Comparison of [¹²⁵I]I-labeled trastuzumab and pertuzumab for targeted Auger electron therapy of cancers overexpressing HER2 receptors

• Autorzy: Shanjani Sahar Nosrati , Majka Emilia , Lyczko Monika , Walczak Rafał , Majkowska-Pilip Agnieszka , Bilewicz Aleksander

Identyfikatory

DOI

10.5604/01.3001.0054.9271

• Języki publikacji: EN

Abstrakty

EN

Objectives: The HER2 receptor is often overexpressed in various cancers, particularly in breast and ovarian cancers, and this overexpression significantly contributes to the growth and spread of these tumors. Trastuzumab (Herceptin) and pertuzumab (Perjeta) are widely used humanized monoclonal antibodies (mAbs) that have shown promise in treating patients with HER2-positive breast cancer. To enhance their effectiveness, mAbs have recently been combined with chemotherapeutic agents and radionuclides. The aim of our studies was to investigate the potential therapeutic use of trastuzumab and pertuzumab labeled with the Auger electron emitter - ¹²⁵I. Methods: The radioimmunoconjugates synthesized using ¹²⁵I and ¹³¹I were tested in various in vitro studies on SKOV-3 cells. These studies included tests for specificity, binding affinity, internalization, cytotoxicity (MTS assay) and confocal imaging. Results: The results confirmed that radio-iodinated mAbs have high affinity and internalization properties in an HER2+ cell line. In contrast to trastuzumab, significant localization of iodinated pertuzumab on the cell membrane was observed. MTS assay and spheroid studies demonstrated minor toxic effects from both radio-conjugates resulting from the combination of the mAbs' immuno-toxic effect and the interaction of Auger electrons. However, [[¹²⁵I]I-pertuzumab exhibited higher cytotoxicity. Conclusions: Despite high internalization, both radio-bioconjugates showed low cytotoxicity due to the lack of radionuclide localization in the cell nucleus. However, [[¹²⁵I]I-pertuzumab accumulated in the cell membrane, resulting in slightly higher cytotoxicity. To improve therapeutic efficacy, modifying [[¹²⁵I]I-trastuzumab and [¹²⁵I]I-pertuzumab to transport them to the cell nucleus, e.g., using nuclear localization signal (NLS) peptides, is crucial.

Słowa kluczowe

EN

[125I]I-trastuzumab; [125I]I-pertuzumab; HER-2 receptor; Auger electron emitter therapy; radioimmunotherapy

• Wydawca: Uniwersytet Jagielloński - Collegium Medicum ; Index Copernicus Sp. z o.o.
• Czasopismo: Bio-Algorithms and Med-Systems
• Rocznik: 2024
• Tom: Vol. 20, no. 1
• Strony: 118--128
• Opis fizyczny: Bibliogr. 36 poz., rys., tab.

Twórcy

autor

Shanjani Sahar Nosrati

• Institute of Nuclear Chemistry and Technology, Warsaw, Poland

• https://orcid.org/0000-0002-3016-4757

autor

Majka Emilia

• Institute of Nuclear Chemistry and Technology, Warsaw, Poland

• https://orcid.org/0000-0003-1904-7987

autor

Lyczko Monika

• Institute of Nuclear Chemistry and Technology, Warsaw, Poland

• https://orcid.org/0000-0002-7262-4854

autor

Walczak Rafał

• Institute of Nuclear Chemistry and Technology, Warsaw, Poland

• https://orcid.org/0000-0002-0308-7223

autor

Majkowska-Pilip Agnieszka

• Institute of Nuclear Chemistry and Technology; Dorodna street 16, 03-195 Warsaw, Poland

