Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, CH-8093 Zürich, Switzerland.
Institute of Pathology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland.
J Control Release. 2017 Oct 28;264:211-218. doi: 10.1016/j.jconrel.2017.08.040. Epub 2017 Sep 1.
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.
抗体药物偶联物通常被认为严重依赖于内化进入癌细胞以发挥治疗活性。在这里，我们表明，基于针对 tenascin-C 的交替剪接 A1 结构域的 F16 抗体的非内化抗体药物偶联物，在配备蒽环类药物 PNU159682 时具有很强的治疗活性。将 F16 抗体以 IgG 形式连接到特定半胱氨酸残基的肽接头在血清中稳定，但可以被由死亡肿瘤细胞释放的蛋白酶在亚内皮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应用可能比以前假设的更广泛。
