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Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2

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 diagnosti...

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Autores principales: Vilhelmsson Timmermand, O., Larsson, E., Ulmert, D., Tran, T. A., Strand, SE.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4797400/
https://www.ncbi.nlm.nih.gov/pubmed/26983637
http://dx.doi.org/10.1186/s13550-016-0181-z
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author Vilhelmsson Timmermand, O.
Larsson, E.
Ulmert, D.
Tran, T. A.
Strand, SE.
author_facet Vilhelmsson Timmermand, O.
Larsson, E.
Ulmert, D.
Tran, T. A.
Strand, SE.
author_sort Vilhelmsson Timmermand, O.
collection PubMed
description 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 (177)Lu-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 (177)Lu. Therapy planning was done from a biokinetic study in LNCaP xenografts, and therapeutic activities of (177)Lu-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 (177)Lu-m11B6. No therapeutic effect was seen in the control groups. The median survival for the lowest given activity of (177)Lu-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. (177)Lu-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.
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spelling pubmed-47974002016-07-06 Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2 Vilhelmsson Timmermand, O. Larsson, E. Ulmert, D. Tran, T. A. Strand, SE. EJNMMI Res Original Research 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 (177)Lu-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 (177)Lu. Therapy planning was done from a biokinetic study in LNCaP xenografts, and therapeutic activities of (177)Lu-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 (177)Lu-m11B6. No therapeutic effect was seen in the control groups. The median survival for the lowest given activity of (177)Lu-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. (177)Lu-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. Springer Berlin Heidelberg 2016-03-17 /pmc/articles/PMC4797400/ /pubmed/26983637 http://dx.doi.org/10.1186/s13550-016-0181-z Text en © Vilhelmsson Timmermand et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research
Vilhelmsson Timmermand, O.
Larsson, E.
Ulmert, D.
Tran, T. A.
Strand, SE.
Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2
title Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2
title_full Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2
title_fullStr Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2
title_full_unstemmed Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2
title_short Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2
title_sort radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4797400/
https://www.ncbi.nlm.nih.gov/pubmed/26983637
http://dx.doi.org/10.1186/s13550-016-0181-z
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