Clinical Cancer Research Infection and Cancer: Biology, Therapeutics, and Prevention
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ma, D.
Right arrow Articles by Olson, W. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ma, D.
Right arrow Articles by Olson, W. C.
Clinical Cancer Research Vol. 12, 2591-2596, April 15, 2006
© 2006 American Association for Cancer Research

Cancer Therapy: Preclinical

Potent Antitumor Activity of an Auristatin-Conjugated, Fully Human Monoclonal Antibody to Prostate-Specific Membrane Antigen

Dangshe Ma1, Christine E. Hopf1, Andrew D. Malewicz1, Gerald P. Donovan1, Peter D. Senter2, William F. Goeckeler1, Paul J. Maddon1 and William C. Olson1

Authors' Affiliations: 1 PSMA Development Co. LLC, Tarrytown, New York, and 2 Seattle Genetics, Inc., Bothell, Washington

Requests for reprints: Dangshe Ma, Progenics Pharmaceutiques, Inc., 777 Old Saw Mill River Road, Tarrytown, NY, 10591. Phone: 914-789-2800; Fax: 914-789-2807; E-mail: dma{at}progenics.com.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Prostate-specific membrane antigen (PSMA) is the prototypic cell-surface marker of prostate cancer and provides an attractive target for monoclonal antibody (mAb) targeted therapies. In this study, a novel antibody-drug conjugate (ADC) was generated by linking a fully human PSMA mAb to monomethylauristatin E (MMAE), a potent inhibitor of tubulin polymerization. The PSMA ADC was evaluated for antitumor activity in vitro and in a mouse xenograft model of androgen-independent human prostate cancer. The PSMA ADC eliminated PSMA-expressing cells with picomolar potency and >700-fold selectivity in culture. When used to treat mice with established human C4-2 tumors, the PSMA ADC significantly improved median survival 9-fold relative to vehicle or isotype-matched ADC (P = 0.0018) without toxicity. Treatment effects were also manifest as significant (P = 0.0068) reduction in serum levels of prostate-specific antigen (PSA). Importantly, 40% of treated animals had no detectable tumor or measurable PSA at day 500 and could be considered cured. The findings support development of PSMA antibody-auristatin conjugates for therapy of prostate cancer.

Prostate cancer is the most common malignancy and the second leading cause of cancer death in men in the United States (1). Localized prostate cancer typically is treated with surgery or radiation, and recurrent disease can be controlled temporarily with androgen ablation (2). However, almost all prostate carcinomas eventually become hormone refractory and then rapidly progress (3). Hormone-refractory or androgen-independent prostate cancer has proven to be largely resistant to conventional chemotherapy. With the exception of palliative care, the only approved chemotherapy is docetaxel in combination with prednisone, which offers a modest (2.4 months) survival benefit (4, 5). New molecularly targeted therapies are urgently needed.

Monoclonal antibody (mAb) therapies have shown considerable use in the treatment of non-Hodgkin's lymphoma (6), B-cell chronic lymphocytic leukemia (7), colorectal carcinoma (8, 9), and breast cancer (10). In addition, mAbs have proven effective as vehicles to deliver therapeutic drugs or radionuclides in acute myeloid leukemia (11) and non-Hodgkin's lymphoma (12, 13). Antibody-drug conjugates (ADC) combine the molecular targeting of mAbs with the chemotherapeutic properties of potent cytotoxins and hold great promise as molecularly targeted therapies of cancer.

Prostate-specific membrane antigen (PSMA) is a very well characterized cell surface marker of prostate cancer (14–17). PSMA is a homodimeric type II integral membrane glycoprotein whose expression is largely restricted to the prostate and is highly up-regulated in prostate carcinomas (17, 18). Its expression increases with disease progression, becoming highest in metastatic, hormone-refractory disease (19). In addition, PSMA is abundantly expressed on the neovasculature of most other solid tumors but not on normal vasculature (20–24). Importantly, PSMA is rapidly and constitutively internalized, facilitating delivery of ADCs into the cell interior (25, 26). These properties render PSMA an attractive target for ADC therapy of prostate and other cancers.

