摘要

Acute myeloid leukemia (AML) is a high-risk disease with a poor prognosis, particularly in elderly patients. Because current AML treatment relies primarily on untargeted therapies with severe side effects that limit patient eligibility, identification of novel therapeutic AML targets is highly desired. We recently described AT1413, an antibody produced by donor B cells of a patient with AML cured after allogeneic hematopoietic stem cell transplantation. AT1413 binds CD43s, a unique sialylated epitope on CD43, which is weakly expressed on normal myeloid cells and overexpressed on AML cells. Because of its selectivity for AML cells, we considered CD43s as a target for a bispecific T-cell-engaging antibody (bTCE) and generated a bTCE by coupling AT1413 to two T-cell-targeting fragments using chemo-enzymatic linkage. In vitro, AT1413 bTCE efficiently induced T-cell-mediated cytotoxicity toward different AML cell lines and patient-derived AML blasts, whereas endothelial cells with low binding capacity for AT1413 remained unaffected. In the presence of AML cells, AT1413 bTCE induced upregulation of T-cell activation markers, cytokine release, and T-cell proliferation. AT1413 bTCE was also effective in vivo. Mice either coinjected with human peripheral blood mononuclear cells or engrafted with human hematopoietic stem cells [human immune system (HIS) mice] were inoculated with an AML cell line or patient-derived primary AML blasts. AT1413 bTCE treatment strongly inhibited tumor growth and, in HIS mice, had minimal effects on normal human hematopoietic cells. Taken together, our results indicate that CD43s is a promising target for T-cell-engaging antibodies and that AT1413 holds therapeutic potential in a bTCE-format. SIGNIFICANCE: These findings offer preclinical evidence for the therapeutic potential of a bTCE antibody that targets a sialylated epitope on CD43 in AML.

译文

急性髓系白血病 (AML) 是一种预后不良的高危疾病,尤其是老年患者。因为目前的 AML 治疗主要依赖于具有严重副作用的非靶向治疗,这些副作用限制了患者的资格,所以非常需要确定新的治疗 AML 靶点。我们最近描述了 AT1413,一种由异基因造血干细胞移植后治愈的 AML 患者的供体细胞产生的抗体。AT1413 结合 CD43s,CD43 上独特的唾液酸化表位,在正常髓系细胞上弱表达,在 AML 细胞上过度表达。由于其对 AML 细胞的选择性,我们认为 CD43s 是双特异性 T 细胞结合抗体 (bTCE) 的靶标并通过使用化学酶连接将 AT1413 偶联到两个 T 细胞靶向片段来产生 bTCE。在体外,AT1413 bTCE 有效地诱导 T 细胞介导的细胞毒性对不同的 AML 细胞系和患者来源的 AML 肿瘤,而 AT1413 结合能力低的内皮细胞仍然不受影响。在 AML 细胞存在的情况下,AT1413 bTCE 诱导 T 细胞激活标记物、细胞因子释放和 T 细胞增殖的上调。AT1413 bTCE 在体内也有效。与人外周血单个核细胞共同注射或移植人造血干细胞的小鼠 [人类免疫系统 (HIS) 小鼠] 接种 AML 细胞系或患者来源的原发性 AML blasts。AT1413 bTCE 治疗强烈抑制肿瘤生长,在他的小鼠中,对正常人造血细胞的影响最小。综上所述,我们的结果表明 CD43s 是 T 细胞结合抗体的一个有前途的靶点,AT1413 在 bTCE 格式中具有治疗潜力。意义: 这些发现为 bTCE 抗体的治疗潜力提供了临床前证据,bTCE 抗体针对 AML 中 CD43 上的唾液酸化表位。

bispecific antibody

肿瘤 新型抗体 临床研究术语
概述  :  

双特异性抗体(BsAb)是指具有两个不同的抗原结合部位,能有效介导效应物和靶分子结合的新型抗体。在自然状态下不存在双特异性抗体,只能通过人工制备。双特异性抗体能够起到特殊的生物学功能,如(1)免疫细胞的招募和激活,通过同时靶向肿瘤和免疫细胞达到召集免疫细胞清除肿瘤细胞的目的;(2)受体共刺激或抑制,利用BsAb拮抗2种或多种信号传导配体,避免逃逸机制从而改善治疗效果;(3)促进蛋白复合物形成;(4)多价病毒中和等方式等。目前BsAb的临床开发主要集中于癌症和炎性疾病,主要作用机制是同时干涉病

Bispecific

释    义   adj. 双特异的

例    句   Objective: To study bidirectional binding ability and immunoactivity of anti-CD3/anti-glioma bispecific antibodies(BsAb), and to study its effect on T lymphocytes cells. 目的:鉴定自制的抗CD3-抗胶质瘤双特异性抗体(BsAb)的双向结合能力,测定其免疫活性及其对T淋巴细胞的作用。

 

Antibody   英 /'æntɪbɒdɪ/   美 /'æntɪ'bɑdi/

释    义   n. [免疫] 抗体;复数 antibodies

例    句   Each antibody in this kit recognizes only its specific target and does not cross-react with other family members. 本试剂盒中的每个抗体只识别其特异靶标蛋白,不与其他家族成员交叉反应。

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