Recognition of Mesothelin by the Therapeutic Antibody MORAb-009

Ma, Jiangfeng; Tang, Wai Kwan; Esser, Lothar; Pastan, Ira; Xia, Di

doi:10.1074/jbc.m112.381756

Cited by 36 publications

(45 citation statements)

References 33 publications

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“…We used V H −V L sequences from the anti-folate-receptor alpha (FRa) antibody [7] (MORAb-003) codon-optimized for human expression. To demonstrate flexibility of the T-cell Biofactory platform (Figure 2E), we also redirected its specificity to target mesothelin (MSLN) by exchanging the V H −V L portion with that of the anti-MSLN antibody [8] (MORAb-009). The rationale for the choice of these two antigens was based on the fact that they are overexpressed on multiple cancers and their expression on healthy tissues is rather limited.…”

Section: Resultsmentioning

confidence: 99%

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Modular Antigen‐Specific T‐cell Biofactories for Calibrated In Vivo Synthesis of Engineered Proteins

et al. 2018

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An artificial cell-signaling pathway is developed that capitalizes on the T-cell’s innate extravasation ability and transforms it into a vector (T-cell Biofactory) for synthesizing calibrated amounts of engineered proteins in vivo. The modularity of this pathway enables reprogramming of the T-cell Biofactory to target biomarkers on different disease cells, e.g. cancer, viral infections, autoimmune disorders. It can be expected that the T-cell Biofactory leads to a “living drug” that extravasates to the disease sites, assesses the disease burden, synthesizes the calibrated amount of engineered therapeutic proteins upon stimulation by the diseased cells, and reduces targeting of normal cells.

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Section: Resultsmentioning

confidence: 99%

“…[7]) (MORAb-003) or the anti-MSLN antibody (ref. [8]) (MORAb-009). (v) Effector : Comprises of a reporter transgene that can be exchanged with a therapeutic transgene to neutralize the pathology that triggered the T-cell Biofactory .…”

Section: Figurementioning

confidence: 99%

Modular Antigen‐Specific T‐cell Biofactories for Calibrated In Vivo Synthesis of Engineered Proteins

et al. 2018

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“…Different approaches include SS1P (anti-mesothelin immunotoxin), MORAb-009 (a highaffinity chimeric monoclonal IgG1/k Ab), anti-mesothelin antibody drug conjugate (ADC) BAY94-9343, a mesothelin tumor vaccine (CRS-207) as well as a mesothelin adoptive Tcell immunotherapy using mesothelin-specific CARs, are being evaluated in phase I clinical trials. 9,19,[28][29][30][31][32] Some of these compounds have shown promising results without unfavorable toxicities in preclinical or early clinical trials and should be tested in patients with TNBC. These ongoing clinical trials will help customizing the potential treatment of mesothelinexpressing malignancies.…”

Section: Discussionmentioning

confidence: 99%

Mesothelin expression and survival outcomes in triple-receptor negative breast cancer.

Parinyanitikul

Blumenschein

et al. 2013

JCO

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e12002 Background: Mesothelin is an ideal tumor-associated marker for the development of targeted therapy due to its limited expression in normal tissues. Identify the frequency of mesothelin expression in triple negative breast cancer may lead the path to customize the drug development in this lack of effective targeted subgroup. The aim of this study was to evaluate mesothelin expression in triple-negative breast cancer (TNBC) and its correlation with survival outcomes. Methods: Mesothelin expression was completed using immunohistochemistry on formalin fixed paraffin tumor sections, and quantified by H-score. An H-score >10 was considered positive. Patient’s characteristics were compared by mesothelin expression. Kaplan-Meier product limit method was used to estimate survival outcomes. Cox proportional hazards models was used to adjust for patient and tumor characteristics. Results: Median age was 52 years. Of the 109 TNBC, 37 (34%) were positive for mesothelin expression. There were no differences on patient/tumor characteristics by mesothelin expression with the exception of high frequency of lymphovascular space invasion in mesothelin-negative tumors (P=0.03). At a median follow up of 75.8 months 20 (18.3%) had experienced a recurrence and 22 (20.2%) had died. Five-year progression-free survival was 87% and 92% in patients with mesothelin-positive and mesothelin-negative tumors (P=0.43), and 5-year overall survival was 85% and 91% patients with mesothelin-positive and mesothelin-negative tumors (P=0.57), respectively. Mesothelin expression was not independently associated with PFS or OS in TNBC after adjustment for other patient and disease characteristics including grade, pathologic stage, lymphovascular invasion, and adjuvant chemotherapy survival outcomes. Conclusions: There was mesothelin expression in 34% of TNBC. No significant differences in the clinical characteristics by mesothelin expression with the exception of high lymphovascular invasion in mesothelin-negative tumors. Mesothelin expression did not correlate with survival outcomes in TNBC.

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“…The crystal structure of the complex between the mesothelin N-terminal fragment and amatuximab Fab at 2.6 Å resolution revealed that amatuximab recognizes a non-linear epitope that is contained in the first 64-residue fragment of mesothelin [23]. It has been shown that the N-terminal 64-residue fragment of mesothelin is also responsible for CA125 recognition [24] and that this interaction can be interrupted by amatuximab [25].…”

Section: Novel Antibody Therapeutics Targeting Mesothlin As Cancer Drmentioning

confidence: 99%

Novel Antibody Therapeutics Targeting Mesothelin In Solid Tumors

Zhao

Subramanyam

Sarapa³

et al. 2016

CCAND

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BackgroundMonoclonal 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).MethodsMesothelin 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.ResultsNovel 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.ConclusionThese 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.

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Recognition of Mesothelin by the Therapeutic Antibody MORAb-009

Cited by 36 publications

References 33 publications

Modular Antigen‐Specific T‐cell Biofactories for Calibrated In Vivo Synthesis of Engineered Proteins

Modular Antigen‐Specific T‐cell Biofactories for Calibrated In Vivo Synthesis of Engineered Proteins

Mesothelin expression and survival outcomes in triple-receptor negative breast cancer.

Novel Antibody Therapeutics Targeting Mesothelin In Solid Tumors

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