ABSTRACT
BACKGROUND: PD-1/PD-L1 engagement and overexpression of galectin-3 (Gal-3) are critical mechanisms of tumor-induced immune suppression that contribute to immunotherapy resistance. We hypothesized that Gal-3 blockade with belapectin (GR-MD-02) plus anti-PD-1 (pembrolizumab) would enhance tumor response in patients with metastatic melanoma (MM) and head and neck squamous cell carcinoma (HNSCC). METHODS: We performed a phase I dose escalation study of belapectin+pembrolizumab in patients with advanced MM or HNSCC (NCT02575404). Belapectin was administered at 2, 4, or 8 mg/kg IV 60 min before pembrolizumab (200 mg IV every 3 weeks for five cycles). Responding patients continued pembrolizumab monotherapy for up to 17 cycles. Main eligibility requirements were a functional Eastern Cooperative Oncology Group status of 0-2, measurable or assessable disease, and no active autoimmune disease. Prior T-cell checkpoint antibody therapy was permitted. RESULTS: Objective response was observed in 50% of MM (7/14) and and 33% of HNSCC (2/6) patients. Belapectin+pembrolizumab was associated with fewer immune-mediated adverse events than anticipated with pembrolizumab monotherapy. There were no dose-limiting toxicities for belapectin within the dose range investigated. Significantly increased effector memory T-cell activation and reduced monocytic myeloid-derived suppressor cells (M-MDSCs) were observed in responders compared with non-responders. Increased baseline expression of Gal-3+ tumor cells and PD-1+CD8+ T cells in the periphery correlated with response as did higher serum trough levels of pembrolizumab. CONCLUSIONS: Belapectin+pembrolizumab therapy has activity in MM and HNSCC. Increased Gal-3 expression, expansion of effector memory T cells, and decreased M-MDSCs correlated with clinical response. Further investigation is planned.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Blood Proteins/antagonists & inhibitors , Galectins/antagonists & inhibitors , Head and Neck Neoplasms/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Multiple Myeloma/drug therapy , Pectins/therapeutic use , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Squamous Cell Carcinoma of Head and Neck/drug therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Blood Proteins/immunology , Female , Galectins/immunology , Head and Neck Neoplasms/diagnosis , Head and Neck Neoplasms/immunology , Humans , Immune Checkpoint Inhibitors/adverse effects , Male , Memory T Cells/drug effects , Memory T Cells/immunology , Middle Aged , Multiple Myeloma/diagnosis , Multiple Myeloma/immunology , Myeloid-Derived Suppressor Cells/drug effects , Myeloid-Derived Suppressor Cells/immunology , Pectins/adverse effects , Programmed Cell Death 1 Receptor/immunology , Squamous Cell Carcinoma of Head and Neck/diagnosis , Squamous Cell Carcinoma of Head and Neck/immunology , Time Factors , Treatment OutcomeABSTRACT
INTRODUCTION: Galectin-3 (Gal-3) is a ß-galactoside binding protein associated with many disease pathologies, including chronic inflammation and fibrogenesis. It has been implicated in the disease severity of NASH, although its precise role is unknown. Inhibition of Gal-3 has shown to improve and prevent fibrosis progression and has now reached phase III clinical trial in NASH patients. AREAS COVERED: This discusses the role of Gal-3 in NASH. It brings together the current findings of Gal-3 in NASH and hepatic fibrosis by analyzing recent data from animal model studies and clinical trials. EXPERT OPINION: Gal-3 inhibitors, in particular, Belapectin (GR-MD-02), have shown promising results for NASH with advanced fibrosis. In a phase 2 trial, Belapectin did not meet the primary endpoint. However, a sub-analysis of Belapectin among a separate group of patients without esophageal varices showed 2 mg/kg of GR-MD-02 reduced HVPG and the development of new varices. A subsequent study is under way, aiming to replicate the positive findings in phase 2 and demonstrate greater efficacy. If Belapectin is shown to be effective, it will be coupled with other drugs that target steatohepatitis to maximize efficacy and disease reversal.
Subject(s)
Blood Proteins/antagonists & inhibitors , Galectins/antagonists & inhibitors , Liver Cirrhosis/drug therapy , Non-alcoholic Fatty Liver Disease/drug therapy , Animals , Disease Models, Animal , Disease Progression , Humans , Liver Cirrhosis/metabolism , Liver Cirrhosis/physiopathology , Non-alcoholic Fatty Liver Disease/physiopathology , Pectins/administration & dosage , Pectins/pharmacology , Severity of Illness IndexABSTRACT
Rhamnogalacturonan I (RG-I) pectin are regarded as strong galectin-3 (Gal-3) antagonist because of galactan sidechains. The present study focused on discussing the effects of more structural regions in pectin on the anti-Gal-3 activity. The water-soluble pectin (WSP) recovered from citrus canning processing water was categorized as RG-I pectin. The controlled enzymatic hydrolysis was employed to sequentially remove the α-1,5-arabinan, homogalaturonan and ß-1,4-galactan in WSP. The Gal-3-binding affinity KD (kd/ka) of WSP and debranched pectins were calculated to be 0.32 µM, 0.48 µM, 0.56 µM and 1.93 µM. Moreover, based on the more sensitive cell line (MCF-7) model, the IC30 value of WSP was lower than these of modified pectins, indicating decreased anti-Gal-3 activity. Our results suggested that the total amount of neutral sugar sidechains, the length of arabinan and cooperation between HG and RG-I played important roles in the anti-Gal-3 activity of WSP, not the Gal/Ara ratio or RG-I/HG ratio. These results provided a new insight into structure-activity relationship of citrus segment membrane RG-I as a galectin-3 antagonist and a new functional food.
