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Characterization of site-specifically conjugated monomethyl auristatin E- and duocarmycin-based anti-PSMA antibody-drug conjugates for treatment of PSMA-expressing tumors.
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Characterization of site-specifically conjugated monomethyl auristatin E- and duocarmycin-based anti-PSMA antibody-drug conjugates for treatment of PSMA-expressing tumors.

J Nucl Med. 2017 Nov 16;:

Authors: Lütje S, Gerrits D, Molkenboer-Kuenen JD, Herrmann K, Fracasso G, Colombatti M, Boerman OC, Heskamp S

Abstract
Rationale: Prostate cancer (PCa) is the most common cancer in men worldwide. In general, PCa responds poorly to chemotherapy. Therefore, antibody-drug conjugates (ADCs) have been developed to specifically deliver highly cytotoxic drugs to the tumor. As the prostate-specific membrane antigen (PSMA) is overexpressed in PCa, it represents a promising target for ADC-based therapies. The aim of this study was to evaluate the therapeutic efficacy of site-specifically conjugated duocarmycin- and monomethyl auristatin E (MMAE)-based anti-PSMA ADCs with drug-antibody ratios (DARs) of 2 and 4. Methods: The glycan group of the anti-PSMA antibody D2B was chemoenzymatically conjugated with duocarmycin or MMAE. Preservation of the immunoreactivity of the antibody upon site-specific conjugation was investigated in vitro. Biodistribution and microSPECT/CT imaging (18.5 ± 2.6 MBq) with 25 µg of (111)In-labeled ADCs were performed in BALB/c nude mice with s.c. PSMA(+) LS174T-PSMA xenografts. Finally, the therapeutic efficacy of the four different ADCs was assessed in mice with LS174T-PSMA tumors. Results: The immunoreactivity of the anti-PSMA antibody was preserved upon site-specific conjugation. Biodistribution revealed high tumor uptake of all agents, highest tumor uptake was observed in mice administered with (111)In-DTPA-D2B-DAR2-MMAE, reaching 119.7 ± 37.4 %ID/g at 3 days p.i. Tumors of mice injected with (111)In-DTPA-D2B, (111)In-DTPA-D2B-DAR2-duocarmycin, (111)In-DTPA-D2B-DAR4-duocarmycin, (111)In-DTPA-D2B-DAR2-MMAE, and (111)In-DTPA-D2B-DAR4-MMAE could clearly be visualized with microSPECT/CT. In contrast to unconjugated D2B or vehicle, treatment with either MMAE-based ADC, but not with a duocarmycin-based ADC, significantly impaired the tumor growth and prolonged median survival from 13 days (PBS) to 20 and 29 days for DAR2 and DAR4 ADC, respectively. Tumor doubling time increased from 3.5 ± 0.5 days to 5.2 ± 1.8 and 9.2 ± 2.1 days after treatment with D2B-DAR2-MMAE and D2B-DAR4-MMAE, respectively. Conclusion: The site-specifically conjugated anti-PSMA ADCs D2B-DAR2-MMAE and D2B-DAR4-MMAE efficiently targeted PSMA-expressing xenografts, effectively inhibited tumor growth of PSMA-expressing tumors, and significantly prolonged survival of mice.

PMID: 29146698 [PubMed - as supplied by publisher]




Challenging Nuclear Cardiology Research: Stimulating Discovery, Validation and Clinical Relevance.
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Challenging Nuclear Cardiology Research: Stimulating Discovery, Validation and Clinical Relevance.

J Nucl Med. 2017 Nov 16;:

Authors: Dilsizian V

PMID: 29146697 [PubMed - as supplied by publisher]




Optimizing Strategies for Immune Checkpoint Imaging with Immumo-PET in Preclinical Study.
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Optimizing Strategies for Immune Checkpoint Imaging with Immumo-PET in Preclinical Study.

J Nucl Med. 2017 Nov 16;:

Authors: Chen J, Wang N, Yang X, Li Y

PMID: 29146696 [PubMed - as supplied by publisher]




First-in-human HER2-targeted imaging using (89)Zr-pertuzumab PET/CT: Dosimetry and clinical application in patients with breast cancer.
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First-in-human HER2-targeted imaging using (89)Zr-pertuzumab PET/CT: Dosimetry and clinical application in patients with breast cancer.

J Nucl Med. 2017 Nov 16;:

Authors: Ulaner GA, Lyashchenko SK, Riedl C, Ruan S, Zanzonico PB, Lake D, Jhaveri K, Zeglis B, Lewis JS, O'Donoghue JA

