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Raffit Hassan - One of the best experts on this subject based on the ideXlab platform.
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First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody-Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors.
Journal of Clinical Oncology, 2020Co-Authors: Raffit Hassan, Anish Thomas, George R. Blumenschein, Kathleen N. Moore, Alessandro D. Santin, Hedy L. Kindler, John Nemunaitis, Shelly Seward, Prabhu RajagopalanAbstract:Purpose This phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody-drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid Tumors known to express the Tumor-Differentiation Antigen mesothelin. Patients and methods This phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid Tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid Tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week. Results Forty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non-small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of Tumor mesothelin expression were detected in patients with clinical activity. Conclusion Anetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antiTumor activity in heavily pretreated patients with mesothelin-expressing solid Tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.
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Immunotherapeutic Approaches to Mesothelioma
Asbestos and Mesothelioma, 2017Co-Authors: Anish Thomas, Madhuri Badrinath, Raffit HassanAbstract:Several lines of evidence indicate the activation of a host humoral and cellular response in mesothelioma patients. Tumor cells employ a number of mechanisms to promote immune tolerance and to escape host immune surveillance. These include immune checkpoints—molecules expressed on the surface of immune cells and Tumor cells—that curb effector T-cell responses. The emerging category of drugs that inhibit immune checkpoints and their ligands have shown preliminary clinical activity in patients with mesothelioma. Among Antigen-specific approaches, therapies targeting a Tumor Differentiation Antigen mesothelin, which is differentially expressed in mesothelioma, are farthest along in clinical development. Included among the mesothelin-targeted immunotherapies that are under clinical investigation are immunotoxins, Tumor vaccine, chimeric Antigen receptor T cell, and antibody-based therapies. Of these, the monoclonal antibody amatuximab and an antibody-drug conjugate anetumab ravtansine are undergoing registration trials. Ongoing research is focused on better understanding the antiTumor responses to immune-based approaches and to prospectively identify patients who are more likely to respond to these interventions. Parallel efforts are also investigating ways to therapeutically improve mesothelioma immunogenicity.
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Abstract 3103: The reduced immunogenicity anti-mesothelin immunotoxin RG7787 in combination with nab-paclitaxel has significant anti-Tumor efficacy against primary mesothelioma cell lines and patient derived mesothelioma Tumor xenografts
Cancer Research, 2016Co-Authors: Jingli Zhang, Ira Pastan, Anish Thomas, Qun Jiang, Christine Alewine, Swati Khanna, Betsy Morrow, Raffit HassanAbstract:Mesothelin is a Tumor Differentiation Antigen that is highly expressed in many cancers including malignant mesothelioma. RG7787 is a second-generation anti-mesothelin immunotoxin that is designed to be less immunogenic in patients and has reduced non-specific toxicity in pre-clinical studies. In this study, we evaluated the anti-Tumor efficacy of RG7787 alone and in combination with nab-paclitaxel using primary mesothelioma cell lines obtained from patients with pleural or peritoneal mesothelioma. Four early passage malignant mesothelioma cell lines: NCI-Meso16, NCI-Meso19, NCI-Meso21 and NCI-Meso29 were evaluated for mesothelin expression and have 18×103- 56×103 mesothelin sites/cell. All four cell lines were sensitive to RG7787 with IC50s of 0.3 to 10 ng/ml. Three of the cell lines: NCI-Meso 16, NCI-Meso 21 and NCI-Meso 29 were also sensitive to nab-paclitaxel with IC50s of 4, 40 and 2 ng/ml respectively while, NCI-Meso 19 was resistant with IC50 >100 ng/ml. Synergistic in vitro