Pretargeted alpha emitting radioimmunotherapy using (213)Bi 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-biotin.
OBJECTIVE
The use of an alpha emitter for radioimmunotherapy has potential advantages compared with beta emitters. When administered systemically optimal targeting of intact antibodies requires >24 h, therefore limiting the use of short-lived alpha emitters. This study investigated the biodistribution of bismuth-labeled biotin in A431 tumor-bearing mice pretargeted with antibody B3-streptavidin (B3-SA) and examined the therapeutic efficacy of the alpha emitter, (213)Bi-labeled biotin.


METHODS
Biotinidase-resistant 7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)-biotin was radiolabeled with (205,206)Bi or (213)Bi. Treatment of tumor-bearing mice began by administration of B3-SA (400 micro g) to target the tumor sites for 24 h. Then, an agent containing biotin and galactose groups was used to clear the conjugate from the circulation. Four h later, bismuth-radiolabeled DOTA-biotin was given, and biodistribution or therapy was evaluated. Dose escalation treatment from 3.7-74 MBq was performed, and the effects on tumors of different sizes were investigated. Tumor growth, complete blood cell counts, toxicity, and survival were monitored.


RESULTS
Radiolabeled biotin cleared rapidly. Rapid tumor uptake resulted in much higher tumor:nontumor targeting ratios than achieved with the directly labeled monoclonal antibody. Dose escalation revealed that 74 MBq caused acute death of mice, whereas 0.37-37 MBq doses inhibited tumor growth and prolonged survival significantly. Evidence of mild hematological toxicity was noted. At therapeutically effective doses renal toxicity was observed.


CONCLUSIONS
(213)Bi-DOTA-biotin, directed by the Pretarget method to tumor-targeted B3-SA, showed a therapeutic effect, although the therapeutic index was low. The source of the toxicity was most likely related to the renal toxicity.
Yao
Zhengsheng
Z
Department of Nuclear Medicine, Warren G. Magnuson Clinical Center, NIH, Bethesda, Maryland 20892, USA.
Zhang
Meili
M
Garmestani
Kayhan
K
Axworthy
Donald B
DB
Mallett
Robert W
RW
Fritzberg
Alan R
AR
Theodore
Lou J
LJ
Plascjak
Paul S
PS
Eckelman
William C
WC
Waldmann
Thomas A
TA
Pastan
Ira
I
Paik
Chang H
CH
Brechbiel
Martin W
MW
Carrasquillo
Jorge A
JA
D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics; D001710:Biotin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001729:Bismuth / Q000737:chemistry / Q000493:pharmacokinetics; D001853:Bone Marrow / Q000473:pathology / Q000528:radiation effects; D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016499:Radioimmunotherapy / Q000009:adverse effects / Q000379:methods*; D011868:Radioisotopes; D013154:Spleen / Q000473:pathology / Q000528:radiation effects; D016019:Survival Analysis; D013997:Time Factors; D014018:Tissue Distribution; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; C405616:DOTA-biotin; D009942:Organometallic Compounds; D011868:Radioisotopes; D001710:Biotin; D001729:Bismuth