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: 10011266
• 负责人: Joe G. N. Garcia
• 金额: $ 30万
• 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 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011266
• 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; 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; Treatment Efficacy; Universities; Vascular Permeabilities; Whole-Body Irradiation; base; companion diagnostics; cytokine; cytokine release syndrome; design; extracellular; humanized monoclonal antibodies; irradiation; lung injury; mouse model; multidisciplinary; new therapeutic target; nicotinamide phosphoribosyltransferase; novel; novel therapeutics; pharmacokinetics and pharmacodynamics; phase 2 study; polyclonal antibody; pre-clinical; precision medicine; preclinical study; stable cell line; standard of care; therapeutic target

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 放射性肺损伤 (RILI) 的发展对癌症患者来说是一种潜在的致命毒性 接受胸部放射治疗或因核事故而暴露于电离辐射 (IR) 的个体。 放射性肺炎和放射性肺纤维化 (RILF) 的病理学很复杂，但包括 不受控制的炎症（活性氧、细胞因子、炎症细胞）的有害影响 增加血管通透性，损害气体传输并促进纤维化。 细胞因子是减少 RILI 的潜在治疗靶点，中和 IR- 的实验和临床策略 诱导促炎细胞因子作用或阻止炎症细胞浸润的效果令人失望。 由于长期并发症和频繁发生，高剂量皮质类固醇的护理标准仍然存在争议。 因此，确定新的 RILI 治疗靶点和有效的治疗需求尚未得到满足。 我们的临床前研究利用全肺胸部照射（WTLI）， 确定了一种细胞酶烟酰胺磷酸核糖转移酶 (NAMPT) 作为新的 RILI 治疗靶点。 NAMPT 作为催化烟酰胺腺嘌呤二核苷酸 (NAD) 的细胞内酶 (iNAMPT) 存在 合成并作为细胞外炎症细胞因子 (eNAMPT) 我们已经证明 eNAMPT 是一种损伤- 相关分子模式蛋白 (DAMP) 和 TLR4 配体可有效诱导失调 炎症反应导致细胞因子风暴、器官功能障碍和严重危重疾病的死亡。 我们还表明，NAMPT 表达和分泌通过辐射显着增加，是关键 由于 NAMPT 杂合子小鼠表现出 WTLI 诱导的 RILI 减少，因此对 RILI 的发展和严重程度做出了贡献。 此外，多克隆 eNAMPT pAb 可以有效减少 WTLI 诱导的肺炎和纤维化。 开发了 eNamptorTM，一种有效的 eNAMPT 中和人源化单克隆抗体，现已在稳定细胞系中使用 该 STTR 快速通道 I/II 期申请旨在确认 eNamptorTM 是一种新颖的产品。 WTLI和PBI/BM5临床前模型的治疗策略（部分身体照射，5%骨髓 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 早期生物技术初创公司 Aqualung Therapeutics (ALT) 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来评估 eNamptorTM 作为 WTLI (SA #1) 和 PBI/BM5 (SA #2) 临床前小鼠模型的治疗策略。 还将评估放射性标记 NAMPT mAb 探针 ProNAmptorTM 作为伴随诊断的效用 定义 IR 诱导的 NAMPT 表达的器官特异性位点的策略 STTR II 期研究将进行分析。 eNamptorTM 的药效学 (PD) 和药代动力学 (PK) (SA #4) 以及毒理学特征 mAb（SA #5）。eNamptorTM 在 RILI 中的实用性概念验证将导致 FDA IND 申请成功。