cell cytotoxicity was observed with both NCI-Meso16 and NCI-Meso21 cells, when treated with the combination of RG7787 and nab-paclitaxel. To evaluate the efficacy of RG7787 with nab-paclitaxel in vivo, athymic nude mice were inoculated subcutaneously with 5×106 NCI-Meso 16 cells. When the Tumors reached 100 mm3 in size, mice (n = 7 in each group) were treated with 2 cycles (separated by 3 days) of either RG7787 2.5 mg/kg every other day x 3 doses, nab-paclitaxel 100 mg/kg on day 1, a combination of RG7787 and nab-paclitaxel at the same dose and schedule as for single agent therapy, or received no treatment (control). Although treatment with RG7787 and nab-paclitaxel alone resulted in Tumor shrinkage compared to control mice, none of the mice had complete Tumor regressions. However, in mice treated with RG7787 plus nab-paclitaxel all mice had complete Tumor regressions by day 64 that persisted in 7/7 mice when the experiment was terminated 100 days after starting treatment. In the slow growing NCI-Meso 21 in-vivo model, we also observed similar synergistic anti-Tumor effects with the combination of RG7787 and nab-paclitaxel. Taken together, our findings show that RG7787 in combination with nab-paclitaxel has significant anti-Tumor activity against primary mesothelioma cell lines both in vitro and in vivo, suggesting that this combination treatment could be useful to treat patients with mesothelioma. Citation Format: Jingli Zhang, Qun Jiang, Christine Alewine, Swati Khanna, Betsy Morrow, Anish Thomas, Ira Pastan, Raffit Hassan. The reduced immunogenicity anti-mesothelin immunotoxin RG7787 in combination with nab-paclitaxel has significant anti-Tumor efficacy against primary mesothelioma cell lines and patient derived mesothelioma Tumor xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3103.
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Loss of Mesothelin Expression by Mesothelioma Cells Grown In Vitro Determines Sensitivity to Anti-Mesothelin Immunotoxin SS1P
Anticancer Research, 2012Co-Authors: Jingli Zhang, Ira Pastan, Yujian Zhang, Maria J. Merino, Patricia Fetsch, Itzhak Avital, Armando C. Filie, Raffit HassanAbstract:Background/Aim: To determine if early passage Tumor cells obtained from patients with mesothelioma continue to express the Tumor Differentiation Antigen mesothelin and their sensitivity to the anti-mesothelin immunotoxin SS1P. Materials and Methods: Cell cultures were established from ascites or pleural effusion of 6 peritoneal and 3 pleural mesothelioma patients, respectively. These cells were evaluated for mesothelin expression by immunohistochemistry and flow cytometry. Results: Although mesothelin was highly expressed in Tumor biopsies of all patients, only 3 out of 9 malignant effusions from these patients when grown in short-term culture showed strong mesothelin positivity by IHC. By flow cytometry, the number of mesothelin sites per cell was variable ranging from 580 to 210,000 sites/cell. Cells with strong mesothelin expression by IHC and increased number of mesothelin sites/cell were sensitive to SS1P. Conclusions: Most mesothelioma Tumors loose mesothelin when grown in vitro and the sensitivity of these cells to SS1P is dependent on the number of mesothelin sites/cell.
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Mesothelin-Targeted Agents in Clinical Trials and in Preclinical Development
Molecular Cancer Therapeutics, 2012Co-Authors: Ronan J. Kelly, Elad Sharon, Ira Pastan, Raffit HassanAbstract:Mesothelin is a Tumor Differentiation Antigen that is highly expressed in several malignant diseases in humans, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. The limited expression of mesothelin on normal human tissues and its high expression in many common cancers make it an attractive candidate for cancer therapy. Several agents, including an immunotoxin, monoclonal antibody, antibody drug conjugate, and Tumor vaccine, are in various stages of development to treat patients with mesothelin-expressing Tumors. This review highlights ongoing clinical trials, as well as other approaches to exploit mesothelin for cancer therapy, that are in preclinical development. Mol Cancer Ther; 11(3); 517–25. ©2012 AACR .
Ira Pastan - One of the best experts on this subject based on the ideXlab platform.
