2. Academic Validation
  3. A Cathepsin-Targeted Quenched Activity-Based Probe Facilitates Enhanced Detection of Human Tumors during Resection

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-102087
    99.06%, Cysteine Cathepsin 抑制剂
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