Showing papers by "Jeffrey V. Ravetch published in 2014"
TL;DR: DiLillo et al. as mentioned in this paper showed that anti-stalk mAbs can mediate antibody-dependent cell cytotoxicity and require interactions with Fc receptors for their in vivo neutralizing activity.
Abstract: Monoclonal antibodies (mAbs) that bind the stalk domain of the influenza hemagglutinin glycoprotein have been shown to have broadly neutralizing activity against diverse influenza subtypes. In this study, DiLillo et al. report that, unlike strain-specific anti–hemagglutinin head domain mAbs, anti-stalk mAbs can mediate antibody-dependent cell cytotoxicity and require interactions with Fc receptors for their in vivo neutralizing activity.
648 citations
Journal Article•
TL;DR: Results suggest that FcγR binding capacity by anti-HA antibodies was dependent on the interaction of the cognate Fab with antigen, a previously uncharacterized property of bNAbs, and guide an approach toward enhancing mAb-mediated antiviral therapeutics.
Abstract: Neutralizing antibodies (Abs) against influenza viruses have traditionally been thought to provide protection exclusively through their variable region; the contributions of mechanisms conferred by the Fc domain remain controversial We investigated the in vivo contributions of Fc interactions with their cognate receptors for a collection of neutralizing anti-influenza Abs Whereas five broadly neutralizing monoclonal Abs (bNAbs) targeting the conserved stalk region of hemagglutinin (HA) required interactions between the Ab Fc and Fcγ-receptors for IgG (FcγR) to confer protection from lethal H1N1 challenge, three strain-specific monoclonal Abs (mAbs) against the variable head domain of HA were equally protective in the presence or absence of FcγR interactions Although all Abs blocked infection, only anti-stalk bNAbs were able to mediate cytotoxicity of infected cells, which accounts for their FcγR dependence Immune complexes generated with anti-HA stalk mAb efficiently interacted with FcγRs, but anti-HA head immune complexes did not These results suggest that FcγR binding capacity by anti-HA Ab was dependent on the interaction of the cognate Fab with antigen We exploited these disparate mechanisms of mAb-mediated protection to reengineer an anti-stalk bNAb to selectively enhance FcγR engagement to augment its protective activity These findings reveal a previously uncharacterized property of bNAbs and guide an approach toward enhancing mAb-mediated anti-viral therapies
465 citations
TL;DR: Assessment of the in-vivo activity of several broadly neutralizing antibodies against HIV-1 revealed that FcγR-mediated effector function contributes substantially to their capacity to block viral entry, suppress viremia, and confer therapeutic activity.
431 citations
TL;DR: The diverse downstream proinflammatory, anti-inflammatory and immunomodulatory consequences of the engagement of type I and type II Fc receptors in the context of infectious, autoimmune, and neoplastic disorders are discussed.
Abstract: Antibodies produced in response to a foreign antigen are characterized by polyclonality, not only in the diverse epitopes to which their variable domains bind but also in the various effector molecules to which their constant regions (Fc domains) engage. Thus, the antibody's Fc domain mediates diverse effector activities by engaging two distinct classes of Fc receptors (type I and type II) on the basis of the two dominant conformational states that the Fc domain may adopt. These conformational states are regulated by the differences among antibody subclasses in their amino acid sequence and by the complex, biantennary Fc-associated N-linked glycan. Here we discuss the diverse downstream proinflammatory, anti-inflammatory and immunomodulatory consequences of the engagement of type I and type II Fc receptors in the context of infectious, autoimmune, and neoplastic disorders.
416 citations
TL;DR: It is shown that broadly neutralizing antibodies (bNAbs) can interfere with establishment of a silent reservoir by Fc-FcR-mediated mechanisms, and combinations of inducers and bNAbs constitute a therapeutic strategy that impacts the establishment and maintenance of the HIV-1 reservoir in humanized mice.
325 citations
TL;DR: Comparison of the structures of asialylated Fc, sialylation Fc and F241A Fc suggests that increased conformational flexibility of the CH2 domain is associated with the switch from pro-inflammatory to anti-inflammatory activity of the Fc.
