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Nature Communications Feb 2022Premature ovarian failure (POF) is a leading cause of women's infertility without effective treatment. Here we show that intravenous injection of Ab4B19, an agonistic...
Premature ovarian failure (POF) is a leading cause of women's infertility without effective treatment. Here we show that intravenous injection of Ab4B19, an agonistic antibody for the BDNF receptor TrkB, penetrates into ovarian follicles, activates TrkB signaling, and promotes ovary development. In both natural aging and cyclophosphamide-induced POF models, treatment with Ab4B19 completely reverses the reduction of pre-antral and antral follicles, and normalizes gonadal hormone. Ab4B19 also attenuates gonadotoxicity and inhibits apoptosis in cyclophosphamide-induced POF ovaries. Further, treatment with Ab4B19, but not BDNF, restores the number and quality of oocytes and enhances fertility. In human, BDNF levels are high in granulosa cells and TrkB levels increase in oocytes as they mature. Moreover, BDNF expression is down-regulated in follicles of aged women, and Ab4B19 activates TrkB signaling in human ovary tissue ex vivo. These results identify TrkB as a potential target for POF with differentiated mechanisms, and confirms superiority of TrkB activating antibody over BDNF as therapeutic agents.
Topics: Adult; Animals; Female; Humans; Male; Mice; Middle Aged; Young Adult; Aging; Apoptosis; Brain-Derived Neurotrophic Factor; Cell Line, Tumor; Cyclophosphamide; Disease Models, Animal; Fertility; Fertility Agents, Female; Membrane Glycoproteins; Organ Culture Techniques; Ovary; Primary Ovarian Insufficiency; Receptor, trkB
PubMed: 35177657
DOI: 10.1038/s41467-022-28611-2 -
Cell Feb 2021Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter...
Ligand-gated ion channels mediate signal transduction at chemical synapses and transition between resting, open, and desensitized states in response to neurotransmitter binding. Neurotransmitters that produce maximum open channel probabilities (Po) are full agonists, whereas those that yield lower than maximum Po are partial agonists. Cys-loop receptors are an important class of neurotransmitter receptors, yet a structure-based understanding of the mechanism of partial agonist action has proven elusive. Here, we study the glycine receptor with the full agonist glycine and the partial agonists taurine and γ-amino butyric acid (GABA). We use electrophysiology to show how partial agonists populate agonist-bound, closed channel states and cryo-EM reconstructions to illuminate the structures of intermediate, pre-open states, providing insights into previously unseen conformational states along the receptor reaction pathway. We further correlate agonist-induced conformational changes to Po across members of the receptor family, providing a hypothetical mechanism for partial and full agonist action at Cys-loop receptors.
Topics: Animals; Binding Sites; Cell Line; Cryoelectron Microscopy; Glycine; HEK293 Cells; Humans; Imaging, Three-Dimensional; Ion Channel Gating; Maleates; Models, Molecular; Mutant Proteins; Mutation; Neurotransmitter Agents; Protein Domains; Receptors, Glycine; Styrene; Zebrafish; gamma-Aminobutyric Acid
PubMed: 33567265
DOI: 10.1016/j.cell.2021.01.026 -
MAbs 2023The clinical development of 4-1BB agonists for cancer immunotherapy has raised substantial interest during the past decade. The first generation of 4-1BB agonistic... (Review)
Review
The clinical development of 4-1BB agonists for cancer immunotherapy has raised substantial interest during the past decade. The first generation of 4-1BB agonistic antibodies entering the clinic, urelumab (BMS-663513) and utomilumab (PF-05082566), failed due to (liver) toxicity or lack of efficacy, respectively. The two antibodies display differences in the affinity and the 4-1BB receptor epitope recognition, as well as the isotype, which determines the Fc-gamma-receptor (FcγR) crosslinking activity. Based on this experience a very diverse landscape of second-generation 4-1BB agonists addressing the liabilities of first-generation agonists has recently been developed, with many entering clinical Phase 1 and 2 studies. This review provides an overview focusing on differences and their scientific rationale, as well as challenges foreseen during the clinical development of these molecules.
