Antibodies are an important class of therapeutics that are widely used for treatment of cancer, autoimmune diseases, and infectious diseases. Compelling experimental data have demonstrated that Fc glycosylation is a critical structural determinant for modulating antibody?s effector functions, including antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), activation of apoptosis, and anti- inflammatory activities. However, progress in understanding the functional roles of antibody glycosylation is hampered by the tremendous structural heterogeneity of Fc glycosylation. To address this problem, we have developed a chemoenzymatic method that permits site-specific Fc and Fab glycan remodeling to generate homogeneous antibody glycoforms. In ths application, we propose to exploit the site-specific chemoenzymatic glycan remodeling method as a key platform technology to address three important questions related to antibody functions, as highlighted in the following three specific aims.
Aim 1 is to understand how Fc glycosylation modulate Fc? receptor binding and ADCC activity by selective modification of the core fucose, by performing structural studies, and by synthesizing novel glycoforms, coupled with Fc receptor binding and ADCC assays.
Aim 2 is to evaluate how site-specific sialylation of Fc glycans affects antibody?s anti- inflammatory activity by constructing asymmetrically sialylated or multiply sialylated glycoforms, coupled with animal studies.
Aim 3 is to augment antibody?s complement-dependent cytotoxicity (CDC) by constructing structurally well-defined ?Gal/rhamnose antigen-antibody conjugates to recruit natural IgG and IgM antibodies in circulation. These studies will yield important new knowledge in glyco-immunology, which will facilitate the development of more effective antibody-based therapeutics.

Public Health Relevance

Antibodies are an important class of therapeutics for treating cancer, autoimune diseases, and infectious diseases. The proposed research aims to exploit glycoengineering to understand how antibody glycosylation modulates antibody?s effector functions and to use the knowledge gained to improve antibody?s therapeutic efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI155716-01
Application #
10099594
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Ferguson, Stacy E
Project Start
2020-09-17
Project End
2025-08-31
Budget Start
2020-09-17
Budget End
2021-08-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Maryland College Park
Department
Chemistry
Type
Earth Sciences/Resources
DUNS #
790934285
City
College Park
State
MD
Country
United States
Zip Code
20742