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间隙形成和沉积不溶性纤维蛋白(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，以减少或消除产生淀粉样变轻链的细胞。尽管新药物的开发提高了存活率，但由于病理性纤维沉积的堆积，预后仍然很差。 以及由此导致的重要器官功能丧失。为了诱导淀粉样蛋白快速从体内清除，所罗门博士开发了一种针对轻链淀粉样蛋白纤维的鼠源性抗轻链抗体(命名为11-1F4)。此外，在由人AL淀粉样蛋白组成的诱发皮下肿瘤的小鼠中，给药该药可导致病理物质的消除，即淀粉样变性，而没有明显的不良副作用。为其提供便利 在人类中使用，鼠源单抗11-1f4已在国家癌症研究所生物资源分部开发治疗计划的赞助下嵌合，并已生产出足以进行1a/1b期治疗临床试验的GMP级嵌合(CH)单抗11-1f4。 这项临床试验建议(1)在1a期研究中确定(CH)Ab11-1f4的MTD和安全性；(2)在1b期研究中确定(CH)Ab11-1f4的MTD的安全性、耐受性和可能的临床益处；(3)通过酶联免疫吸附试验(ELISA)确定接受治疗的患者在作为单一静脉输液(1a阶段)或作为一系列每周4次静脉输注(1b阶段)时的(CH)mAb11-1f4的血清水平。AL纤维特异性单抗治疗的有效性的证据将是治疗AL淀粉样变性患者的辅助(结合抗浆细胞药物)，并可能导致改善对这种不治之症和致命疾病的医疗管理。

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.