A re-engineered immunotoxin shows promising preclinical activity in ovarian cancer

Kollmorgen, Gwendlyn; Palme, Klara; Seidl, Annette; Scheiblich, Stefan; Birzele, Fabian; Wilson, Sabine; Clemens, Christian; Voß, Edgar; Kaufmann, Martin; Hirzel, Klaus; Rieder, Natascha; Krippendorff, Ben‐Fillippo; Herting, Frank; Niederfellner, Gerhard

doi:10.1038/s41598-017-17329-7

Cited by 8 publications

(8 citation statements)

References 42 publications

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“…The cytotoxicity and antitumor effects of LMB-100 were verified on different cancer types including breast ( 126 ), gastric ( 126 ), lung ( 127 ), ovarian ( 128 ), and colorectal ( 129 ) cancers, as well as pancreatic ductal adenocarcinoma ( 130 – 133 ). Almost all cell lines corresponding to these malignancies were affected by LMB-100 at concentrations in the picomolar range (as low as 6.8 pmol/lit) ( 130 – 133 ).…”

Section: Pseudomonas Exotoxin Amentioning

confidence: 99%

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

2021

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Cancer is one of the prominent causes of death worldwide. Despite the existence of various modalities for cancer treatment, many types of cancer remain uncured or develop resistance to therapeutic strategies. Furthermore, almost all chemotherapeutics cause a range of side effects because they affect normal cells in addition to malignant cells. Therefore, the development of novel therapeutic agents that are targeted specifically toward cancer cells is indispensable. Immunotoxins (ITs) are a class of tumor cell-targeted fusion proteins consisting of both a targeting moiety and a toxic moiety. The targeting moiety is usually an antibody/antibody fragment or a ligand of the immune system that can bind an antigen or receptor that is only expressed or overexpressed by cancer cells but not normal cells. The toxic moiety is usually a protein toxin (or derivative) of animal, plant, insect, or bacterial origin. To date, three ITs have gained Food and Drug Administration (FDA) approval for human use, including denileukin diftitox (FDA approval: 1999), tagraxofusp (FDA approval: 2018), and moxetumomab pasudotox (FDA approval: 2018). All of these ITs take advantage of bacterial protein toxins. The toxic moiety of the first two ITs is a truncated form of diphtheria toxin, and the third is a derivative of Pseudomonas exotoxin (PE). There is a growing list of ITs using PE, or its derivatives, being evaluated preclinically or clinically. Here, we will review these ITs to highlight the advances in PE-based anticancer strategies, as well as review the targeting moieties that are used to reduce the non-specific destruction of non-cancerous cells. Although we tried to be as comprehensive as possible, we have limited our review to those ITs that have proceeded to clinical trials and are still under active clinical evaluation.

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Section: Pseudomonas Exotoxin Amentioning

confidence: 99%

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

2021

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“…7 Besides, due to unique combination of high expression in different solid tumors and its complete lack of vital normal tissues, MSLN is being widely desirable for tumor-selective toxic payload delivery and tumor immunotherapy approaches. 20 Numerous research has investigated serum MSLN as a diagnostic marker for EOC; [21][22][23][24][25][26][27][28][29] however, very few studies have investigated tumor MSLN gene expression in EOC, and to date, no report has addressed its level in peritoneal fluid (PF) of ovarian cancer patients. In this study, we comprehensively investigated tumor MSLN gene expression and the plasma and PF MSLN level in EOC patients with different clinicopathological features including FIGO staging (FIGO I-IV), Shimizu-Silverberg grading (grades I-III), histological type of tumor (serous, mucinous, endometrioid, and undifferentiated), and Kurman and Shih type of EOC (types 1 and 2).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Assessment of the clinicopathological relevance of mesothelin level in plasma, peritoneal fluid, and tumor tissue of epithelial ovarian cancer patients

