Antibody mass escalation study in patients with castration-resistant prostate cancer using 111In-J591: lesion detectability and dosimetric projections for 90Y radioimmunotherapy.
J591, a monoclonal antibody that targets the external domain of the prostate-specific membrane antigen, has potential as an agent for radioimmunotherapy. A pilot trial was performed in patients with prostate cancer using repetitive administrations of escalating masses of J591. An analysis was performed to assess lesion detectability by (111)In-J591 gamma-camera imaging compared with standard imaging methods and the effect of increasing antibody mass on lesion detectability, biodistribution, and dosimetry.


METHODS
Fourteen patients with metastatic prostate cancer received escalating amounts (10, 25, 50, and 100 mg) of J591 in a series of administrations each separated by 3 wk. All antibody administrations included a fixed amount of the radiolabeled antibody (111)In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-J591 ((111)In-DOTA-J591) (2 mg of J591 labeled with 185 MBq [5 mCi] of (111)In via the chelating agent DOTA). Three whole-body gamma-camera scans with at least 1 SPECT scan together with multiple whole-body counting-rate measurements and serum activity-concentration measurements were obtained in all patients. Images were analyzed for distribution and lesion targeting. Estimates of clearance rates and liver and lesion uptake were made for each treatment cycle. These estimates were used to generate dosimetric projections for radioimmunotherapy with (90)Y-labeled J591.


RESULTS
A total of 80 lesions in 14 patients were detected. Both skeletal and soft-tissue diseases were targeted by the antibody as seen on (111)In-J591 scans. The antibody localized to 93.7% of skeletal lesions detected by conventional imaging. Clearance of radioactivity from the whole body, serum, and liver was dependent on antibody mass. Normalized average values of the ratio of residence times between lesion and liver for 10, 25, 50, and 100 mg of antibody were 1.0, 1.9, 3.2, and 4.0. Dosimetric projections for radioimmunotherapy with (90)Y-labeled J591 suggested similar absorbed doses to lesions for treatment at the maximally tolerated activity (MTA), irrespective of antibody mass. However, absorbed doses to liver at the MTA would be antibody mass-dependent with estimates of 20, 10, 7, and 5 Gy for 10, 25, 50, and 100 mg of J591.


CONCLUSIONS
The proportion of the amount of antibody increased in lesions and decreased in the liver with increasing mass of administered antibody up to a dose of 50 mg. Proportional hepatic uptake continued to decrease with increasing antibody mass up to 100 mg. The optimal antibody mass for radioimmunotherapy would therefore appear to be greater than or equal to 50 mg.
Nuclear Medicine Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. pandit-n@mskcc.org
Neeta
N
Pandit-Taskar
Joseph A
JA
O'Donoghue
Michael J
MJ
Morris
Eze A
EA
Wills
Lawrence H
LH
Schwartz
Mithat
M
Gonen
Howard I
HI
Scher
Steven M
SM
Larson
Chaitanya R
CR
Divgi
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics; D000954:Antigens, Surface / Q000276:immunology*; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000532:radiotherapy / Q000556:secondary; D005240:Feasibility Studies; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006801:Humans; D007205:Indium Radioisotopes / Q000493:pharmacokinetics; D008207:Lymphatic Metastasis; D008297:Male; D009919:Orchiectomy; D010865:Pilot Projects; D017430:Prostate-Specific Antigen / Q000097:blood*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology / Q000532:radiotherapy; D016499:Radioimmunotherapy; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D011879:Radiotherapy Dosage; D015899:Tomography, Emission-Computed, Single-Photon
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D007205:Indium Radioisotopes; C478680:J591 monoclonal antibody; D019275:Radiopharmaceuticals; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II; D017430:Prostate-Specific Antigen