Development of the 99mTc-Labelled SST2 Antagonist TECANT-1 for a First-in-Man Multicentre Clinical Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Chemicals and Materials
2.2. Analytical Methods
2.3. Study Design
2.4. Preformulation Studies
2.5. Kit Preparation
2.6. Kit Radiolabelling
2.7. Stability Studies
2.8. Toxicity of TECANT- 1
3. Results
3.1. Analytical Methods Development
3.2. Preformulation Studies
3.3. Kit Preparation
3.4. Stability Studies
3.5. Toxicity of TECANT-1
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Parameter | Method | Acceptance Criteria | Result |
---|---|---|---|
Accuracy (Identity) | Comparison of Rt of TECANT-1 with Rt of [99mTc]Tc-TECANT-1 | Rt shift [99mTc]Tc-TECANT-1 over TECANT-1 +10–20% (n ≥ 5) | Rt TECANT-1: 4.89 ± 0.04 min Rt [99mTc]Tc-TECANT-1: 5.74 ± 0.07 min Rt shift: +17.6% (mean n = 6) |
Specificity (Identity) | Resolution of TECANT-1 and TECANT-2 | Resolution > 2 (n = 3) | Rt TECANT-1: 4.9 min Rt TECANT-2: 5.4 min Resolution (range): 2.94–3.45 |
Accuracy (T) | Recovery of [99mTc]TcO4− eluate of a sample (n = 6) | Recovery > 95% | 98.67 ± 0.30% |
Precision (T) | Sequential analysis of a sample of [99mTc]TcO4− (n = 6) | Area of peak CV ≤1% (n ≥ 6) | mean area (n = 8): 72.84 + 0.42 CV = 0.57% |
Specificity (T) | Sequential analysis of a sample of [99mTc]TcO4− (n = 6) | Rt impurity CV < 5% | Rt impurity: 1.0 ± 0.006 min CV = 0.62% |
LOQ (T) | Analysis of a dilution series of radioactivity, LOQ according to Ph. Eur. 10× height of background | LOQ < 0.5% of a peak with an activity from a sample with diluted 1:5 with 750 MBq/mL * | LOD = 0.45 kBq LOQ = 1.5 kBq ** LOQ 0.1% of a sample with minimum activity |
Linearity (T) | Analysis of a dilution series of [99mTc]TcO4− (450 MBq/mL to 45 kBq/mL) | R2 > 0.99 | 0.9991 |
Range (T) | Analysis of a dilution series (450 MBq/mL to 45 kBq/mL) | Linearity within 1:10,000 dilution | 1:10,000 |
Robustness | Rt variation on different day and with different operator | CV ≤ 1% (n ≥ 6) | Original Rt [99mTc]Tc-TECANT-1: 5.74 ± 0.01 min Different operator [99mTc]Tc-TECANT-1: 5.71 ± 0.01 min Different day [99mTc]Tc-TECANT-1: 5.74 ± 0.02 min CV < 0.5% |
Parameter | Method | Acceptance Criteria | Result |
---|---|---|---|
Accuracy (B) | Comparison of Rf value of [99mTc]Tc-TECANT-1 | Rf sd < 0.1 | mean = 0.82 sd = 0.02 |
Precision (B) | Analysis of 99mTc-colloid species (n = 6) | RCP sd < 0.5% | mean: 2.97% sd: 0.32% |
Specificity | Rf-value [99mTc]Tc-TECANT-1 Rf-value 99mTc-colloid species | >0.6 <0.4 | 0.80–0.85 (n = 6) 0.01–0.04 (n = 6) |
