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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Genitourinary Oncology Service, Department of Medicine; 2 Nuclear Medicine Service, Department of Radiology; 3 Department of Radiology; 4 Clinical Immunology Service, Department of Medicine; 5 Department of Medical Physics, Memorial Sloan-Kettering Cancer Center; and 6 Department of Medicine, Weill Medical College of Cornell University, New York, New York
Requests for reprints: Michael J. Morris, Genitourinary Oncology Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Box 444, New York, NY 10021. Phone: 646-422-4469; Fax: 212-988-0701; E-mail: morrism{at}mskcc.org.
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Abstract |
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Patients and Methods: Patients with progressive metastatic prostate cancer despite androgen deprivation were eligible. Each patient received 10, 25, 50, and 100 mg of J591. Two milligrams of antibody, conjugated with the chelate 1,4,7,10-tetraazacyclododecane-N, N',N'',N'''-tetraacetic acid, were labeled with 5 mCi indium-111 (111In) as a tracer. One group of patients received unlabeled J591 before the labeled antibody; the other received both together. Toxicities, pharmacokinetic properties, biodistribution, ADCC induction, immunogenicity, and clinical antitumor effects were assessed.
Results: Fourteen patients were treated (seven in each group). Treatment was well tolerated. Biodistribution of 111In-labeled J591 was comparable in both groups. The mean T1/2 was .96, 1.9, 2.75, and 3.47 days for the 10, 25, 50, and 100 mg doses, respectively. Selective targeting of 111In-labeled J591 to tumor was seen. Hepatic saturation occurred by the 25-mg dose. ADCC activity was proportional to dose. One patient showed a >50% prostate-specific antigen decline.
Conclusions: J591 is well tolerated in repetitive dose-escalating administrations. The rate of serum clearance decreases with increasing antibody mass. ADCC activation is proportional to antibody mass. The optimal dose is 25 mg for radioimmunotherapy and 100 mg for immunotherapy. Phase II studies using J591 as a radioconjugate are under way.
20 amino acids long. The external domain, which is comprised of over 700 amino acids, is much larger and is responsible for its enzymatic action as a hydrolase (2). PSMA is present on both benign and malignant prostatic tissue and is expressed across the entire spectrum of the natural history of prostate cancer, from localized to metastatic disease. Expression increases following androgen withdrawal and is only minimally expressed in nonprostate tissues (3–6). For these reasons, antibodies against PSMA have been developed for both diagnostic and therapeutic purposes. Monoclonal antibodies can potentially treat prostate cancer either by inducing antibody-dependent cellular cytotoxicity (ADCC) using unlabeled antibody, or as carriers of radioactivity or chemotherapy. One such antibody is termed J591 (MLN591, Millennium Pharmaceuticals, Cambridge, MA), a monoclonal IgG1 molecule that targets the external domain of PSMA (7). To abrogate the possibility of inducing anti-J591 antibody responses in patients, J591 was "deimmunized" (DeImmunisation, Biovation Ltd., Aberdeen, United Kingdom) by replacing individual amino acid sequences in the antibody variable domains to remove helper T-cell epitopes. The deimmunized J591 retained the parent antibody's specificity and affinity. J591 can be covalently coupled with 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA), a chelating agent that stably binds radiometals. Preliminary studies have shown that the DOTA-antibody conjugate can be labeled with a variety of radioisotopes, such as yttrium-90 (90Y), indium-111 (111In), and lutetium-177 (177Lu), to form stable complexes, which are rapidly internalized after binding to PSMA at the cell surface (8–10). Such studies have shown that the antibody localizes well to established sites of disease seen on standard imaging and have shown hepatic uptake as well (10). Whether the hepatic uptake represents the isotope only or the conjugated antibody has not been definitively established. In theory, pretreating patients with unlabeled antibody could saturate such binding sites thereby minimizing binding of radiolabeled antibody to the liver.
