Patent ID: 6287536
Filing Date: 2001-09-11
Classification: A61K,B82Y,Y10S

Abstract:
An improved method of increasing active agent localization at a target cell site of mammalian recipient, which method comprises:administering to the recipient a first conjugate comprising a receptor ligand and streptavidin, wherein the receptor ligand binds to a defined target cell population;allowing an amount of time to pass that is sufficient for localization of the first conjugate to the target site; andsubsequently administering to the recipient a second conjugate comprising an active agent and biotin, wherein the second conjugate localizes to target site-localized first conjugate, and wherein the improvement comprises that the second conjugate comprises a biotinidase-resistant biotin-DOTA compound of the following formula: ##STR65##and further wherein a linker L is selected from the group consisting of:1) a D-amino acid-containing linker of the formula: ##STR66##2) a linker of the formula: ##STR67##wherein n ranges from 0-4;3) a linker of the formula: ##STR68##4) a linker of the formula: ##STR69##wherein L.sup.1 is selected from the group consisting of:a) --NH--CO--(CH.sub.2).sub.n --O--, wherein n ranges from 1-5;b) --NH--;c) ##STR70##d) --NH--CS--NH--; ande) --NH--CO--(CH.sub.2).sub.n --NH--, wherein n ranges from 1-5;wherein R.sup.1 is hydrogen; lower alkyl; lower alkyl substituted with one or more hydrophilic groups including (CH.sub.2).sub.m --OH, (CH.sub.2).sub.m --OSO.sub.3, (CH.sub.2).sub.m --SO.sub.3, and ##STR71##where m is 1 or 2;glucuronide-substituted amino acids; or other glucuronide derivatives;R.sup.2 is hydrogen; lower alkyl; substituted lower alkyl having one or more substituents selected from the group consisting of hydroxy, sulfate, and phosphonate, or a hydrophilic moiety;R.sup.3 is hydrogen; an amine; a lower alkyl; a hydroxy-, sulfate- or phosphonate-substituted lower alkyl; a glucuronide; or a glucuronide-derivatized amino acid;R.sup.4 is hydrogen, lower alkyl or ##STR72##wherein n ranges from 0-4;R' is hydrogen; --(CH.sub.2).sub.2 --OH or sulfate or phosphonate derivative thereof; or ##STR73##R"" is a bond --(CH.sub.2).sub.n --CO--NH-- wherein n ranges from 0-5; andwherein R.sup.3 and R.sup.4 cannot both be hydrogen, and wherein the active agent is a radionuclide.