Recombinant Hyperimmune Gammaglobulin for Primary Immunodeficiency

重组超免疫丙种球蛋白治疗原发性免疫缺陷

基本信息

批准号：
9304957
负责人：
David Scott Johnson
金额：
$ 74.97万
依托单位：
GIGAGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9304957
关键词：
Address Adult Affect American Antibiotics Antibodies Antibody Repertoire Antibody titer measurement Antigens Bacteria Binding Biochemistry Biological Assay CLIA certified Capital Cells Chronic Chronic lung disease Clinical Cohort Studies Congenital Disorders Cytomegalovirus DNA Library Data Diagnostic Diagnostic tests Doctor of Philosophy Drug Kinetics Europe Exclusion FDA approved Failure Family Flow Cytometry Genomics Hemophilus High Pressure Liquid Chromatography Immune Immune System Diseases Immunocompromised Host Immunoglobulin A Immunologist In Vitro Infection Influenza Intravenous Immunoglobulins Ion Exchange Libraries Light-Chain Immunoglobulins Lung Methods Microfluidics Morbidity - disease rate Outcome Patients Pharmaceutical Preparations Phase Plasma Pneumonia Prophylactic treatment Proteins Recombinants Recurrence Rodent Scientist Sequoia Small Business Innovation Research Grant Specialist Streptococcus Testing Therapeutic Time Toxicology Transplant Recipients United States National Institutes of Health Vaccinated Virus West Nile virus Work X-Linked Agammaglobulinemia antibody libraries combat congenital immunodeficiency efficacy study improved meetings monomer mortality new technology novel strategies pathogen polyclonal antibody preclinical efficacy product development prophylactic public health relevance response seropositive transcriptome sequencing

项目摘要

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.

描述（由适用提供）：该SBIR直接到相位II项目的具体目的是开发自然曲目重组静脉性免疫球蛋白（Rivig）“ Hyperimmunes”针对原发性免疫缺陷（PID）患者的常见病原体。 PID是一个先天性疾病的潜水家族，包括常见的可变免疫缺陷（CVID）和X连接的Agammaglobloblobloblinemia（XLA），其特征是抗体滴度大大降低。免疫学家用预防性的静脉免疫球蛋白（IVIG）治疗体液PID，这是从数千个供体的血浆中分离出来的蛋白质池。尽管如此，有40％的患者复发性肺炎，由于慢性肺部疾病而导致肺部衰竭36％。大多数复发感染的PID患者接受预防性抗生素以解决慢性感染。高免疫是血浆来源的γ球蛋白，可用于针对特定病原体的活性。不幸的是，九个FDA批准的高免疫并不能解决PID患者最造成发病率和死亡率的病原体。以前，我们开发了GigAlink（TM），该Gigalink（TM）使用微流体和多重PCR来构建抗体库中的大规模多克隆DNA文库，并具有完整的天然重链和轻链免疫球蛋白（IG）配对。在我们的初步工作中，我们利用了Gigalink（TM）来产生和表征具有> 40倍富集的结合活性的高免疫影响。在这个SBIR直接到相位II项目中，我们将增加两种对PID结果至关重要的病原体，生产多个Rivig的测试批次，并进行毒理学，药代动力学和病原体结合研究。尽管PID是主要的临床指示，但这些药物可用于其他类型的免疫功能低下的患者，例如移植受者。最后，我们的治疗方法将有助于对抗新兴的病原体，即西尼罗河快速反应。