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Abstract 3103: The reduced immunogenicity anti-mesothelin immunotoxin RG7787 in combination with nab-paclitaxel has significant anti-Tumor efficacy against primary mesothelioma cell lines and patient derived mesothelioma Tumor xenografts
Cancer Research, 2016Co-Authors: Jingli Zhang, Ira Pastan, Anish Thomas, Qun Jiang, Christine Alewine, Swati Khanna, Betsy Morrow, Raffit HassanAbstract:Mesothelin is a Tumor Differentiation Antigen that is highly expressed in many cancers including malignant mesothelioma. RG7787 is a second-generation anti-mesothelin immunotoxin that is designed to be less immunogenic in patients and has reduced non-specific toxicity in pre-clinical studies. In this study, we evaluated the anti-Tumor efficacy of RG7787 alone and in combination with nab-paclitaxel using primary mesothelioma cell lines obtained from patients with pleural or peritoneal mesothelioma. Four early passage malignant mesothelioma cell lines: NCI-Meso16, NCI-Meso19, NCI-Meso21 and NCI-Meso29 were evaluated for mesothelin expression and have 18×103- 56×103 mesothelin sites/cell. All four cell lines were sensitive to RG7787 with IC50s of 0.3 to 10 ng/ml. Three of the cell lines: NCI-Meso 16, NCI-Meso 21 and NCI-Meso 29 were also sensitive to nab-paclitaxel with IC50s of 4, 40 and 2 ng/ml respectively while, NCI-Meso 19 was resistant with IC50 >100 ng/ml. Synergistic in vitro cell cytotoxicity was observed with both NCI-Meso16 and NCI-Meso21 cells, when treated with the combination of RG7787 and nab-paclitaxel. To evaluate the efficacy of RG7787 with nab-paclitaxel in vivo, athymic nude mice were inoculated subcutaneously with 5×106 NCI-Meso 16 cells. When the Tumors reached 100 mm3 in size, mice (n = 7 in each group) were treated with 2 cycles (separated by 3 days) of either RG7787 2.5 mg/kg every other day x 3 doses, nab-paclitaxel 100 mg/kg on day 1, a combination of RG7787 and nab-paclitaxel at the same dose and schedule as for single agent therapy, or received no treatment (control). Although treatment with RG7787 and nab-paclitaxel alone resulted in Tumor shrinkage compared to control mice, none of the mice had complete Tumor regressions. However, in mice treated with RG7787 plus nab-paclitaxel all mice had complete Tumor regressions by day 64 that persisted in 7/7 mice when the experiment was terminated 100 days after starting treatment. In the slow growing NCI-Meso 21 in-vivo model, we also observed similar synergistic anti-Tumor effects with the combination of RG7787 and nab-paclitaxel. Taken together, our findings show that RG7787 in combination with nab-paclitaxel has significant anti-Tumor activity against primary mesothelioma cell lines both in vitro and in vivo, suggesting that this combination treatment could be useful to treat patients with mesothelioma. Citation Format: Jingli Zhang, Qun Jiang, Christine Alewine, Swati Khanna, Betsy Morrow, Anish Thomas, Ira Pastan, Raffit Hassan. The reduced immunogenicity anti-mesothelin immunotoxin RG7787 in combination with nab-paclitaxel has significant anti-Tumor efficacy against primary mesothelioma cell lines and patient derived mesothelioma Tumor xenografts. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3103.