• https://orcid.org/0000-0001-9449-6411

autor

Bilewicz Aleksander

• Institute of Nuclear Chemistry and Technology, Warsaw, Poland

• https://orcid.org/0000-0003-2490-3303

Bibliografia

• 1. Güleç BA, Yurt F. Treatment with Radiopharmaceuticals and Radionuclides in Breast Cancer: Current Options. Eur J Breast Health. 2021;17(3):214-9.
• 2. Nimmagadda S, Penet M-F. Ovarian Cancer Targeted Theranostics. Front. Oncol. 2020;9:1-13.
• 3. Sharma R, Kumbhakar M, Mukherjee A. Toward Understanding the Binding Synergy of Trastuzumab and Pertuzumab to Human Epidermal Growth Factor Receptor 2. Mol. Pharmaceutics. 2021;18:4553-63.
• 4. Pedersen MW, Jacobsen HJ, Koefoed K, Dahlman A, Kjær I, Poulsen TT, et al. Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance. Mol. Cancer Ther. 2015;14(3):669-80.
• 5. Wang X, Aldrich MB, Marshall MV, Sevick-Muraca EM. Preclinical characterization and validation of a dual-labeled trastuzumab-based imaging agent for diagnosing breast cancer. Chin J Cancer Res. 2015;27(1):74-82.
• 6. Heyerdahl H, Krogh C, Borrebæk J, Larsen Å, Dahle J. Treatment of HER2-expressing breast cancer and ovarian cancer cells with alpha particle-emitting 227Th-trastuzumab. Int J Radiat Oncol Biol Phys. 2011;79(2):563-70.
• 7. Mitri Z, Constantine T, O’Regan R. The HER2 Receptor in Breast Cancer: Pathophysiology, Clinical Use, and New Advances in Therapy. Chemother Res Pract. 2012:2012:743193.
• 8. Hsu JL, Hung MC. The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer. Cancer Metastasis Rev. 2016;35(4):575-88.
• 9. Miladinova D. Molecular imaging of HER2 receptor: Targeting HER2 for imaging and therapy in nuclear medicine. Front. Mol. Biosci. 2023;10:1144817.
• 10. Aboudaram A, Loap P, Loirat D, Dhia SB, Cao K, Fourquet, et al. Pertuzumab and Trastuzumab Combination with Conco mitant Locoregional Radiotherapy for the Treatment of Breast Cancers with HER2 Receptor Overexpression. Cancers. 2021;13:4790.
• 11. Hamilton GS. Antibody-Drug Conjugates for Cancer Therapy: The Technological and Regulatory Challenges of Developing Drug-Biologic Hybrids. Biologicals. 2015;43:318-32.
• 12. Siddiqui T, Rani P, Ashraf T, Ellahi A. Enhertu (Fam-Trastuzumab-Deruxtecan-Nxki) - Revolutionizing Treatment Paradigm for HER2-Low Breast Cancer. Ann. Med. Surg. 2022;82:104665.
• 13. FDA D.I.S.C.O. Burst Edition: FDA Approvals of Tukysa (Tucatinib) with Trastuzumab for Colorectal Cancer and Brukinsa (Zanubrutinib) for Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma. [Internet]. 16 February 2023 [cited 12 November 2024]. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-discoburst-edition-fda-approvals-tukysa-tucatinib-trastuzumab-colorectalcancer-and-brukinsa.
• 14. DePolo J. Kadcyla Continues to Improve Survival in HER2-Positive Early-Stage Breast Cancer. [Internet]. 18 December 2023 [cited 12 November 2024]. Available at: https://www.breastcancer.org/research-news/kadcyla-better-survival-her2-positive-early-stage-breast-cancer.
• 15. Borchardt PE, Yuan RR, Miederer M, McDevitt MR, Scheinberg DA. Targeted actinium-225 in vivo generators for therapy of ovarian cancer. Cancer Res. 2003;63:5084-90.
• 16. Sharma R, Kameswaran M, Dash A. Comparative in vitro cytotoxicity studies of 177Lu-CHX-A”-DTPA-trastuzumab and 177Lu-CHX-A”-DTPA-F(ab’)2-trastuzumab in HER2-positive cancer cell lines. Cancer Biother Radiopharm. 2020;35:177-89.
• 17. Chan C, Prozzo V, Aghevlian S, Reilly RM. Formulation of a kit under Good Manufacturing Practices. EJNMMI Radiopharm. Chem. 2022;7:33.
• 18. Wright BD, Lapi SE. Designing the magic bullet? The advancement of immuno PET in clinical use. J. Nucl. Med. 2013;54:1171-4.
• 19. Ray GL, Baidoo KE, Keller LM, Albert PS, Brechbiel MW, Milenic DE. Pre-Clinical assessment of Lu-labeled trastuzumab targeting HER2 for treatment and management of cancer patients with disseminated intraperitoneal disease. Pharmaceuticals. 2011;5(1):1-15.
