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Journal of Clinical Oncology : Official... Dec 2016Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is... (Review)
Review
Mesothelin is a tumor antigen that is highly expressed in many human cancers, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. It is an attractive target for cancer immunotherapy because its normal expression is limited to mesothelial cells, which are dispensable. Several antibody-based therapeutic agents as well as vaccine and T-cell therapies directed at mesothelin are undergoing clinical evaluation. These include antimesothelin immunotoxins (SS1P, RG7787/LMB-100), chimeric antimesothelin antibody (amatuximab), mesothelin-directed antibody drug conjugates (anetumab ravtansine, DMOT4039A, BMS-986148), live attenuated Listeria monocytogenes-expressing mesothelin (CRS-207, JNJ-64041757), and chimeric antigen receptor T-cell therapies. Two antimesothelin agents are currently in multicenter clinical registration trials for malignant mesothelioma: amatuximab in the first-line setting and anetumab ravtansine as second-line therapy. Phase II randomized clinical trials of CRS-207 as a boosting agent and in combination with immune checkpoint inhibition for pancreatic cancer are nearing completion. These ongoing studies will define the utility of mesothelin immunotherapy for treating cancer.
Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Antineoplastic Agents; Clinical Trials as Topic; GPI-Linked Proteins; Humans; Immunoconjugates; Immunotherapy; Maytansine; Mesothelin; Neoplasms
PubMed: 27863199
DOI: 10.1200/JCO.2016.68.3672 -
OncoTargets and Therapy 2017Mesothelin (MSLN) is considered a promising target for cancer therapy. Originally extracted in 1992 after the immunization of mice with a human ovarian cancer (OC) cell... (Review)
Review
Mesothelin (MSLN) is considered a promising target for cancer therapy. Originally extracted in 1992 after the immunization of mice with a human ovarian cancer (OC) cell line and cloned in 1996, MSLN seems to be involved in cell adhesion and metastasis. MSLN is prevalent in mesothelia tissues but is expressed in several human cancers, such as OC, pancreatic cancer, mesothelioma, and lung cancer. Amatuximab (MORAb-009) is a mouse-human chimeric monoclonal antibody with a selective affinity for MSLN. The principal mechanism of action comprises inhibition of binding of MSLN with the antigen CA125/MUC16. The highest phase of development is actually a Phase II trial (MORAb-009-201, Europe). In this review, we describe the mechanism of action of amatuximab and other MSLN-targeting novel drugs, along with a discussion about the expected efficacy, safety, and toxicity of this promising group of agents and implications for future research and clinical practice.
PubMed: 29184420
DOI: 10.2147/OTT.S145105 -
Frontiers in Immunology 2023Mesothelin (MSLN) is overexpressed in a wide variety of cancers with few therapeutic options and has recently emerged as an attractive target for cancer therapy, with a...
INTRODUCTION
Mesothelin (MSLN) is overexpressed in a wide variety of cancers with few therapeutic options and has recently emerged as an attractive target for cancer therapy, with a large number of approaches currently under preclinical and clinical investigation. In this respect, developing mesothelin specific tracers as molecular companion tools for predicting patient eligibility, monitoring then response to mesothelin-targeting therapies, and tracking the evolution of the disease or for real-time visualisation of tumours during surgery is of growing importance.
METHODS
We generated by phage display a nanobody (Nb S1) and used enzymatic approaches were used to site-directed conjugate Nb S1 with either ATTO 647N fluorochrome or NODAGA chelator for fluorescence and positron emission tomography imaging (PET) respectively.
RESULTS
We demonstrated that Nb S1 displays a high apparent affinity and specificity for human mesothelin and demonstrated that the binding, although located in the membrane distal domain of mesothelin, is not impeded by the presence of MUC16, the only known ligand of mesothelin, nor by the therapeutic antibody amatuximab. experiments showed that both ATTO 647N and [Ga]Ga-NODAGA-S1 rapidly and specifically accumulated in mesothelin positive tumours compared to mesothelin negative tumours or irrelevant Nb with a high tumour/background ratio. The biodistribution profile analysis also confirmed a significantly higher uptake of Nb S1 in MSLN-positive tumours than in MSLN tumours.
