Improved efficacy of α‐particle–targeted radiation therapy

Abstract

BACKGROUND Human epidermal growth factor receptor–2 (HER-2) and tumor-associated glycoprotein 72 (TAG-72) have proven to be excellent molecular targets for cancer imaging and therapy. Trastuzumab, which binds to HER-2, is effective in the treatment of disseminated intraperitoneal disease when labeled with 213Bi or 212Pb. 213Bi-humanized CC49 monoclonal antibody (HuCC49ΔCH2), which binds to TAG-72, inhibits the growth of subcutaneous xenografts. A next logical step to improve therapeutic benefit would be to target tumors with both molecules simultaneously. METHODS Athymic mice bearing intraperitoneal human colon carcinoma xenografts were treated with a combination of trastuzumab and HuCC49ΔCH2 labeled with 213Bi administered through an intraperitoneal route. The sequence of administration also was examined. RESULTS Before combining the 2 monoclonal antibodies, the effective doses of 213Bi-CC49ΔCH2 and 213Bi-trastuzumab for the treatment of peritoneal disease were determined to be 500 μCi for each labeled antibody. Treatment with 213Bi-HuCC49ΔCH2 resulted in a median survival of 45 days and was comparable to the median survival achieved with 213Bi-trastuzumab. Each combination provided greater therapeutic efficacy than either of the agents given alone. However, the greatest therapeutic benefit was achieved when 213Bi-HuCC49ΔCH2 and 213Bi-trastuzumab were coinjected, and a median survival of 147 days was obtained. CONCLUSIONS Dual targeting of 2 distinct molecules in tumors such as TAG-72 and HER-2 with α-particle radiation resulted in an enhanced, additive, therapeutic benefit. The authors also observed that this radioimmunotherapeutic strategy was well tolerated.

Renal uptake of bismuth-213 and its contribution to kidney radiation dose following administration of actinium-225-labeled antibody

“…There is, however, growing interest in the development of therapies using antibodies labeled with α -particle-emitting radionuclides (Miederer et al 2008, Sgouros 2008, Boskovitz et al 2009, Song et al 2009, Milenic et al 2010, McDevitt et al 2001). Alpha particles have a relatively short range in tissue ( < 90 μ m) and a high linear energy transfer (LET), depositing large amounts of energy per unit track length.…”

A Fas Ligand (FasL)-Fused Humanized Antibody Against Tumor-Associated Glycoprotein 72 Selectively Exhibits the Cytotoxic Effect Against Oral Cancer Cells with a Low FasL/Fas Ratio

“…For example, the anti-TAG-72 antibody was used as a radioimmunotherapeutic agent to treat ovarian cancer (37). Moreover, several nanoparticles conjugated with the anti-TAG-72 antibody were also used as targeting agents for radioimmunotherapy and tumor imaging (13, 38). The CC49 mAb recognizes the sialyl-Tn and sialyl-T epitopes, which are disaccharide carbohydrate antigens present on TAG-72.…”

“…The tumor-associated glycoprotein (TAG)-72 is a membrane protein complex of approximately 220–400 kDa (13). It was demonstrated that TAG-72 is overexpressed in a number of human tumors such as colon cancer, ductal breast cancer, lung cancer, epithelial ovarian cancer, hepatocellular carcinoma, and oral cancer, but is not expressed by most normal tissues (14–18).…”

Extension of the in vivo half-life of endostatin and its improved anti-tumor activities upon fusion to a humanized antibody against tumor-associated glycoprotein 72 in a mouse model of human colorectal carcinoma

“…Adenovirus carrying fused CC49, a humanized anti-TAG-72 monoclonal antibody, can transfer a target gene selectively to ovarian carcinoma cells without Coxsackie-adenovirus receptor and significantly decreased adenovirus-mediated toxicity was observed [26]. Moreover, several nanoparticles conjugated with the anti-TAG-72 antibody, as well as a fluorophore-labeled anti-TAG-72 antibody have also been used as targeting agents for radioimmunotherapy and tumor imaging [27–30]. Because TAG-72 is specifically expressed in colon carcinoma tissues, we attempted to target colon carcinoma using 3E8-mEndo in an effort to improve the anti-tumor efficacy of this fusion protein.…”