Alpha-particle emitting atomic generator (Actinium-225)-labeled trastuzumab (herceptin) targeting of breast cancer spheroids: efficacy versus HER2/neu expression.
OBJECTIVE
The humanized monoclonal antibody, trastuzumab (Herceptin), directed against HER2/neu, has been effective in the treatment of breast cancer malignancies. However, clinical activity has depended on HER2/neu expression. Radiolabeled trastuzumab has been considered previously as a potential agent for radioimmunotherapy. The objective of this study was to investigate the efficacy of trastuzumab labeled with the alpha-particle emitting atomic generator, actinium-225 ((225)Ac), against breast cancer spheroids with different HER2/neu expression levels. (225)Ac has a 10-day half-life and a decay scheme yielding four alpha-particles.


METHODS
The breast carcinoma cell lines MCF7, MDA-MB-361 (MDA), and BT-474 (BT) with relative HER2/neu expression (by flow cytometry) of 1:4:18 were used. Spheroids of these cell lines were incubated with different concentrations of (225)Ac-trastuzumab, and spheroid growth was measured by light microscopy over a 50-day period.


RESULTS
The activity concentration required to yield a 50% reduction in spheroid volume at day 35 was 18.1, 1.9, and 0.6 kBq/ml (490, 52, 14 nCi/ml) for MCF7, MDA, and BT spheroids, respectively. MCF7 spheroids continued growing but with a 20-30 day growth delay at 18.5 kBq/ml. MDA spheroid growth was delayed by 30-40 days at 3.7 kBq/ml; at 18.5 kBq/ml, 12 of 12 spheroids disaggregated after 70, days and cells remaining from each spheroid failed to form colonies within 2 weeks of being transferred to adherent dishes. Eight of 10 BT spheroids failed to regrow at 1.85 kBq/ml. All of the BT spheroids at activity concentrations 3.7 kBq/ml failed to regrow and to form colonies. The radiosensitivity of these three lines as spheroids was evaluated as the activity concentration required to reduce the treated to untreated spheroid volume ratio to 0.37, denoted DVR(37). An external beam radiosensitivity of 2 Gy was found for spheroids of all three of the cell lines. After alpha-particle irradiation a DVR(37) of 1.5, 3.0, and 2.0 kBq/ml was determined for MCF7, MDA, and BT, respectively.


CONCLUSIONS
These studies suggest that (225)Ac-labeled trastuzumab may be a potent therapeutic agent against metastatic breast cancer cells exhibiting intermediate to high HER2/neu expression.
Ballangrud
Ase M
AM
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Yang
Wei-Hong
WH
Palm
Stig
S
Enmon
Richard
R
Borchardt
Paul E
PE
Pellegrini
Virginia A
VA
McDevitt
Michael R
MR
Scheinberg
David A
DA
Sgouros
George
G
D000186:Actinium / Q000627:therapeutic use*; D000512:Alpha Particles; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D017248:Enzyme Multiplied Immunoassay Technique; D005434:Flow Cytometry; D006801:Humans; D018613:Microscopy, Confocal; D016499:Radioimmunotherapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis*; D013997:Time Factors; D000068878:Trastuzumab
D000186:Actinium; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab