| 1. |
- Bragina, Olga D., et al.
(författare)
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The Evolution of Targeted Radionuclide Diagnosis of HER2-Positive Breast Cancer
- 2022
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Ingår i: ACTA NATURAE. - : RUSSIAN FEDERATION AGENCY SCIENCE & INNOVATION. - 2075-8251 .- 2075-8243. ; 14:2, s. 4-15
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Forskningsöversikt (refereegranskat)abstract
- This review examines the evolution of the radionuclide diagnosis of HER2-positive breast cancer using various compounds as a targeting module in clinical practice: from full-length antibodies to a new group of small synthetic proteins called alternative scaffold proteins. This topic is of especial relevance today in view of the problems attendant to the detection of breast cancer with HER2/neu overexpression, which, in most cases, introduce errors in the treatment of patients. The results of clinical studies of radiopharmaceuticals based on affibody molecules, ADAPTs, and DARPins for SPECT and PET have demonstrated good tolerability of the compounds, their rapid excretion from the body, and the possibility to differentiate tumor sites depending on the HER2/neu status. This indicates that targeted radionuclide diagnosis holds promise and the need to continue research in this direction.
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| 2. |
- Bragina, Olga, et al.
(författare)
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Direct Intra-Patient Comparison of Scaffold Protein-Based Tracers, [99mTc]Tc-ADAPT6 and [99mTc]Tc-(HE)3-G3, for Imaging of HER2-Positive Breast Cancer
- 2023
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Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 15:12
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary The receptor HER2 is overexpressed in some breast cancers. Tumours with a high HER2 expression can be successfully treated with the antibodies trastuzumab and pertuzumab. The radionuclide imaging of HER2 in disseminated cancer could help to select patients for treatment using these antibodies. Novel radiolabelled small-sized tracers, scaffold proteins, have shown excellent imaging properties in preclinical studies. The scaffold proteins [Tc-99m]Tc-ADAPT6 and DARPin [Tc-99m]Tc-(HE)(3)-G3 have been found to be safe in Phase I clinical trials. They showed promising results in the imaging of HER2. In this study, we compared the distribution of both tracers in the same patients with breast cancer to evaluate whether one of them has any decisive advantage. We found that both tracers provide an excellent visualization of tumours, but the accumulation of [Tc-99m]Tc-ADAPT6 in tumours is higher. The data from this study are essential for researchers developing imaging agents. Previous Phase I clinical evaluations of the radiolabelled scaffold proteins [Tc-99m]Tc-ADAPT6 and DARPin [Tc-99m]Tc-(HE)(3)-G3 in breast cancer patients have demonstrated their safety and indicated their capability to discriminate between HER2-positive and HER2-negative tumours. The objective of this study was to compare the imaging of HER2-positive tumours in the same patients using [Tc-99m]Tc-ADAPT6 and [Tc-99m]Tc-(HE)(3)-G3. Eleven treatment-naive female patients (26-65 years) with HER2-positive primary and metastatic breast cancer were included in the study. Each patient was intravenously injected with [Tc-99m]Tc-ADAPT6, followed by an [Tc-99m]Tc-(HE)(3)-G3 injection 3-4 days later and chest SPECT/CT was performed. All primary tumours were clearly visualized using both tracers. The uptake of [Tc-99m]Tc-ADAPT6 in primary tumours (SUVmax = 4.7 & PLUSMN; 2.1) was significantly higher (p < 0.005) than the uptake of [Tc-99m]Tc-(HE)(3)-G3 (SUVmax = 3.5 & PLUSMN; 1.7). There was no significant difference in primary tumour-to-contralateral site values for [Tc-99m]Tc-ADAPT6 (15.2 & PLUSMN; 7.4) and [Tc-99m]Tc-(HE)(3)-G3 (19.6 & PLUSMN; 12.4). All known lymph node metastases were visualized using both tracers. The uptake of [Tc-99m]Tc-ADAPT6 in all extrahepatic soft tissue lesions was significantly (p < 0.0004) higher than the uptake of [Tc-99m]Tc-(HE)(3)-G3. In conclusion, [Tc-99m]Tc-ADAPT6 and [Tc-99m]Tc-(HE)(3)-G3 are suitable for the visualization of HER2-positive breast cancer. At the selected time points, [Tc-99m]Tc-ADAPT6 has a significantly higher uptake in soft tissue lesions, which might be an advantage for the visualization of small metastases.