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Loss of Mesothelin Expression by Mesothelioma Cells Grown In Vitro Determines Sensitivity to Anti-Mesothelin Immunotoxin SS1P
Anticancer Research, 2012Co-Authors: Jingli Zhang, Ira Pastan, Yujian Zhang, Maria J. Merino, Patricia Fetsch, Itzhak Avital, Armando C. Filie, Raffit HassanAbstract:Background/Aim: To determine if early passage Tumor cells obtained from patients with mesothelioma continue to express the Tumor Differentiation Antigen mesothelin and their sensitivity to the anti-mesothelin immunotoxin SS1P. Materials and Methods: Cell cultures were established from ascites or pleural effusion of 6 peritoneal and 3 pleural mesothelioma patients, respectively. These cells were evaluated for mesothelin expression by immunohistochemistry and flow cytometry. Results: Although mesothelin was highly expressed in Tumor biopsies of all patients, only 3 out of 9 malignant effusions from these patients when grown in short-term culture showed strong mesothelin positivity by IHC. By flow cytometry, the number of mesothelin sites per cell was variable ranging from 580 to 210,000 sites/cell. Cells with strong mesothelin expression by IHC and increased number of mesothelin sites/cell were sensitive to SS1P. Conclusions: Most mesothelioma Tumors loose mesothelin when grown in vitro and the sensitivity of these cells to SS1P is dependent on the number of mesothelin sites/cell.
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Recognition of Mesothelin by the Therapeutic Antibody MORAb-009 STRUCTURAL AND MECHANISTIC INSIGHTS
Journal of Biological Chemistry, 2012Co-Authors: Jichun Ma, Wai Kwan Tang, Lothar Esser, Ira PastanAbstract:Abstract Mesothelin is a Tumor Differentiation Antigen that is highly expressed in many epithelial cancers, with limited expression in normal human tissues. Binding of mesothelin on normal mesothelial cells lining the pleura or peritoneum to the Tumor-associated cancer Antigen 125 (CA-125) can lead to heterotypic cell adhesion and Tumor metastasis within the pleural and peritoneal cavities. This binding can be prevented by MORAb-009, a humanized monoclonal antibody against mesothelin currently under clinical trials. We show here that MORAb-009 recognizes a non-linear epitope that is contained in the first 64-residue fragment of the mesothelin. We further demonstrate that the recognition is independent of glycosylation state of the protein but sensitive to the loss of a disulfide bond linking residues Cys-7 and Cys-31. The crystal structure of the complex between the mesothelin N-terminal fragment and Fab of MORAb-009 at 2.6 A resolution reveals an epitope encompassing multiple secondary structural elements of the mesothelin, including residues from helix α1, the loops linking helices α1 and α2, and between helices α4 and α5. The mesothelin fragment has a compact, right-handed superhelix structure consisting of five short helices and connecting loops. A residue essential for complex formation has been identified as Phe-22, which projects its side chain into a hydrophobic niche formed on the antibody recognition surface upon Antigen-antibody contact. The overlapping binding footprints of both the monoclonal antibody and the cancer Antigen CA-125 explains the therapeutic effect and provides a basis for further antibody improvement.
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Mesothelin-Targeted Agents in Clinical Trials and in Preclinical Development
Molecular Cancer Therapeutics, 2012Co-Authors: Ronan J. Kelly, Elad Sharon, Ira Pastan, Raffit HassanAbstract:Mesothelin is a Tumor Differentiation Antigen that is highly expressed in several malignant diseases in humans, including malignant mesothelioma and pancreatic, ovarian, and lung adenocarcinomas. The limited expression of mesothelin on normal human tissues and its high expression in many common cancers make it an attractive candidate for cancer therapy. Several agents, including an immunotoxin, monoclonal antibody, antibody drug conjugate, and Tumor vaccine, are in various stages of development to treat patients with mesothelin-expressing Tumors. This review highlights ongoing clinical trials, as well as other approaches to exploit mesothelin for cancer therapy, that are in preclinical development. Mol Cancer Ther; 11(3); 517–25. ©2012 AACR .
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Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers.
