An α-particle emitting antibody ([213bi]j591) for radioimmunotherapy of prostate cancer

Michael R. McDevitt, Els Barendswaard, Dangshe Ma, Lawrence Lai, Michael J. Curcio, George Sgouros, Åse M. Ballangrud, Wei Hong Yang, Ronald D. Finn, Virginia Pellegrini, Maurits W. Geerlings, Mona Lee, Martin W. Brechbiel, Neil H. Bander, Carlos Cordon-Cardo, David A. Scheinberg

Research output: Contribution to journalArticle

Abstract

A novel α-particle emitting monoclonal antibody construct targeting the external domain of prostate-specific membrane antigen (PSMA) was prepared and evaluated in vitro and in vivo. The chelating agent, N-[2-amino-3-(p-isothiocyanatophen-yl)propyl]-trans-cyclohexane-1,2-diamine-N, N', N', N'', N''-pentaacetic acid, was appended to J591 monoclonal antibody to stably bind the 213Bi radiometal ion. Bismuth-213 is a short-lived (t(1/2) = 46 min) radionuclide that emits high energy α-particles with an effective range of 0.07-0.10 mm that are ideally suited to treating single-celled neoplasms and micrometastatic carcinomas. The LNCaP prostate cancer cell line had an estimated 180,000 molecules of PSMA per cell; J591 bound to PSMA with a 3-nM affinity. After binding, the radio-labeled construct-antigen complex was rapidly internalized into the cell, carrying the radiometal inside. [213Bi]J591 was specifically cytotoxic to LNCaP. The LD50 value of [213Bi]J591 was 220 nCi/ml at a specific activity of 6.4 Ci/g. The potency and specificity of [213Bi]J591 directed against LNCaP spheroids, an in vitro model for micrometastatic cancer, also was investigated. [213Bi]J591 effectively stopped growth of LNCaP spheroids relative to an equivalent dose of the irrelevant control [213Bi]HuM195 or unlabeled J591. Cytotoxicity experiments in vivo were carried out in an athymic nude mouse model with an i.m. xenograft of LNCaP cells. [213Bi]J591 was able to significantly improve (P < 0.0031) median tumor-free survival (54 days) in these experiments relative to treatment with irrelevant control [213Bi]HuM195 (33 days), or no treatment (31 days). Prostate-specific antigen (PSA) was also specifically reduced in treated animals. At day 51, mean PSA values were 104 ng/ml +/- 54 ng/ml (n = 4, untreated animals), 66 ng/ml +/- 16 ng/ml (n = 6, animals treated with [213Bi]HuM195), and 28 ng/ml +/- 22 ng/ml (n = 6, animals treated with [213Bi]J591). The reduction of PSA levels in mice treated with [213Bi]J591 relative to mice treated with [213Bi]HuM195 and untreated control animals was significant with P < 0.007 and P < 0.0136, respectively. In conclusion, a novel [213Bi]-radiolabeled J591 has been constructed that selectively delivers α-particles to prostate cancer cells for potent and specific killing in vitro and in vivo.

Original languageEnglish (US)
Pages (from-to)6095-6100
Number of pages6
JournalCancer Research
Volume60
Issue number21
StatePublished - Nov 1 2000

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    McDevitt, M. R., Barendswaard, E., Ma, D., Lai, L., Curcio, M. J., Sgouros, G., Ballangrud, Å. M., Yang, W. H., Finn, R. D., Pellegrini, V., Geerlings, M. W., Lee, M., Brechbiel, M. W., Bander, N. H., Cordon-Cardo, C., & Scheinberg, D. A. (2000). An α-particle emitting antibody ([213bi]j591) for radioimmunotherapy of prostate cancer. Cancer Research, 60(21), 6095-6100.