Delving into the Latest Updates on Amatuximab with Synapse

Overview

Basic Info

Drug Type

Monoclonal antibody

Synonyms

Amatuximab (USAN), Anti-mesothelin monoclonal antibody

+ [1]

Target

MSLN

Mechanism

MSLN inhibitors(Mesothelin inhibitors), ADCC(Antibody-dependent cell-mediated cytotoxicity (ADCC) effects)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease

Active Indication

MesotheliomaPancreatic Cancer

Inactive Indication

Malignant Pleural MesotheliomaMesothelin positive NeoplasmsNon-Small Cell Lung Cancer+ [3]

Originator Organization

National Cancer Institute

Active Organization

National Cancer Institute

Inactive Organization

Morphotek, Inc.

Eisai Co., Ltd.

Drug Highest PhasePhase 2

First Approval Date-

RegulationOrphan Drug (EU)

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Structure/Sequence

Sequence Code 13007365L

Source: *****

Sequence Code 13006901H

Source: *****

This study was originally designed as a multicenter, double-blind, randomized, parallel-group study, using a placebo control or amatuximab 5 milligrams per kilogram (mg/kg), administered weekly, designed to evaluate the safety and efficacy of amatuximab in combination with pemetrexed and cisplatin in participants with unresectable Malignant Pleural Mesothelioma (MPM) who have not received prior systemic therapy.
Per a business decision made by the Sponsor, participants who were randomized to amatuximab and were still on active treatment at the time of the protocol amendment may have consented to continue to receive weekly treatment with amatuximab until disease progression or intolerable toxicity at the discretion of the principal investigator. Participants randomized to placebo or who were in follow-up at the time of the amendment have been discontinued from the study.

Start Date03 Nov 2015

Sponsor / Collaborator

Morphotek, Inc.

NCT01521325

/ CompletedPhase 1

A Single-Dose Pilot Study of Radiolabeled Amatuximab (MORAb-009) in Mesothelin Over Expressing Cancers

This research is being conducted to determine the biodistribution of radiolabeled amatuximab in tumor and non-tumor tissues in subjects with mesothelin over expressing cancer including mesothelioma, pancreatic, ovarian or non small cell lung cancer.

Start Date01 Sep 2011

Sponsor / Collaborator

Morphotek, Inc.

NCT01018784

/ CompletedPhase 1

A Phase 1 Study of MORAb-009 in Patients With Solid Tumor

MORAb-009 is intravenously administered to patients with solid tumor once a week for 4 weeks as 1 cycle in order to investigate dose-limiting toxicity and estimate maximum tolerated dose.

Start Date01 Nov 2009

Sponsor / Collaborator

Eisai Co., Ltd.

100 Clinical Results associated with Amatuximab

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100 Translational Medicine associated with Amatuximab

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100 Patents (Medical) associated with Amatuximab

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42

Literatures (Medical) associated with Amatuximab

01 Dec 2024·International Journal of Pharmaceutics

Preclinical evaluation of 89Zr/177Lu-labeled amatuximab for theranostic application in pancreatic ductal adenocarcinoma

Article

Author: Wang, Jiali ; Zou, Zhiyan ; Liang, Yuanyuan ; Luo, Rui ; Shi, Mingsong ; Lu, Zhou ; Zheng, Xueting ; Feng, Maosen ; Yang, Xia ; Li, Xiaoan ; Zhou, Yan

Pancreatic ductal adenocarcinoma (PDAC) remains a significant clinical challenge, urgently requiring effective intervention strategies. In recent years, the application of radiopharmaceuticals has emerged as a promising modality for the accurate diagnosis and treatment of malignancies. Due to its high expression on pancreatic cancer cells, mesothelin (MSLN) has become an appealing target for radioimmunotherapy (RIT). In this study, we report the development of a novel radiotracer by conjugating amatuximab with zirconium-89 (⁸⁹Zr) to facilitate the non-invasive detection of MSLN expression. Immuno-positron emission tomography (immunoPET) imaging demonstrated a specific accumulation of ⁸⁹Zr-DFO- amatuximab in PANC-1-MSLN tumors. Subsequently, Lutetium-177 (¹⁷⁷Lu)-labeled amatuximab was utilized for MSLN- targeted radioimmunotherapy (RIT), resulting in a significant suppression of PANC-1-MSLN xenograft growth. Furthermore, in vivo studies indicated that ¹⁷⁷Lu-DOTA-amatuximab exhibited limited side effects. The development of ⁸⁹Zr/¹⁷⁷Lu-labeled amatuximab may provide novel insights into the formulation of precision diagnostic and therapeutic strategies for MSLN- overexpressing tumors, including PDAC.

