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

eNamptorTM：一种降低放射性肺炎和纤维化严重程度的人源化单克隆抗体

• 批准号: 10274779
• 负责人: Joe G. N. Garcia
• 金额: $ 100万
• 依托单位: AQUALUNG THERAPEUTICS CORP.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10274779
• 关键词: Address; Adrenal Cortex Hormones; Anti-Inflammatory Agents; Arizona; Attenuated; Biotechnology; Bone Marrow; Cancer Patient; Canis familiaris; Cells; Cessation of life; Characteristics; Chest; Clinic; Clinical; Collaborations; Complex; Critical Illness; Data; Detection; Development; Dose; Enzymes; Exhibits; Exposure to; Fibrosis; Functional disorder; Gases; Impairment; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Ionizing radiation; Ligands; Lung; Lung Inflammation; Malignant Neoplasms; Modality; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Nicotinamide adenine dinucleotide; Nuclear Accidents; Organ; Outcome; Patients; Pattern; Pharmacology and Toxicology; Phase; Pre-Clinical Model; Proteins; Pulmonary Fibrosis; Pulmonary Inflammation; Radiation; Radiation Fibrosis; Radiation Pneumonitis; Radiation exposure; Radiation therapy; Radiolabeled; Rattus; Reactive Oxygen Species; Relapse; Risk; Severities; Site; Small Business Technology Transfer Research; Solid; Steroids; TLR4 gene; Therapeutic; Tissues; Toll-like receptors; Toxic effect; Toxicology; Universities; Vascular Permeabilities; Whole-Body Irradiation; base; companion diagnostics; cytokine; cytokine release syndrome; design; extracellular; humanized monoclonal antibodies; irradiation; mouse model; multidisciplinary; new therapeutic target; nicotinamide phosphoribosyltransferase; novel; novel therapeutic intervention; novel therapeutics; pharmacokinetics and pharmacodynamics; phase 2 study; polyclonal antibody; pre-clinical; precision medicine; preclinical study; radiation-induced lung injury; stable cell line; standard of care; systemic inflammatory response; therapeutic target; therapeutically effective

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.

抽象的 辐射引起的肺损伤（RILI）的发展是癌症患者的潜在致命毒性 接受胸部放射疗法或暴露于核事件的离子化放射疗法（IR）的个体。这 辐射肺炎和辐射诱导的肺纤维化（RILF）的病理生物学很复杂，但包括 未检查注射的有害作用（活性氧，细胞因子，炎症细胞） 虽然Toll样受体（TLR）和 细胞因子是减少RILI，实验和临床策略的潜在治疗靶标，以中和IR- 诱导的促炎性细胞因子作用或阻止炎症细胞浸润令人失望。这 护理标准，高剂量皮质类固醇，由于长期并发症而存在争议，并且经常 潜在的致命继电器。这是识别新型RILI治疗靶标的未满足的需求和有效的 治疗性抗炎策略。我们利用整个肺胸腔照射（WTLI）的临床前研究， 将细胞酶，烟酰胺磷酸贝糖基转移酶（NAMPT）鉴定为一种新型的RILI治疗靶标。 NAMPT以细胞内酶（INAMPT）催化烟酰胺腺嘌呤二核苷酸（NAD）而存在 合成和细胞外炎性细胞因子（ENAMPT）。我们已经表明，ENAMPT是损害 - 相关的分子图案蛋白（潮湿）和TLR4的配体可能诱导失调的失调 炎症反应会导致严重危重疾病的细胞因子风暴，器官功能障碍和死亡。 我们还表明，NAMPT的表达和分泌因辐射而显着增加，并且是关键 随着NAMPT杂合小鼠暴露于WTLI诱导的RILI，RILI发育和严重程度的贡献者。 此外，多克隆ENAMPT PAB有效地减少了WTLI诱导的肺炎和纤维化。我们有 开发的Enamptortm，一种有效的ENAMPT中和人源mab，现在处于稳定的细胞系中 发展。此STTR快速轨道I/II应用程序旨在确认Enamptortm是一种新颖 WTLI和PBI/BM5的临床前模型中的治疗策略（部分身体辐照，5％骨髓 保证）。我们推测Enamptortm将超过接收高剂量的小鼠中观察到的保护 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满足的需求 接触。 Aqualung Therapeutics（ALT）是一家早期生物技术初创企业，与其合作 学术合作伙伴（亚利桑那大学）已组建了一个高技能的多学科团队来评估 Enamptortm是WTLI（SA＃1）和PBI/BM5（SA＃2）的临床前鼠模型中的治疗策略。我们 还将评估放射性标记的nampt mab探针ponamptortm的效用，作为伴侣诊断 定义了IR诱导的NAMPT表达的器官特异性位点的策略。 STTR II期研究将配置 EnamptortM的药效学（PD）和药代动力学（PK）（SA＃4）和毒理学特征 mab（SA＃5）。 Enamptortm在RILI中实用程序的概念证明将导致成功的FDA IND应用程序。