A First-In-Class, Humanized Antibody Targeting Alternatively Spliced Tissue Factor: Preclinical Evaluation in an Orthotopic Model of Pancreatic Ductal Adenocarcinoma

Clayton S Lewis; Aniruddha Karve; Kateryna Matiash; Timothy Stone; Jingxing Li; Jordon K Wang; Henri H Versteeg; Bruce J Aronow; Syed A Ahmad; Pankaj B Desai; Vladimir Y Bogdanov

doi:10.3389/fonc.2021.691685

A First-In-Class, Humanized Antibody Targeting Alternatively Spliced Tissue Factor: Preclinical Evaluation in an Orthotopic Model of Pancreatic Ductal Adenocarcinoma

Front Oncol. 2021 Jul 29:11:691685. doi: 10.3389/fonc.2021.691685. eCollection 2021.

Authors

Affiliations

¹ Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
² Division of Pharmaceutical Sciences, University of Cincinnati College of Pharmacy, Cincinnati, OH, United States.
³ Department of Environmental Health, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
⁴ Technology Development, LakePharma, Inc., Belmont, CA, United States.
⁵ Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine, Leiden University Medical Center, Leiden, Netherlands.
⁶ Department of Biomedical Informatics, Cincinnati Children's Hospital and Medical Center, Cincinnati, OH, United States.
⁷ Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, United States.

Abstract

In 2021, pancreatic ductal adenocarcinoma (PDAC) is the 3^rd 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 K_D 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.

Keywords: alternative splicing; monoclonal antibodies; orthotopic tumor model; pancreatic ductal adenocarcinoma; tissue factor.

Abstract

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