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Neurology(R) Neuroimmunology &... Nov 2021Costimulation by CD40 and its ligand CD40L (CD154) is important for the functional differentiation of T cells. Preclinical studies have recognized the importance of this... (Clinical Trial)
Clinical Trial
BACKGROUND AND OBJECTIVES
Costimulation by CD40 and its ligand CD40L (CD154) is important for the functional differentiation of T cells. Preclinical studies have recognized the importance of this costimulatory interaction in the pathogenesis of experimental models of multiple sclerosis (MS). To determine safety, pharmacokinetics, and immune effect of a humanized monoclonal antibody (mAb) against CD40 ligand (toralizumab/IDEC-131) in patients with relapsing-remitting MS (RRMS).
METHODS
This single-institution open-label dose-escalation study (phase I) enrolled 12 patients with RRMS to receive 4 doses of 1, 5, 10, or 15 mg/kg of humanized αCD40L (toralizumab) IV infusion every other week. Patients were followed up to 18 weeks, annually, and finally at 5 years. In addition to safety and pharmacokinetics, other secondary and exploratory measurements are immune effects, clinical, MRI, laboratory, and neuropsychological evaluations.
RESULTS
Fifteen adverse events, all of mild to moderate severity, were considered to be of possible or of unknown relationship to treatment. No serious adverse events, including thromboembolic events, occurred during the 18-week defined study period. Annual and long-term follow-up at 5 years revealed no delayed toxicity. Pharmacokinetics were nonlinear between the 5 and 10 mg/kg dose groups. The serum half-life of toralizumab was consistent between the dose groups with a mean of 15.3 days (SD = 1.9). Flow cytometry revealed no depletion of lymphocyte subsets. An increase in the CD25+/CD3+ and CD25+/CD4+ ratio and a shift toward an anti-inflammatory cytokine response were seen after treatment.
DISCUSSION
Our study suggests that blocking CD40L is safe and well tolerated in patients with RRMS while increasing CD25 T cells and anti-inflammatory cytokine profile. These findings support further studies to assess the efficacy of blocking CD40L as a potential treatment of RRMS.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence on the safety, pharmacokinetics, and immune effects of an mAb to CD40L in patients with RRMS.
Topics: Adult; Antibodies, Blocking; Antibodies, Monoclonal, Humanized; CD40 Ligand; Female; Follow-Up Studies; Humans; Immunologic Factors; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Outcome Assessment, Health Care
PubMed: 34654708
DOI: 10.1212/NXI.0000000000001096 -
Journal of Molecular Endocrinology Oct 2019FSH has a primary function in procreation, wherein it induces estrogen production in females and regulates spermatogenesis in males. However, in line with our... (Review)
Review
FSH has a primary function in procreation, wherein it induces estrogen production in females and regulates spermatogenesis in males. However, in line with our discoveries over the past decade of non-unitary functions of pituitary hormones, we and others have described hitherto uncharacterized functions of FSH. Through high-affinity receptors, some of which are variants of the ovarian FSH receptor (FSHR), FSH regulates bone mass, adipose tissue function, energy metabolism, and cholesterol production in both sexes. These newly described actions of FSH may indeed be relevant to the pathogenesis of bone loss, dysregulated energy homeostasis, and disordered lipid metabolism that accompany the menopause in females and aging in both genders. We are therefore excited about the possibility of modulating circulating FSH levels toward a therapeutic benefit for a host of age-associated diseases, including osteoporosis, obesity and dyslipidemia, among other future possibilities.
Topics: Animals; Antibodies, Blocking; Bone Resorption; Cholesterol; Follicle Stimulating Hormone; Humans; Menopause; Thermogenesis
PubMed: 31454787
DOI: 10.1530/JME-19-0152 -
Nature Communications May 2023Antibody-based blocking of vascular endothelial growth factor (VEGF) reduces choroidal neovascularization (CNV) and retinal edema, rescuing vision in patients with...
Antibody-based blocking of vascular endothelial growth factor (VEGF) reduces choroidal neovascularization (CNV) and retinal edema, rescuing vision in patients with neovascular age-related macular degeneration (nAMD). However, poor response and resistance to anti-VEGF treatment occurs. We report that targeting the Notch ligand Jagged1 by a monoclonal antibody reduces neovascular lesion size, number of activated phagocytes and inflammatory markers and vascular leakage in an experimental CNV mouse model. Additionally, we demonstrate that Jagged1 is expressed in mouse and human eyes, and that Jagged1 expression is independent of VEGF signaling in human endothelial cells. When anti-Jagged1 was combined with anti-VEGF in mice, the decrease in lesion size exceeded that of either antibody alone. The therapeutic effect was solely dependent on blocking, as engineering antibodies to abolish effector functions did not impair the therapeutic effect. Targeting of Jagged1 alone or in combination with anti-VEGF may thus be an attractive strategy to attenuate CNV-bearing diseases.
