Direct In Vivo Comparison of 99mTc-Labeled Scaffold Proteins, DARPin G3 and ADAPT6, for Visualization of HER2 Expression and Monitoring of Early Response for Trastuzumab Therapy
Abstract
:1. Introduction
2. Results
2.1. Protein Production and Labeling
2.2. In Vitro Binding and Saturation Experiments
2.3. Measurement of [99mTc]Tc-(HE)3-G3 Affinity to HER2 in the Presence of Trastuzumab
2.4. In Vivo Experiments
3. Discussion
4. Materials and Methods
4.1. Protein Production and Labeling
4.2. Cell Lines
4.3. In Vitro Binding Saturation Experiments
4.4. Measurement of [99mTc]Tc-(HE)3-G3 Affinity to HER2 in the Presence of Trastuzumab
4.5. In Vivo Experiments
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Edmonds, C.E.; O’Brien, S.R.; Mankoff, D.A.; Pantel, A.R. Novel applications of molecular imaging to guide breast cancer therapy. Cancer Imaging Off. Publ. Int. Cancer Imaging Soc. 2022, 22, 31. [Google Scholar] [CrossRef] [PubMed]
- Tolmachev, V.; Orlova, A.; Sorensen, J. The emerging role of radionuclide molecular imaging of HER2 expression in breast cancer. Semin. Cancer Biol. 2021, 72, 185–197. [Google Scholar] [CrossRef] [PubMed]
- Henry, K.E.; Ulaner, G.A.; Lewis, J.S. Clinical Potential of Human Epidermal Growth Factor Receptor 2 and Human Epidermal Growth Factor Receptor 3 Imaging in Breast Cancer. PET Clin. 2018, 13, 423–435. [Google Scholar] [CrossRef] [PubMed]
- Yan, M.; Parker, B.A.; Schwab, R.; Kurzrock, R. HER2 aberrations in cancer: Implications for therapy. Cancer Treat. Rev. 2014, 4, 770–780. [Google Scholar] [CrossRef]
- Giordano, S.H.; Temin, S.; Chandarlapaty, S.; Crews, J.R.; Esteva, F.J.; Kirshner, J.J.; Krop, I.E.; Levinson, J.; Lin, N.U.; Modi, S.; et al. Systemic Therapy for Patients With Ad-vanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: ASCO Clinical Practice Guideline Update. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2018, 36, 2736–2740. [Google Scholar] [CrossRef]
- Al-Batran, S.E.; Moorahrend, E.; Maintz, C.; Goetze, T.O.; Hempel, D.; Thuss-Patience, P.; Gaillard, V.E.; Hegewisch-Becker, S. Clinical Practice Observation of Trastuzumab in Patients with Human Epidermal Growth Receptor 2-Positive Metastatic Adenocarcinoma of the Stomach or Gastroesophageal Junction. Oncologist 2020, 25, e1181–e1187. [Google Scholar] [CrossRef] [Green Version]
- Li, B.T.; Smit, E.F.; Goto, Y.; Nakagawa, K.; Udagawa, H.; Mazières, J.; Nagasaka, M.; Bazhenova, L.; Saltos, A.N.; Felip, E.; et al. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N. Engl. J. Med. 2022, 386, 241–251. [Google Scholar] [CrossRef]
- Lorusso, D.; Hilpert, F.; González Martin, A.; Rau, J.; Ottevanger, P.; Greimel, E.; Lück, H.J.; Selle, F.; Colombo, N.; Kroep, J.R.; et al. Patient-reported outcomes and final overall survival results from the randomized phase 3 PENELOPE trial evaluating pertuzumab in low tumor human epidermal growth factor receptor 3 (HER3) mRNA-expressing platinum-resistant ovarian cancer. Int. J. Gynecol. Cancer Off. J. Int. Gynecol. Cancer Soc. 2019, 29, 1141–1147. [Google Scholar] [CrossRef]
- Tymon-Rosario, J.; Siegel, E.R.; Bellone, S.; Harold, J.; Adjei, N.; Zeybek, B.; Mauricio, D.; Altwerger, G.; Menderes, G.; Rat-ner, E.; et al. Trastuzumab tolera-bility in the treatment of advanced (stage III-IV) or recurrent uterine serous carcinomas that overexpress HER2/neu. Gynecol. Oncol. 2021, 163, 93–99. [Google Scholar] [CrossRef]
