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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：
10622455
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/10622455
关键词：
Affinity Animals Anti-CD47 Autoimmune Award Back Binding Biochemical Biological Bispecific Antibodies Blocking Antibodies CD47 gene CD47-SIRPα 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 Macrophage 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 Tyrosine Phosphorylation antagonist anti-PD-1 anti-PD1 antibodies bench to bedside cancer infiltrating T cells cancer therapy cancer type checkpoint inhibition checkpoint receptors cytokine effector T cell efficacy evaluation extracellular immune checkpoint blockade improved in vivo in vivo evaluation interest melanoma mouse model novel novel strategies novel therapeutics programmed cell death ligand 1 programmed cell death protein 1 receptor receptor-mediated signaling recruit small cell lung carcinoma synergism 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.

摘要：尽管最近在免疫治疗方面取得了进展，例如检查点阻断，但仍有一些激进的新方法被发现。需要既提高现有治疗的疗效，又提供全新的治疗方式。在在该奖项的前一个学期，我们开发了一种免疫抑制剂，利用骨髓分支，通过阻断SIRPa/CD 47轴，增强巨噬细胞对肿瘤的攻击，增强免疫系统。我们设计了一种独特的、高亲和力的CD 47 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点毒性，这是目前大多数抗CD 47 mAb的局限性。这种分子现在正在进行几项临床试验，癌症类型，从而完成周期的板凳到床边在一个任期的奖项。在这次更新申请中，我们请求支持开发肿瘤学中受体抑制的新范例。我们提出了一种新的方法免疫检查点阻断（ICB），并拮抗CD 47/SIRPa轴，通过利用未开发的抑制免疫受体信号传导的天然生物学机制。我们发现含有ITIM/ITAM/ITSM/ITTM的免疫受体，如检查点受体PD 1和CTLA 4，在没有配体接合的情况下的信号。因此，用抗PD 1抗体阻断PD-L1结合， T细胞活化未完全“松开刹车”：配体非依赖性PD 1紧张性信号传导显著减弱 T细胞活化。我们设计了一种减少或消除紧张性信号传导的策略，称为受体抑制，磷酸酶募集（RIPR），依赖于激酶介导的信号受体与细胞的顺式连接表面磷酸酶，如CD 45，以通过细胞内信号传导实现完全的信号抑制靶受体胞内ITAM/ITIM/ITSM/ITTM结构域的去磷酸化。RIPR分子是双- 特异性抗体，迫使靶受体二聚化为细胞表面磷酸酶，抑制两者配体结合和紧张性信号传导。使用PD 1系统作为我们的第一个目标，我们发现我们实现了显着 - 使用使PD 1与T细胞磷酸酶CD 45二聚化的RIPR对检查点阻断的更大抑制，与抗PD 1抗体的配体阻断相比。此外，我们还看到了比抗- PD 1在几种小鼠肿瘤模型中的表达。在本提案中，我们寻求支持，以更好地了解 RIPR在生化和细胞水平，以评估其在一系列小鼠肿瘤模型中的治疗效果单独使用和与治疗性抗体联合使用，并探索RIPR在检查点之外的应用抑制其他受体，如CTLA 4和SIRPa，它们是肿瘤药物靶标。

项目成果

期刊论文数量（19）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

TCR ligand potency differentially impacts PD-1 inhibitory effects on diverse signaling pathways.

TCR 配体效力对不同信号通路的 PD-1 抑制作用有不同的影响。

DOI：
10.1084/jem.20231242
发表时间：
2023
期刊：
The Journal of experimental medicine
影响因子：
0
作者：
Chan,Waipan;Cao,YuqiM;Zhao,Xiang;Schrom,EdwardC;Jia,Dongya;Song,Jian;Sibener,LeahV;Dong,Shen;Fernandes,RicardoA;Bradfield,ClintonJ;Smelkinson,Margery;Kabat,Juraj;Hor,JyhLiang;Altan-Bonnet,Grégoire;Garcia,KChristopher;G
通讯作者：
G

Improving macrophage responses to therapeutic antibodies by molecular engineering of SIRPα variants.

DOI：
10.4161/onci.25773
发表时间：
2013-09-01
期刊：
Oncoimmunology
影响因子：
7.2
作者：
Weiskopf K;Ring AM;Schnorr PJ;Volkmer JP;Volkmer AK;Weissman IL;Garcia KC
通讯作者：
Garcia KC

Induced CD45 Proximity Potentiates Natural Killer Cell Receptor Antagonism.

DOI：
10.1021/acssynbio.2c00337
发表时间：
2022-10-21
期刊：
ACS SYNTHETIC BIOLOGY
影响因子：
4.7
作者：
Ren, Junming;Jo, Yeara;Picton, Lora K.;Su, Leon L.;Raulet, David H.;Garcia, K. Christopher
通讯作者：
Garcia, K. Christopher

cIAP1/2 Antagonism Induces Antigen-Specific T Cell-Dependent Immunity.

cIAP1/2 拮抗作用诱导抗原特异性 T 细胞依赖性免疫。

DOI：
10.4049/jimmunol.2200646
发表时间：
2023
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Ventre,KatherineS;Roehle,Kevin;Bello,Elisa;Bhuiyan,AladdinM;Biary,Tamara;Crowley,StephanieJ;Bruck,PatrickT;Heckler,Max;Lenehan,PatrickJ;Ali,LestatR;Stump,CourtneyT;Lippert,Victoria;Clancy-Thompson,Eleanor;ConceAlberto,Wi
通讯作者：
ConceAlberto,Wi

Evaluation of appendectomy as a potential risk factor for immune checkpoint inhibitor-associated enterocolitis.