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The aim of this pilot study was to evaluate whether the uptake of (89)Zr-bevacizumab in non-small cell lung cancer (NSCLC) tumors could be visualized and quantified. The correlation between tumor (89)Zr-bevacizumab uptake and tumor response to antitumor therapy with a bevacizumab-based regimen was explored. Seven NSCLC patients underwent static PET scans at days 4 and 7 after injection of 36.4 ± 0.9 MBq (mean ± SD) (89)Zr-bevacizumab, prior to commencing carboplatin-paclitaxel-bevacizumab chemotherapy (CPB). Overall survival (OS) and progression-free survival (PFS) to CPB followed by bevacizumab maintenance therapy was correlated to tumor tracer uptake, quantified using peak standardized uptake values (SUVpeak). Zr-bevacizumab uptake (SUVpeak) was approximately four times higher in tumor tissues (primary tumor and metastases) than in non-tumor tissues (healthy muscle, lung, and fat) on days 4 and 7. A positive trend but no significant correlation could be found between SUVpeak and OS or PFS. This pilot study shows that (89)Zr-bevacizumab PET imaging in NSCLC is feasible. Further investigation to validate this technique as a predictive biomarker for selecting patients for bevacizumab treatment is warranted.

The uptake on a [sup.89]Zr-immuno-PET scan is not just the result of the binding of a radiolabeled antibody with its target (i.e., target engagement) but also includes background factors such as non-specific binding (for example, catabolism of antibodies inside endothelial cells). In this study, we wanted to isolate target engagement. We used data from five previously performed [sup.89]Zr-immuno-PET studies with immune-targeting [sup.89]Zr-radiolabeled antibodies. First, via Patlak analysis, we separated reversible from irreversible uptake, and by using a baseline of target-negative organs, we further defined target-specific irreversible uptake. Second, we compared different mass doses (ratios of labeled and unlabeled antibody) and looked for saturation effects. Evidence for target engagement was based on the following two things: (1) when the target-specific irreversible uptake exceeded the baseline, and (2) when the signal showed saturation. We found target engagement for the different antibodies in several lymphoid organs, for example, in the spleen, while the brain had close to zero target engagement. We propose a new baseline for bone marrow and brain. In conclusion, we promote the use of Patlak analysis for [sup.89]Zr-immuno-PET studies, or similar simplified outcomes such as a tissue-to-blood ratio. Introduction: [sup.89]Zr-immuno-PET (positron emission tomography with zirconium-89-labeled monoclonal antibodies ([[sup.89]Zr]Zr-mAbs)) can be used to study the biodistribution of mAbs targeting the immune system. The measured uptake consists of target-specific and non-specific components, and it can be influenced by plasma availability of the tracer. To find evidence for target-specific uptake, i.e., target engagement, we studied five immune-checkpoint-targeting [[sup.89]Zr]Zr-mAbs to (1) compare the uptake with previously reported baseline values for non-specific organ uptake (ns-baseline) and (2) look for saturation effects of increasing mass doses. Method: [sup.89]Zr-immuno-PET data from five [[sup.89]Zr]Zr-mAbs, i.e., nivolumab and pembrolizumab (anti-PD-1), durvalumab (anti-PD-L1), BI 754,111 (anti-LAG-3), and ipilimumab (anti-CTLA-4), were analysed. For each mAb, 2–3 different mass doses were evaluated. PET scans and blood samples from at least two time points 24 h post injection were available. In 35 patients, brain, kidneys, liver, spleen, lungs, and bone marrow were delineated. Patlak analysis was used to account for differences in plasma activity concentration and to quantify irreversible uptake (K[sub.i]). To identify target engagement, K[sub.i] values were compared to ns-baseline K[sub.i] values previously reported, and the effect of increasing mass doses on K[sub.i] was investigated. Results: All mAbs, except ipilimumab, showed K[sub.i] values in spleen above the ns-baseline for the lowest administered mass dose, in addition to decreasing K[sub.i] values with higher mass doses, both indicative of target engagement. For bone marrow, no ns-baseline was established previously, but a similar pattern was observed. For kidneys, most mAbs showed K[sub.i] values within the ns-baseline for both low and high mass doses. However, with high mass doses, some saturation effects were seen, suggestive of a lower ns-baseline value. K[sub.i] values were near zero in brain tissue for all mass doses of all mAbs. Conclusion: Using Patlak analysis and the established ns-baseline values, evidence for target engagement in (lymphoid) organs for several immune checkpoint inhibitors could be demonstrated. A decrease in the K[sub.i] values with increasing mass doses supports the applicability of Patlak analysis for the assessment of target engagement for PET ligands with irreversible uptake behavior.

In the context of precision diagnosis for various subtypes of melanoma, identifying biomarkers with clinical translational potential from a molecular standpoint is crucial for a more comprehensive characterization of the disease. Mucin 18 (MUC18) is highly expressed in both tumor cells and tumor vasculature in major melanoma subtypes and is restricted to normal tissues. A noninvasive imaging approach for MUC18 in melanoma utilizing an immune positron emission tomography (PET) radionuclide‐conjugated drug (RDC) with an 89Zr‐labeled humanized anti‐MUC18 monoclonal antibody (mAb) was developed. A375, Sk‐Mel‐28, HMVII, and A549 cells and tumor model mice were conducted. Immuno‐PET was employed to assess the specificity and targeting of three distinct melanoma cell line‐derived xenografts (CDXs) and patient‐derived tumor xenografts (PDXs) in immunodeficient mice. The developed RDC, named 89Zr‐IP150, demonstrated robust in vitro stability and high binding affinity, ensuring reliable and specific PET imaging of small, medium, and large subcutaneous tumors in human melanoma mouse xenotransplantation models. Notably, for the first time, the clinical translational potential of 89Zr‐IP150 was successfully validated using PDX models. These findings present a noninvasive, real‐time method for the early screening of MUC18 (+) melanoma patients and are important for studying the early‐stage biological distribution of MUC18‐targeted antibody‐drug conjugates. The developed radiopharmaceutical conjugate, targeting Mucin 18 and named 89Zr‐IP150, demonstrates robust in vitro stability and high binding affinity, ensuring reliable and specific positron emission tomography imaging of each tumor model. For the first time, the clinical translational potential of 89Zr‐IP150 is successfully validated using patient‐derived tumor xenograft models.

Non-invasive imaging of atherosclerosis can help in the identification of vulnerable plaque lesions. CD40 is a co-stimulatory molecule present on various immune and non-immune cells in the plaques and is linked to inflammation and plaque instability. We hypothesize that a 89Zr-labeled anti-CD40 monoclonal antibody (mAb) tracer has the potential to bind to cells present in atherosclerotic lesions and that CD40 Positron Emission Tomography (PET) can contribute to the detection of vulnerable atherosclerotic plaque lesions. To study this, wild-type (WT) and ApoE−/− mice were fed a high cholesterol diet for 14 weeks to develop atherosclerosis. Mice were injected with [89Zr]Zr-anti-CD40 mAb and the aortic uptake was evaluated and quantified using PET/Computed Tomography (CT) imaging. Ex vivo biodistribution was performed post-PET imaging and the uptake in the aorta was assessed with autoradiography and compared with Oil red O staining to determine the tracer potential to detect atherosclerotic plaques. On day 3 and 7 post injection, analysis of [89Zr]Zr-anti-CD40 mAb PET/CT scans showed a more pronounced aortic signal in ApoE−/− compared to WT mice with an increased aorta-to-blood uptake ratio. Autoradiography revealed [89Zr]Zr-anti-CD40 mAb uptake in atherosclerotic plaque areas in ApoE−/− mice, while no signal was found in WT mice. Clear overlap was observed between plaque areas as identified by Oil red O staining and autoradiography signal of [89Zr]Zr-anti-CD40 mAb in ApoE−/− mice. In this proof of concept study, we showed that PET/CT with [89Zr]Zr-anti-CD40 mAb can detect atherosclerotic plaques. As CD40 is associated with plaque vulnerability, [89Zr]Zr-anti-CD40 mAb has the potential to become a tracer to detect vulnerable atherosclerotic plaques.

CD73 is a cell-surface ectoenzyme that hydrolyzes the conversion of extracellular adenosine monophosphate to adenosine, which in turn can promote resistance to immune checkpoint blockade therapy. Immune response may therefore be improved by targeting tumor CD73, and this possibility underlines the need to non-invasively assess tumor CD73 level. In this study, we developed a cysteine site-specific 89 Zr-labeled anti-CD73 ( 89 Zr-CD73) IgG immuno-PET technique that can image tumor CD73 expression in living bodies. Anti-CD73 IgG was reduced with tris(2-carboxyethyl)phosphine, underwent sulfohydryl moiety–specific conjugation with deferoxamine–maleimide, and was radiolabeled with 89 Zr. CT26 mouse colon cancer cells, CT26/CD73 cells engineered to constitutively overexpress CD73, and 4T1.2 mouse breast cancer cells underwent cell binding assays and western blotting. Balb/c nude mice bearing tumors underwent 89 Zr-CD73 IgG PET imaging and biodistribution studies. 89 Zr-CD73 IgG showed 20-fold higher binding to overexpressing CT26/CD73 cells compared to low-expressing CT26 cells, and moderate expressing 4T1.2 cells showed uptake that was 38.9 ± 1.51% of CT26/CD73 cells. Uptake was dramatically suppressed by excess unlabeled antibody. CD73 content proportionately increased in CT26 and CT26/CD73 cell mixtures was associated with linear increases in 89 Zr-CD73 IgG uptake. 89 Zr-CD73 IgG PET/CT displayed clear accumulation in CT26/CD73 tumors with greater uptake compared to CT26 tumors (3.13 ± 1.70%ID/g vs. 1.27 ± 0.31%ID/g at 8 days; P  = 0.04). Specificity was further supported by low CT26/CD73 tumor-to-blood ratio of 89 Zr-isotype-IgG compared to 89 Zr-CD73 IgG (0.48 ± 0.08 vs. 2.68 ± 0.52 at 4 days and 0.53 ± 0.07 vs. 4.81 ± 1.02 at 8 days; both P  < 0.001). Immunoblotting and immunohistochemistry confirmed strong CD73 expression in CT26/CD73 tumors and low expression in CT26 tumors. 4T1.2 tumor mice also showed clear 89 Zr-CD73 IgG accumulation at 8 days (3.75 ± 0.70%ID/g) with high tumor-to-blood ratio compared to 89 Zr-isotype-IgG (4.91 ± 1.74 vs. 1.20 ± 0.28; P  < 0.005). 89 Zr-CD73 IgG specifically targeted CD73 on high expressing cancer cells in vitro and tumors in vivo. Thus, 89 Zr-CD73 IgG immuno-PET may be useful for the non-invasive monitoring of CD73 expression in tumors of living subjects.

Recent advances in molecular characterization of tumors have allowed identification of new molecular targets on tumor cells or biomarkers. In medical practice, the identification of these biomarkers slowly but surely becomes a prerequisite before any treatment decision, leading to the concept of personalized medicine. Immuno-positron emission tomography (PET) fits perfectly with this approach. Indeed, monoclonal antibodies (mAbs) labelled with radionuclides represent promising probes for theranostic approaches, offering a non-invasive solution to assess in vivo target expression and distribution. Immuno-PET can potentially provide useful information for patient risk stratification, diagnosis, selection of targeted therapies, evaluation of response to therapy, prediction of adverse effects or for titrating doses for radioimmunotherapy. This paper reviews some aspects and recent developments in labelling methods, biological targets, and clinical data of some novel PET radiopharmaceuticals.

Background/Objectives: Radiolabeled bevacizumab-based immuno-PET tracers enable a non-invasive quantification of VEGF-A expression in gynecologic malignancies. While the previously reported [52Mn]Mn-DOTAGA-bevacizumab demonstrated selective VEGF-A-targeted uptake in a KB-3-1 cervix carcinoma mouse model, further improvements in chelator stability and tumor-to-background contrast remain desirable. The recently developed BPPA chelator exhibits exceptionally high Mn(II) complex stability and favorable radiolabeling characteristics. This study aimed to characterize the in vivo biodistribution of [52Mn]Mn-BPPA-bevacizumab, and to compare the tumor-to-background ratios of [52Mn]Mn-BPPA-bevacizumab with the previously published values of [52Mn]Mn-DOTAGA-bevacizumab in VEGF-A-expressing cervix carcinoma. Methods: Female KB-3-1 tumor-bearing CB17 SCID mice underwent PET/MRI imaging following intravenous administration of [52Mn]Mn-BPPA-bevacizumab. SUVmean values were measured in various organs and in the subcutaneously injected tumor, and tumor-to-organ ratios were calculated at various time points up to 10 days post-injection. Results: [52Mn]Mn-BPPA-bevacizumab demonstrated sustained tumor uptake, with tumor SUVmean values increasing from approximately 1.0 at 4 h to peak values of approximately 2.4–2.5 at 72 h post-injection. Tumor-to-background ratios increased progressively over time and were significantly higher for [52Mn]Mn-BPPA-bevacizumab compared with previously reported [52Mn]Mn-DOTAGA-bevacizumab, particularly for tumor-to-blood, tumor-to-liver and tumor-to-lung ratios at later imaging time points (p < 0.0001). Conclusions: The novel [52Mn]Mn-BPPA-bevacizumab tracer exhibits satisfactory in vitro and in vivo stability for PET imaging, high VEGF-A-specific tumor uptake, and markedly improved tumor-to-background ratios compared to the previously published DOTAGA-based probe. These results position [52Mn]Mn-BPPA-bevacizumab as a highly promising next-generation immuno-PET agent for imaging VEGF-A-expressing gynecologic malignancies and for guiding anti-angiogenic therapies.

Background Despite advances in breast cancer imaging, reliable detection of sentinel lymph node (SLN) metastasis remains challenging. This study aimed to determine the ability of immuno-positron emission tomography (PET) using 64 Cu-labeled cetuximab to detect SLN metastasis in a model of epidermal growth factor receptor (EGFR)-positive breast cancer. Methods The SLN metastasis model was established using the EGFR-strongly-expressing MDA-MB-468 breast cancer cell line. In this xenograft model, [ 64 Cu]Cu-PCTA-cetuximab was administered intravenously (5.8 ± 0.9 MBq; n  = 12) or both intradermally and subdermally into the parapapillary region of the tumor-containing mammary gland (4.3 ± 0.4 MBq; n  = 11), after which PET was performed. 18 F-FDG PET was also performed intravenously (9.1 ± 1.4 MBq; n  = 4) or intradermally/subdermally (5.4 ± 2.2 MBq; n  = 3) in the same cohort before [ 64 Cu]Cu-PCTA-cetuximab PET. PET/computed tomography was performed 60 min after administration of 18 F-FDG and 24 h after administration of [ 64 Cu]Cu-PCTA-cetuximab. Delayed PET/CT scans were conducted 48 h after administration for all mice in the intradermally/subdermally administered [ 64 Cu]Cu-PCTA-cetuximab group and for four of the 12 mice in the intravenously administered [ 64 Cu]Cu-PCTA-cetuximab group. SLNs were identified using blue dye, and PET and pathological evaluations of the resected SLN were performed to confirm metastases. Results After intravenous administration of [ 64 Cu]Cu-PCTA-cetuximab ( n  = 12), accumulation was detected in the primary tumor in all mice and in the axilla of eight mice (67%, SUV max 1.24 ± 0.51), all of which were found to have SLNs with histologically confirmed metastasis. The sensitivity, specificity, accuracy, and negative and positive predictive values for PET with intravenously administered [ 64 Cu]Cu-PCTA-cetuximab were 89%, 100%, 92%, 75%, and 100%, respectively. In contrast, all mice with intradermal/subdermal administration ( n  = 11) showed high accumulation in both the primary tumor and axillary lymph nodes (SUV max 4.28 ± 1.19), with six mice (55%, SUV max 5.01 ± 1.12) having histologically confirmed metastasis. The sensitivity, specificity, accuracy, and positive predictive values for PET with intradermally/subdermally administered [ 64 Cu]Cu-PCTA-cetuximab were 100%, 0%, 55% and 55%, respectively. SLN metastasis was not detectable by intravenous or intradermal/subdermal 18 F-FDG PET. Conclusions PET with intravenously administered [ 64 Cu]Cu-PCTA-cetuximab demonstrated high precision for diagnosis of SLN metastasis in a xenograft model of EGFR-positive human breast cancer. Although further evaluation is necessary, intradermal/subdermal administration could be a useful therapeutic approach owing to its high accumulation in SLNs.

Purpose CD30 serves as an ideal therapeutic target for lymphoma, but its variable expression and high relapse rate pose challenges in targeted therapy. This study aims to label the anti-CD30 monoclonal antibody with 64 Cu/ 177 Lu for immuno-positron emission tomography (immuno-PET) and radioimmunotherapy (RIT). Methods CD30 binding kinetics of anti-CD30-IgG (IMB16) were measured by Biolayer interferometry (BLI). Western blotting screened lymphoma cell lines for CD30 expression. Flow cytometry and immunofluorescence validated the specific binding of IMB16. IMB16 was conjugated to p-SCN-Bn-NOTA(NOTA) and p-SCN-Bn-DOTA(DOTA) for radiolabeling with 64 Cu and 177 Lu. [ 64 Cu]Cu-NOTA-IMB16 and [ 177 Lu]Lu-DOTA-IMB16 were used for immuno-PET and RIT in subcutaneous lymphoma NSG mouse models. Results IMB16 had a strong binding affinity to CD30 according to the BLI. Western blotting revealed high CD30 expression in Karpas299 cells and negative expression in Raji cells. Flow cytometry and immunofluorescence confirmed specific binding of IMB16 to CD30 on cell surface. Radiochemical purity of [ 64 Cu]Cu-NOTA-IMB16 and [ 177 Lu]Lu-DOTA-IMB16 exceeded 95%. In Immuno-PET imaging, CD30-positive Karpas299 tumours had a mean uptake value of 19.2 ± 0.9%ID/g ( n  = 3) at 24 h post-injection, significantly higher than Karpas299-blocked and Raji-negative groups ( P  < 0.001). A high radiation dose (300µCi) of [ 177 Lu]Lu-DOTA-IMB16 significantly inhibited tumour growth (80.2 ± 17.6% standardized tumour volume, n  = 5) at 10 days post-injection, compared to controls. Ex vivo biodistribution and histological staining supported in vivo PET imaging and RIT results. Conclusions Labelling IMB16 with 64 Cu enabled non-invasive assessment of CD30 expression, while 177 Lu labelling effectively suppressed tumour growth in CD30-positive lymphoma. CD30-targeted theranostic show promise for patient stratification and treatment enhancement, warranting further clinical evaluation.

Inflammatory bowel disease (IBD) is a chronic inflammatory condition requiring accurate and non-invasive imaging for diagnosis and monitoring. Current clinical methods, including Disease Activity Index (DAI) scoring, have limitations due to their subjectivity and inability to detect mild or early inflammation. This study introduces a novel 89 Zr-labeled IL-23p19 monoclonal antibody ([ 89 Zr]Zr-IL-23p19) for targeted immuno-PET imaging in a dextran sulfate sodium-induced murine IBD model. Radiolabeling of IL-23p19 antibody with [ 89 Zr]Zr yielded a stable tracer with high radiochemical purity. PET/MR imaging showed focal accumulation of [ 89 Zr]Zr-IL-23p19 in inflamed colonic regions, aligning closely with histological inflammation and IL-23p19 expression. In contrast, the previous metabolic tracer [ 18 F]FSPG demonstrated diffuse uptake without clear localization to inflamed tissues. Quantitative PET analysis indicated a significant correlation between [ 89 Zr]Zr-IL-23p19 uptake and DAI scores, whereas [ 18 F]FSPG exhibited weak correlations. These results highlight [ 89 Zr]Zr-IL-23p19 immuno-PET imaging as a sensitive, specific, and non-invasive biomarker with strong potential for clinical translation in diagnosing and monitoring chronic intestinal inflammation in patients with IBD.