Differentiated agonistic antibody targeting CD137 eradicates large tumors without hepatotoxicity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA603752 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10985106.fastq.gz | Fastqsanger.gz | |||
| SRR10985107.fastq.gz | Fastqsanger.gz | |||
| SRR10985108.fastq.gz | Fastqsanger.gz | |||
| SRR10985109.fastq.gz | Fastqsanger.gz | |||
| SRR10985110.fastq.gz | Fastqsanger.gz |
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Project description:CD137 (4-1BB) is a member of the TNFR superfamily that represents a promising target for cancer immunotherapy. Recent insights into the function of TNFR agonist antibodies implicate epitope, affinity, and IgG subclass as critical features, and these observations help explain the limited activity and toxicity seen with clinically tested CD137 agonists. Here we describe the preclinical characterization of CTX-471, a fully human IgG4 agonist of CD137 that engages a unique epitope that is shared by human, cynomolgus monkey, and mouse and is associated with a differentiated pharmacology and toxicology profile. In vitro, CTX-471 increased IFN-γ production by human T cells in an FcγR-dependent manner, displaying an intermediate level of activity between two clinical-stage anti-CD137 antibodies. In mice, CTX-471 exhibited curative monotherapy activity in various syngeneic tumor models and showed a unique ability to cure mice of very large (~500 mm3) tumors compared to validated antibodies against checkpoints and TNFR superfamily members. Extremely high doses of CTX-471 were well-tolerated, with no signs of hepatic toxicity. Collectively, these data demonstrate that CTX-471 is a unique CD137 agonist that display an excellent safety profile and an unprecedented level of monotherapy efficacy against very large tumors.
2020-01-30 | GSE144473 | GEO
Project description:CD137 (4-1BB) is a member of the TNFR superfamily that represents a promising target for cancer immunotherapy. Recent insights into the function of TNFR agonist antibodies implicate epitope, affinity, and IgG subclass as critical features, and these observations help explain the limited activity and toxicity seen with clinically tested CD137 agonists. Here, we describe the preclinical characterization of CTX-471, a fully human IgG4 agonist of CD137 that engages a unique epitope that is shared by human, cynomolgus monkey, and mouse and is associated with a differentiated pharmacology and toxicology profile. In vitro, CTX-471 increased IFN-γ production by human T cells in an Fcγ receptor-dependent (FcγR-dependent) manner, displaying an intermediate level of activity between 2 clinical-stage anti-CD137 antibodies. In mice, CTX-471 exhibited curative monotherapy activity in various syngeneic tumor models and showed a unique ability to cure mice of very large (~500 mm3) tumors compared with validated antibodies against checkpoints and TNFR superfamily members. Extremely high doses of CTX-471 were well tolerated, with no signs of hepatic toxicity. Collectively, these data demonstrate that CTX-471 is a unique CD137 agonist that displays an excellent safety profile and an unprecedented level of monotherapy efficacy against very large tumors.
| S-EPMC7141404 | biostudies-literature
Project description:CD137 is a costimulatory receptor expressed on natural killer cells, T cells, and subsets of dendritic cells. An agonistic monoclonal antibody (mAb) against CD137 has been used to reduce tumor burden or reverse autoimmunity in animal models and clinical trials. When testing the ability of agonistic anti-CD137 mAb to promote clearance of persistent virus infection, we recently reported reduced numbers of germinal center B (GC B) cells and follicular dendritic cells (FDC) in lymphoid tissues. Here, we show that agonistic anti-CD137 agonistic mAb treatment impairs antibody responses with multiple T cell-dependent antigens including virus infection, recombinant viral antigens, and conjugated haptens but not with a T cell-independent antigen or at homeostasis. These effects were not due to enhanced apoptosis or impaired proliferation of B cells but instead correlated with disorganization of the stromal cell compartment of the GC, and were mediated by CD137 signaling in CD4+ and CD8+ T cells. Anti-CD137 treatment in the context of acute infection also resulted in reduced numbers of marginal zone B cells, greater numbers of antibody-secreting plasmablasts, and pro-inflammatory signatures in several myeloid and lymphoid cell populations of the spleen. Our experiments in mice suggest that agonistic anti-CD137 mAbs used in cancer and autoimmunity therapy may alter stromal cell populations to causes GC collapse and impaired long-term antibody and B cell memory responses.
2019-12-31 | GSE141111 | GEO
Project description:CD137 is a costimulatory receptor expressed on natural killer cells, T cells, and subsets of dendritic cells. An agonistic monoclonal antibody (mAb) against CD137 has been used to reduce tumor burden or reverse autoimmunity in animal models and clinical trials. When testing the ability of agonistic anti-CD137 mAb to promote clearance of persistent virus infection, we recently reported reduced numbers of germinal center B (GC B) cells and follicular dendritic cells (FDC) in lymphoid tissues. Here, we show that agonistic anti-CD137 agonistic mAb treatment impairs antibody responses with multiple T cell-dependent antigens including virus infection, recombinant viral antigens, and conjugated haptens but not with a T cell-independent antigen or at homeostasis. These effects were not due to enhanced apoptosis or impaired proliferation of B cells but instead correlated with disorganization of the stromal cell compartment of the GC, and were mediated by CD137 signaling in CD4+ and CD8+ T cells. Anti-CD137 treatment in the context of acute infection also resulted in reduced numbers of marginal zone B cells, greater numbers of antibody-secreting plasmablasts, and pro-inflammatory signatures in several myeloid and lymphoid cell populations of the spleen. Our experiments in mice suggest that agonistic anti-CD137 mAbs used in cancer and autoimmunity therapy may alter stromal cell populations to causes GC collapse and impaired long-term antibody and B cell memory responses.
