Targeting strategies for cancer radiotherapy

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 (HuCC49ΔCH2), 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-HuCC49ΔCH2 showed a median tumor uptake of 5.5% ID/g which was similar to that of ¹³¹IHuCC49 at 5.2% ID/g. However, the median blood concentration of ¹³¹I-HuCC49ΔCH2 was 0.2% ID/g which was significantly lower than 0.8% ID/g for ¹³¹I-HuCC49. The uptake of the constructs in other normal tissues were similar. The ¹⁷⁷Lu-HuCC49ΔCH2 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-HuCC49ΔCH2 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-HuCC49ΔCH2 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.