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dc.contributor.authorTolbert, William D
dc.contributor.authorNguyen, Dung N
dc.contributor.authorTuyishime, Marina
dc.contributor.authorCrowley, Andrew R
dc.contributor.authorChen, Yaozong
dc.contributor.authorJha, Shalini
dc.contributor.authorGoodman, Derrick
dc.contributor.authorBekker, Valerie
dc.contributor.authorMudrak, Sarah V
dc.contributor.authorDeVico, Anthony L
dc.contributor.authorLewis, George K
dc.contributor.authorTheis, James F
dc.contributor.authorPinter, Abraham
dc.contributor.authorMoody, M Anthony
dc.contributor.authorEasterhoff, David
dc.contributor.authorWiehe, Kevin
dc.contributor.authorPollara, Justin
dc.contributor.authorSaunders, Kevin O
dc.contributor.authorTomaras, Georgia D
dc.contributor.authorAckerman, Margaret
dc.contributor.authorFerrari, Guido
dc.contributor.authorPazgier, Marzena
dc.date.accessioned2022-01-26T15:01:14Z
dc.date.available2022-01-26T15:01:14Z
dc.date.issued2022-01-06
dc.identifier.urihttp://hdl.handle.net/10713/17794
dc.description.abstractPassive 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.en_US
dc.description.urihttps://doi.org/10.3389/fimmu.2021.787603en_US
dc.language.isoenen_US
dc.publisherFrontiers Media S.A.en_US
dc.relation.ispartofFrontiers in Immunologyen_US
dc.rightsCopyright © 2022 Tolbert, Nguyen, Tuyishime, Crowley, Chen, Jha, Goodman, Bekker, Mudrak, DeVico, Lewis, Theis, Pinter, Moody, Easterhoff, Wiehe, Pollara, Saunders, Tomaras, Ackerman, Ferrari and Pazgier.en_US
dc.subjectFc-effector functionen_US
dc.subjectHIVen_US
dc.subjectantibody engineeringen_US
dc.subjectnon-human primatesen_US
dc.subjectrhesusizationen_US
dc.titleStructure and Fc-Effector Function of Rhesusized Variants of Human Anti-HIV-1 IgG1s.en_US
dc.typeArticleen_US
dc.identifier.doi10.3389/fimmu.2021.787603
dc.identifier.pmid35069563
dc.source.journaltitleFrontiers in immunology
dc.source.volume12
dc.source.beginpage787603
dc.source.endpage
dc.source.countrySwitzerland


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