Biostability and pharmacokinetics of LJP 920, an octameric Gal (alpha 1-3)Gal conjugate for the inhibition of xenotransplantation rejection

Antibodies to an alpha -galactosyl saccharide structure present in human se rum are associated with hyperacute rejection and delayed xenograft rejectio n after pig-to-primate xenotransplantation. To overcome this major barrier to the xenotransplantation, LJP 920, a galactosyl alpha1-3 galactose (Gal ( alpha1-3) Gal) coupled to a non-immunogenic platform at a valency of eight Gal (alpha1-3) Gal molecules/platform, was synthesized to clear circulating antibodies and to inhibit their production by B cells that produce these a ntibodies. Herein we report on the stability of UP 920 in biological media and its pharmacokinetic profile. Incubation of UP 920 with mouse serum or l iver microsomes at 37 degreesC for 2 days showed no indication of degradati on of the conjugate as detected by a reversed-phase HPLC method, indicating that the conjugate is not subject to enzymatic metabolism. After intraveno us administration of UP 920 to mice at the doses of 20 and 100 mg kg(-1), U P 920 serum concentration decreased rapidly, showing a biphasic pattern, wi th a distribution half-life of 3 min and an elimination half-life of more t han 30 min, respectively. The serum-to-erythrocyte concentration ratio of U P 920 was 33- and 36-fold excess at 0.5 and 5 min, respectively, after intr avenous administration (100 mg kg(-1)). Both C-max and AUC values increased in a dose-proportional manner. UP 920 displayed a great distribution to we ll-perfused tissues. It was eliminated mainly through renal excretion in th e unchanged form, which accounted for 23 % of the total amount within 8 h o f dosing.