LOQ (B) | Analysis of dilution of [99mTc]TcO4− eluate (0.8–800 MBq/mL) | >1% | LOQ = 1.6 MBq/mL LOD = 0.8 MBq/mL |
Linearity (B) | Analysis of dilution of 99mTc-solution (0.8–800 MBq/mL) | >0.9 | 0.9977 |
Range (B) | Analysis of dilution of 99mTc-solution and calculate % of LOQ from maximum activity | <1% | 0.2% (LOQ = 1.6 MBq/mL Max = 800 MBq/mL) |
Robustness | Rf of 99mTc-colloid species different day and operator | Rf < 0.4 | 0.05–0.12 (n = 6) |
TECANT-2 Content [µg] | SnCl2 × 2H2O Content [µg] | Trisodium Citrate Dihydrate Content [mg] | % [99mTc]Tc–TECANT-2 [HPLC] |
---|---|---|---|
10 | 5 | 0.13 | 93.6 |
10 | 10 | 0.13 | 93.8 |
10 | 15 | 0.13 | 93.2 |
10 | 20 | 0.13 | 88.0 |
10 | 15 | 0.26 | 92.5 |
10 | 15 | 0.39 | 88.8 |
Production Details | Quality Control Results | ||||||||
---|---|---|---|---|---|---|---|---|---|
Vial 1 | Vial 2 | Vial 3 | [99mTc]Tc–TECANT-1 [%] HPLC | 99mTc-Colloid Species [%] iTLC | RCP [%] | ||||
Batch No. | TECANT-1 [µg] | SnCl2 × 2H2O [µg] | Trisodium Citrate dihydrate [mg] | Na2HPO4 × 12H2O [µg] | NaOH [mg] | NaH2PO4 × 2H2O [mg] | |||
05a/20 | 10 a | 20 | 0.13 b | 1.77 | 0.4 | 1.6 | 89.3 ± 1.1 | n.d. | n.d. |
05/20 | 10 | 15 | 0.13 | 1.77 | 0.4 | 1.6 | 95.3 ± 0.6 | 6.3 ± 0.3 | 89.0 ± 0.4 |
06/20 | 15 | 15 | 0.13 | 1.77 | 0.4 | 1.6 | 93.6 ± 0.0 | 4.7 ± 0.6 | 88.9 ± 0.5 |
07/20 | 50 | 15 | 0.13 | 1.77 | 0.4 | 1.6 | 93.0 ± 0.8 | 5.3 ± 1.4 | 87.7 ± 1.1 |
08/20 | 20 | 20 | 0.13 | 1.77 | 0.4 | 1.6 | 91.6 ± 0.1 | 10.8 ± 1.8 | 80.8 ± 1.6 |
09a/20 | 30 | 15 | 0.13 | 1.77 | 0.4 | 1.6 | 94.4 ± 0.2 | 3.5 ± 0.5 | 90.9 ± 0.3 |
09b/20 | 40 | 15 | 0.13 | 1.77 | 0.4 | 1.6 | 97.0 ± 0.3 | 7.9 ± 1.1 | 89.1 ± 1.0 |
10/20 | 20 | 15 | 0.13 | 1.77 | 0.4 | 1.6 | 99.0 ± 0.2 | 5.1 ± 0.3 | 93.9 ± 0.2 |
Name of ingredients | Amount | Function | Reference to Standards |
---|---|---|---|
Vial 1 | |||
TECANT-1 TFA salt | 20 μg (net peptide) | Active substance | / |
Trisodium citrate dihydrate | 0.13 mg | Pre-chelator | Ph. Eur., current valid edition |
Stannous chloride dihydrate (SnCl2 × 2H2O) | 15 μg | Excipient Reducing agent | Ph. Eur., current valid edition |
Nitrogen | q.s. | Protective gas | Ph. Eur., current valid edition |
Vial 2 | |||
Disodium phosphate (Na2HPO4 × 12H2O) | 4.5 mg | Excipient Buffer component | Ph. Eur., current valid edition |
Sodium hydroxide (NaOH) | 0.4 mg | Excipient Buffer component | Ph. Eur., current valid edition |
Nitrogen | q.s. | Protective gas | Ph. Eur., current valid edition |
Vial 3 | |||
Sodium phosphate dihydrate (NaH2PO4 × 2H2O) | 1.56 mg | Excipient Buffer component | Ph. Eur., current valid edition |
Nitrogen | q.s. | Protective gas | Ph. Eur., current valid edition |
BATCH No. | ||||
---|---|---|---|---|
Test | Requirements | 01B/21 | 02B/21 | TEC-01/01/22 |
Lyophilisate | ||||
Appearance | White freeze-dried powder | |||
Vial 1 | Conforms | Conforms | Conforms | |
Vial 2 | Conforms | Conforms | Conforms | |
Vial 3 | Conforms | Conforms | Conforms | |
Identity Vial 1 | Retention time RT of the sample complies with the standard RT (RT(TECANT-1) ÷ RTS 1 ± 0.05) | 1.04 | 1.01 | 1.00 |
Assay Vial 1 | 20 µg ± 2 µg | 18.4 µg | 18.7 µg | 19.9 µg |
Sn content (as SnCl2 × 2H2O) | 15 µg ± 1.5 µg | 15.1 µg | 15.1 µg | 15.4 µg |
pH after reconstitution with 1 mL of water for injection | ||||
Vial 1 | 6.4–7.4 | 6.7 | 6.4 | 6.6 |
Vial 2 | 10.7–11.7 | 10.4 | 11.2 | 10.8 |
Vial 3 | 4.5–5.5 | 5.1 | 4.9 | 5.0 |
Water content Vial 2 | ≤10% | 7.0% | 5.5% | 9.2% |
Sterility | ||||
Vial 1 | Sterile | Sterile | Sterile | Sterile |
Vial 2 | Sterile | Sterile | Sterile | Sterile |
Vial 3 | Sterile | Sterile | Sterile | Sterile |
Bacterial endotoxins | <20 EU/kit | |||
Vial 1 | 0.5 EU/kit | 0.75 EU/kit | 0.75 EU/kit | |
Vial 2 | 0.5 EU/kit | 0.75 EU/kit | 0.75 EU/kit | |
Vial 3 | 0.5 EU/kit | 0.75 EU/kit | 0.75 EU/kit | |
Kit after 99mTc-labelling | ||||
% [99mTc]Tc-TECANT-1 (HPLC) [%] | ≥95 | 99.1 ± 0.5 | 99.7 ± 0.1 | 99.8 ± 0.2 |
%99mTc-colloid species [%] | ≤7 | 6.9 ± 1.2 | 3.2 ± 0.5 | 2.0 ± 0.5 |
RCP [%] | ≥90 | 92.2 ± 0.6 | 96.5 ± 0.5 | 97.8 ± 0.5 |
pH after 99mTc-labelling | 6.0–8.0 | 7.2 | 7.5 | 7.3 |
Results | ||||||
---|---|---|---|---|---|---|
Test | Requirements | 0 | 3 m | 6 m | 9 m | 12 m |
BATCH No. 01B/21 | ||||||
% [99mTc]Tc-TECANT-1 (HPLC) [%] | ≥95 | 99.1 ± 0.5 | 99.6 ± 0.2 | 99.9 ± 0.1 | 99.5 ± 0.2 | 99.9 ± 0.1 |
% 99mTc-colloid species [%] | ≤7 | 6.9 ± 1.2 | 5.8 ± 0.4 | 6.8 ± 1.1 | 4.5 ± 0.6 | 6.5 ± 0.5 |
RCP [%] | ≥90 | 92.2 ± 0.6 | 93.8 ± 0.3 | 93.2 ± 0.9 | 95.1 ± 0.4 | 93.4 ± 0.5 |
pH after 99mTc-labelling | 6.0–8.0 | 7.2 | n.d. | n.d. | n.d. | 7.2 |
BATCH No. 02B/21 | ||||||
% [99mTc]Tc-TECANT-1 (HPLC) [%] | ≥95 | 99.7 ± 0.1 | 99.7 ± 0.03 | 99.7 ± 0.1 | 99.9 ± 0.1 | 99.9 ± 0.1 |
% 99mTc-colloid species [%] | ≤7 | 3.2 ± 0.5 | 1.7 ± 0.1 | 5.1 ± 0.3 | 5.4 ± 0.9 | 4.9 ± 0.6 |
RCP [%] | ≥90 | 96.5 ± 0.5 | 98.0 ± 0.2 | 94.5 ± 0.3 | 94.5 ± 0.5 | 95.2 ± 0.6 |
pH after 99mTc-labelling | 6.0–8.0 | 7.5 | n.d. | n.d. | n.d. | 7.3 |
