CRLF2重排的B-淋巴急性淋巴细胞白血病（B-ALL）患者的5年生存率仅为20％。尽管已经在B-ALL治疗中取得了重大进展，如定位靶向治疗，但仍然需要持续努力开发具有改善应答持久性的治疗选择。在这里，我们首先证明CRLF2重排的Ph-like ALL患者携带升高的胸腺基质淋巴向前分化因子受体（TSLPR）表达，与CD19相当。然后，我们介绍并评估了1B7/CD3这种新型CD3重定向双特异性抗体（BsAb）的抗肿瘤特性，其共靶向TSLPR。体外实验显示，1B7/CD3能够优异结合人类和恒河猴的CD3和TSLPR。此外，1B7/CD3能够在细胞系和原发性B-ALL患者样本中诱导T细胞活化和肿瘤溶解活性。利用人源细胞或患者来源的异种移植模型，1B7/CD3治疗表明可以触发剂量依赖性的肿瘤缓解或生长抑制，并诱导T细胞活化和扩增。小鼠模型的药代动力学研究显示，1B7/CD3具有延长的半衰期。最后，针对恒河猴的毒理学研究发现，1B7/CD3的最大耐受剂量为≤1 mg/kg。总体而言，我们的临床前数据为CRLF2重排的B-ALL患者中1B7/CD3的临床评估提供了框架。 © 2023年作者。

Patients harboring CRLF2-rearranged B-lineage acute lymphocytic leukemia (B-ALL) face a 5-year survival rate as low as 20%. While significant gains have been made to position targeted therapies for B-ALL treatment, continued efforts are needed to develop therapeutic options with improved duration of response. Here, first we have demonstrated that patients with CRLF2-rearranged Ph-like ALL harbor elevated thymic stromal lymphopoietin receptor (TSLPR) expression, which is comparable with CD19. Then we present and evaluate the anti-tumor characteristics of 1B7/CD3, a novel CD3-redirecting bispecific antibody (BsAb) that co-targets TSLPR. In vitro, 1B7/CD3 exhibits optimal binding to both human and cynomolgus CD3 and TSLPR. Further, 1B7/CD3 was shown to induce potent T cell activation and tumor lytic activity in both cell lines and primary B-ALL patient samples. Using humanized cell- or patient-derived xenograft models, 1B7/CD3 treatment was shown to trigger dose-dependent tumor remission or growth inhibition across donors as well as induce T cell activation and expansion. Pharmacokinetic studies in murine models revealed 1B7/CD3 to exhibit a prolonged half-life. Finally, toxicology studies using cynomolgus monkeys found that the maximum tolerated dose of 1B7/CD3 was ≤1 mg/kg. Overall, our preclinical data provide the framework for the clinical evaluation of 1B7/CD3 in patients with CRLF2-rearranged B-ALL.© 2023. The Author(s).