eNamptorTM: A Humanized mAb To Reduce the Severity of Radiation Pneumonitis and Fibrosis

摘要 放射性肺损伤(Rili)是癌症患者的一种潜在的致命毒性。 正在接受胸部放射治疗或因核事故而暴露于电离辐射(IR)的个人。这个 放射性肺炎和放射性肺纤维化(RILF)的病理生物学很复杂，但包括 无节制的炎症(活性氧、细胞因子、炎症细胞)的有害影响 增加血管通透性，损害气体转运，促进纤维化。尽管Toll样受体(TLRs)和 细胞因子是降低RILI的潜在治疗靶点，实验和临床策略是中和IR- 诱导促炎细胞因子的作用或阻断炎性细胞的浸润一直令人失望。这个 标准的护理，大剂量皮质类固醇，由于长期的并发症和频繁的， 潜在的致命复发。因此，确定新的rILI治疗靶点和有效的需求尚未得到满足。 治疗性抗炎策略。我们的临床前研究使用了全肺胸腔照射(WTLI)， 确定了一种细胞酶，烟酰胺磷酸核糖基转移酶(NAMPT)，作为RILI治疗的新靶点。 NAMPT以一种胞内酶(INAMPT)的形式存在，它催化烟酰胺腺嘌呤二核苷酸(NAD) 合成并作为一种细胞外炎性细胞因子(ENAMPT)。我们已经证明了eNAMPT是一种损害- 相关分子模式蛋白(DAMP)和TLR4的一个配体有效地诱导调节失调 导致细胞因子风暴、器官功能障碍和严重危重疾病死亡的炎症反应。 我们还表明，辐射显著增加NAMPT的表达和分泌，这是一个关键 由于NAMPT杂合子小鼠表现出WTLI诱导的RILI减少，导致RILI发生和严重程度的因素。 此外，多克隆eNAMPT抗体有效地减轻了WTLI诱导的肺炎和纤维化。我们有 开发了eNamptorTM，一种有效的eNAMPT中和人源化mAb，目前正在稳定的细胞系中 发展。这份STTR Fast Track第一阶段/第二阶段申请旨在确认eNamptorTM是一种新的 WTLI和PBI/BM5(5%骨髓局部照射)临床前模型的治疗策略 备用)。我们推测eNamptorTM将超过在接受高剂量治疗的小鼠中观察到的保护作用 皮质类固醇，从而解决了降低IR后RILI的风险和严重性的严重未得到满足的需求 曝光。Aquung Treateutics(ALT)，一家处于早期阶段的生物技术初创公司，与其 学术伙伴(大学)已经组建了一支高技能的多学科团队来评估 ENamptorTM作为临床前WTLI(SA#1)和PBI/BM5(SA#2)小鼠模型的治疗策略。我们 还将评估放射性标记NAMPT单抗探针ProNAmptorTM作为辅助诊断的实用性 定义IR诱导的NAMPT表达的器官特定部位的策略。沙田至大老山第二期研究将简介 ENamptorTM的药效学(PD)、药动学(PK)(SA#4)和毒理学特性 MAb(SA#5)。ENamptorTM在RILI中的效用的概念证明将导致FDA IND的成功应用。

ABSTRACT The development of radiation-induced lung injury (RILI) is a potentially fatal toxicity in cancer patients undergoing thoracic radiotherapy or in individuals exposed to ionizing radiation (IR) from a nuclear incident. The pathobiology of radiation pneumonitis and radiation-induced lung fibrosis (RILF) is complex but includes the deleterious effects of unchecked inflammation (reactive oxygen species, cytokines, inflammatory cells) that increase vascular permeability, impair gas transfer and promote fibrosis. Although Toll-like receptors (TLRs) and cytokines are potential therapeutic targets for reducing RILI, experimental and clinical strategies to neutralize IR- induced proinflammatory cytokine effects or to block inflammatory cell infiltration have been disappointing. The standard of care, high dose corticosteroids, remains controversial due to long term complications and frequent, potentially fatal relapses. Thus, there is an unmet need to identify novel RILI therapeutic targets and effective therapeutic anti-inflammatory strategies. Our preclinical studies utilizing whole lung thoracic irradiation (WTLI), identified a cytozyme, nicotinamide phosphoribosyltransferase (NAMPT), as a novel RILI therapeutic target. NAMPT exists as both an intracellular enzyme (iNAMPT) catalyzing nicotinamide adenine dinucleotide (NAD) synthesis and as an extracellular inflammatory cytokine (eNAMPT). We have shown that eNAMPT is a damage- associated molecular pattern protein (DAMP) and a ligand for TLR4 to potently induce the dysregulated inflammatory response that results in cytokine storm, organ dysfunction, and death in severe critical illnesses. We have also shown that NAMPT expression and secretion is markedly increased by radiation and is a key contributor to RILI development and severity as NAMPT heterozygous mice exhibit reduced WTLI-induced RILI. Furthermore, a polyclonal eNAMPT pAb effectively reduces WTLI-induced pneumonitis and fibrosis. We have developed eNamptorTM, an effective eNAMPT-neutralizing humanized mAb that is now in stable cell line development. This STTR Fast Track Phase I/II application seeks to confirm that eNamptorTM is a novel therapeutic strategy in preclinical models of WTLI and PBI/BM5 (partial body irradiation, 5% bone marrow sparing). We speculate that eNamptorTM will surpass the protection observed in mice receiving high dose corticosteroids, thereby addressing a serious unmet need to reduce the risk and severity of RILI following IR exposure. Aqualung Therapeutics (ALT), an early stage biotechnology start-up, in collaboration with its academic partner (Univ. of Arizona) has assembled a highly skilled multidisciplinary team to evaluate eNamptorTM as a therapeutic strategy in preclinical murine models of WTLI (SA #1) and PBI/BM5 (SA #2). We will also assess the utility of a radiolabeled-NAMPT mAb probe, ProNAmptorTM, as a companion diagnostic strategy that defines organ-specific sites of IR-induced NAMPT expression. STTR Phase II studies will profile the pharmacodynamic (PD) and pharmacokinetic (PK) (SA #4) and toxicological characteristics of eNamptorTM mAb (SA #5). The proof of concept of eNamptorTM’s utility in RILI will lead to a successful FDA IND application.