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 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.

Role of glypican-1 in regulating multiple cellular signaling pathways

“…In addition to its potential diagnostic value, GPC1 has been evaluated as a potential target for antibody-based strategies, including anti-GPC1 mAb (11,88), antibodydrug conjugates (ADC) (89,90), CAR-T cell therapy (88,91), radiotherapy (92), photoimmunotherapy (93), and bispecific T cell engager (BiTE) (94) in preclinical settings (Table 2).…”

Radioimmunotherapy for solid tumors: spotlight on Glypican-1 as a radioimmunotherapy target

“…Importantly, the treatment was well tolerated with no adverse safety signals, which included assessment of organ histopathology. 117 Rationale for the targeting of GPC-1 for the delivery of therapeutic radiolabel is supported The use of alpha-emitters such as 213 Bi and Actinium-225 ( 225 Ac) as a component of targeted therapy has shown great promise both preclinically and clinically. 121 In prostate cancer (with metastatic bone disease), for example, the United States Food and Drug Administration (FDA) in 2018 approved the use of the first alpha-emitter, Radium 223 ( 223 Ra).…”

“…Preclinical studies have demonstrated the utility of GPC-1 as an RIT target for the imaging and therapy of prostate tumors. 117 Miltuximab® radiolabeled with 89 Zirconium via a DFO chelate was used for the PET visualization of DU-145 tumor xenografts in mice. The study demonstrated specific accumulation and retention of the antibody in the tumor out to 7 days, which was the experimental endpoint, as well as expected clearance in normal organs including the liver.…”

“…Importantly, the treatment was well tolerated with no adverse safety signals, which included assessment of organ histopathology. 117 …”

RetroSPECT: Gallium-67 As A Theranostic Imaging Agent

“…GPC-1 is a heparan sulfate proteoglycan (HSPGs) that is not expressed in normal adult tissues but is overexpressed in a range of tumours (39) . Pre-clinical studies have demonstrated potential for Miltuximab® as a radioimmunotherapy for solid tumours (40). We undertook the study to assess the safety, tolerability and biodistribution of gallium-67-labelled Miltuximab in patients with advanced solid tumours.…”