et al. 2018

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Ovarian cancer remains the most lethal gynecologic malignancy. This is due to lack of effective screening, diagnosis predominance in late stage of disease, a high recurrence rate after primary therapy, and poor treatment response in platinum-resistant tumor. Thus, unique biomarkers, predictive of individual disease course, and prognosis are urgently needed. The aim of our study was to assess the clinicopathological significance of plasma, peritoneal fluid, and tumor tissue levels of mesothelin in epithelial ovarian cancer patients. Plasma and peritoneal fluid levels of mesothelin were measured by enzyme-linked immunosorbent assay. Tissue expression of MSLN was evaluated using quantitative real-time polymerase chain reaction. Preoperative plasma mesothelin levels were significantly higher in epithelial ovarian cancer patients in comparison to the patients with benign tumor and controls. There have been noticed significant differences in the plasma mesothelin levels based on International Federation of Gynecology and Obstetrics stage, grade, and histology type. No significant changes were observed between Kurman and Shih type I versus type II epithelial ovarian cancer. Interestingly, peritoneal fluid mesothelin levels revealed significant differences based on both grade and Kurman and Shih-type epithelial ovarian cancer. There were no relevant changes in the mesothelin level in peritoneal fluid between different stages and histology types compared to benign tumor. MSLN expression level in tumor tissue was significantly higher based on stage, grade, and Kurman and Shih-type epithelial ovarian cancer than in the benign masses. In addition, data showed significant higher MSLN expression in endometrioid tumors compared to benign masses and serous tumors. Plasma, peritoneal fluid, and tumor tissue levels of mesothelin positively correlated with level of CA125. Low mesothelin concentrations in plasma were also associated with prolonged patient survival. More importantly, we revealed that plasma mesothelin level was correlated with both peritoneal fluid mesothelin level and tumor MSLN expression. This study highlights that plasma mesothelin level may be a useful noninvasive biomarker surrogate for local tumor mesothelin status in monitoring of epithelial ovarian cancer patients.

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“…When combined with cytotoxic chemotherapy, tumor regressions were seen in mesothelioma xenograft models [ 71 ]. Kollmorgen et al found that the combination of LMB-100 and cisplatin or paclitaxel showed striking tumor growth inhibition in a PDX model of ovarian cancer as well [ 73 ]. Furthermore, synergistic activity was observed with taxanes, such that the combination produced complete tumor responses in a mouse model of pancreatic cancer [ 74 ].…”

Section: Pre-clinical Development Pipelinementioning

confidence: 99%

Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors

Hagerty

Pegna

et al. 2020

Biomolecules

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Mesothelin (MSLN) is a cell surface glycoprotein normally expressed only on serosal surfaces, and not found in the parenchyma of vital organs. Many solid tumors also express MSLN, including mesothelioma and pancreatic adenocarcinoma. Due to this favorable expression profile, MSLN represents a viable target for directed anti-neoplastic therapies, such as recombinant immunotoxins (iToxs). Pre-clinical testing of MSLN-targeted iTox’s has yielded a strong body of evidence for activity against a number of solid tumors. This has led to multiple clinical trials, testing the safety and efficacy of the clinical leads SS1P and LMB-100. While promising clinical results have been observed, neutralizing anti-drug antibody (ADA) formation presents a major challenge to overcome in the therapeutic development process. Additionally, on-target, off-tumor toxicity from serositis and non-specific capillary leak syndrome (CLS) also limits the dose, and therefore, impact anti-tumor activity. This review summarizes existing pre-clinical and clinical data on MSLN-targeted iTox’s. In addition, we address the potential future directions of research to enhance the activity of these anti-tumor agents.

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A re-engineered immunotoxin shows promising preclinical activity in ovarian cancer

Cited by 8 publications

References 42 publications

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

Pseudomonas Exotoxin-Based Immunotoxins: Over Three Decades of Efforts on Targeting Cancer Cells With the Toxin

Assessment of the clinicopathological relevance of mesothelin level in plasma, peritoneal fluid, and tumor tissue of epithelial ovarian cancer patients

Mesothelin-Targeted Recombinant Immunotoxins for Solid Tumors

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