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Novel strategy to block AAV neutralizing anitbody activity

阻止 AAV 中和抗体活性的新策略

基本信息

批准号：
10080225
负责人：
Chengwen Li
金额：
$ 30万
依托单位：
NABGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080225
关键词：
Address Adoptive Transfer Affect Affinity Animal Model Antibodies Antibody titer measurement Antigen-Antibody Complex Antigens B-Lymphocytes Binding Binding Proteins Biological Blindness Blocking Antibodies Blood Blood Coagulation Disorders Blood Component Removal Canis familiaris Capsid Cell Nucleus Cells Cellular Tropism Chemicals Chromosomes Clinic Clinical Clinical Research Clinical Trials Control Groups DNA Sequence Alteration Data Dependence Dependovirus Development Disease Dose FDA approved Family suidae Gene Delivery Genetic Diseases Hemophilia A Hemorrhage Hereditary Disease High Prevalence Human Immunization Immunize Immunoglobulin Variable Region Immunoglobulins Immunologics In Situ In Vitro Individual Injections Intramuscular Intramuscular Injections Intravenous Immunoglobulins Light Luciferases Mediating Medicine Mendelian disorder Modification Mus Muscle Muscular Atrophy Mutagenesis Mycoplasma Myopathy Nature Neurologic Orphan Drugs Patients Pharmaceutical Preparations Pharmacological Treatment Phase Plasma Population Preparation Production Property Proteins Quality of life Route Safety Serotyping Serum Spinal Structure Surface Testing Therapeutic Time Tissues Transgenes Treatment Efficacy Virion Work adeno-associated viral vector analog base clinical development combinatorial design dosage efficacy testing gene therapy improved improved outcome in vitro activity in vivo mortality multiple myeloma M Protein mutant neutralizing antibody novel strategies pre-clinical prevent protective effect side effect success technology development tissue tropism tool trafficking transduction efficiency transgene expression vector virus tropism

项目摘要

Adeno-associated virus (AAV) vectors have been successfully applied in clinical trials in patients with blindness, neurological/muscular disorders and bleeding diseases. Two AAV based gene therapy drugs have been recently approved by the FDA, Luxturna has been valued at $850,000 for a one-time treatment for a rare form of blindness and Zolgensma at $2,100,000 for spinal muscle atrophy. Gene therapy with AAV vectors has shown a potentially huge market. Although successful in clinical studies, one of major concerns for broader AAV vector application for patients is high prevalence of neutralizing antibody (Nab). AAV Nabs are able to bind to the surface of virions and interfere with AAV binding to target cells or intracellular trafficking or uncoating in the nucleus, and then block effective AAV transduction. In the general human population, over 95% of individuals have been infected by AAV and, on average, 50% of them have Nabs. Several approaches have been explored to evade AAV Nabs, including chemical modification, different serotype of AAV vector, rational design and combinatorial mutagenesis of the capsid in situ, as well as biological depletion of Nab titer (empty capsid utilization, B cell depletion and plasma-apheresis). Generally, these approaches have low efficiency, troubling side effects, or alter beneficial AAV properties like infectivity and production yield. Therefore, it is imperative to develop ideal strategies to evade Nabs, but without a changing tissue tropism from modification of capsids or negative side-effects of pharmacological treatment. Recently, we have developed a vector independent protein-based strategy to universally block Nabs. We have pioneered the use of a unique mycoplasma derived protein and its analogues, termed Protein-M, to enable successful gene delivery by preventing AAV neutralization of Nabs. Protein-M is able to interact with immunoglobulins from any species without antigen dependence by universally binding to variable regions on the antibody light and heavy chains. We have validated Protein-M mediated Nab escape in vitro using human IVIG and serum from AAV immunized mice, and found that Protein-M protected AAV vector neutralization over 100-fold when compared to control group without Protein-M. Most importantly, we found that 1000-fold protection of AAV transduction could be achieved in vivo when using Protein-M in mice after adoptive transfer of Nab positive serum. So far, this is the most effective strategy to evade AAV Nabs. To explore the application of Protein-M in clinical trials, it is imperative to address the efficacy of Protein-M for Nab blockage in subjects with pre-immunization. In this proposal, we will first study the effect of Protein-M on AAV Nabs blockage for systemic AAV gene delivery (Aim 1). Preliminary results have also shown that circulating Nabs block transduction during local administration of AAV vectors. Next, we will study the effect of Protein-M administered via different routes on muscle transduction after direct muscular injection of AAV vectors (Aim 2). If successful in preclinical animal models, these AAV mutants can be immediately transitioned to the clinic.

腺相关病毒（AAV）载体已成功应用于临床试验