Antibody-drug conjugates are generally believed to crucially rely on internalization into cancer cells for therapeutic activity. Here, we show that a non-internalizing antibody-drug conjugate, based on the F16 antibody specific to the alternatively spliced A1 domain of tenascin-C, mediates a potent therapeutic activity when equipped with the anthracycline PNU159682. The peptide linker, connecting the F16 antibody in IgG format at a specific cysteine residue to the drug, was stable in serum but could be efficiently cleaved in the subendothelial extracellular matrix by proteases released by the dying tumor cells. The results indicate that there may be a broader potential applicability of non-internalizing antibody-drug conjugates for cancer therapy than what had previously been assumed.

通常认为抗体-药物偶联物主要依赖于内化到癌细胞中来获得治疗活性。在这里，我们展示了一种非内化抗体-药物偶联物，基于对生腱蛋白-C 的可变剪接 A1 结构域特异的 F16 抗体，在配备蒽环类 PNU159682 时可介导有效的治疗活性。肽接头在特定半胱氨酸残基处将 IgG 形式的 F16 抗体连接到药物，在血清中是稳定的，但可以在垂死的肿瘤细胞释放的蛋白酶在内皮下细胞外基质中有效切割。结果表明，非内化抗体-药物偶联物在癌症治疗中的潜在适用性可能比先前假设的更广泛。