Topics: Humans; Mice; Animals; Vascular Endothelial Growth Factor A; Endothelial Cells; Choroidal Neovascularization; Antibodies, Blocking; Signal Transduction; Disease Models, Animal; Angiogenesis Inhibitors
PubMed: 37253747
DOI: 10.1038/s41467-023-38563-w -
Proceedings of the National Academy of... Nov 2017The TGF-β family ligands myostatin, GDF11, and activins are negative regulators of skeletal muscle mass, which have been reported to primarily signal via the ActRIIB...
The TGF-β family ligands myostatin, GDF11, and activins are negative regulators of skeletal muscle mass, which have been reported to primarily signal via the ActRIIB receptor on skeletal muscle and thereby induce muscle wasting described as cachexia. Use of a soluble ActRIIB-Fc "trap," to block myostatin pathway signaling in normal or cachectic mice leads to hypertrophy or prevention of muscle loss, perhaps suggesting that the ActRIIB receptor is primarily responsible for muscle growth regulation. Genetic evidence demonstrates however that both ActRIIB- and ActRIIA-deficient mice display a hypertrophic phenotype. Here, we describe the mode of action of bimagrumab (BYM338), as a human dual-specific anti-ActRIIA/ActRIIB antibody, at the molecular and cellular levels. As shown by X-ray analysis, bimagrumab binds to both ActRIIA and ActRIIB ligand binding domains in a competitive manner at the critical myostatin/activin binding site, hence preventing signal transduction through either ActRII. Myostatin and the activins are capable of binding to both ActRIIA and ActRIIB, with different affinities. However, blockade of either single receptor through the use of specific anti-ActRIIA or anti-ActRIIB antibodies achieves only a partial signaling blockade upon myostatin or activin A stimulation, and this leads to only a small increase in muscle mass. Complete neutralization and maximal anabolic response are achieved only by simultaneous blockade of both receptors. These findings demonstrate the importance of ActRIIA in addition to ActRIIB in mediating myostatin and activin signaling and highlight the need for blocking both receptors to achieve a strong functional benefit.
Topics: Activin Receptors, Type II; Activins; Animals; Antibodies, Blocking; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Morphogenetic Proteins; Crystallography, X-Ray; Dose-Response Relationship, Drug; Growth Differentiation Factors; HEK293 Cells; Humans; Hypertrophy; Male; Mice; Mice, SCID; Muscle, Skeletal; Myostatin; Rats; Rats, Wistar; Recombinant Proteins; Signal Transduction; Wasting Syndrome
PubMed: 29109273
DOI: 10.1073/pnas.1707925114 -
Hormone and Metabolic Research =... Dec 2018Autoantibodies (Ab) against the thyroid-stimulating hormone receptor (TSHR) are frequently found in autoimmune thyroid disease (AITD). Autoantibodies to the TSHR... (Review)
Review
Autoantibodies (Ab) against the thyroid-stimulating hormone receptor (TSHR) are frequently found in autoimmune thyroid disease (AITD). Autoantibodies to the TSHR (anti-TSHR-Ab) may mimic or block the action of TSH or be functionally neutral. Measurement of anti-TSHR-Ab can be done either via competitive-binding immunoassays or with functional cell-based bioassays. Antibody-binding assays do not assess anti-TSHR-Ab functionality, but rather measure the concentration of total anti-TSHR binding activity. In contrast, functional cell-based bioassays indicate whether anti-TSHR-Ab have stimulatory or blocking activity. Historically bioassays for anti-TSHR-Ab were research tools and were used to study the pathophysiology of Graves' disease and Hashimoto's thyroiditis. In the past, bioassays for anti-TSHR-Abs were laborious and time-consuming and varied widely in performance from laboratory to laboratory. Recent advances in the development of cell-based assays, including the application of molecular engineering, have led to significant improvements that have enabled bioassays to be employed routinely in clinical laboratories. The prevalence and functional significance of TSHR blocking autoantibodies (TBAb) in autoimmune hypothyroidism has been less well investigated compared to TSHR stimulating Ab. There is an increasing body of data, however, that demonstrate the clinical utility and relevance of TBAb, and thus the importance of TBAb bioassays, in the diagnosis and management of patients with AITD. In the present review, we summarize the different methods used to measure TBAb, and discuss their prevalence and clinical relevance.
Topics: Animals; Antibodies, Blocking; Autoantibodies; Biological Assay; Hashimoto Disease; Humans; Receptors, Thyrotropin
PubMed: 30286485
DOI: 10.1055/a-0723-9023 -
Journal of Immunology Research 2017HLA (Human Leucocyte Antigen) sensitization is a significant barrier to successful kidney transplantation. It often translates into difficult crossmatch before... (Review)
Review
HLA (Human Leucocyte Antigen) sensitization is a significant barrier to successful kidney transplantation. It often translates into difficult crossmatch before transplant and increased risk of acute and chronic antibody mediated rejection after transplant. Over the last decade, several immunomodulatory therapies have emerged allowing for increased access to kidney transplantation for the immunologically disadvantaged group of HLA sensitized end stage kidney disease patients. These include IgG inactivating agents, anti-cytokine antibodies, costimulatory molecule blockers, complement inhibitors, and agents targeting plasma cells. In this review, we discuss currently available agents for desensitization and provide a brief analysis of data on novel biologics, which will likely improve desensitization outcomes, and have potential implications in treatment of antibody mediated rejection.
Topics: Antibodies, Blocking; Antibody-Dependent Cell Cytotoxicity; Graft Rejection; HLA Antigens; Histocompatibility Testing; Humans; Immunization; Immunomodulation; Immunotherapy; Isoantibodies; Kidney Failure, Chronic; Organ Transplantation
PubMed: 28127571
DOI: 10.1155/2017/6804678 -
European Journal of Immunology Jun 2021Therapeutic antibodies that block PD-1-mediated inhibition of T cells have revolutionized cancer therapy. Murine cancer models are an essential tool for testing the...
Therapeutic antibodies that block PD-1-mediated inhibition of T cells have revolutionized cancer therapy. Murine cancer models are an essential tool for testing the efficacy of PD-1 blockers alone or in combination with other treatments. Depending on the isotype of the antibody and the host species, blocking antibodies can also exert cytotoxic activity towards cells expressing the target molecule. In the current issue of the European Journal of Immunology [Eur. J. Immunol. 2021. 51: 1473-1481], Polesso et al. demonstrate that depletion of PD-1 T cells by "blocking" PD-1 antibodies can greatly impact the outcome of preclinical immunotherapy experiments. Whereas some PD-1 antibodies promoted activation and proliferation of PD-1-expressing murine T cells, the authors report that administration of a particular PD-1 antibody can result in a significant loss of antigen-specific CD8 T cells in different in vivo models. These findings once more highlight that a comprehensive characterization of antibodies is warranted to avoid misinterpretation of immunotherapy studies.
Topics: Animals; Antibodies, Blocking; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Immunotherapy; Mice; Programmed Cell Death 1 Receptor
PubMed: 33954999
DOI: 10.1002/eji.202149276 -
Molecular Metabolism Feb 2024Glucagon-like peptide 1 (GLP-1) receptor agonists reduce food intake, producing remarkable weight loss in overweight and obese individuals. While much of this weight...
OBJECTIVE
Glucagon-like peptide 1 (GLP-1) receptor agonists reduce food intake, producing remarkable weight loss in overweight and obese individuals. While much of this weight loss is fat mass, there is also a loss of lean mass, similar to other approaches that induce calorie deficit. Targeting signaling pathways that regulate skeletal muscle hypertrophy is a promising avenue to preserve lean mass and modulate body composition. Myostatin and Activin A are TGFβ-like ligands that signal via the activin type II receptors (ActRII) to antagonize muscle growth. Pre-clinical and clinical studies demonstrate that ActRII blockade induces skeletal muscle hypertrophy and reduces fat mass. In this manuscript, we test the hypothesis that combined ActRII blockade and GLP-1 receptor agonism will preserve muscle mass, leading to improvements in skeletomuscular and metabolic function and enhanced fat loss.
METHODS
In this study, we explore the therapeutic potential of bimagrumab, a monoclonal antibody against ActRII, to modify body composition alone and during weight loss induced by GLP-1 receptor agonist semaglutide in diet-induced obese mice. Mechanistically, we define the specific role of the anabolic kinase Akt in mediating the hypertrophic muscle effects of ActRII inhibition in vivo.
