Abstract
Programmed cell death protein 1 (PD-1) expression is considered a prognostic marker of tumor response to the immuno-blocking therapy. In this study, nivolumab was conjugated with diethylenetriamine pentaacetate (DTPA) via condensation reaction between amidogen and p-SCN-Bn-DTPA, which provided labeling sites for 99mTc4+ or Gd3+ ions. SPECT and magnetic resonance T1 weighted imaging (T1WI) analyses were performed on mouse models of colorectal carcinoma expressing humanized PD-1 antigen. Furthermore, PD-1 expression in intestinal tracks was assessed by immunohistochemistry, and then compared with the imageological findings. Nivolumab-DTPA was synthesized with varying molar ratios and was labeled with Gd or 99mTc with a chemical purity of 96.28 ± 1.16% and good stability. In SPECT images, lesions with high 99mTc-DTPA-nivolumab uptake and relatively clear background were shown at 6 h. Thereafter, the suspected intestinal thickening in Gd-free T1WI was observed at 2 h after the addition of Gd-DTPA-nivolumab. Notably, the results of both SPECT and T1WI analyses were consistent with the postmortem examination and immunohistochemistry results (for linear correlation with target to non-target ratios, R 2 = 0.8038, p < 0.05). In conclusion, nivolumab-DTPA could act as a probe precursor for identifying PD-1-positive lesions, not only through integrating the advantages of immunohistochemistry and molecular imaging but also by providing a noninvasive method for monitoring systemic changes.
Highlights
Until recently, Food and Drug Administration (FDA)-approved therapeutic agents targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis have achieved impressive results in clinical immune checkpoint inhibitor (ICI) treatments, and serve as a crucial treatment for increasing cancer types, such as advanced melanoma (MM), non-small cell lung cancer (NSCLC), and colorectal carcinoma (CRC) (Constantinidou et al, 2019)
Nivolumab was purchased from SelleckChem, and p-SCN-BnDTPA was purchased from Macrocyclics, Inc., Plano, Texas. 18F-FDG and 99mTcO4- were purchased from Xinke Pharmaceutical Ltd., Shanghai, China
We evaluated the pharmacokinetic properties of I-125 labeled nivolumab using the nude mouse xenograft model of colorectal carcinoma
Summary
Food and Drug Administration (FDA)-approved therapeutic agents targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis have achieved impressive results in clinical immune checkpoint inhibitor (ICI) treatments, and serve as a crucial treatment for increasing cancer types, such as advanced melanoma (MM), non-small cell lung cancer (NSCLC), and colorectal carcinoma (CRC) (Constantinidou et al, 2019). Clinical failure in Nivolumab-DTPA-Based PD-1 Imaging many patients is not solely due to the inability to induce immune reactivation, but rather to an imbalance between T-cell reactivation and tumor burden (Huang et al, 2017). Several studies have previously demonstrated that antigen expression is a prognostic marker for the therapeutic response of PD-1/PD-L1-based IBT (Gandini et al, 2016; Herbst et al, 2016). Due to the diversity of tumor microenvironment and the dynamic changes in PD-1/PD-L1 expression resulting from concomitant treatments (Lim et al, 2016; Thomas et al, 2019), the spatial and temporal limitations of IHC analysis lead to uncertainty in decision-making for carrying out IBT. Molecular imaging of PD-1/PD-L1 expression could timely assist in analyzing tumor lesions and metastasis as a whole, providing reproducible and non-invasive systemic monitoring of PD-1/PD-L1 expression
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