Abstract
In this first-in-human study, we evaluate the safety and dosimetry of (89)Zr-pertuzumab PET/CT for HER2-targeted imaging in patients with HER2-postive breast cancer. Materials and Methods: Patients with HER2-positive breast cancer and evidence of distant metastases were enrolled in an Institutional Review Board (IRB)-approved prospective clinical trial. Pertuzumab was conjugated with deferoxamine and radiolabeled with (89)Zr. Patients underwent (89)Zr-pertuzumab PET/CT with 74 MBq of (89)Zr-pertuzumab in a total antibody mass of 20-50 mg of pertuzumab. PET/CT, whole-body probe counts, and blood draws were performed over 8 days to assess pharmacokinetics, biodistribution, and dosimetry. PET/CT images were evaluated for ability to visualize HER2-positive metastases. Results: Six patients with HER2-positive metastatic breast cancer were enrolled and administered (89)Zr-pertuzumab. No toxicities occurred. Dosimetry estimates from Organ Level Internal Dose Assessment (OLINDA) demonstrated the organs receiving the highest doses (mGy/MBq) were liver (1.75 ± 0.21), kidneys (1.27 ± 0.28), and heart wall (1.22 ± 0.16) with an average effective dose of 0.54 ± 0.07 mSv/MBq. PET/CT demonstrated optimal imaging 5-8 days post-administration. (89)Zr-pertuzumab was able to image multiple sites of HER2-positive malignancy. In two patients with both known HER2-positive and HER2-negative primary breast cancers and brain metastases, (89)Zr-pertuzumab PET/CT was able to distinguish the brain metastases as HER2-positive. Conclusion: This first-in-human study demonstrated safety, dosimetry, biodistribution, and successful HER2-targeted imaging with (89)Zr-pertuzumab PET/CT. Potential clinical applications include assessment of HER2 status of lesions which may not be accessible to biopsy and assessment of HER2 heterogeneity.

PMID: 29146695 [PubMed - as supplied by publisher]




Spatiotemporal distribution of β-amyloid in Alzheimer's disease results from heterogeneous regional carrying capacities.
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Spatiotemporal distribution of β-amyloid in Alzheimer's disease results from heterogeneous regional carrying capacities.

J Nucl Med. 2017 Nov 16;:

Authors: Whittington A, Sharp DJ, Gunn RN

Abstract
β-amyloid (Aβ) accumulation in the brain is one of two pathological hallmarks of Alzheimer's Disease (AD) and its spatial distribution has been studied extensively ex vivo. We apply mathematical modelling to Aβ in vivo PET imaging data in order to investigate competing theories of Aβ spread in AD. Our results provide evidence that Aβ accumulation starts in all brain regions simultaneously and that its spatiotemporal distribution is a result of heterogeneous regional carrying capacities (regional maximum possible concentration of Aβ) for the aggregated protein rather than longer term spreading from seed regions.

PMID: 29146694 [PubMed - as supplied by publisher]




Reply: Advantages and Limits of Targeted Radionuclide Therapy with Somatostatin Antagonists.
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Reply: Advantages and Limits of Targeted Radionuclide Therapy with Somatostatin Antagonists.

J Nucl Med. 2017 Nov 16;:

Authors: Nicolas G, Wild D, Fani M

PMID: 29146693 [PubMed - as supplied by publisher]




Prediction of (90)Y-Radioembolization Outcome from Pre-therapeutic Factors with Random Survival Forests.
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Prediction of (90)Y-Radioembolization Outcome from Pre-therapeutic Factors with Random Survival Forests.

J Nucl Med. 2017 Nov 16;:

Authors: Ingrisch M, Schöppe F, Paprottka KJ, Fabritius M, Strobl FF, de Toni E, Ilhan H, Todica A, Michl M, Paprottka P

Abstract
To predict outcome of (90)Y radioembolization (RE) in patients with intrahepatic tumors from pre-therapeutic baseline parameters and to identify predictive variables using a machine-learning approach based on random survival forests (RSF). Materials and Methods: In this retrospective study, 366 patients with primary (n = 92) or secondary (n = 274) liver tumors who had received (90)Y radioembolization were analyzed. A random survival forest was trained to predict individual risk from baseline values of cholinesterase (CHE), bilirubin, type of primary tumor, age at radioembolization, hepatic tumor burden, presence of extrahepatic disease (EHD) and sex. The predictive importance of each baseline parameter was determined using the minimal depth concept, and the partial dependency of predicted risk on the continuous variables bilirubin level and cholinesterase level was determined. Results: Median overall survival was 11.4 months (95% C.I. 9.7-14.2 months) with 228 deaths observed during the observation period. The random survival forest analysis identified baseline cholinesterase and bilirubin as the most important variables with the forest-averaged lowest minimal depth of 1.2 and 1.5, followed by the type of primary tumor (1.7), age (2.4), tumor burden (2.8) and presence of extrahepatic disease (3.5). Sex had the highest forest-averaged minimal depth (5.5), indicating little predictive value. Baseline bilirubin levels above 1.5 mg/dl were associated with a steep increase in predicted mortality. Similarly, cholinesterase levels below 7.5 U/ predicted a strong increase in mortality. The trained random survival forest achieved a concordance index of c=0.657, with a standard error of 0.02, comparable to c=0.652 (0.02) of a previously published Cox proportional hazards model. Conclusion: Random survival forests are a simple and straightforward machine learning approach for prediction of overall survival. Predictive performance of the trained model was similar to a previously published Cox regression model. The model has revealed a strong predictive value of baseline cholinesterase and bilirubin levels with a highly nonlinear influence of each parameter.

PMID: 29146692 [PubMed - as supplied by publisher]