Related Experiment Video
Updated: Nov 20, 2025
Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression
Published on: February 3, 2023
Preclinical PET imaging with the novel human antibody 89Zr-DFO-REGN3504 sensitively detects PD-L1 expression in
Marcus P Kelly1, Sosina Makonnen2, Carlos Hickey2
1Regeneron Pharmaceuticals Inc, Tarrytown, New York, USA marcus.kelly@regeneron.com.
Background:
Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blocking antibodies including cemiplimab have generated profound clinical activity across diverse cancer types. Tumorous PD-L1 expression, as assessed by immunohistochemistry (IHC), is an accepted predictive marker of response to therapy in some cancers. However, expression is often dynamic and heterogeneous, and therefore not reliably captured by IHC from tumor biopsies or archival samples. Thus, there is significant need for accurate whole-body quantification of PD-L1 levels.
Methods:
We radiolabeled the novel human anti-PD-L1 antibody REGN3504 with zirconium-89 (89Zr) using the chelator p-SCN-Bn-Deferoxamine to enable non-invasive immuno-positron emission tomography (immuno-PET) of PD-L1 expression. PET imaging assessed the localization of 89Zr-REGN3504 to multiple human tumor xenografts. Mice genetically humanized for PD-1 and PD-L1 were used to assess the biodistribution of 89Zr-REGN3504 to normal tissues and the estimated human radiation dosimetry of 89Zr-REGN3504 was also determined. Pharmacokinetics of REGN3504 was assessed in monkeys.
Results:
Clear localization of 89Zr-REGN3504 to human tumor xenografts was observed via PET imaging and ex vivo biodistribution studies demonstrated high (fourfold to sixfold) tumor:blood ratios. 89Zr-REGN3504 specifically localized to spleen and lymph nodes in the PD-1/PD-L1 humanized mice. 89Zr-REGN3504 immuno-PET accurately detected a significant reduction in splenic PD-L1 positive cells following systemic treatment with clodronate liposomes. Radiation dosimetry suggested absorbed doses would be within guidelines for other 89Zr radiolabeled, clinically used antibodies. Pharmacokinetics of REGN3504 was linear.
Conclusion:
This work supports the clinical translation of 89Zr-REGN3504 immuno-PET for the assessment of PD-L1 expression. Future clinical studies will aim to investigate the utility of 89Zr-REGN3504 immuno-PET for predicting and monitoring response to anti-PD-1 therapy.
Insights
This study developed a novel imaging agent, 89Zr-REGN3504, for non-invasively assessing Programmed Death-Ligand 1 (PD-L1) expression throughout the body. This new method accurately detects PD-L1 levels, offering a promising tool for cancer immunotherapy.
Area of Science:
- Oncology
- Immunology
- Radiochemistry
Background:
- Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) blocking antibodies show significant clinical activity in various cancers.
- Immunohistochemistry (IHC) for tumor PD-L1 expression is an accepted predictive marker, but its dynamic and heterogeneous nature limits reliability.
- There is a critical need for accurate, whole-body quantification of PD-L1 levels.
Purpose of the Study:
- To develop and evaluate a novel non-invasive imaging agent for assessing PD-L1 expression.
- To enable whole-body quantification of PD-L1 levels using immuno-positron emission tomography (immuno-PET).
Main Methods:
- Radiolabeling of the anti-PD-L1 antibody REGN3504 with zirconium-89 (89Zr).
- Assessment of 89Zr-REGN3504 localization in human tumor xenografts using PET imaging.
- Evaluation of biodistribution in PD-1/PD-L1 humanized mice and radiation dosimetry determination.
- Pharmacokinetic assessment of REGN3504 in non-human primates.
Main Results:
- 89Zr-REGN3504 demonstrated clear localization to human tumor xenografts with high tumor-to-blood ratios.
- Specific uptake was observed in spleen and lymph nodes in humanized mice.
- Immuno-PET accurately detected reduced splenic PD-L1 following treatment.
- Radiation dosimetry estimates were within acceptable limits for clinical use.
Conclusions:
- 89Zr-REGN3504 immuno-PET is a viable tool for assessing PD-L1 expression.
- This imaging approach supports clinical translation for evaluating PD-L1.
- Future studies will explore its utility in predicting and monitoring response to anti-PD-1 therapies.
