A Universal Strategy for Inducing Tolerance to Therapeutic Mab

诱导治疗性单克隆抗体耐受的通用策略

基本信息

批准号：
9017352
负责人：
Lawrence J Wysocki
金额：
$ 23.78万
依托单位：
NATIONAL JEWISH HEALTH
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：
2016-01-01 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9017352
关键词：
Accounting Adjuvant Adverse effects Affinity Antibodies Antibody Response Antigen-Antibody Complex Antigens Antirheumatic Agents Autoimmunity Binding Binding Sites Biological CD4 Positive T Lymphocytes Cells Cognition Complex Cyclosporine Development Disease Dose Drug Addiction Effectiveness Endotoxins Evaluation Explosion Generic Drugs Genes Haptens Heating Human Immune Immune response Immune system Immunization Immunoglobulin G Immunoglobulin Somatic Hypermutation Incidence Individual Infusion procedures Injection of therapeutic agent Laboratories Libraries Light Link Malignant Neoplasms Measures Methotrexate Modeling Monoclonal Antibodies Monoclonal Antibody Therapy Mus Mutate Nature Patients Peptide Phage Display Library Peptides Phage Display Positioning Attribute Proteins Reaction Reagent Receptors, Antigen, B-Cell Research Somatic Mutation Staging Testing Therapeutic Therapeutic Effect Therapeutic Monoclonal Antibodies Thinking Thrombosis Time Tolerogen Transgenic Organisms Transplantation Treatment Step Variant Work base clinical application design efficacy evaluation experience human monoclonal antibodies humanized monoclonal antibodies immunogenic immunogenicity immunoglobulin B in vivo mouse model nature therapy neutralizing monoclonal antibodies novel physical state polypeptide prototype public health relevance research study response seal tool

项目摘要

DESCRIPTION (provided by applicant): The past two-plus decades have witnessed an explosion of research into the development of monoclonal antibodies (mAb) for therapies ranging from cancer and autoimmunity to transplantation, thrombosis and drug addiction. At least 35 such mAb have obtained FDA approval, and many more are in various stages of development and evaluation. A recurring issue with mAb therapy is that patients frequently generate immune responses against the mAb, often reducing their effectiveness, sometimes with serious consequences. Due to the proteinaceous nature of the therapy, these reactions to passive mAb therapy are dependent upon CD4 T cells that perceive part of the mAb as foreign. These reactions still occur despite extensive efforts to eliminate foreignness from the mAb heavy and light chain polypeptides. Even fully human mAb, derived from human antibody genes expressed in mice or from phage display libraries of human antibody genes, can be perceived as foreign by human CD4 T cells due to extensive CDR3 diversity and somatic mutations. Eliminating these somatic alterations is risky because they are often necessary for conferring a high binding affinity to the mAb. My laboratory has many years of experience with somatic hypermutation and CD4 T cell cognition and responses to mutated sequences within V regions of soluble immunoglobulin and B cell receptors. We are well-positioned to exploit this experience and recent progress to develop a strategy for generating reagents that can induce tolerance to mAb in the CD4 T cell repertoire, so that unwanted immune reactions to therapeutic mAb can be averted. We will test the feasibility of our tolerance strategy in a well-defined mouse model. Our strategy is simple, can be applied to any mAb, and is expected to present few regulatory hurdles, enabling potential widespread clinical application.

描述（由申请人提供）：在过去的二十多年里，单克隆抗体（mAb）的研究呈爆炸式增长，其治疗范围从癌症和自身免疫到移植、血栓形成和药物成瘾，目前已经获得了至少 35 种单克隆抗体（mAb）。 FDA 批准的单克隆抗体疗法，以及许多处于不同开发和评估阶段的单克隆抗体疗法反复出现的问题是，患者经常产生针对单克隆抗体的免疫反应，往往会降低其有效性，有时还会因蛋白质性质而产生严重后果。就治疗而言，这些对被动单克隆抗体治疗的反应依赖于将部分单克隆抗体视为外来物的 CD4 T 细胞，尽管我们付出了大量努力来消除单克隆抗体重链和轻链多肽中的外来物，甚至是完全人源单克隆抗体。由于广泛的 CDR3 多样性和体细胞突变，来自小鼠表达的人抗体基因或来自人抗体基因噬菌体展示文库的抗体可能被人 CD4 T 细胞视为外来物，消除这些体细胞改变是有风险的，因为它们通常是赋予体细胞所必需的。我的实验室在体细胞超突变和 CD4 T 细胞认知以及对可溶性免疫球蛋白和 B 细胞受体 V 区突变序列的反应方面拥有多年的经验。在开发一种策略来生成能够诱导 CD4 T 细胞库中的 mAb 耐受的试剂方面取得了进展，从而可以避免对治疗性 mAb 的不良免疫反应。我们将在一个实验中测试我们的耐受策略的可行性。我们的策略很简单，可以应用于任何单克隆抗体，并且预计不会出现任何监管障碍，从而实现潜在的广泛临床应用。