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Cancer Immunology Research Oct 2022Novel therapeutic approaches combining immune-checkpoint inhibitors are needed to improve clinical outcomes for patients with cancer. Lymphocyte-activation gene 3...
Novel therapeutic approaches combining immune-checkpoint inhibitors are needed to improve clinical outcomes for patients with cancer. Lymphocyte-activation gene 3 (LAG-3) is an immune-checkpoint molecule that inhibits T-cell activity and antitumor immune responses, acting through an independent mechanism from that of programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4). Here, we describe the development and preclinical characterization of relatlimab, a human antibody that binds to human LAG-3 with high affinity and specificity to block the interaction of LAG-3 with the ligands MHC II and fibrinogen-like protein-1, and to reverse LAG-3-mediated inhibition of T-cell function in vitro. Consistent with previous reports, in mouse models, the combined blockade of LAG-3 and PD-1 with surrogate antibodies resulted in enhanced antitumor activity greater than the individual blockade of either receptor. In toxicity studies in cynomolgus monkeys, relatlimab was generally well tolerated when combined with nivolumab. These results are consistent with findings from the RELATIVITY-047 phase II/III trial showing that relatlimab combined with nivolumab is a well-tolerated regimen that demonstrates superior progression-free survival compared with nivolumab monotherapy in patients with unresectable or metastatic melanoma.
Topics: Animals; Antibodies, Blocking; Antibodies, Monoclonal; CTLA-4 Antigen; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Fibrinogen; Humans; Immune Checkpoint Inhibitors; Macaca fascicularis; Melanoma; Mice; Nivolumab; Programmed Cell Death 1 Receptor
PubMed: 35981087
DOI: 10.1158/2326-6066.CIR-22-0057 -
Molecular and Cellular Biology Feb 2014The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and...
The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings.
Topics: Activin Receptors, Type II; Activins; Animals; Antibodies, Blocking; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Atrophy; Cell Differentiation; Humans; Hypertrophy; Mice; Muscle, Skeletal; Myoblasts, Skeletal; Signal Transduction; Smad2 Protein; Smad3 Protein
PubMed: 24298022
DOI: 10.1128/MCB.01307-13 -
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 -
International Archives of Allergy and... Sep 2003Formation of IgE antibodies against per se harmless antigens (i.e. allergens) is the hallmark and key pathomechanism of type I allergy, a hypersensitivity disease... (Review)
Review
Formation of IgE antibodies against per se harmless antigens (i.e. allergens) is the hallmark and key pathomechanism of type I allergy, a hypersensitivity disease affecting more than 25% of the population. Classical experiments performed more than 65 years ago demonstrated that allergen-specific IgG antibodies, termed blocking antibodies, can antagonize the cascade of allergic inflammation resulting from allergen recognition by IgE antibodies. However, controversial results have questioned the protective role of IgG antibodies in allergic diseases. Here, we review recent data demonstrating that blocking antibodies inhibit allergen-induced release of inflammatory mediators from basophils and mast cells as well as IgE-facilitated allergen presentation to T cells, thus leading to suppression of T cell activation. Furthermore, it has been reported that the development of blocking antibodies is associated with reduced boosts of allergen-specific IgE production in patients receiving allergen-specific immunotherapy. These findings suggest that blocking antibodies have protective activity by inhibiting immediate as well as late inflammatory responses and long-term ameliorating activity on the allergic immune response by antagonizing the underlying IgE production. Induction of blocking antibodies is thus an important mechanism underlying allergen-specific immunotherapy. In addition, passive administration of blocking antibodies may be considered as a potential therapeutic strategy for allergic diseases.
Topics: Allergens; Antibodies, Blocking; Humans; Hypersensitivity; Immunoglobulin E; Immunotherapy
PubMed: 14555854
DOI: 10.1159/000073260 -
Biochemical and Biophysical Research... Jul 2017The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in many cellular functions including cell growth and migration. EGFR may be activated...
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase involved in many cellular functions including cell growth and migration. EGFR may be activated by EGF family ligands such as EGF and epiregulin (EREG). EREG is overexpressed in human colon and breast cancers, implying that EREG plays roles in tumorigenesis. Although EGF family members share a receptor, it is not well known whether their signaling pathways differ. In order to investigate EREG signaling, we established the anti-EREG antibody that inhibits EGFR downstream signaling stimulated by EREG but not by EGF. While the anti-EREG antibody has little effect on cell growth, it inhibits cell adhesion of EREG-expressing autocrine cancer cell lines. Our results suggest that anti-EREG antibodies represent valuable tools for elucidating EREG-specific signaling pathways, and may serve as therapeutic candidates for the treatment of cancers.
Topics: Animals; Antibodies, Blocking; Cell Adhesion; Epiregulin; ErbB Receptors; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Signal Transduction; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 28274874
DOI: 10.1016/j.bbrc.2017.03.006 -
Science Translational Medicine Jul 2018Vitiligo is an autoimmune disease of the skin mediated by CD8 T cells that kill melanocytes and create white spots. Skin lesions in vitiligo frequently return after...
