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EJNMMI Research
Published in: EJNMMI Research 1/2014

Open Access 01-12-2014 | Original research

Design and preclinical evaluation of a 99mTc-labelled diabody of mAb J591 for SPECT imaging of prostate-specific membrane antigen (PSMA)

Authors: Florian Kampmeier, Jennifer D Williams, John Maher, Gregory E Mullen, Philip J Blower

Published in: EJNMMI Research | Issue 1/2014

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Abstract

Background

Sensitive and specific detection of nodal status, sites of metastases and low-volume recurrent disease could greatly improve management of patients with advanced prostate cancer. Prostate-specific membrane antigen (PSMA) is a well-established marker for prostate carcinoma with increased levels of expression in high-grade, hormone-refractory and metastatic disease. The monoclonal antibody (mAb) J591 is directed against an extracellular epitope of PSMA and has been shown to efficiently target disseminated disease including metastases in lymph nodes and bone. Its use as a diagnostic imaging agent however is limited due to its slow pharmacokinetics. In this study a diabody derived from mAb J591 was developed as a single photon emission computed tomography (SPECT) tracer with improved pharmacokinetics for the detection of PSMA expression in prostate cancer.

Methods

A diabody in VH-VL orientation and with a C-terminal cysteine was expressed in HEK293T cells and purified by a combination of metal ion affinity and size exclusion chromatography. Specificity and affinity were determined in cell binding studies. For SPECT imaging, the diabody was site-specifically labelled with [99mTc(CO)3]+ via the C-terminal His tag and evaluated in a subcutaneous DU145/DU145-PSMA prostate carcinoma xenograft model.

Results

J591C diabody binds to PSMA-expressing cells with low nanomolar affinity (3.3 ± 0.2 nM). SPECT studies allowed imaging of tumour xenografts with high contrast from 4 h post injection (p.i.). Ex vivo biodistribution studies showed peak tumour uptake of the tracer of 12.1% ± 1.7% injected dose (ID)/g at 8 h p.i. with a tumour to blood ratio of 8.0. Uptake in PSMA-negative tumours was significantly lower with 6.3% ± 0.5% at 8 h p.i. (p < 0.001).

