Improved Efficacy of α-Particle–Targeted Radiation Therapy: Dual Targeting of Human Epidermal Growth Factor Receptor–2 and Tumor-Associated Glycoprotein 72*

Targeted α-particle radiation therapy is proving to be an appropriate therapy for disseminated disease and micrometastatic disease and for the eradication of single, malignant cells, as evidenced by the increasing reports from preclinical and clinical studies.1–5 Improving monoclonal antibody (MoAb) targeting and therapeutic efficacy and reducing toxicity to normal tissues, however, remain objectives for investigators in the field of radioimmunotherapy. The strategies for doing so include 1) the administration of radiosensitizers, 2) combining MoAb monotherapy with radiolabeled MoAb, 3) altering the density of the target molecule, 4) administering multiple doses of the radiolabeled MoAb, and 5) targeting multiple antigens using a “cocktail” of radiolabeled MoAbs.6–16 The rationale for the administration of MoAb mixtures is to overcome the heterogeneous nature of tumors and to deliver what should be a more homogeneous distribution of radiation throughout the tumor if complementary molecules are targeted. Blumenthal et al6 were able to achieve greater therapeutic efficacy targeting carcinoembryonic antigen (CEA) and colon-specific antigen-p (CSAp) with a mixture of 131I-labeled MoAbs specific for these antigens. Patients with metastatic colorectal cancer received a combination of 131I-labeled MoAb against CEA and tumor-associated glycoprotein 72 (TAG-72) as well as α-interferon.11 When these patients were compared with historic controls, it appeared that there was an increase in radiation doses at tumor sites along with an increase in localization intensity as measured by γ-scintigraphy. Unfortunately, the radiation dose delivered to tumor lesions still was insufficient to result in tumor regression. Previous studies from this laboratory have demonstrated the efficacy of high linear energy transfer radiation delivered by MoAb targeting of TAG-72 and human epidermal growth factor–2 (HER-2) to treat colon carcinoma xenografts.3–5 TAG-72 is a mucin-like glycoprotein that is overexpressed on the majority of ovarian, colorectal, gastric, pancreatic, endometrial, nonsmall cell lung, and breast carcinomas.17,18 The genetically engineered MoAb, domain-deleted, humanized CC49 (HuCC49ΔCH2), was effective in either delaying and/or causing tumor regression in a dose-dependent manner of subcutaneous LS-174T xenografts when radiolabeled with 213Bi.4,19 HER-2, a member of the epidermal growth factor receptor family, also is overexpressed in a wide range of carcinomas of epithelial origin, which includes from 25% to 30% of breast and ovarian cancers, from 35% to 45% of pancreatic cancers, and up to 90% of colorectal cancers.20,21 Trastuzumab, a well recognized MoAb that reacts with HER-2, has been highly effective in increasing the survival of athymic mice bearing intraperitoneal LS-174T tumors when radiolabeled with 213Bi or 212Pb.3,5 On the basis of the success in this laboratory with each of these MoAbs used for α-particle–targeted therapy, the next logical step was to evaluate both MoAbs in a dual-targeted radioimmunotherapy regimen with α-emitting radiation. This report presents the results from that study.