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Pretargeted Trop-2 ImmunoPET for Rapid, Selective Detection of Pancreatic Tumors
Edwin C Pratt1, Komal Mandleywala1, David Bauer1
1Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.
Purpose:
Recent clinical advances with the approval of antibody-drug conjugates targeting trophoblast cell-surface antigen 2 (Trop-2), such as sacituzumab govitecan and datopotamab deruxtecan, have garnered tremendous interest for their therapeutic efficacy in numerous tumor types, including breast and lung cancers. ImmunoPET can stratify tumor avidity, clarifying patient eligibility for antibody-drug conjugate therapy as well as a diagnostic companion during therapy. Slow antibody circulation requires days to reach optimal imaging timepoints. To overcome this shortfall, bioorthogonal click chemistry for pretargeting can be employed, decoupling antibody circulation time and the delivery of the radionuclide.
Experimental Design:
Here, we report the characterization of a new full-length Trop-2.2 antibody showing high affinity for Trop-2-positive cancers and leverage different site-selective labeling and pretargeting radionuclide combinations to yield rapid imaging with minimal radionuclide footprint after imaging. Three pretargeting strategies for fluorine-18, copper-64, and zirconium-89 were explored in addition to site-specific bioconjugation.
Results:
We found that pretargeting with [64Cu]Cu-sarcophagine-tetrazine yielded the best images, identifying Trop-2-positive tumors with optimal tumor-to-background ratios. Intriguingly, we found that the full-length antibody, when directly conjugated, yielded rapid accumulation, starting at 3 hours after injection, and led to more than 50% injected activity per gram in the tumor before 24 hours.
Conclusions:
[89Zr]Zr-deferoxamine-Trop-2 and pretargeting with [64Cu]Cu-sarcophagine-tetrazine are viable imaging strategies to quickly identify Trop-2-positive tumors for subsequent Trop-2 therapies. See related commentary by Mori et al., p. 2547.
Insights
New antibody-drug conjugates targeting Trop-2 show promise. ImmunoPET imaging can identify eligible patients, but slow antibody circulation is a challenge. Pretargeting strategies offer rapid imaging of Trop-2 positive tumors.
Area of Science:
- Oncology
- Radiochemistry
- Immunology
Background:
- Antibody-drug conjugates (ADCs) targeting Trop-2, like sacituzumab-govitecan and datopotomab-deruxtecan, are emerging therapies for breast and lung cancers.
- ImmunoPET imaging can assess tumor Trop-2 expression, aiding patient selection for ADC therapy and monitoring treatment response.
- A limitation of current ImmunoPET strategies is the slow circulation of antibodies, delaying optimal imaging timepoints.
Purpose of the Study:
- To develop rapid ImmunoPET imaging strategies for Trop-2 positive tumors.
- To overcome the challenge of slow antibody circulation in ImmunoPET imaging.
- To evaluate pretargeting strategies and site-selective bioconjugation for efficient radionuclide delivery.
Main Methods:
- Characterization of a novel full-length Trop-2.2 antibody with high affinity for Trop-2 positive cancers.
- Exploration of three pretargeting strategies using Fluorine-18, Copper-64, and Zirconium-89.
- Assessment of site-specific bioconjugation techniques for antibody labeling.
Main Results:
- Pretargeting with [64Cu]Cu-Sar-Tz demonstrated optimal tumor-to-background ratios for identifying Trop-2 positive tumors.
- Direct conjugation of the full-length antibody resulted in rapid tumor accumulation, with over 50% injected activity per gram within 24 hours.
- Both pretargeting and direct conjugation strategies yielded rapid imaging of Trop-2 positive tumors.
Conclusions:
- [89Zr]Zr-DFO-Trop-2 and pretargeting with [64Cu]Cu-Sar-Tz are effective ImmunoPET strategies for rapid identification of Trop-2 positive tumors.
- These imaging approaches can facilitate patient selection for Trop-2 targeted therapies.
- The developed methods offer a solution to the slow circulation issue in ImmunoPET imaging.