Conclusion

The presented diabody has favourable properties required to warrant its further development for antibody-based imaging of PSMA expression in prostate cancer, including PSMA-specific uptake, favourable pharmacokinetics compared to the parental antibody and efficient site-specific radiolabelling with 99mTc.
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Literature
1.
Howlader N, Noone AM, Krapcho M, Garshell J, Neyman N, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA: SEER Cancer Statistics Review, 1975–2010. Bethesda, MD: National Cancer Institute;
2.
Wright GL Jr, Haley C, Beckett ML, Schellhammer PF: Expression of prostate-specific membrane antigen in normal, benign, and malignant prostate tissues. Urol Oncol 1995, 1: 18–28. 10.1016/1078-1439(95)00002-YCrossRefPubMed
3.
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: 81–85.PubMed
4.
Bostwick DG, Pacelli A, Blute M, Roche P, Murphy GP: Prostate specific membrane antigen expression in prostatic intraepithelial neoplasia and adenocarcinoma: a study of 184 cases. Cancer 1998, 82: 2256–2261. 10.1002/(SICI)1097-0142(19980601)82:11<2256::AID-CNCR22>3.0.CO;2-SCrossRefPubMed
5.
Sweat SD, Pacelli A, Murphy GP, Bostwick DG: Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases. Urology 1998, 52: 637–640. 10.1016/S0090-4295(98)00278-7CrossRefPubMed
6.
Mhawech-Fauceglia P, Zhang S, Terracciano L, Sauter G, Chadhuri A, Herrmann FR, Penetrante R: Prostate-specific membrane antigen (PSMA) protein expression in normal and neoplastic tissues and its sensitivity and specificity in prostate adenocarcinoma: an immunohistochemical study using mutiple tumour tissue microarray technique. Histopathology 2007, 50: 472–483. 10.1111/j.1365-2559.2007.02635.xCrossRefPubMed
7.
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: 3192–3198.PubMed
8.
Sacha P, Zamecnik J, Barinka C, Hlouchova K, Vicha A, Mlcochova P, Hilgert I, Eckschlager T, Konvalinka J: Expression of glutamate carboxypeptidase II in human brain. Neuroscience 2007, 144: 1361–1372. 10.1016/j.neuroscience.2006.10.022CrossRefPubMed
9.
Barrett JA, Coleman RE, Goldsmith SJ, Vallabhajosula S, Petry NA, Cho S, Armor T, Stubbs JB, Maresca KP, Stabin MG, Joyal JL, Eckelman WC, Babich JW: First-in-man evaluation of two high-affinity PSMA-avid small molecules for imaging prostate cancer. J Nucl Med 2013, 54: 380–387. 10.2967/jnumed.112.111203CrossRefPubMed
10.
Afshar-Oromieh A, Malcher A, Eder M, Eisenhut M, Linhart HG, Hadaschik BA, Holland-Letz T, Giesel FL, Kratochwil C, Haufe S, Haberkorn U, Zechmann CM: PET imaging with a [(68)Ga]gallium-labelled PSMA ligand for the diagnosis of prostate cancer: biodistribution in humans and first evaluation of tumour lesions. Eur J Nucl Med Mol Imaging 2012, 40: 486–495.CrossRefPubMed
11.
Ross JS, Sheehan CE, Fisher HA, Kaufman RP Jr, Kaur P, Gray K, Webb I, Gray GS, Mosher R, Kallakury BV: Correlation of primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate cancer. Clin Cancer Res 2003, 9: 6357–6362.PubMed
12.
Perner S, Hofer MD, Kim R, Shah RB, Li H, Moller P, Hautmann RE, Gschwend JE, Kuefer R, Rubin MA: Prostate-specific membrane antigen expression as a predictor of prostate cancer progression. Hum Pathol 2007, 38: 696–701. 10.1016/j.humpath.2006.11.012CrossRefPubMed
13.
Holmes EH: PSMA specific antibodies and their diagnostic and therapeutic use. Expert Opin Investig Drugs 2001, 10: 511–519. 10.1517/13543784.10.3.511CrossRefPubMed
14.
Elsasser-Beile U, Wolf P, Gierschner D, Buhler P, Schultze-Seemann W, Wetterauer U: A new generation of monoclonal and recombinant antibodies against cell-adherent prostate specific membrane antigen for diagnostic and therapeutic targeting of prostate cancer. Prostate 2006, 66: 1359–1370. 10.1002/pros.20367CrossRefPubMed
