Delivery of the alpha-emitting radioisotope bismuth-213 to solid tumors via single-chain Fv and diabody molecules.
Intravenously administered anti-tumor single-chain Fv (scFv) and diabody molecules exhibit rapid clearance kinetics and accumulation in tumors that express their cognate antigen. In an attempt to fit the rate of isotope decay to the timing of delivery and duration of tumor retention, anti-HER2/neu CHX-A" DTPA-C6.5K-A scFv and diabody conjugates were labeled with the alpha-particle emitter (213)Bi (t(1/2) = 47 min). Radioimmunotherapy studies employing 0.64, 0.35, or 0.15 microCi of (213)Bi-labeled C6.5K-A diabody or 1.1, 0.6, or 0. 3 microCi of (213)Bi-labeled C6.5K-A scFv were performed in nude mice bearing early, established SK-OV-3 tumors. Only the 0.3 microCi dose of (213)Bi-labeled C6.5K-A scFv resulted in both acceptable toxicity and a reduction in tumor growth rate. The specificity of the anti-tumor effects was determined by comparing the efficacy of treatment with 0.3 and 0.15 microCi doses of (213)Bi-labeled C6.5K-A scFv and (213)Bi-labeled NM3E2 (an irrelevant scFv) in nude mice bearing large established tumors. The 0.3 microCi dose of (213)Bi on both the C6.5K-A and NM3E2 scFvs resulted in similar anti-tumor effects (p = 0.46) indicating that antigen-specific targeting was not a factor. This suggests that the physical half-life of (213)Bi may be too brief to be effectively paired with systemically-administered diabody or scFv molecules.
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA. gp_adams@fccc.edu
G P
GP
Adams
C C
CC
Shaller
L L
LL
Chappell
C
C
Wu
E M
EM
Horak
H H
HH
Simmons
S
S
Litwin
J D
JD
Marks
L M
LM
Weiner
M W
MW
Brechbiel
D000512:Alpha Particles; D000818:Animals; D001729:Bismuth / Q000627:therapeutic use*; D007128:Immunoglobulin Fragments / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000532:radiotherapy*; D016499:Radioimmunotherapy
D007128:Immunoglobulin Fragments; C055966:immunoglobulin Fv; D001729:Bismuth