Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Antitumor activities of agonistic anti-TNFR antibodies require differential Fc?RIIB coengagement in vivo.

ABSTRACT: Agonistic anti-TNF receptor (TNFR) superfamily member antibodies are a class of promising antitumor therapies in active clinical investigation. An unexpected requirement for inhibitory Fc? receptor Fc?RIIB coengagement has recently been described for their in vivo antitumor activities. Although these findings have informed the design of more potent antitumor agonistic, anti-TNFR therapies, the underlying mechanism has remained obscure. Through detailed genetic analysis of strains conditionally deleted for Fc?RIIB on defined cellular populations or mutated in specific signaling components, we now demonstrate that different agonistic anti-TNFR antibodies have specific requirements for Fc?RIIB expression on defined cellular populations and function in trans in the absence of Fc?RIIB signaling components, thus supporting a general mechanism of Fc?RIIB cross-linking in vivo for the activities of these antibodies.

SUBMITTER: Li F

PROVIDER: S-EPMC3845179 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Antitumor activities of agonistic anti-TNFR antibodies require differential FcγRIIB coengagement in vivo.

Li Fubin F Ravetch Jeffrey V JV

Proceedings of the National Academy of Sciences of the United States of America 20131111 48

Agonistic anti-TNF receptor (TNFR) superfamily member antibodies are a class of promising antitumor therapies in active clinical investigation. An unexpected requirement for inhibitory Fcγ receptor FcγRIIB coengagement has recently been described for their in vivo antitumor activities. Although these findings have informed the design of more potent antitumor agonistic, anti-TNFR therapies, the underlying mechanism has remained obscure. Through detailed genetic analysis of strains conditionally d ...[more]

PMID: 24218606

Similar Datasets

The Antitumor Activities of Anti-CD47 Antibodies Require Fc-FcγR interactions.

Project description:While anti-CD47 antibodies hold promise for cancer immunotherapy, early phase clinical trials have shown limited signs of clinical benefit, suggesting that blockade of CD47 alone may not be sufficient for effective tumor control. Here, we investigate the contributions of the Fc domain of anti-CD47 antibodies required for optimal in vivo antitumor activity across multiple species-matched models, providing new insights into the mechanisms underlying the efficacy of this emerging class of therapeutic antibodies. Using a novel mouse model humanized for CD47, SIRPα and FcγRs, we demonstrate that local administration of an Fc-engineered anti-CD47 antibody with enhanced binding to activating FcγRs modulates myeloid and T-cell subsets in the tumor microenvironment, resulting in improved long-term systemic antitumor immunity and minimal on-target off-tumor toxicity. Our results highlight the importance of Fc optimization in the development of effective anti-CD47 therapies and provide a novel approach for enhancing the antitumor activity of this promising immunotherapy.

| S-EPMC10347539 | biostudies-literature

Fc?RIIB engagement drives agonistic activity of Fc-engineered ?OX40 antibody to stimulate human tumor-infiltrating T cells.

Project description:BACKGROUND:OX40 (CD134) is a costimulatory molecule of the tumor necrosis factor receptor superfamily that is currently being investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic ?OX40 antibodies in the treatment of patients with cancer has fallen short of the high expectation in earlier-stage trials. METHODS:Using lymphocytes from resected tumor, tumor-free (TF) tissue and peripheral blood mononuclear cells (PBMC) of 96 patients with hepatocellular and colorectal cancers, we determined OX40 expression and the in vitro T-cell agonistic activity of OX40-targeting compounds. RNA-Seq was used to evaluate OX40-mediated transcriptional changes in CD4+ and CD8+ human tumor-infiltrating lymphocytes (TILs). RESULTS:Here, we show that OX40 was overexpressed on tumor-infiltrating CD4+ T cells compared with blood and TF tissue-derived T cells. In contrast to a clinical candidate ?OX40 antibody, treatment with an Fc-engineered ?OX40 antibody (?OX40_v12) with selectively enhanced Fc?RIIB affinity, stimulated in vitro CD4+ and CD8+ TIL expansion, as well as cytokine and chemokine secretions. The activity of ?OX40_v12 was dependent on Fc?RIIB engagement and intrinsic CD3/CD28 signals. The transcriptional landscape of CD4+ and CD8+ TILs shifted toward a prosurvival, inflammatory and chemotactic profile on treatment with ?OX40_v12. CONCLUSIONS:OX40 is overexpressed on CD4+ TILs and thus represents a promising target for immunotherapy. Targeting OX40 with currently used agonistic antibodies may be inefficient due to lack of OX40 multimerization. Thus, Fc engineering is a powerful tool in enhancing the agonistic activity of ?OX40 antibody and may shape the future design of antibody-mediated ?OX40 immunotherapy.

| S-EPMC7478034 | biostudies-literature

Broadly neutralizing anti-influenza antibodies require Fc receptor engagement for in vivo protection.

