Evaluation of a new biotin-DOTA conjugate for pretargeted antibody-guided radioimmunotherapy (PAGRIT).
OBJECTIVE
A novel biotin-DOTA conjugate (r-BHD: reduced biotinamidohexylamine-DOTA) was investigated in order to provide an efficient pretargeted antibody-guided radioimmunotherapy (PAGRIT) application. Preclinical and clinical results are described.


METHODS
(90)Y and (177)Lu were used to label r-BHD. The effect of pH and a wide range of specific activities were studied. Radiolabelled r-BHD was tested for affinity towards avidin and for stability in saline or in human serum with and without ascorbic acid. Pharmacokinetic data were collected and organ biodistribution evaluated in a tumour-bearing pretargeted animal model. A pilot study was performed in a metastatic melanoma patient and dosimetry was estimated.


RESULTS
High radiochemical purity (>99%) was routinely achieved with (90)Y or (177)Lu in sodium acetate buffer (1.0 M, pH 5.0) at a specific activity of 2.6 MBq/nmol. Both (90)Y- and (177)Lu-r-BHD were also prepared at higher specific activities. Radiolabelled r-BHD was stable up to 96 h in human serum and saline with the addition of ascorbic acid. The structural modifications proposed for the r-BHD stabilised it against enzymatic degradation while retaining high binding affinity for avidin. Renal clearance appeared to be the main route of excretion in animals, and high tumour uptake was observed in the pretargeted animals. The patient study showed a total body clearance of approximately 85% in 24 h, with a kidney absorbed dose of 1.5 mGy/MBq. Tumour uptake was rapid and the calculated dose to a 10-mm tumour lesion was approximately 12 mGy/MBq.


CONCLUSIONS
These results indicate that the new biotin-DOTA conjugate may be a suitable candidate for pretargeting trials.
Urbano
Nicoletta
N
Division of Nuclear Medicine, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy.
Papi
Stefano
S
Ginanneschi
Mauro
M
De Santis
Rita
R
Pace
Silvia
S
Lindstedt
Ragnar
R
Ferrari
Liliana
L
Choi
Sunju
S
Paganelli
Giovanni
G
Chinol
Marco
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use; D001710:Biotin / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods; D004353:Drug Evaluation, Preclinical; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D016499:Radioimmunotherapy / Q000379:methods; D011868:Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D006573:Heterocyclic Compounds, 1-Ring; D011868:Radioisotopes; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D001710:Biotin