We previously described the preparation and characterization of fully human mAbs to conformational and dimer-specific epitopes within the extracellular domain of PSMA (17). Fully human mAbs are indistinguishable from naturally occurring human antibodies and thus offer the potential for repeat administration without the development of a neutralizing immune response. The auristatins are synthetic antimitotic agents related to the natural product dolastatin 10 (27) and are ~200 times more potent in vitro than conventional chemotherapeutic agents (28). A dipeptide linkage cleavable by lysosomal proteases has recently been applied to link auristatin-based drugs to mAbs (29–33). In this report, a novel ADC was generated by conjugating a PSMA mAb to monomethylauristatin E (MMAE) through a valine-citrulline (Val-Cit) linkage designed to maintain serum stability while maximizing intracellular drug release by human cathepsin B. We report that the PSMA ADC potently and specifically eliminated human prostate cancer cells in in vitro and in vivo models of androgen-independent prostate cancer.


   Materials and Methods
Top
 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Cell lines and antibodies. LNCaP, PC-3, and 3T3 were obtained from the American Type Culture Collection (Rockville, MD). C4-2 cell line, a subcell line from LNCaP, was provided by Dr. Warren D.W. Heston (The Cleveland Clinic Foundation, Cleveland, OH). A 3T3-PSMA cell line was a generous gift of Dr. Michel Sadelain (Memorial Sloan-Kettering Cancer Center, New York, NY). LNCaP, C4-2, and PC-3 were cultured in RPMI 1640 (Life Technologies, Gaithersburg, MD), and 3T3 and 3T3-PSMA were cultured in DMEM (Life Technologies). Culture media were supplemented with 10% fetal bovine serum (Hyclone, Logan, UT), L-glutamine, penicillin, and streptomycin (Life Technologies). C4-2, LNCaP, and 3T3-PSMA cells were determined to express PSMA at levels of ~2 x 105, 6 x 105, and >1 x 106 copies per cell, respectively, according to published methods (34). C4-2 is an androgen-independent subclone of androgen-dependent LNCaP cells (35). PC-3 is a dedifferentiated prostate cancer cell line that does not express PSMA. A fully human PSMA mAb (IgG1, {kappa}) was raised in mice transgenic for the human immunoglobulin gene locus (XenoMice, Abgenix, Inc., Fremont, CA) following immunization with recombinant soluble PSMA and LNCaP cells as previously described (17). PSMA mAb binds a conformation-dependent epitope within the extracellular domain of PSMA.

PSMA internalization. mAbs were modified with bifunctional chelates of cyclohexyl-diethylenetriamine pentaacetic acid (CHX-DTPA) generously provided by Dr. Martin Brechbiel (National Cancer Institute, Bethesda, MD) and labeled with 111In (Perkin-Elmer, Boston, MA) as previously described (34, 36). 111In-labeled mAb was determined to be >90% immunoreactive by incubating the radioconjugate with an excess of 3T3-PSMA cells and measuring the bound fraction according to published methods (34). For internalization analysis, 111In-labeled mAb was incubated with 2 x 105 C4-2 cells at 37°C in 5% CO2. At sequential time points, unbound mAb was removed by washing in PBS, and cell surface mAb was eluted using low pH buffer (pH 2.4, glycine/NaCl). The low pH eluate was counted separately from the cell pellet, and percent internalization was calculated as previously described (37).

