Recombinant Hyperimmune Gammaglobulin for Pneumococcal Disease

用于治疗肺炎球菌疾病的重组超免疫丙种球蛋白

• 批准号: 8979450
• 负责人: David Scott Johnson
• 金额: $ 22.48万
• 依托单位: GIGAGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8979450
• 关键词: Acute; Antibiotics; Antibodies; Antibody Formation; Antibody Repertoire; B cell repertoire; B-Lymphocytes; Bacteria; Biological Assay; Blood donor; Capital; Cells; Child; Chronic; Clinical; Cyclic GMP; DNA Library; Diagnostic; Disease; Doctor of Philosophy; Dose; Drug Kinetics; Ebola virus; Engineering; Family; Fertilization in Vitro; Frequencies; Genomics; Human; Immune; Immune System Diseases; Immunocompromised Host; Immunoglobulin G; Immunoglobulins; Immunologist; In Vitro; Infection; Intravenous Immunoglobulins; Libraries; Licensing; Light-Chain Immunoglobulins; Linear Regressions; Logistics; Market Research; Marketing; Microfluidics; Patients; Phase; Pneumococcal Infections; Pneumovax; Polyvalent pneumococcal vaccine; Prevention; Proteins; Protocols documentation; Publishing; Recombinants; Recurrence; Refractory; Research; Serum; Services; Small Business Innovation Research Grant; Streptococcus pneumoniae; System; Technology; Testing; Toxicology; Transcript; United States National Institutes of Health; Vaccinated; Viral; X-Linked Agammaglobulinemia; cGMP production; commercialization; in vitro activity; innovation; lot production; new technology; pediatrician; polyclonal antibody; programs; prophylactic; public health relevance; response

 DESCRIPTION (provided by applicant): Recombinant Hyperimmune Gammaglobulin for Pneumococcal Disease Organization: GigaGen Inc. PI: David S. Johnson, Ph.D. The Specific Aim of this SBIR Phase I project is to make and test a pilot batch of natural repertoire recombinant Streptococcus pneumonia immunoglobulin (rSpIg), or "hyperimmune", for treatment and prevention of pneumococcal infections. Humoral primary immune deficiency (PID) is a diverse family of disorders, including common variable immune deficiency (CVID) and X-linked agammaglobulinemia (XLA), characterized clinically by recurrent infections. Immunologists treat humoral PID with prophylactic intravenous immunoglobulin (IVIg), which is a pool of proteins isolated from the sera of thousands of donors. IVIg reduces pneumococcal infections in CVID and XLA patients by at least 75% (Busse et al., 2002; Bayrakci et al., 2005; Lucas et al., 2010). Presumably because <0.1% of the antibodies in IVIg have activity against pneumococcus (Mikolajczyk et al., 2004), many PID patients require higher IVIg doses to reduce rates of pneumococcal infections (Orange et al., 2010; Tuerlinckx et al., 2014). A targeted pneumococcal hyperimmune, i.e., a gammaglobulin enriched for anti- pneumococcal antibodies, might have even higher efficacy without requiring costly doses. Previously, we developed GigaLink(tm) (Johnson et al., 2013), which uses microfluidics and multiplexed PCR to build DNA libraries from antibody repertoires, with native heavy and light chain immunoglobulin paring intact. We market the technology as a research service for big pharma. This Phase I SBIR will adapt GigaLink(tm) specifically to create a recombinant pneumococcal hyperimmune. Our technical innovation is to express GigaLinkTM natural human repertoire DNA libraries in a stable CHO expression system. To make rSpIg, we will first use GigaLinkTM to capture B cells from donors recently vaccinated with Pneumovax(r) 23. We will then stably express the antibody sequences en masse in CHO to produce an anti-pneumococcal hyperimmune protein product. The stable CHO can be passaged and used repeatedly to produce thousands of rSpIg protein preps. The resulting pneumococcal hyperimmune, or rSpIg, will first enable clinical innovations that will help patients with immune deficiency or who are otherwise immunocompromised. Phase I will demonstrate that we can produce a test batch of rSpIg that shows in vitro activity. In Phase II, we will take steps to build a cGMP production protocol and perform toxicology, pharmacokinetic, and efficacy studies on cGMP rSpIg. At first, rSpIg will act as a pneumococcal booster for conventional IVIg in primary humoral deficiency patients, both in chronic and acute settings. We also envision that pediatricians would use rSpIg for specific antibody deficiency (SAD) in children who are refractory to antibiotics (Sorensen & Moore, 2000). Finally, experts tell us that our technology will also be useful to develop viral hyperimmune gammaglobulins, i.e., for Ebola rapid response.

 描述（由申请人提供）：用于肺炎球菌疾病的重组超免疫丙种球蛋白 组织：GigaGen Inc. PI：David S. Johnson, Ph.D.该 SBIR 第一阶段项目的具体目标是制备和测试一批中试批次的天然重组肺炎链球菌免疫球蛋白 (rSpIg)，或“超免疫”，用于治疗和预防肺炎球菌感染。体液原发性免疫缺陷 (PID) 是一个多样化的疾病家族，包括常见变异免疫缺陷 (CVID) 和 X 连锁无丙种球蛋白血症 (XLA)，其临床特征为反复感染。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 是从数千名捐献者的血清中分离出来的蛋白质库。 IVIg 可使 CVID 和 XLA 患者的肺炎球菌感染减少至少 75%（Busse 等人，2002 年；Bayrakci 等人，2005 年；Lucas 等人，2010 年）。据推测，由于 IVIg 中 <0.1% 的抗体具有抗肺炎球菌活性（Mikolajczyk 等，2004），许多 PID 患者需要更高的 IVIg 剂量来降低肺炎球菌感染率（Orange 等，2010；Tuerlinckx 等，2014）。靶向肺炎球菌超免疫，即富含抗肺炎球菌抗体的丙种球蛋白，可能具有更高的功效，而不需要昂贵的剂量。此前，我们开发了 GigaLink(tm)（Johnson 等人，2013），它使用微流体和多重 PCR 从抗体库构建 DNA 文库，天然重链和轻链免疫球蛋白配对完整。我们将该技术作为大型制药公司的研究服务进行营销。该 I 期 SBIR 将专门采用 GigaLink(tm) 来创建重组肺炎球菌超免疫疫苗。我们的技术创新是在稳定的 CHO 表达系统中表达 GigaLinkTM 天然人类库 DNA 文库。为了制备 rSpIg，我们将首先使用 GigaLinkTM 捕获最近接种 Pneumovax(r) 23 疫苗的捐赠者的 B 细胞。然后，我们将在 CHO 中稳定表达抗体序列，以生产抗肺炎球菌超免疫蛋白产品。稳定的 CHO 可以传代并重复使用，以生产数千种 rSpIg 蛋白制剂。由此产生的肺炎球菌超免疫（rSpIg）将首先实现临床创新，帮助免疫缺陷或免疫功能低下的患者。第一阶段将证明我们可以生产一批具有体外活性的 rSpIg 测试批次。在 第二阶段，我们将采取措施建立cGMP生产方案，并对cGMP rSpIg进行毒理学、药代动力学和功效研究。首先，rSpIg 将作为原发性体液缺乏症患者中传统 IVIg 的肺炎球菌增强剂，无论是慢性还是急性情况。我们还设想儿科医生将使用 rSpIg 治疗对抗生素耐药的儿童的特异性抗体缺乏症 (SAD)（Sorensen & Moore，2000）。最后，专家告诉我们，我们的技术也将有助于开发病毒超免疫丙种球蛋白，即用于埃博拉病毒的快速反应。