Project description:In vivo protection by antimicrobial neutralizing Abs can require the contribution of effector functions mediated by Fc-Fcγ receptor (Fc-FcγR) interactions for optimal efficacy. In influenza, broadly neutralizing anti-hemagglutinin (anti-HA) stalk mAbs require Fc-FcγR interactions to mediate in vivo protection, but strain-specific anti-HA head mAbs do not. Whether this rule applies only to anti-stalk Abs or is applicable to any broadly neutralizing Ab (bNAb) against influenza is unknown. Here, we characterized the contribution of Fc-FcγR interactions during in vivo protection for a panel of 13 anti-HA mAbs, including bNAbs and non-neutralizing Abs, against both the stalk and head domains. All classes of broadly binding anti-HA mAbs required Fc-FcγR interactions to provide protection in vivo, including those mAbs that bind the HA head and those that do not neutralize virus in vitro. Further, a broadly neutralizing anti-neuraminidase (anti-NA) mAb also required FcγRs to provide protection in vivo, but a strain-specific anti-NA mAb did not. Thus, these findings suggest that the breadth of reactivity of anti-influenza Abs, regardless of their epitope, necessitates interactions with FcγRs on effector cell populations to mediate in vivo protection. These findings will guide the design of antiviral Ab therapeutics and inform vaccine design to elicit Abs with optimal binding properties and effector functions.

| S-EPMC4731186 | biostudies-literature

Fc? receptor IIB (Fc?RIIB) maintains humoral tolerance in the human immune system in vivo.

Project description:Maintenance of immunological tolerance is crucial to prevent development of autoimmune disease. The production of autoantibodies is a hallmark of many autoimmune diseases and studies in mouse model systems suggest that inhibitory signaling molecules may be important checkpoints of humoral tolerance. By generating humanized mice with normal and functionally impaired Fc? receptor IIB (Fc?RIIB) variants, we show that the inhibitory Fc?-receptor is a checkpoint of humoral tolerance in the human immune system in vivo. Impaired human Fc?RIIB function resulted in the generation of higher levels of serum immunoglobulins, the production of different autoantibody specificities, and a higher proportion of human plasmablasts and plasma cells in vivo. Our results suggest that the inhibitory Fc?RIIB may be an important checkpoint of humoral tolerance in the human immune system.

| S-EPMC3219118 | biostudies-literature

Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity.

Project description:Broadly neutralizing antibodies (bNAbs) against HIV-1 provide both effective pre-exposure prophylaxis and treatment of HIV-1 infection in murine and nonhuman primate models, suggesting their potential use in humans. Although much is known about the role of variable domains in the neutralization breadth and potency of these bNAbs, the contribution of Fc domains to their activities is, by contrast, poorly characterized. Assessment of the in vivo activity of several bNAbs revealed that Fc?R-mediated effector function contributes substantially to their capacity to block viral entry, suppress viremia, and confer therapeutic activity. Enhanced in vivo potency of anti-HIV-1 bNAbs was associated with preferential engagement of activating, but not inhibitory Fc?Rs, and Fc domain-engineered bNAb variants with selective binding capacity for activating Fc?Rs displayed augmented protective activity. These findings reveal key roles for Fc effector function in the in vivo activity of anti-HIV-1 bNAbs and provide strategies for generating bNAbs with improved efficacy.

| S-EPMC4167398 | biostudies-literature

Cutting edge: Expression of Fc?RIIB tempers memory CD8 T cell function in vivo.

Project description:During reinfection, high-affinity IgG Abs form complexes with both soluble Ag and Ag displayed on the surface of infected cells. These interactions regulate cellular activation of both innate cells and B cells, which express specific combinations of activating Fc?Rs (Fc?RI, Fc?RIII, Fc?RIV) and/or the inhibitory Fc?R (Fc?RIIB). Direct proof for functional expression of Fc?R by Ag-specific CD8 T cells is lacking. In this article, we show that the majority of memory CD8 T cells generated by bacterial or viral infection express only Fc?RIIB, and that Fc?RIIB could be detected on previously activated human CD8 T cells. Of note, Fc?R stimulation during in vivo Ag challenge not only inhibited the cytotoxicity of memory CD8 T cells against peptide-loaded or virus-infected targets, but Fc?RIIB blockade during homologous virus challenge enhanced the secondary CD8 T cell response. Thus, memory CD8 T cells intrinsically express a functional Fc?RIIB, permitting Ag-Ab complexes to regulate secondary CD8 T cell responses.

| S-EPMC3874719 | biostudies-literature

Effects of Fc glycosylation on the activity of WNT mimetic agonistic antibodies

Project description: Not available

| S-EPMC10873268 | biostudies-literature

Transmembrane domain dependent inhibitory function of Fc?RIIB.