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| 3. |
- Bragina, Olga, et al.
(författare)
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Evaluation of Approaches for the Assessment of HER2 Expression in Breast Cancer by Radionuclide Imaging Using the Scaffold Protein [99mTc]Tc-ADAPT6
- 2024
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 16:4
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Tidskriftsartikel (refereegranskat)abstract
- Due to its small size and high affinity binding, the engineered scaffold protein ADAPT6 is a promising targeting probe for radionuclide imaging of human epidermal growth factor receptor type 2 (HER2). In a Phase I clinical trial, [Tc-99m]Tc-ADAPT6 demonstrated safety, tolerability and capacity to visualize HER2 expression in primary breast cancer. In this study, we aimed to select the optimal parameters for distinguishing between breast cancers with high and low expression of HER2 using [Tc-99m]Tc-ADAPT6 in a planned Phase II study. HER2 expression was evaluated in primary tumours and metastatic axillary lymph nodes (mALNs). SPECT/CT imaging of twenty treatment-naive breast cancer patients was performed 2 h after injection of [Tc-99m]Tc-ADAPT6. The imaging data were compared with the data concerning HER2 expression obtained by immunohistochemical evaluation of samples obtained by core biopsy. Maximum Standard Uptake Values (SUVmax) afforded the best performance for both primary tumours and mALNs (areas under the receiver operating characteristic curve (ROC AUC) of 1.0 and 0.97, respectively). Lesion-to-spleen ratios provided somewhat lower performance. However, the ROC AUCs were still over 0.90 for both primary tumours and mALNs. Thus, lesion-to-spleen ratios should be further evaluated to find if these could be applied to imaging using stand-alone SPECT cameras that do not permit SUV calculations.
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| 4. |
- Bragina, Olga, et al.
(författare)
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Phase I clinical evaluation of 99mTc-labeled Affibody molecule for imaging HER2 expression in breast cancer
- 2023
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Ingår i: Theranostics. - : Ivyspring International Publisher. - 1838-7640. ; 13:14, s. 4858-4871
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Tidskriftsartikel (refereegranskat)abstract
- The determination of tumor human epidermal growth factor receptor type 2 (HER2) status is of increasing importance with the recent approval of more efficacious HER2-targeted treatments. There is a lack of suitable methods for clinical in vivo HER2 expression assessment. Affibody molecules are small affinity proteins ideal for imaging detection of receptors, which are engineered using a small (molecular weight 6.5 kDa) nonimmunoglobulin scaffold. Labeling of Affibody molecules with positron emitters enabled the development of sensitive and specific agents for molecular imaging. The development of probes for SPECT would permit the use of Affibody-based imaging in regions where PET is not available. In this first-in-human study, we evaluated the safety, biodistribution, and dosimetry of the Tc-99m-ZHER2:41071 Affibody molecule developed for SPECT/CT imaging of HER2 expression.Methods: Thirty-one patients with primary breast cancer were enrolled and divided into three cohorts (injected with 500, 1000, or 1500 mu g ZHER2:41071) comprising at least five patients with high (positive) HER2 tumor expression (IHC score 3+ or 2+ and ISH positive) and five patients with low (IHC score 2+ or 1+ and ISH negative) or absent HER2 tumor expression. Patients were injected with 451 +/- 71 MBq Tc-99m-ZHER2:4107. Planar scintigraphy was performed after 2, 4, 6 and 24 h, and SPECT/CT imaging followed planar imaging 2, 4 and 6 h after injection.Results: Injections of Tc-99m-ZHER2:41071 were well tolerated and not associated with adverse events. Normal organs with the highest accumulation were the kidney and liver. The effective dose was 0.019 +/- 0.004 mSv/MBq. Injection of 1000 mu g provided the best standard discrimination between HER2-positive and HER2-low or HER2-negative tumors 2 h after injection (SUVmax 16.9 +/- 7.6 vs. 3.6 +/- 1.4, p < 0.005). The Tc-99m-ZHER2:41071 uptake in HER2-positive lymph node metastases (SUVmax 6.9 +/- 2.4, n = 5) was significantly (p < 0.05) higher than that in HER2-low/negative lymph nodes (SUVmax 3.5 +/- 1.2, n = 4). Tc-99m-ZHER2:41071 visualized hepatic metastases in a patient with liver involvement.Conclusions: Injections of Tc-99m-ZHER2:41071 appear safe and exhibit favorable dosimetry. The protein dose of 1000 mu g provides the best discrimination between HER2-positive and HER2-low/negative expression of HER2 according to the definition used for current HER2-targeting drugs.
