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Title: Radioimmunotherapy with alpha-particle emitting 213Bi-C-functionalized trans-cyclohexyl-diethylenetriaminepentaacetic acid-humanized 3S193 is enhanced by combination with paclitaxel chemotherapy.
Austin Authors: Kelly, Marcus P;Lee, Fook-Thean;Tahtis, Kiki;Smyth, Fiona E;Brechbiel, Martin W;Scott, Andrew M 
Affiliation: Tumour Targeting Program, Ludwig Institute for Cancer Research, Austin Hospital, Heidelberg, Victoria, Australia
Issue Date: 15-Sep-2007
Publication information: Clinical Cancer Research; 13(18 Pt 2): 5604s-5612s
Abstract: 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).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.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.These studies show the potency of alpha-particle radioimmunotherapy and warrant its further exploration in the treatment of micrometastatic disease in Ley-positive malignancies.
Gov't Doc #: 17875796
DOI: 10.1158/1078-0432.CCR-07-1071
Type: Journal Article
Subjects: Alpha Particles
Antibodies, Monoclonal
Antineoplastic Agents, Phytogenic.therapeutic use
Cell Line, Tumor
Combined Modality Therapy
Immunoglobulin Fab Fragments.immunology.therapeutic use
Isothiocyanates.therapeutic use
Lewis Blood-Group System.immunology
Mammary Neoplasms, Experimental.immunology.pathology.therapy
Mice, Inbred BALB C
Mice, Nude
Paclitaxel.therapeutic use
Pentetic Acid.analogs & derivatives.therapeutic use
Survival Rate
Tissue Distribution
Xenograft Model Antitumor Assays
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