Radioimmunotherapy with -Particle-Emitting 213Bi-C-Functionalized trans-Cyclohexyl-Diethylenetriaminepentaacetic Acid-Humanized 3S193 Is Enhanced by Combination with Paclitaxel Chemotherapy
PURPOSE: Previous experience in solid tumor radioimmunotherapy studies has indicated that greatest therapeutic efficacy is achieved in the treatment of small-volume disease. alpha-Particle-emitting radioisotopes possess several physical characteristics ideally suited to the treatment of minimal residual disease. Therefore, we have investigated the efficacy of the alpha-particle-emitting bismuth-213 (213Bi) radioimmunotherapy using the humanized anti-Lewis Y (Ley) monoclonal antibody humanized 3S193 (hu3S193). EXPERIMENTAL DESIGN: The intracellular localization of hu3S193 in Ley-positive MCF-7 breast carcinoma cells was assessed by confocal microscopy. Cytotoxicity of 213Bi-hu3S193 and apoptosis was assessed using [3H]thymidine incorporation assay and ELISA, respectively. Immunoblotting for gamma-H2AX assessed DNA strand breaks. In vivo efficacy of 213Bi-hu3S193 was assessed using a minimal residual disease model in BALB/c nude mice, with radioconjugate [15, 30, and 60 microCi (9.2 microg)] injected 2 days after s.c. implantation of MCF-7 cells. Radioimmunotherapy was also combined with a single injection of 300 microg paclitaxel to explore improved efficacy. Further, mice with established tumors received 30, 60, or 120 microCi (14.5 microg) of 213Bi-hu3S193 to assess the effect of tumor volume on treatment efficacy. RESULTS: hu3S193 is internalized via an endosomal and lysosomal trafficking pathway. Treatment with 213Bi-hu3S193 results in >90% cytotoxicity in vitro and induces apoptosis and increased gamma-H2AX expression. 213Bi-hu3S193 causes specific and significant retardation of tumor growth even in established tumors, and efficacy was enhanced by paclitaxel to produce defined complete responses. CONCLUSIONS: These studies show the potency of alpha-particle radioimmunotherapy and warrant its further exploration in the treatment of micrometastatic disease in Ley-positive malignancies.