Cancer patients with malignant involvement of tumor-draining lymph nodes (TDLNs) and distant metastases have the poorest prognosis. A drug delivery platform that targets the primary tumor, TDLNs, and metastatic niches simultaneously, remains to be developed. Here, we generated a novel monoclonal antibody (MHA112) against peripheral node addressin (PNAd), a family of glycoproteins expressed on high endothelial venules (HEVs), which are present constitutively in the lymph nodes (LNs) and formed ectopically in the tumor stroma. MHA112 was endocytosed by PNAd-expressing cells, where it passed through the lysosomes. MHA112 conjugated antineoplastic drug Paclitaxel (Taxol) (MHA112-Taxol) delivered Taxol effectively to the HEV-containing tumors, TDLNs, and metastatic lesions. MHA112-Taxol treatment significantly reduced primary tumor size as well as metastatic lesions in a number of mouse and human tumor xenografts tested. These data indicate that human metastatic lesions contain HEVs and provide a platform that permits simultaneous targeted delivery of antineoplastic drugs to the three key sites of primary tumor, TDLNs, and metastases.

中文翻译：

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通过高内皮小静脉靶向递送同时靶向原发肿瘤、引流淋巴结和远处转移瘤

肿瘤引流淋巴结（TDLN）恶性受累和远处转移的癌症患者预后最差。同时针对原发肿瘤、TDLN 和转移灶的药物递送平台仍有待开发。在这里，我们产生了一种针对外周淋巴结寻址蛋白（PNAd）的新型单克隆抗体（MHA112），PNAd是在高内皮小静脉（HEV）上表达的糖蛋白家族，组成性存在于淋巴结（LN）中并在肿瘤基质中异位形成。 MHA112 被表达 PNAd 的细胞内吞，并通过溶酶体。 MHA112 偶联抗肿瘤药物紫杉醇 (Taxol) (MHA112-Taxol) 将紫杉醇有效地递送至含有 HEV 的肿瘤、TDLN 和转移性病灶。 MHA112-紫杉醇治疗显着减小了所测试的许多小鼠和人类肿瘤异种移植物中的原发肿瘤大小以及转移病灶。这些数据表明，人类转移性病灶含有 HEV，并提供了一个平台，允许将抗肿瘤药物同时靶向递送至原发肿瘤、TDLN 和转移瘤的三个关键部位。