Document Type
Thesis - Open Access
Award Date
2021
Degree Name
Master of Science (MS)
Department / School
Chemistry and Biochemistry
First Advisor
Adam Hoppe
Third Advisor
Antibody, Fcγ receptors, Microcluster, Mobility, Phagocytosis
Abstract
Therapeutic antibodies are rapidly growing class of drugs for treating cancers and immunological disorders by targeting specific antigens or blocking certain pathway to inhibit the tumor growth. In cancer immunotherapy, it was found that Fcγ receptor (FcγR) in immune cells play an important role in antibody dependent cell toxicity against tumor cells. Therefore, understanding FcγR activation mechanism, which requires ligation with immunoglobulin (IgG), is crucial to enhance potency of therapeutic antibodies. One crucial immune responses triggered upon FcγR ligation with IgG is phagocytosis which indicates clearing targets by engulfment. It is known that FcγRs form microclusters which gets rearranged during engagement (J. Lin et al., 2016). Receptor microclustering is important for other immune receptors such as B cell receptor (BCR) and T cell receptor (TCR) (Bolger-Munro et al., 2019; Hashimoto-Tane & Saito, 2016). However, the implications of FcγR rearrangement for antibody-based therapies and cellular effector mechanisms has not been studied. This thesis, examined the dynamics of IgG microclustering and recruitment of Syk kinase to microclusters during antibody dependent cellular phagocytosis (ADCP) using confocal and lattice light sheet (LLS) imaging. Additionally, Total Internal Reflection Fluorescence (TIRF) imaging was used to image the organization of IgG and Syk microclusters during engagement on IgG opsonized supported lipid bilayers (SLBs). The major findings is that surface mobility of the IgG/FcγR complexes enhances ADCP. Moreover, proper Syk and Arp2/3 activity is required for organizing IgG/FcγR complexes during target engulfment and suppressing trogocytic clearance of IgG from the target cell. Together, this study uncovers an important role of antibody mobility in contributing to effective ADCP of target cells.
Library of Congress Subject Headings
Immunotherapy.
Phagocytosis.
Fc receptors.
Immunoglobulin G.
Format
application/pdf
Number of Pages
81
Publisher
South Dakota State University
Recommended Citation
Jo, Seongwan, "Therapeutic Immunoglobulin G Surface Mobility Promotes Antibody-Dependent Cellular Phagocytosis by Arp2/3 and Syk Mediated Rearrangement of Fcγ Receptors" (2021). Electronic Theses and Dissertations. 5215.
https://openprairie.sdstate.edu/etd/5215
Rights Statement
