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Radioimmunoimaging and Radioimmunotherapy of Prostate Cancer Preclinical evaluation of kallikrein related peptidase 2 targeting

Vilhelmsson Timmermand, Oskar LU (2014)
Abstract (Swedish)
Popular Abstract in Swedish

Prostatacancer är Sveriges vanligaste cancersjukdom bland män. Många av de som diagnosticeras med prostatacancer får inga besvär men cirka 2400 män dör årligen av sjukdomen. Det finns flera behandlingsmetoder mot prostatacancer, men för kastrationsresistent prostatacancer, en avancerad form av prostatacancer, finns idag ingen botande behandling. Det utvecklas dock allt fler nya behandlingsmetoder. Det saknas också metoder för att på ett pålitligt sätt kunna utvärdera behandlingseffekten.

De bildgivande metoderna PET/CT och SPECT/CT har blivit allt mer viktigt inom cancerdiagnostik och bygger på användning av radioaktivt målsökande ämnen som tas upp specifikt av cancerceller. Genom att... (More)
Popular Abstract in Swedish

Prostatacancer är Sveriges vanligaste cancersjukdom bland män. Många av de som diagnosticeras med prostatacancer får inga besvär men cirka 2400 män dör årligen av sjukdomen. Det finns flera behandlingsmetoder mot prostatacancer, men för kastrationsresistent prostatacancer, en avancerad form av prostatacancer, finns idag ingen botande behandling. Det utvecklas dock allt fler nya behandlingsmetoder. Det saknas också metoder för att på ett pålitligt sätt kunna utvärdera behandlingseffekten.

De bildgivande metoderna PET/CT och SPECT/CT har blivit allt mer viktigt inom cancerdiagnostik och bygger på användning av radioaktivt målsökande ämnen som tas upp specifikt av cancerceller. Genom att fästa terapeutiskt radioaktiva spårämnen på samma målsökande molekyler kan dessa användas för behandling. Användning av dessa metoder skulle kunna ge möjlighet att effektivt behandla avancerad prostatacancer vid tidigt stadium liksom möjlighet till att utvärdera sjukdomens förlopp, något som är svårt idag.

Den här doktorsavhandlingen beskriver utveckling av radiomärkta målsökande antikroppar för diagnostik och behandling av prostatacancer i djurmodeller. Här används antikroppen 11B6 för att målsöka ett protein, humant kallikrein peptidas 2 (hK2), som det finns mycket av i prostatacancer. För diagnostik används radionukliden indium-111 och för behandling används radionukliden lutetium-177. Dessa s.k. radio-immunokonjugat har sedan testats i möss, som delvis saknar immunförsvar så att mänskliga prostatacancerceller kan växa i dem. Dessa prostatacancerceller har fått växa under huden eller i ben, och bilda tumörer i mössen. Antikroppens förmåga att tas upp i cancern jämfört med mängden i vanliga organ studerades i dessa möss. Detta kan i vårt fall göras med SPECT-kamera men också genom direkt mätning av hur mycket radioaktivt ämne som finns ansamlat i olika organ.

Resultat visade att den indium-märkta antikroppen specifikt målsökte prostatacancertumörer och tydligt kunde avbilda prostatacancertumörerna. Vi utvärderade även de lutetium-märkta antikropparna för behandling. Det visade en tydlig effekt då tumörerna minskade i storlek och de behandlade djuren överlevde längre jämfört med icke behandlade. Vi räknade också ut ungefär hur giftig den mängd injicerad radioaktiv antikropp var för musen, så kallad dosimetriberäkning. I en studie utvärderades en ny metod för att titta på upptag av radioaktiva ämnen i subkutana tumörer som är snabbare och billigare än SPECT denna kallas och utnyttjar det synliga ljus, sk CLI, som avges när en viss strålning rör sig genom vävnad. Resultatet visade att CLI gav värden som överensstämde med SPECT detta kan användas för att snabbt avgöra upptaget och uppskatta dosen av till exempel den lutetium inmärkta antikroppen.

Sammanfattningsvis är resultaten lovande och hK2 kommer antagligen att fortsätta undersökas som mål för radioimmunoterapi och diagnostik (Less)
Abstract
Prostate cancer is one of the major causes of cancer related deaths in men in Europe and the United States. In this doctoral thesis, radioimmunoimaging and -therapy of prostate cancer was investigated pre-clinically by targeting the human kallikrein-related peptidase 2 (hK2) with radiolabelled monoclonal antibodies. hK2 is an antigen that is over-expressed in prostatic neoplasms and is closely related to prostate-specific antigen. The anti-hK2 monoclonal antibody 11B6 was radiolabelled with 111In or 177Lu for targeting of hK2-expressing LNCaP xenografts in nude or SCID mice.

Biodistribution, pre-clinical SPECT/CT imaging, Cerenkov Luminescence Imaging (CLI), dosimetry calculations and therapy studies were performed to evaluate the... (More)
Prostate cancer is one of the major causes of cancer related deaths in men in Europe and the United States. In this doctoral thesis, radioimmunoimaging and -therapy of prostate cancer was investigated pre-clinically by targeting the human kallikrein-related peptidase 2 (hK2) with radiolabelled monoclonal antibodies. hK2 is an antigen that is over-expressed in prostatic neoplasms and is closely related to prostate-specific antigen. The anti-hK2 monoclonal antibody 11B6 was radiolabelled with 111In or 177Lu for targeting of hK2-expressing LNCaP xenografts in nude or SCID mice.

