| 1. |
- Timmermand, Oskar Vilhelmsson, et al.
(författare)
-
Preclinical efficacy of hK2 targeted [177Lu]hu11B6 for prostate cancer theranostics
- 2019
-
Ingår i: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 9:8, s. 2129-2142
-
Tidskriftsartikel (refereegranskat)abstract
- 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 (225Ac), 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 (177Lu) and investigated whether similar tumor killing and AR-enhancement is produced. Moreover, single-photon emission computed tomography (SPECT) imaging of 177Lu is quantitatively accurate and can be used to perform treatment planning. [177Lu]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 [177Lu]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 [177Lu]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 [177Lu]hu11B6 revealed no peak in tumor accumulation at 7 d, probably due to cellular retention of 177Lu and decreasing tumor volumes. For [177Lu]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 177Lu 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 225Ac labeled hu11B6, however emerging at a later timepoint.
|
|
| 2. |
- Fagerberg, Björn, 1943, et al.
(författare)
-
Extremvärme ett ökande problem för globala folkhälsan
- 2016
-
Ingår i: Läkartidningen. - 0023-7205. ; 113:31-33
-
Tidskriftsartikel (refereegranskat)abstract
- High temperatures have a direct impact on body functions. Heat waves increase mortality risks due to myocardial infarction, stroke, and pulmonary disease. Cold temperatures also increase mortality, but with a longer latency. A recent study found only a small difference between the minimal mortality temperature (MMT) and the temperatures at which mortality rose steeply, although the majority of deaths occurred at temperatures below MMT. Global climate change with increasing temperatures seriously threatens health, work capacity, and generation of household incomes, particularly among poor people in hot countries. In Sweden, heat waves increase mortality in vulnerable groups of elderly people and patients with chronic heart and lung diseases, as well as those performing intensive physical work in hot environments. The medical profession can play an important role not only in prevention of climate change, but also in adaptation to climate change with the goal of minimizing health risks. © 2016, Swedish Medical Association. All rights reserved.
|
|
| 3. |
- Vilhelmsson Timmermand, O., et al.
(författare)
-
Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2
- 2016
-
Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 6:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Prostate cancer ranks as the second most lethal malignancy in the Western world. Previous targeting of prostate-specific antigen and human kallikrein-related peptidase 2, two related enzymes abundantly expressed in prostatic malignancies, with radioimmunoconjugates intended for diagnostic purposes, have proven successful in rodent prostate cancer (PCa) models. In this study, we investigated the uptake and therapeutic efficacy of 177Lu-m11B6, a human kallikrein-related peptidase 2 (hK2)-targeting radioimmunoconjugate in a pre-clinical setting. Methods: The murine 11B6 antibody, m11B6, with high affinity for hK2, was labeled with 177Lu. Therapy planning was done from a biokinetic study in LNCaP xenografts, and therapeutic activities of 177Lu-m11B6 were administered to groups of mice. Body weight and general conditions of the mice were followed over a period of 120 days. Results: The tumor uptake in LNCaP xenografts was 30 ± 8.2 % injected activity per gram 1 week post-injection. In vivo targeting was hK2-specific as verified by a 2.5-fold decrease in tumor uptake in pre-dosed xenografts or by a fourfold lower tumor accumulation in hK2-negative DU 145 xenografts. Therapy showed a dose-dependent efficacy in LNCaP xenografts treated with 177Lu-m11B6. No therapeutic effect was seen in the control groups. The median survival for the lowest given activity of 177Lu-m11B6 was 88 days compared to that of 38 days in mice given labeled non-specific IgG. For the higher administrated activities, total tumor regression was seen with minimal normal organ toxicity. Conclusions: We have proven the possibility of radioimmunotherapy targeting hK2 in subcutaneous prostate cancer xenografts. 177Lu-m11B6 exhibited high therapeutic efficacy, with low observed toxicity. Additionally, an evaluation of the concept of pre-therapy planning using a dosimetry model was included in this radioimmunotherapy study.
|
|
