Preclinical Evaluation and Dosimetry of [111In]CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1)

Cicone, Francesco; Denoël, Thibaut; Gnesin, Silvano; Riggi, Nicolò; Irving, Melita; Jakka, Gopinadh; Schaefer, Niklaus; Viertl, David; Coukos, George; Prior, John O.

doi:10.1007/s11307-020-01479-8

Cited by 16 publications

(18 citation statements)

References 55 publications

(75 reference statements)

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“…Organ receiving the highest doses were liver and uterus. Two other anti TEM-1 antibodies, 78Fc labeled with 111 In and Morab-004 labeled with 124 I showed similar results in these organs [ 26 , 37 ].…”

Section: Discussionmentioning

confidence: 70%

Impact of DOTA Conjugation on Pharmacokinetics and Immunoreactivity of [177Lu]Lu-1C1m-Fc, an Anti TEM-1 Fusion Protein Antibody in a TEM-1 Positive Tumor Mouse Model

et al. 2021

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1C1m-Fc, an anti-tumor endothelial marker 1 (TEM-1) scFv-Fc fusion protein antibody, was previously successfully radiolabeled with 177Lu. TEM-1 specific tumor uptake was observed together with a non-saturation dependent liver uptake that could be related to the number of dodecane tetraacetic acid (DOTA) chelator per 1C1m-Fc. The objective of this study was to verify this hypothesis and to find the best DOTA per 1C1m-Fc ratio for theranostic applications. 1C1m-Fc was conjugated with six concentrations of DOTA. High-pressure liquid chromatography, mass spectrometry, immunoreactivity assessment, and biodistribution studies in mice bearing TEM-1 positive tumors were performed. A multi-compartment pharmacokinetic model was used to fit the data and a global pharmacokinetic model was developed to illustrate the effect of liver capture and immunoreactivity loss. Organ absorbed doses in mice were calculated from biodistribution results. A loss of immunoreactivity was observed with the highest DOTA per 1C1m-Fc ratio. Except for the spleen and bone, an increase of DOTA per 1C1m-Fc ratio resulted in an increase of liver uptake and absorbed dose and a decrease of uptake in tumor and other tissues. Pharmacokinetic models correlated these results. The number of DOTA per antibody played a determining role in tumor targeting. One DOTA per 1C1m-Fc gave the best pharmacokinetic behavior for a future translation of [177Lu]Lu-1C1m-Fc in patients.

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Section: Discussionmentioning

confidence: 70%

Impact of DOTA Conjugation on Pharmacokinetics and Immunoreactivity of [177Lu]Lu-1C1m-Fc, an Anti TEM-1 Fusion Protein Antibody in a TEM-1 Positive Tumor Mouse Model

et al. 2021

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“…Endosialin/TEM-1 is a marker of tumour-associated stromal fibroblasts and pericytes [ 30 ]. Radiolabelling and full preclinical characterization of [ 111 In]CHX-DTPA-scFv78-Fc were reported in [ 24 ]. This radiopharmaceutical has not yet been translated into clinic.…”

Section: Methodsmentioning

confidence: 99%

“…Biodistribution of [ 111 In]CHX-DTPA-scFv78-Fc was assessed in female common gamma KO Balb/c mice, grafted with the human TEM-1-positive Ewing’s sarcoma RD-ES. Mice were killed 4, 24, 48 and 96 h after intravenous radiopharmaceutical injection (3–5 mice per group) [ 24 ]. For both experiments, organs were harvested and weighed, and radioactivity was counted in a calibrated gamma-counter (Wallac Wizard, PerkinElmer).…”

Section: Methodsmentioning

confidence: 99%

“…The aim of the present study was twofold. Firstly, we compared five reference computational methods for AD extrapolations from mice to humans, using two different radiopharmaceuticals, namely [ 68 Ga]NODAGA-RGDyK and [ 111 In]CHX-DTPA-scFv78-Fc, that were previously characterized in vitro and in vivo in our centre [ 24 , 25 ]. In the second instance, for one of these radiopharmaceuticals, i.e.…”

