A First-In-Class, Humanized Antibody Targeting Alternatively Spliced Tissue Factor: Preclinical Evaluation in an Orthotopic Model of Pancreatic Ductal Adenocarcinoma
Frontiers in Oncology, vol. 11, pp. 691685
Abstract
In 2021, pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer deaths in the United States. This is largely due to a lack of symptoms and limited treatment options, which extend survival by only a few weeks. There is thus an urgent need to develop new therapies effective against PDAC. Previously, we have shown that the growth of PDAC cells is suppressed when they are co-implanted with RabMab1, a rabbit monoclonal antibody specific for human alternatively spliced tissue factor (asTF). Here, we report on humanization of RabMab1, evaluation of its binding characteristics, and assessment of its in vivo properties. hRabMab1 binds asTF with a KD in the picomolar range; suppresses the migration of high-grade Pt45.P1 cells in Boyden chamber assays; has a long half-life in circulation (~ 5 weeks); and significantly slows the growth of pre-formed orthotopic Pt45.P1 tumors in athymic nude mice when administered intravenously. Immunohistochemical analysis of tumor tissue demonstrates the suppression of i) PDAC cell proliferation, ii) macrophage infiltration, and iii) neovascularization, whereas RNAseq analysis of tumor tissue reveals the suppression of pathways that promote cell division and focal adhesion. This is the first proof-of-concept study whereby a novel biologic targeting asTF has been investigated as a systemically administered single agent, with encouraging results. Given that hRabMab1 has a favorable PK profile and is able to suppress the growth of human PDAC cells in vivo, it comprises a promising candidate for further clinical development.
Authors 11
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Affiliation as printed
Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Affiliation as printed
Division of Pharmaceutical Sciences, University of Cincinnati College of Pharmacy, Cincinnati, OH, United States
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Affiliation as printed
Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Affiliation as printed
Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Affiliation as printed
Technology Development, LakePharma, Inc., Belmont, CA, United States
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Affiliation as printed
Technology Development, LakePharma, Inc., Belmont, CA, United States
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Henri H. Versteeg Aachen Einthoven Laboratory for Experimental Vascular Medicine Department of Internal Medicine
Leiden University Medical Center
Affiliation as printed
Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands
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Cincinnati Children's Hospital Medical Center
Affiliation as printed
Department of Biomedical Informatics, Cincinnati Children's Hospital and Medical Center, Cincinnati, OH, United States
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Affiliation as printed
Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Affiliation as printed
Division of Pharmaceutical Sciences, University of Cincinnati College of Pharmacy, Cincinnati, OH, United States
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Vladimir Y. Bogdanov corresponding
Affiliation as printed
Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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