Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Yeh MC

PROVIDER: S-EPMC7206480 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Yeh Mei-Chun MC Tse Brian W C BWC Fletcher Nicholas L NL Houston Zachary H ZH Lund Maria M Volpert Marianna M Stewart Chelsea C Sokolowski Kamil A KA Jeet Varinder V Thurecht Kristofer J KJ Campbell Douglas H DH Walsh Bradley J BJ Nelson Colleen C CC Russell Pamela J PJ

EJNMMI research 20200507 1

<h4>Purpose</h4>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 <sup>89</sup>Zr-labelled Miltuximab® as an imaging agent, and <sup>177</sup>Lu-labelled Miltuximab® as a targeted beta therapy, in a mouse ...[more]

PMID: 32382920

Similar Datasets

Project description:RIT has become an attractive strategy in cancer treatment, but still faces important drawbacks due to poor tumor penetration and undesirable pharmacokinetics of the targeting vehicles. Smaller radiolabeled antibody fragments and peptides feature highly specific target accumulation, resulting in low accumulation in healthy tissue, except for the kidneys. Nanobodies are the smallest (MW<15 kDa) functional antigen-binding fragments that are derived from heavy chain-only camelid antibodies. Here, we show that the extend of kidney retention of nanobodies is predominantly dictated by the number of polar residues in the C-terminal amino acid tag. Three nanobodies were produced with different C-terminal amino-acid tag sequences (Myc-His-tagged, His-tagged, and untagged). Dynamic planar imaging of Wistar rats with 111In-DTPA-nanobodies revealed that untagged nanobodies showed a 70% drop in kidney accumulation compared to Myc-His-tagged nanobodies at 50 min p.i.. In addition, coinfusion of untagged nanobodies with the plasma expander Gelofusin led to a final reduction of 90%. Similar findings were obtained with different 177Lu-DTPA-2Rs15d nanobody constructs in HER2pos tumor xenografted mice at 1 h p.i.. Kidney accumulation decreased 88% when comparing Myc-His-tagged to untagged 2Rs15d nanobody, and 95% with a coinfusion of Gelofusin, without affecting the tumor targeting capacity. Consequently, we identified a generic method to reduce kidney retention of radiolabeled nanobodies. Dosimetry calculations of Gelofusin-coinfused, untagged 177Lu-DTPA-2Rs15d revealed a dose of 0.90 Gy/MBq that was delivered to both tumor and kidneys and extremely low doses to healthy tissues. In a comparative study, 177Lu-DTPA-Trastuzumab supplied 6 times more radiation to the tumor than untagged 177Lu-DTPA-2Rs15d, but concomitantly also a 155, 34, 80, 26 and 4180 fold higher radioactivity burden to lung, liver, spleen, bone and blood. Most importantly, nanobody-based targeted radionuclide therapy in mice bearing small estiblashed HER2pos tumors led to an almost complete blockade of tumor growth and a significant difference in event-free survival between the treated and the control groups (P<0.0001). Based on histology analyses, no evidence of renal inflammation, apoptosis or necrosis was obtained. In conclusion, these data highlight the importance of the amino acid composition of the nanobody's C-terminus, as it has a predominant effect on kidney retention. Moreover, we show successful nanobody-based targeted radionuclide therapy in a xenograft model and highlight the potential of radiolabeled nanobodies as a valuable adjuvant therapy candidate for treatment of minimal residual and metastatic disease.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets