Abstract
BackgroundImmunotherapy is a valuable option for cancer treatment, and the curative effect of anti-PD-1/PD-L1 therapy correlates closely with PD-L1 expression levels. Positron emission tomography (PET) imaging of PD-L1 expression is feasible using 68Ga-NOTA-Nb109 nanobody. 68Ga-NOTA-Nb109 was generated by radionuclide (68Ga) labeling of Nb109 using a NOTA chelator. To facilitate clinical trials, we explored the optimal dose range of 68Ga-NOTA-Nb109 in BALB/c A375-hPD-L1 tumor-burdened nude mice and C57-hPD-L1 transgenic MC38-hPD-L1 tumor-burdened mice by administration of a single intravenous dose of 68Ga-NOTA-Nb109 and confirmed the dose in cynomolgus monkeys. The biodistribution data of cynomolgus monkey PET images were extrapolated to estimate the radiation dose for the adult male and female using OLINDA2.1 software.Results68Ga-NOTA-Nb109 was stable in physiologic media and human serum. Ex vivo biodistribution studies showed rapid and specific uptake in A375-hPD-L1 or MC38-hPD-L1 tumors. The estimated ED50 was approximately 5.4 µg in humanized mice. The injected mass (0.3–100 µg in nude mice and approximately 1–100 µg in humanized mice) greatly influenced the general biodistribution, with a better tumor-to-background ratio acquired at lower doses of Nb109 (0.3–10 µg in nude mice and approximately 1 µg in humanized mice), indicating maximum uptake in tumors at administered mass doses below the estimated ED50. Therefore, a single 15-μg/kg dose was adopted for the PET/CT imaging in the cynomolgus monkey. The highest specific and persistent uptake of the tracer was detected in the spleen, except the levels in the kidney and urine bladder, which was related to metabolism and excretion. The spleen-to-muscle ratio of the tracer exceeded 10 from immediately to 4 h after administration, indicating that the dose was appropriate. The estimated effective dose was calculated to yield a radiation dose of 4.1 mSv to a patient after injecting 185 MBq of 68Ga-NOTA-Nb109.Conclusion68Ga-NOTA-Nb109 showed specific accumulation in hPD-L1 xenografts in ex vivo biodistribution studies and monkey PET/CT imaging. The dose escalation distribution data provided a recommended dose range for further use, and the safety of the tracer was confirmed in dosimetry studies.
Highlights
Immunotherapy is a valuable option for cancer treatment, and the curative effect of anti-Programmed cell death protein 1 (PD-1)/PD-L1 therapy correlates closely with PD-L1 expression levels
The in vitro stability of 68Ga-NOTA-Nb109 was generated by radionuclide (68Ga)-NOTA-Nb109 in human serum and 0.9% NaCl solution was demonstrated by radiochemical purity of > 95% over 240 min at < 25 °C
The urine analysis of 68Ga-NOTA-Nb109 in ICR mice after a single intravenous injection showed the high in vivo stability by the radiochemical purity results of > 93% within 120 min and 82.27% at 240 min, indicating the excretion mainly in the parental form (Additional file 1: Fig. S1)
Summary
Immunotherapy is a valuable option for cancer treatment, and the curative effect of anti-PD-1/PD-L1 therapy correlates closely with PD-L1 expression levels. Positron emission tomography (PET) imaging of PD-L1 expression is feasible using 68Ga-NOTA-Nb109 nanobody. Immunotherapy, especially inhibitors targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1), has become the focus of cancer research in recent years. Tracers for radioimmune imaging have provided a non-invasive alternative to traditional immunohistochemical (IHC) staining to monitor PD-L1 expression. Several specific imaging agents, including monoclonal antibodies (mAbs; such as 89Zr-avelumab [4], 89Zr-atezolizumab [5], 89Zr-nivolumab [6]), mAb fragments (such as minibodies and nanobodies [7, 8]), small proteins (such as 18F-BMS-986192 [6, 9]), and peptides (such as 64Cu-WL12 [10]), have been developed and investigated in preclinical models in addition to some early clinical studies
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