Novel Target, New Therapy: Anti- Renalase Antibody for Tumors Resistant to PD-1Inhibitors

新靶点、新疗法：抗肾酶抗体治疗对 PD-1 抑制剂耐药的肿瘤

基本信息

批准号：
10323421
负责人：
BARRY A BERKOWITZ
金额：
$ 132.78万
依托单位：
BESSOR PHARMA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-02 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10323421
关键词：
Acute Advanced Development Advanced Malignant Neoplasm Affinity Antibodies Antineoplastic Agents Attenuated BRAF gene Binding Biological Assay Businesses CD4 Positive T Lymphocytes CTLA4 gene Cancer Patient Cell Survival Chinese Hamster Ovary Cell Clinical Combined Modality Therapy Data Development Dose Drug Kinetics Drug Targeting Endotoxins Enzyme-Linked Immunosorbent Assay Female Flavoproteins Future Grant High Pressure Liquid Chromatography Human Immune checkpoint inhibitor Immunologic Memory Immunooncology Immunotherapy In Vitro Inflammatory Intervention Knock-out Knockout Mice Lead Malignant Neoplasms Maximum Tolerated Dose Measures Melanoma Cell Modeling Monoclonal Antibodies Mus Oncologist Outcome PD-1 inhibitors Pathogenicity Pathway interactions Patient-Focused Outcomes Patients Peptides Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Phenotype Plasma Play Pre-Clinical Model Proteins RNA Interference Recombinants Regimen Research Design Resistance Resistance development Role Signal Transduction Small Business Innovation Research Grant T-Cell Activation T-Lymphocyte Testing Therapeutic Therapeutic Index Time Toxic effect Toxicology Tumor Antibodies Tumor-associated macrophages Work analytical method anti-CTLA4 anti-PD-1 anti-PD1 therapy anticancer activity assay development base cancer therapy clinical candidate clinical development cost effectiveness drug development effective therapy improved in vivo inhibitor/antagonist innovation macrophage male melanoma mutant neoplastic cell new therapeutic target novel novel anticancer drug novel strategies novel therapeutics pre-clinical product development programmed cell death protein 1 refractory cancer research and development research clinical testing response scale up success synergism systemic intervention translational study tumor tumor growth

项目摘要

ABSTRACT Most patients with advanced cancer either do not respond durably or do not respond to current interventions, including immune-oncology checkpoint inhibitors. For melanoma, a major focus for immunotherapies, five-year survival improved dramatically, yet only ~ 40% of patients respond to PD-1 inhibitors, and many develop resistance over time. The combination with another checkpoint inhibitor of CTLA-4 yields a higher response rate, but with a higher rate of toxicities, and > 40% of patients have resistant tumors. In most other tumor types, responses are seen less frequently, and duration of response is shorter. There is, therefore, a great need for additional systemic interventions. In prior studies, including from a Phase 1 grant, the team established the role of the secreted flavoprotein renalase (RNLS) as a new target in melanoma and proof of concept that inhibiting RNLS signaling blocks tumor growth. RNLS knock-out mice also rejected these murine melanomas, providing a rationale for targeting RNLS in tumors. Moreover, RNLS levels inversely correlate with patient outcomes, thus, increased RNLS expression in human tumors, melanoma cells and/or tumor associated macrophages are associated with decreased survival including patients treated with anti-PD-1- based regimens. Anti-RNLS antibodies (anti-RNLS mAb) developed in the project and used as single agents regressed murine melanoma tumors resistant to PD-1 inhibitors. In combination with anti-PD-1, anti-RNLS mAb showed synergy with no apparent toxicity. Tumor rejection was driven by both macrophages and T cells. In Phase I progress was made towards developing a humanized anti-RNLS monoclonal Ab (anti-RNLS mAb) as a 1st in class clinical candidate for tumors resistant to PD-1 inhibitors. Additional studies have yielded a lead anti-RNLS mAb (K16). K16 was effective in two murine melanoma models. Also, two new sensitive and selective ELISA assays were developed and used to: measure plasma RNLS levels and anti-RNLS mAb levels. These will be available for future use. In this grant, non GMP K16 will be scaled up and two murine melanoma models will be used to confirm and extend studies of the mAb. Additionally, pharmacokinetic, and dose-ranging and acute toxicology studies on K16 will be performed and an estimate of a therapeutic Index (≥10x desired) will be calculated. The outcomes from this project, with continuing success, have considerable value, including: 1) elucidation and utility of a new and novel anticancer drug target - RNLS; 2) development of a unique anticancer therapy—anti-RNLS mAb; 3) significantly extending and improving the anticancer activity and cost effectiveness of checkpoint inhibitors and in checkpoint inhibitor resistant cancer patients.

抽象的大多数晚期癌症患者要么没有持久反应，要么对当前的干预措施没有反应，包括免疫肿瘤学检查点抑制剂对于黑色素瘤（免疫疗法的主要焦点），为期五年。生存率显着提高，但只有约 40% 的患者对 PD-1 抑制剂有反应，并且许多患者发展为随着时间的推移，与另一种 CTLA-4 检查点抑制剂的组合会产生更高的反应。率，但毒性率较高，并且在大多数其他肿瘤中，> 40% 的患者患有耐药肿瘤。类型、响应频率较低且响应持续时间较短。在之前的研究中，包括来自第一阶段资助的研究，团队需要额外的系统干预措施。确立了分泌性黄素蛋白肾酶（RNLS）作为黑色素瘤新靶点的作用，并证明了抑制 RNLS 信号传导可阻止肿瘤生长的概念也排斥这些小鼠。黑色素瘤，为靶向肿瘤中的 RNLS 提供了理论基础，此外，RNLS 水平呈负相关。与患者的结果相关，因此，人类肿瘤、黑色素瘤细胞和/或肿瘤中的 RNLS 表达增加相关巨噬细胞与生存率降低相关，包括接受抗 PD-1 治疗的患者该项目中开发了抗 RNLS 抗体（抗 RNLS mAb）并用作单一药物。与抗 PD-1、抗 RNLS 联合使用，可使对 PD-1 抑制剂耐药的小鼠黑色素瘤肿瘤消退。 mAb 显示出协同作用，且无明显毒性。肿瘤排斥是由巨噬细胞和 T 细胞共同驱动的。在第一阶段，在开发人源化抗 RNLS 单克隆抗体（抗 RNLS mAb）方面取得了进展作为对 PD-1 抑制剂耐药的肿瘤的一流临床候选药物，其他研究已取得领先地位。抗 RNLS mAb (K16) 在两种小鼠黑色素瘤模型中也有效。开发了选择性 ELISA 测定并用于：测量血浆 RNLS 水平和抗 RNLS mAb 这些将可供将来使用，在本次拨款中，非 GMP K16 将被扩大规模，并有两只小鼠。黑色素瘤模型将用于确认和扩展单克隆抗体的研究。将进行 K16 的剂量范围和急性毒理学研究，并估计治疗指数（≥10 倍期望）将被计算，该项目的成果将持续取得成功，具有相当大的意义。价值，包括：1）新的抗癌药物靶点——RNLS的阐明和应用；2）独特的抗癌疗法——抗RNLS mAb；3）显着延长并提高抗癌活性；检查点抑制剂和检查点抑制剂耐药癌症患者的成本效益。