Previously published phase I studies of J591 have dose escalated the radioconjugate and have examined the safety and antitumor effects of increasing amounts of radiation (10, 11). To develop J591 as a naked antibody, radioconjugate, or chemoconjugate, we sought to explore the effect of dose escalating the antibody mass on pharmacokinetics, biodistribution, and ADCC activation, the putative mechanism by which unlabeled antibody would mediate antitumor effects. We also sought to explore the relationship between the administration sequence of the unlabeled and labeled antibody on hepatic uptake.
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Patients and Methods |
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4 weeks apart or three measurements 1 week apart. A minimum PSA of 4 ng/mL was required for study entry. Progressive disease by bone scintigraphy was defined as new osseous lesions on a bone scan and by soft tissue imaging as an increase of >25% in bidimensional measurable soft tissue disease, or the appearance of new lesions by computed tomography and magnetic resonance imaging. Patients were required to have adequate functionality of the bone marrow (WBC count > 3,500/mm3, platelet count > 100,000/mm3), liver (bilirubin < 1.5 mg/d and aspartate aminotransferase <1.5 times the upper limit of normal), and kidneys (creatinine < 1.5 mg/d or creatinine clearance > 60 mL/min). Serum testosterone was required to be <50 ng/mL. Patients who had undergone diagnostic ProstaScint scans or had undergone any other prior administration of a murine protein for diagnostic or therapeutic purposes were excluded. Patients were required to have recovered from the acute toxicities of any prior therapy and to have not received chemotherapy, radiation, therapy, or other investigational anticancer therapeutic drugs for at least 4 weeks before entry into the trial.
All patients provided written informed consent. The protocol was approved by the Institutional Review Board of the Memorial Sloan-Kettering Cancer Center.
Treatment
To explore the relationship between the administration sequence of the unlabeled and labeled antibody on hepatic uptake, patients were divided into two groups: seven patients received the radiolabeled antibody concurrently with the unlabeled protein and another seven patients received the labeled antibody after the unlabeled antibody. The tracer was comprised of 5 mCi of 111In on 2 mg of J591. Patients were randomly assigned to receive the unlabeled antibody with the labeled antibody, or to receive the unlabeled antibody first, followed by the labeled antibody (at an interval of <10 minutes).
Intrapatient dose escalations were used. Each patient received four doses of antibody, which were 10, 25, 50, and 100 mg. These dose levels included the 2 mg of radiolabeled antibody. Other studies of J591, ongoing at the time that our trial was designed, showed that 10 to 20 mg of antibody has a T1/2 of up to 44 hours (10–12). Thus, a dosing schedule of 21 days was selected for this trial, as it was felt to represent an ample number of half-lives such that pharmacokinetic properties and biodistribution of a given dose level would not be altered by previous doses. To ensure that this was indeed the case, baseline whole body and serum radioactivity was measured before each subsequent dose after the first infusion (and were indeed found to be negative). All antibody infusions were administered at a rate of 5 mg/min.
Patients were not permitted to receive any therapeutic investigational anticancer agents other than J591, such as immunotherapy, chemotherapy, and hormonal therapy (other than protocol specified) while on study.
Labeling procedure
Two milligrams of antibody in each dose were labeled with 5 mCi of 111In. The radiolabeling of DOTA-huJ591 with 111In was achieved by adding the radionuclide (in diluted HCl) to the ammonium acetate–buffered DOTA-J591 (supplied by BZL Biologics, Inc., Framingham, MA). The volume of 111InCl3 (typically 10 mCi, 0.05 mol/L HCl) was buffered by 1 mol/L adding ammonium acetate (pH 7.0) and was allowed to react at 37°C for 20 minutes with 225 µL DOTA-hu-J591 [8 mg/mL, 0.3 mol/L NH4OAc (pH 7.0)]. The reaction mixture was then separated on a 20-mL polyacrylamide P6 gel column (Bio-Rad, Hercules, CA) equilibrated with 6 x 5 mL of sterile 1% human serum albumin in PBS. Once the reaction mixture was loaded onto the column, it was washed with 1% human serum albumin in PBS until the first 5 mL were collected, before the main 111In-DOTA-hu-J591 fraction was eluted with 3 mL of 1% human serum albumin in PBS. The purified 111In-DOTA-hu-J591 was terminally filtered to achieve sterility.