Preparation of ADCs. The conjugation of mAbs with maleimidocaproyl-Val-Cit-monomethylauristatin E was done as described elsewhere (28). Briefly, PSMA mAb and isotype-control human IgG1 (Calbiochem, San Diego, CA) in PBS containing 50 mmol/L borate (pH 8) were treated with DTT (10 mmol/L final) at 37°C for 30 minutes. The mAbs were exchanged into PBS containing 1 mmol/L DTPA (Aldrich, Milwaukee, WI) by passage through a Sephadex G-25 column (Amersham Biosciences, Piscataway, NJ). The mAb solutions were chilled to 4°C and combined with the maleimido drug derivative in cold CH3CN. After 1 hour, the reactions were quenched with excess cysteine, and the conjugates were concentrated and exchanged into PBS buffer. The ADCs were determined to have ≥98% monomeric mAb containing 3.0 to 3.5 drugs per mAb using published methods (28). The drug/antibody ratio was selected empirically based on findings for other auristatin ADCs (31).

Reactivity of ADCs with cell-surface PSMA. Binding of PSMA mAb and ADC to 3T3-PSMA and parental 3T3 cells was analyzed using a FACSCalibur flow cytometer (BD Biosciences, San Diego, CA). Briefly, 2 x 105 3T3-PSMA (or 3T3) cells were incubated with different concentrations of mAb or ADC on ice for 1 hour. After washing, the presence of bound antibody was detected using goat anti-human IgG-FITC (Caltag Laboratories, Burlingame, CA). Isotype-control antibody and ADC were examined in parallel.

In vitro cytotoxicity assay. PSMA-positive cells (C4-2, LNCaP, or 3T3-PSMA) and PSMA-negative cells (PC-3 or 3T3) were added to 96-well microplates (Falcon, Franklin Lakes, NJ) at 2.5 x 103 per well and incubated overnight at 37°C and 5% CO2. Cells were then incubated with serially diluted ADCs for 4 days. The cell culture medium was replaced with fresh medium containing 10% Alamar Blue (Biosource International, Camarillo, CA), and cells were incubated for 4 hours. Plates were then read on a fluorescence plate reader using an excitation wavelength of 530 nm and an emission wavelength of 590 nm. Cell survival was compared in treated and untreated cultures, and the concentration of ADC required for 50% cell kill (IC50 value) was determined.

Xenograft model of androgen-independent prostate cancer. All animal studies were carried out in accordance with Institutional Animal Care and Use Committee guidelines. Athymic male nude mice (National Cancer Institute, Frederick, MD) 6 to 8 weeks in age were implanted with an i.m. injection of 5 x 106 C4-2 cells mixed with Matrigel (Beckon Dickinson Labware, Bedford, MA) into the left hind leg as described (37). Before initiation of treatment, animals were randomized according to serum levels of prostate-specific antigen (PSA) as measured by ELISA (Medicorp, Montreal, Quebec, Canada). ADCs, mAb, and vehicle control were administered via tail vein injection. In the first series of experiments, mice were treated in groups of six with 2 or 10 mg/kg PSMA ADC or with vehicle control. Treatment was initiated 17 days after implantation and consisted of three injections at 4-day intervals (q4d x 3). This regimen was selected empirically based on that used in mouse studies of other auristatin ADCs (30). The second series of experiments examined dose levels of 0, 3, or 6 mg/kg. Treatment was initiated 14 days after implantation and consisted of six injections at 4-day intervals (q4d x 6). Animals were monitored for PSA level and tumor size. Survival rates were recorded throughout the studies. Treatment toxicity was assessed by body weight and physical appearance of the animals.

Statistical analyses. Treatment effects were examined for significance via t tests (for PSA levels) or log-rank tests (for animal survival) using two-tailed, paired analyses. Data were considered significant when P < 0.05.


   Results
Top
 Abstract
 Materials and Methods
 Results
Discussion
 References
 
Internalization of the PSMA mAb into human prostate cancer cells. Internalization was examined using 111In-labeled PSMA mAb and C4-2 cells. Total binding and percent internalization over time are illustrated in Fig. 1 . Over half of the bound mAb was internalized within 2 hours (Fig. 1A). Total binding increased over time, presumably due to PSMA recycling (Fig. 1B). Thus, the PSMA mAb is readily internalized into PSMA-expressing cells.


