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Journal of Clinical Oncology, Vol 25, No 5 (February 10), 2007: pp. 540-547 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.07.8097 Vascular Targeted Therapy With Anti–Prostate-Specific Membrane Antigen Monoclonal Antibody J591 in Advanced Solid Tumors
From the Division of Hematology and Medical Oncology, Department of Medicine, Division of Nuclear Medicine, Department of Radiology, Department of Urology, Weill Medical College of Cornell University, New York; and Department of Pathology and Laboratory Medicine, Albany Medical Center, Albany, NY Address reprint requests to Neil H. Bander, MD, Weill Medical College of Cornell University, 525 E 68th St, PO Box 23, New York, NY 10021; e-mail: nhbander{at}med.cornell.edu
Purpose: 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. Patients and 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. Conclusion: 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.
Both antibodies and small molecules that interfere with the signaling of vascular endothelial growth factor have validated the therapeutic benefit of antiangiogenic agents in cancer.1-4 An alternative to approaches that interfere with the basic angiogenic processes that occur in both normal and cancerous tissues is the targeted destruction of established tumor vasculature using vascular-targeting agents (VTAs).5,6 In large experimental tumors, VTAs are more active as they target vessels in the tumor interior, unlike chemotherapy and antiangiogenic therapy, which are most effective against the well-oxygenated tumor periphery and sites of new vessel development.5 While VTAs have demonstrated activity in animals, the approach awaits validation in humans. Ideally, validation of VTAs would require initial demonstration of in vivo targeting of a neovascular-restricted target, followed by a demonstration of the destruction of tumor endothelium. The latter could occur using a naked antibody or by targeted delivery of a radioisotope or cytotoxin. Prostate-specific membrane antigen (PSMA; folate hydrolase 1, glutamate carboxypeptidaase II) is a type II membrane protein first characterized in prostate cancer.7-11 Subsequently, PSMA was found to be expressed by the neovascular endothelium of virtually all solid tumor types without expression by the tumor cells or normal vascular endothelium.10,12-14 PSMA is qualitatively distinct from other neovascular targets, such as vascular endothelial growth factor, endoglin, or the integrins that are involved in the general process of angiogenesis and are not specific to tumor vasculature. PSMA expression has not been reported in normal vasculature and represents the only qualitatively specific neovascular target currently known. This specificity makes PSMA an ideal target for the delivery of a cytotoxic agent designed to destroy tumor vasculature. The development of antibodies to the extracellular domain of PSMA (PSMAext) led to the clinical study of one anti-PSMAext monoclonal antibody (mAb) J591.12 Two phase I trials using radiolabeled mAb J591 in patients with advanced prostate cancer demonstrated acceptable toxicity, excellent targeting of known sites of prostate cancer metastases, and biologic activity.15,16 The current study using 111Indium (111In) labeled mAb J591 as a VTA is the first to examine PSMA as a neovascular target in humans.
Eligibility Those patients eligible for enrollment had advanced solid tumors refractory to conventional therapy, with a tumor type previously shown to express PSMA on the neovasculature,13 measurable or assessable metastatic disease, Karnofsky performance status  60%, absolute neutrophil count 1.5x 109/L, platelet count 100 x 109/L, serum creatinine of < 2.0 mg/dL, serum AST of < 2.0x the upper limit of normal, and serum total bilirubin of < 1.5x the upper limit of normal. Those with active serious infections or significant cardiac, respiratory, CNS, renal, hepatic, or hematologic dysfunction were excluded, as were patients receiving chemotherapy or radiation within 4 weeks of therapy. The institutional review board of Weill Medical College of Cornell University (New York, NY) approved the protocol, and written informed consent was obtained before enrollment.
Trial Design
Study Drug, Dosing Schedule, and Assessment The total dose of deimmunized mAb J591 was escalated in cohorts of three patients at dose levels 5, 10, 20, 40, and 80 mg. On day 1, patients received 5 mCi of 111In-J591 (1 to 2 mg) mixed with a mass of unchelated J591 to reach the total administered dose of antibody as an intravenous infusion at 5 mg per minute. The same dose was repeated two weeks later using a reduced amount of 111In (< 500 mCi) for additional pharmacokinetic (PK) studies. After nine patients, the protocol was amended for patients to receive the initial dose of 111In-J591 followed by weekly administration of unchelated mAb J591 for a total of 6 consecutive weeks with pharmacokinetics (PK) performed during weeks 1 and 5 or 6. Patients were followed for a minimum of 8 weeks after 111In-J591 or until progression. Patients without progression were eligible for re-treatment, using the same dose and schedule, at the discretion of the principal investigator (D.M.N.). Re-treatment required that patients satisfy all of the initial eligibility and exclusion criteria and be human antihuman antibody (HAHA) -negative. Based on three of the four initial patients experiencing infusion-related reactions, an in-line filter was used to administer the mAb J591, and all subsequent patients received premedication with intravenous diphenhydramine (50 mg) and oral acetaminophen (650 mg). Patients were treated in the New York-Presbyterian Hospital General Clinical Research Center (New York, NY). Tumor response was assessed using modified WHO criteria.17 Routine laboratory and clinical assessments, including evaluation of appetite, pain, and analgesic intake, were performed post-treatment weeks 1, 2, 4, 8, and every 8 weeks thereafter until disease progression. A chest x-ray, computed tomography scan, or magnetic resonance imaging (MRI) of the chest, abdomen, pelvis, and bone scan were performed post-treatment week 8.
