<br>双特异性CD33/CD123靶向嵌合抗原受体T细胞治疗急性髓系白血病,Molecular Therapy: Oncology

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双特异性CD33/CD123靶向嵌合抗原受体T细胞治疗急性髓系白血病
Molecular Therapy: Oncology ( IF 5.3 ) Pub Date : 2023-11-20 , DOI: 10.1016/j.omto.2023.100751
Justin C Boucher _{1,

2} , Bishwas Shrestha ₁ , Paresh Vishwasrao _{3,

4} , Mark Leick ₅ , Estelle V Cervantes ₆ , Tayyebb Ghafoor ₆ , Kayla Reid ₁ , Kristen Spitler ₁ , Bin Yu ₁ , Brian C Betts ₇ , Jose A Guevara-Patino ₂ , Marcela V Maus ₅ , Marco L Davila _{1,

8}

Affiliation

CD33 和 CD123 在人急性髓系白血病原始细胞和其他非癌组织（例如造血干细胞）的表面表达。靶向肿瘤外毒性可能会限制同时靶向 CD33 和 CD123 的嵌合抗原受体 T 细胞疗法。为了克服这一限制，我们开发了具有“AND”逻辑门的双特异性人 CD33/CD123 嵌合抗原受体 (CAR) T 细胞。我们从结合 CD33 和 CD123 并激活 T 细胞的单克隆抗体生产了新型 CD33 和 CD123 scFv。对 CD33 和 CD123 CAR T 细胞的细胞毒性、细胞因子产生和增殖进行筛选，我们选择了用于 CD33/CD123 双特异性 CAR 的 scFv。双特异性 CAR 将 4-1BB 共刺激拆分为一个 scFv，而 CD3ze 拆分为另一个。细胞因子分泌和细胞毒性的测试导致选择双特异性 CAR 1 构建体进行分析。 CD33/CD123 双特异性 CAR T 细胞能够在异种移植 AML 小鼠模型中控制急性髓系白血病 (AML)，与单特异性 CD33 和 CD123 CAR T 细胞类似，同时未显示出靶向脱瘤效应。根据我们的研究结果，人类 CD33/CD123 双特异性 CAR T 细胞是一种有前途的基于细胞的方法，可预防 AML 并支持临床研究。

"点击查看英文标题和摘要"

Bispecific CD33/CD123 targeted chimeric antigen receptor T cells for the treatment of acute myeloid leukemia

CD33 and CD123 are expressed on the surface of human acute myeloid leukemia blasts and other noncancerous tissues such as hematopoietic stem cells. On-target off-tumor toxicities may limit chimeric antigen receptor T cell therapies that target both CD33 and CD123. To overcome this limitation, we developed bispecific human CD33/CD123 chimeric antigen receptor (CAR) T cells with an “AND” logic gate. We produced novel CD33 and CD123 scFvs from monoclonal antibodies that bound CD33 and CD123 and activated T cells. Screening of CD33 and CD123 CAR T cells for cytotoxicity, cytokine production, and proliferation was performed, and we selected scFvs for CD33/CD123 bispecific CARs. The bispecific CARs split 4-1BB co-stimulation on one scFv and CD3ζ on the other. testing of cytokine secretion and cytotoxicity resulted in selecting bispecific CAR 1 construct for analysis. The CD33/CD123 bispecific CAR T cells were able to control acute myeloid leukemia (AML) in a xenograft AML mouse model similar to monospecific CD33 and CD123 CAR T cells while showing no on-target off-tumor effects. Based on our findings, human CD33/CD123 bispecific CAR T cells are a promising cell-based approach to prevent AML and support clinical investigation.

更新日期：2023-11-20

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