Removal of anti-Galalpha1,3Gal xenoantibodies with an injectable polymer.
Preformed and elicited Ab's against the Galalpha1,3Gal terminating carbohydrate chains (alphaGal Ab's) are the primary cause of hyperacute and acute vascular xenograft rejection in pig-to-primate transplantation. alphaGal Ab's are produced by long-lived Ab-producing cells that are not susceptible to pharmacological immunosuppression. We reasoned that antigen-specific elimination of alphaGal Ab's might be achieved in vivo by systemic administration of nonimmunogenic polyvalent alphaGal structures with high avidity for alphaGal Ab's. We devised GAS914, a soluble trisaccharide-polylysine conjugate of approximately 500 kDa that effectively competes for alphaGal binding by alphaGal IgM (IC(50), 43 nM) and IgG (IC(50), 28 nM) in vitro. Injections of GAS914 in cynomolgus monkeys, at the dose of 1 mg/kg, resulted in the immediate decrease of more than 90% of circulating alphaGal Ab's and serum anti-pig cytotoxicity. In baboons, repeated injections of GAS914 effectively reduced both circulating alphaGal Ab's and cytotoxicity over several months. Studies with [(14)C]GAS914 in rhesus monkeys and Gal(-/-) mice indicate that GAS914 binds to circulating alphaGal Ab's and that the complex is quickly metabolized by the liver and excreted by the kidney. Remarkably, posttreatment alphaGal Ab titers never exceeded pretreatment levels and no sensitization to either alphaGal or the polylysine backbone has been observed. Furthermore there was no apparent acute or chronic toxicity associated with GAS914 treatment in primates. We conclude that GAS914 may be used therapeutically for the specific removal of alphaGal Ab's.
Katopodis
Andreas G
AG
Novartis Institutes for Biomedical Research, Transplantation Research, Basel, Switzerland. andreas.katopodis@pharma.novartis.com
Warner
Richard G
RG
Duthaler
Rudolf O
RO
Streiff
Markus B
MB
Bruelisauer
Armin
A
Kretz
Olivier
O
Dorobek
Birgit
B
Persohn
Elke
E
Andres
Hendrik
H
Schweitzer
Alain
A
Thoma
Gebhard
G
Kinzy
Willy
W
Quesniaux
Valerie F J
VF
Cozzi
Emanuele
E
Davies
Hugh F S
HF
Mañez
Rafael
R
White
David
D
D000818:Animals; D000910:Antibodies, Heterophile / Q000097:blood* / Q000276:immunology; D001345:Autoradiography / Q000379:methods; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000378:metabolism; D004187:Disaccharides / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000939:Epitopes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007163:Immunosorbent Techniques; D008252:Macaca fascicularis; D008253:Macaca mulatta; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D015394:Molecular Structure; D010215:Papio; D011108:Polymers / Q000008:administration & dosage* / Q000737:chemistry; D051381:Rats; D013552:Swine; D014018:Tissue Distribution; D014181:Transplantation Immunology; D014183:Transplantation, Heterologous; D014312:Trisaccharides / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D000910:Antibodies, Heterophile; D002250:Carbon Radioisotopes; D004187:Disaccharides; D000939:Epitopes; D011108:Polymers; D014312:Trisaccharides; C076569:alpha-galactosyl epitope; C055075:galactosyl-(1-3)galactose