Mouse model recapitulating human Fcγ receptor structural and functional diversity

Smith, Patrick; DiLillo, David J.; Bournazos, Stylianos; Li, Fubin; Ravetch, Jeffrey V.

doi:10.1073/pnas.1203954109

Cited by 265 publications

(355 citation statements)

References 25 publications

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“…The next steps for dengue research could explore the role of FcgRIIa and FcgRIIb in human infections to further the understanding of signaling mechanisms and routing pathways mediated by engagement of DENV immune complexes and to study the effects of different viral serotypes complexed with different human or mouse IgG subclasses. Finally, these results support the development of a mouse model wherein all murine FcgRs are replaced with human FcgRs (31). The addition of FcgRIIa-expressing cells into mice could counterbalance the unopposed inhibitory murine FcgRIIb isoform, enable ADE, and generate a much needed small animal model to advance our understanding of complicated dengue disease.…”

Section: Discussionmentioning

confidence: 63%

Human FcγRII Cytoplasmic Domains Differentially Influence Antibody-Mediated Dengue Virus Infection

Boonnak

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Donofrio

et al. 2013

The Journal of Immunology

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Ab-dependent enhancement (ADE) of dengue virus (DENV) infection is mediated through the interaction of viral immune complexes with FcγRs, with notable efficiency of FcγRII. Most human dengue target cells coexpress activating (FcγRIIa) and inhibitory (FcγRIIb) isoforms, but their relative roles in ADE are not well understood. We studied the effects of FcγRIIa and FcγRIIb by transfecting cells to express each individual receptor isoform or through coexpression of both isoforms. We showed that although both isoforms similarly bind dengue-immune complexes, FcγRIIa efficiently internalized virus leading to productive cellular infection, unlike FcγRIIb. We next focused on the main discriminating feature of these isoforms: their distinct intracytoplasmic tails (FcγRIIa with an immunoreceptor tyrosine-based activation motif [ITAM] and FcγRIIb with an immunoreceptor tyrosine-based inhibitory motif [ITIM]). We engineered cells to express “swapped” versions of their FcγRII by switching the cytoplasmic tails containing the ITAM/ITIM motifs, leaving the remainder of the receptor intact. Our data show that both FcγRIIa and FcγRIIb comparably bind dengue immune complexes. However, wild type FcγRIIa facilitates DENV entry by virtue of the ITAM motif, whereas the swapped version FcγRIIa-ITIM significantly inhibited ADE. Similarly, replacing the inhibitory motif in FcγRIIb with an ITAM (FcγRIIb-ITAM) reconstituted ADE capacity to levels of the wild type activating counterpart, FcγRIIa. Our data suggest that FcγRIIa and FcγRIIb isoforms, as the most abundantly distributed class II Fcγ receptors, differentially influence Ab-mediated DENV infection under ADE conditions both at the level of cellular infection and viral production.

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Section: Discussionmentioning

confidence: 63%

Human FcγRII Cytoplasmic Domains Differentially Influence Antibody-Mediated Dengue Virus Infection

Boonnak

Slike

Donofrio

et al. 2013

The Journal of Immunology

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“…However, the advent of fully humanized FcgR mice on a non-immune compromised mouse background may provide an acceptable model system. 51 An additional consideration for macrophage-mediated ADCR concerns the context in which the antibody Fc is presented to the macrophage. It was previously demonstrated that IL-10 was not elicited from macrophages when an IgG1 mAb was coated directly onto plates.…”

Section: Discussionmentioning

confidence: 99%

An Fc engineering approach that modulates antibody-dependent cytokine release without altering cell-killing functions

Kinder

Greenplate

Strohl

et al. 2015

mAbs

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(2015) An Fc engineering approach that modulates antibodydependent cytokine release without altering cell-killing functions, mAbs, 7:3, 494-504, DOI: 10.1080DOI: 10. /19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 Cytotoxic therapeutic monoclonal antibodies (mAbs) often mediate target cell-killing by eliciting immune effector functions via Fc region interactions with cellular and humoral components of the immune system. Key functions include antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). However, there has been increased appreciation that along with cell-killing functions, the induction of antibody-dependent cytokine release (ADCR) can also influence disease microenvironments and therapeutic outcomes. Historically, most Fc engineering approaches have been aimed toward modulating ADCC, ADCP, or CDC. In the present study, we describe an Fc engineering approach that, while not resulting in impaired ADCC or ADCP, profoundly affects ADCR. As such, when peripheral blood mononuclear cells are used as effector cells against mAb-opsonized tumor cells, the described mAb variants elicit a similar profile and quantity of cytokines as IgG1. In contrast, although the variants elicit similar levels of tumor cell-killing as IgG1 with macrophage effector cells, the variants do not elicit macrophage-mediated ADCR against mAb-opsonized tumor cells. This study demonstrates that Fc engineering approaches can be employed to uncouple macrophage-mediated phagocytic and subsequent cell-killing functions from cytokine release.

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“…To test the in vivo potency of these engineered chimeric antibodies, we used a novel B6 mouse strain in which the mouse Fcgr2b gene was deleted and the human FCGR2B (huFCGR2B) gene was inserted as a transgene. The huFCGR2B gene, driven by its human promoter elements, retains the specific cellular expression pattern seen in the human and is functional for FcγRIIB inhibitory and immunomodulatory activities (38).…”

Section: Fc-engineered Anti-dr5 Antibody With Enhanced Fcγriib Bindinmentioning

confidence: 99%

Apoptotic and antitumor activity of death receptor antibodies require inhibitory Fcγ receptor engagement

Ravetch²

2012

Proc. Natl. Acad. Sci. U.S.A.

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By virtue of their ability to induce apoptosis and regulate growth, differentiation, and cytokine responses, the tumor necrosis factor receptor (TNFR) superfamily members have emerged as attractive targets for anticancer therapeutics. Agonistic antibodies to apoptosisinducing TNFRs, such as death receptor 5 (DR5), although displaying impressive activities against a variety of tumors in preclinical models, appear to be less active in clinical trials. We report that the in vivo apoptotic and antitumor activities of these antibodies have an absolute requirement for the coengagement of an inhibitory Fcγ receptor, FcγRIIB. Anti-DR5 antibodies of the type currently in clinical trials have weak FcγRIIB binding and thus are compromised in their proapoptotic and antitumor activities in both colon and breast carcinoma models. Enhancing FcγRIIB engagement increases apoptotic and antitumor potency. Our results demonstrate that Fc domain interactions are critical to the therapeutic activity of anti-DR5 antibodies and, together with previous reports on agonistic anti-CD40 antibodies, establish a common requirement for FcγRIIB coengagement for optimal biological effects of agonistic anti-TNFR antibodies.cancer immunotherapy | Fc engineering | human FCGR2B | antibody-dependent cell-mediated cytotoxicity

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Mouse model recapitulating human Fcγ receptor structural and functional diversity

Cited by 265 publications

References 25 publications

Human FcγRII Cytoplasmic Domains Differentially Influence Antibody-Mediated Dengue Virus Infection

Human FcγRII Cytoplasmic Domains Differentially Influence Antibody-Mediated Dengue Virus Infection

An Fc engineering approach that modulates antibody-dependent cytokine release without altering cell-killing functions

Apoptotic and antitumor activity of death receptor antibodies require inhibitory Fcγ receptor engagement

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