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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.

ABSTRACT: 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.

SUBMITTER: Delage JA

PROVIDER: S-EPMC7828678 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Delage Judith Anna JA Faivre-Chauvet Alain A Barbet Jacques J Fierle Julie Katrin JK Schaefer Niklaus N Coukos George G Viertl David D Dunn Steven Mark SM Gnesin Silvano S Prior John O JO

Pharmaceutics 20210113 1

1C1m-Fc, an anti-tumor endothelial marker 1 (TEM-1) scFv-Fc fusion protein antibody, was previously successfully radiolabeled with <sup>177</sup>Lu. 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 si ...[more]

PMID: 33451158

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Project description:Recently, great interest has been gained regarding fibroblast activation protein (FAP) as an excellent target for theranostics. Several FAP inhibitor molecules such as [68Ga]Ga-labelled FAPI-02, 04, 46, and DOTA.SA.FAPi have been introduced and are highly promising molecular targets from the imaging point of view. FAP inhibitors introduced via bifunctional DOTA and DOTAGA chelators offer the possibility to complex Lutetium-177 due to an additional coordination site, and are suitable for theranostic applications owing to the increased tumor accumulation and prolonged tumor retention time. However, for therapeutic applications, very little has been accomplished, mainly due to residence times of the compounds. In an attempt to develop a promising therapeutic radiopharmaceutical, the present study aimed to evaluate and compare the biodistribution, pharmacokinetics, and dosimetry of [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 in patients with various cancers. The FAPi agents, [177Lu]Lu-DOTA.SA.FAPi and [177Lu]Lu-DOTAGA.(SA.FAPi)2, were administered in two different groups of patients. Three patients (mean age-50 years) were treated with a median cumulative activity of 2.96 GBq (IQR: 2.2-3 GBq) [177Lu]Lu-DOTA.SA.FAPi and seven (mean age-51 years) were treated with 1.48 GBq (IQR: 0.6-1.5) of [177Lu]Lu-DOTAGA.(SA.FAPi)2. Patients in both the groups underwent serial imaging whole-body planar and SPECT/CT scans that were acquired between 1 h and 168 h post-injection (p.i.). The residence time and absorbed dose estimate in the source organs and tumor were calculated using OLINDA/EXM 2.2 software. Time versus activity graphs were plotted to determine the effective half-life (Te) in the whole body and lesions for both the radiotracers. Physiological uptake of [177Lu]Lu-DOTA.SA.FAPi was observed in the kidneys, colon, pancreas, liver, gall bladder, oral mucosa, lacrimal glands, and urinary bladder contents. Physiological biodistribution of [177Lu]Lu-DOTAGA.(SA.FAPi)2 involved liver, gall bladder, colon, pancreas, kidneys, and urinary bladder contents, lacrimal glands, oral mucosa, and salivary glands. In the [177Lu]Lu-DOTA.SA.FAPi group, the highest absorbed doses were noted in the kidneys (0.618 ± 0.015 Gy/GBq), followed by the colon (right colon: 0.472 Gy/GBq and left colon: 0.430 Gy/GBq). In the [177Lu]Lu-DOTAGA.(SA.FAPi)2 group, the colon received the highest absorbed dose (right colon: 1.160 Gy/GBq and left colon: 2.870 Gy/GBq), and demonstrated a significantly higher mean absorbed dose than [177Lu]Lu-DOTA.SA.FAPi (p < 0.011). [177Lu]Lu-DOTAGA.(SA.FAPi)2 had significantly longer median whole-body Te compared to that of [177Lu]Lu-DOTA.SA.FAPi [46.2 h (IQR: 38.5-70.1) vs. 23.1 h (IQR: 17.8-31.5); p-0.0167]. The Te of tumor lesions was significantly higher for [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi [86.6 h (IQR: 34.3-94.6) vs. 14 h (IQR: 12.8-15.5); p-0.0004]. The median absorbed doses to the lesions were 0.603 (IQR: 0.230-1.810) Gy/GBq and 6.70 (IQR: 3.40-49) Gy/GBq dose per cycle in the [177Lu]Lu-DOTA.SA.FAPi, and [177Lu]Lu-DOTAGA.(SA.FAPi)2 groups, respectively. The first clinical dosimetry study demonstrated significantly higher tumor absorbed doses with [177Lu]Lu-DOTAGA.(SA.FAPi)2 compared to [177Lu]Lu-DOTA.SA.FAPi. [177Lu]Lu-DOTAGA.(SA.FAPi)2 is safe and unveiled new frontiers to treat various end-stage cancer patients with a theranostic approach.

