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

摘要 大多数晚期癌症患者对目前的干预措施要么没有持久的反应，要么没有反应， 包括免疫肿瘤检查点抑制剂。对于黑色素瘤，免疫疗法的主要焦点，五年 生存率显著提高，但只有约40%的患者对PD-1抑制剂有反应，许多患者发生 时间的阻力。与CTLA-4的另一种检查点抑制剂组合产生更高的应答 率，但具有更高的毒性率，并且> 40%的患者具有耐药肿瘤。在大多数其他肿瘤中 类型，反应不太频繁，反应持续时间较短。因此， 需要更多的系统性干预。在之前的研究中，包括第一阶段的研究， 确立了分泌型黄素蛋白肾酶（RNLS）作为黑色素瘤新靶点的作用，并证明了 抑制RNLS信号传导阻断肿瘤生长的概念。RNLS敲除小鼠也排斥这些鼠 黑色素瘤，提供了在肿瘤中靶向RNLS的基本原理。此外，RNLS水平与 因此，在人肿瘤、黑素瘤细胞和/或肿瘤细胞中RNLS表达增加， 相关巨噬细胞与生存期降低相关，包括用抗PD-1治疗的患者， 基础养生项目中开发的抗RNLS抗体（抗RNLS mAb），用作单药 对PD-1抑制剂具有抗性的消退的鼠黑素瘤肿瘤。联合抗PD-1、抗RNLS mAb显示协同作用，没有明显的毒性。肿瘤排斥反应由巨噬细胞和T细胞驱动。 在第一阶段，朝着开发人源化抗RNLS单克隆抗体（抗RNLS mAb）的方向取得了进展。 作为对PD-1抑制剂耐药的肿瘤的一流临床候选药物。进一步的研究发现 抗RNLS mAb（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 程度.这些将可供今后使用。在这项资助中，非GMP K16将被扩大规模， 黑色素瘤模型将用于确认和扩展mAb的研究。此外，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 将计算（≥ 10倍预期值）。这个项目的成果，随着不断的成功，有相当大的 价值，包括：1）一个新的和新的抗癌药物靶点- RNLS的阐明和利用; 2）开发 一种独特的抗癌疗法-抗RNLS mAb; 3）显著延长和提高抗癌活性 和检查点抑制剂耐药癌症患者的成本效益。

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.