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：
10468939
负责人：
BARRY A BERKOWITZ
金额：
$ 67.22万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10468939
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 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不持久反应，要么对当前干预措施没有反应，包括免疫肿瘤检查点抑制剂。对于黑色素瘤，是免疫疗法的主要重点，五年生存率显着改善，但只有约40％的患者对PD-1抑制剂有反应，许多患者发展随着时间的推移阻力。与CTLA-4的另一种检查点抑制剂的组合产生了更高的响应速率，但毒性率较高，> 40％的患者患有耐药性肿瘤。在大多数其他肿瘤中类型，反应的频率较低，响应持续时间较短。因此，有一个很棒的需要其他系统性干预措施。在先前的研究中，包括第一阶段赠款，团队确定了分泌的黄蛋白肾球酶（RNL）作为黑色素瘤的新靶标的作用抑制RNLS信号传导的概念会阻止肿瘤的生长。 RNLS淘汰小鼠也拒绝了这些小鼠黑色素瘤为靶向肿瘤中的RNL提供了理由。此外，RNLS级别呈负相关随着患者的结局，人类肿瘤，黑色素瘤细胞和/或肿瘤中的RNLS表达增加相关的巨噬细胞与生存率降低有关，包括用抗PD-1-治疗的患者基本方案。在项目中开发的抗RNLS抗体（抗RNLS mAb），用作单个药物对PD-1抑制剂的抗鼠类黑色素瘤肿瘤的回变。与抗PD-1结合使用抗RNL mAb表现出协同作用，没有明显的毒性。肿瘤排斥由巨噬细胞和T细胞驱动。在第一阶段，在开发人性化抗RNLS单克隆AB（抗RNLS mAb）方面取得了进展作为抗PD-1抑制剂的肿瘤临床候选者的第一名。其他研究产生了铅抗RNLS mAb（K16）。 K16在两种鼠黑色素瘤模型中有效。另外，两个新的敏感和开发了选择性ELISA分析并用于：测量血浆RNLS水平和抗RNLS mAb 水平。这些将用于将来使用。在这笔赠款中，非GMP K16将缩放和两个鼠黑色素瘤模型将用于确认和扩展MAB的研究。另外，药代动力学和将对K16进行剂量范围和急性毒理学研究，并估计治疗指数（所需的≥10倍）将计算。该项目的结果持续成功，已经考虑了价值，包括：1）新的和新型抗癌药物靶标-RNL的阐明和实用性； 2）开发一种独特的抗癌疗法 - Anti-RNLS mAb； 3）显着扩展和改善抗癌活性检查点抑制剂和检查点抑制剂抗癌患者的成本效益。