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Theranostics 2017; 7(9):2350-2362. doi:10.7150/thno.19119 This issue Cite

Research Paper

[¹⁷⁷Lu]pentixather: Comprehensive Preclinical Characterization of a First CXCR4-directed Endoradiotherapeutic Agent

Margret Schottelius^1✉, Theresa Osl¹, Andreas Poschenrieder¹, Frauke Hoffmann¹, Seval Beykan⁴, Heribert Hänscheid⁴, Andreas Schirbel⁴, Andreas K. Buck⁴, Saskia Kropf⁵, Markus Schwaiger^{3, 6}, Ulrich Keller^{2, 6}, Michael Lassmann⁴, Hans-Jürgen Wester¹

1. Chair for Pharmaceutical Radiochemistry, Technische Universität München, Walther-Meissner-Strasse 3, 85748 Garching, Germany;
2. III. Medical Department, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 Munich, Germany;
3. Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, 81675 Munich, Germany;
4. Department of Nuclear Medicine, Universität Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany;
5. Scintomics GmbH, Lindach 4, 82256 Fürstenfeldbruck, Germany;
6. Deutsches Konsortium für translationale Krebsforschung (DKTK) and Deutsches Krebsforschungszentrum (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.

✉ Corresponding author: PD Dr. Margret Schottelius, Chair for Pharmaceutical Radiochemistry, Technische Universität München, Walther-Meissner-Strasse 3, 85748 Garching, Germany m.schotteliusde Phone 0049 89 289 12258 Fax 0049 89 289 12204 More

Abstract

Purpose: Based on the clinical relevance of the chemokine receptor 4 (CXCR4) as a molecular target in cancer and on the success of [⁶⁸Ga]pentixafor as an imaging probe for high-contrast visualization of CXCR4-expression, the spectrum of clinical CXCR4-targeting was expanded towards peptide receptor radionuclide therapy (PRRT) by the development of [¹⁷⁷Lu]pentixather.

Experimental design: CXCR4 affinity, binding specificity, hCXCR4 selectivity and internalization efficiency of [¹⁷⁷Lu]pentixather were evaluated using different human and murine cancer cell lines. Biodistribution studies (1, 6, 48, 96h and 7d p.i.) and in vivo metabolite analyses were performed using Daudi-lymphoma bearing SCID mice. Extrapolated organ doses were cross-validated with human dosimetry (pre-therapeutic and during [¹⁷⁷Lu]pentixather PRRT) in a patient with multiple myeloma (MM).

Results: [¹⁷⁷Lu]pentixather binds with high affinity, specificity and selectivity to hCXCR4 and shows excellent in vivo stability. Consequently, and supported by >96% plasma protein binding and a logP=-1.76, delaying whole-body clearance of [¹⁷⁷Lu]pentixather, tumor accumulation was high and persistent, both in the Daudi model and the MM patient. Tumor/background ratios (7d p.i.) in mice were 499±202, 33±7, 4.0±0.8 and 116±22 for blood, intestine, kidney and muscle, respectively. In the patient, high tumor/kidney and tumor/liver dose ratios of 3.1 and 6.4 were observed during [¹⁷⁷Lu]pentixather PRRT (7.8 GBq), with the kidneys being the dose-limiting organs.

Conclusions: [¹⁷⁷Lu]pentixather shows excellent in vivo CXCR4-targeting characteristics and a suitable pharmacokinetic profile, leading to high tumor uptake and retention and thus high radiation doses to tumor tissue during PRRT, suggesting high clinical potential of this [⁶⁸Ga]pentixafor/[¹⁷⁷Lu]pentixather based CXCR4-targeted theranostic concept.

Keywords: CXCR4, pentixafor, pentixather, PRRT, endoradiotherapy.

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