End points
Toxicity. Patients were assessed for toxicity on the day of treatment, day 8, and any day between days 15 to 19 of each cycle. A complete blood count, serum electrolytes and creatinine, hepatic panel, lactate dehydrogenase, alkaline phosphatase, and PSA were done on the same day. Bone scintigraphy and soft tissue imaging were done at baseline and following the complete series of infusions, 12 weeks after the start of therapy.
Common Toxicity Criteria version 2 criteria were used. Infusion-related rigors and chills were expected, and if they occurred, were treated with meperidine, diphenhydramine, and acetaminophen. If any grade 3 or 4 drug toxicities occurred, the patient was taken off study. For grade 2 toxicities that reversed after a 2-week break, patients could continue to receive dose-escalated drug. If the toxicity did not reverse, the patient was taken off study. There was no attenuation in the dose escalation scheme for toxicity.
Pharmacokinetics. To establish the pharmacokinetics of the labeled drug, serum 111In levels were drawn on day 1 at 5, 15, 30, 60, and 120 minutes. Four levels were also drawn between days 2 and 6. To determine whole body clearance, four whole body counts were obtained between days 2 and 6. Measurements taken on days of treatment occurred immediately before and 3 hours after each infusion.
Biodistribution. A minimum of two body images were obtained between days 1 and 8. Patients had at least one and no more than three images with bladder catheterization during each cycle to determine the dosimetry of the prostate gland, if the prostate gland was still in place.
Fluorescence-activated cell sorting analysis for unlabeled antibody. Sera were drawn 2 hours after each J591 infusion and on days 4 and 8 and week 3. In addition, sera were drawn during week 4 after the 100-mg dose. Serologic reactivity was determined by fluorescence-activated cell sorting (FACS) after patients received escalating doses of humanized J591 monoclonal antibody. FACS studies showed antibody binding to the cell surface of 3T3 cells transfected with human PSMA (obtained from the Gene Transfer and Somatic Cell Engineering Facility at the Memorial Sloan-Kettering Cancer Center, New York, NY; ref. 13). These cells were used in place of LNCaP cells, as the LNCaP cells grew in clumps, which did not evenly disperse and were not well suited to use in FACS. The PSMA and 3T3 cells were incubated with 20 µL sera for 30 minutes on ice. After washing, 20 µL of 1:25 FITC-conjugated goat anti-human IgG (Southern Biotechnology Associates, Inc., Birmingam, AL) were added, mixed, and incubated for 30 minutes. After washing, the percent positive population and mean fluorescence intensity of the stained cells were analyzed by flow cytometry (FACScan, Becton Dickinson, San Jose, CA). Pre-infusion and post-infusion sera were run together, with the pretreatment percent positive cells set at 10%. Serologic activity was defined 30% positive cells with a mean fluorescence intensity that was 1.5 times greater than seen in the pre-infusion samples.
Antibody-dependent cellular cytotoxicity. All patients underwent leukapheresis before treatment to harvest effector cells for ADCC studies. Serum was drawn on day 1 and then weekly after each dose of J591. Serum was also drawn 4 weeks following the 100-mg dose. ADCC effector activity of all specimens was compared using J591 and LNCaP cells. The optimal effector cells (donor peripheral blood mononuclear cells) were selected to test all sera.
