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 positron emission tomography (PET), to inform on the tumor exposure of anti-PD-L1 therapeutics. Experimental Design: To non-invasively 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 (TNBC) and urothelial carcinoma (UC) with variable PD-L1 expression. We then quantified baseline and accessible PD-L1 levels in tumors as a non-invasive pharmacodynamic measure to assess tumor exposure to two anti-PD-L1 antibodies (avelumab and durvalumab). Results: DK223 exhibited a KD of 1.01±0.83 nM 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 min 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.
This article is part of the Topical Collection on Erratum.
Purpose. We aimed to develop a novel molecular imaging agent to monitor Multiple Myeloma (MM) using CD38, a target that has shown uniform expression in MM. However, only a few molecularly targeted imaging agents are available to take advantage of this high expression and the sensitivity of positron emission tomography (PET), and none of them fit into the standard clinical workflow. To address this, we developed and evaluated a first–in–class peptide-based radiotracer, [68Ga]Ga–AJ206, to noninvasively quantify CD38 levels in MM. Experimental design. To quantify CD38 levels noninvasively, we synthesized a peptide–based high–affinity binder, tested its affinity by surface plasmon resonance, and evaluated a gallium–68–labeled analog for in vitro specificity. We also performed in vivo distribution, pharmacokinetics, and CD38 specificity evaluations in MM preclinical models, and cross–validated imaging data with flow cytometry and immunohistochemistry-based analysis of CD38 expression. Results. [68Ga]Ga–AJ206 demonstrated CD38 binding specificity with a KD of 19.1±0.99 nM and in vitro binding dependent on CD38 expression. PET imaging with [68Ga]Ga–AJ206 showed high contrast within 60 min and suitable radiation dose estimates for clinical use. Additionally, [68Ga]Ga–AJ206 detected CD38 expression in xenograft and disseminated disease models in a manner consistent with immunohistochemistry-based detection. Conclusions. [68Ga]Ga–AJ206 exhibited the salient features required for clinical translation, providing CD38–specific high contrast images and detecting varying levels of CD38 expression in bone disease and soft tissue metastases.
<div>AbstractPurpose:<p>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 <i>in situ</i> 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.</p>Experimental Design:<p>To noninvasively quantify PD-L1 levels, we first developed a novel peptide-based gallium-68–labeled binder, [<sup>68</sup>Ga]Ga-DK223, and evaluated its <i>in vivo</i> 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).</p>Results:<p>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. [<sup>68</sup>Ga]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 [<sup>68</sup>Ga]Ga-DK223-PET revealed that avelumab and durvalumab had similar exposure early during therapy, but only durvalumab exhibited sustained exposure at the tumor.</p>Conclusions:<p>[<sup>68</sup>Ga]Ga-DK223 detected variable PD-L1 levels and exhibited salient features required for clinical translation. [<sup>68</sup>Ga]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.</p></div>
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