Subject(s)
Blood Proteins/antagonists & inhibitors , Cell Membrane/chemistry , Citrus/chemistry , Galactans/pharmacology , Galectins/antagonists & inhibitors , Pectins/chemistry , Pectins/pharmacology , Blood Proteins/metabolism , Cell Wall/chemistry , Fruit/chemistry , Galectins/metabolism , Humans , Hydrolysis , MCF-7 Cells , Pectins/metabolism , Plant Cells , Polysaccharides/chemistry , Protein Binding , Solubility , Structure-Activity Relationship , Water/chemistryABSTRACT
Swertiamarin (SW), a representative component in Flos Lonicerae Japonicae, has been reported to exert significant activity in preventing infections. In this research, we aim to clarify the details of SW and its target to explore SW's underlying anti-inflammatory mechanisms. An azide labeled SW probe was synthesized for protein target fishing, and the results demonstrated that AKT could be captured specifically. Immunofluorescence colocalization with AKT was implemented by a click reaction of the SW probe and alkynyl CY5. The result showed that AKT was one of the targets of SW. Then, a competitive combination experiment using a set of AKT inhibitors and a membrane translocation experiment confirmed that SW might target the pleckstrin homology (PH) domain of AKT. This specific binding directly deactivated the phosphorylation of AKT on both Ser473 and Thr308, which induced the dephosphorylation of IKK and NF-κB. Finally, proinflammatory cytokines (TNF-α, IL-6, and IL-8) were suppressed both in cells and in acute lung injury animal model by targeting AKT-PH domain. This study demonstrated that SW functions as a natural AKT inhibitor and presents significant anti-inflammatory activity by directly regulating the AKT-PH domain and inhibiting downstream inflammatory molecules.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Blood Proteins/antagonists & inhibitors , Inflammation/drug therapy , Iridoid Glucosides/pharmacology , Phosphoproteins/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyrones/pharmacology , Signal Transduction/drug effects , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Blood Proteins/metabolism , Cells, Cultured , HEK293 Cells , Humans , Inflammation/metabolism , Iridoid Glucosides/chemistry , Lonicera/chemistry , Mice , Molecular Structure , Phosphoproteins/metabolism , Plants, Medicinal/chemistry , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-akt/metabolism , Pyrones/chemistry , RAW 264.7 CellsSubject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Catechin/analogs & derivatives , ErbB Receptors/antagonists & inhibitors , Gene Rearrangement/drug effects , Lung Neoplasms/drug therapy , Anaplastic Lymphoma Kinase , Animals , Blood Proteins/antagonists & inhibitors , Blotting, Western , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Catechin/genetics , Catechin/pharmacology , Cell Line, Tumor , Crizotinib , Disease Models, Animal , ErbB Receptors/genetics , Female , Gene Rearrangement/genetics , Heterografts , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Mutation/genetics , Oncogene Proteins, Fusion/analysis , Oncogene Proteins, Fusion/genetics , Polyphenols/chemistry , Protein S , Protein-Tyrosine Kinases/administration & dosage , Pyrazoles/administration & dosage , Pyridines/administration & dosage , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Tea/chemistrySubject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Blood Proteins/administration & dosage , Blood , Complementary Therapies , Osteoarthritis, Knee/therapy , Receptors, Interleukin-1/antagonists & inhibitors , Bias , Blood Proteins/antagonists & inhibitors , Conflict of Interest , Double-Blind Method , Fraud , Germany , Humans , Injections, Intra-Articular , Middle Aged , Multicenter Studies as Topic , Randomized Controlled Trials as Topic/statistics & numerical dataABSTRACT
Glycation of liver proteins by reactive aldehydes formed from the metabolism of ethanol and lipid peroxidation has been implicated in the development of both alcoholic and nonalcoholic liver cirrhosis. Modified proteins are targeted to the proteasome for proteolysis. Release of glycation-free adducts into the circulation may provide a diagnostic "signature" of hepatic protein damage. We quantitatively screened protein glycation, oxidation, and nitrosation adduct residues and free adducts in portal, hepatic, and peripheral venous blood plasma of cirrhotic patients; we also screened the hepatic and peripheral venous blood plasma of control subjects by liquid chromatography-mass spectrometry. There was a remarkable 14-16-fold increase of glyoxal-derived, hydroimidazolone-free adduct in portal and hepatic venous plasma of cirrhotic patients with respect to normal controls. There was only a twofold increase of glycation adduct residues in plasma proteins in cirrhotic patients, which was attributed mainly to decreased albumin turnover. Therapeutic strategies to decrease dicarbonyl compounds may be beneficial, such as dicarbonyl scavengers, glutathione repleting agents, and high-dose thiamine therapy.