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

• 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
• 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

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，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 随着时间的推移产生的阻力。与另一种 CTLA-4 检查点抑制剂联合使用可产生更高的反应 率，但毒性发生率较高，并且 > 40% 的患者患有耐药肿瘤。在大多数其他肿瘤中 类型、响应频率较低且响应持续时间较短。因此，有一个伟大的 需要额外的系统干预措施。在之前的研究中，包括第一阶段的资助，该团队 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。 RNLS 基因敲除小鼠也排斥这些小鼠 黑色素瘤，为靶向肿瘤中的 RNLS 提供了理论依据。此外，RNLS 水平与 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 为基础的治疗方案。项目中开发的抗RNLS抗体（抗RNLS mAb）并作为单药使用 消退对 PD-1 抑制剂耐药的小鼠黑色素瘤肿瘤。与抗 PD-1、抗 RNLS 联合使用 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 作为针对 PD-1 抑制剂耐药肿瘤的一流临床候选药物。其他研究已取得领先成果 抗 RNLS 单克隆抗体 (K16)。 K16 在两种小鼠黑色素瘤模型中有效。此外，两个新的敏感和 开发了选择性 ELISA 测定并用于：测量血浆 RNLS 水平和抗 RNLS mAb 水平。这些将可供将来使用。在这笔赠款中，非 GMP K16 将被扩大规模，并且两只小鼠 黑色素瘤模型将用于确认和扩展单克隆抗体的研究。此外，药代动力学和 将进行 K16 的剂量范围和急性毒理学研究，并估计治疗指数 （≥10x 所需）将被计算。该项目的成果不断取得成功，具有相当大的意义 价值，包括：1）一种新型抗癌药物靶点——RNLS的阐明和应用； 2）发展 独特的抗癌疗法——抗RNLS单克隆抗体； 3）显着延长和提高抗癌活性 检查点抑制剂和检查点抑制剂耐药癌症患者的成本效益。