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

Sammanfattning: 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.