Project description:BACKGROUND:Survival and linear-quadratic model fitting parameters implemented in treatment planning for targeted radionuclide therapy depend on accurate cellular dosimetry. Therefore, we have built a refined cellular dosimetry model for [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE) in vitro experiments, accounting for specific cell morphologies and sub-cellular radioactivity distributions. METHODS:Time activity curves were measured and modeled for medium, membrane-bound, and internalized activity fractions over 6?days. Clonogenic survival assays were performed at various added activities (0.1-2.5?MBq/ml). 3D microscopy images (stained for cytoplasm, nucleus, and Golgi) were used as reference for developing polygonal meshes (PM) in 3DsMax to accurately render the cellular and organelle geometry. Absorbed doses to the nucleus per decay (S values) were calculated for 3 cellular morphologies: spheres (MIRDcell), truncated cone-shaped constructive solid geometry (CSG within MCNP6.1), and realistic PM models, using Geant4-10.03. The geometrical set-up of the clonogenic survival assays was modeled, including dynamic changes in proliferation, proximity variations, and cell death. The absorbed dose to the nucleus by the radioactive source cell (self-dose) and surrounding source cells (cross-dose) was calculated applying the MIRD formalism. Finally, the correlation between absorbed dose and survival fraction was fitted using a linear dose-response curve (high ?/? or fast sub-lethal damage repair half-life) for different assumptions, related to cellular shape and localization of the internalized fraction of activity. RESULTS:The cross-dose, depending on cell proximity and colony formation, is a minor (15%) contributor to the total absorbed dose. Cellular volume (inverse exponential trend), shape modeling (up to 65%), and internalized source localization (up to +?149% comparing cytoplasm to Golgi) significantly influence the self-dose to nucleus. The absorbed dose delivered to the nucleus during a clonogenic survival assay is 3-fold higher with MIRDcell compared to the polygonal mesh structures. Our cellular dosimetry model indicates that 177Lu-DOTATATE treatment might be more effective than suggested by average spherical cell dosimetry, predicting a lower absorbed dose for the same cellular survival. Dose-rate effects and heterogeneous dose delivery might account for differences in dose-response compared to x-ray irradiation. CONCLUSION:Our results demonstrate that modeling of cellular and organelle geometry is crucial to perform accurate in vitro dosimetry.

Project description:PurposeAfter peptide receptor radionuclide therapy (PRRT), renal toxicity may occur, particular in PRRT with (90)Y-labelled somatostatin analogues. Risk factors have been identified for increased probability of developing renal toxicity after PRRT, including hypertension, diabetes and age. We investigated the renal function over time, the incidence of nephrotoxicity and associated risk factors in patients treated with PRRT with [(177)Lu-DOTA(0),Tyr(3)]-Octreotate ((177)Lu-Octreotate). Also, radiation dose to the kidneys was evaluated and compared with the accepted dose limits in external beam radiotherapy and PRRT with (90)Y-radiolabelled somatostatin analogues.MethodsThe annual decrease in creatinine clearance (CLR) was determined in 209 Dutch patients and the incidence of grade 3 or 4 renal toxicity (according to CTCAE v4.03) was evaluated in 323 patients. Risk factors were analysed using a nonlinear mixed effects regression model. Also, radiation doses to the kidneys were calculated and their association with high annual decrease in renal function were analysed.ResultsOf the 323 patients, 3 (1 %) developed (subacute) renal toxicity grade 2 (increase in serum creatinine >1.5 - 3.0 times baseline or upper limit of normal). No subacute grade 3 or 4 nephrotoxicity was observed. The estimated average baseline CLR (± SD) was 108 ± 5 ml/min and the estimated average annual decrease in CLR (± SD) was 3.4 ± 0.4 %. None of the risk factors (hypertension, diabetes, high cumulative injected activity, radiation dose to the kidneys and CTCAE grade) at baseline had a significant effect on renal function over time. The mean absorbed kidney dose in 228 patients was 20.1 ± 4.9 Gy.ConclusionNephrotoxicity in patients treated with (177)Lu-octreotate was low. No (sub)acute grade 3 or 4 renal toxicity occurred and none of the patients had an annual decrease in renal function of >20 %. No risk factors for renal toxicity could be identified. Our data support the idea that the radiation dose threshold, adopted from external beam radiotherapy and PRRT with (90)Y-labelled somatostatin analogues, does not seem valid for PRRT with (177)Lu-octreotate.

Dataset Information

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.

Publications

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

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Dataset Information

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.

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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.