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首页> 外文会议>Protein Engineering Summit. >A Chemo-Enzymatically Linked AT1413 T-Cell Engaging Antibody Targeting a Unique Sialylated Epitope on CD43 Present in Acute Myeloid Leukemia and Melanoma
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A Chemo-Enzymatically Linked AT1413 T-Cell Engaging Antibody Targeting a Unique Sialylated Epitope on CD43 Present in Acute Myeloid Leukemia and Melanoma

机译：AT1413 T细胞接合抗体的化学酶促连接，靶向急性髓细胞白血病和黑色素瘤中的CD43上的独特唾液酸化表位

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The antibody AT1413 was isolated from the donor B-cells of an acute myeloid leukemia (AML) patient in long-term remission after stem cell transplantation. AT1413 recognizes a novel AML-associated target, CD43s, a unique sialylated variant of CD43 which is present on AML and healthy myeloid, but not B and T cells. Besides AML, CD43s expression was also detected on other cancer types including melanoma. To investigate the therapeutic potential of AT1413 not only as a naked antibody, but also in a T-cell engaging format, we have generated an AT1413 bispecific T-cell engaging antibody (bTCE). For maintaining the native functional affinity of AT1413, a bispecific-format which conserves its bivalent binding to CD43s was selected. First, the antibody Fc-region was modified to abolish Fcg-receptor interaction. Second, the bispecific was assembled by linking this modified AT1413 to two single-chain variable fragments (scFv) against CD3e using a combination of a sortase-catalyzed transpeptidation and a subsequent cycloaddition reaction.The AT1413 bTCE retained dual binding capacity to cancer cells and CD3e-expressing Jurkat cells. In vitro, AT1413 bTCE successfully induced T-cell mediated cytotoxicity against different AML cell lines and primary AML blasts as well as a melanoma cell line. Efficacy was observed at E:T ratios as low as 0.5:1 human PBMC:cancer cells. Endothelial cells, that have a detectable but considerably lower binding capacity for AT1413, remained unaffected. T-cell activation and proliferation were observed and were dependent on the presence of CD43s expressing target cells. In vivo, biweekly treatment with 2 mg/kg AT1413 bTCE induced potent tumor growth inhibitory effects of 89-99 % in two AML-xenograft mouse models in comparison with a control bTCE. In one model, NSG mice were inoculated with AML cells and co-injected with human peripheral blood mononuclear cells at the start of bTCE treatment. In the other model, sub-lethally irradiated newborn NSG mice were reconstituted with human hematopoietic stem cells to establish a human immune system (HIS) and subsequently engrafted with AML cells. In this model, normal human hematopoietic cells remained present in mice treated with AT1413 bTCE. Our results indicate that CD43s is a potential new target for T-cell engaging antibodies.
机译：在干细胞移植后的长期缓解后，从急性髓性白血病（AML）患者的供体B细胞中分离1413抗体。 AT1413识别新的AML相关靶，CD43s，CD43的独特唾液酸化变体，其存在于AML和健康的骨髓内，但不是B和T细胞。除了AML，还在包括黑素瘤的其他癌症类型上检测到CD43S表达。为了探讨AT1413的治疗潜力不仅作为裸抗体，而且还以T细胞接合格式，我们已经产生AT1413双特异性T细胞接合抗体（BTCE）。为了保持AT1413的天然功能亲和力，选择了节省其与CD43s的二价结合的双特异性形式。首先，修饰抗体Fc区以消除Fcg受体相互作用。其次，通过使用分子催化的型灭绝的转扣肽和随后的环加成反应将该修饰的AT1413至两个单链可变片段（SCFV）连接到CD3E的两种单链可变片段（SCFV）来组装双特异性。AT1413 BTCE保留对癌细胞和CD3E的双重结合能力 - 表达Jurkat细胞。体外，AT1413 BTCE成功地诱导了针对不同AML细胞系的T细胞介导的细胞毒性，以及原发性AML爆炸以及黑色素瘤细胞系。在E：T比例低至0.5：1人PBMC：癌细胞的效果是低至0.5：1的疗效。具有可检测但相当低的AT1413具有可检测但相当低的结合能力的内皮细胞仍未受到影响。观察到T细胞活化和增殖，取决于表达靶细胞的CD43的存在。在体内，双周治疗，2mg / kg AT1413 BTCE诱导有效的肿瘤生长抑制作用89-99％的两种AML-异种移植小鼠模型与对照BTCE相比。在一种模型中，用AML细胞接种NSG小鼠并在BTCE治疗开始时与人外周血单核细胞共注射。在其他模型中，将亚致命辐照的新生儿NSG小鼠重构用人造造血干细胞重构，以建立人免疫系统（他）并随后与AML细胞移植。在该模型中，正常的人造血细胞仍存在于用AT1413 BTCE处理的小鼠中存在。我们的结果表明CD43S是T细胞接合抗体的潜在新靶标。

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