Preformed and elicited Ab’s against the Galα1,3Gal terminating carbohydrate chains (αGal Ab’s) are the primary cause of hyperacute and acute vascular xenograft rejection in pig-to-primate transplantation. αGal Ab’s are produced by long-lived Ab-producing cells that are not susceptible to pharmacological immunosuppression. We reasoned that antigen-specific elimination of αGal Ab’s might be achieved in vivo by systemic administration of nonimmunogenic polyvalent αGal structures with high avidity for αGal Ab’s. We devised GAS914, a soluble trisaccharide-polylysine conjugate of approximately 500 kDa that effectively competes for αGal binding by αGal IgM (IC50, 43 nM) and IgG (IC50, 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 αGal Ab’s and serum anti-pig cytotoxicity. In baboons, repeated injections of GAS914 effectively reduced both circulating αGal Ab’s and cytotoxicity over several months. Studies with [14C]GAS914 in rhesus monkeys and Gal–/– mice indicate that GAS914 binds to circulating αGal Ab’s and that the complex is quickly metabolized by the liver and excreted by the kidney. Remarkably, posttreatment αGal Ab titers never exceeded pretreatment levels and no sensitization to either αGal 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 αGal Ab’s
Carrier-free LiEt3BT and LiAIT4 have been generated and used to reduce methyl 2-naphthoate to 2-( hydroxymethy1)naphthalene containing two tritium atoms per molecule.
The highly positively charged, cell-penetrating beta3-octaarginine has been prepared with a radioactive label by acetylation at the N-terminus with a doubly (14)C-labeled acetyl group ((14)CH3-(14)CO). With the radioactive compound, an ADME study (Absorption, Distribution, Metabolism, Excretion) was performed in male rats following an intravenous or oral dose of 1 mg/kg. Sampling was carried out after periods ranging from 5 min to 4 d or 7 d for blood/excretia and quantitative whole-body autoradioluminography (QWBA), respectively. After p.o. dosing, no systemic exposure to peptide-related radioactivity was observed, and the dose was completely excreted in the feces within 24 h suggesting the absence of relevant absorption; less than 3% of the i.v. dose was excreted from the animals within 4 d. Blood levels, after i.v. dosing, dropped within 4 d to less than 2% of Cmax and decreased afterwards only very slowly. No metabolites were observed in the systemic circulation. QWBA Data indicated that the distribution of the acetyl-beta-octaarginine-related radioactivity in the organs and tissues shifted over time. Notably, after 7 d, the highest concentration was measured in the lymph nodes, and the largest amount was found in the liver. A comparison with the results of two previous ADME investigations of beta-peptides (cf. Table 1) reveals that the distribution of the compounds within the animals is structure-dependent, and that there is a full range from oral availability with rather rapid excretion (of a tetrapeptide) to essentially complete lack of both oral absorption and excretion after i.v. administration (of a highly charged octapeptide). A discussion is presented about the in vivo stability and 'drug-ability' of peptides. In general, beta-peptides bearing proteinogenic side chains are compared with peptides consisting entirely of D-alpha-amino acid residues (the enantiomers of the 'natural' building blocks), and suggestions are made regarding a possible focus of future biomedical investigations with beta-peptides.
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