Radioimmunotherapy of A431 xenografted mice with pretargeted B3 antibody-streptavidin and (90)Y-labeled 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)-biotin.
We investigated the biodistribution of (88)Y/(111)In-labeled 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA)-biotin and therapy with (90)Y-labeled DOTA-biotin in tumor-bearing mice after B3-streptavidin antibody conjugate (B3-SA) pretargeting. B3 antibody, recognizing Lewis(y) antigen, was conjugated to streptavidin (B3-SA). For pretargeting, 400 micro g of the B3-SA was injected i.v. into mice bearing A431 tumor xenografts. After tumor localization of B3-SA, 100 micro g of synthetic clearing agent was injected i.v. to clear the unbound B3-SA from the circulation. Four h later, 1 micro g of radiolabeled DOTA-biotin was injected i.v. Radioimmunotherapy was performed with doses of 9.25 to 37 MBq of (90)Y-labeled DOTA-biotin. As a result, radiolabeled DOTA-biotin cleared rapidly. All of the normal tissues had <2.6% of the injected dose per gram, whereas tumor uptake reached approximately 15% ID/g. The total tumor uptake of radioactivity remained similar for 96 h or longer. In the first study, the median survival of the control group was 8 days, whereas it increased to >163 days in the 37 MBq (90)Y group (P < 0.005). In a second therapy group, 7 of 10 mice receiving 37 MBq of (90)Y and B3-SA were cured, and remained healthy for >180 days after therapy, compared with control groups, with </=29.2 days mean survival time (P < 0.001). Tumor pretargeting with B3-SA and radiolabeled DOTA-biotin has shown favorable, specific, and fast targeting that has resulted in good tumor responses and, thus, serves as a rationale for human studies with the B3-SA pretargeting approach.
Yao
Zhengsheng
Z
Nuclear Medicine Department of the Warren G. Magnuson Clinical Center, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Zhang
Meili
M
Axworthy
Donald B
DB
Wong
Karen J
KJ
Garmestani
Kayhan
K
Park
Luke
L
Park
Chang W
CW
Mallett
Robert W
RW
Theodore
Louis J
LJ
Yau
Eric K
EK
Waldmann
Thomas A
TA
Brechbiel
Martin W
MW
Paik
Chang H
CH
Pastan
Ira
I
Carrasquillo
Jorge A
JA
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001710:Biotin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy; D004357:Drug Synergism; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007205:Indium Radioisotopes / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D009942:Organometallic Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016499:Radioimmunotherapy / Q000379:methods*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019809:Streptavidin / Q000494:pharmacology*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D015018:Ytterbium / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; C405616:DOTA-biotin; D018796:Immunoconjugates; D007205:Indium Radioisotopes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D001710:Biotin; D019809:Streptavidin; D015018:Ytterbium