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Phase I Clinical Evaluation of Designed Ankyrin Repeat Protein [^99mTc]Tc(CO)₃-(HE)₃-Ec1 for Visualization of EpCAM-Expressing Lung Cancer.

ABSTRACT: A high level of EpCAM overexpression in lung cancer makes this protein a promising target for targeted therapy. Radionuclide visualization of EpCAM expression would facilitate the selection of patients potentially benefiting from such treatment. Single-photon computed tomography (SPECT) using ^99mTc-labeled engineered scaffold protein DARPin Ec1 has shown its effectiveness in imaging tumors with overexpression of EpCAM in preclinical studies, providing high contrast just a few hours after injection. This first-in-human study aimed to evaluate the safety and distribution of [^99mTc]Tc(CO)₃-(HE)₃-Ec1 in patients with primary lung cancer. Twelve lung cancer patients were injected with 300.7 ± 103.2 MBq of [^99mTc]Tc(CO)₃-(HE)₃-Ec1. Whole-body planar imaging (at 2, 4, 6 and 24 h after injection) and SPECT/CT of the lung (at 2, 4, and 6 h) were performed. The patients' vital signs and possible side effects were monitored up to 7 days after injection. The patients tolerated the injection of [^99mTc]Tc(CO)₃-(HE)₃-Ec1 well, and their somatic condition remained normal during the entire follow-up period. There were no abnormalities in blood and urine tests after injection of [^99mTc]Tc(CO)₃-(HE)₃-Ec1. The highest absorbed doses were in the kidneys, liver, pancreas, thyroid, gallbladder wall, and adrenals. There was also a relatively high accumulation of [^99mTc]Tc(CO)₃-(HE)₃-Ec1 in the small and large intestines, pancreas and thyroid. According to the SPECT/CT, accumulation of [^99mTc]Tc(CO)₃-(HE)₃-Ec1 in the lung tumor was found in all patients included in the study. Intensive accumulation of [^99mTc]Tc(CO)₃-(HE)₃-Ec1 was also noted in regional metastases. [^99mTc]Tc(CO)₃-(HE)₃-Ec1 can potentially be considered a diagnostic tracer for imaging EpCAM expression in lung cancer patients and other tumors with overexpression of EpCAM.

SUBMITTER: Zelchan R

PROVIDER: S-EPMC11353007 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Phase I Clinical Evaluation of Designed Ankyrin Repeat Protein [99mTc]Tc(CO)3-(HE)3-Ec1 for Visualization of EpCAM-Expressing Lung Cancer.

Zelchan Roman R Chernov Vladimir V Medvedeva Anna A Rybina Anastasia A Bragina Olga O Mishina Elizaveta E Larkina Mariia M Varvashenya Ruslan R Fominykh Anastasia A Schulga Alexey A Konovalova Elena E Vorobyeva Anzhelika A Orlova Anna A Tashireva Liubov L Deyev Sergey M SM Tolmachev Vladimir V

Cancers 20240810 16

A high level of EpCAM overexpression in lung cancer makes this protein a promising target for targeted therapy. Radionuclide visualization of EpCAM expression would facilitate the selection of patients potentially benefiting from such treatment. Single-photon computed tomography (SPECT) using 99mTc-labeled engineered scaffold protein DARPin Ec1 has shown its effectiveness in imaging tumors with overexpression of EpCAM in preclinical studies, providing high contrast just a few hours af ...[more]

