Recombinant Hyperimmune Gammaglobulin for Primary Immunodeficiency

 描述(申请人提供)：这个SBIR直接到第二阶段的项目的具体目标是开发天然的重组静脉免疫球蛋白(RIVIg)针对主要免疫缺陷(PID)患者的常见病原体的“超级免疫”。PID是一种不同的先天性疾病家族，包括常见变量免疫缺陷(CVID)和X连锁无丙种球蛋白血症(XLA)，其特征是抗体效价显著降低。免疫学家使用预防性静脉免疫球蛋白(IVIg)治疗体液性早泄，IVIg是从数千名捐赠者的血浆中分离出来的蛋白质池。尽管如此，40%的患者患有复发性肺炎，36%的患者死于慢性肺部疾病导致的肺衰竭。大多数反复感染的盆腔炎患者接受预防性抗生素治疗，以应对慢性感染。超级免疫是一种血浆衍生的丙种球蛋白，它被浓缩以对抗特定的病原体。不幸的是，FDA批准的9种超级免疫疗法并没有解决导致产后妊娠综合征患者发病率和死亡率的最主要病原体。此前，我们开发了GigaLink(Tm)，它使用微流控和多重PCR从抗体库中构建大规模多克隆DNA文库，天然的重链和轻链免疫球蛋白(Ig)配对完好无损。在我们的初步工作中，我们利用GigaLink(Tm)生产并鉴定了具有&gt；40倍丰富结合活性的高免疫流感病毒rIVIg。在这个SBIR直接进入第二阶段的项目中，我们将为另外两种对PID结果至关重要的病原体添加超级免疫，生产几个测试批次的rIVIg，并进行毒理学、药代动力学和病原体结合研究。虽然PID是主要的临床适应症，但这些药物也可以用于其他类型的免疫低下患者，如移植受者。最后，我们的治疗方法将有助于对抗新出现的病原体，即西尼罗河的快速反应。

 DESCRIPTION (provided by applicant): The Specific Aim of this SBIR direct-to-Phase II project is to develop natural repertoire recombinant intravenous immunoglobulin (rIVIg) "hyperimmunes" against common pathogens for patients with primary immune deficiency (PID). PID is a diverse family of congenital disorders, including common variable immune deficiency (CVID) and X- linked agammaglobulinemia (XLA), which are characterized by significantly reduced antibody titers. Immunologists treat humoral PID with prophylactic intravenous immunoglobulin (IVIg), which is a pool of proteins isolated from the plasma of thousands of donors. Still, 40% of patients suffer recurrent pneumonia, and 36% die from lung failure due to chronic lung disease. Most PID patients with recurrent infections receive prophylactic antibiotics to address chronic infection. Hyperimmunes are plasma-derived gammaglobulins that are enriched for activity against a particular pathogen. Unfortunately, the nine FDA-approved hyperimmunes do not address the pathogens that are most responsible for morbidity and mortality in PID patients. Previously, we developed GigaLink(tm), which uses microfluidics and multiplexed PCR to build massively polyclonal DNA libraries from antibody repertoires, with native heavy and light chain immunoglobulin (Ig) pairing intact. In our preliminary work, we leveraged GigaLink(tm) to produce and characterize hyperimmune influenza rIVIg with >40× enriched binding activity. In this SBIR direct-to-Phase II project, we will add hyperimmunes for two more pathogens of critical importance to PID outcomes, manufacture several test batches of rIVIg, and perform toxicology, pharmacokinetic, and pathogen binding studies. Though PID is the primary clinical indication, these drugs could be used for other kinds of immunocompromised patients, such as transplant recipients. Finally, our therapeutic approach will be useful to combat emerging pathogens, i.e., for West Nile rapid response.