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Objective To explore the role of endothelial cells in angiogenesis and myocardial remodeling in heart failure based on MAPKs pathway mediated by tumor endothelial marker 1 （TEM1）. Methods Sixty-four mice were equally randomized into four groups: sham operation, myocardial infarction （MI）, MI+sh-NC and MI+ sh-TEM1. On the 7th day after MI, the changes of EndMT in the infarct border area were detected by immunofluorescence staining, and the cardiac function of mice was evaluated by echocardiography on the 28th day. Mouse aortic endothelial cells （MAECs） were divided into three groups: control, Vector and rTEM1. In addition, MAECs were pretreated with MAPK inhibitor SB203580, and the cells were treated with rTEM1 for 48 h. The changes of EndMT and MAPKs signaling pathways in endothelial cells were evaluated by Western blot. Results In the myocardium at the border of infarction, the level of TEM1-1 increased slightly on the 1st day after MI, reached the peak on the 7th day, and then decreased on the 28th day. Compared with Vector group, the expression of VECadherin protein in the rTEM1 group decreased significantly （P < 0.05）, and the levels of α-SMA and vimentin, relative migration distance, the number of invading cells, and the number of branching formation increased significantly （P < 0.05）. SB203580 reversed these changes of MAECs induced by rTEM1. Compared with the MI group, the co-staining level of CD31+Vimentin+ in the MI+sh-TEM1 group decreased significantly （P < 0.01）. On the 28th day, the LVEF and LVFS in the MI+sh-TEM1 group were significantly higher than those in MI group （P < 0.05）. Compared with the MI group, the expressions of p-P38/P38 and p-JNK/JNK in the endothelial cells of the MI+sh- TEM1 group decreased. Conclusion EndMT and angiogenesis induced by TEM1 participate in the pathogenesis of cardiac fibroblasts induced by MI, which may be mechanically related to the activation of MAPKs signaling pathway. [ABSTRACT FROM AUTHOR]

Abstract The development of diagnostic and therapeutic radiopharmaceuticals is an hot topic in nuclear medicine. Several radiolabeled antibodies are under development necessitating both biokinetic and dosimetry extrapolations for effective human translation. The validation of different animal-to-human dosimetry extrapolation methods still is an open issue. This study reports the mice-to-human dosimetry extrapolation of 64Cu/177Lu 1C1m-Fc anti-TEM-1 for theranostic application in soft-tissue sarcomas. We adopt four methods; direct mice-to-human extrapolation (M1); dosimetry extrapolation considering a relative mass scaling factor (M2), application of a metabolic scaling factor (M3) and combination of M2 and M3 (M4). Predicted in-human dosimetry for the [64Cu]Cu-1C1m-Fc resulted in an effective dose of 0.05 mSv/MBq. Absorbed dose (AD) extrapolation for the [177Lu]Lu-1C1m-Fc indicated that the AD of 2 Gy and 4 Gy to the red-marrow and total-body can be reached with 5–10 GBq and 25–30 GBq of therapeutic activity administration respectively depending on applied dosimetry method. Dosimetry extrapolation methods provided significantly different absorbed doses in organs. Dosimetry properties for the [64Cu]Cu-1C1m-Fc are suitable for a diagnostic in-human use. The therapeutic application of [177Lu]Lu-1C1m-Fc presents challenges and would benefit from further assessments in animals’ models such as dogs before moving into the clinic.

The development of diagnostic and therapeutic radiopharmaceuticals is an hot topic in nuclear medicine. Several radiolabeled antibodies are under development necessitating both biokinetic and dosimetry extrapolations for effective human translation. The validation of different animal-to-human dosimetry extrapolation methods still is an open issue. This study reports the mice-to-human dosimetry extrapolation of 64Cu/177Lu 1C1m-Fc anti-TEM-1 for theranostic application in soft-tissue sarcomas. We adopt four methods; direct mice-to-human extrapolation (M1); dosimetry extrapolation considering a relative mass scaling factor (M2), application of a metabolic scaling factor (M3) and combination of M2 and M3 (M4). Predicted in-human dosimetry for the [64Cu]Cu-1C1m-Fc resulted in an effective dose of 0.05 mSv/MBq. Absorbed dose (AD) extrapolation for the [177Lu]Lu-1C1m-Fc indicated that the AD of 2 Gy and 4 Gy to the red-marrow and total-body can be reached with 5–10 GBq and 25–30 GBq of therapeutic activity administration respectively depending on applied dosimetry method. Dosimetry extrapolation methods provided significantly different absorbed doses in organs. Dosimetry properties for the [64Cu]Cu-1C1m-Fc are suitable for a diagnostic in-human use. The therapeutic application of [177Lu]Lu-1C1m-Fc presents challenges and would benefit from further assessments in animals' models such as dogs before moving into the clinic. [ABSTRACT FROM AUTHOR]