Results (mean ± SD) | ||||
---|---|---|---|---|
Parameters | 0 h | 1 h | 2 h | 4 h |
BATCH No. 01B/21 (Activity range: ~1000–1400 MBq, labelling volume: 0.5–1.5 mL, final molar radioactivity range: 67–95 GBq/µmol), n = 6 | ||||
Appearance | Conforms | Conforms | Conforms | Conforms |
pH 7–8 | Conforms | n.d. | n.d. | n.d. |
% [99mTc]Tc-TECANT-1 (HPLC) [%] | 98.9 ± 0.7 | 99.4 ± 0.6 | 98.5 ± 0.3 | 96.3 ± 1.0 |
% 99mTc-colloid species [%] | 2.2 ± 1.1 | 4.2 ± 1.1 | 4.6 ± 1.1 | 5.1 ± 1.7 |
RCP [%] | 96.7 ± 0.7 | 95.2 ± 1.2 | 94.0 ± 1.3 | 91.4 ± 2.3 |
BATCH No. 02B/21 (Activity range: ~900–1100 MBq, labelling volume: 0.5–0.9 mL, final molar radioactivity range: 60–74 GBq/µmol), n = 3 | ||||
Appearance | Conforms | Conforms | Conforms | Conforms |
pH 7–8 | Conforms | n.d. | n.d. | n.d. |
% [99mTc]Tc-TECANT-1 (HPLC) [%] | 98.6 ± 0.5 | 98.3 ± 1.0 | 96.7 ± 0.3 | 95.5 ± 0.4 |
% 99mTc-colloid species [%] | 2.9 ± 1.0 | 3.6 ± 1.7 | 3.7 ± 1.4 | 4.0 ± 1.1 |
RCP [%] | 95.8 ± 0.54 | 94.8 ± 0.7 | 93.8 ± 0.3 | 92.3 ± 0.2 |
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Novak, D.; Janota, B.; Hörmann, A.A.; Sawicka, A.; Kroselj, M.; Hubalewska-Dydejczyk, A.; Fani, M.; Mikolajczak, R.; Kolenc, P.; Decristoforo, C.; et al. Development of the 99mTc-Labelled SST2 Antagonist TECANT-1 for a First-in-Man Multicentre Clinical Study. Pharmaceutics 2023, 15, 885. https://doi.org/10.3390/pharmaceutics15030885
Novak D, Janota B, Hörmann AA, Sawicka A, Kroselj M, Hubalewska-Dydejczyk A, Fani M, Mikolajczak R, Kolenc P, Decristoforo C, et al. Development of the 99mTc-Labelled SST2 Antagonist TECANT-1 for a First-in-Man Multicentre Clinical Study. Pharmaceutics. 2023; 15(3):885. https://doi.org/10.3390/pharmaceutics15030885
Chicago/Turabian StyleNovak, Doroteja, Barbara Janota, Anton Amadeus Hörmann, Agnieszka Sawicka, Marko Kroselj, Alicja Hubalewska-Dydejczyk, Melpomeni Fani, Renata Mikolajczak, Petra Kolenc, Clemens Decristoforo, and et al. 2023. "Development of the 99mTc-Labelled SST2 Antagonist TECANT-1 for a First-in-Man Multicentre Clinical Study" Pharmaceutics 15, no. 3: 885. https://doi.org/10.3390/pharmaceutics15030885
APA StyleNovak, D., Janota, B., Hörmann, A. A., Sawicka, A., Kroselj, M., Hubalewska-Dydejczyk, A., Fani, M., Mikolajczak, R., Kolenc, P., Decristoforo, C., & Garnuszek, P. (2023). Development of the 99mTc-Labelled SST2 Antagonist TECANT-1 for a First-in-Man Multicentre Clinical Study. Pharmaceutics, 15(3), 885. https://doi.org/10.3390/pharmaceutics15030885