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| 5. |
- Bragina, Olga, et al.
(författare)
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Phase I study of 99mTc-ADAPT6, a scaffold protein-based probe for visualization of HER2 expression in breast cancer
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Radionuclide molecular imaging of human epidermal growth factor (HER2) expression may be helpful to stratify breast and gastroesophageal cancer patients for HER2-targeting therapies. ADAPTs (albumin-binding domain derived affinity proteins) are a new type of small (46-59 amino acids) proteins useful as probes for molecular imaging. The aim of this first in-human study was to evaluate biodistribution, dosimetry, and safety of HER2-specific 99mTc-ADAPT6.METHODS. Twenty-two patients with HER2-positive (n=11) or HER2-negative (n=11) primary breast cancer were intravenously injected with 385125 MBq. The injected amount of protein was either 500 μg (n=11) or 1000 μg (n=11). Planar scintigraphy followed by SPECT imaging was performed after 2, 4, 6 and 24 h. An additional cohort received a dose of 250 μg, and the planar scintigraphy followed by SPECT imaging was performed after 2 h only.RESULTS. Injection of 99mTc-ADAPT6 was well tolerated for all doses evaluated in the study, and was not associated with any adverse effects. 99mTc-ADAPT6 cleared rapidly from the blood and the majority of tissues. The normal organs with the highest accumulation were kidney, liver and lung. The effective doses were determined to 0.0090.002 and 0.0100.003 mSv/MBq when injecting protein amounts of 500 and 1000 μg, respectively. Injection of 500 μg resulted in excellent discrimination between HER2-positive and HER2-negative tumors already 2 h after injection (tumor-to-contralateral breast ratio was 3719 vs 52, p < 0.01). The tumor-to-contralateral breast ratios for HER2-positive tumors were significantly (p < 0.5) higher for the injected mass of 500 μg than for both 250 and 1000 μg. In one patient, the imaging using 99mTc-ADAPT6 revealed three bone metastases, which were not found at the time of diagnosis by CT or 99mTcpyrophosphate bone scan. MRI imaging confirmed this finding.CONCLUSION. Injections of 99mTc-ADAPT6 are safe and associated with low absorbed and effective doses. A protein dose of 500 μg is preferable for discrimination between tumors with high and low expression of HER2. 99mTc-ADAPT6 is a promising imaging probe for the stratification of patients for HER2-targeting therapy.
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| 6. |
- Bragina, Olga, et al.