Section: Introductionmentioning

confidence: 99%

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Comparison of absorbed dose extrapolation methods for mouse-to-human translation of radiolabelled macromolecules

et al. 2022

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Background Extrapolation of human absorbed doses (ADs) from biodistribution experiments on laboratory animals is used to predict the efficacy and toxicity profiles of new radiopharmaceuticals. Comparative studies between available animal-to-human dosimetry extrapolation methods are missing. We compared five computational methods for mice-to-human AD extrapolations, using two different radiopharmaceuticals, namely [111In]CHX-DTPA-scFv78-Fc and [68Ga]NODAGA-RGDyK. Human organ-specific time-integrated activity coefficients (TIACs) were derived from biodistribution studies previously conducted in our centre. The five computational methods adopted are based on simple direct application of mice TIACs to human organs (M1), relative mass scaling (M2), metabolic time scaling (M3), combined mass and time scaling (M4), and organ-specific allometric scaling (M5), respectively. For [68Ga]NODAGA-RGDyK, these methods for mice-to-human extrapolations were tested against the ADs obtained on patients, previously published by our group. Lastly, an average [68Ga]NODAGA-RGDyK-specific allometric parameter αnew was calculated from the organ-specific biological half-lives in mouse and humans and retrospectively applied to M3 and M4 to assess differences in human AD predictions with the α = 0.25 recommended by previous studies. Results For both radiopharmaceuticals, the five extrapolation methods showed significantly different AD results (p < 0.0001). In general, organ ADs obtained with M3 were higher than those obtained with the other methods. For [68Ga]NODAGA-RGDyK, no significant differences were found between ADs calculated with M3 and those obtained directly on human subjects (H) (p = 0.99; average M3/H AD ratio = 1.03). All other methods for dose extrapolations resulted in ADs significantly different from those calculated directly on humans (all p ≤ 0.0001). Organ-specific allometric parameters calculated using combined experimental [68Ga]NODAGA-RGDyK mice and human biodistribution data varied significantly. ADs calculated with M3 and M4 after the application of αnew = 0.17 were significantly different from those obtained by the application of α = 0.25 (both p < 0.001). Conclusions Available methods for mouse-to-human dosimetry extrapolations provided significantly different results in two different experimental models. For [68Ga]NODAGA-RGDyK, the best approximation of human dosimetry was shown by M3, applying a metabolic scaling to the mouse organ TIACs. The accuracy of more refined extrapolation algorithms adopting model-specific metabolic scaling parameters should be further investigated.

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“…TEM-1 was thus considered by the research community as a potential therapeutic target, and several anti-TEM-1 antibodies have been developed [ 13 ]. Antibody drug conjugates [ 14 , 15 ], ScFv-Fc fragments for optical imaging and radionuclide imaging [ 16 , 17 , 18 ] and a radiolabeled humanized anti-TEM-1 monoclonal antibody MORAb-004 [ 19 , 20 ] have been tested preclinically. Currently, no clinical trial has been conducted with radiopharmaceuticals targeting TEM-1.…”

Section: Introductionmentioning

confidence: 99%

Copper-64-Labeled 1C1m-Fc, a New Tool for TEM-1 PET Imaging and Prediction of Lutetium-177-Labeled 1C1m-Fc Therapy Efficacy and Safety

Delage

Gnesin

Prior

et al. 2021

Cancers

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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.

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Preclinical Evaluation and Dosimetry of [111In]CHX-DTPA-scFv78-Fc Targeting Endosialin/Tumor Endothelial Marker 1 (TEM1)

Cited by 16 publications

References 55 publications

Impact of DOTA Conjugation on Pharmacokinetics and Immunoreactivity of [177Lu]Lu-1C1m-Fc, an Anti TEM-1 Fusion Protein Antibody in a TEM-1 Positive Tumor Mouse Model

Impact of DOTA Conjugation on Pharmacokinetics and Immunoreactivity of [177Lu]Lu-1C1m-Fc, an Anti TEM-1 Fusion Protein Antibody in a TEM-1 Positive Tumor Mouse Model

Comparison of absorbed dose extrapolation methods for mouse-to-human translation of radiolabelled macromolecules

Copper-64-Labeled 1C1m-Fc, a New Tool for TEM-1 PET Imaging and Prediction of Lutetium-177-Labeled 1C1m-Fc Therapy Efficacy and Safety

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