PLA2G2D Antibodies for Cancer Immunotherapy

用于癌症免疫治疗的 PLA2G2D 抗体

基本信息

批准号：
10699504
负责人：
LI-FEN LEE
金额：
$ 39.96万
依托单位：
APEXIMMUNE THERAPEUTICS 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：
2023-06-09 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10699504
关键词：
Affinity Animals Anti-Inflammatory Agents Antibodies Autoimmunity Biochemical Biological Assay Biological Response Modifiers Biology CD3 Antigens CD8B1 gene CT26 CTLA4 gene Cell physiology Cells Chronic Clinical Data Dendritic Cells Development Enzyme-Linked Immunosorbent Assay Evaluation Exhibits Family Generations Genetic Engineering Genetically Engineered Mouse Grant Head and Neck Cancer Histologic Human Immune Immune checkpoint inhibitor Immunooncology Immunosuppression Immunotherapy In Vitro Inflammation Knowledge Lead Lymphocyte Macaca fascicularis Macrophage Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of ovary Malignant neoplasm of pancreas Maximum Tolerated Dose Medical Modality Modeling Monoclonal Antibodies Mus Myeloid Cells Natural Immunity New Agents Patients Phase Phospholipase Phospholipase A2 Pilot Projects Polyunsaturated Fatty Acids Population Proteins Publishing Resistance Sampling Series Serum Small Business Innovation Research Grant T-Lymphocyte Therapeutic Therapeutic Monoclonal Antibodies Toxic effect Toxicokinetics Transgenic Mice Transgenic Organisms Tumor Immunity Tumor Promotion anti-PD-1 anti-PD1 antibodies antitumor effect cancer immunotherapy cancer therapy candidate identification clinical application clinical development cross reactivity drug candidate effector T cell efficacy evaluation experience follow-up gain of function humanized mouse immune checkpoint in vivo lipid mediator malignant breast neoplasm melanoma member neoplasm immunotherapy novel pembrolizumab pre-clinical programmed cell death ligand 1 programmed cell death protein 1 protein distribution protein expression restraint success therapeutic target tumor tumor growth

项目摘要

PROJECT SUMMARY / ABSTRACT Currently approved immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. However, most patients do not respond to these treatments because of primary or acquired resistance. Identifying new immune regulators and developing therapeutics targeting such molecules is a current focus in immuno-oncology. We have found that the secreted phospholipase A2 PLA2G2D is highly expressed in various human tumors and positively correlated with that of classic checkpoints such as CTLA-4, PD-1, and PD-L1. PLA2G2D potently diminishes dendritic cell function, suppresses T cell activity, and promotes macrophage M2 polarization. Accordingly, studies using genetically-engineered loss- or gain-of-function mice demonstrate that PLA2G2D strongly enhances tumor growth, indicating that PLA2G2D is a novel, targetable checkpoint for tumor immunotherapy. We have generated more than 700 anti-PLA2G2D monoclonal antibodies, and using a series of in vitro biochemical and immune cell functional assays we have identified 39 leading function-blocking candidates. This proposal seeks to evaluate the anti-tumor efficacy of the 5 most functionally potent drug candidates (which do not cross-react with mouse PLA2G2D), alone and in combination with existing ICIs, using syngeneic tumor models in transgenic PLA2G2D-humanized mice. We will also assess how anti-PLA2G2D changes the tumor immune profile and histologically evaluate PLA2G2D protein expression in various human tumors using our drug candidate (Aim 1). The best drug candidate identified in Aim 1 will then be subjected to non-GLP maximum tolerated dose toxicity and toxicokinetic evaluation in cynomolgus monkeys (Aim 2). Collectively, the successful execution of this proposal will enable us to nominate our final lead molecule and begin IND-enabling studies as part of a follow-up phase II SBIR proposal. Ultimately, an efficacious therapeutic anti-PLA2G2D antibody will comprise a new treatment for patients resistant to currently available ICIs.

项目概要/摘要目前批准的免疫检查点抑制剂（ICIs）已经彻底改变了癌症治疗。然而，大多数由于原发性或获得性耐药，患者对这些治疗没有反应。识别新的免疫调节剂和开发针对此类分子的治疗方法是免疫肿瘤学当前的焦点。我们发现分泌型磷脂酶 A2 PLA2G2D 在多种人类肿瘤中高表达与 CTLA-4、PD-1 和 PD-L1 等经典检查点呈正相关。 PLA2G2D 有效减弱树突状细胞功能，抑制 T 细胞活性，并促进巨噬细胞 M2 极化。因此，使用基因工程丧失或获得功能的小鼠进行的研究表明，PLA2G2D 强烈促进肿瘤生长，表明 PLA2G2D 是一种新型的、可靶向的肿瘤检查点免疫疗法。我们已经生成了 700 多种抗 PLA2G2D 单克隆抗体，并使用一系列通过体外生化和免疫细胞功能测定，我们已经确定了 39 种主要的功能阻断候选人。该提案旨在评估 5 种功能最有效的药物的抗肿瘤功效候选药物（不与小鼠 PLA2G2D 发生交叉反应），单独使用或与现有 ICI 组合使用转基因 PLA2G2D 人源化小鼠的同基因肿瘤模型。我们还将评估如何抗 PLA2G2D 改变肿瘤免疫特征并组织学评估各种人类中 PLA2G2D 蛋白的表达使用我们的候选药物治疗肿瘤（目标 1）。然后，目标 1 中确定的最佳候选药物将受到食蟹猴中非 GLP 最大耐受剂量毒性和毒代动力学评估（目标 2）。总的来说，该提案的成功执行将使我们能够提名我们的最终主导分子和作为后续第二阶段 SBIR 提案的一部分，开始 IND 支持研究。最终找到有效的治疗方法抗 PLA2G2D 抗体将成为对目前可用的 ICI 耐药的患者的一种新疗法。