01 Apr 2024·Cytotherapy

Mesothelin antigen density influences anti-mesothelin chimeric antigen receptor T cell cytotoxicity

Article

Author: Metierre, Cynthia ; Nagarajah, Rajini ; Bailey, Charles G ; Yeo, Dannel ; Adelstein, Stephen ; Liang, Oliver ; Rasko, John E J ; Sagnella, Sharon M ; Castelletti, Laura ; Chu, Gerard J

BACKGROUND AIMSSeveral anti-mesothelin (MSLN) chimeric antigen receptor (CAR) T cells are in phase 1/2 clinical trials to treat solid-organ malignancies. The effect of MSLN antigen density on MSLN CAR cytotoxicity against tumor cells has not been examined previously, nor are there data regarding the effect of agents that increase MSLN antigen density on anti-MSLN CAR T cell efficacy.METHODSMSLN antigen density was measured on a panel of pancreatic cancer and mesothelioma cell lines by flow cytometry. In parallel, the cytotoxicity and specificity of two anti-MSLN CAR T cells (m912 and SS1) were compared against these cell lines using a real-time impedance-based assay. The effect of two MSLN 'sheddase' inhibitors (lanabecestat and TMI-1) that increase MSLN surface expression was also tested in combination with CAR T cells.RESULTSSS1 CAR T cells were more cytotoxic compared with m912 CAR T cells against cell lines that expressed fewer than ∼170 000 MSLN molecules/cell. A comparison of the m912 and amatuximab (humanized SS1) antibodies identified that amatuximab could detect and bind to lower levels of MSLN on pancreatic cancer and mesothelioma cell lines, suggesting that superior antibody/scFv affinity was the reason for the SS1 CAR's superior cytotoxicity. The cytotoxicity of m912 CAR T cells was improved in the presence of sheddase inhibitors, which increased MSLN antigen density.CONCLUSIONSThese data highlight the value of assessing CAR constructs against a panel of cells expressing varying degrees of target tumor antigen as occurs in human tumors. Furthermore, the problem of low antigen density may be overcome by concomitant administration of drugs that inhibit enzymatic shedding of MSLN.

01 Apr 2023·International Journal of Gynecological Cancer

Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study

Article

Author: Coleman, Robert L ; Santin, Alessandro D ; González-Martín, Antonio ; Monk, Bradley J ; Kasten, Linda ; Diab, Sami ; Vergote, Ignace ; Moore, Kathleen ; Copeland, Larry J ; Schulz, Anke ; Bulat, Iurie ; Siegel, Jonathan ; Köchert, Karl ; Herzog, Thomas J ; Oaknin, Ana ; Walter, Annette O ; Elbi, Cem ; Romero, Ignacio ; Schlicker, Andreas ; Childs, Barrett H

ObjectivesAnetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer.MethodsAnetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m2) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing.ResultsIn dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months.ConclusionsAnetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer.Trial registration numberNCT02751918.

1

News (Medical) associated with Amatuximab

08 Sep 2023

·pipelinereview.com

Mesothelin: an old solid tumor target for next generation drug modalities – a pipeline review

BARCELONA, Spain I September 08, 2023 I La Merie Publishing released its newest product reviewing the pipeline of mesothelin-targeted immunotherapy candidates in R&D: Mesothelin-Targeted Immunotherapy Pipeline Review Target: Mesothelin Product Category: Antibody; Cells; Vaccine This product provides basic information on immunotherapy candidates in research and development targeting mesothelin. This product consists of: This product is delivered on the very same day of purchase by e-mail containing competitor and project history reports in pdf format and database credentials. Reports are prepared on the same day. Mesothelin, is a 40 kD glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein overexpressed in many cancers, potentially involved in adhesion and metastasis. The well-known interacting partner of mesothelin is CA125/MUC16, a member of the mucin family of glycoproteins which is expressed in ovarian cancer and malignant mesothelioma Given the limited expression of mesothelin in normal tissues and overexpression in several tumor cells, mesothelin presents a desirable target for tumor-specific therapy. Mesothelin expression has been identified in approximately 30% of cancers, including mesothelioma, ovarian, pancreatic, gastric, and non–small cell lung tumors, uterine malignancies as well as cholangiocarcinoma. In high grade ovarian cancer, mesothelin is overexpressed in 75% to 80% of patients. Normal expression of mesothelin is on mesothelial cells lining pleura, peritoneum, and pericardium. Low expression may be found on some other tissues, but anti-mesothelin antibodies or antibody-toxin conjugates have not shown much toxicity. Although several first generation drug modalities used for targeting mesothelin eventually have failed in clinical studies, such as immunotoxins, thorium-targeted therapies, antibody-drug conjugates, chimeric antigen receptor T cells, natural killer cells as well as T-cell engaging antibodies, improved next generation versions of such drug modalities have been developed and are applied to novel immunotherapy candidates for mesothelin-expressing cancers. The report “ Mesothelin-Targeted Immunotherapy Pipeline Review ” can be acquired at La Merie Publishing’s online store: https://lamerie.com/report/mesothelin-targeted-immunotherapy-pipeline-review/ About La Merie Publishing La Merie Publishing is an independent business information provider for the biotechnology and pharmaceutical industry. La Merie Publishing prepares brief and full reports. La Merie Publishing products can be purchased in the online store www.lamerie.com and from selected Resellers. La Merie Publishing offers the service of custom report preparation for corporate clients, including, but not limited to, pipeline analysis reports, drug profiles and any other competitive intelligence elaboration of interest. SOURCE: La Merie Publishing

