A Chemo-enzymatically Linked Bispecific Antibody Retargets T Cells to a Sialylated Epitope on CD43 in Acute Myeloid Leukemia
A Chemo-enzymatically Linked Bispecific Antibody Retargets T Cells to a Sialylated Epitope on CD43 in Acute Myeloid Leukemia
复制标题
一种化学-酶联双特异性抗体在急性髓系白血病中将T细胞重定向至CD 43上的唾液酸化表位
DOI：
10.1158/0008-5472.can-18-0189
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发表时间：
2019-07-01
期刊：
影响因子：
11.2
通讯作者：
Wagner, Koen
中科院分区：
文献类型：
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作者：
Bartels, Lina;de Jong, Greta;Wagner, Koen
急性髓性白血病（AML）是一种预后不良的高危疾病，尤其是老年患者。由于目前的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，因此非常需要鉴定新的治疗性AML靶点。我们最近描述了AT 1413，一种由异基因造血干细胞移植后治愈的AML患者的供体B细胞产生的抗体。AT 1413结合CD 43 s，CD 43 s是CD 43上的一种独特唾液酸化表位，在正常骨髓细胞上弱表达，在AML细胞上过表达。由于其对AML细胞的选择性，我们认为CD 43作为双特异性T细胞接合抗体（bTCE）的靶点，并通过使用化学-酶联将AT 1413偶联到两个T细胞靶向片段来产生bTCE。在体外，AT 1413 bTCE可有效诱导T细胞介导的对不同AML细胞系和患者源性AML原始细胞的细胞毒性，而与AT 1413结合能力低的内皮细胞不受影响。在存在AML细胞的情况下，AT 1413 bTCE诱导T细胞活化标志物上调、细胞因子释放和T细胞增殖。AT 1413 bTCE在体内也有效。用AML细胞系或患者来源的原代AML母细胞接种共注射人外周血单核细胞或植入人造血干细胞的小鼠[人免疫系统（HIS）小鼠]。AT 1413 bTCE处理强烈抑制肿瘤生长，在HIS小鼠中，对正常人造血细胞的影响极小。两者合计，我们的研究结果表明，CD 43是一个有前途的目标T细胞接合抗体和AT 1413持有治疗潜力的bTCE格式。意义：这些发现提供了临床前证据的治疗潜力的bTCE抗体，靶向CD 43在AML的唾液酸化表位。
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.