Vitiligo is an autoimmune disease of the skin mediated by CD8 T cells that kill melanocytes and create white spots. Skin lesions in vitiligo frequently return after discontinuing conventional treatments, supporting the hypothesis that autoimmune memory is formed at these locations. We found that lesional T cells in mice and humans with vitiligo display a resident memory (T) phenotype, similar to those that provide rapid, localized protection against reinfection from skin and mucosal-tropic viruses. Interleukin-15 (IL-15)-deficient mice reportedly have impaired T formation, and IL-15 promotes T function ex vivo. We found that both human and mouse T express the CD122 subunit of the IL-15 receptor and that keratinocytes up-regulate CD215, the subunit required to display the cytokine on their surface to promote activation of T cells. Targeting IL-15 signaling with an anti-CD122 antibody reverses disease in mice with established vitiligo. Short-term treatment with anti-CD122 inhibits T production of interferon-γ (IFNγ), and long-term treatment depletes T from skin lesions. Short-term treatment with anti-CD122 can provide durable repigmentation when administered either systemically or locally in the skin. On the basis of these data, we propose that targeting CD122 may be a highly effective and even durable treatment strategy for vitiligo and other tissue-specific autoimmune diseases involving T.
Topics: Animals; Antibodies, Blocking; Antigens, CD; CD8-Positive T-Lymphocytes; Disease Models, Animal; Epidermis; Humans; Immunologic Memory; Interferon-gamma; Interleukin-15; Melanocytes; Mice, Inbred C57BL; Phenotype; Receptors, Interleukin-15; Signal Transduction; Vitiligo
PubMed: 30021889
DOI: 10.1126/scitranslmed.aam7710 -
Virologica Sinica Feb 2017Dengue virus (DENV) is a mosquito-borne virus belonging to the Flaviviridae family. There are 4 serotypes of DENV that cause human disease through transmission by... (Review)
Review
Dengue virus (DENV) is a mosquito-borne virus belonging to the Flaviviridae family. There are 4 serotypes of DENV that cause human disease through transmission by mosquito vectors. DENV infection results in a broad spectrum of clinical symptoms, ranging from mild fever to dengue hemorrhagic fever (DHF), the latter of which can progress to dengue shock syndrome (DSS) and death. Researchers have made unremitting efforts over the last half-century to understand DHF pathogenesis. DHF is probably caused by multiple factors, such as virus-specific antibodies, viral antigens and host immune responses. This review summarizes the current progress of studies on DHF pathogenesis, which may provide important information for achieving effective control of dengue in the future.
Topics: Antibodies, Blocking; Antibodies, Viral; Dengue Virus; Host-Pathogen Interactions; Humans; Severe Dengue
PubMed: 27853992
DOI: 10.1007/s12250-016-3855-9 -
Cancer Research Communications Nov 2022Tumor-associated macrophages (TAM) are the most abundant immune cells in the tumor microenvironment. They consist of various subsets but primarily resemble the M2...
UNLABELLED
Tumor-associated macrophages (TAM) are the most abundant immune cells in the tumor microenvironment. They consist of various subsets but primarily resemble the M2 macrophage phenotype. TAMs are known to promote tumor progression and are associated with poor clinical outcomes. CD47 on tumor cells and SIRPα on TAMs facilitate a "don't-eat-me" signal which prevents cancer cells from immune clearance. Therefore, blockade of the CD47-SIRPα interaction represents a promising strategy for tumor immunotherapy. Here, we present the results on ZL-1201, a differentiated and potent anti-CD47 antibody with improved hematologic safety profile compared with 5F9 benchmark. ZL-1201 enhanced phagocytosis in combination with standards of care (SoC) therapeutic antibodies in coculture systems using a panel of tumor models and differentiated macrophages, and these combinational effects are Fc dependent while potently enhancing M2 phagocytosis. xenograft studies showed that enhanced antitumor activities were seen in a variety of tumor models treated with ZL-1201 in combination with other therapeutic mAbs, and maximal antitumor activities were achieved in the presence of chemotherapy in addition to the combination of ZL-1201 with other mAbs. Moreover, tumor-infiltrating immune cells and cytokine analysis showed that ZL-1201 and chemotherapies remodel the tumor microenvironment, which increases antitumor immunity, leading to augmented antitumor efficacy when combined with mAbs.
SIGNIFICANCE
ZL-1201 is a novel anti-CD47 antibody that has improved hematologic safety profiles and combines with SoC, including mAbs and chemotherapies, to potently facilitate phagocytosis and antitumor efficacy.
Topics: Humans; Tumor-Associated Macrophages; Cell Line, Tumor; Macrophages; Phagocytosis; Antibodies, Monoclonal; Antineoplastic Agents; Antibodies, Blocking
PubMed: 36970051
DOI: 10.1158/2767-9764.CRC-22-0266 -
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 -
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