PMID: 39199590

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Project description:PurposeSentinel lymph node (SLN) biopsy has proven to reliably stage the clinically negative neck in early-stage oral squamous cell carcinoma (OSCC). [99mTc]Tc-tilmanocept may be of benefit in OSCC with complex lymphatic drainage patterns and close spatial relation to SLNs.MethodsA prospective within-patient evaluation study was designed to compare [99mTc]Tc-tilmanocept with [99mTc]Tc-nanocolloid for SLN detection. A total of 20 patients with early-stage OSCC were included, who underwent lymphoscintigraphy with both tracers. Both lymphoscintigraphic images of each patient were evaluated for SLN detection and radiotracer distribution at 2-4 h post-injection.ResultsThe injection site's remaining radioactivity was significantly lower for [99mTc]Tc-tilmanocept (29.9%), compared with [99mTc]Tc-nanocolloid (60.9%; p < 0.001). Radioactive uptake in SLNs was significantly lower for [99mTc]Tc-tilmanocept (1.95%) compared with [99mTc]Tc-nanocolloid (3.16%; p = 0.010). No significant difference was seen in SLN to injection site ratio in radioactivity between [99mTc]Tc-tilmanocept (0.066) and [99mTc]Tc-nanocolloid (0.054; p = 0.232). A median of 3.0 and 2.5 SLNs were identified with [99mTc]Tc-tilmanocept and [99mTc]Tc-nanocolloid, respectively (p = 0.297). Radioactive uptake in higher echelon nodes was not significantly different between [99mTc]Tc-tilmanocept (0.57%) and [99mTc]Tc-nanocolloid (0.86%) (p = 0.052). A median of 2.0 and 2.5 higher echelon nodes was identified with [99mTc]Tc-tilmanocept and [99mTc]Tc-nanocolloid, respectively (p = 0.083).Conclusion[99mTc]Tc-tilmanocept had a higher injection site clearance, but at the same time a lower uptake in the SLN, resulting in an SLN to injection site ratio, which was not significantly different from [99mTc]Tc-nanocolloid. The relatively low-radioactive uptake in SLNs of [99mTc]Tc-tilmanocept may limit intraoperative detection of SLNs, but can be overcome by a higher injection dose.

Project description:PurposeThe clinical success non-invasive imaging of CXCR4 expression using [68 Ga]Ga-PentixaFor-PET warrants an expansion of the targeting concept towards conventional scintigraphy/SPECT with their lower cost and general availability. To this aim, we developed and comparatively evaluated a series of 99mTc-labeled cyclic pentapeptides based on the PentixaFor scaffold.MethodsSix mas3-conjugated CPCR4 analogs with different 4-aminobenzoic acid (Abz)-D-Ala-D-Arg-aa3 linkers (L1-L6) as well as the corresponding HYNIC- and N4-analogs of L6-CPCR4 were synthesized via standard SPPS. Competitive binding studies (IC50 and IC50inv) were carried out using Jurkat T cell lymphoma cells and [125I]FC-131 as radioligand. Internalization kinetics were investigated using hCXCR4-overexpressing Chem-1 cells. Biodistribution studies and small animal SPECT/CT imaging (1 h p.i.) were carried out using Jurkat xenograft bearing CB17/SCID mice. Based on the preclinical results, [99mTc]Tc-N4-L6-CPCR4 ([99mTc]Tc-PentixaTec) was selected for an early translation to the human setting. Five patients with hematologic malignancies underwent [99mTc]Tc-N4-L6-CPCR4 SPECT/planar imaging with individual dosimetry.ResultsOf the six mas3-conjugated peptides, mas3-L6-CPCR4 (mas3-dap-r-a-Abz-CPCR4) showed the highest CXCR4 affinity (IC50 = 5.0 ± 1.3 nM). Conjugation with N4 (N4-L6-CPCR4) further improved hCXCR4 affinity to 0.6 ± 0.1 nM. [99mTc]Tc-N4-L6-CPCR4 also showed the most efficient internalization (97% of total cellular activity at 2 h) and the highest tumor accumulation (8.6 ± 1.3% iD/g, 1 h p.i.) of the compounds investigated. Therefore, [99mTc]Tc-N4-L6-CPCR4 (termed [99mTc]Tc-PentixaTec) was selected for first-in-human application. [99mTc]Tc-PentixaTec was well tolerated, exhibits a favorable biodistribution and dosimetry profile (2.1-3.4 mSv per 500 MBq) and excellent tumor/background ratios in SPECT and planar imaging.ConclusionThe successive optimization of the amino acid composition of the linker structure and the N-terminal 99mTc-labeling strategies (mas3 vs HYNIC vs N4) has provided [99mTc]Tc-PentixaTec as a novel, highly promising CXCR4-targeted SPECT agent for clinical application. With its excellent CXCR4 affinity, efficient internalization, high uptake in CXCR4-expressing tissues, suitable clearance/biodistribution characteristics, and favorable human dosimetry, it holds great potential for further clinical use.

Dataset Information

Phase I Clinical Evaluation of Designed Ankyrin Repeat Protein [^99mTc]Tc(CO)₃-(HE)₃-Ec1 for Visualization of EpCAM-Expressing Lung Cancer.

Publications

Phase I Clinical Evaluation of Designed Ankyrin Repeat Protein [<sup>99m</sup>Tc]Tc(CO)<sub>3</sub>-(HE)<sub>3</sub>-Ec1 for Visualization of EpCAM-Expressing Lung Cancer.

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