Figure 1
View larger version (9K):
[in this window]
[in a new window]
  		Fig. 1. Percent internalization and total binding of 111In-labeled PSMA mAb on C4-2 cells. C4-2 cells were incubated with 111In-labeled mAb at 37°C, 5% CO2. At the designated times, cells were washed to remove unbound mAb, and surface-bound mAb was eluted using low pH buffer. The radioactivity (counts per minute or CPM) of the low pH eluate and cell pellet was counted separately using a gamma counter. Percent internalization (A) was calculated as the counts per minute cell pellet / (counts per minute cell pellet + counts per minute low pH eluate) x 100. Total binding (B) represents the counts per minute of the cell pellet plus the counts per minute of the low pH eluate.

 
Reactivity of the PSMA ADC with PSMA-expressing cells. Flow cytometry was used to compare the binding of PSMA mAb and ADC. The unmodified mAb and ADC showed comparable levels of binding to 3T3-PSMA over a broad range of dilutions (Fig. 2 ). Neither the maximal amount of binding nor the concentration required for half-maximal binding was appreciably affected by conjugation. No significant binding was observed for the isotype control ADC or antibody on 3T3-PSMA cells or for PSMA mAb or ADC on parental 3T3 cells (data not shown).


Figure 2
View larger version (11K):
[in this window]
[in a new window]
  		Fig. 2. Binding of PSMA mAb and ADC to 3T3-PSMA cells. 3T3-PSMA cells were incubated with increasing concentrations of the PSMA mAb ({blacksquare}), PSMA ADC ({square}), or isotype-control ADC ({triangleup}). Cells were incubated on ice for 1 hour and washed to remove unbound mAb or ADC. The cells were then incubated with goat anti-human IgG-FITC, washed again, and examined by a flow cytometry. The mean fluorescence intensities are plotted as a function of mAb or ADC concentration.

 
In vitro potency and selectivity of the PSMA ADC. PSMA and control ADCs were tested for cytotoxicity in vitro against human prostate cancer cells lines and 3T3-PSMA cells. Figure 3 illustrates dose-response curves for PSMA-positive C4-2 cells (Fig. 3A) and PSMA-negative PC-3 cells (Fig. 3B) in a representative experiment, and IC50 values for the various cell lines are listed in Table 1 . The PSMA ADC potently eliminated all PSMA-positive cell lines examined at IC50 values of 65 to 210 pmol/L, whereas these concentrations had no effect on PSMA-negative cells. In contrast, nearly 1,000-fold higher concentrations were required for the control ADC, whose activity was independent of PSMA expression (Fig. 3; Table 1).


Figure 3
View larger version (12K):
[in this window]
[in a new window]
  		Fig. 3. In vitro cytotoxicity of the PSMA ADC and control ADC on PSMA-positive and PSMA-negative prostate cancer cell lines. PSMA-positive C4-2 cells (A) and PSMA-negative PC-3 cells (B) in 96-well microplates were exposed to ADCs at various concentrations. After 96 hours, cell survival in treated and untreated cultures was assayed using Alamar Blue.

 

View this table:
[in this window]
[in a new window]
  		Table 1. Summary of in vitro cytotoxicity (IC50 values in pmol/L)

 
Efficacy of the PSMA ADC in xenograft models of androgen-independent prostate cancer. In vivo efficacy of the PSMA ADC was evaluated in a mouse model of androgen-independent human prostate cancer. Nude mice were engrafted with C4-2 cells i.m. in the left hind leg. Fourteen or 17 days later, serum PSA levels were measured and used to randomly assign animals to treatment groups. Animals were treated i.v. with the PSMA ADC, and animals were monitored for tumor burden, PSA levels and other variables for as long as 500 days.

In the first experiment, animals were randomized at day 17 and treated q4d x 3 with 0, 2, or 10 mg/kg PSMA ADC. In vehicle control group, tumors grew rapidly, and animals had a median survival of 32 days. In contrast, the groups treated with 2 and 10 mg/kg PSMA ADC had median survivals of 58 days (P = 0.0035) and 95 days (P = 0.0010), respectively (Table 2 ; Fig. 4A ). The PSMA ADC significantly improved median survival up to 5-fold post-treatment in a dose-dependent fashion. There was no evidence of treatment-related toxicity.


