An α-particle emitting antibody ([213Bi]J591) for radioimmunotherapy of prostate cancer Journal Article
| Authors: | McDevitt, M. R.; Barendswaard, E.; Ma, D.; Lai, L.; Curcio, M. J.; Sgouros, G.; Ballangrud, A. 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. |
| Article Title: | An α-particle emitting antibody ([213Bi]J591) for radioimmunotherapy of prostate cancer |
| 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. |
| Keywords: | controlled study; unclassified drug; human cell; drug efficacy; nonhuman; prostate specific antigen; mouse; animals; mice; cell death; animal experiment; animal model; antineoplastic activity; drug potency; xenograft model antitumor assays; monoclonal antibody; prostate cancer; prostatic neoplasms; antibodies, monoclonal; kinetics; isotope labeling; nude mouse; mice, nude; substrate specificity; binding sites; radioimmunotherapy; radioisotopes; drug conjugation; alpha radiation; spheroids, cellular; immunotoxins; bismuth; alpha particles; chelating agent; antigen-antibody complex; humans; human; male; priority journal; article; monoclonal antibody j591 bi 213; monoclonal antibody hum195 bi 213; n [2 amino 3 (4 isothiocyanatophen yl)propyl]cyclohexane 1,2 diamine n,n',n',n'',n'' pentaacetic acid |
| Journal Title: | Cancer Research |
| Volume: | 60 |
| Issue: | 21 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2000-11-01 |
| Start Page: | 6095 |
| End Page: | 6100 |
| Language: | English |
| PUBMED: | 11085533 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
Citation Impact
MSK Authors
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146Sgouros -
13
Barendswaard -
5
Lee -
279
Finn -
144Mcdevitt -
21
Ma -
612
Cordon-Cardo -
499Scheinberg -
28Curcio -
19
Yang -
20
Lai
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