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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 -
Clinical Cancer Drugs Oct 2016Monoclonal antibodies have become attractive clinical anti-cancer drugs in the last 3 decades due to their targeting specificity and suitable pharmacokinetic properties....
ABSTRACT BACKGROUND
Monoclonal antibodies have become attractive clinical anti-cancer drugs in the last 3 decades due to their targeting specificity and suitable pharmacokinetic properties. Mesothelin is a tumor-associated antigen with limited expression in normal tissues. It is frequently over-expressed on the cell membrane of a number of epithelial malignancies (e.g. mesothelioma, pancreatic, ovarian, lung, triple negative breast and gastric cancers).
METHODS
Mesothelin is validated as a suitable antibody target for cancer therapy. A number of novel antibody therapeutics targeting mesothelin in development are compared and their mechanisms of action are also discussed. Both basic science and clinical data are provided to give a complete veiw of how an agent is developed from bench to bedside.
RESULTS
Novel antibody therapeutics, including unconjugated monoclonal antibodies, recombinant immunotoxins and antibody-drug conjugates, targeting mesothelin exert anti-tumor activities by different mechanisms of action. Based on the convincing preclinical data generated with these molecules, the antibody therapeutics have been brought into early clinical evaluation where initial promising results were obtained.
CONCLUSION
These antibody therapeutics directed against mesothelin are expected to have different safety profiles, based on their different mechanism of action. Further clinical development will reveal which of these molecules shows the best efficacy and widest therapeutic window and thus is best suited to bring benefit to the patients.
PubMed: 27853672
DOI: 10.2174/2212697X03666160218215744 -
Expert Review of Anticancer Therapy Nov 2016
PubMed: 27718761
DOI: 10.1080/14737140.2016.1241150 -
Journal of the National Cancer Institute Aug 2016
Topics: Antibodies, Monoclonal; GPI-Linked Proteins; Humans; Immunotherapy; Lung Neoplasms; Mesothelin; Mesothelioma; Mesothelioma, Malignant; Pleural Neoplasms
PubMed: 27510518
DOI: 10.1093/jnci/djw198 -
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 -
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 -
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 -
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