Topics: Humans; Tumor Necrosis Factor Receptor Superfamily, Member 9; Receptors, IgG; Epitopes; Neoplasms; Immunotherapy
PubMed: 36727218
DOI: 10.1080/19420862.2023.2167189 -
Journal of Hepatology May 2021While cholangiocarcinomas (CCAs) commonly express programmed cell death 1 (PD-1) and its ligand (PD-L1), they respond poorly to immune checkpoint inhibitors (ICIs). We...
BACKGROUND & AIMS
While cholangiocarcinomas (CCAs) commonly express programmed cell death 1 (PD-1) and its ligand (PD-L1), they respond poorly to immune checkpoint inhibitors (ICIs). We aimed to determine whether stimulating antigen-presenting cells, including macrophages and dendritic cells, using a CD40 agonist could improve this response.
METHODS
We compared treatment responses in subcutaneous, orthotopic, and 2 plasmid-based murine intrahepatic CCA (iCCA) models. Mice were treated for 4 weeks with weekly IgG control, a CD40 agonistic antibody, anti-PD-1, or the combination of both (anti-CD40/PD-1). Flow cytometric (FACS) analysis of lymphocytes and myeloid cell populations (including activation status) was performed. We used dendritic cell knockout mice, and macrophage, CD4 and CD8 T cell depletion models to identify effector cells. Anti-CD40/PD-1 was combined with chemotherapy (gemcitabine/cisplatin) to test for improved therapeutic efficacy.
RESULTS
In all 4 models, anti-PD-1 alone was minimally efficacious. Mice exhibited a moderate response to CD40 agonist monotherapy. Combination anti-CD40/PD-1 therapy led to a significantly greater reduction in tumor burden. FACS demonstrated increased number and activation of CD4 and CD8 T cells, natural killer cells, and myeloid cells in tumor and non-tumor liver tissue of tumor-bearing mice treated with anti-CD40/PD-1. Depletion of macrophages, dendritic cells, CD4+ T cells, or CD8+ T cells abrogated treatment efficacy. Combining anti-CD40/PD-1 with gemcitabine/cisplatin resulted in a significant survival benefit compared to gemcitabine/cisplatin alone.
CONCLUSION
CD40-mediated activation of macrophages and dendritic cells in iCCA significantly enhances response to anti-PD-1 therapy. This regimen may enhance the efficacy of first-line chemotherapy.
LAY SUMMARY
Checkpoint inhibition, a common form of immune therapy, is generally ineffective for the treatment of cholangiocarcinoma. These tumors suppress the infiltration and function of surrounding immune cells. Stimulating immune cells such as macrophages and dendritic cells via the CD40 receptor activates downstream immune cells and enhances the response to checkpoint inhibitors.
Topics: Animals; Antimetabolites, Antineoplastic; CD40 Antigens; Cell Line, Tumor; Cholangiocarcinoma; Cisplatin; Dendritic Cells; Deoxycytidine; Drug Collateral Sensitivity; Immune Checkpoint Inhibitors; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Macrophage Activation; Macrophage-Activating Factors; Mice; Mice, Knockout; Tumor Microenvironment; Gemcitabine
PubMed: 33276030
DOI: 10.1016/j.jhep.2020.11.037 -
Cancers Mar 2021CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased... (Review)
Review
CD40 is expressed on a variety of antigen-presenting cells. Stimulation of CD40 results in inflammation by upregulation of other costimulatory molecules, increased antigen presentation, maturation (licensing) of dendritic cells, and activation of CD8+ T cells. Here we analyzed gene expression data from The Cancer Genome Atlas in melanoma, renal cell carcinoma, and pancreatic adenocarcinoma and found correlations between CD40 and several genes involved in antigen presentation and T cell function, supporting further exploration of CD40 agonists to treat cancer. Agonist CD40 antibodies have induced anti-tumor effects in several tumor models and the effect has been more pronounced when used in combination with other treatments (immune checkpoint inhibition, chemotherapy, and colony-stimulating factor 1 receptor inhibition). The reduction in tumor growth and ability to reprogram the tumor microenvironment in preclinical models lays the foundation for clinical development of agonistic CD40 antibodies (APX005M, ChiLob7/4, ADC-1013, SEA-CD40, selicrelumab, and CDX-1140) that are currently being evaluated in early phase clinical trials. In this article, we focus on CD40 expression and immunity in cancer, agonistic human CD40 antibodies, and their pre-clinical and clinical development. With the broad pro-inflammatory effects of CD40 and its ligand on dendritic cells and macrophages, and downstream B and T cell activation, agonists of this pathway may enhance the anti-tumor activity of other systemic therapies.