Introduction: Tumor endothelial marker 1 (TEM1) is expressed by tumor vascular endothelial cells in various cancers. Methods: Here, we developed poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) PEGylated with polyethylene glycol (PEG) and functionalized with anti-TEM1 antibody fragment (78Fc) and loaded them with necroptosis-inducing agent shikonin (SHK) (78Fc-PLGA-SHK NPs). Results: The nanoformulation showed a smooth spherical shape (~120 nm; the ζ potential of –30 mV) with high drug entrapment and bioconjugation efficiencies (~92% and ~90%, respectively) and a sustained-release profile in serum. Having significant toxicity in vitro (e.g., MS1 and TC1 cells), the nanoformulation dramatically increased the cytotoxicity in the TC1 murine lung carcinoma subcutaneous and intravenous/metastatic models as aggressive tumor models. The injection of the 78Fc-PLGA-SHK NPs to the MS1-xenograft mice resulted in significantly higher accumulation and effects in the TEM1-positive tumor targets, while they were excreted via urine track without retaining in the liver/spleen. In the TC1 subcutaneous model, C57/BL6 mice treated with the 78Fc-PLGA-SHK NPs revealed a significant therapeutic effect. The mice, which were tumor-free after receiving the nanoformulation, were re-challenged with the TC1 cells to investigate the immune response. These animals became tumor-free a week after the injection of TC1 cells. Conclusion: Based on these findings, we propose the 78Fc-PLGA-SHK NPs as a highly effective immunostimulating nanomedicine against the TEM1-expressing cells for targeted therapy of solid tumors including ovarian cancer.

Introduction: Tumor endothelial marker 1 (TEM1) is expressed by tumor vascular endothelial cells in various cancers. Methods: Here, we developed poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) PEGylated with polyethylene glycol (PEG) and functionalized with anti-TEM1 antibody fragment (78Fc) and loaded them with necroptosis-inducing agent shikonin (SHK) (78Fc-PLGA-SHK NPs). Results: The nanoformulation showed a smooth spherical shape (~120 nm; the ζ potential of -30 mV) with high drug entrapment and bioconjugation efficiencies (~92% and ~90%, respectively) and a sustained-release profile in serum. Having significant toxicity in vitro (e.g., MS1 and TC1 cells), the nanoformulation dramatically increased the cytotoxicity in the TC1 murine lung carcinoma subcutaneous and intravenous/metastatic models as aggressive tumor models. The injection of the 78Fc-PLGA-SHK NPs to the MS1-xenograft mice resulted in significantly higher accumulation and effects in the TEM1-positive tumor targets, while they were excreted via urine track without retaining in the liver/spleen. In the TC1 subcutaneous model, C57/BL6 mice treated with the 78Fc- PLGA-SHK NPs revealed a significant therapeutic effect. The mice, which were tumor-free after receiving the nanoformulation, were re-challenged with the TC1 cells to investigate the immune response. These animals became tumor-free a week after the injection of TC1 cells. Conclusion: Based on these findings, we propose the 78Fc-PLGA-SHK NPs as a highly effective immunostimulating nanomedicine against the TEM1-expressing cells for targeted therapy of solid tumors including ovarian cancer. [ABSTRACT FROM AUTHOR]

Ovarian cancer is a gynecological genital malignancy, with high incidence and high mortality. Because of the concealment of ovarian cancer and the lack of effective detection methods, the patients were found in the middle and late stage of the disease. Therefore, to improve the early diagnosis of ovarian cancer can effectively improve the prognosis and survival rate of patients. Tumor endothelial marker 1 (TEM1) is a newlyfound tumor specific marker of ovarian cancer. TEM1 can be expressed on the surface of ovarian cancer cells, but not expressed or lowly expressed in normal tissues, suggesting that TEM1 is a potential target for the diagnosis and treatment of ovarian cancer. The specific antibody of TEM1 combined with imaging technology and genetic engineering technology has shown the excellent anti-tumor effect on ovarian cancer. At the same time, a large number of clinical trials based on the targeted TEM1 are being in progress. In this article, we review the discovery, structure and tissue expression of TEM1, and its research progress, in the diagnosis and treatment of ovarian cancer, in order to provide new ideas for the future treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

The development of diagnostic and therapeutic radiopharmaceuticals is an hot topic in nuclear medicine. Several radiolabeled antibodies are under development necessitating both biokinetic and dosimetry extrapolations for effective human translation. The validation of different animal-to-human dosimetry extrapolation methods still is an open issue. This study reports the mice-to-human dosimetry extrapolation of 64 Cu/ 177 Lu 1C1m-Fc anti-TEM-1 for theranostic application in soft-tissue sarcomas. We adopt four methods; direct mice-to-human extrapolation (M1); dosimetry extrapolation considering a relative mass scaling factor (M2), application of a metabolic scaling factor (M3) and combination of M2 and M3 (M4). Predicted in-human dosimetry for the [ 64 Cu]Cu-1C1m-Fc resulted in an effective dose of 0.05 mSv/MBq. Absorbed dose (AD) extrapolation for the [ 177 Lu]Lu-1C1m-Fc indicated that the AD of 2 Gy and 4 Gy to the red-marrow and total-body can be reached with 5-10 GBq and 25-30 GBq of therapeutic activity administration respectively depending on applied dosimetry method. Dosimetry extrapolation methods provided significantly different absorbed doses in organs. Dosimetry properties for the [ 64 Cu]Cu-1C1m-Fc are suitable for a diagnostic in-human use. The therapeutic application of [ 177 Lu]Lu-1C1m-Fc presents challenges and would benefit from further assessments in animals' models such as dogs before moving into the clinic., (© 2023. The Author(s).)

