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步，例如检查站封锁，但根本的新方法是需要提高现有治疗的效率，并提供全新的治疗方式。在该奖项的上一个学期我们开发了一种免疫治疗剂，探索了髓样分支免疫系统通过阻断SIRPA/CD47轴，对肿瘤的潜在巨噬细胞攻击。我们设计了一个独特的高亲和力SIRPA拮抗剂CD47，极大地推动了抗肿瘤效率几种临床批准的抗肿瘤抗体，但提供了肿瘤选择性和非肿瘤的优势有毒，这是大多数当前抗CD47 mAb的局限性。该分子现在正在临床试验中癌症类型，从而在奖励的一个学期内完成了长凳到床边的周期。在此续签应用中，我们要求支持肿瘤学受体抑制的新范式。我们提出了一种新方法通过利用未开头自然生物学机制，用于污染免疫接收器信号传导。我们发现 ITIM/ITAM/ITM/ITSM/ITTM免疫受体，例如检查点受体PD1和CTLA4，倾斜在没有配体参与度的情况下发出信号。结果，与抗PD1抗体结合的PD-L1结合，DO 无法完全“脱离T细胞激活的刹车”：非配体无依赖的PD1滋补信号传导明显更多 T细胞激活。我们已经设计了一种策略减少或消除了补品信号传导，称为受体抑制磷酸酶募集（RIPR），依赖于激酶介导的信号受体的顺式连接到细胞表面磷酸酶，例如CD45，以实现通过细胞内的完全信号抑制目标受体细胞内ITAM/ITIM/ITSM/ITTM域的去磷酸化。 RIPR分子是双在细胞表面磷酸酶中促进靶受体二聚化的特定抗体，抑制配体结合和滋补信号传导。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实现使用RIPR更大的抑制检查点阻断，该RIPR用T细胞磷酸酶CD45二聚抗PD1抗体与配体阻断。此外，我们看到抗抗的治疗效率提高了 PD1在几种小鼠肿瘤模型中。在此提案中，我们寻求支持以更好地了解 RIPR在生化和细胞水平上，以评估其在一系列小鼠肿瘤模型中的治疗效率单独并与治疗抗体结合使用，并探索检查点以外的RIPR应用抑制其他受体，例如CTLA4和SIRPA，即肿瘤药物靶标。