ISB 2001 三特异性 T 细胞接合器显示出强大的肿瘤细胞毒性，并克服了多发性骨髓瘤细胞的免疫逃逸机制。
ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells.
发表日期：2024 Sep 11
作者：
Laura Carretero-Iglesia, Olivia J Hall, Jérémy Berret, Daniela Pais, Carole Estoppey, Myriam Chimen, Thierry Monney, Jeremy Loyau, Cyrille Dreyfus, Julie Macoin, Cynthia Perez, Vinu Menon, Isabelle Gruber, Amélie Laurendon, Lydia N Caro, Girish S Gudi, Tomomi Matsuura, Piet H van der Graaf, Stanislas Blein, M Lamine Mbow, Rebecca Croasdale-Wood, Ankita Srivastava, Michael R Dyson, Thomas Matthes, Zeynep Kaya, Claire M Edwards, James R Edwards, Sophie Maiga, Catherine Pellat-Deceunynck, Cyrille Touzeau, Philippe Moreau, Cyril Konto, Adam Drake, Eugene A Zhukovsky, Mario Perro, Maria Pihlgren
来源：
Nature Cancer
摘要：
尽管针对单一肿瘤相关抗原的免疫疗法最近取得了进展，但多发性骨髓瘤患者最终还是会复发。 ISB 2001 是一种 CD3 T 细胞接合剂 (TCE)，共同靶向 BCMA 和 CD38，旨在提高针对多发性骨髓瘤的细胞毒性。通过单一 TCE 靶向两种肿瘤相关抗原，可在模拟自然肿瘤异质性的不同范围的 BCMA 和 CD38 肿瘤表达谱中产生优异的细胞毒性效力，改善对竞争性可溶性因子的抵抗力，并对患者来源的样品和在鼠标模型。尽管 CD38 在人体组织中广泛表达，但与仅靶向 CD38 的 TCE 相比，ISB 2001 在没有肿瘤细胞的情况下表现出 T 细胞激活谱降低。为了确定正在进行的临床试验（NCT05862012）的最佳首次人体剂量，我们利用临床前数据开发了一种创新的定量系统药理学模型，采用最小药理活性剂量方法，从而减少患者接触低效剂量的治疗。© 2024。作者。
Despite recent advances in immunotherapies targeting single tumor-associated antigens, patients with multiple myeloma eventually relapse. ISB 2001 is a CD3+ T cell engager (TCE) co-targeting BCMA and CD38 designed to improve cytotoxicity against multiple myeloma. Targeting of two tumor-associated antigens by a single TCE resulted in superior cytotoxic potency across a variable range of BCMA and CD38 tumor expression profiles mimicking natural tumor heterogeneity, improved resistance to competing soluble factors and exhibited superior cytotoxic potency on patient-derived samples and in mouse models. Despite the broad expression of CD38 across human tissues, ISB 2001 demonstrated a reduced T cell activation profile in the absence of tumor cells when compared to TCEs targeting CD38 only. To determine an optimal first-in-human dose for the ongoing clinical trial ( NCT05862012 ), we developed an innovative quantitative systems pharmacology model leveraging preclinical data, using a minimum pharmacologically active dose approach, therefore reducing patient exposure to subefficacious doses of therapies.© 2024. The Author(s).