation. This article will first review recent progress in the development of specific strategies to overcome hyperacute lung rejection (HALR), through production of genetically engineered pig organs, modification of the host innate immunity and control of antibody and complement. Additional therapeutic targets identified in HALR are reviewed, with particular emphasis on recent studies describing a critical role for the coagulation cascade in HAR.

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“…Up to now, however, the maximal xenograft survival time never reached more than 3 months. This limited survival time is, at least in part, due to both IgG and IgM anti‐porcine antibodies which play a major role in the onset of acute vascular rejection (AVR) [1–7].…”

Section: Introductionmentioning

confidence: 99%

Characterization of baboon anti-porcine IgG antibodies during acute vascular rejection of porcine kidney xenograft

Dehoux

Parra

Latinne

et al. 2002

Xenotransplantation

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In the pig-to-baboon model, the removal of anti-porcine natural antibodies abrogates hyperacute vascular rejection (HAVR), but the xenograft then undergoes an acute vascular rejection (AVR) concomitantly to the appearance of newly formed anti-porcine antibodies. The use of anti-IgM monoclonal antibody (mAb) in baboons allowed to avoid HAVR of pig-to-baboon renal xenografts, but, at post-operative day 6, AVR occurred because of a rapid return of anti-porcine antibodies. The aim of this work was to characterize the anti-porcine antibodies during AVR. Sera from anti-IgM-treated animals were assessed prior to the graft and at the time of AVR by enzyme linked immunosorbent assay (ELISA) to determine anti-porcine antibodies concentration as well as the IgG subtypes. The same sera were tested on confluent cultures of porcine aortic endothelial cells (PAECs) to assess (i) the cytolytic complement-dependent activity and (ii) the E-selectin expression. The K affinity of anti-Gal IgG antibodies was measured by ELISA. Anti-porcine (Gal and non-Gal) IgG antibodies were tested on PAECs by flow cytometry to discriminate the presence of Gal epitopes from the recognition of other porcine epitopes. We found that both anti-porcine IgM and IgG antibodies presented a significantly increased cytolytic activity and E-selectin expression on PAECs during AVR. These characteristics are related to an important increase of the antibody (Ab) titer (especially anti-galactosyl) and a switch to anti-galactosyl IgG1 subclass production, whereas the K affinity remained unchanged. The deleterious effects of both IgM and IgG antibodies observed during AVR showed the crucial need for treatment controlling the cells producing anti-porcine antibodies.

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Glycans Derived From Porcine Stomach Mucin Are Effective Inhibitors of Natural Anti-??-Galactosyl Antibodies in Vitro and After Intravenous Infusion in Baboons1

Cited by 20 publications

References 16 publications

In vivo Neutralization of Naturally Existing Antibodies against Linear ?(1,3)-Galactosidic Carbohydrate Epitopes by Multivalent Antigen Presentation: A Solution for the First Hurdle of Pig-to-Human Xenotransplantation

In vivo Neutralization of Naturally Existing Antibodies against Linear ?(1,3)-Galactosidic Carbohydrate Epitopes by Multivalent Antigen Presentation: A Solution for the First Hurdle of Pig-to-Human Xenotransplantation

Beyond Antibody-Mediated Rejection: Hyperacute Lung Rejection as a Paradigm for Dysregulated Inflammation

Characterization of baboon anti-porcine IgG antibodies during acute vascular rejection of porcine kidney xenograft

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