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（适用提供）：肺炎球菌疾病组织的重组超免疫伽马卢蛋白：Gigagen Inc. PI：David S. Johnson，博士该SBIR I期项目的具体目的是制造和测试一批天然曲目重组肺炎肺炎链球菌免疫球蛋白（RSPIG）或“ Hypermmune”，以治疗和预防肺炎球菌感染。体液原发性免疫学家用预防性静脉内免疫球蛋白（IVIG）治疗体液PID，该蛋白是从数千个供体的血清中分离出来的蛋白质池。 IVIG将CVID和XLA患者的肺炎球菌感染降低至少75％（Busse等，2002； Bayrakci等，2005； Lucas等，2010）。大概是因为IVIG中<0.1％的抗体具有对肺炎球菌的活性（Mikolajczyk等人，2004年），许多PID患者需要更高的IVIG剂量来降低肺炎球菌感染的发生率（Orange等，2010; Tuerlinckx等，2014; Tuerlinckx等，2014）。靶向性肺炎球菌超免疫，即富含抗巨炎抗体的γ球蛋白可能具有更高的效率，而无需昂贵的剂量。以前，我们开发了GigAlink（TM）（Johnson等，2013），该链接使用微流体和多重PCR来构建来自抗体库的DNA库，其天然重链和轻型链免疫球蛋白完整。我们将该技术作为大型制药的研究服务推销。该阶段I SBIR将专门适应Gigalink（TM），以创建重组肺炎球菌超免疫。我们的技术创新是在稳定的CHO表达系统中表达gigalinktm天然人类曲目DNA库。为了制作RSPIG，我们将首先使用gigalinktm捕获最近接种肺炎疫苗（R）23的供体的B细胞。然后，我们将在CHO中稳定地表达抗体序列，以产生抗Pneumocococococcal Hypermmune蛋白质产物。稳定的CHO可以通过并反复使用以产生数千种RSPIG蛋白准备。由此产生的肺炎球菌超免疫或RSPIG将首先实现临床创新，以帮助免疫缺陷或以其他方式进行免疫功能。第一阶段将证明我们可以生成一批显示体外活性的RSPIG。在 第二阶段，我们将采取措施构建CGMP生产方案，并对CGMP RSPIG进行毒理学，药代动力学和有效研究。首先，在慢性和急性环境中，RSPIG将作为原发性体液缺陷患者的常规IVIG的肺炎球菌助推器。我们还设想儿科医生将使用RSPIG来解决对抗生素难治性儿童的特定抗体缺乏症（SAD）（Sorensen＆Moore，2000）。最后，专家告诉我们，我们的技术对于开发病毒性超免疫γ球蛋白，即埃博拉病毒快速反应也将很有用。