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. α-Particle–emitting radioisotopes possess several physical characteristics ideally suited to the treatment of minimal residual disease. Therefore, we have investigated the efficacy of the α-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 γ-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 γ-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 α-particle radioimmunotherapy and warrant its further exploration in the treatment of micrometastatic disease in Ley-positive malignancies.

[1]  M. Zalutsky.  Targeted alpha-particle therapy of microscopic disease: Providing a further rationale for clinical investigation. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[2]  L. Jacobsson,et al.  Alpha-radioimmunotherapy of intraperitoneally growing OVCAR-3 tumors of variable dimensions: Outcome related to measured tumor size and mean absorbed dose. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[3]  A. Scott,et al.  Enhanced efficacy of 90Y-radiolabeled anti-Lewis Y humanized monoclonal antibody hu3S193 and paclitaxel combined-modality radioimmunotherapy in a breast cancer model. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[4]  J. Harper,et al.  Induction and quantification of γ-H2AX foci following low and high LET-irradiation , 2006 .

[5]  M. Brechbiel,et al.  Alpha-particle radioimmunotherapy of disseminated peritoneal disease using a (212)Pb-labeled radioimmunoconjugate targeting HER2. , 2005, Cancer biotherapy & radiopharmaceuticals.

[6]  Yong Li,et al.  Intralesional targeted alpha therapy for metastatic melanoma , 2005, Cancer biology & therapy.

[7]  J. Chatal,et al.  Mechanisms of Cell Sensitization to α Radioimmunotherapy by Doxorubicin or Paclitaxel in Multiple Myeloma Cell Lines , 2005, Clinical Cancer Research.

[8]  M. Schwaiger,et al.  Fractionated Locoregional Low-Dose Radioimmunotherapy Improves Survival in a Mouse Model of Diffuse-Type Gastric Cancer Using a 213Bi-Conjugated Monoclonal Antibody , 2005, Clinical Cancer Research.

[9]  A. Scott,et al.  Treatment of Human Tumor Xenografts with Monoclonal Antibody 806 in Combination with a Prototypical Epidermal Growth Factor Receptor–Specific Antibody Generates Enhanced Antitumor Activity , 2005, Clinical Cancer Research.

[10]  K. Lamborn,et al.  High-Dose Radioimmunotherapy Combined with Fixed, Low-Dose Paclitaxel in Metastatic Prostate and Breast Cancer by Using a MUC-1 Monoclonal Antibody, m170, Linked to Indium-111/Yttrium-90 via a Cathepsin Cleavable Linker with Cyclosporine to Prevent Human Anti-mouse Antibody , 2005, Clinical Cancer Research.

[11]  Robert Jones,et al.  A Phase I Trial of Humanized Monoclonal Antibody A33 in Patients with Colorectal Carcinoma: Biodistribution, Pharmacokinetics, and Quantitative Tumor Uptake , 2005, Clinical Cancer Research.

[12]  O. Couturier,et al.  Cancer radioimmunotherapy with alpha-emitting nuclides , 2005, European Journal of Nuclear Medicine and Molecular Imaging.

[13]  S. Denardo.  Radioimmunodetection and therapy of breast cancer. , 2005, Seminars in nuclear medicine.

[14]  D. Scheinberg,et al.  The promise of targeted {alpha}-particle therapy. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[15]  D. Goldenberg,et al.  Perspectives on cancer therapy with radiolabeled monoclonal antibodies. , 2005, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[16]  D. Scheinberg,et al.  The Promise of Targeted α-Particle Therapy , 2005 .

[17]  P. Smith-Jones.  Radioimmunotherapy of prostate cancer. , 2004, The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of....

[18]  M. Zalutsky,et al.  Radioimmunotherapy with alpha-particle emitting radionuclides. , 2004, The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of....

[19]  M. Brechbiel,et al.  Targeting of HER2 Antigen for the Treatment of Disseminated Peritoneal Disease , 2004, Clinical Cancer Research.

[20]  Yong Li,et al.  Targeted alpha therapy for cancer , 2004, Physics in medicine and biology.

[21]  P. Frost,et al.  Antibody-Targeted Chemotherapy with the Calicheamicin Conjugate hu3S193-N-Acetyl γ Calicheamicin Dimethyl Hydrazide Targets Lewisy and Eliminates Lewisy-Positive Human Carcinoma Cells and Xenografts , 2004, Clinical Cancer Research.

[22]  William C Eckelman,et al.  Pretargeted α Emitting Radioimmunotherapy Using 213Bi 1,4,7,10-Tetraazacyclododecane-N,N′,N″,N‴-Tetraacetic Acid-Biotin , 2004, Clinical Cancer Research.

[23]  Yong Li,et al.  Cytotoxicity of human prostate cancer cell lines in vitro and induction of apoptosis using 213Bi-Herceptin alpha-conjugate. , 2004, Cancer letters.

[24]  B. Sandmaier,et al.  Targeted cancer therapy and immunosuppression using radiolabeled monoclonal antibodies. , 2004, Seminars in oncology.

