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

• Published in: EJNMMI research Vol. 10; no. 1; p. 46
• Main Authors: Yeh, Mei-Chun, Tse, Brian W. C., Fletcher, Nicholas L., Houston, Zachary H., Lund, Maria, Volpert, Marianna, Stewart, Chelsea, Sokolowski, Kamil A., Jeet, Varinder, Thurecht, Kristofer J., Campbell, Douglas H., Walsh, Bradley J., Nelson, Colleen C., Russell, Pamela J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 07.05.2020; Springer Nature B.V; SpringerOpen
• Subjects: Abnormalities; Accumulation; Antibodies; Apoptosis; Bearing; Body weight; Cardiac Imaging; Computed tomography; Glypican-1; Imaging; Lutetium isotopes; Medical imaging; Medicine; Medicine & Public Health; MIL-38; Miltuximab; Novel Theragnostic Drugs; Nuclear Medicine; Oncology; Organs; Original Research; Orthopedics; Positron emission; Prostate cancer; Radiology; Radionuclide therapy; Survival; Therapy; Tomography; Tumors; Xenotransplantation; Zirconium isotopes; Miltuximab; Radionuclide therapy; Glypican-1; Prostate cancer; MIL-38
• DOI: 10.1186/s13550-020-00637-x
• ISSN: 2191-219X

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 89 Zr-labelled Miltuximab® as an imaging agent, and 177 Lu-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 [ 89 Zr]Zr-DFO-Miltuximab® followed by PET-CT imaging, or (b) 6 MBq [ 177 Lu]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 [ 177 Lu]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 [ 177 Lu]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 [ 89 Zr]Zr-DFO-Miltuximab® and confirmed by Cerenkov luminescence imaging post injection of [ 177 Lu]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 [ 177 Lu]Lu-DOTA-Miltuximab® significantly inhibited tumour growth as compared with DOTA-Miltuximab® (control). In the survival study, mice treated with 10 MBq [ 177 Lu]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 [ 177 Lu]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 ([ 89 Zr]Zr-DFO-Miltuximab®) and a beta therapy ([ 177 Lu]Lu-DOTA-Miltuximab®) in patients with PCa or other GPC-1 expressing tumours.