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    Structure and Fc-Effector Function of Rhesusized Variants of Human Anti-HIV-1 IgG1s.

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    Author
    Tolbert, William D
    Nguyen, Dung N
    Tuyishime, Marina
    Crowley, Andrew R
    Chen, Yaozong
    Jha, Shalini
    Goodman, Derrick
    Bekker, Valerie
    Mudrak, Sarah V
    DeVico, Anthony L
    Lewis, George K
    Theis, James F
    Pinter, Abraham
    Moody, M Anthony
    Easterhoff, David
    Wiehe, Kevin
    Pollara, Justin
    Saunders, Kevin O
    Tomaras, Georgia D
    Ackerman, Margaret
    Ferrari, Guido
    Pazgier, Marzena
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    Date
    2022-01-06
    Journal
    Frontiers in Immunology
    Publisher
    Frontiers Media S.A.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.3389/fimmu.2021.787603
    Abstract
    Passive transfer of monoclonal antibodies (mAbs) of human origin into Non-Human Primates (NHPs), especially those which function predominantly by a Fc-effector mechanism, requires an a priori preparation step, in which the human mAb is reengineered to an equivalent NHP IgG subclass. This can be achieved by changing both the Fc and Fab sequence while simultaneously maintaining the epitope specificity of the parent antibody. This Ab reengineering process, referred to as rhesusization, can be challenging because the simple grafting of the complementarity determining regions (CDRs) into an NHP IgG subclass may impact the functionality of the mAb. Here we describe the successful rhesusization of a set of human mAbs targeting HIV-1 envelope (Env) epitopes involved in potent Fc-effector function against the virus. This set includes a mAb targeting a linear gp120 V1V2 epitope isolated from a RV144 vaccinee, a gp120 conformational epitope within the Cluster A region isolated from a RV305 vaccinated individual, and a linear gp41 epitope within the immunodominant Cys-loop region commonly targeted by most HIV-1 infected individuals. Structural analyses confirm that the rhesusized variants bind their respective Env antigens with almost identical specificity preserving epitope footprints and most antigen-Fab atomic contacts with constant regions folded as in control RM IgG1s. In addition, functional analyses confirm preservation of the Fc effector function of the rhesusized mAbs including the ability to mediate Antibody Dependent Cell-mediated Cytotoxicity (ADCC) and antibody dependent cellular phagocytosis by monocytes (ADCP) and neutrophils (ADNP) with potencies comparable to native macaque antibodies of similar specificity. While the antibodies chosen here are relevant for the examination of the correlates of protection in HIV-1 vaccine trials, the methods used are generally applicable to antibodies for other purposes.
    Rights/Terms
    Copyright © 2022 Tolbert, Nguyen, Tuyishime, Crowley, Chen, Jha, Goodman, Bekker, Mudrak, DeVico, Lewis, Theis, Pinter, Moody, Easterhoff, Wiehe, Pollara, Saunders, Tomaras, Ackerman, Ferrari and Pazgier.
    Keyword
    Fc-effector function
    HIV
    antibody engineering
    non-human primates
    rhesusization
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17794
    ae974a485f413a2113503eed53cd6c53
    10.3389/fimmu.2021.787603
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