Clinical Cancer Research, 2010Co-Authors: Raffit Hassan, Ronan J. Kelly, Charles Schweizer, Elad Sharon, Steven J Cohen, Martin Phillips, Ira Pastan, Susan C. Weil, Daniel LaheruAbstract:Purpose: MORAb-009 is a chimeric monoclonal antibody that targets mesothelin, a Tumor Differentiation Antigen overexpressed in pancreatic cancer, ovarian cancer, mesothelioma, and other malignancies. We conducted a phase I clinical trial of MORAb-009 in patients with advanced mesothelin-expressing cancers to determine its safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD). Methods: Cohorts consisting of 3 to 6 subjects each received MORAb-009 intravenously on days 1, 8, 15, and 22 at progressively increasing doses ranging from 12.5 to 400 mg/m 2 . Disease evaluation with computed tomography occurred on day 35. Subjects with responding or stable disease could receive additional cycles of MORAb-009. Results: A total of 24 subjects were treated including 13 mesothelioma, 7 pancreatic cancer, and 4 ovarian cancer patients. The median number of MORAb-009 infusions was 4 (range 1–24 infusions). At the 400 mg/m 2 dose level, 2 subjects experienced DLT (grade 4 transaminitis and a grade 3 serum sickness). Thus, although there were other contributing causes of these adverse events, 200 mg/m 2 was considered the MTD. Other adverse events at least possibly related to MORAb-009 included 7 drug hypersensitivity events (all grade 1 or 2) and a thromboembolic event (grade 4). Eleven subjects had stable disease. There was a dose-dependent increase in serum MORAb-009 concentration. Conclusion: MORAb-009 is well tolerated and the MTD when administered weekly is conservatively set at 200 mg/m 2 . In this group of previously treated patients, 11 subjects had stable disease. Phase II studies of MORAb-009 in different mesothelin-expressing cancers are ongoing.
Daniel Laheru - One of the best experts on this subject based on the ideXlab platform.
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Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers.
Clinical Cancer Research, 2010Co-Authors: Raffit Hassan, Ronan J. Kelly, Charles Schweizer, Elad Sharon, Steven J Cohen, Martin Phillips, Ira Pastan, Susan C. Weil, Daniel LaheruAbstract:Purpose: MORAb-009 is a chimeric monoclonal antibody that targets mesothelin, a Tumor Differentiation Antigen overexpressed in pancreatic cancer, ovarian cancer, mesothelioma, and other malignancies. We conducted a phase I clinical trial of MORAb-009 in patients with advanced mesothelin-expressing cancers to determine its safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD). Methods: Cohorts consisting of 3 to 6 subjects each received MORAb-009 intravenously on days 1, 8, 15, and 22 at progressively increasing doses ranging from 12.5 to 400 mg/m 2 . Disease evaluation with computed tomography occurred on day 35. Subjects with responding or stable disease could receive additional cycles of MORAb-009. Results: A total of 24 subjects were treated including 13 mesothelioma, 7 pancreatic cancer, and 4 ovarian cancer patients. The median number of MORAb-009 infusions was 4 (range 1–24 infusions). At the 400 mg/m 2 dose level, 2 subjects experienced DLT (grade 4 transaminitis and a grade 3 serum sickness). Thus, although there were other contributing causes of these adverse events, 200 mg/m 2 was considered the MTD. Other adverse events at least possibly related to MORAb-009 included 7 drug hypersensitivity events (all grade 1 or 2) and a thromboembolic event (grade 4). Eleven subjects had stable disease. There was a dose-dependent increase in serum MORAb-009 concentration. Conclusion: MORAb-009 is well tolerated and the MTD when administered weekly is conservatively set at 200 mg/m 2 . In this group of previously treated patients, 11 subjects had stable disease. Phase II studies of MORAb-009 in different mesothelin-expressing cancers are ongoing.