LNCaP tumor cells, cultured in RPMI plus 10% fetal bovine serum, were labeled with 100 µCi 51Cr for 1 hour. After washing thrice with culture medium, cells were resuspended at 105/mL and 100 µL per well and plated onto 96-well round-bottomed plates (Corning, Inc., Corning, NY). Donor peripheral blood mononuclear cells were plated at a 100:1 ratio; 10 to 20 µL per well of pretreatment or posttreatment patient sera were added. After 18 hours of incubation at 37°C, supernatants (30 µL per well) were collected and transferred onto Lumaplate 96 (Perkin-Elmer, Boston, MA), dried, and read in a Packard Top-Count NXT gamma counter (Packard Instrument Company, Meriden, CT). Spontaneous release was determined by cpm of tumor cells incubated with medium, and maximum release by cpm of tumor cells plus 1% Triton. Specific lysis was defined as:
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15% after subtracting spontaneous and pretreatment lysis. Immunogenicity. Anti-J591 antibody response was tested before treatment on days 4 and 8 and then any day between days 15 and 19 during each cycle.
Human anti-J591 antibodies in the serum of patients were assayed using surface- enhanced laser desorption/ionization mass spectrometry technology. The details of this technique have been published in previous studies using J591 and may be found there (11).
Complement activation. C3 and C4 were tested before treatment on days 4 and 8 and then any day between days 15 and 19 during each cycle. C3 and C4 were analytically determined by rate nephelometry. Both C3 and C4 were standardized to the International Federation of Clinical Cancer International Reference Preparation for plasma protein using CRM#470 certified by the Bureau of Reference of the European Community and the College of American Pathologists. Within-run precision has a variation of <2.5% at the upper limit of the respective reference range.
Treatment effects were assessed on the basis of changes in PSA, bone scintigraphy, and soft tissue imaging with computed tomography or magnetic resonance imaging. Posttreatment PSA changes were categorized as (a) normalization for three successive evaluations at least 2 weeks apart, decrease by >50% (without normalization); (b) three successive increases >50%; or (c) neither (a) nor (b).
Antitumor effects. Per WHO criteria, patients with measurable disease were categorized as having had (a) complete response if all measurable lesions disappeared; (b) partial response if they showed a 50% reduction in the sum of the products of the longest perpendicular diameters of measurable lesions in the absence of new lesions; (c) stable disease if they did not meet either of the above two criteria; or (d) progressive disease if they showed a >25% increase in the sum of the products of the longest perpendicular diameters of the measurable lesions, or the appearance of new lesions. When the response decision was based on post-therapy PSA changes, the outcomes were normalization, decrease, or stabilization in PSA.
Biostatistical considerations
Despite the fact that significant toxicity, pharmacokinetic, biodistribution, and ADCC data were collected and analyzed in this trial, the sample size was intentionally made large enough to allow a determination of efficacy, which therefore was the trial's primary end point. Treatment schedules were combined for the purpose of evaluating efficacy; thus, a total of 14 patients were treated for the purposes of the efficacy analysis. With this sample size, the true response rate could be estimated within ±0.26. For the safety analysis, all patients who received at least one dose of huJ591 were included. Any incidence of adverse events was recorded and classified according to body system, severity, and dose received. The pharmacokinetic and biodistribution analyses were considered to be exploratory in this pilot study.
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5 lesions, seven had 6 to 25 lesions, and one patient had 25 lesions. The five patients with soft tissue lesions had low volume nodal disease; no patient had parenchymal involvement. One patient was not evaluable for response, as he had a presumed hypersensitivity reaction following his first dose.
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Pharmacokinetics. The serum T1/2, Cmax, and AUC are shown in Table 3, as grouped by administered dose. The T1/2 for each antibody mass was calculated from the serum clearance curves shown in Fig. 1, which are expressed as % injected dose/L of serum. As can be seen, serum clearance is not constant but rather varies according to the antibody mass administered. The most rapid serum clearance occurred at the 10-mg dose level, with a T1/2 of 0.96 days. At doses of 25, 50, and 100 mg, the T1/2 was 1.9, 2.75, and 3.47 days, respectively. These differences in T1/2 between the 10 and 25, 25 and 50, and 50 and 100 mg doses all met statistical significance, as shown in Table 3. Baseline serum and whole body counts were negative before the 25-, 50-, and 100-mg doses, suggesting that the alterations in pharmacokinetic properties were not due to residual antibody from previous treatments. The sequence of administration of labeled and unlabeled antibody had no effect on serum clearance (data not shown).