PK and Biodistribution
HAHA
Immunohistochemistry
Patient Characteristics Twenty-seven patients with advanced solid tumor malignancies were enrolled onto the study between March 2001 and June 2003 (Table 1; Table A1, online only). The initial nine patients received two doses, and the subsequent 18 patients received six weekly doses. The median age was 63 years, with 10 women and 17 men. Tumor types included kidney (10 patients), colorectal (four patients), lung (three patients), bladder (three patients), pancreas (three patients), breast (three patients), and melanoma (one patient).
Safety Table 2 summarizes toxicity. The most common adverse events were disease-related fatigue, pain, anemia, and mild liver function test abnormalities. Table A1 summarizes dose-limiting toxicities at all dose levels. Six patients experienced infusion-related reactions. The initial patient at the 10-mg dose level experienced a grade 3 infusion reaction and did not receive a second dose. The protocol was amended to premedicate all patients. An additional five patients were treated at the 10-mg dose level without significant toxicity. At the 80-mg dose level, one patient experienced grade 3 hypertension and received only one of the planned six doses, one patient received two of the planned six doses due to progression of disease, and one patient missed dose three of six due to an episode of vasovagal syncope. One patient developed a mediport infection unrelated to treatment.
Radiolabeled J591 and PK and Biodistribution The radiochemical purity of 111In-J591was 99.0% ± 1.83%, and the specific activity was 3.23 ± 0.96 mCi/mg. The immunoreactivity based on an in vitro assay using PSMA-positive LNCaP cells was 87.1% ± 8.3%. Each patient was treated with 5 mCi (5.01 ± 1.8) of sterile, pyrogen-free 111In-J591 in 20 mL of physiologic saline solution. The rate of clearance from plasma was very dependent on the total mass of J591 antibody administered. Monoexponential plasma clearance rates (hours) after administering mAb 111In-J591 were 12.6 ± 9.8 at 5 mg, 23.1 ± 6.0 at 10 mg, 38.4 ± 9.3 at 20 mg, 60.5 ± 17.2 at 40 mg, and 86.4 ± 13.5 at 80 mg. The biodistribution of 111In-J591 was studied based on the whole body gamma camera images obtained during a period of 6 to 7 days. Within 24 hours postinjection, radioactivity was predominantly in the blood pool as seen by the increased activity in heart and major blood vessels compared with uptake of the radioactivity by the organs. Subsequently, there was a decrease in blood-pool activity, with a gradual accumulation of activity in the liver, spleen, kidneys, and bone or bone marrow. Liver is the major organ accumulating the highest amount of radioactivity, and the percentage of injected dose accumulated in liver had an inverse relationship to the mass of J591 antibody administered. At 7 days, the uptake in liver was significantly higher with 5 mg of J591 mAb (40% ± 12%) compared with 80 mg of mAb J591 (15% ± 2%).
J591 Vascular Targeting
Formation of HAHA No HAHA response was seen. In patients who received multiple doses, there was no HAHA detected and no change in drug clearance or targeting.
