Response of LNCaP spheroids after treatment with an alpha-particle emitter (213Bi)-labeled anti-prostate-specific membrane antigen antibody (J591).
A theoretical drawback to alpha-particle therapy with 213Bi is the short range of the particle track coupled with the short half-life of the radionuclide, thereby potentially limiting effective cytotoxicity to rapidly accessible, disseminated individual tumor cells (e.g., as in leukemia). In this work, a prostate carcinoma spheroid model was used to evaluate the feasibility of targeting micrometastatic clusters of tumor cells using 213Bi-labeled anti-prostate-specific membrane antigen (PSMA) antibody, J591. In prostate cancer, vascular dissemination of tumor cells or tumor cell clusters to the marrow constitutes an important step in the progression of this disease to widespread skeletal involvement, an incurable state. Such prevascularized clusters are ideal targets for radiolabeled antibodies because the barriers to antibody penetration that are associated with the capillary basal lamina have not yet formed. Beta- and gamma-emitting radionuclides such as 131I, which are widely used in radioimmunotherapy, are not expected to be effective when targeting single cells or small cell clusters. This is because the range of the emissions is one to two orders of magnitude greater than the target size, and the energy deposited per traversal is insufficient to produce any significant radiobiological effect. Spheroids of the prostate cancer cell line, LNCaP-LN3, were used as a model of prevascularized micrometastases; their response to an anti-PSMA antibody, J591, radiolabeled with the alpha-particle emitter 213Bi (T(1/2), 45.6 min.) has been measured. The time course of spheroid volume reductions was found to be sensitive to the initial spheroid volume. J591 labeled with 0.9 MBq/ml 213Bi resulted in a 3-log reduction in spheroid volume on day 33, relative to control, for spheroids with an initial diameter of 130 microm; 1.8 MBq/ml were required to achieve a similar response for spheroids with an initial diameter of 180 microm. Equivalent spheroid responses were observed after 12 Gy of acute external beam photon irradiation. Monte Carlo-based microdosimetric analyses of the 213Bi decay distribution in individual spheroids of 130-microm diameter yielded an average alpha-particle dose of 3.7 Gy to the spheroids, resulting in a relative biological effectiveness factor of 3.2 over photon irradiation. The activity concentrations used in the experiments were clinically relevant, and this work supports the possibility of using 213Bi-labeled antibodies not only for disseminated single tumor cells, as found in patients with leukemia, but also for micrometastatic tumor deposits up to 180 microm in diameter (1200 cells).
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
A M
AM
Ballangrud
W H
WH
Yang
D E
DE
Charlton
M R
MR
McDevitt
K A
KA
Hamacher
K S
KS
Panageas
D
D
Ma
N H
NH
Bander
D A
DA
Scheinberg
G
G
Sgouros
D000512:Alpha Particles / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D000954:Antigens, Surface; D001729:Bismuth / Q000494:pharmacology*; D002268:Carboxypeptidases / Q000276:immunology*; D002455:Cell Division / Q000528:radiation effects; D043425:Glutamate Carboxypeptidase II; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000276:immunology / Q000532:radiotherapy*; D016499:Radioimmunotherapy; D011868:Radioisotopes / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000276:immunology / Q000528:radiation effects; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D000922:Immunotoxins; D011868:Radioisotopes; D002268:Carboxypeptidases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D001729:Bismuth