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Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2

Vilhelmsson Timmermand, O. LU ; Larsson, Erik LU ; Ulmert, D.; Tran, T. A. LU and Strand, S. E. LU (2016) In EJNMMI Research 6(1).
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Lu, Lu-m11B6, 11B6, Dosimetry, hK2, Human kallikrein-related peptidase 2, Prostate cancer, Radioimmunotherapy
in
EJNMMI Research
volume
6
issue
1
publisher
BioMed Central
external identifiers
  • scopus:84961678006
  • wos:000373425100002
ISSN
2191-219X
DOI
10.1186/s13550-016-0181-z
language
English
LU publication?
yes
id
abc1d0fd-9fa4-41bd-bb0b-ebb24ba2196c
date added to LUP
2016-04-27 14:56:08
date last changed
2017-01-01 08:23:50
@article{abc1d0fd-9fa4-41bd-bb0b-ebb24ba2196c,
  abstract     = {<p>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 <sup>177</sup>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 <sup>177</sup>Lu. Therapy planning was done from a biokinetic study in LNCaP xenografts, and therapeutic activities of <sup>177</sup>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 <sup>177</sup>Lu-m11B6. No therapeutic effect was seen in the control groups. The median survival for the lowest given activity of <sup>177</sup>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. <sup>177</sup>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.</p>},
  articleno    = {27},
  author       = {Vilhelmsson Timmermand, O. and Larsson, Erik and Ulmert, D. and Tran, T. A. and Strand, S. E.},
  issn         = {2191-219X},
  keyword      = {Lu,Lu-m11B6,11B6,Dosimetry,hK2,Human kallikrein-related peptidase 2,Prostate cancer,Radioimmunotherapy},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {EJNMMI Research},
  title        = {Radioimmunotherapy of prostate cancer targeting human kallikrein-related peptidase 2},
  url          = {http://dx.doi.org/10.1186/s13550-016-0181-z},
  volume       = {6},
  year         = {2016},
}