PubMed: 33804039
DOI: 10.3390/cancers13061302 -
Frontiers in Endocrinology 2021
Topics: Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptides; Hypoglycemic Agents
PubMed: 34630338
DOI: 10.3389/fendo.2021.760153 -
Frontiers in Immunology 2023Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs. It is often called "immortal cancer" due to the difficulties in disease... (Review)
Review
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs. It is often called "immortal cancer" due to the difficulties in disease treatment. As the cornerstone of immune regulation, the programmed cell death protein 1 (PD-1) has been extensively studied in the context of chronic inflammation due to its ability of regulating immune response and immunosuppression. Recently, more and more studies on rheumatic immune related complications have also focused on PD-1 and proposed that the use of PD-1 agonist could inhibit the activation of lymphocytes and alleviate SLE disease activity. In this review, we summarized the role of PD-1 in SLE, implicating its potential application as a biomarker to predict SLE disease activity; we also proposed that the combination of PD-1 agonist and low-dose IL-2 may have better therapeutic efficacy, shining light on a new direction for developing specific treatment approaches.
Topics: Humans; Inflammation; Interleukin-2; Lupus Erythematosus, Systemic; Programmed Cell Death 1 Receptor
PubMed: 36969198
DOI: 10.3389/fimmu.2023.1111005 -
Scientific Reports May 2023Muscle-specific kinase (MuSK) is crucial for acetylcholine receptor (AChR) clustering and thereby neuromuscular junction (NMJ) function. NMJ dysfunction is a hallmark of...
Muscle-specific kinase (MuSK) is crucial for acetylcholine receptor (AChR) clustering and thereby neuromuscular junction (NMJ) function. NMJ dysfunction is a hallmark of several neuromuscular diseases, including MuSK myasthenia gravis. Aiming to restore NMJ function, we generated several agonist monoclonal antibodies targeting the MuSK Ig-like 1 domain. These activated MuSK and induced AChR clustering in cultured myotubes. The most potent agonists partially rescued myasthenic effects of MuSK myasthenia gravis patient IgG autoantibodies in vitro. In an IgG4 passive transfer MuSK myasthenia model in NOD/SCID mice, MuSK agonists caused accelerated weight loss and no rescue of myasthenic features. The MuSK Ig-like 1 domain agonists unexpectedly caused sudden death in a large proportion of male C57BL/6 mice (but not female or NOD/SCID mice), likely caused by a urologic syndrome. In conclusion, these agonists rescued pathogenic effects in myasthenia models in vitro, but not in vivo. The sudden death in male mice of one of the tested mouse strains revealed an unexpected and unexplained role for MuSK outside skeletal muscle, thereby hampering further (pre-) clinical development of these clones. Future research should investigate whether other Ig-like 1 domain MuSK antibodies, binding different epitopes, do hold a safe therapeutic promise.
