Strategies for Receptor inhibition in immunotherapy

免疫治疗中的受体抑制策略

基本信息

批准号：
10379372
负责人：
Michael Lawrence Dougan
金额：
$ 36.78万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10379372
关键词：
Address Affinity Animals Anti-CD47 Autoimmune Award Back Binding Biochemical Biological Bispecific Antibodies Blocking Antibodies CD47 gene CTLA4 gene Cell surface Clinical Clinical Trials Collection Colon Colonic inflammation Combination immunotherapy Dimerization Drug Targeting Eating Engineering Exhibits Extracellular Domain Goals Grant Homeostasis Human ITAM ITIM Immune Immune response Immune system Immunologic Receptors Immunotherapeutic agent Immunotherapy In Vitro Inflammatory Insulin-Dependent Diabetes Mellitus Interleukin-2 Ligand Binding Ligands Ligation Link MC38 Malignant neoplasm of pancreas Mediating Modality Modeling Molecular Monoclonal Antibodies Mus Myelogenous Myeloid Cells Oncology Organoids PD-1 blockade PTPNS1 gene PTPRC gene Patients Performance Phosphoric Monoester Hydrolases Phosphotransferases Play Production Protein Dephosphorylation Protein Engineering Proteins Receptor Inhibition Receptor Signaling Role Signal Transduction Structure-Activity Relationship System T-Cell Activation T-Lymphocyte Technology Therapeutic Therapeutic antibodies Toxic effect Treatment Efficacy Tumor Antibodies Tumor Cell Line Tumor Immunity Tumor-Derived Tyrosine Phosphorylation antagonist anti-PD-1 anti-PD1 antibodies base bench to bedside cancer therapy cancer type checkpoint inhibition checkpoint receptors cytokine dimer effector T cell extracellular immune checkpoint blockade improved in vivo in vivo evaluation interest lung small cell carcinoma macrophage melanoma mouse model novel novel strategies novel therapeutics programmed cell death ligand 1 programmed cell death protein 1 receptor receptor-mediated signaling recruit tumor

项目摘要

Abstract: Despite the recent advances in immunotherapy, such as checkpoint blockade, radical new approaches are needed to both improve the efficacy of existing treatments, and to offer entirely new therapeutic modalities. In the previous term of this award we developed an immunotherapeutic agent that exploited the myeloid branch of the immune system by blocking the SIRPa/CD47 axis, potentiating macrophage attack on tumors. We engineered a unique, high-affinity SIRPa antagonist of CD47 that greatly potentiated the anti-tumor efficacy of several clinically approved anti-tumor antibodies, yet offered the advantage of being tumor selective and non- toxic, which is a limitation of most current anti-CD47 mAbs. This molecule is now in clinical trials for several cancer types, thus completing the cycle of bench to bedside in one term of the award. In this renewal application, we request support to develop a new paradigm for receptor inhibition in oncology. We present a new approach to immune checkpoint blockade (ICB), and antagonizing the CD47/SIRPa axis, by exploiting an untapped natural biological mechanism for dampening immune receptor signaling. We have found that ITIM/ITAM/ITSM/ITTM-containing immunoreceptors, such as the checkpoint receptors PD1 and CTLA4, tonically signal in the absence of ligand engagement. As a result, blocking PD-L1 binding with anti-PD1 antibodies, does not fully “take the brakes off” of T cell activation: ligand-independent PD1 tonic signaling significantly blunts T cell activation. We have devised a strategy reduce or eliminate tonic signaling, termed Receptor Inhibition by Phosphatase Recruitment (RIPR), that relies on the cis-ligation of kinases-mediated signaling receptors to a cell surface phosphatase, such as CD45, to achieve complete signal inhibition through intracellular dephosphorylation of the target receptor intracellular ITAM/ITIM/ITSM/ITTM domains. RIPR molecules are bi- specific antibodies that compel dimerization of a target receptor to a cell-surface phosphatase, inhibiting both ligand binding and tonic signaling. Using the PD1 system as our first target, we find that we achieve significantly greater inhibition of checkpoint blockade using a RIPR that dimerizes PD1 with the T cell phosphatase CD45, versus ligand blocking by anti-PD1 antibodies. Furthermore, we see enhanced therapeutic efficacy over anti- PD1 in several mouse tumor models. In this proposal we seek support to better understand the mechanism of RIPR at the biochemical and cellular level, to assess its therapeutic efficacy in a range of mouse tumor models both alone and in combination with therapeutic antibodies, and to explore RIPR applications beyond checkpoint inhibition to other receptors, such as CTLA4 and SIRPa, that are oncology drug targets.

抽象的：尽管免疫疗法最近取得了进展，例如检查点封锁，但激进的新方法仍然存在需要提高现有治疗的功效，并提供全新的治疗方式。在该奖项的上一期，我们开发了一种利用骨髓分支的免疫治疗剂我们通过阻断 SIRPa/CD47 轴来增强巨噬细胞对肿瘤的攻击。设计了一种独特的、高亲和力的 CD47 SIRPa 拮抗剂，大大增强了几种临床批准的抗肿瘤抗体，但具有肿瘤选择性和非肿瘤性的优势有毒，这是大多数当前抗 CD47 mAb 的局限性，该分子目前正处于多种临床试验中。癌症类型，从而在该奖项的一个期限内完成从实验室到临床的周期。我们请求支持开发肿瘤学受体抑制的新范例。我们提出了一种新方法。通过利用未开发的免疫检查点阻断 (ICB) 并拮抗 CD47/SIRPa 轴我们发现抑制免疫受体信号传导的自然生物机制。含有ITIM/ITAM/ITSM/ITTM的免疫受体，例如检查点受体PD1和CTLA4，强效因此，阻断 PD-L1 与抗 PD1 抗体的结合确实有效。 T 细胞激活并未完全“停止”：配体独立的 PD1 强直信号显着减弱我们设计了一种减少或消除强直信号传导的策略，称为受体抑制。磷酸酶募集 (RIPR)，依赖于激酶介导的信号传导受体与细胞的顺式连接表面磷酸酶，如CD45，通过细胞内实现完全的信号抑制靶受体细胞内 ITAM/ITIM/ITSM/ITTM 结构域的去磷酸化是双结构的。特异性抗体，迫使目标受体与细胞表面磷酸酶二聚化，从而抑制两者使用 PD1 系统作为我们的第一个目标，我们发现我们取得了显着的成果。使用 RIPR 使 PD1 与 T 细胞磷酸酶 CD45 二聚化，从而更好地抑制检查点阻断，配体阻断与抗 PD1 抗体相比，我们发现其治疗效果优于抗 PD1 抗体。在此提案中，我们寻求支持以更好地理解 PD1 的机制。在生化和细胞水平上进行 RIPR，以评估其在一系列小鼠肿瘤模型中的治疗效果单独或与治疗性抗体联合使用，并探索检查点之外的 RIPR 应用对作为肿瘤药物靶标的其他受体（例如 CTLA4 和 SIRPa）的抑制。