ORCID Profile
0000-0001-7678-2609
Current Organisations
National Institute for Communicable Diseases
,
University of the Witwatersrand
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Publisher: Cold Spring Harbor Laboratory
Date: 17-08-2022
DOI: 10.1101/2022.08.17.504233
Abstract: Antibodies with the same variable region can exist as multiple isotypes with varying neutralization potencies, though the mechanism for this is not fully defined. We previously isolated an HIV-directed IgA1 monoclonal antibody (mAb), CAP88-CH06, and showed that IgA1 and IgG3 isotypes of this antibody demonstrated enhanced neutralization compared to IgG1. To explore the mechanism behind this, hinge region and constant heavy chain (CH1) chimeras were constructed between the IgA1, IgG3 and IgG1 mAbs and assessed for neutralization activity, antibody-dependent cellular phagocytosis (ADCP) and antibodydependent cellular cytotoxicity (ADCC). Hinge chimeras revealed that the increased neutralization potency and phagocytosis of the IgG3 isotype was attributed to its longer hinge region. In contrast, for IgA1, CH1 chimeras showed that this region was responsible both for enhanced neutralization potency and decreased ADCP, though ADCC was not affected. Overall, these data show that the enhanced neutralization potency of CAP88-CH06 IgG3 and IgA1, compared to IgG1, is achieved through distinct mechanisms. Understanding the influence of the hinge and CH1 regions on Fab domain function may provide insights into the engineering of therapeutic antibodies with increased neutralization potency.
Publisher: Elsevier BV
Date: 12-2018
DOI: 10.1016/J.JIM.2018.09.009
Abstract: Antibody Fc effector functions contribute to HIV control and have been implicated in the partial efficacy seen in the RV144 vaccine trial. Fc-mediated trogocytosis has been previously described for anti-cancer antibodies and results in the removal of membrane fragments from target cells. Here we developed a flow cytometry-based assay which measures the transfer of membrane fragments from a gp120-coated CD4+ lymphocytic cell line (CEM.NKR-CCR5 cells stained with a membrane dye PKH26) to monocytic cells (THP-1 cells stained with CFSE). We showed that this transfer occurred rapidly, within 1 h, and was mediated through engagement of the FcγRIIa/b receptors on the THP-1 cells. HIV-specific IgG as well as gp120 and CD4 could be detected on the surface of THP-1 cells in a process that we demonstrated was distinct from phagocytosis. Furthermore, while the THP-1 effector cells remained intact following the receipt of new membrane proteins, the viability of the target CEM.NKR-CCR5 cells decreased over time. Analysis of HIV-specific plasma revealed that antibodies with trogocytic activity were common in acute and chronic HIV infection but were higher in in iduals with broadly neutralizing antibody responses We also examined trogocytosis mediated by broadly neutralizing antibodies (bNAbs) targeting multiple epitopes on the BG505.SOSIP.664 trimer and show that levels of binding correlated with the trogocytosis score. Overall, our data describe a new antiviral Fc effector function mediated by HIV-specific antibodies that could be harnessed for vaccination and cure strategies.
Publisher: Public Library of Science (PLoS)
Date: 09-04-2018
Publisher: Public Library of Science (PLoS)
Date: 16-12-2019
Publisher: Springer Science and Business Media LLC
Date: 24-06-2015
Publisher: Elsevier BV
Date: 12-2019
Publisher: Elsevier BV
Date: 06-2021
No related grants have been discovered for Simone Richardson.