(författare)
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Phase I study of 99mTc-ADAPT6, a scaffold protein-based probe for visualization of HER2 expression in breast cancer
- 2021
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 62:4, s. 493-499
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Tidskriftsartikel (refereegranskat)abstract
- Radionuclide molecular imaging of human epidermal growth factor (HER2) expression may be helpful to stratify breast and gastroesophageal cancer patients for HER2-targeting therapies. ADAPTs (albumin-binding domain derived affinity proteins) are a new type of small (46-59 amino acids) proteins useful as probes for molecular imaging. The aim of this first-in-human study was to evaluate biodistribution, dosimetry, and safety of the HER2-specific 99mTc-ADAPT6.METHODS: Twenty-nine patients with primary breast cancerwere included. In 22 patients with HER2-positive (n = 11) or HER2-negative (n = 11) histopathology an intravenous injection with 385±125 MBq 99mTc-ADAPT6 was performed, randomized to an injected protein mass of either 500 µg (n = 11) or 1000 µg (n = 11). Planar scintigraphy followed by SPECT imaging was performed after 2, 4, 6 and 24 h. An additional cohort (n = 7) was injected with 165±29 MBq (injected protein mass 250 µg) and imaging was performed after 2 h only.RESULTS: Injections of 99mTc-ADAPT6 at all injected mass levels were well tolerated and not associated with adverse effects. 99mTc-ADAPT6 cleared rapidly from blood and most other tissues. The normal organs with the highest accumulation were kidney, liver and lung. Effective doses were 0.009±0.002 and 0.010±0.003 mSv/MBq for injected protein masses of 500 and 1000 µg, respectively. Injection of 500 µg resulted in excellent discrimination between HER2-positive and HER2-negative tumors already 2 h after injection (tumor-to-contralateral breast ratio was 37±19 vs 5±2, p<0.01). The tumor-to-contralateral breast ratios for HER2-positive tumors were significantly (p<0.05) higher for injected mass of 500 µg than for both 250 and 1000 µg.CONCLUSION: Injections of 99mTc-ADAPT6 are safe and associated with low absorbed and effective doses. Protein dose of 500 µg is preferable for discrimination between tumors with high and low expression of HER2. Further studies are justified to evaluate if 99mTc-ADAPT6 can be used as an imaging probe for stratification of patients for HER2-targeting therapy in the areas where PET imaging is not readily available.
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| 7. |
- Bragina, Olga, et al.
(författare)
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Phase I Trial of 99mTc-(HE)3-G3, a DARPin-Based Probe for Imaging of HER2 Expression in Breast Cancer
- 2022
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 63:4, s. 528-535
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Tidskriftsartikel (refereegranskat)abstract
- Radionuclide molecular imaging of human epidermal growth factor receptor type 2 (HER2) expression may enable a noninvasive discrimination between HER2-positive and HER2-negative breast cancers for stratification of patients for HER2-targeted treatments. DARPin (designed ankyrin repeat proteins) G3 is a small (molecular weight, 14 kDa) scaffold protein with picomolar affinity to HER2. The aim of this first-in-humans study was to evaluate the safety, biodistribution, and dosimetry of 99mTc-(HE)3-G3.Methods: Three cohorts of patients with primary breast cancer (each including at least 4 patients with HER2-negative and 5 patients with HER2-positive tumors) were injected with 1,000, 2,000, or 3,000 μg of 99mTc-(HE)3-G3 (287 ± 170 MBq). Whole-body planar imaging followed by SPECT was performed at 2, 4, 6, and 24 h after injection. Vital signs and possible side effects were monitored during imaging and up to 7 d after injection.Results: All injections were well tolerated. No side effects were observed. The results of blood and urine analyses did not differ before and after studies. 99mTc-(HE)3-G3 cleared rapidly from the blood. The highest uptake was detected in the kidneys and liver followed by the lungs, breasts, and small intestinal content. The hepatic uptake after injection of 2,000 or 3,000 μg was significantly (P < 0.05) lower than the uptake after injection of 1,000 μg. Effective doses did not differ significantly between cohorts (average, 0.011 ± 0.004 mSv/MBq). Tumor–to–contralateral site ratios for HER-positive tumors were significantly (P < 0.05) higher than for HER2-negative at 2 and 4 h after injection.Conclusion: Imaging of HER2 expression using 99mTc-(HE)3-G3 is safe and well tolerated and provides a low absorbed dose burden on patients. This imaging enables discernment of HER2-positive and HER2-negative breast cancer. Phase I study data justify further clinical development of 99mTc-(HE)3-G3.
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| 8. |
- Chernov, Vladimir, et al.
