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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.

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