Topics: Male; Animals; Mice; Mice, SCID; Receptor Protein-Tyrosine Kinases; Mice, Inbred C57BL; Mice, Inbred NOD; Myasthenia Gravis; Receptors, Cholinergic; Autoantibodies; Muscle Weakness; Acetylcholine
PubMed: 37156800
DOI: 10.1038/s41598-023-32641-1 -
JCI Insight Jan 2023Podocyte injury and loss are key drivers of primary and secondary glomerular diseases, such as focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease...
Podocyte injury and loss are key drivers of primary and secondary glomerular diseases, such as focal segmental glomerulosclerosis (FSGS) and diabetic kidney disease (DKD). We previously demonstrated the renoprotective role of protein S (PS) and its cognate tyrosine-protein kinase receptor, TYRO3, in models of FSGS and DKD and that their signaling exerts antiapoptotic and antiinflammatory effects to confer protection against podocyte loss. Among the 3 TAM receptors (TYRO3, AXL, and MER), only TYRO3 expression is largely restricted to podocytes, and glomerular TYRO3 mRNA expression negatively correlates with human glomerular disease progression. Therefore, we posited that the agonistic PS/TYRO3 signaling could serve as a potential therapeutic approach to attenuate glomerular disease progression. As PS function is not limited to TYRO3-mediated signal transduction but includes its anticoagulant activity, we focused on the development of TYRO3 agonists as an optimal therapeutic approach to glomerular disease. Among the small-molecule TYRO3 agonistic compounds screened, compound 10 (C-10) showed a selective activation of TYRO3 without any effects on AXL or MER. We also confirmed that C-10 directly binds to TYRO3, but not the other receptors. In vivo, C-10 attenuated proteinuria, glomerular injury, and podocyte loss in mouse models of Adriamycin-induced nephropathy and a db/db model of type 2 diabetes. Moreover, these renoprotective effects of C-10 were lost in Tyro3-knockout mice, indicating that C-10 is a selective agonist of TYRO3 activity that mitigates podocyte injury and glomerular disease. Therefore, C-10, a TYRO3 agonist, could be potentially developed as a new therapy for glomerular disease.
Topics: Mice; Animals; Humans; Glomerulosclerosis, Focal Segmental; Diabetes Mellitus, Type 2; Kidney Glomerulus; Podocytes; Mice, Knockout; Carrier Proteins; Disease Progression; Receptor Protein-Tyrosine Kinases
PubMed: 36454644
DOI: 10.1172/jci.insight.165207 -
Pharmacology, Biochemistry, and Behavior Sep 2022Obesity is a prevalent disease, but effective treatments remain limited. Agonists of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) promote negative energy...
Obesity is a prevalent disease, but effective treatments remain limited. Agonists of the alpha-7 nicotinic acetylcholine receptor (α7nAChR) promote negative energy balance in mice, but these effects are not well-studied in rats. We tested the hypothesis that the α7nAChR agonist GTS-21 would decrease food intake and body weight in adult male Sprague Dawley rats. Contrary to our hypothesis, acute systemic administration of GTS-21 produced no significant effects on chow or high-fat diet (HFD) intake. Acute intracerebroventricular (ICV) GTS-21 also had no impact on chow intake, and actually increased body weight at the highest dose tested. Previous studies suggest that GTS-21 engages the food intake-suppressive glucagon-like peptide-1 (GLP-1) system in mice. As there are known species differences in GLP-1 physiology between mice and rats, we tested the ability of GTS-21 to elicit GLP-1 secretion in rats. Our results showed that plasma levels of total GLP-1 in rats were not significantly altered by peripheral GTS-21 injection. These results represent an advance in understanding how α7nAChR activation impacts energy balance control in rodents and suggest that there may be important differences between rats and mice in the ability of GTS-21/α7nAChR activation to increase secretion of GLP-1.
Topics: Animals; Benzylidene Compounds; Body Weight; Eating; Glucagon-Like Peptide 1; Male; Mice; Pyridines; Rats; Rats, Sprague-Dawley; alpha7 Nicotinic Acetylcholine Receptor
PubMed: 35944617
DOI: 10.1016/j.pbb.2022.173444