Antitumor Activity
PSMA Expression in Tumor Samples
This trial is the first successful demonstration of specific targeting of tumor neovasculature in humans. It represents proof-of-principle confirmation of the ability to direct a ligand to a neovascular-specific target such as PSMA. The current study demonstrates that mAb J591 specifically targets PSMA on the vascular endothelium of metastases in patients with multiple solid tumor types and with minimal toxicity. Moreover, it confirms that PSMA is a valid target for VTA therapy. The adverse events seen were predominantly cancer related, with the exception of six patients who experienced infusion-related reactions. Although infusion reactions are commonly seen with mAbs, it is interesting to note that only three (5%) of 64 patients experienced grade 1 infusion reactions on the mAb J591-related prostate cancer trials at similar doses.15,16 Like the prior prostate cancer trials, no patient on the current trial developed a HAHA response. One may speculate that in the case of mAb J591—an immunoglobulin G1 that is known to induce antibody-dependent cellular cytotoxicity—the antibody-mediated, cytokine-release syndrome may be more pronounced when targeting endothelial cells with the resulting release of cytokines than when targeting prostate cancer cells. Infusion reactions were managed effectively using diphenhydramine and acetaminophen, and premedication will be included in subsequent studies. Targeting of at least one known site of metastases was seen in six (100%) of six patients at 40 mg and three (50%) of six patients at 80 mg. As only minimal toxicity was seen at all dose levels, the trial did not establish a formal maximum tolerated dose, however, based on the neovascular targeting data, a J591 dose of 40 mg should be considered for future trials. We suspect that the apparent decrease in imaging efficiency at the 80-mg dose reflects the competition from a 40-fold excess of unlabeled antibody. Consistent with our findings in prostate cancer trials, the plasma clearance and liver uptake of 111In-J591 was very dependent on the total mass of J591 antibody administered. With higher antibody mass, the plasma clearance rate is decreased with a substantial relative reduction in the nonspecific uptake by the liver. As a result, more of the antibody is potentially available for targeting PSMA on the vascular endothelium. PSMA is not the only target available for VTAs.20 Unlike other neovascular targets currently being explored—such as endoglin and the integrins that are quantitatively upregulated in neovasculature but present in normal vasculature—PSMA expression in the neovasculature is qualitatively unique. While PSMA is expressed in some normal tissues—such as prostatic glands, renal proximal tubules, small bowel, and brain—its expression in these tissues is on the luminal surface, beyond the epithelial tight junctions and the blood-brain barrier, and is not accessible to the circulating antibody. Imaging studies in well more than 100 prostate and nonprostate cancer patients confirm a lack of targeting these normal sites. Although none of these patients was selected by screening for PSMA expression, targeting of known sites of metastatic disease with mAb J591 was seen in the majority of patients, including those with kidney, colorectal, lung, bladder, pancreas, and breast cancers, and melanoma. With regard to sites of imaging, 13 of 18 patients with pulmonary involvement and eight (57%) of 14 patients with lymph node involvement had lung and lymph nodes targeted by mAb J591, respectively. Only one (12.5%) of eight assessable patients with bone involvement on conventional imaging demonstrated mAb J591 targeting. Another interesting distinction between targeting prostate cancer and tumor vascular endothelium is that, in the latter case, optimal imaging occurred on day 2, whereas in prostate cancer, imaging was best between days 5 and 7. This likely reflects more rapid tumor localization in the case where the target antigen is in direct contact with the circulation. The greater rapidity of localization may allow for further imaging optimization by the use of antibody fragments or constructs of lower molecular weight than whole immunoglobulin as well as different imaging agents such as Technicium99m. It has become apparent when using novel therapies targeting tumor blood supply that standard clinical trial end points require modification.21 This was clearly demonstrated in the phase II study of bevacizumab in metastatic renal cancer, which revealed a significant prolongation in time to progression yet only a 10% objective-response rate.1 Consistent with this observation, in the current phase I study, no objective tumor regressions were seen; however, several patients experienced signs consistent with biologic activity. Two patients at the 10-mg dose level had stable disease, and one patient with metastatic colon cancer had a 53% decline in carcinoembryonic antigen, carboxylesterase. Future trials evaluating VTAs, including the anti-PSMA mAb J591, should incorporate appropriate end points and newer ways to monitor response, including novel imaging modalities such as functional computed tomography, dynamic-contrast–enhanced MRI, positron emission tomography, as well as other surrogate markers. In summary, VTAs represent a promising therapeutic approach to the management of solid tumor malignancies, with the anti-PSMA mAb J591 demonstrating excellent targeting of metastatic sites in multiple advanced solid tumors without significant toxicity. Although excellent targeting was demonstrated at the 40-mg dose level with minimal toxicity, future trials should further evaluate the dose and schedule using mAb J591 as a naked antibody alone or in combination with chemotherapy and as a targeted delivery system for a cytotoxic agent or radioisotope. In addition, these trials should explore the use of PSMA immunohistochemistry and/or imaging as a basis for patient selection for therapy and the use of appropriate end points for vascular targeting therapies.