MILGa-01: A first-in-human study assessing the safety and tolerability of chMIL-38 in metastatic prostate, bladder, and pancreatic cancers.

Sabanathan, Dhanusha; Gillatt, David; Poursoultan, Pirooz; Ho‐Shon, Kevin; Walsh, Bradley J.; Velonas, Vicki; Thurecht, Kristofer J.; Campbell, Douglas Houghton

doi:10.1200/jco.2017.35.6_suppl.e565

Cited by 3 publications

(5 citation statements)

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“…It should be noted that Miltuximab® does not cross-react with mouse GPC-1, so the safety data must be interpreted carefully, as the impact of any potential binding of the conjugate to normal tissue has not been assessed. However, expression of GPC-1 is not expected in normal tissue [7] and Miltuximab® labelled with 67 Ga has proven safe in first in a human study [16]. Expression of GPC-1 in PCa is well established and correlates with Gleason score [7,8,29], in line with the known role of GPC-1 in tumour growth, invasion and metastasis.…”

Section: Discussionmentioning

confidence: 93%

“…Bismuth-213 ( 213 Bi)-labelled MIL-38 also showed promising results in a prostate cancer metastatic model using a multiple targeted alpha radioimmunotherapy approach [15]. The chimeric antibody Miltuximab® conjugated to gallium-67 ( 67 Ga) for imaging has proven safe in first in human clinical trials, and targeting to active prostate cancer lesions was observed [16]. Pairing of an imaging and therapeutic agent would allow for patient selection, disease monitoring, and personalised dosimetry.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 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 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.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“… 106 Miltuximab® conjugated to 67 Ga for imaging has progressed through a first-in-human phase I clinical trial, demonstrating targeting to prostate cancer lesions. 107 …”

Section: Gpc-1 In Solid Tumors: Expression and Biologymentioning

confidence: 99%

“…106 Miltuximab ® conjugated to 67 Ga for imaging has progressed through a first-in-human phase I clinical trial, demonstrating targeting to prostate cancer lesions. 107 Bladder cancer BLCA-38 (also known as MIL-38) is an IgG1 murine monoclonal antibody (mAb) raised against the human bladder cancer cell line, UCRU-BL-17CL, and is the murine parent antibody to clinical stage antibody Miltuximab ® (GlyTherix Ltd). 22,108 BLCA-38 antibody detected cells in the voided urine from patients with transitional cell carcinoma of the bladder but showed no reactivity to cell sediments from normal control patients.…”

Section: Prostate Cancermentioning

confidence: 99%

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

Sabanathan

Lund²,

Campbell³

et al. 2021

Ther Adv Med Oncol

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Radioimmunotherapy (i.e., the use of radiolabeled tumor targeting antibodies) is an emerging approach for the diagnosis, therapy, and monitoring of solid tumors. Often using paired agents, each targeting the same tumor molecule, but labelled with an imaging or therapeutic isotope, radioimmunotherapy has achieved promising clinical results in relatively radio-resistant solid tumors such as prostate. Several approaches to optimize therapeutic efficacy, such as dose fractionation and personalized dosimetry, have seen clinical success. The clinical use and optimization of a radioimmunotherapy approach is, in part, influenced by the targeted tumor antigen, several of which have been proposed for different solid tumors. Glypican-1 (GPC-1) is a heparan sulfate proteoglycan that is expressed in a variety of solid tumors, but whose expression is restricted in normal adult tissue. Here, we discuss the preclinical and clinical evidence for the potential of GPC-1 as a radioimmunotherapy target. We describe the current treatment paradigm for several solid tumors expressing GPC-1 and suggest the potential clinical utility of a GPC-1 directed radioimmunotherapy for these tumors.

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“…Indeed, several preclinical studies have examined the effect of targeting GPC-1 in animal models showing no adverse effects [ 15 , 16 ]. Moreover, a first in human clinical trial using the chimeric anti-GPC-1 antibody Miltuximab ® (Glytherix Ltd) was shown to be safe and well tolerated, exhibiting no drug related adverse events [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

A bispecific T cell engager targeting Glypican-1 redirects T cell cytolytic activity to kill prostate cancer cells

Lund¹,

Howard²,

Thurecht³

et al. 2020

BMC Cancer

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Background Glypican-1 is a heparan sulfate proteoglycan that is overexpressed in prostate cancer (PCa), and a variety of solid tumors. Importantly, expression is restricted in normal tissue, making it an ideal tumor targeting antigen. Since there is clinical and preclinical evidence of the efficacy of Bispecific T cell Engager (BiTE) therapy in PCa, we sought to produce and test the efficacy of a GPC-1 targeted BiTE construct based on the Miltuximab® sequence. Miltuximab® is a clinical stage anti-GPC-1 antibody that has proven safe in first in human trials. Methods The single chain variable fragment (scFv) of Miltuximab® and the CD3 binding sequence of Blinatumomab were combined in a standard BiTE format. Binding of the construct to immobilised recombinant CD3 and GPC-1 antigens was assessed by ELISA and BiaCore, and binding to cell surface-expressed antigens was measured by flow cytometry. The ability of MIL-38-CD3 to activate T cells was assessed using in vitro co-culture assays with tumour cell lines of varying GPC-1 expression by measurement of CD69 and CD25 expression, before cytolytic activity was assessed in a similar co-culture. The release of inflammatory cytokines from T cells was measured by ELISA and expression of PD-1 on the T cell surface was measured by flow cytometry. Results Binding activity of MIL-38-CD3 to both cell surface-expressed and immobilised recombinant GPC-1 and CD3 was retained. MIL-38-CD3 was able to mediate the activation of peripheral blood T cells from healthy individuals, resulting in the release of inflammatory cytokines TNF and IFN-g. Activation was reliant on GPC-1 expression as MIL-38-CD3 mediated only low level T cell activation in the presence of C3 cells (constitutively low GPC-1 expression). Activated T cells were redirected to lyse PCa cell lines PC3 and DU-145 (GPC-1 moderate or high expression, respectively) but could not kill GPC-1 negative Raji cells. The expression of PD-1 was up-regulated on the surface of MIL-38-CD3 activated T cells, suggesting potential for synergy with checkpoint inhibition. Conclusions This study reports preclinical findings into the efficacy of targeting GPC-1 in PCa with BiTE construct MIL-38-CD3. We show the specificity and efficacy of the construct, supporting its further preclinical development.

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MILGa-01: A first-in-human study assessing the safety and tolerability of chMIL-38 in metastatic prostate, bladder, and pancreatic cancers.

Cited by 3 publications

References 0 publications

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

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

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

A bispecific T cell engager targeting Glypican-1 redirects T cell cytolytic activity to kill prostate cancer cells

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