title: Proof of Therapeutic Efficacy of a177Lu-Labeled Neurotensin Receptor 1 Antagonist in a Colon Carcinoma Xenograft Model.
abstract: Increased expression of neurotensin receptor 1 (NTR1) has been shown in a large number of tumor entities such as pancreatic or colon carcinoma. Hence, this receptor is a promising target for diagnostic imaging and radioligand therapy. Using the favorable biodistribution data of the NTR1-targeting agent111In-3BP-227, we investigated the therapeutic effect of its177Lu-labeled analog on the tumor growth of NTR1-positive HT29 colon carcinoma xenografts.Methods:3BP-227 was labeled with177Lu. To assess its biodistribution properties, SPECT and CT scans of HT29-xenografted nude mice injected with177Lu-3BP-227 were acquired, and ex vivo tissue activity was determined. To evaluate therapeutic efficacy, 2 groups of mice received the radiopharmaceutical in a median dose of either 165 MBq (129-232 MBq,n= 10) or 110 MBq (82-116 MBq,n= 10), whereas control mice were injected with vehicle (n= 10). Tumor sizes and body weights were monitored for up to 49 d. Renal function and histologic morphology were evaluated.Results:Whole-body SPECT/CT images allowed clear tumor visualization with low background activity and high tumor-to-kidney and -liver ratios. Ex vivo biodistribution data confirmed high and persistent uptake of177Lu-3BP-227 in HT29 tumors (19.0 ± 3.6 vs. 2.7 ± 1.6 percentage injected dose per gram at 3 and 69 h after injection, respectively). The application of177Lu-3BP-227 resulted in a distinct delay of tumor growth. Median tumor doubling time for controls was 5.5 d (interquartile range [IQR], 2.8-7.0), compared with 17.5 d (IQR, 5.5-22.5 d) for the 110-MBq and 41.0 d (IQR, 27.5-55.0) for the 165-MBg group. Compared with controls, median relative tumor volume at day 23 after injection was reduced by 55% (P= 0.034) in the 110-MBq and by 88% (P< 0.01) in the 165-MBq group. Renal histology and clinical chemistry results did not differ between radiotherapy groups and controls, suggesting absence of therapy-induced acute renal damage.Conclusion:These data demonstrate that the novel NTR1-targeting theranostic agent 3BP-227 is an effective and promising candidate for radioligand therapy, with a favorable preliminary safety profile and high potential for clinical translation.
authors.affiliation: Klinik für Radiologie und Nuklearmedizin, Otto-von-Guericke Universität, Magdeburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schulz
authors.affiliation: Klinik für Radiologie und Nuklearmedizin, Otto-von-Guericke Universität, Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Rohracker
authors.affiliation: Klinik für Radiologie und Nuklearmedizin, Otto-von-Guericke Universität, Magdeburg, Germany.
authors.forename: Marvin
authors.initials: M
authors.lastname: Stiebler
authors.affiliation: Leibniz-Institut für Neurobiologie, Magdeburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Goldschmidt
authors.affiliation: Klinik für Radiologie und Nuklearmedizin, Otto-von-Guericke Universität, Magdeburg, Germany.|Leibniz-Institut für Neurobiologie, Magdeburg, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Stöber
authors.affiliation: Institut für Pathologie, Universitätsklinik Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Noriega
authors.affiliation: Klinik für Radiologie und Nuklearmedizin, Otto-von-Guericke Universität, Magdeburg, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Pethe
authors.affiliation: Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.|Siemens Healthcare GmbH, Erlangen, Germany; and.
authors.forename: Mathias
authors.initials: M
authors.lastname: Lukas
authors.affiliation: 3B Pharmaceuticals GmbH, Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Osterkamp
authors.affiliation: 3B Pharmaceuticals GmbH, Berlin, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Reineke
authors.affiliation: 3B Pharmaceuticals GmbH, Berlin, Germany.
authors.forename: Aileen
authors.initials: A
authors.lastname: Höhne
authors.affiliation: 3B Pharmaceuticals GmbH, Berlin, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Smerling
authors.affiliation: Klinik für Radiologie und Nuklearmedizin, Otto-von-Guericke Universität, Magdeburg, Germany holger.amthauer@charite.de.|Department of Nuclear Medicine, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Amthauer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D019073:HT29 Cells; D006801:Humans; D008187:Lutetium / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy / Q000379:methods*; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D000068936:Theranostic Nanomedicine / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D019275:Radiopharmaceuticals; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D008187:Lutetium
keywords: NTR1 radiotracer; SPECT/CT; oncology; theranostic; xenograft