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Jeffrey S. Ross, Millennium Pharmaceutical, Inc; Neil H. Bander, BZL Biologics Inc Stock: Neil H. Bander, BZL Biologics Inc Honoraria: N/A Research Funds: Jeffrey S. Ross, Millennium Pharmaceutical, Inc Testimony: N/A Other: N/A
Conception and design: Matthew I. Milowsky, David M. Nanus, Neil H. Bander Provision of study materials or patients: Matthew I. Milowsky, David M. Nanus, Lale Kostakoglu, Shankar Vallabhajosula, Stanley J. Goldsmith, Neil H. Bander Collection and assembly of data: Matthew I. Milowsky, Christine E. Sheehan, Shankar Vallabhajosula, Jeffrey S. Ross Data analysis and interpretation: Matthew I. Milowsky, David M. Nanus, Lale Kostakoglu, Christine E. Sheehan, Shankar Vallabhajosula, Stanley J. Goldsmith, Jeffrey S. Ross, Neil H. Bander Manuscript writing: Matthew I. Milowsky, David M. Nanus, Shankar Vallabhajosula, Jeffrey S. Ross, Neil H. Bander Final approval of manuscript: Matthew I. Milowsky, David M. Nanus, Neil H. Bander
Supported in part by National Center for Research Resources Grant No. M01RR00047 from the National Institutes of Health's General Clinical Research Center Program, Grant No. DAMD17-98-1-8594 from the US Department of Army, Cancer Research Institute, David H. Koch Foundation, Peter Sacerdote Foundation, Robert McCooey Cancer Research Fund, Laurent and Alberta Gerschel Foundation, the Yablans Family Foundation, and BZL Biologics Inc. Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 349:427-434, 2003 2. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004 3. Sandler AB, Gray R, Brahmer J, et al: Randomized phase II/III trial of paclitaxel (P) plus carboplatin (C) with or without bevacizumab (NSC # 704865) in patients with advanced non-squamous non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology Group (ECOG) Trial - E4599. J Clin Oncol 23:2s, 2005 (abstr 4) 4. Favaro JP, George DJ: Targeted therapy in renal cell carcinoma. Expert Opin Investig Drugs 14:1251-1258, 2005[CrossRef][Medline] 5. Thorpe PE: Vascular targeting agents as cancer therapeutics. Clin Cancer Res 10:415-427, 2004 6. Siemann DW, Bibby MC, Dark GG, et al: Differentiation and definition of vascular-targeted therapies. Clin Cancer Res 11:416-420, 2005 7. Israeli RS, Powell CT, Fair WR, et al: Molecular cloning of a complementary DNA encoding a prostate-specific membrane antigen. Cancer Res 53:227-230, 1993 8. Israeli RS, Powell CT, Corr JG, et al: Expression of the prostate-specific membrane antigen. Cancer Res 54:1807-1811, 1994 9. Troyer JK, Beckett ML, Wright GL Jr: Detection and characterization of the prostate-specific membrane antigen (PSMA) in tissue extracts and body fluids. Int J Cancer 62:552-558, 1995[Medline] 10. Silver DA, Pellicer I, Fair WR, et al: Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 3:81-85, 1997[Abstract] 11. Sokoloff RL, Norton KC, Gasior CL, et al: A dual-monoclonal sandwich assay for prostate-specific membrane antigen: Levels in tissues, seminal fluid and urine. Prostate 43:150-157, 2000[CrossRef][Medline] 12. Liu H, Moy P, Kim S, et al: Monoclonal antibodies to the extracellular domain of prostate-specific membrane antigen also react with tumor vascular endothelium. Cancer Res 57:3629-3634, 1997 13. Chang SS, Reuter VE, Heston WD, et al: Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res 59:3192-3198, 1999 14. Chang SS, O'Keefe DS, Bacich DJ, et al: Prostate-specific membrane antigen is produced in tumor-associated neovasculature. Clin Cancer Res 5:2674-2681, 1999 15. Milowsky MI, Nanus DM, Kostakoglu L, et al: Phase I trial of yttrium-90-labeled anti-prostate-specific membrane antigen monoclonal antibody J591 for androgen-independent prostate cancer. J Clin Oncol 22:2522-2531, 2004 16. Bander NH, Milowsky MI, Nanus DM, et al: Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer. J Clin Oncol 23:4591-4601, 2005 17. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 18. Vallabhajosula S, Kuji I, Hamacher KA, et al: Pharmacokinetics and biodistribution of 111In- and 177Lu-labeled J591 antibody specific for prostate-specific membrane antigen: Prediction of 90Y-J591 radiation dosimetry based on 111In or 177Lu? J Nucl Med 46:634-641, 2005 19. Ross JS, Sheehan CE, Fisher HA, et al: Correlation of primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate cancer. Clin Cancer Res 9:6357-6362, 2003 20. St Croix B, Rago C, Velculescu V, et al: Genes expressed in human tumor endothelium. Science 289:1197-1202, 2000 21. Schilsky RL: End points in cancer clinical trials and the drug approval process. Clin Cancer Res 8:935-938, 2002 Submitted June 23, 2006; accepted November 17, 2006. This article has been cited by other articles:
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
