Vascular targeted therapy with anti-prostate-specific membrane antigen monoclonal antibody J591 in advanced solid tumors.
OBJECTIVE
Based on prostate-specific membrane antigen (PSMA) expression on the vasculature of solid tumors, we performed a phase I trial of antibody J591, targeting the extracellular domain of PSMA, in patients with advanced solid tumor malignancies. This was a proof-of-principle evaluation of PSMA as a potential neovascular target. The primary end points were targeting,toxicity, maximum-tolerated dose, pharmacokinetics (PK), and human antihuman antibody (HAHA) response.


METHODS
Patients had advanced solid tumors previously shown to express PSMA on the neovasculature. They received 111Indium (111ln)-J591 for scintigraphy and PK, followed 2 weeks later by J591 with a reduced amount of 111In for additional PK measurements. J591 dose levels were 5, 10, 20, 40, and 80 mg. The protocol was amended for six weekly administrations of unchelated J591. Patients with a response or stable disease were eligible for re-treatment. Immunohistochemistry assessed PSMA expression in tumor tissues.


RESULTS
Twenty-seven patients received monoclonal antibody (mAb) J591. Treatment was well tolerated. Twenty (74%) of 27 patients had at least one area of known metastatic disease targeted by 111In-J591, with positive imaging seen in patients with kidney, bladder, lung, breast, colorectal, and pancreatic cancers, and melanoma. Seven of 10 patient specimens available for immunohistochemical assessment of PSMA expression in tumor-associated vasculature demonstrated PSMA staining. No HAHA response was seen. Three patients of 27 with stable disease received re-treatment.


CONCLUSIONS
Acceptable toxicity and excellent targeting of known sites of metastases were demonstrated in patients with multiple solid tumor types, highlighting a potential role for the anti-PSMA antibody J591 as a vascular-targeting agent.
Milowsky
Matthew I
MI
Division of Hematology and Medical Oncology, Department of Medicine, Weill Medical College of Cornell University, New York 10021, USA.
Nanus
David M
DM
Kostakoglu
Lale
L
Sheehan
Christine E
CE
Vallabhajosula
Shankar
S
Goldsmith
Stanley J
SJ
Ross
Jeffrey S
JS
Bander
Neil H
NH
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology*; D000954:Antigens, Surface / Q000276:immunology*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D005260:Female; D043425:Glutamate Carboxypeptidase II / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D009519:New York City; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D013997:Time Factors; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D000970:Antineoplastic Agents; C478680:J591 monoclonal antibody; D019275:Radiopharmaceuticals; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II