Targeted beta therapy of prostate cancer with (177)Lu-labelled Miltuximab(R) antibody against glypican-1 (GPC-1)

Yeh, M. C. and Tse, B. W. C. and Fletcher, N. L. and Houston, Z. H. and Lund, M. and Volpert, M. and Stewart, C. and Sokolowski, K. A. and Jeet, V. and Thurecht, K. J. and Campbell, D. H. and Walsh, B. J. and Nelson, C. C. and Russell, P. J.
EJNMMI Res 10, 46 (2020).
Publication year: 2020
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Purpose

Chimeric antibody Miltuximab®, a human IgG1 engineered from the parent antibody MIL-38, is in clinical development for solid tumour therapy. Miltuximab® targets glypican-1 (GPC-1), a cell surface protein involved in tumour growth, which is overexpressed in solid tumours, including prostate cancer (PCa). This study investigated the potential of 89Zr-labelled Miltuximab® as an imaging agent, and 177Lu-labelled Miltuximab® as a targeted beta therapy, in a mouse xenograft model of human prostate cancer.

Methods

Male BALB/c nude mice were inoculated subcutaneously with GPC-1-positive DU-145 PCa cells. In imaging and biodistribution studies, mice bearing palpable tumours received (a) 2.62 MBq [89Zr]Zr-DFO-Miltuximab® followed by PET-CT imaging, or (b) 6 MBq [177Lu]Lu-DOTA-Miltuximab® by Cerenkov imaging, and ex vivo assessment of biodistribution. In an initial tumour efficacy study, mice bearing DU-145 tumours were administered intravenously with 6 MBq [177Lu]Lu-DOTA-Miltuximab® or control DOTA-Miltuximab® then euthanised after 27 days. In a subsequent survival efficacy study, tumour-bearing mice were given 3 or 10 MBq of [177Lu]Lu-DOTA-Miltuximab®, or control, and followed up to 120 days.

Results

Antibody accumulation in DU-145 xenografts was detected by PET-CT imaging using [89Zr]Zr-DFO-Miltuximab® and confirmed by Cerenkov luminescence imaging post injection of [177Lu]Lu-DOTA-Miltuximab®. Antibody accumulation was higher (% IA/g) in tumours than other organs across multiple time points. A single injection with 6 MBq of [177Lu]Lu-DOTA-Miltuximab® significantly inhibited tumour growth as compared with DOTA-Miltuximab® (control). In the survival study, mice treated with 10 MBq [177Lu]Lu-DOTA-Miltuximab® had significantly prolonged survival (mean 85 days) versus control (45 days), an effect associated with increased cancer cell apoptosis. Tissue histopathology assessment showed no abnormalities associated with [177Lu]Lu-DOTA-Miltuximab®, in line with other observations of tolerability, including body weight stability.

Conclusion

These findings demonstrate the potential utility of Miltuximab® as a PET imaging agent ([89Zr]Zr-DFO-Miltuximab®) and a beta therapy ([177Lu]Lu-DOTA-Miltuximab®) in patients with PCa or other GPC-1 expressing tumours.