Amatuximab
(Synonyms: MORab-009) 目录号 : GC68370Amatuximab (MORab-009) 是一种针对细胞表面间皮素 (MSLN) 的嵌合人源化 IgG1/k 单抗。Mesothelin 是一种糖基磷脂酰肌醇 (GPI) 锚定的膜糖蛋白，存在于有限的正常成人组织中，如间皮。
Cas No.:931402-35-6
Sample solution is provided at 25 µL, 10mM.
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Amatuximab (MORab-009) is a chimeric, humanized IgG1/k MAb that targets the cell surface mesothelin (MSLN). Mesothelin is a glycosylphosphatidyl inositol (GPI)-anchored membrane glycoprotein, which is present in a restricted set of normal adult tissues such as the mesothelium[1][2].
Amatuximab (MORAb-009) is a mouse-human chimeric monoclonal antibody with a selective affinity for MSLN. In vitro, amatuximab elicits antibody-dependent cellular cytotoxicity (ADCC) against mesothelin expressing tumor cell lines and inhibits heterotypic cell adhesion of mesothelin-positive tumor cells to CA125-expressing tumor cells[1].
In tumor xenograft studies, combination treatment with amatuximab plus chemotherapy led to a greater reduction in the growth of mesothelin-expressing tumors than either Amatuximab or chemotherapy alone[1].
[1]. Hassan R, et al. Phase II clinical trial of amatuximab, a chimeric antimesothelin antibody with pemetrexed and cisplatin in advanced unresectable pleural mesothelioma. Clin Cancer Res. 2014;20(23):5927-5936.
[2]. Baldo P, et al. Amatuximab and novel agents targeting mesothelin for solid tumors. Onco Targets Ther. 2017;10:5337-5353. Published 2017 Nov 8.
| Cas No. | 931402-35-6 | SDF | Download SDF |
| 别名 | MORab-009 | ||
| 分子式 | 分子量 | ||
| 溶解度 | 储存条件 | Store at -20°C | |
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Amatuximab and novel agents targeting mesothelin for solid tumors
Onco Targets Ther 2017 Nov 8;10:5337-5353.PMID:29184420DOI:10.2147/OTT.S145105.
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.
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
Invest New Drugs 2021 Oct;39(5):1256-1266.PMID:33905019DOI:10.1007/s10637-021-01118-1.
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.
Mesothelin blockage by Amatuximab suppresses cell invasiveness, enhances gemcitabine sensitivity and regulates cancer cell stemness in mesothelin-positive pancreatic cancer cells
BMC Cancer 2021 Feb 26;21(1):200.PMID:33637083DOI:10.1186/s12885-020-07722-3.
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.
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
Cancer Chemother Pharmacol 2016 Apr;77(4):733-43.PMID:26898299DOI:10.1007/s00280-016-2984-z.
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.
CA125 suppresses Amatuximab immune-effector function and elevated serum levels are associated with reduced clinical response in first line mesothelioma patients
Cancer Biol Ther 2018 Jul 3;19(7):622-630.PMID:29652548DOI:10.1080/15384047.2018.1449614.
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.