Activation of TRAILR2 has emerged as an important therapeutic concept in cancer treatment. TRAILR2 agonistic molecules have only had limited clinical success, to date, due either to lack of efficacy or hepatotoxicity. BI 905711 is a novel tetravalent bispecific antibody targeting both TRAILR2 and CDH17 and represents a novel liver-sparing TRAILR2 agonist specifically designed to overcome the disadvantages of previous strategies. Here, we show that BI 905711 effectively triggered apoptosis in a broad panel of CDH17-positive colorectal cancer tumor cells in vitro. Efficient induction of apoptosis was dependent on the presence of CDH17, as exemplified by the greater than 1,000-fold drop in potency in CDH17-negative cells. BI 905711 demonstrated single-agent tumor regressions in CDH17-positive colorectal cancer xenografts, an effect that was further enhanced upon combination with irinotecan. Antitumor efficacy correlated with induction of caspase activation, as measured in both the tumor and plasma. Effective tumor growth inhibition was further demonstrated across a series of different colorectal cancer PDX models. BI 905711 induced apoptosis in both a cis (same cell) as well as trans (adjacent cell) fashion, translating into significant antitumor activity even in xenograft models with heterogeneous CDH17 expression. In summary, we demonstrate that BI 905711 has potent and selective antitumor activity in CDH17-positive colorectal cancer models both in vitro and in vivo. The high prevalence of over 95% CDH17-positive tumors in patients with colorectal cancer, the molecule preclinical efficacy together with its potential for a favorable safety profile, support the ongoing BI 905711 phase I trial in colorectal cancer and additional CDH17-positive cancer types (NCT04137289).

中文翻译：

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使用 BI 905711（一种新型保肝 TRAILR2 激动剂）在 CDH17 阳性结直肠癌模型中选择性肿瘤细胞凋亡和肿瘤消退

TRAILR2 的激活已成为癌症治疗中的一个重要治疗概念。迄今为止，由于缺乏疗效或肝毒性，TRAILR2 激动剂分子的临床成功率有限。BI 905711 是一种针对 TRAILR2 和 CDH17 的新型四价双特异性抗体，代表了一种新型的保肝 TRAILR2 激动剂，专门设计用于克服先前策略的缺点。在这里，我们表明 BI 905711 在体外有效地触发了大量 CDH17 阳性结直肠癌肿瘤细胞的细胞凋亡。细胞凋亡的有效诱导取决于 CDH17 的存在，例如 CDH17 阴性细胞的效力下降超过 1,000 倍。BI 905711 在 CDH17 阳性结直肠癌异种移植物中证明了单药肿瘤消退，与伊立替康联合使用时效果进一步增强。如在肿瘤和血浆中测量的，抗肿瘤功效与半胱天冬酶激活的诱导相关。在一系列不同的结直肠癌 PDX 模型中进一步证明了有效的肿瘤生长抑制。BI 905711 以顺式（相同细胞）和反式（相邻细胞）方式诱导细胞凋亡，即使在具有异质 CDH17 表达的异种移植模型中也转化为显着的抗肿瘤活性。总之，我们证明 BI 905711 在体外和体内 CDH17 阳性结直肠癌模型中具有有效和选择性的抗肿瘤活性。结直肠癌患者中超过 95% 的 CDH17 阳性肿瘤的高患病率，该分子的临床前疗效及其潜在的良好安全性，