Recombinant Hyperimmune Gammaglobulin for Primary Immunodeficiency

 描述（由申请方提供）：该SBIR直接进入II期项目的具体目的是为原发性免疫缺陷（PID）患者开发针对常见病原体的天然重组静脉内免疫球蛋白（rIVIg）“超免疫”。PID是一种多样的先天性疾病家族，包括常见可变免疫缺陷（CVID）和X连锁无丙种球蛋白血症（XLA），其特征在于抗体滴度显著降低。免疫学家用预防性静脉注射免疫球蛋白（IVIg）治疗体液性PID，IVIg是从数千名献血者的血浆中分离出来的一种蛋白质。尽管如此，40%的患者患有复发性肺炎，36%的患者死于慢性肺病引起的肺衰竭。大多数复发性感染的PID患者接受预防性抗生素治疗以解决慢性感染。超免疫是血浆来源的γ球蛋白，其富集针对特定病原体的活性。不幸的是，FDA批准的九种超免疫药物并没有解决PID患者发病率和死亡率最高的病原体。先前，我们开发了GigaLink（tm），其使用微流体和多重PCR从抗体库构建大规模多克隆DNA文库，其中天然重链和轻链免疫球蛋白（IG）配对完整。在我们的初步工作中，我们利用GigaLink（TM）生产和表征具有>40倍富集结合活性的超免疫流感rIVIg。在这个SBIR直接进入II期项目中，我们将为另外两种对PID结果至关重要的病原体添加超免疫，生产几批rIVIg测试批次，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，但这些药物可用于其他类型的免疫功能低下患者，如移植受者。最后，我们的治疗方法将有助于对抗新兴病原体，即，西尼罗河快速反应

 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.