CD3 bispecific for the treatment of ROR2-positive NSCLC

项目摘要 我们正在开发一种新的CD3双特异性抗体产品TB-Bs1，用于治疗肺癌。肺 癌症是美国每年男性和女性癌症死亡的主要原因，其中非小细胞肺癌是主要原因。 肺癌（NSCLC）占大多数病例。非小细胞肺癌的生存率也是最低的，只有5- 新诊断患者的年生存率仅为18%。治疗方案在过去保持相对不变 十年来，尽管出现了新的免疫疗法，如检查点抑制剂和CAR-T细胞疗法。 这些方法的成功充其量是异质性的，主要是由于肿瘤的复杂性 微环境（TME）。具体地，靶向肿瘤外毒性和免疫刺激减少在肿瘤细胞内是可能的。 肿瘤的免疫治疗成功率有限。因此，探索新的靶点和治疗方式， 可以特异性和有效地指导肿瘤部位免疫介导的癌细胞死亡， 非小细胞肺癌患者急需的选择。 在此I期申请中，我们正在通过临床前概念验证体内研究推进TB-Bs1， NSCLC。TB-Bs1建立在Fc惰性CD3 DuoBodyAb双特异性抗体平台上，具有独特的肿瘤特异性。 相关抗原（TAA）靶点，受体酪氨酸激酶孤儿受体2（ROR2）。ROR2，Wnt信号转导 一种膜受体，在胚胎发生过程中表达并有活性，但在健康组织中不存在， 成年人，是一个新的目标，尚未得到验证。我们在这里提出了一种高度特异性的抗ROR2抗体， 建立在临床验证的双特异性平台上。我们将首先确定ROR2在一组NSCLC中的表达， 肿瘤以及正常人组织样品中。然后我们将评估抗肿瘤治疗效果 TB-Bs1在ROR2阳性NSCLC人源化小鼠模型中的概念验证。这些结果将支持 将TB-Bs1投入临床前全面开发，用于未来ROR2阳性NSCLC的治疗 第二阶段应用。

Project Summary We are developing a novel CD3-bispecific antibody product, TB-Bs1, for the treatment of lung cancer. Lung cancer is the leading cause of cancer deaths in both men and women in the U.S. each year, with non-small cell lung cancer (NSCLC) making up the majority of cases. NSCLC also has one of the lowest survival rates, with 5- year survival for new diagnoses at only 18%. Treatment options remain relatively unchanged over the past decade, despite the emergence of new immunotherapies such as checkpoint inhibitors and CAR-T cell therapy. The success of these modalities is heterogeneous at best, largely due to the complexity of the tumor microenvironment (TME). Specifically, on-target off-tumor toxicity and reduced immune stimulation within the tumor have limited immunotherapy success. Therefore, exploration of new targets and therapeutic modalities that can specifically and potently direct immune-mediated cancer cell death at the tumor site would provide NSCLC patients with a much-needed option. Herein this Phase I application, we are advancing TB-Bs1 through preclinical proof-of-concept in vivo studies in NSCLC. TB-Bs1 is built on the Fc-inert CD3 DuoBodyÒ bispecific antibody platform and has a unique tumor associated antigen (TAA) target, receptor tyrosine kinase orphan receptor 2 (ROR2). ROR2, a Wnt signaling membrane receptor that is expressed and active during embryogenesis but is absent from healthy tissues in adults, is a new target that has yet to be validated. We present here a highly specific anti-ROR2 antibody that is built on a clinically validated bispecific platform. We will first determine ROR2 expression in a panel of NSCLC tumors as well as in normal human tissue samples. Then we will evaluate the anti-tumor therapeutic effect of TB-Bs1 in a proof-of-concept ROR2-positive NSCLC humanized mouse model. These results will support the launch of TB-Bs1 into full-scale preclinical development for the treatment of ROR2-positive NSCLC in a future Phase II application.