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  • Because of its role in tumor

    2024-06-24

    Because of its role in tumor growth, proliferation and metastasis, Axl is considered a therapeutic target. Several Axl inhibitors, including low-molecular-weight agents and antibodies, have been reported. Axl inhibition, using low-molecular-weight inhibitors or shRNA knockdown, resulted in reduced tumor growth, metastasis and angiogenesis in a variety of tumor models [14], [15], [17], [18], [19], [20], [21]. Recently a Phase I clinical trial of the Axl inhibitor R428 (also known as BGB324) has been initiated [22]. Due to the emerging role of Axl in cancer, we envisioned that the development of a corresponding imaging agent is timely. In proof-of-principle studies, we demonstrate that graded levels of Axl expression could be imaged using a radiolabeled mouse anti-human Axl monoclonal antibody ([125I]Axl mAb) in subcutaneous pancreatic and prostate tumor xenografts and in orthotopic pancreatic tumor xenografts by single photon emission computed tomography/computed tomography (SPECT/CT). Biodistribution studies performed ex vivo confirmed the imaging results, which were further validated through immunohistochemistry.
    Materials and methods
    Results
    Discussion We report the preclinical evaluation of a radiolabeled antibody demonstrating the feasibility of imaging graded levels of Axl expression in both pancreatic and prostate tumors in vivo. Axl is overexpressed in cancer from a variety of tissues of origin. There is accumulating literature supporting the role of Axl in tumor growth, angiogenesis, metastasis and acquired resistance to therapy. The first low-molecular-weight inhibitor of Axl is in clinical trials, and humanized, monoclonal Betamethasone are in development to block Axl signaling in cancer [22]. Our studies suggest that Axl imaging may provide a new strategy for characterizing Axl-positive tissues in vivo, such as for selecting appropriate patients for anti-Axl therapy, staging and therapeutic monitoring. Pancreatic cancer is one of the leading causes of cancer death in the United States with a median survival of less than six months and a five year survival rate that is <5% [25]. Pancreatic cancer is nearly undetectable in early stages, with few diagnostic options available. Previously we have shown that 55% of pancreatic cancers demonstrate overexpression of Axl [12], and now extend these observations with the development of a noninvasive tool that may aid in clinical staging and monitoring of pancreatic cancer. Over the past decade immunoPET has been gaining attention in the detection and management of cancer [26]. This is particularly important for cell surface targets with few readily available low-molecular-weight agents or peptide-based antagonists that are amenable for radiolabeling. Although several low-molecular-weight inhibitors have been generated that target Axl [27], they are highly hydrophobic, which can produce significant, unwanted non-specific binding in imaging studies, further prompting us to pursue immunoimaging as proof of principle for detection of this important target. In this study we demonstrated that [125I]Axl mAb specifically bound to and accumulated within the Axlhigh CFPAC xenografts compared to the Axllow Panc1 tumors within the same mouse. The ability of the [125I]Axl mAb to image graded levels of Axl expression was also confirmed in orthotopic pancreatic tumor xenografts. In the pancreatic tumor models, tumor uptake was closely associated with Axl expression as confirmed by immunohistochemistry, further supporting the utility of using radiolabeled antibodies as imaging agents. Although we have pursued radioiodination with 125I, due to its ready availability, ease of introduction to antibodies and low expense, radiolabeling of these antibodies with more suitable radionuclides such as the long-lived, positron-emitting isotope, 89Zr (t1/2 3.8days), may minimize the continuous clearance of radioactivity we noted due to de-iodination of the Axl-targeted antibody. Furthermore, 89Zr radiolabeling will allow for imaging at higher sensitivity and resolution as well as fully quantitative kinetic analysis, all of which are in the domain of positron emission tomography (PET) [28].