View this table:
[in this window]
[in a new window]
  		Table 2. Median survival times of C4-2 tumor-bearing animals treated with PSMA ADC

 

Figure 4
View larger version (15K):
[in this window]
[in a new window]
  		Fig. 4. Kaplan-Meier survival and serum PSA levels in xenograft study 1. Nude mice were implanted i.m. with C4-2 cells, randomly assigned to treatment groups (six mice per group) according to serum PSA on day 17 and then treated q4d x 3 with PSMA ADC or vehicle. A, survival of animals treated with 0 mg/kg (vehicle control, dashed line), 2 mg/kg (thin solid line), and 10 mg/kg PSMA ADC (thick solid line). B, mean PSA values over 30 days in mice treated with 0 mg/kg (filled columns), 2 mg/kg (striped columns), and 10 mg/kg (open columns) PSMA ADC. The day 30 data for the control group include day 27 evaluations for two mice that did not survive 30 days. The experiment was conducted as described in Materials and Methods.

 
Serum PSA levels were measured over time by ELISA. Figure 4B depicts the mean PSA concentration in each group at study days 17, 23, and 30. Treatment at 10 mg/kg reduced PSA levels >10-fold from 8.8 ± 11.7 ng/mL at day 17 to 0.7 ± 0.9 ng/mL at day 30, whereas PSA levels in control group increased >60-fold over the same time period. An intermediate response was observed with 2 mg/kg PSMA ADC. The differences in PSA levels at day 30 were significant for both the 2 mg/kg (P = 0.0048) and 10 mg/kg (P = 0.0006) dose groups. Three of six animals in the 10 mg/kg group had undetectable PSA through day 52 of the study.

To extend these findings, a second PSMA ADC study that also included unmodified mAb and isotype-control ADC was conducted. After randomization at day 14 with a mean PSA level of 2.0 ± 1.1 ng/mL in each group (n = 5), animals were treated with a regimen of q4d x 6. Kaplan-Meier survival curves for each group are depicted in Fig. 5 . Animals treated with vehicle control, 6 mg/kg unmodified PSMA mAb and 6 mg/kg control ADC had similar median survival times of 29, 31, and 31 days, respectively; in addition, these differences were not significant. However, median survival was extended to 49 and 148 days for animals treated with 3 and 6 mg/kg PSMA ADC, respectively (Table 2). Treatment with 6 mg/kg PSMA ADC group improved post-randomization survival 9-fold relative to the vehicle control group (P = 0.0018). At day 500, two of five animals had no evidence of tumor, had no measurable PSA, and were considered cured by treatment. As in the first study, treatment had a significant effect on PSA levels on day 29 (P = 0.0068 for 6 mg/kg PSMA and vehicle groups). Moreover, in the 6 mg/kg PSMA ADC group, serum PSA decreased to undetectable levels post-treatment and remained undetectable through day 63 in four of five animals.


Figure 5
View larger version (12K):
[in this window]
[in a new window]
  		Fig. 5. Kaplan-Meier survival curves of animals treated in xenograft study 2. Nude mice were implanted i.m. with C4-2 cells, randomly assigned to treatment groups (five mice per group) according to serum PSA on day 14 and then treated q4d x 6 with PSMA ADC and controls. Mice were treated with 0 mg/kg (vehicle control, bullet), 6 mg/kg unmodified PSMA mAb ({blacktriangleup}), 6 mg/kg control ADC ({triangleup}), 3 mg/kg PSMA ADC ({square}), and 6 mg/kg PSMA ADC ({blacksquare}). The experiment was conducted as described in Materials and Methods.

