Radioimmunotherapy with α-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 (Bi-213) radioimmunotherapy using the humanized anti-Lewis Y (Le(y)) monoclonal antibody humanized 3S193 (hu3S193). Experimental Design: The intracellular localization of hu3S193 in Le(y)-positive MCF-7 breast carcinoma cells was assessed by confocal microscopy. Cytotoxicity of Bi-213-hu3S193 and apoptosis was assessed using [3 H] thymidine incorporation assay and ELISA, respectively. Immunoblotting for gamma-H2AX assessed DNA strand breaks. In vivo efficacy of Bi-213-hu3S193 was assessed using a minimal residual disease model in BALB/c nude mice, with radioconjugate [15, 30, and 60 mu Ci (9.2 mu g)] injected 2 days after s.c. implantation of MCF-7 cells. Radioimmunotherapy was also combined with a single injection of 300 lug paclitaxel to explore improved efficacy. Further, mice with established tumors received 30, 60, or 120 mu Ci (14.5 mu g) of Bi-213-hu3S193 to assess the effect of tumor volume on treatment efficacy. Results: hu3S193 is internalized via an endosomal and lysosomal trafficking pathway. Treatment with Bi-213-hu3S193 results in >90% cytotoxicity in vitro and induces apoptosis and increased gamma-112AX expression, Bi-213-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 Le(y)-positive malignancies.