2019-12-31 | GSE141117 | GEO
Project description:The cell surface glycoprotein CD137, which is also known as 4-1BB, belongs to the group of co-stimulatory immune receptors and is a member of the TNF receptor superfamily (TNFRSF). It is preferentially found on activated T-cells and regulatory T-cells. In T-cells, CD137-crosslinking delivers a potent co-stimulatory signal as it promotes T-cell proliferation, formation of memory cells and enhances survival. Despite numerous studies investigating the effects of co-stimulatory CD137 in T-cells, little is known regarding the role of CD137 in human monocytes/macrophages. To investigate the effect of CD137 triggering on human monocytes, monocytes were isolated and treated with an agonistic CD137 mAb and subsequently analyzed by RNA-seq.
2021-06-17 | GSE171108 | GEO
Project description:An agonistic anti-CD137 antibody promotes inflammatory signatures in immune cells that disrupt germinal center formation and T cell-dependent antibody responses
| PRJNA592146 | ENA
Project description:An agonistic anti-CD137 antibody promotes inflammatory signatures in immune cells that disrupt germinal center formation and T cell-dependent antibody responses II
| PRJNA592161 | ENA
Project description:Rapid CD137 upregulation on alloreactive T-cells upon allogeneic stimulation suggests that their selective elimination could prevent acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Here, we developed a novel aGVHD prophylactic regimen consisting of a single dose of an anti-CD137 antibody-drug conjugate (CD137-ADC) administered on the day of transplant without additional immunosuppression. The CD137-ADC depleted both human and non-human primate (NHP) activated T-cells and proved highly effective in preventing xenogeneic aGVHD in mice receiving human hematopoietic stem cell grafts, as well as in NHP undergoing MHC-haploidentical HCT. Flow cytometry analysis of NHP T-cells indicated specific depletion of activated PD-1+ CD4 and CD8 T-cells, while sparing naïve and PD-1-OX40+ memory T-cell subsets. CD137-ADC-treated NHP recipients demonstrated robust hematopoietic and immune reconstitution. Hallmarks of T-cell recovery after CD137-ADC, which were associated with long-term aGVHD-free survival, included reconstitution of CD4 memory T-cells expressing TRAIL, terminally-differentiated CD8 T-cells expressing CX3CR1, and CD4 FoxP3+ Tregs – cell types not expected to be involved in aGVHD pathogenesis. CD137-ADC-treated recipients demonstrated a higher risk of reactivation of rhLCV (the rhesus macaque EBV analogue), which was associated with reconstitution of follicular helper T-cells, interferon signaling-associated memory, and gamma-delta T-cell subsets. This reactivation was controllable with rituximab administration. These results document effective depletion of alloreactive T-cells and prevention of aGVHD following a single dose of CD137-ADC, suggesting that clinical translation should be carefully explored.
2025-05-27 | GSE298158 | GEO
Project description:Rapid CD137 upregulation on alloreactive T-cells upon allogeneic stimulation suggests that their selective elimination could prevent acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HCT). Here, we developed a novel aGVHD prophylactic regimen consisting of a single dose of an anti-CD137 antibody-drug conjugate (CD137-ADC) administered on the day of transplant without additional immunosuppression. The CD137-ADC depleted both human and non-human primate (NHP) activated T-cells and proved highly effective in preventing xenogeneic aGVHD in mice receiving human peripheral blood mononuclear cells (PBMC), as well as in NHP undergoing MHC-haploidentical HCT. Flow cytometry analysis of NHP T-cells indicated specific depletion of activated PD-1+ CD4 and CD8 T-cells, while sparing naïve and PD-1-OX40+ memory T-cell subsets during the first week after HCT. CD137-ADC-treated NHP recipients demonstrated robust hematopoietic and immune reconstitution. Hallmarks of T-cell recovery after CD137-ADC, which were associated with long-term aGVHD-free survival, included reconstitution of CD4 memory T-cells expressing TRAIL, terminally-differentiated CD8 T-cells expressing CX3CR1, and CD4 FoxP3+ Tregs – cell types not expected to be involved in aGVHD pathogenesis. CD137-ADC-treated recipients demonstrated a higher risk of reactivation of rhLCV (the rhesus macaque EBV analogue), which was associated with reconstitution of follicular helper T-cells, interferon signaling-associated memory, and gamma-delta T-cell subsets. This reactivation was controllable with rituximab administration. These results document effective depletion of alloreactive T-cells and prevention of aGVHD following a single dose of CD137-ADC, suggesting that clinical translation should be carefully explored.
2025-05-28 | GSE298063 | GEO
Project description:CD137 cis-costimulation is superior to trans-costimulation at inducing transcriptomic differences in T-cell proliferation and DNA repair programs We used microarrays to detail differentially expressed genes of cis- and trans CD137-costimulated CD8 T cells with respect to CD3-TCR stimulation
2021-09-28 | GSE158041 | GEO