Project description:Fc?RIIB, the only inhibitory IgG Fc receptor, functions to suppress the hyper-activation of immune cells. Numerous studies have illustrated its inhibitory function through the ITIM motif in the cytoplasmic tail of Fc?RIIB. However, later studies revealed that in addition to the ITIM, the transmembrane (TM) domain of Fc?RIIB is also indispensable for its inhibitory function. Indeed, recent epidemiological studies revealed that a non-synonymous single nucleotide polymorphism (rs1050501) within the TM domain of Fc?RIIB, responsible for the I232T substitution, is associated with the susceptibility to systemic lupus erythematosus (SLE). In this review, we will summarize these epidemiological and functional studies of Fc?RIIB-I232T in the past few years, and will further discuss the mechanisms accounting for the functional loss of Fc?RIIB-I232T. Our review will help the reader gain a deeper understanding of the importance of the TM domain in mediating the inhibitory function of Fc?RIIB and may provide insights to a new therapeutic target for the associated diseases.

| S-EPMC6251803 | biostudies-literature

Regulation of allograft survival by inhibitory Fc?RIIb signaling.

Project description:Fc? receptors (Fc?R) provide important immunoregulation. Targeting inhibitory Fc?RIIb may therefore prolong allograft survival, but its role in transplantation has not been addressed. Fc?RIIb signaling was examined in murine models of acute or chronic cardiac allograft rejection by transplanting recipients that either lacked Fc?RIIb expression (Fc?RIIb(-/-)) or overexpressed Fc?RIIb on B cells (B cell transgenic [BTG]). Acute heart allograft rejection occurred at the same tempo in Fc?RIIb(-/-) C57BL/6 (B6) recipients as wild type recipients, with similar IgG alloantibody responses. In contrast, chronic rejection of MHC class II-mismatched bm12 cardiac allografts was accelerated in Fc?RIIb(-/-) mice, with development of more severe transplant arteriopathy and markedly augmented effector autoantibody production. Autoantibody production was inhibited and rejection was delayed in BTG recipients. Similarly, whereas MHC class I-mismatched B6.K(d) hearts survived indefinitely and remained disease free in B6 mice, much stronger alloantibody responses and progressive graft arteriopathy developed in Fc?RIIb(-/-) recipients. Notably, Fc?RIIb-mediated inhibition of B6.K(d) heart graft rejection was abrogated by increasing T cell help through transfer of additional H2.K(d)-specific CD4 T cells. Thus, inhibitory Fc?RIIb signaling regulates chronic but not acute rejection, most likely because the supra-optimal helper CD4 T cell response in acute rejection overcomes Fc?RIIb-mediated inhibition of the effector B cell population. Immunomodulation of Fc?RIIb in clinical transplantation may hold potential for inhibiting progression of transplant arteriopathy and prolonging transplant survival.

| S-EPMC3605772 | biostudies-literature

The Complex Association of Fc?RIIb With Autoimmune Susceptibility.

Project description:Fc?RIIb is the only inhibitory Fc receptor and controls many aspects of immune and inflammatory responses. The observation 19 years ago that Fc ? RIIb -/- mice generated by gene targeting in 129 derived ES cells developed severe lupus like disease when backcrossed more than 7 generations into C57BL/6 background initiated extensive research on the functional understanding of this strong autoimmune phenotype. The genomic region in the distal part of Chr1 both in human and mice in which the Fc ? R gene cluster is located shows a high level of complexity in relation to the susceptibility to SLE. Specific haplotypes of closely linked genes including the Fc ? RIIb and Slamf genes are associated with increased susceptibility to SLE both in mice and human. Using forward and reverse genetic approaches including in human GWAS and in mice congenic strains, KO mice (germline and cell type specific, on different genetic background), knockin mice, overexpressing transgenic mice combined with immunological models such as adoptive transfer of B cells from Ig transgenic mice the involved genes and the causal mutations and their associated functional alterations were analyzed. In this review the results of this 19 years extensive research are discussed with a focus on (genetically modified) mouse models.

| S-EPMC6803437 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data