Radiolabeled
monoclonal antibodies reactive with
tumor-associated
antigens can selectively deliver cytotoxic or diagnostic
isotopes to malignant cells in vivo. To achieve maximum retention of radiolabel in
tumor and a more rapid clearance of
radioisotope from normal tissues, six linker
immunoconjugates were evaluated in studies using nude mice and beagle dogs. All
radioimmunoconjugates contained a mouse monoclonal
IgG (QCI) reactive with human
ferritin. Different chemical linkages were inserted between
immunoglobulins and the radiolabeled chelate (
DTPA). Three linkers (ITCB, DSS and
BSOCOES) were stable in in vitro and in vivo studies. Three linkers (EGS, DST and DSP) were labile in in vitro and in vivo studies.
Indium-111 labeled antiferritin-containing ITCB or DSS linker showed high uptake in human
hepatoma xenografts in nude mice. In addition, long blood half-lives and higher normal liver uptakes were noted. Studies of whole body retention of
radioimmunoconjugates showed approximately three-fold faster elimination of
radioimmunoconjugates containing a labile linker (EGS). EGS linker is the labile linker with the highest therapeutic ratio: higher
tumor uptake, but low normal liver uptake and a shortened blood half-life of the
radioimmunoconjugate. The differences in normal tissue uptake (liver) between EGS and ITCB were confirmed in beagle dogs. Urine elimination studies and incubation or
radioimmunoconjugates in serum or tissue homogenates of
tumor, liver or muscle, showed that
enzymes in serum and liver homogenates were able to cleave the labile linkers, which led to a more rapid elimination of low molecular weight radioactive metabolites in urine. The metabolism of linker
radioimmunoconjugates in
tumor was less effective. The labile linker DSP appears less useful because sulphydryl groups that are generated by cleavage of cause higher uptake radioactivity in normal kidney. Biodistribution studies in nude mice were confirmed by serial immunoscintigraphy studies on individual mice. The immunoscintigraphy studies are semi-quantitative only, but enable the use of lower numbers of experimental animals. This is of particular significance in large experimental animals such as beagle dogs. The labile linker approach can reduce normal tissue radiation exposure. The study also provides an example of preclinical optimization of
radioimmunoconjugates. Continued use of the appropriate preclinical animal models will accelerate more successful applications of
radioimmunoconjugates in
cancer patients.