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Updated: Aug 19, 2025
Development of a 68Gallium-Labeled D-Peptide PET Tracer for Imaging Programmed Death-Ligand 1 Expression
Published on: February 3, 2023
Gallium-68-labeled Peptide PET Quantifies Tumor Exposure of PD-L1 Therapeutics
Akhilesh Mishra1,2, Dhiraj Kumar1, Kuldeep Gupta1
1The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Purpose:
Immune checkpoint therapy (ICT) is currently ineffective in a majority of patients. Tumor drug exposure measurements can provide vital insights into mechanisms involved in the resistance of solid tumors to those therapeutics; however, tools to quantify in situ drug exposure are few. We have investigated the potential of programmed death-ligand 1 (PD-L1) pharmacodynamics, quantified using PET, to inform on the tumor exposure of anti-PD-L1 (aPD-L1) therapeutics.
Experimental Design:
To noninvasively quantify PD-L1 levels, we first developed a novel peptide-based gallium-68-labeled binder, [68Ga]Ga-DK223, and evaluated its in vivo distribution, pharmacokinetics, and PD-L1 specificity in preclinical models of triple-negative breast cancer and urothelial carcinoma with variable PD-L1 expression. We then quantified baseline and accessible PD-L1 levels in tumors as a noninvasive pharmacodynamic measure to assess tumor exposure to two aPD-L1 antibodies (avelumab and durvalumab).
Results:
DK223 exhibited a KD of 1.01±0.83 nmol/L for PD-L1 and inhibited the PD-1:PD-L1 interaction in a dose-dependent manner. [68Ga]Ga-DK223 provides high-contrast PET images within 60 minutes of administration and detects PD-L1 in an expression-dependent manner in xenograft models. PD-L1 pharmacodynamics measured using [68Ga]Ga-DK223-PET revealed that avelumab and durvalumab had similar exposure early during therapy, but only durvalumab exhibited sustained exposure at the tumor.
Conclusions:
[68Ga]Ga-DK223 detected variable PD-L1 levels and exhibited salient features required for clinical translation. [68Ga]Ga-DK223-PET could be useful for quantifying total PD-L1 levels at baseline and accessible PD-L1 levels during therapy to understand drug exposure at the tumor, thus supporting its use for guiding and optimizing ICT.
Insights
A novel PET tracer, [68Ga]Ga-DK223, quantifies programmed death-ligand 1 (PD-L1) levels to assess anti-PD-L1 (aPD-L1) drug exposure in tumors. This tool can guide immune checkpoint therapy (ICT) optimization for better patient outcomes.
Area of Science:
- Oncology
- Radiochemistry
- Immunotherapy
Background:
- Immune checkpoint therapy (ICT) is often ineffective for many patients with solid tumors.
- Understanding tumor drug exposure is crucial for identifying resistance mechanisms to ICT.
- Current tools for quantifying in situ drug exposure are limited.
Purpose of the Study:
- To investigate programmed death-ligand 1 (PD-L1) pharmacodynamics using Positron Emission Tomography (PET) to inform on tumor exposure of anti-PD-L1 (aPD-L1) therapeutics.
- To develop and validate a novel PET tracer for quantifying PD-L1 levels in tumors.
- To assess the utility of this PET tracer in guiding and optimizing ICT.
Main Methods:
- Development of a novel peptide-based gallium-68-labeled binder, [68Ga]Ga-DK223, for PD-L1 quantification.
- Evaluation of [68Ga]Ga-DK223 in preclinical models of triple-negative breast cancer and urothelial carcinoma.
- Quantification of baseline and accessible PD-L1 levels using [68Ga]Ga-DK223-PET to assess tumor exposure to avelumab and durvalumab.
Main Results:
- [68Ga]Ga-DK223 demonstrated high affinity for PD-L1 (KD of 1.01±0.83 nmol/L) and enabled high-contrast PET imaging within 60 minutes.
- The tracer detected PD-L1 in an expression-dependent manner in xenograft models.
- PET imaging revealed similar early exposure for avelumab and durvalumab, but only durvalumab showed sustained tumor exposure.
Conclusions:
- [68Ga]Ga-DK223 is a promising PET tracer for quantifying PD-L1 levels with features suitable for clinical translation.
- [68Ga]Ga-DK223-PET can noninvasively measure PD-L1 levels at baseline and during therapy.
- This approach can enhance understanding of drug exposure at the tumor site, supporting ICT optimization.
