Tesirine is an antibody-drug conjugate (ADC) pyrrolobenzodiazepine (PBD) dimer payload[1]. PBD dimers are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity[2]. Tesirine combines potent antitumor activity with desirable physicochemical properties, such as favorable hydrophobicity and improved conjugation characteristics, and is usually used in the research of various cancers[3-5].
In vitro, treatment of lymphoma cells with Loncastuximab Tesirine (0-15nM) for 96h demonstrates potent cytotoxicity in B-cell lymphoma cell lines, with a median IC50 of 4.1pM and a negative correlation between IC50 values and CD19 surface density. While in T-cell lymphoma cell lines, the median IC50 is significantly higher at 3.5nM[6].
In vivo, single doses of Loncastuximab Tesirine(1.5mg/kg; i.v.) demonstrated highly potent, dose-dependent antitumor activity in various several subcutaneous and disseminated human tumor models, and showed excellent stability and tolerability in pharmacokinetic studies in rats and monkeys, with DNA crosslinks and g-H2AX DNA damage response detected in tumors but not in peripheral blood mononuclear cells by 24 hours after administration[7].
References:
[1] Tiberghien, A. C., Levy, J. N., Masterson, L. A., Patel, N. V., Adams, L. R., Corbett, S., Williams, D. G., Hartley, J. A., & Howard, P. W. (2016). Design and Synthesis of Tesirine, a Clinical Antibody-Drug Conjugate Pyrrolobenzodiazepine Dimer Payload. ACS medicinal chemistry letters, 7(11), 983–987.
[2] Hartley, J. A., Flynn, M. J., Bingham, J. P., Corbett, S., Reinert, H., Tiberghien, A., Masterson, L. A., Antonow, D., Adams, L., Chowdhury, S., Williams, D. G., Mao, S., Harper, J., Havenith, C. E. G., Zammarchi, F., Chivers, S., van Berkel, P. H., & Howard, P. W. (2018). Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine. Scientific reports, 8(1), 10479.
[3] Lee A. (2021). Loncastuximab Tesirine: First Approval. Drugs, 81(10), 1229–1233.
[4] Rudin, C. M., Pietanza, M. C., Bauer, T. M., Ready, N., Morgensztern, D., Glisson, B. S., Byers, L. A., Johnson, M. L., Burris, H. A., 3rd, Robert, F., Han, T. H., Bheddah, S., Theiss, N., Watson, S., Mathur, D., Vennapusa, B., Zayed, H., Lally, S., Strickland, D. K., Govindan, R., … SCRX16-001 investigators (2017). Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. The Lancet. Oncology, 18(1), 42–51.
[5] Juárez-Salcedo, L. M., Nimkar, S., Corazón, A. M., & Dalia, S. (2024). Loncastuximab Tesirine in the Treatment of Relapsed or Refractory Diffuse Large B-Cell Lymphoma. International journal of molecular sciences, 25(14), 7580.
[6] Tarantelli, C., Wald, D., Munz, N., Spriano, F., Bruscaggin, A., Cannas, E., Cascione, L., Gaudio, E., Arribas, A. J., Manjappa, S., Golino, G., Scalise, L., Cacciapuoti, M. T., Zucca, E., Stathis, A., Inghirami, G., Van Berkel, P. H., Rossi, D., Caimi, P. F., Zammarchi, F., … Bertoni, F. (2024). Targeting CD19-positive lymphomas with the antibodydrug conjugate loncastuximab tesirine: preclinical evidence of activity as a single agent and in combination therapy. Haematologica, 109(10), 3314–3326.
[7] Zammarchi, F., Corbett, S., Adams, L., Tyrer, P. C., Kiakos, K., Janghra, N., Marafioti, T., Britten, C. E., Havenith, C. E. G., Chivers, S., D'Hooge, F., Williams, D. G., Tiberghien, A., Howard, P. W., Hartley, J. A., & van Berkel, P. H. (2018). ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. Blood, 131(10), 1094–1105.