Simple Summary: The prevalence of TEM-1 in the vasculature and the stroma of solid tumors and in malignant cells of sarcomas suggests that targeting TEM-1 could have therapeutic benefit. In this context, an anti-TEM-1 companion diagnostic may assist in the personalized medicine approach, whereby TEM-1 expression is exploited as a biomarker to select patients that would most benefit from a treatment directed toward the TEM-1 antigen. In our previous works, we have selected 1C1m-Fc, a fusion protein antibody, radiolabeled it with 177Lu and demonstrated that [177Lu]Lu-1C1m-Fc has interesting therapeutic performance. To define a suitable radiopharmaceutical companion for theranostic applications, 64Cu was chosen to radiolabel the fusion protein antibody. The aim of this work was thus to determine if [64Cu]Cu-1C1m-Fc can be considered for TEM-1 PET imaging and to predict the dosimetry of the [177Lu]Lu-1C1m-Fc companion therapy. 1C1m-Fc, a promising anti-TEM-1 DOTA conjugate, was labeled with 64Cu to target cancer cells for PET imaging and predicting the efficacy and safety of a previously studied [177Lu]Lu-1C1m-Fc companion therapy. DOTA-conjugated 1C1m-Fc was characterized by mass spectrometry, thin layer chromatography and immunoreactivity assessment. PET/CT and biodistribution studies were performed in human neuroblastoma xenografted mice. Absorbed doses were assessed from biodistribution results and extrapolated to 177Lu based on the [64Cu]Cu-1C1m-Fc data. The immunoreactivity was ≥ 70% after 48 h of incubation in serum, and the specificity of [64Cu]Cu-1C1m-Fc for the target was validated. High-resolution PET/CT images were obtained, with the best tumor-to-organ ratios reached at 24 or 48 h and correlated with results of the biodistribution study. Healthy organs receiving the highest doses were the liver, the kidneys and the uterus. [64Cu]Cu-1C1m-Fc could be of interest to give an indication of 177Lu dosimetry for parenchymal organs. In the uterus and the tumor, characterized by specific TEM-1 expression, the 177Lu-extrapolated absorbed doses are overestimated because of the lack of later measurement time points. Nevertheless, 1C1m-Fc radiolabeled with 64Cu for imaging would appear as an interesting radionuclide companion for therapeutic application with [177Lu]Lu-1C1m-Fc. [ABSTRACT FROM AUTHOR]

Abstract: Tumor endothelial marker 1 (TEM1) is a protein predominantly expressed on the cell surface of endothelial cells in newly developing blood vessels and on tumor cells. It is therefore ideally suited as a target for anti-angiogenic tumor therapy. Using phage display technology a single chain antibody fragment (scFv-CM6) was isolated that specifically binds to the extracellular part of TEM1. Antibody specificity was determined in ELISA, by Western analysis, fluorescence microscopy and flow cytometry performed with TEM1-expressing cells. ScFv-CM6 was further functionalized and coupled to liposomes. Such immunoliposomes loaded with the cytotoxic drug N4-octadecyl-1-β-d-arabinofuranosylcytosine-(5′-5′)-3′-C-ethinylcytidine showed increased binding affinity and up to 80% higher cytotoxic activity towards TEM1-expressing IMR-32 tumor cells compared with control liposomes. [Copyright &y& Elsevier]

Colorectal cancer (CRC) is one of the most common cancers worldwide usually diagnosed in the advanced stage. In this study, the serum concentration of tumor endothelial marker 1 (TEM1) was measured and correlated with clinicopathological features to evaluate whether TEM1 might serve as a biomarker for early CRC diagnosis, progression, and prognosis. The concentration of TEM1 was measured in the serum samples of 45 patients with CRC and 35 healthy individuals using enzyme-linked immunosorbent assay test. The mean serum concentration of TEM1 was significantly higher in the patients with CRC compared to the healthy individuals (1.31 ± 0.16 vs 0.92 ± 0.90 ng/mL; P < .001). The mean concentration of TEM1 significantly increased in the patients having CRC with early stage (stage I + II) compared to noncancer control individuals (stage I + II vs control 1.21 ± 0.13 ng/mL: 0.92 ± 0.90 ng/mL; P < .001). The TEM1 concentration in blood serum also showed a significant association with the development of T stages ( P < .001), N stages ( P < .001), and M stages ( P = .006). The TEM1 sensitivity and specificity in CRC detection are higher than routinely used blood markers (carcinoembryonic antigen [CEA] and carbohydrate antigen [Ca 19-9]). Patients with high TEM1 concentration (≥1.055 ng/mL) had a worse overall survival rate compared to the patients having CRC with low TEM1 concentration (<1.055 ng/mL). In conclusion, TEM1 can act as a potential diagnostic, progression, and prognostic serum biomarker for patients with CRC; TEM1 might be a good supplement for commonly used markers CEA and Ca 19-9.