In vivo evaluation of 177Lu-labeled h11B6, a humanized antibody for hK2 targeting in prostate cancer

Objectives Human kallikrein-related peptidase 2 (hK2) is an androgen receptor (AR) regulated serine protease, that is abundantly and highly specifically expressed in both healthy and malignant prostatic tissues. Earlier work by our group showed that radioimmunotherapy with a 177Lu-labelled murine version of the hK2-targeting 11B6 antibody resulted in complete regression or significant reduction of tumor burden in prostate cancer (PCa) xenografted mice. Here we performed a preparative in vivo evaluation of the humanized version of 11B6 antibody, h11B6 for future radioimmunotherapy

Methods The h11B6 antibody was conjugated with CHX-A''-DTPA and labeled with 177Lu. Affinity measurements of the unconjugated and DTPA-conjugated h11B6 were investigated using Biacore. Biodistribution studies with 177Lu-DTPA-h11B6 were performed in an AR-regulated (LNCaP) PCa xenograft model up to 168 h post-injection (hpi). The absorbed dose to organs was calculated using Monte Carlo simulated S-factors from the Moby mouse phantom.

Results The affinity (KD) was 65 ± 25 x 10-11 M for h11B6 and 93 ± 78 x 10-11 M for DTPA-h11B6. Tumor uptake of 177Lu-DTPA-h11B6 was increasing from 7.11 ± 2.57 %IA/g at 4 hpi to 27.6 ± 8.82 %IA/g at 168 hpi, giving a tumor-to-blood ratio of 0.39 and 3.53 respectively. Lower uptake in other organs was seen, except for the salivary glands. The calculated absorbed dose was 2.2 Gy/MBq for the tumor and 0.39 Gy/MBq for the bone marrow

Conclusions 177Lu-labeled h11B6 targets hK2-expressing AR-regulated PCa xenografts as well as the parental murine 11B6. Radioimmunotherapy in animals are under investigation.

Research Support Swedish Cancer Foundation, Swedish Research Council, Mrs. Berta Kamprad Foundation, Gunnar Nilsson Cancer Foundation, Medical Faculty ALF grant, Lund University and Percy Falk Foundation.