CD3 bispecific for the treatment of ROR2-positive NSCLC

CD3 双特异性用于治疗 ROR2 阳性 NSCLC

基本信息

批准号：
10760580
负责人：
Jean-Loup Romet-Lemonne
金额：
$ 40万
依托单位：
TRAVERSE BIOTECH II INC
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10760580
关键词：
Adult Affinity Antibodies Antibody Affinity Antigen Targeting Antitumor Response Binding Biotechnology Bispecific Antibodies CAR T cell therapy CD3 Antigens Cancer Etiology Cancer Patient Cell Death Cell-Mediated Cytolysis Cells Cessation of life Clinical Collaborations Complex Development Disease Dose Embryonic Development Environment Evaluation Family member Future Goals Guidelines Human Immune Immune checkpoint inhibitor Immune system Immunohistochemistry Immunologic Stimulation Immunotherapy In Vitro Industry Standard Invaded Letters Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Mediating Membrane Messenger RNA Modality Modeling Newly Diagnosed Non-Small-Cell Lung Carcinoma Oncology Orphan Patients Phase Prognosis ROR1 gene Receptor Protein-Tyrosine Kinases Receptor Signaling Research Research Personnel Resources Risk Role Sampling Sequence Homology Signal Transduction Site Solid Solid Neoplasm Squamous Cell Lung Carcinoma Survival Rate T-Lymphocyte Therapeutic Therapeutic Effect Tissue Microarray Tissue Sample Tissues Toxic effect Tumor Antigens Tumor Cell Line Tumor Volume Validation WNT Signaling Pathway Woman anti-PD-L1 antibodies antitumor effect arm cancer cell cancer diagnosis cell motility chimeric antigen receptor T cells clinical application cross reactivity design human tissue humanized mouse improved outcome in vivo in vivo Model innovation men mouse model nanomolar neoplastic cell nonhuman primate novel novel therapeutics polarized cell pre-clinical preclinical development receptor reconstitution success targeted treatment therapy development tumor tumor growth tumor microenvironment tumor xenograft validation studies

项目摘要

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.

项目摘要我们正在开发一种新型的CD3三特异性抗体产品TB-BS1，用于治疗肺癌。肺癌症是每年在美国男性和女性癌症死亡的主要原因，有非小细胞肺癌（NSCLC）构成大多数病例。 NSCLC的存活率也最低，为5- 新诊断的年份仅为18％。治疗方案在过去保持相对不变十年，使命是新的免疫疗法的出现，例如检查点抑制剂和CAR-T细胞疗法。这些方式的成功充其量是异质的，这主要是由于肿瘤的复杂性微环境（TME）。具体而言，靶向非肿瘤毒性和降低的免疫刺激肿瘤的免疫疗法成功有限。因此，探索新目标和治疗方式可以在肿瘤部位具体而可能直接直接直接的免疫介导的癌细胞死亡 NSCLC患者具有急需的选择。在此I阶段应用中，我们正在通过体内研究中的临床前概念验证来推进TB-BS1 NSCLC。 TB-BS1建立在FC-int CD3Duobodyò双特异性抗体平台上，具有独特的肿瘤相关抗原（TAA）靶标，受体酪氨酸激酶孤儿受体2（ROR2）。 ROR2，WNT信号在胚胎发生过程中表达和活性的膜受体，但在健康组织中不存在成人是尚未得到验证的新目标。我们在这里提出一种高度特异的抗ROR2抗体建立在经过临床验证的双特异性平台上。我们将首先确定NSCLC面板中的ROR2表达肿瘤以及正常的人体组织样品。然后，我们将评估抗肿瘤的治疗作用概念验证ROR2阳性NSCLC人源化小鼠模型中的TB-BS1。这些结果将支持将TB-BS1推入全尺度临床前开发，以便将来治疗ROR2阳性NSCLC II期应用。