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Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers
Clinical Cancer Research, 2010Co-Authors: Raffit Hassan, Ronan J. Kelly, Charles Schweizer, Susan Weil, Elad Sharon, Steven J Cohen, Martin Phillips, Ira Pastan, Daniel LaheruAbstract:PURPOSE: MORAb-009 is a chimeric monoclonal antibody that targets mesothelin, a Tumor Differentiation Antigen overexpressed in pancreatic cancer, ovarian cancer, mesothelioma, and other malignancies. We conducted a phase I clinical trial of MORAb-009 in patients with advanced mesothelin-expressing cancers to determine its safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD).\n\nMETHODS: Cohorts consisting of 3 to 6 subjects each received MORAb-009 intravenously on days 1, 8, 15, and 22 at progressively increasing doses ranging from 12.5 to 400 mg/m(2). Disease evaluation with computed tomography occurred on day 35. Subjects with responding or stable disease could receive additional cycles of MORAb-009.\n\nRESULTS: A total of 24 subjects were treated including 13 mesothelioma, 7 pancreatic cancer, and 4 ovarian cancer patients. The median number of MORAb-009 infusions was 4 (range 1-24 infusions). At the 400 mg/m(2) dose level, 2 subjects experienced DLT (grade 4 transaminitis and a grade 3 serum sickness). Thus, although there were other contributing causes of these adverse events, 200 mg/m(2) was considered the MTD. Other adverse events at least possibly related to MORAb-009 included 7 drug hypersensitivity events (all grade 1 or 2) and a thromboembolic event (grade 4). Eleven subjects had stable disease. There was a dose-dependent increase in serum MORAb-009 concentration.\n\nCONCLUSION: MORAb-009 is well tolerated and the MTD when administered weekly is conservatively set at 200 mg/m(2). In this group of previously treated patients, 11 subjects had stable disease. Phase II studies of MORAb-009 in different mesothelin-expressing cancers are ongoing.
Charles Schweizer - One of the best experts on this subject based on the ideXlab platform.
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Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers.
Clinical Cancer Research, 2010Co-Authors: Raffit Hassan, Ronan J. Kelly, Charles Schweizer, Elad Sharon, Steven J Cohen, Martin Phillips, Ira Pastan, Susan C. Weil, Daniel LaheruAbstract:Purpose: MORAb-009 is a chimeric monoclonal antibody that targets mesothelin, a Tumor Differentiation Antigen overexpressed in pancreatic cancer, ovarian cancer, mesothelioma, and other malignancies. We conducted a phase I clinical trial of MORAb-009 in patients with advanced mesothelin-expressing cancers to determine its safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD). Methods: Cohorts consisting of 3 to 6 subjects each received MORAb-009 intravenously on days 1, 8, 15, and 22 at progressively increasing doses ranging from 12.5 to 400 mg/m 2 . Disease evaluation with computed tomography occurred on day 35. Subjects with responding or stable disease could receive additional cycles of MORAb-009. Results: A total of 24 subjects were treated including 13 mesothelioma, 7 pancreatic cancer, and 4 ovarian cancer patients. The median number of MORAb-009 infusions was 4 (range 1–24 infusions). At the 400 mg/m 2 dose level, 2 subjects experienced DLT (grade 4 transaminitis and a grade 3 serum sickness). Thus, although there were other contributing causes of these adverse events, 200 mg/m 2 was considered the MTD. Other adverse events at least possibly related to MORAb-009 included 7 drug hypersensitivity events (all grade 1 or 2) and a thromboembolic event (grade 4). Eleven subjects had stable disease. There was a dose-dependent increase in serum MORAb-009 concentration. Conclusion: MORAb-009 is well tolerated and the MTD when administered weekly is conservatively set at 200 mg/m 2 . In this group of previously treated patients, 11 subjects had stable disease. Phase II studies of MORAb-009 in different mesothelin-expressing cancers are ongoing.
