Phase 1a/1b Study of 11-1F4 mAb for the Treatment of AL Amyloidosis

11-1F4 mAb 治疗 AL 淀粉样变性的 1a/1b 期研究

• 批准号: 9137618
• 负责人: Suzanne Lentzsch
• 金额: $ 20万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9137618
• 关键词: Phase; 1a; 1b; Study; 11

DESCRIPTION (provided by applicant): Amyloid Light-chain (AL) amyloidosis is a rare disease characterized by the formation and deposition of insoluble fibrillary proteins (amyloid) in extracellular spaces of tissues and organs resulting in severe structural and functional organ damage. Currently, treatment of patients with AL amyloidosis is limited to anti-plasma cell chemotherapy to reduce or eliminate the amyloidogenic light chain producing cells. Although the development of new agents has improved survival, the prognosis is still poor due to accumulation of pathologic fibrillar deposits and the resultant loss of vital organ function. In an effort to induce rapid removal of amyloid fro the body, Dr. Solomon developed a murine monoclonal anti-light chain antibody (designated 11-1F4) that is specific for light-chain amyloid fibrils. Moreover, administration of this agent into mice with induced subcutaneous tumors composed of human AL amyloid led to elimination, i.e., amyloidolysis, of the pathologic material with no apparent untoward side effects. To facilitate its use in humans, the murine mAb 11-1F4 has been chimerized under the auspices of the National Cancer Institute's Biological Resource Branch Developmental Therapeutic Program and amounts of GMP-grade chimeric (Ch) mAb 11-1F4 have been produced that are sufficient for a Phase 1a/1b therapeutic clinical trial. The clinical trial proposes to (1) define the MTD and safety of (Ch) Ab 11-1F4 in a Phase 1a study; (2) determine the safety, tolerance and possible clinical benefit of the MTD of (Ch) Ab 11-1F4 in a Phase 1b study; and (3) determine the serum levels of (Ch) mAb 11-1F4 in treated patients by enzyme-linked immunosorbent assay (ELISA) when given as a single intravenous infusion (Phase 1a) or as a series of four weekly intravenous infusions (Phase 1b). Proof of the efficacy of AL-fibril-specific mAb treatment would be an adjunct (in combination with anti-plasma cell drugs) in the treatment of patients with AL amyloidosis and may lead to improved medical management of this incurable and fatal disease.

描述（由申请人提供）： 淀粉样蛋白轻链（AL）淀粉样变性是一种罕见疾病，其特征是不溶性纤维蛋白（淀粉样蛋白）在组织和器官的细胞外空间形成和沉积 导致严重的结构和功能器官损伤。目前，AL淀粉样变性患者的治疗仅限于抗浆细胞化疗，以减少或消除产生淀粉样蛋白轻链的细胞。尽管新药的开发提高了生存率，但由于病理性纤维沉积物的积累，预后仍然很差 以及由此导致的重要器官功能的丧失。为了促使淀粉样蛋白从体内快速去除，Solomon 博士开发了一种针对轻链淀粉样原纤维的鼠单克隆抗轻链抗体（命名为 11-1F4）。此外，将该药物注射到具有由人 AL 淀粉样蛋白组成的诱导皮下肿瘤的小鼠中，导致病理物质的消除，即淀粉样蛋白溶解，并且没有明显的不良副作用。为方便其 在人类中使用时，在美国国家癌症研究所生物资源分部发展治疗计划的支持下，鼠 mAb 11-1F4 已被嵌合，并且已生产出足以用于一个阶段的 GMP 级嵌合 (Ch) mAb 11-1F4 数量1a/1b 治疗性临床试验。 临床试验建议 (1) 在 1a 期研究中定义 (Ch) Ab 11-1F4 的 MTD 和安全性； (2) 在 1b 期研究中确定 (Ch) Ab 11-1F4 的 MTD 的安全性、耐受性和可能的​​临床益处； (3) 当作为单次静脉输注（第 1a 阶段）或每周四次静脉输注（第 1 阶段）时，通过酶联免疫吸附测定 (ELISA) 测定治疗患者中 (Ch) mAb 11-1F4 的血清水平。 1b). AL 原纤维特异性单克隆抗体治疗的有效性证明将成为 AL 淀粉样变性患者治疗的辅助手段（与抗浆细胞药物联合），并可能改善这种无法治愈的致命疾病的医疗管理。