cMet is a well-characterized oncogene that is the target of many drugs including small molecule and biologic pathway inhibitors, and, more recently, antibody-drug conjugates (ADCs). However, the clinical benefit from cMet-targeted therapy has been limited. We developed a novel cMet-targeted 'third-generation' ADC, TR1801-ADC, that was optimized at different levels including specificity, stability, toxin-linker, conjugation site, and in vivo efficacy. Our nonagonistic cMet antibody was site-specifically conjugated to the pyrrolobenzodiazepine (PBD) toxin-linker tesirine and has picomolar activity in cancer cell lines derived from different solid tumors including lung, colorectal, and gastric cancers. The potency of our cMet ADC is independent of MET gene copy number, and its antitumor activity was high not only in high cMet-expressing cell lines but also in medium-to-low cMet cell lines (40 000-90 000 cMet/cell) in which a cMet ADC with tubulin inhibitor payload was considerably less potent. In vivo xenografts with low-medium cMet expression were also very responsive to TR1801-ADC at a single dose, while a cMet ADC using a tubulin inhibitor showed a substantially reduced efficacy. Furthermore, TR1801-ADC had excellent efficacy with significant antitumor activity in 90% of tested patient-derived xenograft models of gastric, colorectal, and head and neck cancers: 7 of 10 gastric models, 4 of 10 colorectal cancer models, and 3 of 10 head and neck cancer models showed complete tumor regression after a single-dose administration. Altogether, TR1801-ADC is a new generation cMet ADC with best-in-class preclinical efficacy and good tolerability in rats.

中文翻译：

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TR1801-ADC：一种高效的cMet抗体-药物偶联物，在源自患者的实体瘤异种移植模型中具有高活性。

cMet是一个特征明确的致癌基因，是许多药物（包括小分子和生物途径抑制剂）以及最近的抗体-药物偶联物（ADC）的靶标。但是，以cMet为靶标的疗法的临床获益有限。我们开发了靶向cMet的新型“第三代” ADC TR1801-ADC，并在不同水平进行了优化，包括特异性，稳定性，毒素连接子，结合位点和体内功效。我们的非激动性cMet抗体与吡咯并苯并二氮杂（PBD）毒素接头tesirine特异性结合，并且在源自不同实体瘤（包括肺癌，结肠直肠癌和胃癌）的癌细胞系中具有皮摩尔活性。我们的cMet ADC的效能与MET基因的拷贝数无关，并且它的抗肿瘤活性不仅在表达高cMet的细胞系中高，而且在中等至低的cMet细胞系（40 000-90000 cMet /细胞）中都很高，其中具有微管蛋白抑制剂有效载荷的cMet ADC的效力明显较低。低剂量cMet表达的体内异种移植对TR1801-ADC的单剂量反应也非常好，而使用微管蛋白抑制剂的cMet ADC则显着降低了疗效。此外，TR1801-ADC在90％的胃癌，结肠直肠癌和头颈癌患者源异种移植模型中，具有90％的显着抗肿瘤活性，具有显着的抗肿瘤活性：10种胃癌模型中的7种，10种结肠直肠癌模型中的4种以及10种胃癌中的3种头颈癌模型在单剂量给药后显示出完全的肿瘤消退。共，