ImmunotherapyAACR

100 Deals associated with Amatuximab

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External Link

KEGG	Wiki	ATC	Drug Bank
D09767	Amatuximab	-	DB12845

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Mesothelioma	Phase 2	-	National Cancer Institute	-
Pancreatic Cancer	Phase 2	-	National Cancer Institute	-
Malignant Pleural Mesothelioma	Preclinical	CA	Morphotek, Inc.	31 Dec 2008
Pancreatic carcinoma non-resectable	Preclinical	ES	Morphotek, Inc.	01 Dec 2007
Pancreatic carcinoma non-resectable	Preclinical	BE	Morphotek, Inc.	01 Dec 2007
Pancreatic carcinoma non-resectable	Preclinical	CA	Morphotek, Inc.	01 Dec 2007
Pancreatic carcinoma non-resectable	Preclinical	US	Morphotek, Inc.	01 Dec 2007
Pancreatic carcinoma non-resectable	Preclinical	DE	Morphotek, Inc.	01 Dec 2007
Malignant Pleural Mesothelioma	Discovery	NL	Morphotek, Inc.	31 Dec 2008
Malignant Pleural Mesothelioma	Discovery	ES	Morphotek, Inc.	31 Dec 2008

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT00738582 (Amatuximab, CTgov)	Phase 2	Malignant Pleural Mesothelioma	89	amatuximab+cisplatin+pemetrexed (All Participants)	jvgewguvmt(qqpyncmnoj) = uybifboubo icnjchfgat (ikvhdpjscl, zygvfhnlxl - vfciequskq) View more	-	22 Sep 2022
NCT00738582 (Amatuximab, CTgov)	Phase 2	Malignant Pleural Mesothelioma	89	Amatuximab+Cisplatin+Pemetrexed (Amatuximab/Pemetrexed/Cisplatin)	mitjliqarq(ojshgparfh) = lwnwvfyoby mxbicmgocv (dbggwqvvas, jzhdygnksm - tafwdohjri) View more	-	22 Sep 2022
NCT02357147 (ARTEMIS, CTgov)	Phase 2	Unresectable Pleural Malignant Mesothelioma	124	Amatuximab+Cisplatin+Pemetrexed (Combination Treatment Phase:Amatuximab + Pemetrexed +Cisplatin)	(djbtunzcyq) = stmjdvznps zqgeuogucd (ntleqynwff, bkxakwswdt - wbqwfvdnhs) View more	-	17 Mar 2020
NCT02357147 (ARTEMIS, CTgov)	Phase 2	Unresectable Pleural Malignant Mesothelioma	124	Placebo+Cisplatin+Pemetrexed (Combination Treatment Phase: Placebo + Pemetrexed + Cisplatin)	(djbtunzcyq) = qydakzinpm zqgeuogucd (ntleqynwff, ujzqjxwlsq - fkdqlpqbwt) View more	-	17 Mar 2020
NCT02357147 (ASCO2016)	Phase 2	Malignant Pleural Mesothelioma	560	Amatuximab + P/C	(wtmunstevm) = zwzrcsqgdm uuqbucbuvt (sixqfnrycl )	-	20 May 2016
NCT01018784 (Pubmed \| Invest New Drugs)	Phase 1	Advanced Malignant Solid Neoplasm	17	Amatuximab	(yfksusnljh) = wviogdwuts isgxesmxqv (vlfrgzprii ) View more	-	01 Apr 2015
WCLC2013	Not Applicable	Unresectable Pleural Malignant Mesothelioma	89	Amatuximab 5mg/kg	(eiymfznsdc) = fpbzrulowd eplmgafldr (pbfvfbnndi ) View more	-	29 Oct 2013
ASCO2012	Phase 2	Unresectable Pleural Malignant Mesothelioma	89	Amatuximab + Pemetrexed + Cisplatin	(ywpkwsnyap) = otbsnuvdyz jwrvfwvowj (nhgvsmwjzs ) View more	-	20 May 2012
NCT00570713 (CTgov)	Phase 2	Pancreatic carcinoma non-resectable \| Pancreatic Cancer	155	MORAb-009+Gemcitabine (MORAb-009 Plus Gemcitabine ('MORAb-009'))	(hvdqdchknw) = eqgednqzjx bjapbtpjye (dwfkndftte, caclnlrprd - tcbczcjciv) View more	-	27 Mar 2012
NCT00570713 (CTgov)	Phase 2	Pancreatic carcinoma non-resectable \| Pancreatic Cancer	155	Placebo+Gemcitabine (Placebo Plus Gemcitabine ('Placebo'))	(hvdqdchknw) = ggglpnwygr bjapbtpjye (dwfkndftte, ybckjcxcgl - gddgjfbzle) View more	-	27 Mar 2012