 
There was no overt toxicity associated with ADC therapy in either study. Physical appearance and activity were unaffected by treatment, and body weights of treated and vehicle-control animals were not significantly different at any time point (data not shown).


   Discussion
Top
 Abstract
 Materials and Methods
 Results
 Discussion
References
 
This report describes initial preclinical evaluations of a novel ADC comprising a fully human PSMA mAb and an auristatin chemotherapeutic agent. In in vitro and in vivo models of human prostate cancer, the PSMA ADC showed potent and selective antitumor activity. These findings are consistent with the abundant expression and rapid internalization of PSMA in prostate cancer cells, and the results support further development of this strategy for prostate and other cancers.

The PSMA ADC showed picomolar potency against three PSMA-expressing cells in culture with nearly 1,000-fold selectivity compared with an isotype control ADC. This result shows the specificity of mAb binding and the stability of the drug linker. Comparable activity was observed using androgen-dependent and androgen-independent prostate cancer cell lines. The PSMA ADC was ~3-fold more active against prostate cancer cells that express PSMA endogenously compared with 3T3-PSMA transfectants. There was no obvious dependence of ADC activity over a >4-fold range of PSMA expression.

The selective cytotoxicity of PSMA ADC also reflects efficient internalization of the antigen. PSMA is rapidly internalized in the presence and absence of PSMA mAb (Fig. 1A) and other antibodies (25, 38). Rapid internalization in prostate and nonprostate cell lines has been mapped to the MWNLL sequence in the cytoplasmic domain of PSMA (39).

The PSMA ADC showed therapeutic efficacy in a mouse xenograft model of androgen-independent prostate cancer. The C4-2 model was used because these tumors (a) grow aggressively, (b) are androgen independent and therefore mimic our intended patient population, and (c) secrete PSA that can be monitored as a surrogate marker of tumor progression. Each of the two regimens tested were effective in increasing median survival and decreasing serum PSA in a dose-dependent fashion. Remarkably, a 40% cure rate was observed in animals with established tumors following treatment with 6 mg/kg PSMA ADC (or ~100 µg MMAE equivalents/kg) administered via a q4d x 6 regimen. Cured animals had no detectable tumor or serum PSA for as long as 500 days after implantation. The dose of 6 mg/kg with a q4d x 6 regimen was comparable with or less intensive than some agents evaluated for prostate cancer therapy in preclinical models [12.9 mg/kg with q3d x 5 (26) or 5 mg/kg with q4d x 13 (29)]. Because no apparent toxicities were observed with this regimen, further improvements in antitumor activity may be attainable. Antitumor effects were observed at lower doses as well, and the findings indicate that this agent possesses an appropriate therapeutic window in this model.

In addition to being expressed on malignant epithelial cells in prostate cancer, PSMA also is abundantly expressed in association with most other solid tumors on the endothelial cells of the tumor neovasculature. The tumor endothelium constitutes a single-layer target that represents another attractive setting for PSMA ADC therapy.

Our findings show that mAb-auristatin conjugates have potent and selective antitumor activity in in vitro and in vivo models of androgen-independent human prostate cancer. This approach merits further development as a molecularly targeted therapy of prostate and other cancers.


   Acknowledgments
 
We thank Drs. David A. Scheinberg (Memorial Sloan-Kettering Cancer Center) and Warren D.W. Heston for providing comments on the article and Drs. Michel Sadelain, Warren D.W. Heston, and Martin Brechbiel for providing 3T3-PSMA cell line, C4-2 cell line, and cyclohexyl-DTPA bifunctional chelate, respectively.


   Footnotes
 
Grant support: NIH grants CA107653 (D. Ma) and CA96075 (G.P. Donovan and D. Ma).

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.

Note: PSMA Development Co., LLC is a joint venture between Cytogen Corp. (Princeton) and Progenics Pharmaceuticals, Inc.

Received 9/27/05; revised 12/ 1/05; accepted 1/ 4/06.


