CD123包含三个胞外结构域(287氨基酸),一个跨膜结构域(30氨基酸),一个短的胞内结构域(53氨基酸)。 CD123是白细胞介素3受体(IL-3R)的α链, IL-3R是β共同受体家族成员。这种膜受体家族调节造血细胞的生长、增殖、存活和分化,以及免疫和炎症反应。白细胞介素3(IL-3)是一种可溶性和多向性细胞因子,调节造血和免疫细胞的功能。IL-3与配体特异性α亚基结合,与β亚基形成异二聚体。激活细胞内受体级联下游信号,进而激活JAK/STAT、Ras-MAPK和磷脂酰肌醇3-激酶通路。 相对于非肿瘤造血干细胞,CD123在白血病干细胞中的表达上调,使其成为血液恶性肿瘤中有用的诊断和治疗生物标志物。CD123靶向治疗是一种很有前途的治疗方法。 NCT02152956,Flotetuzumab in Primary Induction Failure (PIF) or Early Relapse (ER) Acute Myeloid Leukemia (AML),Phase1/2 靶向CD123XCD3,采用Cross-over dual variable (CODV)-Fab-TL技术。
NCT03594955,First in Human Testing of Dose-escalation of SAR440234 in Patients With Acute Myeloid Leukemia, Acute Lymphoid Leukemia and Myelodysplastic Syndrome,Phase1/2 靶向CD123XCD3,采用Hetero H, HL exchange IgG4 bispecific antibody。
NCT02715011,Dose Escalation Study of JNJ-63709178, a Humanized CD123 x CD3 DuoBody in Participants With Relapsed or Refractory Acute Myeloid Leukemia (AML),Phase1 靶向CD123XCD3,采用了(scFv)4-Fc。
NCT03647800,Study of APVO436 in Patients With AML or MDS,phase1 NCT02730312,PH 1 Study to Evaluate Safety and Tolerability of XmAb14045 in Patients With CD123-expressing Hematologic Malignancies,phase1
之前研发代码CSL362(CSL Limited),CD123中和抗体。在患者体内含有较多成熟NK细胞时,可以通过ADCC发挥杀伤作用。
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