Design and synthesis of metabolically stable chelate-biotin conjugates for pretargeted tumor radioimmunotherapy

Conference · Fri Dec 01 04:00:00 EST 1995

OSTI ID:126656

Gustavson, L M; Su, F M; Reno, J M ^[1]

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1. NeoRx Corporation, Seattle, WA (United States); and others

The use of radiolabeled chelate biotin conjugates for targeting antibody-avidin complexes prelocalized on tumors offers the advantage of delivering the radioactivity on a small molecule which exhibits fast tumor localization and rapid whole body clearance. To maximize efficacy, the radiolabeled biotin conjugate should exhibit high serum stability, rapid renal excretion, and uncompromised avidin binding capacity. we determined that the Y-90 labeled 2-(benzylamidocaproyl-biotin)-tetraatzacyclododecane-N, N`, N``, N```- tetraacetic acid conjugate, DOTA-LC-biotin, incubated in serum for 15 minutes, was 98% degraded to a fragment which no longer binds avidin. The synthesis of standards DOTA-benzylamine and 6- amninocaproamido benzyl-DOTA permitted the identification of the site of cleavage as the biotin carboxylamide. To prevent the enzymatic cleavage of the biotin-amide functionality, we designed four amide stabilized DOTA-biotin analogs. The analogs retained favorable biodistribution and avidin binding and showed excellent serum stability. The design of stable chelate biotin conjugates resulted in improved therapeutic efficacy in mice and a Phase I clinical trial has been initiated with a N-methyl biotinamide stabilized conjugate.

• OSTI ID: 126656
• Report Number(s): CONF-950402--
• Country of Publication: United States
• Language: English

Related Subjects

40 CHEMISTRY
55 BIOLOGY AND MEDICINE
BASIC STUDIES
BIOTIN
EXCRETION
LABELLED COMPOUNDS
LABELLING
MICE
NEOPLASMS
RADIOIMMUNOTHERAPY
SYNTHESIS
YTTRIUM 90