143 citations
TL;DR: It is demonstrated that mice with selective deletion of FcγRIIB expression in B cells and DCs have increased Ab and T cell responses, respectively, and display enhanced susceptibility to disease in distinct models, suggesting that FcβRIIBs expression in distinct cellular populations contributes to the maintenance of peripheral tolerance through different mechanisms.
Abstract: The inhibitory FcγR FcγRIIB is widely expressed on B cells, dendritic cells (DCs), and myeloid effector cells and modulates a variety of Ab-driven in vivo functions. Although it has been established that FcγRIIB plays an important role in the maintenance of peripheral tolerance, the responsible cell-specific FcγRIIB expression remains to be determined. In this study, we generated mice with selective deletion of FcγRIIB in B cells, DCs, and myeloid effector cells and evaluated these novel strains in models of tolerance and autoimmune diseases. Our results demonstrate that mice with selective deletion of FcγRIIB expression in B cells and DCs have increased Ab and T cell responses, respectively, and display enhanced susceptibility to disease in distinct models, suggesting that FcγRIIB expression in distinct cellular populations contributes to the maintenance of peripheral tolerance through different mechanisms.
59 citations
TL;DR: It is determined that Fc domain variants that were capable of selectively engaging activating FcγRs substantially enhanced the in vitro and in vivo activity of anthrax toxin-neutralizing antibodies.
Abstract: The effector activity of antibodies is dependent on engagement with Fcγ receptors (FcγRs) and activation of the associated intracellular signaling pathways. Preclinical evaluation of therapeutic humanized or chimeric mAbs to study the interactions of their Fc regions with FcγRs is hampered by substantial structural and functional FcγR diversity among species. In this report, we used mice expressing only human FcγRs to evaluate the contribution of FcγR-mediated pathways to the neutralizing activity of an anti-anthrax toxin chimeric mAb. We observed that the protective activity of this mAb was highly dependent upon FcγR engagement, with minimal protection against anthrax toxin observed in FcγR-deficient mice following mAb administration. We generated anti-anthrax toxin mAbs with specific Fc domain variants with selectively enhanced affinity for particular human FcγRs and assessed their activity in FcγR-humanized mice. We determined that Fc domain variants that were capable of selectively engaging activating FcγRs substantially enhanced the in vitro and in vivo activity of anthrax toxin-neutralizing antibodies. These findings indicate that the application of Fc domain engineering is a feasible strategy to enhance toxin-neutralizing activity and suggest that engineered antitoxin antibodies will have improved therapeutic efficacy.
57 citations
TL;DR: The development and evaluation of an FcγR-humanized mouse model is described, which has become a vital preclinical model for testing therapeutic human antibodies to treat malignancies, autoimmunity, inflammation, and infectious disease.
Abstract: Passive immunotherapy represents a promising therapeutic intervention for a number of neoplastic, chronic inflammatory, and infectious diseases, with several monoclonal antibodies currently under development or already in use in the clinic. While Fab–antigen interactions play a crucial role in the activity of an antibody, it has become clear that Fc-mediated effector functions are involved during antibody-mediated activities in vivo. A complete understanding of the contributions of effector activities mediated by an antibody during its in vivo function is required for the development of antibodies with improved therapeutic efficacies. Animal models that are commonly used for the preclinical evaluation of antibodies include murine and non-human primate species, whose FcγRs present substantial structural, functional, and genetic variation compared with their human counterparts. Therefore, the use of such animal models provides limited information on the role of human IgG Fc–FcγR interactions during the in vivo activities of antibodies intended for human therapeutics. In this chapter, we describe the development and evaluation of an FcγR-humanized mouse model for the study of human FcγR function in vivo. In this model, endogenous mouse FcγR genes have been deleted and human FcγRs are expressed as transgenes that faithfully recapitulate the unique pattern of human FcγR expression. Evaluation of the in vivo activities of a number of cytotoxic or therapeutic antibodies using FcγR-humanized mice provided useful insights into human IgG Fc effector function. This mouse model has become a vital preclinical model for testing therapeutic human antibodies to treat malignancies, autoimmunity, inflammation, and infectious disease.
31 citations