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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 -
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 -
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 -
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 -
Investigational New Drugs Apr 2015Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of...
Amatuximab is a chimeric monoclonal antibody that targets mesothelin, which is expressed in virtually all mesotheliomas and pancreatic adenocarcinomas. The objective of this study was to determine the dose-limiting toxicity and the maximum tolerated dose. Patients with mesothelioma, pancreatic adenocarcinoma or other mesothelin-positive solid tumors were eligible for this study. Amatuximab was administered weekly as an intravenous infusion in 4-week cycles at progressively increasing doses ranging from 50 to 200 mg/m(2). Seventeen patients received amatuximab. Two dose-limiting toxicities were observed: one at 50 mg/m(2) and one at 200 mg/m(2); the maximum tolerated dose of this study was determined to be 200 mg/m(2). Of the 17 patients, 13 patients (76.5%) experienced treatment-related adverse events. The most common adverse events were grade 1 fatigue (29.4%) and pyrexia (23.5%). The maximum serum concentration and area under the concentration curve values increased in an almost dose-proportional manner. Three patients had stable disease. Amatuximab was generally well tolerated at doses up to 200 mg/m(2). The pharmacokinetic profile of amatuximab in the Japanese population was similar to that seen in the United States population (Clinical Trials.gov Identifier: NCT01018784).
Topics: Aged; Antibodies, Monoclonal; Antineoplastic Agents; Asian People; Dose-Response Relationship, Drug; Female; GPI-Linked Proteins; Half-Life; Humans; Japan; Male; Maximum Tolerated Dose; Mesothelin; Metabolic Clearance Rate; Middle Aged; Neoplasms
PubMed: 25502863
DOI: 10.1007/s10637-014-0196-0 -
Oncotarget Feb 2015Amatuximab is a chimeric high-affinity monoclonal IgG1/k antibody targeting mesothelin that is being developed for treatment of mesothelin-expressing cancers.... (Clinical Trial)
Clinical Trial
Safety and biodistribution of 111In-amatuximab in patients with mesothelin expressing cancers using single photon emission computed tomography-computed tomography (SPECT-CT) imaging.
Amatuximab is a chimeric high-affinity monoclonal IgG1/k antibody targeting mesothelin that is being developed for treatment of mesothelin-expressing cancers. Considering the ongoing clinical development of amatuximab in these cancers, our objective was to characterize the biodistribution, and dosimetry of 111Indium (111In) radiolabelled amatuximab in mesothelin-expressing cancers. Between October 2011 and February 2013, six patients including four with malignant mesothelioma and two with pancreatic adenocarcinoma underwent Single Photon Emission Computed Tomography-Computed Tomography (SPECT/CT) imaging following administration of 111In amatuximab. SPECT/CT images were obtained at 2-4 hours, 24-48 hours and 96-168 hours after radiotracer injection. In all patients, tumor to background ratios (TBR) consistently met or exceeded an uptake of 1.2 (range 1.2-62.0) which is considered the minimum TBR that can be visualized. TBRs were higher in tumors of patients with mesothelioma than pancreatic adenocarcinoma. 111In-amatuximab uptake was noted in both primary tumors and metastatic sites. The radiotracer dose was generally well-tolerated and demonstrated physiologic uptake in the heart, liver, kidneys and spleen. This is the first study to show tumor localization of an anti-mesothelin antibody in humans. Our results show that 111In-amatuximab was well tolerated with a favorable dosimetry profile. It localizes to mesothelin expressing cancers with a higher uptake in mesothelioma than pancreatic cancer.
Topics: Adenocarcinoma; Aged; Antibodies, Monoclonal; Female; GPI-Linked Proteins; Humans; Indium Radioisotopes; Lung Neoplasms; Male; Mesothelin; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Pancreatic Neoplasms; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon
PubMed: 25756664
DOI: 10.18632/oncotarget.2883 -
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 -
Clinical Cancer Research : An Official... Dec 2014Amatuximab is a chimeric monoclonal antibody to mesothelin, a cell surface glycoprotein highly expressed in malignant pleural mesothelioma (MPM). On the basis of its...
PURPOSE
Amatuximab is a chimeric monoclonal antibody to mesothelin, a cell surface glycoprotein highly expressed in malignant pleural mesothelioma (MPM). On the basis of its synergy with chemotherapy in preclinical studies, we evaluated the antitumor activity of amatuximab plus pemetrexed and cisplatin in patients with unresectable MPM.
EXPERIMENTAL DESIGN
In a single-arm phase II study, amatuximab (5 mg/kg) was administered on days 1 and 8 with pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on day 1 of 21-day cycles for up to six cycles. Patients with response or stable disease received amatuximab maintenance until disease progression. Primary endpoint was progression-free survival (PFS) at 6 months. Secondary endpoints were overall survival (OS), response rate, and safety.
RESULTS
Eighty-nine patients were enrolled at 26 centers. Median of five cycles (range, 1-6) of combination treatment was administered, and 56 (63%) patients received amatuximab maintenance. Combination therapy resulted in no overlapping toxicities. Eleven patients (12.4%) had amatuximab-related hypersensitivity reactions. Responses included partial responses in 33 (40%) and stable disease in 42 (51%). Six-month PFS rate was 51% [95% confidence interval (CI), 39.1-62.3)], median PFS was 6.1 months (95% CI, 5.8-6.4), and median OS was 14.8 months (95% CI, 12.4-18.5) with 29 patients alive at data cut-off.
CONCLUSIONS
Amatuximab with pemetrexed and cisplatin was well tolerated with objective tumor response or stable disease rate of 90% by independent radiologic review. Although PFS was not significantly different from historical controls, the median OS was 14.8 months with a third of patients alive and 5 continuing to receive amatuximab at the time of analysis.
Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Cisplatin; Female; GPI-Linked Proteins; Glutamates; Guanine; Humans; Lung Neoplasms; Male; Mesothelin; Mesothelioma; Mesothelioma, Malignant; Middle Aged; Neoplasm Staging; Pemetrexed; Pleural Neoplasms; Prognosis; Risk Factors; Treatment Outcome
PubMed: 25231400
DOI: 10.1158/1078-0432.CCR-14-0804 -
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