Effects of linker chemistry on the pharmacokinetics of radioimmunoconjugates

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 iu. tumor and a more r apid clearance of radioisotope from normal tissues, six Linker immunoconjug ates were evaluated in studies using nude mice and beagle dogs. All radioim munoconjugates contained a mouse monoclonal IgG (QCI) reactive with human f erritin, Different chemical Linkages mere 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 DS P) mere labile in in vitro and in vivo studies. Indium-111 labeled antiferr itin-containing ITCB or DSS Linker showed high uptake in human hepatoma xen ografts in nude mice. In addition, long blood half-lives and higher normal Liver uptakes were noted. Studies of whole body retention of radioimmunocon jugates showed approximately three-fold faster elimination of radioimmunoco njugates containing a labile linker (EGS), EGS linker is the labile linker with the highest therapeutic ratio: higher tumor uptake, but low normal liv er uptake and a shortened blood half-life of the radioimmunoconjugate. The differences in normal tissue uptake (liver) between EGS and ITCB were confi rmed in beagle dogs. Urine elimination studies and incubation of radioimmun oconjugates in serum or tissue homogenates of tumor, liver or muscle, showe d that enzymes in serum and liver homogenates were able to cleave the labil e Linkers, which led to a more rapid elimination of low molecular weight ra dioactive metabolites in urine. The metabolism of linker radioimmunoconjuga tes in tumor was less effective, The labile linker DSP appears less useful because sulphydryl groups that are generated by cleavage of cause higher up take radioactivity in normal kidney. Biodistribution studies in nude mice w ere confirmed by serial immunoscintigraphy studies on individual mice. The immunoscintigraphy studies are semi-quantitative only, but enable the use o f lower numbers of experimental animals, This is of particular significance in large experimental animals such as beagle dogs. The labile linker appro ach can reduce normal tissue radiation exposure. The study also provides an example of preclinical optimization of radioimmunoconjugates. Continued us e of the appropriate preclinical animal models will accelerate more success ful applications of radioimmunoconjugates in cancer patients.