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The liver is a site of significant uptake. Figure 1 shows the mean fraction of the total counts represented by the liver for each dose of antibody. Mean fractional hepatic uptake declines with each dose. If the day 6 fractional hepatic uptake values are compared, there is a statistically significant difference in hepatic uptake between the 10-mg and 25-mg doses (P = 0.001) but not between the 25-mg and 50-mg doses (P = 0.776) or the 25-mg and 100-mg doses (P = 0.101). These findings suggest that hepatic saturation is achieved at an antibody mass between 10 and 25 mg. In addition, these preliminary data indicate that liver dose is no more than 3 cGy/mCi 111In at the 10-mg dose, decreasing to 1.6 cGy/mCi at the 100-mg dose. Therefore, the maximum radiation dose to the liver in patients who received four infusions of 5 mCi 111In was no more than 176 cGy.
Fluorescence-activated cell sorting analysis. The FACS analyses for unlabeled antibody are shown in Table 4. Although patients received increasing doses of antibody, the serologic reactivity data is grouped by administered dose to easily determine differences in reactivity on a dose-by-dose basis. In addition, the median percent 3T3 cells of all patients (not just those with serologic reactivity) is shown, again grouped by dose level. FACS data indicated that most patients showed significant reactivity (>30% binding to PSMA and 3T3 cells) 2 hours after each infusion of HuJ591. All pretreatment samples showed 10% binding of PSMA and 3T3 cells. As can be seen, higher doses of antibody were associated with a higher percent of patients with serologic activity, higher median percent reactive cells, and a greater duration of reactivity. For example, on week 2 (day 8) of each cycle, 0%, 35%, 61%, and 92% of patients were positive at the 10-, 25-, 50-, and 100-mg doses, respectively; >50% of patients at the 100-mg dose remained positive at 3 weeks.
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Complement activation. No significant change in C3 and C4 levels was seen with treatment. This is not surprising because J591 does not bind complement. The median pretreatment C3 level was 126 mg/d (range, 93-202); median C3 level on day 4 was 126 mg/d (range, 65-186) and at week 3 was 125 mg/d (range, 81-165). Median pretreatment C4 level was 27 mg/d (range, 17-42); median C4 level on day 4 was 25 mg/d (range, 17-34) and in week 3 was 26.5 mg/d (range, 18-45).
Antitumor effects. One of 14 patients evaluable for response showed a PSA decline of >50%. He received the labeled and unlabeled antibody concurrently. His PSA declined from a pretreatment level of 83 ng/mL to a nadir of 7.87 ng/mL (90%). The bone scan and soft tissue imaging revealed stable disease. His PSA gradually increased following his last dose of antibody and had not reached pretreatment levels when his treating physician instituted new therapy 6 months following his last dose of antibody. Three other patients achieved PSA stabilization while on study; two showed radiographic progression. Overall, 11 patients progressed, one showed stable disease, and one patient showed a 50% PSA decline without progression by imaging.
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Discussion |
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This trial clarified the optimal antibody mass for two purposes: using the antibody as a radiolabeled conjugate to deliver targeted radiation therapy or as an unlabeled antibody for immunotherapy. Other studies have shown the effect of total antibody protein dose upon biodistribution. Antibodies against CD20 have been shown to target tumor better with increasing mass amount (14), because the normal tissue expression of antigen is considerable. On the other hand, we have shown (13) that the optimum mass amount of antibody for the CD33 system was no more than 3 mg/m2, because the antigen pool on normal and malignant antigen-bearing cells was very low. The determination of the optimum mass amount of an antibody is therefore critical to its development.
