Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with the Novel Antibody NZ-16 for Malignant Mesothelioma

Sudo, Hitomi; Tsuji, Atsushi B.; Sugyo, Aya; Kaneko, Mika K.; Kato, Yukinari; Nagatsu, Kotaro; Suzuki, Hisashi; Higashi, Tatsuya

doi:10.3390/cells10102503

Cited by 16 publications

(10 citation statements)

References 31 publications

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“…For example, the macrocyclic chelator tetraazacyclododecane-1,4,7,10-tetraacetic acid (H 4 DOTA) has been used successfully for both small-molecule and antibody 225 Ac-radioconjugates, albeit with some significant challenges. For example, radiolabeling of H 4 DOTA with 225 Ac either requires high temperatures, which are incompatible with macromolecular biomolecules such as antibodies, or long incubation times, which yields constructs with relatively low specific activities. − Furthermore, serum stability studies have shown that the [ 225 Ac]Ac-DOTA complex dissociates over time, a property that is corroborated by animal studies that show deposition of 225 Ac in the liver and femur after the administration of DOTA-based conjugates . These drawbacks have sparked efforts to develop superior bifunctional chelators for 225 Ac.…”

Section: Introductionmentioning

confidence: 99%

H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

et al. 2022

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Ac) is one of the most promising radionuclides for targeted alpha therapy (TAT). With a half-life of 9.92 days and a decay chain that emits four high-energy α particles, 225 Ac is well-suited for TAT when conjugated to macromolecular targeting vectors that exhibit extended in vivo circulation times. The implementation of 225 Ac in these targeted constructs, however, requires a suitable chelator that can bind and retain this radionuclide in vivo. Previous work has demonstrated the suitability of a diaza-18-crown-6 macrocyclic chelator H 2 macropa for this application. Building upon these prior efforts, in this study, two rigid variants of H 2 macropa, which contain either one (H 2 BZmacropa) or two (H 2 BZ 2 macropa) benzene rings within the macrocyclic core, were synthesized and investigated for their potential use for 225 Ac TAT. The coordination chemistry of these ligands with La 3+ , used as a nonradioactive model for Ac 3+ , was carried out. Both NMR spectroscopic and X-ray crystallographic studies of the La 3+ complexes of these ligands revealed similar structural features to those found for the related complex of H 2 macropa. Thermodynamic stability constants of the La 3+ complexes, however, were found to be 1 and 2 orders of magnitude lower than those of H 2 macropa for H 2 BZmacropa and H 2 BZ 2 macropa, respectively. The decrease in thermodynamic stability was rationalized via the use of density functional theory calculations. 225 Ac radiolabeling and serum stability studies with H 2 BZmacropa showed that this chelator compares favorably with H 2 macropa. Based on these promising results, a bifunctional version of this chelator, H 2 BZmacropa-NCS, was synthesized and conjugated to the antibody codrituzumab (GC33), which targets the liver cancer biomarker glypican-3 (GPC3). The resulting GC33-BZmacropa conjugate and an analogous GC33-macropa conjugate were evaluated for their 225 Ac radiolabeling efficiencies, antigen-binding affinities, and in vivo biodistribution in HepG2 liver cancer tumor-bearing mice. Although both conjugates were comparably effective in their radiolabeling efficiencies, [ 225 Ac]Ac-GC33-BZmacropa showed slightly poorer serum stability and biodistribution than [ 225 Ac]Ac-GC33-macropa. Together, these results establish H 2 BZmacropa-NCS as a new bifunctional chelator for the preparation of 225 Ac radiopharmaceuticals.

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Section: Introductionmentioning

confidence: 99%

H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

et al. 2022

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“…225 Ac -labeled NZ-16 induced larger areas of necrotic cell death, showed reduced tumor volumes, and prolonged survival than 90 Y-labeled NZ-16 without any adverse effects. These results strongly indicate that 225 Ac-mediated RIT with the NZ-16 is an effective and promising therapeutic option for MPM [180].…”

Section: Radioimmunotherapy (Rit)mentioning

confidence: 60%

Roles of Podoplanin in Malignant Progression of Tumor

Suzuki¹,

Kaneko²,

Kato³

2022

Preprint

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Podoplanin (PDPN) is a cell-surface mucin-like glycoprotein that plays a critical role in tumor development and normal development of the lung, kidney, and lymphatic vascular systems. PDPN is overexpressed in several tumors and is involved in their malignancy. PDPN induces platelet aggregation through binding to platelet receptor C-type lectin-like receptor 2. Furthermore, PDPN modulates signal transductions that regulate cell proliferation, differentiation, migration, invasion, epithelial to mesenchymal transition, and stemness, all of which are crucial for the malignant progression of tumor. In the tumor microenvironment (TME), PDPN expression is up-regulated in the tumor stroma, including cancer-associated fibroblasts (CAFs) and immune cells. CAFs play significant roles in the extracellular matrix remodeling and the development of immunosuppressive TME. Additionally, PDPN functions as a co-inhibitory molecule on T cells, indicating the involvement with immune evasion. In this review, we describe the mechanistic basis and diverse roles of PDPN in malignant progression of tumor and discuss the possibility of the clinical application of PDPN-targeted cancer therapy, including cancer-specific monoclonal antibodies, and chimeric antigen receptor T technologies.

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“…225 Ac -labeled NZ-16 induced larger areas of necrotic cell death, showed reduced tumor volumes, and prolonged survival, compared with 90 Y-labeled NZ-16, without any adverse effects. These results strongly indicate that 225 Ac-mediated RIT with NZ-16 is an effective and promising therapeutic option for MPM [187].…”

Section: Radioimmunotherapy (Rit)mentioning

confidence: 62%

Roles of Podoplanin in Malignant Progression of Tumor

Suzuki

Kaneko

Kato

2022

Cells

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Podoplanin (PDPN) is a cell-surface mucin-like glycoprotein that plays a critical role in tumor development and normal development of the lung, kidney, and lymphatic vascular systems. PDPN is overexpressed in several tumors and is involved in their malignancy. PDPN induces platelet aggregation through binding to platelet receptor C-type lectin-like receptor 2. Furthermore, PDPN modulates signal transductions that regulate cell proliferation, differentiation, migration, invasion, epithelial-to-mesenchymal transition, and stemness, all of which are crucial for the malignant progression of tumor. In the tumor microenvironment (TME), PDPN expression is upregulated in the tumor stroma, including cancer-associated fibroblasts (CAFs) and immune cells. CAFs play significant roles in the extracellular matrix remodeling and the development of immunosuppressive TME. Additionally, PDPN functions as a co-inhibitory molecule on T cells, indicating its involvement with immune evasion. In this review, we describe the mechanistic basis and diverse roles of PDPN in the malignant progression of tumors and discuss the possibility of the clinical application of PDPN-targeted cancer therapy, including cancer-specific monoclonal antibodies, and chimeric antigen receptor T technologies.

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Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with the Novel Antibody NZ-16 for Malignant Mesothelioma

Cited by 16 publications

References 31 publications

H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

Roles of Podoplanin in Malignant Progression of Tumor

Roles of Podoplanin in Malignant Progression of Tumor

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Preclinical Evaluation of Podoplanin-Targeted Alpha-Radioimmunotherapy with the Novel Antibody NZ-16 for Malignant Mesothelioma

Cited by 16 publications

References 31 publications

H2BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

H2BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

Roles of Podoplanin in Malignant Progression of Tumor

Roles of Podoplanin in Malignant Progression of Tumor

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H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy

H₂BZmacropa-NCS: A Bifunctional Chelator for Actinium-225 Targeted Alpha Therapy