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 接受胸部放射治疗或暴露于核事故电离辐射（IR）的个体。的 放射性肺炎和放射性肺纤维化（RILF）的病理生物学是复杂的，但包括 未经检查的炎症（活性氧、细胞因子、炎性细胞）的有害作用， 增加血管渗透性、损害气体转移和促进纤维化。尽管Toll样受体（TLR）和 细胞因子是减少RILI的潜在治疗靶点，中和IR-RILI的实验和临床策略是治疗RILI的有效方法。 诱导的促炎细胞因子作用或阻断炎性细胞浸润的效果令人失望。的 护理标准，高剂量皮质类固醇，由于长期并发症和频繁， 可能致命的复发因此，存在未满足的需要，以鉴定新的RILI治疗靶点和有效的RILI治疗靶点。 治疗性抗炎策略。我们的临床前研究采用全肺胸部照射（WTLI）， 确定了一种细胞酶，烟酰胺磷酸核糖转移酶（NAMPT）作为一种新的RILI治疗靶点。 NAMPT作为细胞内酶（iNAMPT）催化烟酰胺腺嘌呤二核苷酸（NAD） 合成和作为细胞外炎性细胞因子（eNAMPT）。我们已经证明了eNAMPT是一种损伤- 相关的分子模式蛋白（DAMP）和TLR 4的配体，以有效地诱导调节失调的 炎症反应导致细胞因子风暴、器官功能障碍和严重危重病中的死亡。 我们还发现NAMPT的表达和分泌在辐射后显著增加，这是NAMPT基因表达的关键。 NAMPT杂合子小鼠表现出降低的WTLI诱导的RILI。 此外，多克隆eNAMPT pAb可有效减少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，目前已在稳定的细胞系中 发展STTR Fast Track Phase I/II申请旨在确认eNamptorTM是一种新的 WTLI和PBI/BM 5（部分身体照射，5%骨髓）临床前模型中的治疗策略 节约）。我们推测eNamptorTM将超过在接受高剂量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风险和严重程度的严重未满足需求 exposure. Aqualung Therapeutics（ALT）是一家处于早期阶段的生物技术初创公司，与其合作， 学术合作伙伴（亚利桑那大学）组建了一支高技能的多学科团队， eNamptorTM作为WTLI（SA #1）和PBI/BM 5（SA #2）临床前小鼠模型的治疗策略。我们 还将评估放射性标记的NAMPT mAb探针ProNAmptorTM作为伴随诊断试剂的实用性。 定义IR诱导的NAMPT表达的器官特异性位点的策略。STTR II期研究将描述 eNamptorTM的药效学（PD）、药代动力学（PK）（SA #4）和毒理学特征 mAb（SA #5）。eNamptorTM在RILI中的实用性概念验证将导致FDA IND申请的成功。

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.