- Amir, E.; Miller, N.; Geddie, W.; Freedman, O.; Kassam, F.; Simmons, C.; Oldfield, M.; Dranitsaris, G.; Tomlinson, G.; Laupacis, A.; et al. Prospective study evaluating the impact of tissue confirmation of metastatic disease in patients with breast cancer. J. Clin. Oncol. 2012, 30, 587–592. [Google Scholar] [CrossRef]
- Erdem, G.U.; Altundag, K.; Ozdemir, N.Y.; Sahin, S.; Demirci, N.S.; Karatas, F.; Bozkaya, Y.; Aytekin, A.; Tasdemir, V.; Aslan, A.C.; et al. Comparative study of receptor discordance between primary and corresponding metastatic lesions in breast cancer. J. BUON 2017, 22, 365–376. [Google Scholar] [PubMed]
- Niikura, N.; Liu, J.; Hayashi, N.; Mittendorf, E.A.; Gong, Y.; Palla, S.L.; Tokuda, Y.; Gonzalez-Angulo, A.M.; Hortobagyi, G.N.; Ueno, N.T. Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. J. Clin. Oncol. 2012, 30, 593–599. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Krasniqi, A.; D’Huyvetter, M.; Devoogdt, N.; Frejd, F.Y.; Sörensen, J.; Orlova, A.; Keyaerts, M.; Tolmachev, V. Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology. J. Nucl. Med. 2018, 59, 885–891. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Debie, P.; Devoogdt, N.; Hernot, S. Targeted Nanobody-Based Molecular Tracers for Nuclear Imaging and Image-Guided Surgery. Antibodies 2019, 8, 12. [Google Scholar] [CrossRef] [Green Version]
- Löfblom, J.; Frejd, F.Y.; Ståhl, S. Non-immunoglobulin based protein scaffolds. Curr. Opin. Biotechnol. 2011, 22, 843–848. [Google Scholar] [CrossRef]
- Tolmachev, V.M.; Chernov, V.I.; Deyev, S.M. Targeted nuclear mediine. Seek and destroy. Russ. Chem. Rev. 2022, 91, RCR5034. [Google Scholar] [CrossRef]
- Keyaerts, M.; Xavier, C.; Heemskerk, J.; Devoogdt, N.; Everaert, H.; Ackaert, C.; Vanhoeij, M.; Duhoux, F.P.; Gevaert, T.; Simon, P.; et al. Phase I Study of 68Ga-HER2-Nanobody for PET/CT Assessment of HER2 Expression in Breast Carcinoma. J. Nucl. Med. 2016, 57, 27–33. [Google Scholar] [CrossRef] [Green Version]
- Zhao, L.; Liu, C.; Xing, Y.; He, J.; O’Doherty, J.; Huang, W.; Zhao, J. Development of a 99mTc-Labeled Single-Domain Antibody for SPECT/CT Assessment of HER2 Expression in Breast Cancer. Mol. Pharm. 2021, 18, 3616–3622. [Google Scholar] [CrossRef]
- Sörensen, J.; Sandberg, D.; Sandström, M.; Wennborg, A.; Feldwisch, J.; Tolmachev, V.; Åström, G.; Lubberink, M.; Garske-Román, U.; Carlsson, J.; et al. First-in-human molecular imaging of HER2 expression in breast cancer metastases using the 111In-ABY-025 affibody molecule. J. Nucl. Med. 2014, 55, 730–735. [Google Scholar] [CrossRef] [Green Version]
- Sörensen, J.; Velikyan, I.; Sandberg, D.; Wennborg, A.; Feldwisch, J.; Tolmachev, V.; Orlova, A.; Sandström, M.; Lubberink, M.; Olofsson, H.; et al. Measuring HER2-Receptor Expression In Metastatic Breast Cancer Using [68Ga]ABY-025 Affibody PET/CT. Theranostics 2016, 6, 262–271. [Google Scholar] [CrossRef]
- Bragina, O.; von Witting, E.; Garousi, J.; Zelchan, R.; Sandström, M.; Orlova, A.; Medvedeva, A.; Doroshenko, A.; Vorobyeva, A.; Lindbo, S.; et al. Phase I Study of 99mTc-ADAPT6, a Scaffold Protein-Based Probe for Visualization of HER2 Expression in Breast Cancer. J. Nucl. Med. 2021, 62, 493–499. [Google Scholar] [CrossRef] [PubMed]
- Bragina, O.; Chernov, V.; Schulga, A.; Konovalova, E.; Garbukov, E.; Vorobyeva, A.; Orlova, A.; Tashireva, L.; Sörensen, J.; Zelchan, R.; et al. Phase I Trial of (99m)Tc-(HE)(3)-G3, a DARPin-Based Probe for Im-aging of HER2 Expression in Breast Cancer. J. Nucl. Med. Off. Publ. Soc. Nucl. Med. 2022, 63, 528–535. [Google Scholar] [CrossRef]
- Ritt, P. Recent Developments in SPECT/CT. Semin. Nucl. Med. 2022, 52, 276–285. [Google Scholar] [CrossRef] [PubMed]
