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Radioimmunotherapy with -Particle–Emitting ²¹³Bi-C-Functionalized trans-Cyclohexyl-Diethylenetriaminepentaacetic Acid-Humanized 3S193 Is Enhanced by Combination with Paclitaxel Chemotherapy

Authors' Affiliations: ¹ Tumour Targeting Program, Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, Victoria, Australia and ² Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Andrew M. Scott, Tumour Targeting Program, Ludwig Institute for Cancer Research, Austin Hospital, Studley Road, Heidelberg, Victoria 3084, Australia. Phone: 61-3-9496-5876; Fax: 61-3-9496-5892; E-mail: andrew.scott{at}ludwig.edu.au.

Purpose: Previous experience in solid tumor radioimmunotherapy studies has indicated that greatest therapeutic efficacy is achieved in the treatment of small-volume disease. -Particle–emitting radioisotopes possess several physical characteristics ideally suited to the treatment of minimal residual disease. Therefore, we have investigated the efficacy of the -particle–emitting bismuth-213 (²¹³Bi) 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 ²¹³Bi-hu3S193 and apoptosis was assessed using [³H]thymidine incorporation assay and ELISA, respectively. Immunoblotting for -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 µCi (9.2 µg)] injected 2 days after s.c. implantation of MCF-7 cells. Radioimmunotherapy was also combined with a single injection of 300 µg paclitaxel to explore improved efficacy. Further, mice with established tumors received 30, 60, or 120 µCi (14.5 µg) 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 -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 -particle radioimmunotherapy and warrant its further exploration in the treatment of micrometastatic disease in Le^y-positive malignancies.