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Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers
Clinical Cancer Research, 2010Co-Authors: Raffit Hassan, Ronan J. Kelly, Charles Schweizer, Susan Weil, Elad Sharon, Steven J Cohen, Martin Phillips, Ira Pastan, Daniel LaheruAbstract:PURPOSE: MORAb-009 is a chimeric monoclonal antibody that targets mesothelin, a Tumor Differentiation Antigen overexpressed in pancreatic cancer, ovarian cancer, mesothelioma, and other malignancies. We conducted a phase I clinical trial of MORAb-009 in patients with advanced mesothelin-expressing cancers to determine its safety, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD).\n\nMETHODS: Cohorts consisting of 3 to 6 subjects each received MORAb-009 intravenously on days 1, 8, 15, and 22 at progressively increasing doses ranging from 12.5 to 400 mg/m(2). Disease evaluation with computed tomography occurred on day 35. Subjects with responding or stable disease could receive additional cycles of MORAb-009.\n\nRESULTS: A total of 24 subjects were treated including 13 mesothelioma, 7 pancreatic cancer, and 4 ovarian cancer patients. The median number of MORAb-009 infusions was 4 (range 1-24 infusions). At the 400 mg/m(2) dose level, 2 subjects experienced DLT (grade 4 transaminitis and a grade 3 serum sickness). Thus, although there were other contributing causes of these adverse events, 200 mg/m(2) was considered the MTD. Other adverse events at least possibly related to MORAb-009 included 7 drug hypersensitivity events (all grade 1 or 2) and a thromboembolic event (grade 4). Eleven subjects had stable disease. There was a dose-dependent increase in serum MORAb-009 concentration.\n\nCONCLUSION: MORAb-009 is well tolerated and the MTD when administered weekly is conservatively set at 200 mg/m(2). In this group of previously treated patients, 11 subjects had stable disease. Phase II studies of MORAb-009 in different mesothelin-expressing cancers are ongoing.
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Inhibition of mesothelin–CA-125 interaction in patients with mesothelioma by the anti-mesothelin monoclonal antibody MORAb-009: Implications for cancer therapy
Lung Cancer, 2009Co-Authors: Raffit Hassan, Charles Schweizer, Kun F. Lu, Barbara Schuler, Alan T. Remaley, Susan C. Weil, Ira PastanAbstract:Background Mesothelin, a Tumor Differentiation Antigen highly expressed in mesothelioma and ovarian cancer, is the receptor for CA-125 (MUC 16) and this interaction may play a role in Tumor metastasis. MORAb-009 is a chimeric anti-mesothelin monoclonal antibody.
Jonathan J Lewis - One of the best experts on this subject based on the ideXlab platform.
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a single heteroclitic epitope determines cancer immunity after xenogeneic dna immunization against a Tumor Differentiation Antigen
Journal of Immunology, 2003Co-Authors: Jason S Gold, Cristina R Ferrone, Jose A Guevarapatino, William G Hawkins, Ruben Dyall, Manuel E Engelhorn, Jedd D Wolchok, Jonathan J LewisAbstract:Successful active immunization against cancer requires induction of immunity against self or mutated self Ags. However, immunization against self Ags is difficult. Xenogeneic immunization with orthologous Ags induces cancer immunity. The present study evaluated the basis for immunity induced by active immunization against a melanoma Differentiation Ag, gp100. Tumor rejection of melanoma was assessed after immunization with human gp100 (hgp100) DNA compared with mouse gp100 (mgp100). C57BL/6 mice immunized with xenogeneic full-length hgp100 DNA were protected against syngeneic melanoma challenge. In contrast, mice immunized with hgp100 DNA and given i.p. tolerizing doses of the hgp100 D b -restricted peptide, hgp100 25–33 , were incapable of rejecting Tumors. Furthermore, mice immunized with DNA constructs of hgp100 in which the hgp100 25–27 epitope was substituted with the weaker D b -binding epitope from mgp100 (mgp100 25–27 ) or a mutated epitope unable to bind D b did not reject B16 melanoma. Mice immunized with a minigene construct of hgp100 25–33 rejected B16 melanoma, whereas mice immunized with the mgp100 25–33 minigene did not develop protective Tumor immunity. In this model of xenogeneic DNA immunization, the presence of an hgp100 heteroclitic epitope with a higher affinity for MHC created by three amino acid (25 to 27) substitutions at predicted minor anchor residues was necessary and sufficient to induce protective Tumor immunity in H-2 b mice with melanoma.