CONCLUSION
We demonstrated for the first time the use of an anti-MSLN nanobody as PET radiotracer for same day imaging of MSLN tumours, targeting an epitope compatible with the monitoring of amatuximab-based therapies and current SS1-derived-drug conjugates.
Topics: Humans; Mesothelin; Tissue Distribution; Positron-Emission Tomography; Neoplasms; Antibodies, Blocking
PubMed: 37388728
DOI: 10.3389/fimmu.2023.1200652 -
Gan To Kagaku Ryoho. Cancer &... Dec 2017Malignant pleural mesothelioma(MPM)is a highly aggressive tumor with a poor prognosis and an increasing incidence worldwide. The only standard first-line chemotherapy... (Review)
Review
Malignant pleural mesothelioma(MPM)is a highly aggressive tumor with a poor prognosis and an increasing incidence worldwide. The only standard first-line chemotherapy for patients with unresectable MPM is cisplatin(CDDP)plus peme- trexed(PEM)(CDDP/PEM), with a median overall survival of about 12months and a median progression-free survival(PFS) of less than 6 months. There are no treatments with proven benefit on survival for relapsed MPM patients. Therefore, novel therapeutic strategies are urgently required. Several molecular pathways involved in MPM have been identified; these include growth factor signaling pathways, cell cycle regulation, apoptosis, and angiogenesis. Fortunately, several agents targeting these processes have yielded promising results in preliminary trials. The addition of vascular endothelial growth factor(VEGF) inhibitor bevacizumab to the standard CDDP/PEM provides a 2.7-month survival benefit. Triple angiokinase inhibitor nintedanib, inhibiting the VEGFR, PDGFR, and FGFR, plus standard chemotherapy demonstrated a significant improvement in median PFS of 3.7 months in the overall study population, and a greater median PFS benefit of 4.0 months in epithelioid MPM. Mesothelin is an attractive target protein expressed on mesothelioma cells. Amatuximab, a chimeric anti-mesothelin antibody, in combination with CDDP/PEM, is currently being tested in randomized, double-blind, placebo-controlled phase II study. Anetumab ravtansine, mesothelin-directed antibody drug conjugate, was evaluated in a randomized trial to compare to vinorelbine in patients with MPM who have high mesothelin expression and have progressed on CDDP/PEM-based first-line chemotherapy. However, anetumab ravtansine was not superior to vinorelbine in primary endpoint of PFS(4.3 months vs 4.5 months). Immune checkpoint blockades have demonstrated promising preclinical and clinical results in several cancer types, and are currently being investigated in clinical trials for MPM patients. PD-L1 expression in tumor tissue of MPM was reported, ranging between 20% and 70%. PD-L1 expression was significantly associated with a worse survival and overexpression was more common in sarcomatoid histology. This review summarizes clinical results for the latest systemic treatments in MPM.
Topics: Antineoplastic Agents; Humans; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant; Neovascularization, Pathologic; Pleural Neoplasms
PubMed: 29361614
DOI: No ID Found -
BMC Cancer Feb 2021Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known.... (Comparative Study)
Comparative Study
Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells.
BACKGROUND
Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model.
METHODS
We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer.
RESULTS
Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes.
CONCLUSIONS
Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Adhesion; Cell Aggregation; Cell Division; Cell Movement; Cell Self Renewal; Deoxycytidine; Drug Resistance, Neoplasm; Drug Synergism; Female; GPI-Linked Proteins; Humans; Mesothelin; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neoplasm Proteins; Neoplastic Stem Cells; Organ Size; Pancreatic Neoplasms; Peritoneal Neoplasms; Peritoneum; Peritonitis; Gemcitabine
PubMed: 33637083
DOI: 10.1186/s12885-020-07722-3 -
Cancer Chemotherapy and Pharmacology Apr 2016To characterize amatuximab pharmacokinetics (PK) and the relationship of amatuximab exposure with response in patients with unresectable malignant pleural mesothelioma...
Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection.
PURPOSE
To characterize amatuximab pharmacokinetics (PK) and the relationship of amatuximab exposure with response in patients with unresectable malignant pleural mesothelioma (MPM) receiving amatuximab with pemetrexed and cisplatin.
METHODS
A nonlinear mixed effects PK model was built using data from all of the amatuximab studies conducted to date. Patients received amatuximab alone or in combination with chemotherapy. The influence of demographic, laboratory and disease characteristics on PK parameters was assessed. Exposure-response analyses explored relationships between amatuximab exposure and overall survival (OS), progression-free survival (PFS) and safety. Alternative amatuximab dosing regimens were explored with simulations using population PK and parametric survival models.
RESULTS
Amatuximab PK was best described by a two-compartment model with parallel linear and nonlinear elimination pathways. Body weight and an antidrug antibodies reaction with the titer >64 affected volume of distribution and clearance, respectively. Exposure-response analyses demonstrated that the amatuximab exposure (C min) showed a significant effect on OS (log-rank test, P = 0.0202). For patients with amatuximab C min above the median (38.2 μg/mL), the median OS was 583 days (90 % CI 418 -NE). For patients with C min ≤ 38.2 μg/mL, the median OS was 375 days (90 % CI 325-486). The amatuximab exposure showed similar significant effect on PFS. Exposure-response analysis for adverse events did not reveal any relationship.
CONCLUSIONS
In patients with MPM, higher amatuximab exposure in combination with chemotherapy was shown to be associated with longer OS, supporting evaluation of more frequent dosing in future trials to achieve higher exposure and subsequently longer OS.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Disease-Free Survival; Female; Humans; Lung Neoplasms; Male; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Models, Biological; Pleural Neoplasms
PubMed: 26898299
DOI: 10.1007/s00280-016-2984-z -
Nuclear Medicine and Biology Nov 2015To investigate the effect of the injection dose of MORAb-009 (amatuximab, an anti-mesothelin monoclonal antibody), the tumor size and the level of shed mesothelin on the...
OBJECTIVES
To investigate the effect of the injection dose of MORAb-009 (amatuximab, an anti-mesothelin monoclonal antibody), the tumor size and the level of shed mesothelin on the uptake of the antibody in mesothelin-positive tumor and organs by biodistribution (BD) and positron emission tomography (PET) imaging studies.
METHODS
2-S-(4-Isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA) was conjugated to amatuximab and labeled with (64)CuCl2 in 0.25 M acetate buffer, pH4.2. The resulting (64)Cu-NOTA-amatuximab was purified with a PD 10 column. To investigate the dose effect or the effect of tumor size, the BD was performed in groups of nude mice (n=5) with mesothelin-expressing A431/H9 tumors (range, 80-300 mm(3)) one day after iv injection of (64)Cu-NOTA-amatuximab (10 μCi) containing a total amatuximab dose of 2, 30, or 60 μg. The BD and PET imaging were also investigated 3, 24 and 48 h after injecting a total dose of 30 μg (10 μCi for BD), and 2 or 60 μg (300 μCi for PET), respectively.
RESULTS
Comparing the results of the BDs from three different injection doses, the major difference was shown in the uptake (%ID/g) of the radiolabel in tumor, liver and blood. The tumor uptake and blood retention from 30 and 60 μg doses were greater than those from 2 μg dose, whereas the liver uptake was smaller. The BD studies also demonstrated a positive correlation between tumor size (or the level of shed mesothelin in blood) and liver uptake. However, there was a negative correlation between tumor size (or the shed mesothelin level) and tumor uptake and between tumor size and blood retention. These findings were confirmed by the PET imaging study, which clearly visualized the tumor uptake with the radiolabel concentrated in the tumor core and produced a tumor to liver ratio of 1.2 at 24h post-injection with 60 μg amatuximab, whereas the injection of 2 μg amatuximab produced a tumor to liver ratio of 0.4 at 24h post-injection.