The optimal dose of an unlabeled antibody for immunotherapy is one which is both safe and which seems to have the maximal immunologic activity. In this study, dose and ADCC activity were positively correlated, as reflected by the proportion of patients with significant LNCaP lysis, the median percent LNCaP cell lysis, and the duration of these effects. The highest dose administered was 100 mg, which was tolerated well, and which induced ADCC activation in >80% of patients at 2 hours. Fifty percent of the patients continued to show ADCC activation at 3 weeks. By contrast, only 8% of the patients showed ADCC activation at 3 weeks following the 50-mg dose. Hence, it seems that the optimal dose for immunotherapy is 100 mg. Indeed, even greater and more durable ADCC effects might be seen with higher doses, but these were not tested in this study. It is possible that increased ADCC activity seen at the 50- and 100-mg doses was, at least in part, is due to immune stimulation from the lower dose levels. The exploration of such additive immune effects could be explored in a trial that used an intercohort (rather than an intrapatient) dose escalation scheme. In such a case, any increase in ADCC activation with repeated doses could be attributed to additive effects, whereas intercohort differences would likely be due to increases in antibody mass. If such additive effects exist, they would likely be beneficial to patients, as a treatment strategy using unlabeled antibody would likely involve a repetitive dosing schedule.
The optimal dose for using the antibody as a vehicle for targeted radiotherapy is more difficult to define. Patients face two hypothetical risks from radiolabeled J591: a risk of hepatoxicity due to hepatic uptake and a risk of bone marrow suppression due to circulating antibody trafficking through the bone marrow. The optimal antibody mass is therefore one that blocks hepatic binding sites (thereby minimizing uptake of the labeled antibody by the liver) yet has the most rapid clearance from the serum (thereby minimizing marrow exposure to the labeled antibody). Note should be made that phase I studies of 177Lu and 90Y radioconjugates have yet to show any hepatoxicity using this antibody (11, 15–17), possibly a result of the relative radioresistance of the liver and the relatively low energy emission of the ß-emitting isotopes. Nonetheless, as the antibody is now being explored as a conjugate with higher-energy radionuclides such as 
-emitters (18, 19), then the liver may suffer from radiation if the dosimetry is not optimized.
Given the statistically insignificant differences in fractional hepatic uptake between the 25- and 50-mg doses and 50- and 100-mg doses, it seems that the liver is primarily saturated between 10 and 25 mg. In addition, it is feasible that further hepatic saturation may occur at doses >25 mg; the tradeoff for higher doses is increased marrow toxicity due to slower serum clearance. Therefore, the happy medium seems to be 25 mg, which both minimizes hepatic uptake and is associated with rapid serum clearance.
It is possible that the hepatic uptake of tracer is unrelated to antibody binding and is due to the radiometal being released and mimicking iron in the liver. Preclinical studies of the 111In would suggest that this scenario is an unlikely one. In vitro, the 111In-DOTA-J591 chelate has a half-life of >1,000 hours. After binding to LNCaP cells, 5% to 10% of the 111In is released with a half-life of 1 hour, but the remaining 90% to 95% is released with a half-life of 520 hours (9). In LNCaP-bearing nude mice, uptake in the liver and spleen quickly wash out over time (as does blood pool), whereas tumoral uptake increases as the chelate is internalized and the 111In is entrapped in the cancer cell. Such washout would be unusual if the 111In were independently binding to the liver (8). These studies have not been replicated in humans. However, the fact that hepatic uptake diminishes as antibody mass increases suggests that the source of uptake is indeed related to antibody binding.
One would expect that as the liver no longer functioned as a sink for antibody, that serum clearance rate would plateau. Surprisingly, we did not see such a plateau, and indeed the T1/2 continued to increase with each increasing dose. This suggests that there is continuing saturation of antigen sites, including perhaps in the tumor. It is also possible that there would not be any increase in serum clearance at a higher mass amount of protein.
