Vascular-targeted radioimmunotherapy with the alpha-particle emitter 211At.
Astatine-211, an alpha-particle emitter, was employed in a model system for vascular-targeted radioimmunotherapy of small tumors in mouse lung to compare its performance relative to other radioisotopes in the same system. Astatine-211 was coupled to the lung blood vessel-targeting monoclonal antibody 201B with N-succinimidyl N-(4-[211At]astatophenethyl) succinamate linker. Biodistribution data showed that the conjugate delivered 211At to the lung (260-418% ID/g), where it remained with a biological half-time of about 30 h. BALB/c mice bearing about 100 lung tumor colonies of EMT-6 cells, each about 2000 cells in size, were treated with 211At-labeled monoclonal antibody 201B. The administered activity of 185 kBq per animal extended the life span of treated mice over untreated controls. Injections of 370 kBq, corresponding to an absorbed dose of 25-40 Gy, were necessary to eradicate all of the lung tumors. Mice receiving 740 kBq of 211At-labeled monoclonal antibody 201B developed pulmonary fibrosis 3-4 months after treatment, as did mice treated with 3700 kBq of the alpha-particle emitter 213Bi-labeled monoclonal antibody 201B in previous work. Animals that were injected with 211At bound to untargeted IgG or to glycine, as control agents, also demonstrated therapeutic effects relative to untreated controls. Control groups that received untargeted 211At required about twice as much administered activity for effective therapy as did groups with lung-targeted radioisotope. These results were not consistent with radioisotope biodistribution and dosimetry calculations that indicated that lung-targeted 211At should be at least 10-fold more efficient for lung colony therapy than 211At bound to nontargeting controls. The data showed that 211At is useful for vascular-targeted radioimmunotherapy because lung tumor colonies were eradicated in the mice. Work in this model system demonstrates that vascular targeting of alpha-particle emitters is an efficient therapy for small perivascular tumors and may be applicable to human disease when specific targeting agents are identified.
Kennel
S J
SJ
Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, USA. SJ9@ornl.gov
Mirzadeh
S
S
Eckelman
W C
WC
Waldmann
T A
TA
Garmestani
K
K
Yordanov
A T
AT
Stabin
M G
MG
Brechbiel
M W
MW
D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D001246:Astatine / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004307:Dose-Response Relationship, Radiation; D005355:Fibrosis / Q000532:radiotherapy; D008175:Lung Neoplasms / Q000098:blood supply* / Q000532:radiotherapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D009928:Organ Specificity; D011836:Radiation Tolerance; D016499:Radioimmunotherapy / Q000379:methods*; D011868:Radioisotopes / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D012995:Solubility; D015996:Survival Rate; D013997:Time Factors
D011868:Radioisotopes; D001246:Astatine