Radiation dosimetry and first therapy results with a 124I/131I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy

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Abstract

Introduction

Since the prostate-specific membrane antigen (PSMA) is frequently over-expressed in prostate cancer (PCa) several PSMA-targeting molecules are under development to detect and treat metastatic castration resistant prostate cancer (mCRPC). We investigated the tissue kinetics of a small molecule inhibitor of PSMA (( S)-2-(3-(( S)-1-carboxy-5-(3-(4-[ ¹²⁴I]iodophenyl)ureido)pentyl)ureido)pentanedioicacid; MIP-1095) using PET/CT to estimate radiation dosimetry for the potential therapeutic use of ¹³¹I-MIP-1095 in men with mCRPC. We also report preliminary safety and efficacy of the first 28 consecutive patients treated under a compassionate-use protocol with a single cycle of ¹³¹I-MIP-1095.

Methods

Sixteen patients with known prostate cancer underwent PET/CT imaging after i.v. administration of ¹²⁴I-MIP-1095 (mean activity: 67.4 MBq). Each patient was scanned using PET/CT up to five times at 1, 4, 24, 48 and 72 h post injection. Volumes of interest were defined for tumor lesions and normal organs at each time point followed by dose calculations using the OLINDA/EXM software. Twenty-eight men with mCRPC were treated with a single cycle of ¹³¹I-MIP-1095 (mean activity: 4.8 GBq, range 2 to 7.2 GBq) and followed for safety and efficacy. Baseline and follow up examinations included a complete blood count, liver and kidney function tests, and measurement of serum PSA.

Results

I-124-MIP-1095 PET/CT images showed excellent tumor uptake and moderate uptake in liver, proximal intestine and within a few hours post-injection also in the kidneys. High uptake values were observed only in salivary and lacrimal glands. Dosimetry estimates for I-131-MIP-1095 revealed that the highest absorbed doses were delivered to the salivary glands (3.8 mSv/MBq, liver (1.7 mSv/MBq) and kidneys (1.4 mSv/MBq). The absorbed dose calculated for the red marrow was 0.37 mSv/MBq. PSA values decreased by >50 % in 60.7 % of the men treated. Of men with bone pain, 84.6 % showed complete or moderate reduction in pain. Hematological toxicities were mild. Of men treated, 25 % had a transient slight to moderate dry mouth. No adverse effects on renal function were observed.

Conclusion

Based on the biodistribution and dose calculations of the PSMA-targeted small molecule ¹²⁴I-MIP-1095 therapy with the authentic analog ¹³¹I-MIP-1095 enables a targeted tumor therapy with unprecedented doses delivered to the tumor lesions. Involved lymph node and bone metastases were exposed to estimated absorbed doses upwards of 300 Gy.

Electronic supplementary material

The online version of this article (doi:10.1007/s00259-014-2713-y) contains supplementary material, which is available to authorized users.

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Most cited references 16

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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.

L Terracciano, G Sauter, A Chadhuri … (2007)

To determine prostate-specific membrane antigen (PSMA) expression in normal tissues and in 3161 benign and malignant tumours and subsequently to define its sensitivity and specificity in prostatic adenocarcinoma (PaC). Multiple tissue microarray sections were stained with a monoclonal antibody to PSMA. PaC was positive in 93/141 cases (66.0%) with various staining patterns including cytoplasmic, apical, apical/cytoplasmic and cytoplasmic with membranous accentuation. Of 2174 various tumour types, 154 expressed PSMA, including 59/346 (17.0%) urothelial carcinomas of the bladder (UBC). In those tumours, the staining pattern was always cytoplasmic. All 846 benign tumours were negative for PSMA. The sensitivity and specificity of PSMA in distinguishing PaC from any other type of malignancy is 65.9% and 94.5%, respectively. Furthermore, its sensitivity and specificity in differentiating PaC from urothelial cancer is 65.9% and 82.9%, respectively. Despite its expression by subsets of various types of malignancies, PSMA is still considered to be fairly sensitive and highly specific for PaC.

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Phase I trial of 177lutetium-labeled J591, a monoclonal antibody to prostate-specific membrane antigen, in patients with androgen-independent prostate cancer.

Cynthia Goldsmith, Neil Bander, Matthew Milowsky … (2005)

To determine the maximum tolerated dose (MTD), toxicity, human anti-J591 response, pharmacokinetics (PK), organ dosimetry, targeting, and biologic activity of (177)Lutetium-labeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 ((177)Lu-J591) in patients with androgen-independent prostate cancer (PC). Thirty-five patients with progressing androgen-independent PC received (177)Lu-J591. All patients underwent (177)Lu-J591 imaging, PK, and biodistribution determinations. Patients were eligible for up to three retreatments. Thirty-five patients received (177)Lu-J591, of whom 16 received up to three doses. Myelosuppression was dose limiting at 75 mCi/m(2), and the 70-mCi/m(2) dose level was determined to be the single-dose MTD. Repeat dosing at 45 to 60 mCi/m(2) was associated with dose-limiting myelosuppression; however, up to three doses of 30 mCi/m(2) could be safely administered. Nonhematologic toxicity was not dose limiting. Targeting of all known sites of bone and soft tissue metastases was seen in all 30 patients with positive bone, computed tomography, or magnetic resonance images. No patient developed a human anti-J591 antibody response to deimmunized J591 regardless of number of doses. Biologic activity was seen with four patients experiencing >or= 50% declines in prostate-specific antigen (PSA) levels lasting from 3+ to 8 months. An additional 16 patients (46%) experienced PSA stabilization for a median of 60 days (range, 1 to 21+ months). The MTD of (177)Lu-J591 is 70 mCi/m(2). Multiple doses of 30 mCi/m(2) are well tolerated. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation.

