Preclinical efficacy of hK2 targeted [ 177 Lu]hu11B6 for prostate cancer theranostics.

Autor: Timmermand OV; Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden., Elgqvist J; Department of Medical Physics and Biomedical Engineering, Sahlgrenska University Hospital, Gothenburg, Sweden., Beattie KA; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Örbom A; Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden., Larsson E; Division of Medical Radiation Physics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden., Eriksson SE; Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden., Thorek DLJ; Department of Radiology, Washington University School of Medicine, Saint Louis, MO, 63108, USA., Beattie BJ; Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA., Tran TA; Department of Radiopharmacy, Karolinska University Hospital, Stockholm, Sweden.; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden., Ulmert D; Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.; Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles (UCLA), CA, USA., Strand SE; Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.; Division of Medical Radiation Physics, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Jazyk: angličtina
Zdroj: Theranostics [Theranostics] 2019 Apr 06; Vol. 9 (8), pp. 2129-2142. Date of Electronic Publication: 2019 Apr 06 (Print Publication: 2019).
DOI: 10.7150/thno.31179
Abstrakt: Androgen ablating drugs increase life expectancy in men with metastatic prostate cancer, but resistance inevitably develops. In a majority of these recurrent tumors, the androgen axis is reactivated in the form of increased androgen receptor (AR) expression. Targeting proteins that are expressed as a down-stream effect of AR activity is a promising rationale for management of this disease. The humanized IgG1 antibody hu11B6 internalizes into prostate and prostate cancer (PCa) cells by binding to the catalytic cleft of human kallikrein 2 (hK2), a prostate specific enzyme governed by the AR-pathway. In a previous study, hu11B6 conjugated with Actinium-225 ( 225 Ac), a high linear energy transfer (LET) radionuclide, was shown to generate an AR-upregulation driven feed-forward mechanism that is believed to enhance therapeutic efficacy. We assessed the efficacy of hu11B6 labeled with a low LET beta-emitter, Lutetium-177 ( 177 Lu) and investigated whether similar tumor killing and AR-enhancement is produced. Moreover, single-photon emission computed tomography (SPECT) imaging of 177 Lu is quantitatively accurate and can be used to perform treatment planning. [ 177 Lu]hu11B6 therefore has significant potential as a theranostic agent. Materials and Methods : Subcutaneous PCa xenografts (LNCaP s.c.) were grown in male mice. Biokinetics at 4-336 h post injection and uptake as a function of the amount of hu11B6 injected at 72 h were studied. Over a 30 to 120-day treatment period the therapeutic efficacy of different activities of [ 177 Lu]hu11B6 were assessed by volumetric tumor measurements, blood cell counts, molecular analysis of the tumor as well as SPECT/CT imaging. Organ specific mean absorbed doses were calculated, using a MIRD-scheme, based on biokinetic data and rodent specific S-factors from a modified MOBY phantom. Tumor tissues of treated xenografts were immunohistochemically (IHC) stained for Ki-67 (proliferation) and AR, SA-β-gal activity (senescence) and analyzed by digital autoradiography (DAR). Results : Organ-to-blood and tumor-to-blood ratios were independent of hu11B6 specific activity except for the highest amount of antibody (150 µg). Tumor accumulation of [ 177 Lu]hu11B6 peaked at 168 h with a specific uptake of 29 ± 9.1 percent injected activity per gram (%IA/g) and low accumulation in normal organs except in the submandibular gland (15 ± 4.5 %IA/g), attributed to a cross-reaction with mice kallikreins in this organ, was seen. However, SPECT imaging with therapeutic amounts of [ 177 Lu]hu11B6 revealed no peak in tumor accumulation at 7 d, probably due to cellular retention of 177 Lu and decreasing tumor volumes. For [ 177 Lu]hu11B6 treated mice, tumor decrements of up to 4/5 of the initial tumor volume and reversible myelotoxicity with a nadir at 12 d were observed after a single injection. Tumor volume reduction correlated with injected activity and the absorbed dose. IHC revealed retained expression of AR throughout treatment and that Ki-67 staining reached a nadir at 9-14 d which coincided with high SA- β-gal activity (14 d). Quantification of nuclei staining showed that Ki-67 expression correlated negatively with activity uptake. AR expression levels in cells surviving therapy compared to previous timepoints and to controls at 30 d were significantly increased (p = 0.017). Conclusions : This study shows that hu11B6 labeled with the low LET beta-emitting radionuclide 177 Lu can deliver therapeutic absorbed doses to prostate cancer xenografts with transient hematological side-effects. The tumor response correlated with the absorbed dose both on a macro and a small scale dosimetric level. Analysis of AR staining showed that AR protein levels increased late in the study suggesting a therapeutic mechanism, a feed forward mechanism coupled to AR driven response to DNA damage or clonal lineage selection, similar to that reported in high LET alpha-particle therapy using 225 Ac labeled hu11B6, however emerging at a later timepoint.
Competing Interests: Competing interests: Sven-Erik Strand, David Ulmert and Dan Thorek are shareholders in Diaprost AB who owns the commercial rights for hu11B6 and hold patents for its applications. Sven-Erik Strand and David Ulmert are authors on several patents protecting the use of radiolabeled 11B6. Oskar Vilhelmsson Timmermand and Thuy Tran are the co-authors of a patent, held by Diaprost AB, on humanized 11B6.
Databáze: MEDLINE
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