15.
Bander NH, Trabulsi EJ, Kostakoglu L, Yao D, Vallabhajosula S, Smith-Jones P, Joyce MA, Milowsky M, Nanus DM, Goldsmith SJ: Targeting metastatic prostate cancer with radiolabeled monoclonal antibody J591 to the extracellular domain of prostate specific membrane antigen. J Urol 2003, 170: 1717–1721. 10.1097/01.ju.0000091655.77601.0cCrossRefPubMed
16.
Morris MJ, Divgi CR, Pandit-Taskar N, Batraki M, Warren N, Nacca A, Smith-Jones P, Schwartz L, Kelly WK, Slovin S, Solit D, Halpern J, Delacruz A, Curley T, Finn R, O'Donoghue JA, Livingston P, Larson S, Scher HI: Pilot trial of unlabeled and indium-111-labeled anti-prostate-specific membrane antigen antibody J591 for castrate metastatic prostate cancer. Clin Cancer Res 2005, 11: 7454–7461. 10.1158/1078-0432.CCR-05-0826CrossRefPubMed
17.
Pandit-Taskar N, O'Donoghue JA, Morris MJ, Wills EA, Schwartz LH, Gonen M, Scher HI, Larson SM, Divgi CR: 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 2008, 49: 1066–1074. 10.2967/jnumed.107.049502PubMedCentralCrossRefPubMed
18.
Morris MJ, Pandit-Taskar N, Divgi CR, Bender S, O'Donoghue JA, Nacca A, Smith-Jones P, Schwartz L, Slovin S, Finn R, Larson S, Scher HI: Phase I evaluation of J591 as a vascular targeting agent in progressive solid tumors. Clin Cancer Res 2007, 13: 2707–2713. 10.1158/1078-0432.CCR-06-2935CrossRefPubMed
19.
Tagawa ST, Milowsky MI, Morris MJ, Vallabhajosula S, Christos PJ, Akhtar NH, Goldsmith SJ, Osborne J, Larson SM, Pandit-Taskar N, Scher HI, Bander NH, Nanus DM: Phase II study of lutetium-177 labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 for metastatic castration-resistant prostate cancer. Clin Cancer Res 2013, 19: 5182–5191. 10.1158/1078-0432.CCR-13-0231PubMedCentralCrossRefPubMed
20.
Williams LE, Wu AM, Yazaki PJ, Liu A, Raubitschek AA, Shively JE, Wong JY: Numerical selection of optimal tumor imaging agents with application to engineered antibodies. Cancer Biother Radiopharm 2001, 16: 25–35. 10.1089/108497801750095989CrossRefPubMed
21.
Olafsen T, Sirk SJ, Olma S, Shen CK, Wu AM: ImmunoPET using engineered antibody fragments: fluorine-18 labeled diabodies for same-day imaging. Tumour Biol 2012, 33: 669–677. 10.1007/s13277-012-0365-8CrossRefPubMed
22.
Li L, Crow D, Turatti F, Bading JR, Anderson AL, Poku E, Yazaki PJ, Carmichael J, Leong D, Wheatcroft D, Raubitschek AA, Hudson PJ, Colcher D, Shively JE: Site-specific conjugation of monodispersed DOTA-PEGn to a thiolated diabody reveals the effect of increasing peg size on kidney clearance and tumor uptake with improved 64-copper PET imaging. Bioconjug Chem 2011, 22: 709–716. 10.1021/bc100464ePubMedCentralCrossRefPubMed
23.
Adams GP, Schier R, McCall AM, Crawford RS, Wolf EJ, Weiner LM, Marks JD: Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. Br J Cancer 1998, 77: 1405–1412. 10.1038/bjc.1998.233PubMedCentralCrossRefPubMed
24.
Sundaresan G, Yazaki PJ, Shively JE, Finn RD, Larson SM, Raubitschek AA, Williams LE, Chatziioannou AF, Gambhir SS, Wu AM: 124I-labeled engineered anti-CEA minibodies and diabodies allow high-contrast, antigen-specific small-animal PET imaging of xenografts in athymic mice. J Nucl Med 2003, 44: 1962–1969.PubMedCentralPubMed
25.
Girgis MD, Kenanova V, Olafsen T, McCabe KE, Wu AM, Tomlinson JS: Anti-CA19–9 diabody as a PET imaging probe for pancreas cancer. J Surg Res 2011, 170: 169–178. 10.1016/j.jss.2011.03.065CrossRefPubMed
26.
McCabe KE, Liu B, Marks JD, Tomlinson JS, Wu H, Wu AM: An engineered cysteine-modified diabody for imaging activated leukocyte cell adhesion molecule (ALCAM)-positive tumors. Mol Imaging Biol 2012, 14: 336–347. 10.1007/s11307-011-0500-8PubMedCentralCrossRefPubMed
