Amatuximab and novel agents targeting mesothelin for solid tumors

Baldo, Paolo; Cecco, Sara

doi:10.2147/ott.s145105

Cited by 27 publications

(20 citation statements)

References 85 publications

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“…54,55 A number of different MSLN-targeted therapies, including MSLNtargeting antibodies, antibody-drug conjugates, immunotoxins, and chimeric antigen receptor T cells, have been either clinically tested or are currently in early clinical development. 56 Using the anti-MSLN antibody anetumab (BAY 86-1903), a MSLN-targeted 227 Th conjugate (MSLN-TTC) was developed. 36 MSLN-TTC showed strong activity in several in vitro and in vivo preclinical models.…”

Section: Mesothelin-ttcmentioning

confidence: 99%

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

Hagemann

Wickstroem

Hammer

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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Targeted alpha therapy (TAT) offers the potential for the targeted delivery of potent a-particle-emitting radionuclides that emit high linear energy transfer radiation. This leads to a densely ionizing radiation track over a short path. Localized radiation induces cytotoxic, difficult-to-repair, clustered DNA double-strand breaks (DSBs). To date, radium-223 (223 Ra) is the only TAT approved for the treatment of patients with metastatic castration-resistant prostate cancer. Thorium-227 (227 Th), the progenitor nuclide of 223 Ra, offers promise as a wider-ranging alternative due to the availability of efficient chelators, such as octadentate 3,2-hydroxypyridinone (3,2-HOPO). The 3,2-HOPO chelator can be readily conjugated to a range of targeting moieties, enabling the generation of new targeted thorium-227 conjugates (TTCs). This review provides a comprehensive overview of the advances in the preclinical development of TTCs for hematological cancers, including CD22-positive B cell cancers and CD33-positive leukemia, as well as for solid tumors overexpressing renal cell cancer antigen CD70, membrane-anchored glycoprotein mesothelin in mesothelioma, prostate-specific membrane antigen in prostate cancer, and fibroblast growth factor receptor 2. As the mechanism of action for TTCs is linked to the formation of DSBs, the authors also report data supporting combinations of TTCs with inhibitors of the DNA damage response pathways, including those of the ataxia telangiectasia and Rad3-related protein, and poly-ADP ribose polymerase. Finally, emerging evidence suggests that TTCs induce immunogenic cell death through the release of danger-associated molecular patterns. Based on encouraging preclinical data, clinical studies have been initiated to investigate the safety and tolerability of TTCs in patients with various cancers.

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Section: Mesothelin-ttcmentioning

confidence: 99%

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

Hagemann

Wickstroem

Hammer

et al. 2020

Cancer Biotherapy and Radiopharmaceuticals

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“…[46][47][48][49][50] Many clinical trials and experimental therapies have targeted these two tumor markers, including vaccine, CA125/MUC16-or mesothelin-specific antibody and CAR T cell therapy. [51][52][53][54][55][56] Therefore, with these markers highly expressed in our model, this novel system physically recapitulates human HGSC development and spread, allowing for the preclinical screening of new therapies targeting CA125, mesothelin and many other markers.…”

Section: Discussionmentioning

confidence: 98%

Novel, genetically induced mouse model that recapitulates the histological morphology and immunosuppressive tumor microenvironment of metastatic peritoneal carcinomatosis

Tseng

Park

Lam

et al. 2020

J Immunother Cancer

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BackgroundPeritoneal carcinomatosis is a hallmark of advanced peritoneal tumor progression, particularly for tubal/ovarian high-grade serous carcinomas (HGSCs). Patients with peritoneal carcinomatosis have poor survival rates and are difficult to treat clinically due to widespread tumor dissemination in the peritoneal cavity.MethodsWe developed a clinically relevant, genetically induced, peritoneal carcinomatosis model that recapitulates the histological morphology and immunosuppressive state of the tumor microenvironment of metastatic peritoneal HGSCs by intraperitoneally injecting shp53, AKT, c-Myc, luciferase and sleeping beauty transposase, followed by electroporation (EP) in the peritoneal cavity of immunocompetent mice (intraperitoneal (IP)/EP mice).ResultsSimilar to the spread of human ovarian cancers, IP/EP mice displayed multiple tumor nodules attached to the surface of the abdomen. Histopathological analysis indicated that these tumors were epithelial in origin. These IP/EP mice also displayed a loss of CD3+T cell infiltration in tumors, highly expressed inhibitory checkpoint molecules in tumor-infiltrating and global CD4+and CD8+T cells, and increased levels of transforming growth factor-β in the ascites, all of which contribute to the promotion of tumor growth.ConclusionsOverall, our tumor model recapitulates clinical peritoneal HGSC metastasis, which makes it ideal for preclinical drug screening, testing of immunotherapy-based therapeutics and studying of the tumor biology of peritoneal carcinomatosis.

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“…The present results demonstrated that mesothelin, IGFBP2 and PP14 had potential value for diagnosing PROM. Mesothelin is a 40-kDa membrane-glycoprotein; it is reported to associate with a number of types of cancer, although, its biological function in normal conditions is unclear ( 15 ). IGFBP2 is a 36-kDa protein, which is primarily involved in metabolic disease and cancer ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

Placental protein 14 as a potential biomarker for diagnosis of preterm premature rupture of membranes

et al. 2018

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Premature rupture of membranes (PROM) is a common pregnancy complication that frequently results in maternal and perinatal morbidity. The present methods for diagnosing PROM do not satisfy clinical requirements. The present study aimed to examine the proteome profile of amniotic fluid (AF) and maternal plasma, screen unique proteins in AF, and evaluate their diagnostic value for diagnosing PROM. The proteome profiles of AF and maternal plasma were examined via liquid chromatography coupled with tandem mass spectrometry-based proteomic techniques. The protein expression levels of diagnostic candidates in AF, maternal plasma and vaginal fluid were determined by ELISA analysis and Magnetic Luminex® screening assays. The diagnostic value of potential biomarkers was evaluated using receiver operating characteristic curves. A lateral flow assay was developed based on colloidal gold immunochromatography technology. The present study identified 540 unique proteins in AF, 12 of which were chosen for further detection. The present results demonstrated that expression levels of pulmonary surfactant-associated protein B, BPI fold-containing family A member 1, zymogen granule protein 16 homolog B, EGF-containing fibulin-like extracellular matrix protein 1, keratin, type II cytoskeletal 4, keratin, type I cytoskeletal 19, placental protein 14 (PP14), insulin-like growth factor-binding protein 2, mesothelin and serpin family B member 3 were significantly higher in AF compared with in maternal plasma (P<0.01). Furthermore, PP14 was observed to have excellent diagnostic accuracy for preterm PROM (PPROM), with a respective sensitivity and specificity of 100 and 87.5% when the cutoff value was 0.008 µg/ml. The PP14-based lateral flow assay demonstrated a visual detection threshold of 0.008 µg/ml. The results from the present study suggested that PP14 may be a novel potential biomarker for PPROM, and may be developed into a lateral flow assay for bedside application to rapidly diagnose PPROM.

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Amatuximab and novel agents targeting mesothelin for solid tumors

Cited by 27 publications

References 85 publications

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

Novel, genetically induced mouse model that recapitulates the histological morphology and immunosuppressive tumor microenvironment of metastatic peritoneal carcinomatosis

Placental protein 14 as a potential biomarker for diagnosis of preterm premature rupture of membranes

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