An alpha-particle emitting antibody ([213Bi]J591) for radioimmunotherapy of prostate cancer.
A novel alpha-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 alpha-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 radiolabeled 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 alpha-particles to prostate cancer cells for potent and specific killing in vitro and in vivo.
McDevitt
M R
MR
Department of Pharmacology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Barendswaard
E
E
Ma
D
D
Lai
L
L
Curcio
M J
MJ
Sgouros
G
G
Ballangrud
A M
AM
Yang
W H
WH
Finn
R D
RD
Pellegrini
V
V
Geerlings
M W
MW
Lee
M
M
Brechbiel
M W
MW
Bander
N H
NH
Cordon-Cardo
C
C
Scheinberg
D A
DA
D000512:Alpha Particles / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001665:Binding Sites; D001729:Bismuth / Q000494:pharmacology*; D016923:Cell Death / Q000528:radiation effects; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy*; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000528:radiation effects; D013379:Substrate Specificity; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D000922:Immunotoxins; D011868:Radioisotopes; D001729:Bismuth