Small molecule-drug conjugates (SMDCs) represent an alternative to conventional anti-tumor chemotherapeutic agents, with the potential to improve the therapeutic window of cytotoxic payloads through active delivery at the site of the disease. In this article we de-scribe novel combination therapies consisting of anti-Carbonic Anhydrase IX SMDCs combined with different immunomodulatory products. The therapeutic effect of the SMDCs was potentiated by combination with PD-1 blockade and with tumor-homing anti-body-cytokine fusions in mouse models of renal cell carcinoma and colorectal cancer. The combination with L19-IL12, a fusion protein specific to the alternatively-spliced EDB do-main of fibronectin containing the murine interleukin-12 moiety, was active also against large established tumors. Analysis of the microscopic structures of healthy organs per-formed three months after tumor eradication confirmed absence of pathological abnormali-ties in the healthy kidney, liver, lung, stomach and intestine. Our findings may be of clinical significance as they provide motivation for the development of combinations based on small molecule-drug conjugates and immunotherapy for the treatment of renal cell carcino-ma and of hypoxic tumors.

中文翻译：

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免疫细胞因子和PD-1阻滞剂的免疫疗法增强了针对碳酸酐酶IX的小分子药物偶联物的抗癌活性

小分子药物偶联物（SMDC）代表了常规抗肿瘤化学治疗剂的替代品，具有通过在疾病部位主动递送来改善细胞毒性有效载荷的治疗范围的潜力。在本文中，我们描述了由抗碳酸酐酶IX SMDC与不同的免疫调节产物组合而成的新型联合疗法。SMDCs的治疗作用通过与PD-1阻断剂和肿瘤归巢的抗体-细胞因子融合剂在肾细胞癌和结直肠癌的小鼠模型中联合使用而得到增强。与L19-IL12的组合（一种特异性结合纤连蛋白的EDB主体的融合蛋白，含有鼠白细胞介素12部分）也对已建立的大型肿瘤具有活性。对根除肿瘤后三个月进行的健康器官显微结构的分析证实，健康的肾脏，肝脏，肺脏，胃和肠均无病理异常。我们的发现可能具有临床意义，因为它们为开发基于小分子-药物结合物的组合以及为治疗肾细胞癌和缺氧性肿瘤的免疫疗法提供了动力。