Preclinical development of 1B7/CD3, a novel anti-TSLPR bispecific antibody that targets CRLF2-rearranged Ph-like B-ALL

作者：Ze Tian, Chunhua Shi, Guojun Yang, Jason Allen, Qing Shi, Amin Al-Shami, Jill Olson, Melinda Smith, Qing Chang, Jasbir Kaur, Junping You, Timothy Lofton, Michelle A. González, Qi Zhang, Dongxing Zha, Sarah K. Tasian, Nitin Jain, Marina Konopleva, Timothy P. Heffernan, Jeffrey J. Molldrem · 发表于：Leukemia · 年份：2023 · DOI：10.1038/s41375-023-02010-y · 被引用次数：10 · 研究领域：Acute Lymphoblastic Leukemia research、Chronic Lymphocytic Leukemia Research、Lymphoma Diagnosis and Treatment

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.