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Preclinical evaluation of novel glutamate-urea-lysine analogues that target prostate-specific membrane antigen as molecular imaging pharmaceuticals for prostate cancer.

Catherine A Foss, J-S Joyal, John Babich … (2009)

Prostate-specific membrane antigen (PSMA) is expressed in normal human prostate epithelium and is highly up-regulated in prostate cancer. We previously reported a series of novel small molecule inhibitors targeting PSMA. Two compounds, MIP-1072, (S)-2-(3-((S)-1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedioic acid, and MIP-1095, (S)-2-(3-((S)-1carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedioic acid, were selected for further evaluation. MIP-1072 and MIP-1095 potently inhibited the glutamate carboxypeptidase activity of PSMA (K(i) = 4.6 +/- 1.6 nmol/L and 0.24 +/- 0.14 nmol/L, respectively) and, when radiolabeled with (123)I, exhibited high affinity for PSMA on human prostate cancer LNCaP cells (K(d) = 3.8 +/- 1.3 nmol/L and 0.81 +/- 0.39 nmol/L, respectively). The association of [(123)I]MIP-1072 and [(123)I]MIP-1095 with PSMA was specific; there was no binding to human prostate cancer PC3 cells, which lack PSMA, and binding was abolished by coincubation with a structurally unrelated NAALADase inhibitor, 2-(phosphonomethyl)pentanedioic acid (PMPA). [(123)I]MIP-1072 and [(123)I]MIP-1095 internalized into LNCaP cells at 37 degrees C. Tissue distribution studies in mice showed 17.3 +/- 6.3% (at 1 hour) and 34.3 +/- 12.7% (at 4 hours) injected dose per gram of LNCaP xenograft tissue, for [(123)I]MIP-1072 and [(123)I]MIP-1095, respectively. [(123)I]MIP-1095 exhibited greater tumor uptake but slower washout from blood and nontarget tissues compared with [(123)I]MIP-1072. Specific binding to PSMA in vivo was shown by competition with PMPA in LNCaP xenografts, and the absence of uptake in PC3 xenografts. The uptake of [(123)I]MIP-1072 and [(123)I]MIP-1095 in tumor-bearing mice was corroborated by single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. PSMA-specific radiopharmaceuticals should provide a novel molecular targeting option for the detection and staging of prostate cancer.

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Author and article information

Contributors

Uwe Haberkorn: +49-6221-567731 , +49-6221-565473 , uwe.haberkorn@med.uni-heidelberg.de

Journal

Journal ID (nlm-ta): Eur J Nucl Med Mol Imaging

Journal ID (iso-abbrev): Eur. J. Nucl. Med. Mol. Imaging

Title: European Journal of Nuclear Medicine and Molecular Imaging

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 1619-7070

ISSN (Electronic): 1619-7089

Publication date (Electronic): 28 February 2014

Publication date PMC-release: 28 February 2014

Publication date (Print): 2014

Volume: 41

Pages: 1280-1292

Affiliations

[ ]Department of Nuclear Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany

[ ]Molecular Insight Pharmaceuticals, Boston, MA USA

[ ]Radiation Dosimetry Systems RDS, Inc., Apharetta, GA USA

[ ]Department of Urology, University Hospital Heidelberg, Heidelberg, Germany

[ ]Division Radiopharmaceutical Chemistry, DKFZ, Heidelberg, Germany

[ ]Department of Radiation Oncology, University Hospital Heidelberg, Heidelberg, Germany

[ ]Clinical Cooperation Unit Nuclear Medicine, DKFZ, Heidelberg, Germany

[ ]Division of Radiopharmacy, Department of Radiology, Cornell University, New York, NY USA

Article

Publisher ID: 2713

DOI: 10.1007/s00259-014-2713-y

PMC ID: 4052014

PubMed ID: 24577951

SO-VID: 4473643c-c589-408f-924f-7505d76812f7

License:

Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

History

Date received : 2 October 2013

Date accepted : 20 January 2014

Custom metadata

ScienceOpen disciplines: Radiology & Imaging

Keywords: prostate cancer,psma targeting,radioiodinated psma ligand,biodistribution,absorbed dose estimates,dosimetry

Data availability:

ScienceOpen disciplines: Radiology & Imaging

Keywords: prostate cancer, psma targeting, radioiodinated psma ligand, biodistribution, absorbed dose estimates, dosimetry