Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology Zürich, Wolfgang-Pauli-Strasse 10, Zürich 8093, Switzerland.
Br J Cancer. 2011 Mar 29;104(7):1106-15. doi: 10.1038/bjc.2011.78. Epub 2011 Mar 8.
The possibility of eradicating cancer by selective destruction of tumour blood vessels may represent an attractive therapeutic avenue, but most pharmaceutical agents investigated so far did not achieve complete cures and are not completely specific. Antibody conjugates now allow us to evaluate the impact of selective vascular shutdown on tumour viability and to study mechanisms of action.
We synthesised a novel porphyrin-based photosensitiser suitable for conjugation to antibodies and assessed anticancer properties of its conjugate with L19, a clinical-stage human monoclonal antibody specific to the alternatively spliced EDB domain of fibronectin, a marker of tumour angiogenesis.
Here we show in two mouse model of cancer (F9 and A431) that L19 is capable of highly selective in vivo localisation around tumour blood vessels and that its conjugate with a photosensitiser allows selective disruption of tumour vasculature upon irradiation, leading to complete and long-lasting cancer eradication. Furthermore, depletion experiments revealed that natural killer cells are essential for the induction of long-lasting complete responses.
These results reinforce the concept that vascular shutdown can induce a curative avalanche of tumour cell death. Immuno-photodynamic therapy may be particularly indicated for squamous cell carcinoma of the skin, which we show to be strongly positive for markers of angiogenesis.
通过选择性破坏肿瘤血管来消除癌症的可能性可能代表了一种有吸引力的治疗途径，但迄今为止研究的大多数药物制剂都没有实现完全治愈，而且也不是完全特异性的。抗体偶联物现在使我们能够评估选择性血管关闭对肿瘤活力的影响，并研究作用机制。
我们合成了一种新型基于卟啉的光敏剂，适合与抗体偶联，并评估了其与 L19 的偶联物的抗癌特性，L19 是一种针对纤维连接蛋白 EDB 结构域的人源单克隆抗体，该结构域是肿瘤血管生成的标志物。
在这里，我们在两种癌症小鼠模型（F9 和 A431）中显示，L19 能够在肿瘤血管周围高度选择性地定位，并且其与光敏剂的偶联物在照射下允许选择性地破坏肿瘤血管，导致完全和持久的癌症消除。此外，耗竭实验表明自然杀伤细胞对于诱导持久的完全反应是必不可少的。
这些结果强化了这样一种概念，即血管关闭可以诱导肿瘤细胞死亡的治愈性雪崩。免疫光动力疗法可能特别适用于皮肤鳞状细胞癌，我们发现其对血管生成标志物呈强阳性。