[25]  M. Ranson,et al.  In Vitro Cytotoxicity of Bismuth-213 (213bi)-Labeled-Plasminogen Activator Inhibitor Type 2 (Alpha-PAI-2) on Human Breast Cancer Cells , 2004, Breast Cancer Research and Treatment.

[26]  M. Brechbiel,et al.  Experimental therapy of disseminated B-Cell lymphoma xenografts with 213Bi-labeled anti-CD74. , 2003, Nuclear medicine and biology.

[27]  D. Scheinberg,et al.  Targeted actinium-225 in vivo generators for therapy of ovarian cancer. , 2003, Cancer research.

[28]  H. Thierens,et al.  In vitro evaluation of 213Bi-rituximab versus external gamma irradiation for the treatment of B-CLL patients: relative biological efficacy with respect to apoptosis induction and chromosomal damage , 2003, European Journal of Nuclear Medicine and Molecular Imaging.

[29]  M. Ranson,et al.  Preclinical studies of targeted α therapy for breast cancer using 213Bi-labelled-plasminogen activator inhibitor type 2 , 2003, British Journal of Cancer.

[30]  J. Humm,et al.  Targeted α particle immunotherapy for myeloid leukemia , 2002 .

[31]  M. Ranson,et al.  213Bi-PAI2 conjugate selectively induces apoptosis in PC3 metastatic prostate cancer cell line and shows anti-cancer activity in a xenograft animal model , 2002, British Journal of Cancer.

[32]  M. J. Mattes,et al.  Radionuclide‐antibody conjugates for single‐cell cytotoxicity , 2002, Cancer.

[33]  N. Bander,et al.  In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen , 2002, Prostate Cancer and Prostatic Diseases.

[34]  T. Waldmann,et al.  Comparative cellular catabolism and retention of astatine-, bismuth-, and lead-radiolabeled internalizing monoclonal antibody. , 2001, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[35]  G. Goozée,et al.  In vitro and preclinical studies of targeted alpha therapy (TAT) for colorectal cancer , 2001, Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland.

[36]  B. Allen,et al.  Preclinical targeted alpha therapy for subcutaneous melanoma , 2001, Melanoma research.

[37]  C. Cordon-Cardo,et al.  An α-Particle Emitting Antibody ([213Bi]J591) for Radioimmunotherapy of Prostate Cancer , 2000 .

[38]  A. Scott,et al.  In vivo biodistribution of a humanized anti-Lewis Y monoclonal antibody (hu3S193) in MCF-7 xenografted BALB/c nude mice. , 2000, Cancer research.

[39]  A. Scott,et al.  Therapeutic efficacy of anti-Lewis(y) humanized 3S193 radioimmunotherapy in a breast cancer model: enhanced activity when combined with taxol chemotherapy. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[40]  H. Choy.  Combining taxanes with radiation for solid tumors , 2000, International journal of cancer.

[41]  A. Scott,et al.  Construction, production, and characterization of humanized anti-Lewis Y monoclonal antibody 3S193 for targeted immunotherapy of solid tumors. , 2000, Cancer research.

[42]  M Bardiès,et al.  Validation of 213Bi-alpha radioimmunotherapy for multiple myeloma. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[43]  A. Fayyazi,et al.  High-linear energy transfer (LET) alpha versus low-LET beta emitters in radioimmunotherapy of solid tumors: therapeutic efficacy and dose-limiting toxicity of 213Bi- versus 90Y-labeled CO17-1A Fab' fragments in a human colonic cancer model. , 1999, Cancer research.

[44]  D. Scheinberg,et al.  An 225Ac/213Bi generator system for therapeutic clinical applications: construction and operation. , 1999, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[45]  R. Bataille,et al.  Validation of 213Bi-o~ Radioimmunotherapy for Multiple Myeloma I , 1999 .

[46]  D. Scheinberg,et al.  Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-CD33 antibodies: pharmacokinetics, bioactivity, toxicity and chemistry. , 1999, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[47]  E. Rogakou,et al.  DNA Double-stranded Breaks Induce Histone H2AX Phosphorylation on Serine 139* , 1998, The Journal of Biological Chemistry.

[48]  I. Pastan,et al.  Stereochemical influence on the stability of radio-metal complexes in vivo. Synthesis and evaluation of the four stereoisomers of 2-(p-nitrobenzyl)-trans-CyDTPA. , 1997, Bioorganic & medicinal chemistry.

[49]  K. Lamborn,et al.  Synergy of Taxol and radioimmunotherapy with yttrium-90-labeled chimeric L6 antibody: efficacy and toxicity in breast cancer xenografts. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[50]  K. Hellström,et al.  Ley specific antibody with potent anti-tumor activity is internalized and degraded in lysosomes. , 1993, The American journal of pathology.

[51]  G. Kampf.  Induction of DNA double-strand breaks by ionizing radiation of different quality and their relevance for cell inactivation. , 1988, Radiobiologia, radiotherapia.