- Ekoume, F.P.; Rubow, S.M.; Elrefaei, A.; Bentaleb, N.; Korde, A.; Summers, B.; Bouyoucef, S.; Radchenko, V.; Vraka, C.; Pichler, V. Radiopharmacy in Africa: Current status and future directions. Nucl. Med. Biol. 2022, 114–115, 29–33. [Google Scholar] [CrossRef]
- Garousi, J.; Lindbo, S.; Nilvebrant, J.; Åstrand, M.; Buijs, J.; Sandström, M.; Honarvar, H.; Orlova, A.; Tolmachev, V.; Hober, S. ADAPT, a Novel Scaffold Protein-Based Probe for Radionuclide Imaging of Molecular Targets That Are Expressed in Disseminated Cancers. Cancer Res. 2015, 75, 4364–4371. [Google Scholar] [CrossRef] [Green Version]
- Lindbo, S.; Garousi, J.; Åstrand, M.; Honarvar, H.; Orlova, A.; Hober, S.; Tolmachev, V. Influence of Histidine-Containing Tags on the Biodistribution of ADAPT Scaffold Proteins. Bioconjug. Chem. 2016, 27, 716–726. [Google Scholar] [CrossRef]
- Jost, C.; Schilling, J.; Tamaskovic, R.; Schwill, M.; Honegger, A.; Plückthun, A. Structural basis for eliciting a cytotoxic effect in HER2-overexpressing cancer cells via binding to the extracellular domain of HER2. Structure 2013, 21, 1979–1991. [Google Scholar] [CrossRef] [Green Version]
- Vorobyeva, A.; Schulga, A.; Konovalova, E.; Güler, R.; Löfblom, J.; Sandström, M.; Garousi, J.; Chernov, V.; Bragina, O.; Orlova, A.; et al. Optimal composition and position of histidine-containing tags improves biodistribu-tion of (99m)Tc-labeled DARPin G3. Sci. Rep. 2019, 9, 9405. [Google Scholar] [CrossRef] [Green Version]
- Press, D.J.; Miller, M.E.; Liederbach, E.; Yao, K.; Huo, D. De novo metastasis in breast cancer: Occurrence and overall sur-vival stratified by molecular subtype. Clin. Exp. Metastasis 2017, 34, 457–465. [Google Scholar] [CrossRef]
- Riihimäki, M.; Hemminki, A.; Sundquist, K.; Sundquist, J.; Hemminki, K. Metastatic spread in patients with gastric cancer. Oncotarget 2016, 7, 52307–52316. [Google Scholar] [CrossRef]
- Verstegen, M.H.; Harker, M.; van de Water, C.; van Dieren, J.; Hugen, N.; Nagtegaal, I.D.; Rosman, C.; van der Post, R.S. Metastatic pattern in esophageal and gastric cancer: Influenced by site and histology. World J. Gastroenterol. 2020, 26, 6037–6046. [Google Scholar] [CrossRef]
- Riihimäki, M.; Thomsen, H.; Sundquist, K.; Sundquist, J.; Hemminki, K. Clinical landscape of cancer metastases. Cancer Med. 2018, 7, 5534–5542. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Gaykema, S.B.; de Jong, J.R.; Perik, P.J.; Brouwers. A., H.; Schröder, C.P.; Oude Munnink, T.H.; Bongaerts, A.H.; de Vries, E.G.; Lub-de Hooge, M.N. (111)In-trastuzumab scintigraphy in HER2-positive metastatic breast cancer patients remains feasible during trastuzumab treatment. Mol. Imaging 2014, 13, 7290-2014. [Google Scholar] [CrossRef] [PubMed]
- McLarty, K.; Cornelissen, B.; Cai, Z.; Scollard, D.A.; Costantini, D.L.; Done, S.J.; Reilly, R.M. Micro-SPECT/CT with 111In-DTPA-pertuzumab sensitively detects trastuzumab-mediated HER2 downregulation and tumor response in athymic mice bearing MDA-MB-361 human breast cancer xenografts. J. Nucl. Med. 2009, 50, 1340–1348. [Google Scholar] [CrossRef] [Green Version]
- Kramer-Marek, G.; Gijsen, M.; Kiesewetter, D.O.; Bennett, R.; Roxanis, I.; Zielinski, R.; Kong, A.; Capala, J. Potential of PET to predict the response to trastuzumab treatment in an ErbB2-positive human xenograft tumor model. J. Nucl. Med. 2012, 53, 629–637. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Eigenbrot, C.; Ultsch, M.; Dubnovitsky, A.; Abrahmsén, L.; Härd, T. Structural basis for high-affinity HER2 receptor binding by an engineered protein. Proc. Natl. Acad. Sci. USA 2010, 107, 15039–15044. [Google Scholar] [CrossRef] [Green Version]
