Various cancers, including pancreatic ductal adenocarcinoma (PDAC), remain intractable even with costly tumor-targeting antibody drugs. Because the outermost coatings of cancer cells are composed of cell-specific glycan layers (glycocalyx), lectins, proteins with glycan-binding potential, were evaluated for possible use as drug carriers in PDAC treatment. A human PDAC cell line with well-to-moderately differentiated properties (Capan-1) was subjected to lectin microarray analysis to identify specific lectin–glycan pairs. The selected lectin was fused with a bacterial exotoxin for the construction of a lectin–drug conjugate (LDC), and its safety and antitumor effects were evaluated. A specific affinity between a recombinant bacterial C-type lectin (rBC2LC-N) and Capan-1 was identified, and its positivity was confirmed in 69 human samples. In contrast to the belief that all lectins mediate harmful hemagglutination, rBC2LC-N did not cause hemagglutination with human erythrocytes and was safely administered to mice. The 50% inhibitory concentration of LDC to Capan-1 (1.04 pg/mL = 0.0195 pmol/L) was 1/1,000 lower than that reported for conventional immunotoxins. The intraperitoneal administration of LDC reduced the tumor weight from 390 to 130.8 mg (P < 0.01) in an orthotopic model and reduced the number of nodules from 48 to 3 (P < 0.001) and improved survival from 62 to 105 days in a peritoneal dissemination model (P < 0.0001). In addition, the effect of LDC was reproduced in nodules from patient-derived PDAC xenografts through intravenous injection. Herein, we show the concept of utilizing lectins as drug carriers to target glycans on the cancer cell surface, highlighting new insights into cancer treatments. Mol Cancer Ther; 17(1); 183–95. ©2017 AACR.

中文翻译：

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胰腺癌的一种新治疗策略：使用 rBC2LC-N 凝集素-药物偶联物 (LDC) 靶向细胞表面聚糖。

即使使用昂贵的肿瘤靶向抗体药物，包括胰腺导管腺癌 (PDAC) 在内的各种癌症仍然难以治疗。由于癌细胞的最外层由细胞特异性聚糖层（糖萼）组成，因此评估了凝集素（具有聚糖结合潜力的蛋白质）在 PDAC 治疗中作为药物载体的可能用途。对具有良好至中等分化特性的人类 PDAC 细胞系 (Capan-1) 进行凝集素微阵列分析，以鉴定特定的凝集素-聚糖对。选定的凝集素与细菌外毒素融合以构建凝集素-药物偶联物（LDC），并评估其安全性和抗肿瘤作用。鉴定了重组细菌 C 型凝集素 (rBC2LC-N) 和 Capan-1 之间的特异性亲和力，并在 69 个人类样本中证实了其阳性。与所有凝集素介导有害血凝的观点相反，rBC2LC-N 不会引起与人类红细胞的血凝，并且可以安全地施用于小鼠。LDC 对 Capan-1 的 50% 抑制浓度 (1.04 pg/mL = 0.0195 pmol/L) 比传统免疫毒素报告的浓度低 1/1,000。在原位模型中，腹腔注射 LDC 使肿瘤重量从 390 毫克减少到 130.8 毫克（P < 0.01），将结节数从 48 减少到 3 个（P < 0.001），并将腹膜播散的存活时间从 62 天提高到 105 天模型（P < 0.0001）。此外，LDC 的作用在来自患者来源的 PDAC 异种移植物的结节中通过静脉注射重现。在这里，我们展示了利用凝集素作为药物载体来靶向癌细胞表面聚糖的概念，突出对癌症治疗的新见解。摩尔癌症治疗; 17(1); 183-95。©2017 AACR。