CONCLUSION
Our studies using a nude mouse model of A431/H9 tumor demonstrated that the injection of a high amatuximab dose (30 to 60 μg) could provide a beneficial effect in maximizing tumor uptake while maintaining minimum liver and spleen uptakes of the radiolabel, and in facilitating its penetration into the tumor core.
Topics: Animals; Antibodies, Monoclonal; Biological Transport; Cell Line, Tumor; Copper Radioisotopes; GPI-Linked Proteins; Mesothelin; Mice; Tissue Distribution
PubMed: 26307499
DOI: 10.1016/j.nucmedbio.2015.07.008 -
Investigational New Drugs Oct 2021Amatuximab is a promising therapeutic antibody targeting mesothelin, a 40-kDa glycoprotein that is highly expressed in pancreatic cancer. We investigated the...
Early administration of amatuximab, a chimeric high-affinity anti-mesothelin monoclonal antibody, suppresses liver metastasis of mesothelin-expressing pancreatic cancer cells and enhances gemcitabine sensitivity in a xenograft mouse model.
Amatuximab is a promising therapeutic antibody targeting mesothelin, a 40-kDa glycoprotein that is highly expressed in pancreatic cancer. We investigated the effectiveness of early amatuximab treatment, imitating an adjuvant chemotherapy setting, and combination therapy with amatuximab and gemcitabine in liver metastasis of pancreatic cancer. Liver metastasis mouse models were established in 8-week-old male BALB/c nu/nu mice using the hemisplenic injection method. Tridaily amatuximab monotherapy or combination with gemcitabine was administered to the liver metastasis mouse model before metastatic lesions had formed huge masses. Gaussia luciferase-transfected AsPC-1 was used as a mesothelin-overexpressing pancreatic cancer cell line. The amount of liver metastases and the serum luciferase activity were significantly lower in the treatment groups than those in the control IgG group. Notably, the anti-tumor activity of gemcitabine was synergically enhanced by combination therapy with amatuximab. Furthermore, western blotting revealed that the high expression of phosphorylated c-Met and AKT in liver metastatic lesions treated with gemcitabine monotherapy was canceled by its combination with amatuximab. This result indicated that the observed synergic therapeutic effect may have occurred as a result of the inhibitory effect of amatuximab on the phosphorylation of c-Met and AKT, which were promoted by exposure to GEM. In conclusion, our study revealed that early administration of amatuximab alone or in combination with GEM significantly suppressed the liver metastases of mesothelin-expressing pancreatic cancer cells. A phase II clinical trial of amatuximab as part of an adjuvant chemotherapy regimen for resected pancreatic cancer is expected.