(författare)
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Phase I Clinical Trial Using [Tc-99m]Tc-1-thio-D-glucose for Diagnosis of Lymphoma Patients
- 2022
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 14:6
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Tidskriftsartikel (refereegranskat)abstract
- Similar to [F-18]-FDG, [Tc-99m]Tc-1-thio-D-glucose ([Tc-99m]Tc-TG) also binds to GLUT receptors. The aim of this Phase I study was to evaluate the safety, biodistribution and dosimetry of [Tc-99m]Tc-TG. Twelve lymphoma patients were injected with 729 +/- 102 MBq [Tc-99m]Tc-TG. Whole-body planar imaging was performed in 10 patients at 2, 4, 6 and 24 h after injection. In all 12 patients, SPECT/CT (at 2 h) and SPECT (at 4 and 6 h) imaging was performed. Vital signs and possible side effects were monitored during imaging and up to 7 days after injection. [Tc-99m]Tc-TG injections were well-tolerated and no side effects or alterations in blood and urine analyses data were observed. The highest absorbed dose was in the kidneys and urinary bladder wall, followed by the adrenals, prostate, bone marrow, lungs, myocardium, ovaries, uterus, liver and gall bladder wall. [Tc-99m]Tc-TG SPECT/CT revealed foci of high activity uptake in the lymph nodes of all nine patients with known nodal lesions. Extranodal lesions were detected in all nine cases. In one patient, a lesion in the humerus head, which was not detected by CT, was visualized using [Tc-99m]Tc-TG. Potentially, [Tc-99m]Tc-TG can be considered as an additional diagnostic method for imaging GLUT receptors in lymphoma patients.
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| 9. |
- Chernov, Vladimir, et al.
(författare)
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Phase I Trial of [Tc-99m]Tc-maSSS-PEG(2)-RM26, a Bombesin Analogue Antagonistic to Gastrin-Releasing Peptide Receptors (GRPRs), for SPECT Imaging of GRPR Expression in Malignant Tumors
- 2023
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Ingår i: Cancers. - : MDPI. - 2072-6694. ; 15:6
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Tidskriftsartikel (refereegranskat)abstract
- The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer (PCa) and in hormone-driven breast cancer (BCa). The aim of this phase I clinical trial was to evaluate safety, biodistribution, and dosimetry after the administration of the recently developed GRPR-targeting antagonistic bombesin analogue [Tc-99m]Tc-maSSS-PEG(2)-RM26 in PCa and BCa patients. Planar and whole-body SPECT/CT imaging was performed in six PCa patients and seven BCa patients 2, 4, 6, and 24 h post the intravenous administration of 40 mu g of [Tc-99m]Tc-maSSS-PEG(2)-RM26 (600-700 MBq). No adverse events or pathological changes were observed. The rapid blood clearance of [Tc-99m]Tc-maSSS-PEG(2)-RM26 was observed with predominantly hepatobiliary excretion. The effective doses were 0.0053 +/- 0.0007 for male patients and 0.008 +/- 0.003 mSv/MBq for female patients. The accumulation of [Tc-99m]Tc-maSSS-PEG(2)-RM26 in tumors was observed in four out of six PCa and in seven out of seven BCa patients. In four BCa patients, a high uptake of the agent into the axillary lymph nodes was detected. Immunohistochemistry revealed positive GRPR expression in 60% of primary PCa, 71.4% of BCa tumors, and 50% of examined BCa lymph nodes. In conclusion, a single administration of [Tc-99m]Tc-maSSS-PEG(2)-RM26 was safe and well tolerated. [Tc-99m]Tc-maSSS-PEG(2)-RM26 SPECT may be useful for tumor detection in PCa and BCa patients, pending further studies.
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| 10. |
- Eissler, Nina, et al.
(författare)
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Affibody PET Imaging of HER2-Expressing Cancers as a Key to Guide HER2-Targeted Therapy
- 2024
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Ingår i: Biomedicines. - : MDPI. - 2227-9059. ; 12:5
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Forskningsöversikt (refereegranskat)abstract
- Human epidermal growth factor receptor 2 (HER2) is a major prognostic and predictive marker overexpressed in 15-20% of breast cancers. The diagnostic reference standard for selecting patients for HER2-targeted therapy is based on the analysis of tumor biopsies. Previously patients were defined as HER2-positive or -negative; however, with the approval of novel treatment options, specifically the antibody-drug conjugate trastuzumab deruxtecan, many breast cancer patients with tumors expressing low levels of HER2 have become eligible for HER2-targeted therapy. Such patients will need to be reliably identified by suitable diagnostic methods. Biopsy-based diagnostics are invasive, and repeat biopsies are not always feasible. They cannot visualize the heterogeneity of HER2 expression, leading to a substantial number of misdiagnosed patients. An alternative and highly accurate diagnostic method is molecular imaging with radiotracers. In the case of HER2, various studies demonstrate the clinical utility and feasibility of such approaches. Radiotracers based on Affibody((R)) molecules, small, engineered affinity proteins with a size of similar to 6.5 kDa, are clinically validated molecules with favorable characteristics for imaging. In this article, we summarize the HER2-targeted therapeutic landscape, describe our experience with imaging diagnostics for HER2, and review the currently available clinical data on HER2-Affibody-based molecular imaging as a novel diagnostic tool in breast cancer and beyond.
