Cureab GmbH, Benkenstrasse 254c, Technologiezentrum, 4108, Witterswil, Switzerland.
Medical Oncology, University Hospital Basel & Laboratory Cancer Immunology, Department Biomedicine, University Basel, Petersgraben 4, 4031, Basel, Switzerland.
Target Oncol. 2019 Oct;14(5):577-590. doi: 10.1007/s11523-019-00667-z.
Golgi phosphoprotein 2 (GOLPH2) has been shown to be involved in chronic inflammatory processes and carcinogenesis. GOLPH2 is prominently overexpressed in hepatocellular carcinoma, melanoma, glioblastoma, prostate, lung, and colorectal cancer. With a low and tightly regulated expression in non-malignant tissues, GOLPH2 has been proposed as an attractive target for cancer therapy. However, GOLPH2 is predominantly located intracellularly and when situated outside of the cell it is proteolytically cleaved and shed from the cell surface. Until now, GOLPH2 has been regarded as an "undruggable" target.
We sought to create antibodies that specifically bind to GOLPH2 overexpressing tumor cells.
Antibodies binding to membranous GOLPH2 despite shedding of the protein were generated from a scFV library screening. These antibodies target the part of GOLPH2 that remains at the cell surface after proteolytic cleavage. These antibodies were then tested in vitro and in vivo.
Two candidates (G2-1 and G2-2) showed target specific binding in vitro. Utilizing a tumor array (n = 128 tumors) with G2-2 and a reference antibody, a GOLPH2 expression scoring system was established. Rapid internalization of the antibodies was noted so this was exploited to deliver a toxic payload of pyrrolobenzodiazepine (PBD). In two patient-derived xenograft (PDX)-models, colorectal and lung cancer, the G2-2 antibody drug conjugate (ADC) displayed high efficacy with significant tumor responses (P = 0.001; P = 0.013) and improved survival (P = 0.0001; P = 0.0011) compared with controls.
Treatment with GOLPH2-directed antibodies induces durable responses in colorectal and lung cancer models. With a robust companion assay for GOLPH2 positivity at hand our findings prepare for the translation into a clinical trial.
高尔基磷酸蛋白 2（GOLPH2）已被证明参与慢性炎症过程和致癌作用。GOLPH2 在肝癌、黑色素瘤、胶质母细胞瘤、前列腺癌、肺癌和结直肠癌中过度表达。由于在非恶性组织中低表达且受到严格调控，GOLPH2 已被提议作为癌症治疗的有吸引力的靶点。然而，GOLPH2 主要位于细胞内，当位于细胞外时，它会被蛋白水解切割并从细胞表面脱落。到目前为止，GOLPH2 一直被认为是一个“不可成药”的靶点。
我们试图创建专门结合过表达 GOLPH2 的肿瘤细胞的抗体。
从 scFV 文库筛选中生成了针对膜结合 GOLPH2 的抗体，尽管该蛋白发生了脱落。这些抗体针对 GOLPH2 被蛋白水解切割后仍留在细胞表面的部分。然后在体外和体内对这些抗体进行了测试。
两种候选物（G2-1 和 G2-2）在体外显示出针对靶标的特异性结合。利用包含 128 个肿瘤的肿瘤阵列（n=128 个肿瘤）和 G2-2 以及参考抗体，建立了 GOLPH2 表达评分系统。观察到抗体的快速内化，因此利用这一点来递送吡咯并苯二氮杂卓（PBD）的毒性有效载荷。在两个患者来源的异种移植（PDX）模型中，结直肠癌和肺癌，G2-2 抗体药物偶联物（ADC）显示出高疗效，具有显著的肿瘤反应（P=0.001；P=0.013）和改善的生存（P=0.0001；P=0.0011）与对照组相比。
针对 GOLPH2 的抗体治疗在结直肠癌和肺癌模型中诱导持久的反应。由于手头有用于 GOLPH2 阳性的强大伴随测定法，我们的发现为转化为临床试验做好了准备。
