Novel strategies to increase the therapeutic ratio in clinical
radioimmunotherapy studies are needed. Limitations to
radioimmunotherapy include bone marrow suppression due to the long circulating half-life of radiolabeled
monoclonal antibodies (mAbs) and heterogeneous
tumor penetration of the high-molecular-weight mAb. An approach to overcome these problems is the use of genetically engineered mAbs. The engineered mAb discussed in this paper contains a deletion in the constant region of the mAb that increases its
tumor penetration and blood clearance compared with the intact mAb. Radiolabeling of this mAb should lead to a similar radiation-absorbed dose to
tumor compared with the intact mAb, but reduce the radiation absorbed dose to bone marrow. In addition, low or variable expression of
tumor-associated target
antigens or receptors may lead to low or heterogeneous
tumor uptake of radiolabeled mAbs. This report also discusses a novel approach toward systemic
radiotherapy that combines gene transfer techniques (to increase
tumor receptor expression) with radiolabeled
peptides that target the induced receptor. The radiolabeled
peptides achieve good
tumor uptake, rapid
tumor penetration, and rapid blood clearance. A humanized construct of the CC49 (HuCC49) high-affinity anti-TAG-72 mAb, as well as a construct with the CH2 region deleted (HuCC49deltaCH2), were labeled with 131I and 177Lu. Biodistribution of the radiolabeled constructs was evaluated 24 h after regional i.p. injection in athymic nude mice bearing i.p. LS174T human
colon cancer xenografts. The 131I-HuCC49deltaCH2 showed a median
tumor uptake of 5.5% ID/g which was similar to that of 131I-HuCC49 at 5.2% ID/g. However, the median blood concentration of 131I-HuCC49deltaCH2 was 0.2% ID/g which was significantly lower than 0.8% ID/g for 1311-HuCC49. The uptake of the constructs in other normal tissues were similar. The 177Lu-HuCC49deltaCH2 showed a median
tumor uptake of 9.4% ID/g, which was slightly higher than that of 177Lu-HuCC49 at 7.9% ID/g. The median blood concentration of 177Lu-HuCC49deltaCH2 was 0.2% ID/g, which was significantly lower than 0.4% ID/g for 177Lu-HuCC49. The uptake of the antibody constructs in other normal tissues were similar except for the kidney. The
tumor:blood ratios of 177Lu-HuCC49 and 177Lu-HuCC49deltaCH2 were 19.4 and 60.2, respectively, at 24 h after injection. The purpose of the second aspect of the study was to determine the biodistribution of 64Cu-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic
acid (TETA)-
octreotide in a human
ovarian cancer model induced to express human
somatostatin receptor subtype 2 (SSTr2) using gene transfer techniques as a prelude to future
therapy studies. Mice bearing i.p. SKOV3.ip1
tumors transduced with an adenoviral vector encoding the
cDNA for SSTr2 (AdSSTr2) and injected i.p. with
64Cu-TETA-octreotide showed a median uptake of 24.3% ID/g in
tumor at 4 h postinjection compared with 4.9% ID/g at 18 h after injection. Also,
tumor uptake of
64Cu-TETA-octreotide at 4 h was not significantly different when administered either 2 or 4 days after injection of AdSSTr2 (P = 0.076).
64Cu-TETA-octreotide should be useful for
targeted radiotherapy against
tumors that are genetically induced to express high levels of SSTr. These two novel targeting strategies show promise for improved
cancer radioimmunotherapy.