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| 11. |
- Liu, Yongsheng, et al.
(författare)
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Experimental Therapy of HER2-Expressing Xenografts Using the Second-Generation HER2-Targeting Affibody Molecule 188Re-ZHER2:41071
- 2022
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Ingår i: Pharmaceutics. - : MDPI. - 1999-4923. ; 14:5
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Tidskriftsartikel (refereegranskat)abstract
- HER2-targeted radionuclide therapy might be helpful for the treatment of breast, gastric, and ovarian cancers which have developed resistance to antibody and antibody-drug conjugate-based therapies despite preserved high HER2-expression. Affibody molecules are small targeting proteins based on a non-immunoglobulin scaffold. The goal of this study was to test in an animal model a hypothesis that the second-generation HER2-targeting Affibody molecule 188Re-ZHER2:41071 might be useful for treatment of HER2-expressing malignant tumors. ZHER2:41071 was efficiently labeled with a beta-emitting radionuclide rhenium-188 (188Re). 188Re-ZHER2:41071 demonstrated preserved specificity and high affinity (KD = 5 ± 3 pM) of binding to HER2-expressing cells. In vivo studies demonstrated rapid washout of 188Re from kidneys. The uptake in HER2-expressing SKOV-3 xenografts was HER2-specific and significantly exceeded the renal uptake 4 h after injection and later. The median survival of mice, which were treated by three injections of 16 MBq 188Re-ZHER2:41071 was 68 days, which was significantly longer (<0.0001 in the log-rank Mantel-Cox test) than survival of mice in the control groups treated with vehicle (29 days) or unlabeled ZHER2:41071 (27.5 days). In conclusion, the experimental radionuclide therapy using 188Re-ZHER2:41071 enabled enhancement of survival of mice with human tumors without toxicity to the kidneys, which is the critical organ.
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| 12. |
- Tolmachev, Vladimir, et al.
(författare)
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Direct In Vivo Comparison of Tc-99m-Labeled Scaffold Proteins, DARPin G3 and ADAPT6, for Visualization of HER2 Expression and Monitoring of Early Response for Trastuzumab Therapy
- 2022
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 23:23
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Tidskriftsartikel (refereegranskat)abstract
- Non-invasive radionuclide molecular visualization of human epidermal growth factor receptor type 2 (HER2) can provide stratification of patients for HER2-targeting therapy. This method can also enable monitoring of the response to such therapies, thereby making treatment personalized and more efficient. Clinical evaluation in a phase I study demonstrated that injections of two scaffold protein-based imaging probes, [Tc-99m]Tc-(HE)(3)-G3 and [Tc-99m]Tc-ADAPT6, are safe, well-tolerated and cause a low level of radioactivity in healthy tissue. The goal of this preclinical study was to select the best probe for stratification of patients and response monitoring. Biodistribution of both tracers was compared in mice bearing SKOV-3 xenografts with high HER2 expression or MDA-MB-468 xenografts with very low expression. Changes in accumulation of the probes in SKOV-3 tumors 24 h after injection of trastuzumab were evaluated. Both [Tc-99m]Tc-ADAPT6 and [Tc-99m]Tc-(HE)(3)-G3 permitted high contrast imaging of HER2-expressing tumors and a clear discrimination between tumors with high and low HER2 expression. However, [Tc-99m]Tc-ADAPT6 has better preconditions for higher sensitivity and specificity of stratification. On the other hand, [Tc-99m]Tc-(HE)(3)-G3 is capable of detecting the decrease of HER2 expression on response to trastuzumab therapy only 24 h after injection of the loading dose. This indicates that the [Tc-99m]Tc-(HE)(3)-G3 tracer would be better for monitoring early response to such treatment. The results of this study should be considered in planning of further clinical development of HER2 imaging probes.