- Tolmachev, V.; Orlova, A.; Andersson, K. Methods for radiolabelling of monoclonal antibodies. Methods Mol. Biol. 2014, 1060, 309–330. [Google Scholar]
- Tolmachev, V.; Hofström, C.; Malmberg, J.; Ahlgren, S.; Hosseinimehr, S.J.; Sandström, M.; Abrahmsén, L.; Orlova, A.; Gräslund, T. HEHEHE-tagged affibody molecule may be purified by IMAC, is conveniently labeled with [⁹⁹(m)Tc(CO)₃](+), and shows improved biodistribution with reduced hepatic radioactivity accumulation. Bioconjug. Chem. 2010, 21, 2013–2022. [Google Scholar] [CrossRef]
- Jain, R.K. Physiological barriers to delivery of monoclonal antibodies and other macromolecules in tumors. Cancer Res. 1990, 50 (Suppl. S3), 814s–819s. [Google Scholar]
- Jain, M.; Venkatraman, G.; Batra, S.K. Optimization of radioimmunotherapy of solid tumors: Biological impediments and their modulation. Clin. Cancer Res. 2007, 13, 1374–1382. [Google Scholar] [CrossRef] [Green Version]
- Adams, G.P.; Schier, R.; McCall, A.M.; Simmons, H.H.; Horak, E.M.; Alpaugh, R.K.; Marks, J.D.; Weiner, L.M. High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Cancer Res. 2001, 61, 4750–4755. [Google Scholar] [PubMed]
- Rudnick, S.I.; Lou, J.; Shaller, C.C.; Tang, Y.; Klein-Szanto, A.J.; Weiner, L.M.; Marks, J.D.; Adams, G.P. Influence of affinity and antigen internalization on the uptake and penetration of Anti-HER2 antibodies in solid tumors. Cancer Res. 2011, 71, 2250–2259. [Google Scholar] [CrossRef] [PubMed]
Measurement Condition | KD1 (pM) | Weight (%) | KD2 (nM) | Weight (%) |
---|---|---|---|---|
No addition of trastuzumab | 83 ± 28 | 55 ± 3 | 9 ± 1 | 27 ± 2 |
With addition of trastuzumab | 105 ± 29 | 51 ± 3 | 51 ± 3 | 31 ± 3 |
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Tolmachev, V.; Bodenko, V.; Oroujeni, M.; Deyev, S.; Konovalova, E.; Schulga, A.; Lindbo, S.; Hober, S.; Bragina, O.; Orlova, A.; et al. Direct In Vivo Comparison of 99mTc-Labeled Scaffold Proteins, DARPin G3 and ADAPT6, for Visualization of HER2 Expression and Monitoring of Early Response for Trastuzumab Therapy. Int. J. Mol. Sci. 2022, 23, 15181. https://doi.org/10.3390/ijms232315181
Tolmachev V, Bodenko V, Oroujeni M, Deyev S, Konovalova E, Schulga A, Lindbo S, Hober S, Bragina O, Orlova A, et al. Direct In Vivo Comparison of 99mTc-Labeled Scaffold Proteins, DARPin G3 and ADAPT6, for Visualization of HER2 Expression and Monitoring of Early Response for Trastuzumab Therapy. International Journal of Molecular Sciences. 2022; 23(23):15181. https://doi.org/10.3390/ijms232315181
Chicago/Turabian StyleTolmachev, Vladimir, Vitalina Bodenko, Maryam Oroujeni, Sergey Deyev, Elena Konovalova, Alexey Schulga, Sarah Lindbo, Sophia Hober, Olga Bragina, Anna Orlova, and et al. 2022. "Direct In Vivo Comparison of 99mTc-Labeled Scaffold Proteins, DARPin G3 and ADAPT6, for Visualization of HER2 Expression and Monitoring of Early Response for Trastuzumab Therapy" International Journal of Molecular Sciences 23, no. 23: 15181. https://doi.org/10.3390/ijms232315181
APA StyleTolmachev, V., Bodenko, V., Oroujeni, M., Deyev, S., Konovalova, E., Schulga, A., Lindbo, S., Hober, S., Bragina, O., Orlova, A., & Vorobyeva, A. (2022). Direct In Vivo Comparison of 99mTc-Labeled Scaffold Proteins, DARPin G3 and ADAPT6, for Visualization of HER2 Expression and Monitoring of Early Response for Trastuzumab Therapy. International Journal of Molecular Sciences, 23(23), 15181. https://doi.org/10.3390/ijms232315181