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

Research Paper

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

Margret Schottelius1✉, Theresa Osl1, Andreas Poschenrieder1, Frauke Hoffmann1, Seval Beykan4, Heribert Hänscheid4, Andreas Schirbel4, Andreas K. Buck4, Saskia Kropf5, Markus Schwaiger3, 6, Ulrich Keller2, 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.


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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How to cite this article:
Schottelius M, Osl T, Poschenrieder A, Hoffmann F, Beykan S, Hänscheid H, Schirbel A, Buck AK, Kropf S, Schwaiger M, Keller U, Lassmann M, Wester HJ. [177Lu]pentixather: Comprehensive Preclinical Characterization of a First CXCR4-directed Endoradiotherapeutic Agent. Theranostics 2017; 7(9):2350-2362. doi:10.7150/thno.19119. Available from