A Cathepsin-Targeted Quenched Activity-Based Probe Facilitates Enhanced Detection of Human Tumors during Resection

  • Clin Cancer Res. 2022 Sep 1;28(17):3729-3741. doi: 10.1158/1078-0432.CCR-22-1215.
Gregory T Kennedy  1 ,  David E Holt  2 ,  Feredun S Azari  1 ,  Elizabeth Bernstein  1 ,  Bilal Nadeem  1 ,  Ashley Chang  1 ,  Neil T Sullivan  1 ,  Alix Segil  1 ,  Charuhas Desphande  3 ,  Eric Bensen  4 ,  John T Santini  4 ,  John C Kucharczuk  1 ,  Edward J Delikatny  5 ,  Matthew Bogyo  6 ,  A J Matthew Egan  7 ,  Charles W Bradley  8 ,  Evgeniy Eruslanov  1 ,  Jason D Lickliter  9 ,  Gavin Wright  10  11 ,  Sunil Singhal  1
Affiliations
  • 1. Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
  • 2. Department of Clinical Sciences and Advanced Medicine, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania.
  • 3. Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
  • 4. Vergent Bioscience, Minneapolis, Minnesota.
  • 5. Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania.
  • 6. Department of Pathology, Stanford University, Palo Alto, California.
  • 7. Department of Pathology, St. Vincent's Hospital, Melbourne, Australia.
  • 8. Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania.
  • 9. Nucleus Network, Melbourne, Australia.
  • 10. Department of Surgery, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia.
  • 11. Victorian Comprehensive Cancer Centre Alliance, Melbourne, Australia.
PMID: 35792882 DOI: 10.1158/1078-0432.CCR-22-1215
Abstract

Purpose: Fluorescence-guided surgery using tumor-targeted contrast agents has been developed to improve the completeness of oncologic resections. Quenched activity-based probes that fluoresce after covalently binding to tumor-specific Enzymes have been proposed to improve specificity, but none have been tested in humans. Here, we report the successful clinical translation of a Cathepsin activity-based probe (VGT-309) for fluorescence-guided surgery.

Experimental design: We optimized the specificity, dosing, and timing of VGT-309 in preclinical models of Lung Cancer. To evaluate clinical feasibility, we conducted a canine study of VGT-309 during pulmonary tumor resection. We then conducted a randomized, double-blind, dose-escalation study in healthy human volunteers receiving VGT-309 to evaluate safety. Finally, we tested VGT-309 in humans undergoing Lung Cancer surgery.

Results: In preclinical models, we found highly specific tumor cell labeling that was blocked by a broad spectrum Cathepsin inhibitor. When evaluating VGT-309 for guidance during resection of canine Tumors, we found that the probe selectively labeled Tumors and demonstrated high tumor-to-background ratio (TBR; range: 2.15-3.71). In the Phase I human study, we found that VGT-309 was safe at all doses studied. In the ongoing Phase II trial, we report two cases in which VGT-309 localized visually occult, non-palpable Tumors (TBRs = 2.83 and 7.18) in real time to illustrate its successful clinical translation and potential to improve surgical management.

Conclusions: This first-in-human study demonstrates the safety and feasibility of VGT-309 to label human pulmonary Tumors during resection. These results may be generalizable to other cancers due to Cathepsin overexpression in many solid Tumors.

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