27.
Waibel R, Alberto R, Willuda J, Finnern R, Schibli R, Stichelberger A, Egli A, Abram U, Mach JP, Pluckthun A, Schubiger PA: Stable one-step technetium-99 m labeling of His-tagged recombinant proteins with a novel Tc(I)-carbonyl complex. Nat Biotechnol 1999, 17: 897–901. 10.1038/12890CrossRefPubMed
28.
Maher J, Brentjens RJ, Gunset G, Riviere I, Sadelain M: Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat Biotechnol 2002, 20: 70–75. 10.1038/nbt0102-70CrossRefPubMed
29.
Wilkins MR, Gasteiger E, Bairoch A, Sanchez JC, Williams KL, Appel RD, Hochstrasser DF: Protein identification and analysis tools in the ExPASy server. Methods Mol Biol 1999, 112: 531–552.PubMed
30.
Olafsen T, Cheung CW, Yazaki PJ, Li L, Sundaresan G, Gambhir SS, Sherman MA, Williams LE, Shively JE, Raubitschek AA, Wu AM: Covalent disulfide-linked anti-CEA diabody allows site-specific conjugation and radiolabeling for tumor targeting applications. Protein Eng Des Sel 2004, 17: 21–27. 10.1093/protein/gzh009PubMedCentralCrossRefPubMed
31.
Sirk SJ, Olafsen T, Barat B, Bauer KB, Wu AM: Site-specific, thiol-mediated conjugation of fluorescent probes to cysteine-modified diabodies targeting CD20 or HER2. Bioconjug Chem 2008, 19: 2527–2534. 10.1021/bc800113vPubMedCentralCrossRefPubMed
32.
Tavare R, Williams J, Howland K, Blower PJ, Mullen GE: [Re(CO)(3)](+) labelling of a novel cysteine/hexahistidine tag: insights into binding mode by liquid chromatography-mass spectrometry. J Inorg Biochem 2012, 114: 24–27.CrossRefPubMed
33.
Vallabhajosula S, Kuji I, Hamacher KA, Konishi S, Kostakoglu L, Kothari PA, Milowski MI, Nanus DM, Bander NH, Goldsmith SJ: 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 2005, 46: 634–641.PubMed
34.
Holland JP, Divilov V, Bander NH, Smith-Jones PM, Larson SM, Lewis JS: 89Zr-DFO-J591 for immunoPET of prostate-specific membrane antigen expression in vivo. J Nucl Med 2010, 51: 1293–1300. 10.2967/jnumed.110.076174PubMedCentralCrossRefPubMed
35.
Kim KM, McDonagh CF, Westendorf L, Brown LL, Sussman D, Feist T, Lyon R, Alley SC, Okeley NM, Zhang X, Thompson MC, Stone I, Gerber HP, Carter PJ: Anti-CD30 diabody-drug conjugates with potent antitumor activity. Mol Cancer Ther 2008, 7: 2486–2497. 10.1158/1535-7163.MCT-08-0388CrossRefPubMed
36.
Wu AM, Olafsen T: Antibodies for molecular imaging of cancer. Cancer J 2008, 14: 191–197. 10.1097/PPO.0b013e31817b07aeCrossRefPubMed
37.
Kenanova V, Olafsen T, Williams LE, Ruel NH, Longmate J, Yazaki PJ, Shively JE, Colcher D, Raubitschek AA, Wu AM: Radioiodinated versus radiometal-labeled anti-carcinoembryonic antigen single-chain Fv-Fc antibody fragments: optimal pharmacokinetics for therapy. Cancer Res 2007, 67: 718–726. 10.1158/0008-5472.CAN-06-0454CrossRefPubMed
38.
Hillier SM, Maresca KP, Lu G, Merkin RD, Marquis JC, Zimmerman CN, Eckelman WC, Joyal JL, Babich JW: 99mTc-labeled small-molecule inhibitors of prostate-specific membrane antigen for molecular imaging of prostate cancer. J Nucl Med 2013, 54: 1369–1376. 10.2967/jnumed.112.116624CrossRefPubMed
39.
Schafer M, Bauder-Wust U, Leotta K, Zoller F, Mier W, Haberkorn U, Eisenhut M, Eder M: A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer. EJNMMI Res 2012, 2: 23. 10.1186/2191-219X-2-23PubMedCentralCrossRefPubMed
Metadata
Title
Design and preclinical evaluation of a 99mTc-labelled diabody of mAb J591 for SPECT imaging of prostate-specific membrane antigen (PSMA)
Authors
Florian Kampmeier
Jennifer D Williams
John Maher
Gregory E Mullen
Philip J Blower
Publication date
01-12-2014
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2014
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/2191-219X-4-13

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