In terms of antitumor effects, only one patient enjoyed a sustained PSA decline of 90%, in association with ADCC activation at all dose levels. It is quite possible that this is not the optimal patient population in which to study the antitumor effects of an unlabeled antibody. Preclinically, antibodies have been shown to be more effective at protection from progressive disease in the minimal disease setting than at treating established advanced disease (20–23). Patients with a rising PSA after prostatectomy or radiation, but who do not have established metastasis, may be a more suitable population for showing antitumor effects than the patients tested in this study. It is also possible that doses of antibody in excess of 100 mg might be necessary to induce ADCC activation to levels sufficient to produce significant antitumor effects. Further investigations would be necessary to confirm that ADCC activation increases proportionally to dose escalations above 100 mg, but even if it did, drug production and financial considerations would need to studied before treatment with large antibody masses could be undertaken. Rather than pursuing such an approach with unlabeled antibodies, the more fruitful course may be radioconjugated antibodies, which have been shown in phase I studies to induce significant PSA declines in patients using low antibody masses, although at a price of marrow toxicity (11, 12).
In conclusion, the optimal dose antibody mass of J591 depends on the intent of therapy. If it is to be used as immunotherapy, then 100 mg is well tolerated, is associated with the highest levels of ADCC activation at doses that were tested, and can induce PSA declines. Future studies should target patients with a lesser burden of disease than those in this study, to maximize antitumor effects. If used for radiotherapy, in particular if conjugated to a high-energy radioligand, then the optimal antibody mass seems to be 25 mg. Although doses >25 mg would reduce the chances of radiotoxicity to the liver, the low serum clearance rate might result in increased marrow exposure. A 25-mg dose minimizes hepatic uptake and is associated with rapid serum clearance. Presently, phase II studies using 177Lu-radiolabeled antibody are ongoing.
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Acknowledgments |
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4/14/05; revised 6/12/05; accepted 7/15/05.
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therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen. Prostate Cancer Prostatic Dis 2002;5:36–46.[Medline]
-particle emitting antibody ([213Bi]J591) for radioimmunotherapy of prostate cancer. Cancer Res 2000;60:6095–100.This article has been cited by other articles:
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  A. B. Apolo, N. Pandit-Taskar, and M. J. Morris Novel Tracers and Their Development for the Imaging of Metastatic Prostate Cancer J. Nucl. Med., December 1, 2008; 49(12): 2031 - 2041. [Abstract] [Full Text] [PDF]
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N. Pandit-Taskar, J. A. O'Donoghue, M. J. Morris, E. A. Wills, L. H. Schwartz, M. Gonen, H. I. Scher, S. M. Larson, and C. R. Divgi Antibody Mass Escalation Study in Patients with Castration-Resistant Prostate Cancer Using 111In-J591: Lesion Detectability and Dosimetric Projections for 90Y Radioimmunotherapy J. Nucl. Med., July 1, 2008; 49(7): 1066 - 1074. [Abstract] [Full Text] [PDF]
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 M. D. Galsky, M. Eisenberger, S. Moore-Cooper, W. K. Kelly, S. F. Slovin, A. DeLaCruz, Y. Lee, I. J. Webb, and H. I. Scher Phase I Trial of the Prostate-Specific Membrane Antigen-Directed Immunoconjugate MLN2704 in Patients With Progressive Metastatic Castration-Resistant Prostate Cancer J. Clin. Oncol., May 1, 2008; 26(13): 2147 - 2154. [Abstract] [Full Text] [PDF]
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 M. J. Morris, N. Pandit-Taskar, C. R. Divgi, S. Bender, J. A. O'Donoghue, A. Nacca, P. Smith-Jones, L. Schwartz, S. Slovin, R. Finn, et al. Phase I Evaluation of J591 as a Vascular Targeting Agent in Progressive Solid Tumors Clin. Cancer Res., May 1, 2007; 13(9): 2707 - 2713. [Abstract] [Full Text] [PDF]
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 C. P. Tarassoff, P. M. Arlen, and J. L. Gulley Therapeutic vaccines for prostate cancer. Oncologist, May 1, 2006; 11(5): 451 - 462. [Abstract] [Full Text] [PDF]
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