First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma
Alternatively spliced tissue factor (asTF) promotes the progression of pancreatic ductal adenocarcinoma (PDAC) by activating β1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class humanized inhibitory anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a singl...
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| Format: | Article |
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MDPI AG
2024-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/5/2580 |
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| author | Clayton S. Lewis Charles Backman Sabahat Ahsan Ashley Cliff Arthi Hariharan Jen Jen Yeh Xiang Zhang Changchun Xie Davendra P. S. Sohal Vladimir Y. Bogdanov |
| author_facet | Clayton S. Lewis Charles Backman Sabahat Ahsan Ashley Cliff Arthi Hariharan Jen Jen Yeh Xiang Zhang Changchun Xie Davendra P. S. Sohal Vladimir Y. Bogdanov |
| author_sort | Clayton S. Lewis |
| collection | DOAJ |
| description | Alternatively spliced tissue factor (asTF) promotes the progression of pancreatic ductal adenocarcinoma (PDAC) by activating β1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class humanized inhibitory anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown. Following in vivo screening of three asTF-proficient human PDAC cell lines, we chose to make use of KRAS G12V-mutant human PDAC cell line PaCa-44, which yields aggressive primary orthotopic tumors with spontaneous spread to PDAC-relevant anatomical sites, along with concomitant severe leukocytosis. The experimental design featured orthotopic tumors formed by luciferase labeled PaCa-44 cells; administration of hRabMab1 alone or in combination with gemcitabine/paclitaxel (gem/PTX); and the assessment of the treatment outcomes on the primary tumor tissue as well as systemic spread. When administered alone, hRabMab1 exhibited poor penetration of tumor tissue; however, hRabMab1 was abundant in tumor tissue when co-administered with gem/PTX, which resulted in a significant decrease in tumor cell proliferation; leukocyte infiltration; and neovascularization. Gem/PTX alone reduced primary tumor volume, but not metastatic spread; only the combination of hRabMab1 and gem/PTX significantly reduced metastatic spread. RNA-seq analysis of primary tumors showed that the addition of hRabMab1 to gem/PTX enhanced the downregulation of tubulin binding and microtubule motor activity. In the liver, hRabMab1 reduced liver metastasis as a single agent. Only the combination of hRabMab1 and gem/PTX eliminated tumor cell-induced leukocytosis. We here demonstrate for the first time that hRabMab1 may help suppress metastasis in PDAC. hRabMab1’s ability to improve the efficacy of chemotherapy is significant and warrants further investigation. |
| first_indexed | 2024-04-25T00:28:51Z |
| format | Article |
| id | doaj.art-61cac9abac5f41bcbfb690d33986c560 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-25T00:28:51Z |
| publishDate | 2024-02-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-61cac9abac5f41bcbfb690d33986c5602024-03-12T16:45:31ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-02-01255258010.3390/ijms25052580First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal AdenocarcinomaClayton S. Lewis0Charles Backman1Sabahat Ahsan2Ashley Cliff3Arthi Hariharan4Jen Jen Yeh5Xiang Zhang6Changchun Xie7Davendra P. S. Sohal8Vladimir Y. Bogdanov9Division of Hematology/Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USADivision of Hematology/Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USADivision of Hematology/Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USALineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USALineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USALineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USADivision of Environmental Genetics and Molecular Toxicology, Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USADivision of Biostatistics and Bioinformatics, Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USADivision of Hematology/Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USADivision of Hematology/Oncology, Department of Internal Medicine, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USAAlternatively spliced tissue factor (asTF) promotes the progression of pancreatic ductal adenocarcinoma (PDAC) by activating β1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class humanized inhibitory anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown. Following in vivo screening of three asTF-proficient human PDAC cell lines, we chose to make use of KRAS G12V-mutant human PDAC cell line PaCa-44, which yields aggressive primary orthotopic tumors with spontaneous spread to PDAC-relevant anatomical sites, along with concomitant severe leukocytosis. The experimental design featured orthotopic tumors formed by luciferase labeled PaCa-44 cells; administration of hRabMab1 alone or in combination with gemcitabine/paclitaxel (gem/PTX); and the assessment of the treatment outcomes on the primary tumor tissue as well as systemic spread. When administered alone, hRabMab1 exhibited poor penetration of tumor tissue; however, hRabMab1 was abundant in tumor tissue when co-administered with gem/PTX, which resulted in a significant decrease in tumor cell proliferation; leukocyte infiltration; and neovascularization. Gem/PTX alone reduced primary tumor volume, but not metastatic spread; only the combination of hRabMab1 and gem/PTX significantly reduced metastatic spread. RNA-seq analysis of primary tumors showed that the addition of hRabMab1 to gem/PTX enhanced the downregulation of tubulin binding and microtubule motor activity. In the liver, hRabMab1 reduced liver metastasis as a single agent. Only the combination of hRabMab1 and gem/PTX eliminated tumor cell-induced leukocytosis. We here demonstrate for the first time that hRabMab1 may help suppress metastasis in PDAC. hRabMab1’s ability to improve the efficacy of chemotherapy is significant and warrants further investigation.https://www.mdpi.com/1422-0067/25/5/2580pancreatic ductal adenocarcinoma (PDAC)alternatively spliced tissue factor (asTF)humanized monoclonal antibody |
| spellingShingle | Clayton S. Lewis Charles Backman Sabahat Ahsan Ashley Cliff Arthi Hariharan Jen Jen Yeh Xiang Zhang Changchun Xie Davendra P. S. Sohal Vladimir Y. Bogdanov First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma International Journal of Molecular Sciences pancreatic ductal adenocarcinoma (PDAC) alternatively spliced tissue factor (asTF) humanized monoclonal antibody |
| title | First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma |
| title_full | First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma |
| title_fullStr | First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma |
| title_full_unstemmed | First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma |
| title_short | First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma |
| title_sort | first in class humanized antibody against alternatively spliced tissue factor augments anti metastatic efficacy of chemotherapy in a preclinical model of pancreatic ductal adenocarcinoma |
| topic | pancreatic ductal adenocarcinoma (PDAC) alternatively spliced tissue factor (asTF) humanized monoclonal antibody |
| url | https://www.mdpi.com/1422-0067/25/5/2580 |
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