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| 13. |
- Vorobyeva, Anzhelika, et al.
(författare)
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Comparative Evaluation of Radioiodine and Technetium-Labeled DARPin 9_29 for Radionuclide Molecular Imaging of HER2 Expression in Malignant Tumors
- 2018
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Ingår i: Contrast Media & Molecular Imaging. - : WILEY-HINDAWI. - 1555-4309 .- 1555-4317.
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Tidskriftsartikel (refereegranskat)abstract
- High expression of human epidermal growth factor receptor 2 (HER2) in breast and gastroesophageal carcinomas is a predictive biomarker for treatment using HER2-targeted therapeutics (antibodies trastuzumab and pertuzumab, antibody-drug conjugate trastuzumab DM1, and tyrosine kinase inhibitor lapatinib). Radionuclide molecular imaging of HER2 expression might permit stratification of patients for HER2-targeting therapies. In this study, we evaluated a new HER2-imaging probe based on the designed ankyrin repeat protein (DARPin) 9_29. DARPin 9_29 was labeled with iodine-125 by direct radioiodination and with [Tc-99m] Tc(CO)(3) using the C-terminal hexahistidine tag. DARPin 9_29 preserved high specificity and affinity of binding to HER2-expressing cells after labeling. Uptake of [I-125] I-DARPin 9_29 and [Tc-99m] Tc(CO)(3)-DARPin 9_29 in HER2-positive SKOV-3 xenografts in mice at 6 h after injection was 3.4 +/- 0.7 % ID/g and 2.9 +/- 0.7 % ID/g, respectively. This was significantly (p < 0.00005) higher than the uptake of the same probes in HER2-negative Ramos lymphoma xenografts, 0.22 +/- 0.09 % ID/g and 0.30 +/- 0.05 % ID/g, respectively. Retention of [I-125] I-DARPin 9_29 in the lung, liver, spleen, and kidneys was appreciably lower compared with [Tc-99m] Tc(CO)(3)-DARPin 9_29, which resulted in significantly (p < 0.05) higher tumor-to-organ ratios. The biodistribution data were confirmed by SPECT/CT imaging. In conclusion, radioiodine is a preferable label for DARPin 9_29.
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| 14. |
- Vorobyeva, Anzhelika, et al.
(författare)
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Optimal composition and position of histidine-containing tags improves biodistribution of Tc-99m-labeled DARP in G3
- 2019
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Ingår i: Scientific Reports. - : NATURE PUBLISHING GROUP. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Radionuclide molecular imaging of HER2 expression in disseminated cancer enables stratification of patients for HER2-targeted therapies. DARP in G3, a small (14 kDa) engineered scaffold protein, is a promising probe for imaging of HER2. We hypothesized that position (C- or N-terminus) and composition (hexahistidine or (HE)(3)) of histidine-containing tags would influence the biodistribution of [Tc-99m]Tc(CO)(3)-labeled DARP in G3. To test the hypothesis, G3 variants containing tags at N-terminus (H-6-G3 and (HE)(3)-G3) or at C-terminus (G3-H-6 and G3-(HE)(3)) were labeled with [Tc-99m]Tc(CO)(3). Labeling yield, label stability, specificity and affinity of the binding to HER2, biodistribution and tumor targeting properties of these variants were compared side-by-side. There was no substantial influence of position and composition of the tags on binding of [Tc-99m]Tc(CO)(3)-labeled variants to HER2. The specificity of HER2 targeting in vivo was confirmed. The tumor uptake in BALB/c nu/nu mice bearing SKOV3 xenografts was similar for all variants. On the opposite, there was a strong influence of the tags on uptake in normal tissues. The tumor-to-liver ratio for [Tc-99m]Tc(CO)(3)-(HE)(3)-G3 was three-fold higher compared to the hexahistidine-tag containing variants. Overall, [Tc-99m]Tc(CO)(3)-(HE)(3)-G3 variant provided the highest tumor-to-lung, tumor-to-liver, tumor-to-bone and tumor-to-muscle ratios, which should improve sensitivity of HER2 imaging in these common metastatic sites.
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