Tesirine

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.

Tesirine 是一种抗体药物偶联物（ADC）的吡咯苯并二氮杂卓（PBD）二聚体有效载荷^[1]。PBD 二聚体是高效的 DNA 小槽交联剂，具有强大的细胞毒性^[2]。Tesirine 结合了强大的抗肿瘤活性和理想的物理化学特性，例如良好的疏水性和改进的偶联特性，通常用于多种癌症的研究^[3-5]。

在体外实验中，用 Loncastuximab Tesirine(0-15nM) 处理淋巴瘤细胞 96 小时，在 B 细胞淋巴瘤细胞系中表现出强烈的细胞毒性，中位 IC₅₀ 为 4.1pM，且 IC₅₀ 值与细胞表面 CD19 密度呈负相关。然而在 T 细胞淋巴瘤细胞系中，Loncastuximab Tesirine的IC₅₀中位数较高，为3.5nM^[6]。

在体内实验中，Loncastuximab Tesirine（1.5mg/kg；静脉注射）在多种皮下和弥散性人类肿瘤模型中表现出高度有效的、剂量依赖性的抗肿瘤活性，并且在大鼠和猴子的药代动力学研究中显示出良好的稳定性和耐受性。在给药后 24 小时内，肿瘤中检测到 DNA 交联和 γ-H2AX DNA 损伤反应，而外周血单个核细胞中未检测到^[7]。