   References
Top
 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

  1. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin 2005;55:10–30.[Abstract/Free Full Text]
  2. Klein EA, Kupelian PA. Localized prostate cancer: radiation or surgery? Urol Clin North Am 2003;30:315–30.[Medline]
  3. Denmeade SR, Isaacs JT. A history of prostate cancer treatment. Nat Rev Cancer 2002;2:389–96.[CrossRef][Medline]
  4. Gulley J, Dahut WL. Chemotherapy for prostate cancer: finally an advance! Am J Ther 2004;11:288–94.[Medline]
  5. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–20.[Abstract/Free Full Text]
  6. Dillman RO. Magic bullets at last! Finally: approval of a monoclonal antibody for the treatment of cancer!!! Cancer Biother Radiopharm 1997;12:223–5.[Medline]
  7. Dumont FJ. CAMPATH (alemtuzumab) for the treatment of chronic lymphocytic leukemia and beyond. Expert Rev Anticancer Ther 2002;2:23–35.[CrossRef][Medline]
  8. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–45.[Abstract/Free Full Text]
  9. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335–42.[Abstract/Free Full Text]
  10. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127–37.[CrossRef][Medline]
  11. Bross PF, Beitz J, Chen G, et al. Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia. Clin Cancer Res 2001;7:1490–6.[Abstract/Free Full Text]
  12. Grillo-Lopez AJ. Zevalin: the first radioimmunotherapy approved for the treatment of lymphoma. Expert Rev Anticancer Ther 2002;2:485–93.[CrossRef][Medline]
  13. Kaminski MS, Tuck M, Estes J, et al. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005;352:441–9.[Abstract/Free Full Text]
  14. Davis MI, Bennett MJ, Thomas LM, Bjorkman PJ. Crystal structure of prostate-specific membrane antigen, a tumor marker and peptidase. Proc Natl Acad Sci U S A 2005;102:5981–6.[Abstract/Free Full Text]
  15. Freeman LM, Krynyckyi BR, Li Y, et al. The role of 111In Capromab Pendetide (Prosta-ScintR) immunoscintigraphy in the management of prostate cancer. Q J Nucl Med 2002;46:131–7.[Medline]
  16. Horoszewicz JS, Kawinski E, Murphy GP. Monoclonal antibodies to a new antigenic marker in epithelial prostatic cells and serum of prostatic cancer patients. Anticancer Res 1987;7:927–35.[Medline]
  17. Schulke N, Varlamova OA, Donovan GP, et al. The homodimer of prostate-specific membrane antigen is a functional target for cancer therapy. Proc Natl Acad Sci U S A 2003;100:12590–5.[Abstract/Free Full Text]
  18. 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 2003;9:6357–62.[Abstract/Free Full Text]
  19. Su SL, Huang IP, Fair WR, Powell CT, Heston WD. Alternatively spliced variants of prostate-specific membrane antigen RNA: ratio of expression as a potential measurement of progression. Cancer Res 1995;55:1441–3.[Abstract/Free Full Text]
  20. Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 1997;3:81–5.[Abstract]
  21. 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 1997;57:3629–34.[Abstract/Free Full Text]
  22. Chang SS, Reuter VE, Heston WD, Bander NH, Grauer LS, Gaudin PB. Five different anti-prostate-specific membrane antigen (PSMA) antibodies confirm PSMA expression in tumor-associated neovasculature. Cancer Res 1999;59:3192–8.[Abstract/Free Full Text]
  23. Chang SS, O'Keefe DS, Bacich DJ, Reuter VE, Heston WD, Gaudin PB. Prostate-specific membrane antigen is produced in tumor-associated neovasculature. Clin Cancer Res 1999;5:2674–81.[Abstract/Free Full Text]
  24. Chang SS, Reuter VE, Heston WD, Gaudin PB. Metastatic renal cell carcinoma neovasculature expresses prostate-specific membrane antigen. Urology 2001;57:801–5.[CrossRef][Medline]
