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

描述（由申请人提供）： 淀粉样轻链淀粉样变性是一种罕见的疾病，其特征是在组织和器官的细胞外空间形成和沉积不溶性淀粉样蛋白（淀粉样蛋白 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，以减少或消除淀粉样蛋白生成轻链产生细胞。虽然新药物的开发提高了生存率，但由于病理性纤维沉积的积累，预后仍然很差 导致重要器官功能丧失为了诱导淀粉样蛋白从体内快速清除，所罗门博士开发了一种鼠单克隆抗轻链抗体（命名为11- 1F 4），该抗体对轻链淀粉样蛋白原纤维具有特异性。此外，将该药剂施用到具有由人AL淀粉样蛋白组成的诱导皮下肿瘤的小鼠中导致消除，即，病理物质的淀粉样蛋白溶解，没有明显的不良副作用。以促进其 在人类中的应用中，鼠mAb 11- 1F 4已经在国家癌症研究所生物资源分支发展治疗计划的赞助下嵌合，并且已经产生了足以用于1a/1b期治疗临床试验的GMP级嵌合（Ch）mAb 11- 1F 4的量。 该临床试验拟（1）在1a期研究中确定（Ch）Ab 11- 1F 4的MTD和安全性;（2）在1b期研究中确定（Ch）Ab 11- 1F 4的MTD的安全性、耐受性和可能的临床获益;以及（3）通过酶联免疫吸附测定（ELISA）测定单次静脉输注时治疗患者中的（Ch）mAb 11- 1F 4的血清水平（1a期）或作为一系列每周4次静脉输注（1b期）。AL-原纤维特异性mAb治疗有效性的证据将成为AL淀粉样变性患者治疗的辅助（与抗浆细胞药物联合），并可能改善这种不可治愈和致命疾病的医学管理。

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.