• 20. Yoshida T, Jin K, Song H, Park S, Huso DL, Zhang Z, et al. Effective treatment of ductal carcinoma in situ with a HER-2- targeted alpha-particle emitting radionuclide in a preclinical model of human breast cancer. Oncotarget. 2016;7:33306-15.
• 21. Robertson AKH, Ramogida CF, Schaffer P, Radchenko V. Development of 225Ac Radiopharmaceuticals: TRIUMF Perspectives and Experiences. Curr Radiopharm. 2018;11(3):156-72.
• 22. Aghevlian S, Boyle AJ, Reilly RM. Radioimmunotherapy of cancer with high linear energy transfer (LET) radiation delivered by radionuclides emitting α-particles or Auger electrons. Adv. Drug Deliv. Rev. 2017;109:102-18.
• 23. Costantini DL, Chan C, Cai Z, Vallis KA, Reilly RM. 111In-labeled trastuzumab (Herceptin) modified with NLS: an Auger electron-emitting radiotherapeutic agent for HER2/neu-amplified breast cancer. J Nucl Med. 2007;48(8):1357-68.
• 24. Costantini DL, Bateman K, McLarty K, Vallis KA, Reilly RM. Trastuzumab-resistant breast cancer cells remain sensitive to the auger electron-emitting radiotherapeutic agent 111In-NLS-trastuzumab and are radiosensitized by methotrexate. J Nucl Med. 2008;49(9):1498-1505.
• 25. Idrissou MB, Pichard A, Tee B, Kibedi T, Poty S, Pouget J-P. Targeted Radionuclide Therapy Using Auger Electron Emitters: The Quest for the Right Vector and the Right Radionuclide. Pharmaceutics. 2021;13(7):980.
• 26. Ngo Ndjock Mbong G, Lu Y, Chan C, Cai Z, Liu P, Boyle AJ, et al. Trastuzumab labeled to high specificactivity with 111In by site-specific conjugation to a metal-chelating polymer exhibits amplified Auger electron-mediated cytotoxicity on HER2-positive breast cancer cells. Mol. Pharmaceutics. 2015;12(6):1951-60.
• 27. Hoang B, Reilly RM, Allen C. Block copolymer micelles target Auger electron radiotherapy to the nucleus of HER2-positive breast cancer cells. Biomacromol. 2012;13:455-65.
• 28. Chan C, Lam K, Bergstrom D, Done S, Cai Z, Reilly RM. In Vitro Targeting of Trastuzumab-resistant Breast Cancer Cells and In Vivo Biodistribution and Acute Toxicity Studies Using a High Specific Radioactivity Auger Electron Radioimmunotherapeutic Agent Composed of Trastuzumab and PAMAM Dendrimer Displaying Multiple DTPA Chelators for 111In. EJNMMI. 2013;40(Supplement 2):S294.
• 29. Cai Z, Chattopadhyay N, Yang K, Luke Kwon Y, Yook S, Pignol J-P, et al. 111In-labeled trastuzumab-modified gold nanoparticles are cytotoxic in vitro to HER2-positive breast cancer cells and arrest tumor growth in vivo in athymic mice after intratumoral injection. Nucl. Med. Biol. 2016;43(12):818-26.
• 30. Ku A, Facca VJ, Cai Z, Reilly RM. Auger electrons for cancer therapy - a review. EJNMMI Radiopharm Chem. 2019;4,27.
• 31. Żelechowska-Matysiak K, Wawrowicz K, Wierzbicki M, Budlewski T, Bilewicz A, Majkowska-Pilip A. Doxorubicin- and Trastuzumab-Modified Gold Nanoparticles as Potential Multimodal Agents for Targeted Therapy of HER2+ Cancers. Molecules. 2023;28:2451.
• 32. Pruszynski M, D’Huyvetter M, Bruchertseifer F, Morgenstern A, Lahoutte T. Evaluation of an Anti-HER2 Nanobody Labeled with 225Ac for Targeted α-Particle Therapy of Cancer. Mol Pharm. 2018;15(4):1457-66.
• 33. McLarty K, Cornelissen B, Scollard DA, Done SJ, Chun K, Reilly RM. Associations between the uptake of 111In-DTPA-trastuzumab, HER2 density and response to trastuzumab (Herceptin) in athymic mice bearing subcutaneous human tumour xenografts. Eur J Nucl Med Mol Imaging. 2009;36:81-93.
• 34. Le X, Mao W, Lu Y, Mills GB, Bast RC. HER2 antibodies pertuzumab and trastuzumab differ in their effect on cell signaling and growth inhibition in breast cancer cells. Cancer Res. 2006;66(8):902.
• 35. Pouget J-P, Santoro L, Raymond L, Chouin N, Bardiès M, Bascoul-Mollevi C, et al. Cell Membrane is a More Sensitive Target than Cytoplasm to Dense Ionization Produced by Auger Electrons. Radiat. Res. 2008;170(2):192-200.
• 36. Nayak P, Bentivoglio V, Varani M, Signore A. Three-Dimensional In Vitro Tumor Spheroid Models for evaluation of Anticancer Therapy: Recent Updates. Cancers. 2023;15:4846.