  25. Liu H, Rajasekaran AK, Moy P, et al. Constitutive and antibody-induced internalization of prostate-specific membrane antigen. Cancer Res 1998;58:4055–60.[Abstract/Free Full Text]
  26. Henry MD, Wen S, Silva MD, Chandra S, Milton M, Worland PJ. A prostate-specific membrane antigen-targeted monoclonal antibody-chemotherapeutic conjugate designed for the treatment of prostate cancer. Cancer Res 2004;64:7995–8001.[Abstract/Free Full Text]
  27. Vaishampayan U, Glode M, Du W, et al. Phase II study of dolastatin-10 in patients with hormone-refractory metastatic prostate adenocarcinoma. Clin Cancer Res 2000;6:4205–8.[Abstract/Free Full Text]
  28. Doronina SO, Toki BE, Torgov MY, et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol 2003;21:778–84.[CrossRef][Medline]
  29. Afar DE, Bhaskar V, Ibsen E, et al. Preclinical validation of anti-TMEFF2-auristatin E-conjugated antibodies in the treatment of prostate cancer. Mol Cancer Ther 2004;3:921–32.[Abstract/Free Full Text]
  30. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood 2003;102:1458–65.[Abstract/Free Full Text]
  31. Hamblett KJ, Senter PD, Chace DF, et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin Cancer Res 2004;10:7063–70.[Abstract/Free Full Text]
  32. Law CL, Cerveny CG, Gordon KA, et al. Efficient elimination of B-lineage lymphomas by anti-CD20-auristatin conjugates. Clin Cancer Res 2004;10:7842–51.[Abstract/Free Full Text]
  33. Mao W, Luis E, Ross S, et al. EphB2 as a therapeutic antibody drug target for the treatment of colorectal cancer. Cancer Res 2004;64:781–8.[Abstract/Free Full Text]
  34. Ma D, McDevitt MR, Barendswaard E, et al. Radioimmunotherapy for model B cell malignancies using 90Y-labeled anti-CD19 and anti-CD20 monoclonal antibodies. Leukemia 2002;16:60–6.[CrossRef][Medline]
  35. Thalmann GN, Sikes RA, Wu TT, et al. LNCaP progression model of human prostate cancer: androgen-independence and osseous metastasis. Prostate 2000;44:91–103.[CrossRef][Medline]
  36. Nikula TK, McDevitt MR, Finn RD, et al. Alpha-emitting bismuth cyclohexylbenzyl DTPA constructs of recombinant humanized anti-CD33 antibodies: pharmacokinetics, bioactivity, toxicity and chemistry. J Nucl Med 1999;40:166–76.[Abstract/Free Full Text]
  37. McDevitt MR, Barendswaard E, Ma D, et al. An alpha-particle emitting antibody ([213Bi]J591) for radioimmunotherapy of prostate cancer. Cancer Res 2000;60:6095–100.[Abstract/Free Full Text]
  38. Smith-Jones PM, Vallabahajosula S, Goldsmith SJ, et al. In vitro characterization of radiolabeled monoclonal antibodies specific for the extracellular domain of prostate-specific membrane antigen. Cancer Res 2000;60:5237–43.[Abstract/Free Full Text]
  39. Rajasekaran SA, Anilkumar G, Oshima E, et al. A novel cytoplasmic tail MXXXL motif mediates the internalization of prostate-specific membrane antigen. Mol Biol Cell 2003;14:4835–45.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Clin. Cancer Res.Home page
R. J. Durso, S. Andjelic, J. P. Gardner, D. J. Margitich, G. P. Donovan, R. R. Arrigale, X. Wang, M. F. Maughan, T. L. Talarico, R. A. Olmsted, et al.
A Novel Alphavirus Vaccine Encoding Prostate-Specific Membrane Antigen Elicits Potent Cellular and Humoral Immune Responses
Clin. Cancer Res., July 1, 2007; 13(13): 3999 - 4008.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ma, D.
Right arrow Articles by Olson, W. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ma, D.
Right arrow Articles by Olson, W. C.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online