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Rationalizing glycoengineering strategies for immunotherapeutic antibodies

免疫治疗抗体糖工程策略的合理化

基本信息

批准号：
10598482
负责人：
ERIC JOHN SUNDBERG
金额：
$ 47.32万
依托单位：
EMORY UNIVERSITY
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：
2020-04-08 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598482
关键词：
Active Sites Affect Alanine Animal Model Antibodies Autoantibodies Autoimmune Diseases Autoimmunity Bacteria Binding Biotechnology Carbohydrates Chemistry Clinical Complement Complex Coupled Cryoelectron Microscopy Data Development Endoglycosidases Endowment Engineering Enzymes Exhibits Family Future Glycobiology Glycoengineering Glycoproteins Glycoside Hydrolases Health Homologous Gene Human Hybrids IgG Receptors IgG1 Immune response Immune system Immunity Immunoglobulin G Immunologic Receptors Immunotherapeutic agent Inflammatory Knowledge Link Malignant Neoplasms Mannose Molecular Mutagenesis Natural Source Pathologic Processes Pharmaceutical Preparations Physiological Processes Polysaccharides Post-Translational Protein Processing Preparation Property Proteins Rationalization Reaction Reagent Reproducibility Resolution Role Scanning Site Space Perception Specificity Streptococcus pyogenes Structure Substrate Specificity Tertiary Protein Structure Therapeutic Therapeutic antibodies Variant X-Ray Crystallography antibody engineering arm base chemical synthesis clinical efficacy design experimental study falls glycosylation human disease human pathogen immunoreaction immunoregulation insight interest next generation novel novel therapeutics receptor therapeutic protein tool

项目摘要

In order to evade host immunity, many bacteria secrete immunomodulatory enzymes. Streptococcus pyogenes, one of the most common human pathogens, secretes unique endoglycosidases, including EndoS, which removes complex-type glycans in a highly specific manner from human IgG antibodies, and its homolog EndoS2, which can additionally remove IgG-linked high-mannose glycans. This renders antibodies incapable of eliciting host effector functions through either complement or Fc γ receptors (FcγRs), providing the bacteria with a survival advantage. Because antibodies are central players in many human immune responses and bridge the innate and adaptive arms of immunity, the analysis and manipulation of the enzymatic activities of EndoS and EndoS2 impact diverse fields in biomedicine. In particular, modifying antibody glycan structures can have significant impacts on their abilities to bind to FcγRs and the subsequent immune system reactions that they induce. The next generation of therapeutic antibodies is already being constructed with modified glycan chemistries to tailor their immune reactions and to increase their clinical potency. EndoS and EndoS2, as antibody-specific glycosidases, and glycosynthases derived thereof, are key enzymes in the future of antibody engineering. We propose that if the molecular mechanisms by which diverse endoglycosidases specifically recognize and hydrolyze distinct glycoprotein substrates are better understood that EndoS and EndoS2 variants can be rationally engineered to create a new class of antibody-modifying enzymes endowed with unique glycan specificities in order to modify antibodies that exhibit enhanced clinical properties. In this proposal, we will address three Specific Aims: (1) to determine the molecular basis of glycan specificity by endoglycosidases; (2) to define the role of carbohydrate binding modules – non-enzymatic protein domains with glycan binding properties – in endoglycosidase specificity and activity; and (3) to elucidate the molecular basis of protein specificity by endoglycosidases. Progress towards these complementary, yet independent, Specific Aims will significantly advance our understanding of glycan-modifying enzymes. Leveraging this knowledge in the context of EndoS and EndoS2 will enhance our ability to customize antibodies, further unleashing their vast therapeutic utility and expanding their positive impact on human health.

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