Phase I Evaluation ofJ 591 as a Vascular Targeting Agent in Progressive SolidTumors

The antibodyJ591targets the external domain of prostate-specific membrane antigen, which is expressed in the neovasculature of nonprostate solid tumors.This phase I trial tested the hypothesis thatJ591could be used as a vascular targeting platform for patients with nonprostate solid tumors.  Patients with progressive solid tumors were eligible. Twenty patients, divided into six dosage cohorts of 3 to 6 patients each, were treated every 3weeks to amaximum of four doses using either 5, 10, 20, 40, 60, or 100 mg of J591antibody. Two milligrams of antibody were labeled with10 mCi of indium-111. Patientswith awide variety of solid tumorswere tested; all hadgood tumor localization. No dose-limiting toxicities were observed. The serum clearance rate decreased with increasing antibody mass, likely a result of early hepatic uptake of antibody. Half-life for each successive cohort was 0.71, 0.84, 1.86, 1.83, 3.32, and 3.56 days. Hepatic saturation seemed to occur by 60 mg. Seventeen of 18 (94%) patients with soft tissue disease on standard scans showed uptake in the soft tissues on antibody scans as did 6 of 6 patients with bone disease.  The tumoral neovasculature of a variety of solid tumors can be selectively and safely targeted using J591. In planning for future studies using J591as a radiation delivery platform, an antibody mass of 60 mg should be considered, as it would seem to minimize the radiation delivered to the liver while minimizing the radiation dose to bone. Prostate-specific membrane antigen (PSMA) is a 100-kDa transmembrane glycoprotein found in a variety of normal human tissues, such as prostate epithelium, the central nervous system, and the proximal gastrointestinal tract (1–3). To date, PSMA has primarily been used to treat and image prostate cancer. For imaging, it is the basis of the ProstaScint scan, a Food and Drug Administration–approved study for detecting nodal metastases (4). For therapy, it is the target of unlabeled, radiolabeled, and chemoconjugated antibodies (5–7). PSMA is also expressed in the neovascular endothelium of most solid tumors, including lung, colon, breast, renal, transitional cell, and pancreas cancers. It is not expressed in normal vasculature (8, 9). Preclinical data suggest that PSMA may be a key regulator of angiogenic activity, and PSMA-null animals have severely impaired angiogenesis (10). As such, it is a promising means of selectively targeting neoplastic tissue in patients who have nonprostate solid tumors. J591 (MLN591; Millennium Pharmaceuticals) is a monoclonal IgG1 molecule that targets the external domain of PSMA (11), modified to reduce its immunogenicity by replacing individual amino acid sequences in the antibody variable domains (DeImmunisation, Biovation Ltd.). Previous studies have shown that J591 localizes to metastatic prostate cancer, stimulates antibody-dependent cellular cytotoxicity, and induces PSA declines (5). Phase I studies have also shown that J591 conjugated to indium-111 (In), yttrium-90, and lutetium177 is safe, targets prostate cancer metastases to bone and soft tissues, and, when labeled with therapeutic radiation doses, can induce biochemical and objective responses (6, 12). In the current phase I trial, we sought to establish the feasibility of targeting the neovasculature of nonprostate solid tumors using a PSMA-directed monoclonal antibody and to define the relationship between antibody mass, biodistribution, pharmacokinetics, and toxicity.