Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

Wierstra, Peter J.; Sandker, Gerwin W.; Aarntzen, Erik H.J.G.; Gotthardt, Martin; Adema, Gosse J.; Bussink, Johan; Raavé, René; Heskamp, Sandra

doi:10.1186/s41181-019-0078-z

Cited by 30 publications

(34 citation statements)

References 105 publications

(121 reference statements)

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“…The present study demonstrates the utility of a 89 Zr-labelled CDCP1-directed agent (10D7) for CRC and also extends the ovarian and pancreatic cancer studies by demonstrating the selectivity of 89 Zr-10D7 for CDCP1 expressing tumors using unlabelled 10D7. The addition of high dose, unlabelled ligands is a recognized method to demonstrate in vivo target-specific blocking [ 41 – 43 ]. Our results indicate that unlabelled10D7 competes with 89 Zr-10D7 for CDCP1 binding sites, thereby reducing PET signal by ∼60%, comparable to similar experimental design in existing publications [ 42 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer

Cuda

Kryza

et al. 2021

Contrast Media & Molecular Imaging

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Colorectal cancer (CRC) is the third most common malignancy in the world, with 22% of patients presenting with metastatic disease and a further 50% destined to develop metastasis. Molecular imaging uses antigen-specific ligands conjugated to radionuclides to detect and characterise primary cancer and metastases. Expression of the cell surface protein CDCP1 is increased in CRC, and here we sought to assess whether it is a suitable molecular imaging target for the detection of this cancer. CDCP1 expression was assessed in CRC cell lines and a patient-derived xenograft to identify models suitable for evaluation of radio-labelled 10D7, a CDCP1-targeted, high-affinity monoclonal antibody, for preclinical molecular imaging. Positron emission tomography-computed tomography was used to compare zirconium-89 (89Zr)-10D7 avidity to a nonspecific, isotype control 89Zr-labelled IgGκ1 antibody. The specificity of CDCP1-avidity was further confirmed using CDCP1 silencing and blocking models. Our data indicate high avidity and specificity for of 89Zr-10D7 in CDCP1 expressing tumors at. Significantly higher levels than normal organs and blood, with greatest tumor avidity observed at late imaging time points. Furthermore, relatively high avidity is detected in high CDCP1 expressing tumors, with reduced avidity where CDCP1 expression was knocked down or blocked. The study supports CDCP1 as a molecular imaging target for CRC in preclinical PET-CT models using the radioligand 89Zr-10D7.

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Section: Discussionmentioning

confidence: 99%

Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer

Cuda

Kryza

et al. 2021

Contrast Media & Molecular Imaging

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“…Spleen uptake was also only modest, likely because we injected a relatively higher radiotracer dose to reduce splenic accumulation. Indeed, it is known that increasing tracer dose can saturate spleen uptake and restore tumor targeting (24).…”

Section: Discussionmentioning

confidence: 99%

⁸⁹Zr-Labeled Anti-PD-L1 Antibody PET Monitors Gemcitabine Therapy-Induced Modulation of Tumor PD-L1 Expression

et al. 2020

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We developed an 89 Zr-labeled anti-programmed death ligand 1 (anti-PD-L1) immune PET that can monitor chemotherapy-mediated modulation of tumor PD-L1 expression in living subjects. Methods:Anti-PD-L1 underwent sulfohydryl moiety-specific conjugation with maleimide-deferoxamine followed by 89 Zr radiolabeling. CT26 colon cancer cells and PD-L1 overexpressing CT26/PD-L1 cells underwent binding assays, flow cytometry, and Western blotting. In vivo pharmacokinetics, biodistribution, and PET imaging was evaluated in mice. Results: 89 Zr-anti-PD-L1 synthesis was straightforward and efficient. SDS PAGE showed that reduction produced half-antibody fragments, and MALDI-TOF analysis estimated 2.18 conjugations per antibody, indicting specific conjugation at the hinge region disulfide bonds. CT26/PD-L1 cells showed 102.2 ± 6.7-fold greater 89 Zr-anti-PD-L1 binding compared to weak expressing CT26 cells. Excellent target specificity was confirmed by a drastic reduction of binding by excess cold antibody. Intravenous 89 Zr-anti-PD-L1 followed bi-exponential blood clearance. PET/CT image analysis demonstrated decreases in major organ activity over 7 days, whereas high CT26/PD-L1 tumor activity was maintained. Again, this was suppressed by excess cold antibody. Treatment of CT26 cells with gemcitabine for 24 h augmented PD-L1 protein to 592.4 ± 114.2% of controls and increased 89 Zr-anti-PD-L1 binding. This was accompanied by increased AKT activation and reduced PTEN. In CT26 tumor-bearing mice, gemcitabine treatment substantially increased tumor uptake from 1.56 ± 0.48 to 6.24 ± 0.37 %ID/g (tumor/blood ratio: 34.7). Immunoblots revealed significant increases in tumor PD-L1 and activated AKT and a decrease of PTEN. Conclusion: 89 Zr-anti-PD-L1 showed specific targeting with favorable imaging properties. Gemcitabine treatment upregulated cancer cell and tumor PD-L1 expression and increased 89 Zr-anti-PD-L1 uptake. 89 Zr-anti-PD-L1 PET may thus be useful for monitoring chemotherapy-mediated tumor PD-L1 modulation in living subjects.

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“…By Klaus Kopka This review article (Wierstra et al, 2019) highlights one of the current major questions in the field of radiopharmaceutical sciences within nuclear medicine: Can immune checkpoints, which have been targeted for years with biologicals e.g. with nivolumab or atezolizumab, be used as imaging biomarkers for non-invasive molecular imaging too?…”

Section: Check [The] Points [Out]mentioning

confidence: 99%

Highlight selection of radiochemistry and radiopharmacy developments by editorial board (January–June 2020)

Al‐Qahtani

Béhé

Bormans

et al. 2021

EJNMMI radiopharm. chem.

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Background The Editorial Board of EJNMMI Radiopharmacy and Chemistry releases a biyearly highlight commentary to describe trends in the field. Results This commentary of highlights has resulted in 19 different topics selected by each member of the Editorial Board addressing a variety of aspects ranging from novel radiochemistry to first in man application of novel radiopharmaceuticals. Conclusion Trends in radiochemistry and radiopharmacy are highlighted demonstrating the progress in the research field being the scope of EJNMMI Radiopharmacy and Chemistry.

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Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

Cited by 30 publications

References 105 publications

Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer

Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer

⁸⁹Zr-Labeled Anti-PD-L1 Antibody PET Monitors Gemcitabine Therapy-Induced Modulation of Tumor PD-L1 Expression

Highlight selection of radiochemistry and radiopharmacy developments by editorial board (January–June 2020)

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Tracers for non-invasive radionuclide imaging of immune checkpoint expression in cancer

Cited by 30 publications

References 105 publications

Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer

Preclinical Molecular PET-CT Imaging Targeting CDCP1 in Colorectal Cancer

89Zr-Labeled Anti-PD-L1 Antibody PET Monitors Gemcitabine Therapy-Induced Modulation of Tumor PD-L1 Expression

Highlight selection of radiochemistry and radiopharmacy developments by editorial board (January–June 2020)

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⁸⁹Zr-Labeled Anti-PD-L1 Antibody PET Monitors Gemcitabine Therapy-Induced Modulation of Tumor PD-L1 Expression