Removal of anti-Galα1,3Gal xenoantibodies with an injectable polymer

Katopodis, Andreas; Warner, R.G.; Duthaler, Rudolf O.; Streiff, Markus; Bruelisauer, Armin; Kretz, Olivier; Dorobek, Birgit; Persohn, Elke; Andres, Hendrik; Schweitzer, A.; Thoma, Gebhard; Kinzy, Willy; Quesniaux, Valérie; Cozzi, Emanuele; Davies, Huw Alban; Máñez, Rafael; White, David J.

doi:10.1172/jci16526

Cited by 72 publications

(73 citation statements)

References 33 publications

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“…[16] In binding assays competition for antiLinear-B antibodies (pooled human ABserum) between antigenic carbohydrate coated on well plates and the soluble antigen test compounds is measured with an ELISA (enzyme-linked immunosorbent assay) format, selective either for the divalent IgG or the decavalent IgM subtypes. The results shown in Table 1 list inhibitory IC 50 concentrations based on equivalent weight, i.e.…”

Section: + 11mentioning

confidence: 99%

“…without sensitization to GAS914. [16] For pharmacokinetic studies GAS914 was radiolabelled with 14 C, using 14 C-chloroacetic acid for the preparation (cf. Scheme 2).…”

Section: Entrymentioning

confidence: 99%

“…With the aid of monoclonal antibodies raised against the poly-(l)-lysine backbone of GAS914 it could be shown with immuno-histochemical methods that the radioactivity remaining in lymphoid tissue was associated with intact GAS914 and also co-staining with B-cell regions. [16] It might therefore be speculated that such collocation indicates binding of GAS914 to B-cells, and suppression of anti-Gal antibody production, resulting in the observed long term lowering of antibody levels. [16] During these treatments no adverse side effects such as immune complex mediated glomerulonephritis were observed, and complement activation remained very low.…”

Section: Entrymentioning

confidence: 99%

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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: + 11mentioning

confidence: 99%

“…without sensitization to GAS914. [16] For pharmacokinetic studies GAS914 was radiolabelled with 14 C, using 14 C-chloroacetic acid for the preparation (cf. Scheme 2).…”

Section: Entrymentioning

confidence: 99%

Section: Entrymentioning

confidence: 99%

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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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“…Many strategies have been employed to overcome hyperacute rejection. These include removal of the anti-Gala1,3-Gal Abs (8), accommodation (9), transgenesis (10,11), and small interfering RNA silencing of the GalT (12). GalT knockout (KO) donor organs gave a glimpse of hope through extending the life of the transplanted organ but succumbed to rejection, eventually albeit at a considerably later time (13,14).…”

mentioning

confidence: 99%

“…GalT knockout (KO) donor organs gave a glimpse of hope through extending the life of the transplanted organ but succumbed to rejection, eventually albeit at a considerably later time (13,14). Clinical xenotransplantation is controversial owing to the identified rejection problems and the possibility of xenozoonotic diseases (8,15). Neutrophils and NK cells were identified as Gala1,3-Gal-independent players in xenograft rejection.…”

mentioning

confidence: 99%

Identification of the Tetraspanin CD82 as a New Barrier to Xenotransplantation

Saleh

Parhar

Al-Hejailan

et al. 2013

The Journal of Immunology

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Significant immunological obstacles are to be negotiated before xenotransplantation becomes a clinical reality. An initial rejection of transplanted vascularized xenograft is attributed to Galα1,3Galβ1,4GlcNAc-R (Galα1,3-Gal)–dependent and –independent mechanisms. Hitherto, no receptor molecule has been identified that could account for Galα1,3-Gal–independent rejection. In this study, we identify the tetraspanin CD82 as a receptor molecule for the Galα1,3-Gal–independent mechanism. We demonstrate that, in contrast to human undifferentiated myeloid cell lines, differentiated cell lines are capable of recognizing xenogeneic porcine aortic endothelial cells in a calcium-dependent manner. Transcriptome-wide analysis to identify the differentially expressed transcripts in these cells revealed that the most likely candidate of the Galα1,3-Gal–independent recognition moiety is the tetraspanin CD82. Abs to CD82 inhibited the calcium response and the subsequent activation invoked by xenogeneic encounter. Our data identify CD82 on innate immune cells as a major “xenogenicity sensor” and open new avenues of intervention to making xenotransplantation a clinical reality.

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Non‐Covalent Polyvalent Ligands by Self‐Assembly of Small Glycodendrimers: A Novel Concept for the Inhibition of Polyvalent Carbohydrate–Protein Interactions In Vitro and In Vivo

Thoma

Streiff

Katopodis

et al. 2005

Chemistry A European J

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Polyvalent carbohydrate-protein interactions occur frequently in biology, particularly in recognition events on cellular membranes. Collectively, they can be much stronger than corresponding monovalent interactions, rendering it difficult to control them with individual small molecules. Artificial macromolecules have been used as polyvalent ligands to inhibit polyvalent processes; however, both reproducible synthesis and appropriate characterization of such complex entities is demanding. Herein, we present an alternative concept avoiding conventional macromolecules. Small glycodendrimers which fulfill single molecule entity criteria self-assemble to form non-covalent nanoparticles. These particles-not the individual molecules-function as polyvalent ligands, efficiently inhibiting polyvalent processes both in vitro and in vivo. The synthesis and characterization of these glycodendrimers is described in detail. Furthermore, we report on the characterization of the non-covalent nanoparticles formed and on their biological evaluation.

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Removal of anti-Galα1,3Gal xenoantibodies with an injectable polymer

Cited by 72 publications

References 33 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

Identification of the Tetraspanin CD82 as a New Barrier to Xenotransplantation

Non‐Covalent Polyvalent Ligands by Self‐Assembly of Small Glycodendrimers: A Novel Concept for the Inhibition of Polyvalent Carbohydrate–Protein Interactions In Vitro and In Vivo

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