Immuno-PET imaging of 68Ga-labeled nanobody Nb109 for dynamic monitoring the PD-L1 expression in cancers

Liu, Qingzhu; Jiang, Lei; Li, Ké; Li, Hang; Lv, Gaochao; Lin, Jianguo; Qiu, Ling

doi:10.1007/s00262-020-02818-y

Cited by 44 publications

(59 citation statements)

References 43 publications

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“…Previous studies [ 24 , 26 ] have confirmed that the tracer 68 Ga-NOTA-Nb109 is suitable for the specific targeting of endogenous PD-L1 and real-time detection and quantification of PD-L1 expression in different cancers. To further clarify the influence of the protein mass on this tracer, we designed a series of studies to explore the biodistribution of 68 Ga-NOTA-Nb109 at different masses in tumor-bearing nude mice and hPD-L1 humanized mice and confirmed the selected dose in non-human primates.…”

Section: Discussionmentioning

confidence: 88%

“…Although the relationship between PD-L1 level and the radioactive uptake has not been thoroughly investigated, previous studies [ 24 , 26 ] have indicated that 68 Ga-NOTA-Nb109 accumulation accurately reflects the dynamic changes of PD-L1 in real-time. However, this remains to be confirmed in future studies.…”

Section: Discussionmentioning

confidence: 99%

“…Nb109 is a non-blocking nanobody with a high specific affinity for PD-L1 (with an equilibrium dissociation constant (K D ) of 2.9 × 10 –9 M) [ 24 , 26 ]. Nb109 binds well to primate (including human and monkey) PD-L1 but does not cross-react with mouse PD-L1.…”

Section: Introductionmentioning

confidence: 99%

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Dose escalation biodistribution, positron emission tomography/computed tomography imaging and dosimetry of a highly specific radionuclide-labeled non-blocking nanobody

Yang

Wang²,

Wang

et al. 2021

EJNMMI Res

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Background 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. 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. Results 68Ga-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. Conclusion 68Ga-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.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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Dose escalation biodistribution, positron emission tomography/computed tomography imaging and dosimetry of a highly specific radionuclide-labeled non-blocking nanobody

Yang

Wang²,

Wang

et al. 2021

EJNMMI Res

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“…Candidate nanobodies for immuno-PET approaches recognize molecular targets which play important roles in protein biosynthesis (TUFM, TRIM28), DNA repair and cell cycle (NAP1L1), and cellular growth and maintenance (EGFR, DPYSL2, β-Actin) [ 140 , 141 , 142 ]. Recently, a PD-L1-targeting nanobody-based tracer was evaluated to assess the changes in PD-L1 expression sensitively and specifically in different cancer types, which could help screen patients with high expression and guide PD-L1-targeting immunotherapies ( Table 1 ) [ 112 ] ( Figure 5 b).…”

Section: Novel Nanobody-based Immuno-pet Imaging Methods For Glioblastomamentioning

confidence: 99%

Diagnosis of Glioblastoma by Immuno-Positron Emission Tomography

Ruiz-López

Calatayud-Pérez

Castells-Yus

et al. 2021

Cancers

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Neuroimaging has transformed neuro-oncology and the way that glioblastoma is diagnosed and treated. Magnetic Resonance Imaging (MRI) is the most widely used non-invasive technique in the primary diagnosis of glioblastoma. Although MRI provides very powerful anatomical information, it has proven to be of limited value for diagnosing glioblastomas in some situations. The final diagnosis requires a brain biopsy that may not depict the high intratumoral heterogeneity present in this tumor type. The revolution in “cancer-omics” is transforming the molecular classification of gliomas. However, many of the clinically relevant alterations revealed by these studies have not yet been integrated into the clinical management of patients, in part due to the lack of non-invasive biomarker-based imaging tools. An innovative option for biomarker identification in vivo is termed “immunotargeted imaging”. By merging the high target specificity of antibodies with the high spatial resolution, sensitivity, and quantitative capabilities of positron emission tomography (PET), “Immuno-PET” allows us to conduct the non-invasive diagnosis and monitoring of patients over time using antibody-based probes as an in vivo, integrated, quantifiable, 3D, full-body “immunohistochemistry” in patients. This review provides the state of the art of immuno-PET applications and future perspectives on this imaging approach for glioblastoma.

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“…Both, nanobodies and hcAbs are emerging as promising theranostic molecules (31)(32)(33)(34). For example, we have recently shown that human CD38-specific hcAbs can be used to effectively target human MM cells in xenograft mouse models of systemic human lymphoma (35).…”

Section: Introductionmentioning

confidence: 99%

Mouse CD38-Specific Heavy Chain Antibodies Inhibit CD38 GDPR-Cyclase Activity and Mediate Cytotoxicity Against Tumor Cells

et al. 2021

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CD38 is the major NAD+-hydrolyzing ecto-enzyme in most mammals. As a type II transmembrane protein, CD38 is also a promising target for the immunotherapy of multiple myeloma (MM). Nanobodies are single immunoglobulin variable domains from heavy chain antibodies that naturally occur in camelids. Using phage display technology, we isolated 13 mouse CD38-specific nanobodies from immunized llamas and produced these as recombinant chimeric mouse IgG2a heavy chain antibodies (hcAbs). Sequence analysis assigned these hcAbs to five distinct families that bind to three non-overlapping epitopes of CD38. Members of families 4 and 5 inhibit the GDPR-cyclase activity of CD38. Members of families 2, 4 and 5 effectively induce complement-dependent cytotoxicity against CD38-expressing tumor cell lines, while all families effectively induce antibody dependent cellular cytotoxicity. Our hcAbs present unique tools to assess cytotoxicity mechanisms of CD38-specific hcAbs in vivo against tumor cells and potential off-target effects on normal cells expressing CD38 in syngeneic mouse tumor models, i.e. in a fully immunocompetent background.

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Immuno-PET imaging of 68Ga-labeled nanobody Nb109 for dynamic monitoring the PD-L1 expression in cancers

Cited by 44 publications

References 43 publications

Dose escalation biodistribution, positron emission tomography/computed tomography imaging and dosimetry of a highly specific radionuclide-labeled non-blocking nanobody

Dose escalation biodistribution, positron emission tomography/computed tomography imaging and dosimetry of a highly specific radionuclide-labeled non-blocking nanobody

Diagnosis of Glioblastoma by Immuno-Positron Emission Tomography

Mouse CD38-Specific Heavy Chain Antibodies Inhibit CD38 GDPR-Cyclase Activity and Mediate Cytotoxicity Against Tumor Cells

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