Topics: Animals; Antibodies, Monoclonal; Antineoplastic Agents; Deoxycytidine; Drug Synergism; Liver Neoplasms; Male; Mesothelin; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Xenograft Model Antitumor Assays; Gemcitabine
PubMed: 33905019
DOI: 10.1007/s10637-021-01118-1 -
Contrast Media & Molecular Imaging 2018We investigated the effect of shed antigen mesothelin on the tumor uptake of amatuximab, a therapeutic anti-mesothelin mAb clinically tested in mesothelioma patients.... (Comparative Study)
Comparative Study
We investigated the effect of shed antigen mesothelin on the tumor uptake of amatuximab, a therapeutic anti-mesothelin mAb clinically tested in mesothelioma patients. The B3 mAb targeting a nonshed antigen was also analyzed for comparison. The mouse model implanted with A431/H9 tumor, which expresses both shed mesothelin and nonshed Lewis-Y antigen, provided an ideal system to compare the biodistribution and PET imaging profiles of the two mAbs. Our study demonstrated that the tumor and organ uptakes of Zr-B3 were dose-independent when 3 doses, 2, 15, and 60 g B3, were compared at 24 h after injection. In contrast, tumor and organ uptakes of Zr-amatuximab were dose-dependent, whereby a high dose (60 g) was needed to achieve tumor targeting comparable to the low dose (2 g) of Zr-B3, suggesting that shed mesothelin may affect amatuximab tumor targeting as well as serum half-life. The autoradiography analysis showed that the distribution of Zr-B3 was nonuniform with the radioactivity primarily localized at the tumor periphery independent of the B3 dose. However, the autoradiography analysis for Zr-amatuximab showed dose-dependent distribution profiles of the radiolabel; at 10 g dose, the radiolabel penetrated toward the tumor core with its activity comparable to that at the tumor periphery, whereas at 60 g dose, the distribution profile became similar to those of Zr-B3. These results suggest that shed antigen in blood may act as a decoy requiring higher doses of mAb to improve serum half-life as well as tumor targeting. Systemic mAb concentration should be at a severalfold molar excess to the shed Ag in blood to overcome the hepatic processing of mAb-Ag complexes. On the other hand, mAb concentration should remain lower than the shed Ag concentration in the tumor ECS to maximize tumor penetration by passing binding site barriers.
Topics: Animals; Antibodies, Monoclonal; Antigens, Neoplasm; Cell Line, Tumor; Cell-Derived Microparticles; GPI-Linked Proteins; Half-Life; Heterografts; Lewis Blood Group Antigens; Lung Neoplasms; Mesothelin; Mesothelioma; Mesothelioma, Malignant; Mice; Radioisotopes; Tissue Distribution; Zirconium
PubMed: 29720923
DOI: 10.1155/2018/2461257 -
Cancer Biology & Therapy Jul 2018The tumor-shed antigen CA125 has recently been found to bind certain monoclonal antibodies (mAbs) and suppress immune-effector mediated killing through perturbation of...
The tumor-shed antigen CA125 has recently been found to bind certain monoclonal antibodies (mAbs) and suppress immune-effector mediated killing through perturbation of the Fc domain with CD16a and CD32a Fc-γ activating receptors on immune-effector cells. Amatuximab is a mAb targeting mesothelin whose mechanism of action utilizes in part antibody-dependent cellular cytotoxicity (ADCC). It is being tested for its therapeutic activity in patients with mesothelioma in combination with first line standard-of-care. To determine if CA125 has immunosuppressive effects on amatuximab ADCC and associated clinical outcomes, post hoc subgroup analysis of patients from a Phase 2 study with primary diagnosed stage III/IV unresectable mesothelioma treated with amatuximab plus cisplatin and pemetrexed were conducted. Analysis found patients with baseline CA125 levels no greater than 57 U/m (∼3X the upper limit of normal) had a 2 month improvement in progression free survival (HR = 0.43, p = 0.0062) and a 7 month improvement in overall survival (HR = 0.40, p = 0.0022) as compared to those with CA125 above 57 U/mL. In vitro studies found that CA125 was able to bind amatuximab and perturb ADCC activity via decreased Fc-γ-receptor engagement. These data suggest that clinical trial designs of antibody-based drugs in cancers producing CA125, including mesothelioma, should consider stratifying patients on baseline CA125 levels for mAbs that are experimentally determined to be bound by CA125.
Topics: Aged; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Combined Chemotherapy Protocols; CA-125 Antigen; Cell Line, Tumor; Cisplatin; Clinical Trials, Phase II as Topic; Female; GPI-Linked Proteins; Gene Knockdown Techniques; Humans; Lung Neoplasms; Male; Membrane Proteins; Mesothelin; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Pemetrexed; Pleural Neoplasms; Progression-Free Survival; RNA, Small Interfering; Receptors, IgG
PubMed: 29652548
DOI: 10.1080/15384047.2018.1449614