Biological and Biomedical Sciences, Cornell University College of Veterinary Medicine, Ithaca, New York.
Robert F. Smith School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, New York.
Cancer Res. 2019 Apr 15;79(8):1810-1821. doi: 10.1158/0008-5472.CAN-18-3119. Epub 2019 Feb 26.
The specific targeting of differentially expressed glycans in malignant cells has emerged as an attractive anticancer strategy. One such target is the oncodevelopmental antigen polysialic acid (polySia), a polymer of α2,8-linked sialic acid residues that is largely absent during postnatal development but is re-expressed during progression of several malignant human tumors, including small-cell and non-small cell lung carcinomas, glioma, neuroblastoma, and pancreatic carcinoma. In these cancers, expression of polySia correlates with tumor progression and poor prognosis and appears to modulate cancer cell adhesion, invasiveness, and metastasis. To evaluate the potential of PolySia as a target for anticancer therapy, we developed a chimeric human polySia-specific mAb that retained low nanomolar (nmol/L) target affinity and exhibited exquisite selectivity for polySia structures. The engineered chimeric mAb recognized several polySia-positive tumor cell lines and induced rapid endocytosis of polySia antigens. To determine whether this internalization could be exploited for delivery of conjugated cytotoxic drugs, we generated an antibody-drug conjugate (ADC) by covalently linking the chimeric human mAb to the tubulin-binding maytansinoid DM1 using a bioorthogonal chemical reaction scheme. The resulting polySia-directed ADC demonstrated potent target-dependent cytotoxicity against polySia-positive tumor cells . Collectively, these results establish polySia as a valid cell-surface, cancer-specific target for glycan-directed ADC and contribute to a growing body of evidence that the tumor glycocalyx is a promising target for synthetic immunotherapies. SIGNIFICANCE: These findings describe a glycan-specific antibody-drug conjugate that establishes polySia as a viable cell surface target within the tumor glycocalyx.
糖基化特异性靶向恶性细胞中的差异表达聚糖已成为一种有吸引力的抗癌策略。其中一个靶点是肿瘤发生抗原多涎酸（polySia），这是一种由α2,8 连接的唾液酸残基组成的聚合物，在出生后发育过程中基本不存在，但在几种恶性人类肿瘤的进展过程中重新表达，包括小细胞肺癌和非小细胞肺癌、神经母细胞瘤和胰腺癌。在这些癌症中，polySia 的表达与肿瘤进展和预后不良相关，并且似乎调节癌细胞的粘附、侵袭和转移。为了评估 PolySia 作为抗癌治疗靶点的潜力，我们开发了一种嵌合人多涎酸特异性 mAb，该 mAb 保留了低纳摩尔（nmol/L）的靶标亲和力，并对多涎酸结构表现出极高的选择性。该工程化嵌合 mAb 识别几种多涎酸阳性肿瘤细胞系，并诱导多涎酸抗原的快速内吞作用。为了确定这种内化是否可用于递送至缀合的细胞毒性药物，我们使用生物正交化学反应方案将嵌合人 mAb 共价连接到微管结合美登素 DM1 上，生成抗体药物偶联物（ADC）。由此产生的多涎酸导向 ADC 对多涎酸阳性肿瘤细胞表现出强大的靶依赖性细胞毒性。总的来说，这些结果确立了 polySia 作为糖基化靶向 ADC 的有效细胞表面、癌症特异性靶标，并为越来越多的证据表明肿瘤糖萼是合成免疫疗法的有前途的靶标做出了贡献。意义：这些发现描述了一种糖基特异性抗体药物偶联物，该偶联物将 polySia 确立为肿瘤糖萼中可行的细胞表面靶标。