RESULTS
Treatment of obese mice with bimagrumab induced a ∼10 % increase in lean mass while simultaneously decreasing fat mass. Daily treatment of obese mice with semaglutide potently decreased body weight; this included a significant decrease in both muscle and fat mass. Combination treatment with bimagrumab and semaglutide led to superior fat mass loss while simultaneously preserving lean mass despite reduced food intake. Treatment with both drugs was associated with improved metabolic outcomes, and increased lean mass was associated with improved exercise performance. Deletion of both Akt isoforms in skeletal muscle modestly reduced, but did not prevent, muscle hypertrophy driven by ActRII inhibition.
CONCLUSIONS
Collectively, these data demonstrate that blockade of ActRII signaling improves body composition and metabolic parameters during calorie deficit driven by GLP-1 receptor agonism and demonstrate the existence of Akt-independent pathways supporting muscle hypertrophy in the absence of ActRII signaling.
Topics: Animals; Mice; Activin Receptors, Type II; Activins; Antibodies, Blocking; Glucagon-Like Peptide-1 Receptor; Hypertrophy; Mice, Obese; Muscle, Skeletal; Proto-Oncogene Proteins c-akt; Weight Loss; Antibodies, Monoclonal, Humanized; Obesity
PubMed: 38218536
DOI: 10.1016/j.molmet.2024.101880 -
Proceedings of the National Academy of... Nov 2020Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a...
Blocking the action of FSH genetically or pharmacologically in mice reduces body fat, lowers serum cholesterol, and increases bone mass, making an anti-FSH agent a potential therapeutic for three global epidemics: obesity, osteoporosis, and hypercholesterolemia. Here, we report the generation, structure, and function of a first-in-class, fully humanized, epitope-specific FSH blocking antibody with a of 7 nM. Protein thermal shift, molecular dynamics, and fine mapping of the FSH-FSH receptor interface confirm stable binding of the Fab domain to two of five receptor-interacting residues of the FSHβ subunit, which is sufficient to block its interaction with the FSH receptor. In doing so, the humanized antibody profoundly inhibited FSH action in cell-based assays, a prelude to further preclinical and clinical testing.
Topics: Adipose Tissue; Animals; Antibodies, Blocking; Antibodies, Monoclonal; Bone Density; Bone and Bones; Epitopes; Female; Follicle Stimulating Hormone; Follicle Stimulating Hormone, beta Subunit; Humans; Hypercholesterolemia; Mice; Mice, Inbred C57BL; Molecular Dynamics Simulation; Obesity; Osteoporosis; Receptors, FSH
PubMed: 33127753
DOI: 10.1073/pnas.2014588117 -
Allergy and Asthma Proceedings Jul 2023Allergen specific immunotherapy (SIT) has been used for more than a century. Researchers have been working to improve efficacy and reduce the side effects. We have...
Allergen specific immunotherapy (SIT) has been used for more than a century. Researchers have been working to improve efficacy and reduce the side effects. We have reviewed the literature about peptides immunotherapy for inhaled allergens. The mechanism of SIT is to induce regulatory T (Treg) cells and to reduce T helper (Th)2 cells to induce class switching from IgE to IgG and induce blocking antibodies to inhibit allergen binding of IgE. The relevant published literatures on the peptide SIT for aeroallergens have been searched on the medline. Modification of allergens and routes of treatment has been performed. Among them, many researchers were interested in peptide immunotherapy. T-cell epitope peptide has no IgE epitope, that is able to bind IgE, but rather induces Treg and reduces Th2 cells, which was considered an ideal therapy. Results from cellular and animal model studies have been successful. However, in clinical studies, T-cell peptide immunotherapy has failed to show efficacy and caused side effects, because of the high effective rate of placebo and the development of IgE against T-cell epitope peptides. Currently, the modifications of IgE-allergen binding by blocking antibodies are considered for successful allergen immunotherapy. Newly developed hypoallergenic B cell epitope peptides and computational identification methods hold great potential to develop new peptide immunotherapies.
Topics: Animals; Humans; Epitopes, T-Lymphocyte; Antibodies, Blocking; Immunoglobulin E; Allergens; Desensitization, Immunologic; Immunotherapy; Peptides
PubMed: 37480199
DOI: 10.2500/aap.2023.44.230028