Lee Jia, Matthew D. Linnik, Richard M. Jack and Lin Yu

La Jolla Pharmaceutical Company, 6455 Nancy Ridge Drive, San Diego, CA 92121, USA

Antibodies to an a-galactosyl saccharide structure present in human serum are associated with hyperacute rejection and delayed xenograft rejection after pig-to-primate xenotransplantation. To overcome this major barrier to the xenotransplantation, LJP 920, a galactosyl a1-3 galactose (Gal (a1-3) Gal) coupled to a non-immunogenic platform at a valency of eight Gal (a1-3) Gal molecules/platform, was synthesized to clear circulating antibodies and to inhibit their production by B cells that produce these antibodies. Herein we report on the stability of LJP 920 in biological media and its pharmacokinetic profile. Incubation of LJP 920 with mouse serum or liver microsomes at 37°C for 2 days showed no indication of degradation of the conjugate as detected by a reversed-phase HPLC method, indicating that the conjugate is not subject to enzymatic metabolism. After intravenous administration of LJP 920 to mice at the doses of 20 and 100 mg kg-1, LJP 920 serum concentration decreased rapidly, showing a biphasic pattern, with a distribution half-life of 3 min and an elimination half-life of more than 30 min, respectively. The serum-to-erythrocyte concentration ratio of LJP 920 was 33- and 36-fold excess at 0.5 and 5 min, respectively, after intravenous administration (100 mg kg-1). Both Cmax and AUC values increased in a dose-proportional manner. LJP 920 displayed a great distribution to well-perfused tissues. It was eliminated mainly through renal excretion in the unchanged form, which accounted for 23% of the total amount within 8 h of dosing.

Published in Journal of Pharmacy and Pharmacology
53 (2001) 999-1005.