89Zr-DFO-daratumumab

Avian pathogenic Escherichia coli (APEC) is a serious systemic infectious disease in poultry infections, causing severe economic losses to the poultry industry. Previous studies have shown that secretion of virulence proteins was required for the pathogenicity of APEC through the secretion system. Outer membrane vesicles (OMVs) are a generalized secretion system of Gram-negative bacteria that play a key role in the long-distance delivery of virulence factors, but whether they are associated with the pathogenic mechanism of APEC has not been determined. In this study, OMVs were purified and characterized from AE17 (O2 serotype) by ultracentrifugation and density gradient centrifugation and their protein cargo was identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In addition, ⁸⁹Zr was labeled after chelating AE17 OMVs by DFO and positron emission tomography PET imaging was used to track ⁸⁹Zr-DFO-OMVs in chickens and to pathologically analyze the distribution sites. This study showed that AE17 OMVs were membrane vesicles ranging in size from 20 to 200 nm and proteomic analysis revealed the presence of virulence proteins, including adhesion proteins OmpA, OmpC, OmpF, OmpX, FimH, FimC and FigE, and serum resistance proteins OmpT and MliC and immune response regulator proteins (FliC). In addition, in vivo PET imaging to track the biodistribution of AE17 OMVs showed that AE17 OMVs were taken up by the lung region and the gastrointestinal and renal regions but were not detected in other areas. Pathological analysis of the tissue sites where AE17 OMVs were ingested showed inflammatory responses and damage. These findings suggested that AE17 OMVs not only contained a group of virulence proteins associated with AE17 infection but can also deliver these virulence proteins over long distances and caused tissue inflammatory damage. Our study revealed a previously unidentified causative microbial signal in the pathogenesis of APEC that could aid in the development of vaccines and antibiotics effective against APEC.

In this PD-L1 ImagiNg to prediCt durvalumab treatment response in SCCHN (PINCH) study, we performed ⁸⁹Zr-DFO-durvalumab (anti-PD-L1 [programmed death ligand 1]) PET/CT in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) before monotherapy durvalumab treatment. The primary aims were to assess safety and feasibility of ⁸⁹Zr-DFO-durvalumab PET imaging and predict disease control rate during durvalumab treatment. Secondary aims were to correlate ⁸⁹Zr-DFO-durvalumab uptake to tumor PD-L1 expression, ¹⁸F-FDG uptake, and treatment response of individual lesions. Methods: In this prospective multicenter phase I-II study (NCT03829007), patients with incurable R/M SCCHN underwent baseline ¹⁸F-FDG PET and CT or MRI. Subsequently, PD-L1 PET imaging was performed 5 d after administration of 37 MBq of ⁸⁹Zr-DFO-durvalumab. To optimize imaging conditions, dose finding was performed in the first 14 patients. For all patients (n = 33), durvalumab treatment (1,500 mg/4 wk, intravenously) was started within 1 wk after PD-L1 PET imaging and continued until disease progression or unacceptable toxicity (maximum, 24 mo). CT evaluation was assessed according to RECIST 1.1 every 8 wk. PD-L1 expression was determined by combined positive score on (archival) tumor tissue. ⁸⁹Zr-DFO-durvalumab uptake was measured in ¹⁸F-FDG-positive lesions, primary and secondary lymphoid organs, and blood pool. Results: In total, 33 patients with locoregional recurrent (n = 12) or metastatic SCCHN (n = 21) were enrolled. ⁸⁹Zr-DFO-durvalumab injection was safe. A dose of 10 mg of durvalumab resulted in highest tumor-to-blood ratios. After a median follow-up of 12.6 mo, overall response rate was 26%. The disease control rate at 16 wk was 48%, with a mean duration of 7.8 mo (range, 1.7-21.1). On a patient level, ⁸⁹Zr-DFO-durvalumab SUV_peak or tumor-to-blood ratio could not predict treatment response (hazard ratio, 1.5 [95% CI, 0.5-3.9; P = 0.45] and 1.3 [95% CI, 0.5-3.3; P = 0.60], respectively). Also, on a lesion level, ⁸⁹Zr-DFO-durvalumab SUV_peak showed no substantial correlation to treatment response (Spearman ρ, 0.45; P = 0.051). Lesional ⁸⁹Zr-DFO-durvalumab uptake did not correlate to PD-L1 combined positive score but did correlate to ¹⁸F-FDG SUV_peak (Spearman ρ, 0.391; P = 0.005). Conclusion: PINCH is the first, to our knowledge, PD-L1 PET/CT study in patients with R/M SCCHN and has shown the feasibility and safety of ⁸⁹Zr-DFO-durvalumab PET/CT in a multicenter trial. ⁸⁹Zr-DFO-durvalumab uptake did not correlate to durvalumab treatment response.