Biodistribution, pre-clinical SPECT/CT imaging, Cerenkov Luminescence Imaging (CLI), dosimetry calculations and therapy studies were performed to evaluate the targeting properties and therapeutic efficacy of the three tested radioimmunoconjugates (111In-m11B6, 177Lu-m11B6 and 177Lu-h11B6). SPECT/CT imaging showed that 111In-m11B6 targeted specifically hK2 and could clearly visualize the subcutaneous and intra-tibial LNCaP xenografts (paper I).

Therapy studies of LNCaP xenograft models with 177Lu-labelled radioimmunoconjugates showed distinctive effects on the tumor volume and survival compared to the control groups. 177Lu-m11B6 gave a median survival close to 100% at 120 days when 36 MBq of activity was administrated (paper II). The humanized 177Lu-h11B6 showed a median survival of 77 days when 16 MBq was administrated compared to that of 37 days for the control groups and a reversible myeloid toxicity could be seen (paper IV).

The use of CLI for assessment of individual biokinetics was tested. The correlation between CLI and SPECT was good as well as the correlation between CLI and ex vivo specific uptake measurements. The presented normalization schemes can serve as a first approach to relating the CLI radiance to the specific uptake (%IA/g) in subcutaneous xenografts (paper III).

In summary, these studies proved the possibility of hK2 targeting using different radioimmunoconjugates, two murine predecessors and one humanized. A single administration of 177Lu labeled immunoconjugate was enough to significantly prolong the life of the treated mice compared to controls. Human kallikrein-related peptidase 2 targeting was thus shown to be feasible in both radioimmunoimaging and -therapy applications based on 11B6 radioimmunoconjugates. Further, CLI was successfully explored as a rapid and inexpensive tool to evaluate uptake in subcutaneous xenografts and showed high potential for use for absorbed dose estimates. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Prof, MD, PhD Nilsson, Sten, Department of Oncology – Pathology Karolinska Institutet, Stockholm, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Radioimmunoimaging, radioimmunotherapy, antibody, 11B6, indium-111, lutetium-177, kallikrein related peptidase 2, hK2, PSA, prostate cancer, SPECT, KLK2, cherenkov luminescence imaging, CLI
pages
118 pages
publisher
Department of Medical Radiation Physics, Clinical Sciences, Lund, Lund University
defense location
Föreläsningssalen, Nya Strålbehandlingshuset, Klinikgatan 5, Lund
defense date
2014-01-16 09:00
ISBN
978-91-7623-212-5
978-91-7623-213-2
language
English
LU publication?
yes
id
77dcab06-57e1-4044-b76a-bb9845fa93ba (old id 4897246)
date added to LUP
2015-01-12 14:51:39
date last changed
2016-09-19 08:45:02
@misc{77dcab06-57e1-4044-b76a-bb9845fa93ba,
  abstract     = {Prostate cancer is one of the major causes of cancer related deaths in men in Europe and the United States. In this doctoral thesis, radioimmunoimaging and -therapy of prostate cancer was investigated pre-clinically by targeting the human kallikrein-related peptidase 2 (hK2) with radiolabelled monoclonal antibodies. hK2 is an antigen that is over-expressed in prostatic neoplasms and is closely related to prostate-specific antigen. The anti-hK2 monoclonal antibody 11B6 was radiolabelled with 111In or 177Lu for targeting of hK2-expressing LNCaP xenografts in nude or SCID mice.<br/><br>
Biodistribution, pre-clinical SPECT/CT imaging, Cerenkov Luminescence Imaging (CLI), dosimetry calculations and therapy studies were performed to evaluate the targeting properties and therapeutic efficacy of the three tested radioimmunoconjugates (111In-m11B6, 177Lu-m11B6 and 177Lu-h11B6). SPECT/CT imaging showed that 111In-m11B6 targeted specifically hK2 and could clearly visualize the subcutaneous and intra-tibial LNCaP xenografts (paper I).<br/><br>
Therapy studies of LNCaP xenograft models with 177Lu-labelled radioimmunoconjugates showed distinctive effects on the tumor volume and survival compared to the control groups. 177Lu-m11B6 gave a median survival close to 100% at 120 days when 36 MBq of activity was administrated (paper II). The humanized 177Lu-h11B6 showed a median survival of 77 days when 16 MBq was administrated compared to that of 37 days for the control groups and a reversible myeloid toxicity could be seen (paper IV).<br/><br>
The use of CLI for assessment of individual biokinetics was tested. The correlation between CLI and SPECT was good as well as the correlation between CLI and ex vivo specific uptake measurements. The presented normalization schemes can serve as a first approach to relating the CLI radiance to the specific uptake (%IA/g) in subcutaneous xenografts (paper III).<br/><br>
In summary, these studies proved the possibility of hK2 targeting using different radioimmunoconjugates, two murine predecessors and one humanized. A single administration of 177Lu labeled immunoconjugate was enough to significantly prolong the life of the treated mice compared to controls. Human kallikrein-related peptidase 2 targeting was thus shown to be feasible in both radioimmunoimaging and -therapy applications based on 11B6 radioimmunoconjugates. Further, CLI was successfully explored as a rapid and inexpensive tool to evaluate uptake in subcutaneous xenografts and showed high potential for use for absorbed dose estimates.},
  author       = {Vilhelmsson Timmermand, Oskar},
  isbn         = {978-91-7623-212-5},
  keyword      = {Radioimmunoimaging,radioimmunotherapy,antibody,11B6,indium-111,lutetium-177,kallikrein related peptidase 2,hK2,PSA,prostate cancer,SPECT,KLK2,cherenkov luminescence imaging,CLI},
  language     = {eng},
  pages        = {118},
  publisher    = {ARRAY(0xb649650)},
  title        = {Radioimmunoimaging and Radioimmunotherapy of Prostate Cancer Preclinical evaluation of kallikrein related peptidase 2 targeting},
  year         = {2014},
}