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Targeting EndoS to auto-antibodies

将 EndoS 靶向自身抗体

基本信息

批准号：
10356157
负责人：
ERIC JOHN SUNDBERG
金额：
$ 23.48万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-18 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356157
关键词：
Address Affect Animal Model Antibodies Antigens Arthritis Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Binding Chimeric Proteins Chronic Clinical Collagen Complement Complement Activation Complex Development Disease Disease model Endoglycosidases Engineering Ensure Enzyme Kinetics Enzymes Epidermolysis Bullosa Acquisita Fc Receptor Glycoproteins Immune response Immune signaling Immune system Immunity Immunoglobulin G Immunologics Immunosuppression Immunosuppressive Agents In Vitro Infection Inflammation Injections Lead Learning Length Link MS4A1 gene Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Methods Mus N-terminal Neuromyelitis Optica Pathologic Pharmaceutical Preparations Polysaccharides Population Property Protein Engineering Proxy Purpura Risk Specificity Streptococcus pyogenes Symptoms System Systemic Lupus Erythematosus Testing Therapeutic Therapeutic Uses Thrombocytopenia Tissues Translating design diagnostic biomarker expectation experimental study in vivo mouse model preclinical development protein function receptor receptor binding reduce symptoms rituximab side effect sugar therapeutic development

项目摘要

Autoantibodies, which recognize autoantigens (i.e., self-antigens), serve as both hallmarks and diagnostic markers of autoimmune diseases. Although autoimmune disease mechanisms are complex and involve various humoral and cellular immune responses, some are exclusively dependent on the presence of autoantibodies. Upon binding to their cognate autoantigens, self-reactive antibodies induce effector mechanisms of immunity through complement activation and/or Fc receptor binding. The resulting autoantibody-mediated effector mechanisms lead to chronic inflammation and the eventual tissue damage symptomatic of autoimmune disease. The effector functions mediated by IgG antibodies, whether they recognize self or foreign antigens, are entirely dependent on the presence of an N-linked complex type glycan on Asn297 of the IgG Fc region, which enables the antibody to bind Fc γ receptors (FcγRs) and activate complement, endowing the antibody with immune signaling capabilities. Endoglycosidases (i.e., enzymes that remove glycans from glycoproteins) can remove the glycan molecule linked to Asn297 and render IgG antibodies immunologically inert. Of all the known endoglycosidases, Endoglycosidase S (EndoS) is unique in that it removes only the Asn297-linked glycan from IgG antibodies. Due to its IgG-specific properties, EndoS pretreatment of pathological autoantibodies and/or injection of purified EndoS in animal models of autoimmunity has been shown to protect against or alleviate the symptoms of many autoimmune diseases. Although EndoS is exquisitely specific to IgG antibodies, it has no capacity to discriminate between antibodies with different antigen specificities. Instead, EndoS deglycosylates all IgG antibodies, including those that keep cancer in check, as well as those that are specific to foreign antigens that provide defense from infections. Engineering EndoS such that it recognizes and deglycosylates only autoantibodies, as opposed to all IgG antibodies, is essential for making a truly specific autoimmunity drug. We hypothesize that we can translate EndoS from an autoimmune disease therapeutic of great potential to one of actual clinical utility by constructing fusion proteins of EndoS linked to autoantigens (EndoS-autoAg) that will drive the targeted deglycosylation and inactivation of pathological autoantibodies, while leaving the remainder of the immune system functionally intact. We will provide proof-of-principle for this concept by: (1) optimizing EndoS-autoAg fusion protein properties for specificity and activity in vitro; and (2) investigating EndoS-autoAg fusion protein efficacy and specificity in vivo using a mouse model of autoimmune epidermolysis bullosa acquisita (EBA).

自身抗体，识别自身抗原（即自身抗原），作为标志和诊断