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Summary Background BTH1677 is a beta glucan pathogen associated molecular pattern (PAMP) currently being investigated as a novel cancer therapy. Here, the initial safety and pharmacokinetic (PK) results of BTH1677 in healthy subjects are reported. Subjects and Methods In the Phase 1a single-dosing study, subjects were randomized (3:1 per cohort) to a single intravenous (iv) infusion of BTH1677 at 0.5, 1, 2, 4, or 6 mg/kg or placebo, respectively. In the Phase 1b multi-dosing study, subjects were randomized (3:1 per cohort) to 7 daily iv infusions of BTH1677 at 1, 2, or 4 mg/kg or placebo, respectively. Safety and PK non-compartmental analyses were performed. Results Thirty-six subjects ( N  = 24 Phase 1a; N  = 12 Phase 1b) were randomized to treatment. No deaths or serious adverse events occurred in either study. Mild or moderate adverse events (AEs) occurred in 67 % of BTH1677-treated subjects in both studies. Treatment-related AEs (occurring in ≥10 % of subjects) included dyspnea, flushing, headache, nausea, paraesthesia, and rash in Phase 1a and conjunctivitis and headache in Phase 1b. BTH1677 serum concentration was linear with dose. Clearance, serum elimination half-life (t 1/2 ) and volume of distribution (Vss) were BTH1677 dose-independent. In Phase 1b, area under the curve, t 1/2 , and Vss values were larger at steady state on days 6–30 versus day 0. Conclusions BTH1677 was well tolerated after single doses up to 6 mg/kg and after 7 daily doses up to 4 mg/kg.

The fungal cell wall is essential for growth and survival, and is a key target for antifungal drugs and the immune system. The cell wall must be robust but flexible, protective and shielding yet porous to nutrients and membrane vesicles and receptive to exogenous signals. Most fungi have a common inner wall skeleton of chitin and β-glucans that functions as a flexible viscoelastic frame to which a more diverse set of outer cell wall polymers and glycosylated proteins are attached. Whereas the inner wall largely determines shape and strength, the outer wall confers properties of hydrophobicity, adhesiveness, and chemical and immunological heterogeneity. The spatial organization and dynamic regulation of the wall in response to prevailing growth conditions enable fungi to thrive within changing, diverse and often hostile environments. Understanding this architecture provides opportunities to develop diagnostics and drugs to combat life-threatening fungal infections.In this Review, Gow and Lenardon describe how fungal cell walls are organized, focusing on the underlying architectural and mechanical principles that are required to deliver differing and bespoke biochemical and biophysical attributes.

Summary Introduction BTH1677, a 1,3–1,6 beta-glucan immunomodulator, stimulates a coordinated anti-cancer immune response in combination with anti-tumor antibody therapies. This phase II study explored the efficacy, pharmacokinetics (PK), and safety of BTH1677 combined with cetuximab/carboplatin/paclitaxel in untreated stage IIIB/IV non-small cell lung cancer (NSCLC) patients. Methods Patients were randomized 2:1 to the BTH1677 arm ( N =60; BTH1677, 4 mg/kg, weekly; cetuximab, initial dose 400 mg/m 2 and subsequent doses 250 mg/m 2 , weekly; carboplatin, 6 mg/mL/min AUC (area-under-the-curve) by Calvert formula, once each 3-week cycle [Q3W]); and paclitaxel, 200 mg/m 2 , Q3W) or Control arm ( N =30; cetuximab/carboplatin/paclitaxel as above). Carboplatin/paclitaxel was discontinued after 4–6 cycles; patients who responded or remained stable received maintenance therapy with BTH1677/cetuximab (BTH1677 arm) or cetuximab (Control arm). Investigator and blinded central radiology reviews were conducted. Efficacy assessments included objective response rate (ORR; primary endpoint), disease control rate, duration of objective response, time-to-progression and overall survival (OS); safety was assessed by adverse events (AEs). Potential biomarker analysis for BTH1677 response was also conducted. Results Compared to control treatment, the addition of BTH1677 numerically increased ORR by both investigator (47.8% vs 23.1%; p=0.0468) and central (36.6% vs 23.1%; p=0.2895) reviews. No other endpoints differed between arms. PK was consistent with previous studies. BTH1677 was well tolerated, with AEs expected of the backbone therapy predominating. Biomarker-positive patients displayed better ORR and OS than negative patients. Conclusions BTH1677 combined with cetuximab/carboplatin/paclitaxel was well tolerated and improved ORR as first-line treatment in patients with advanced NSCLC. Future patient selection by biomarker status may further improve efficacy ClinicalTrials.gov Identifier: NCT00874848

Biological activities of medicinal mushrooms have been attributed to β-(1→3),(1→6)-glucans that are present in the cell wall of fungi and some plants. Antitumor, immunomodulatory, antimicrobial, antinociception, antiinflammatory, prebiotic, antioxidant, and antidiabetic are some of different properties already described for β-(1→3),(1→6)-glucans. Immune activation systems, including specific β-glucan receptors like Dectin-1, complement (CR3), and Toll (TLR), have been identified to clarify these biological effects. The β-(1→3)-glucans are synthesized by β-(1→3)-glucan synthase (GLS), an enzyme belonging to the glucosyltransferase group, which has a catalytic unit (FKS) and another regulatory (RHO). The mechanisms for adding β-(1→6) branches to the non-reducing ends of the β-(1→3)-glucan chains are unclear until now. Due to the biological importance of β-(1→3),(1→6)-glucan, it is necessary to understand the biochemical and molecular mechanisms of its synthesis, both to optimize the production of bioactive compounds and to develop antifungal drugs that interrupt this process. Therefore, the aim of this review is to gather information about the potential of β-(1→3),(1→6)-glucans, their methods of isolation, purification, and chemical characterization, as well as how these biomolecules are synthesized by fungi and what studies involving biotechnology or molecular biology have contributed to this subject.

•β-glucans are biological response modifiers with rich sources and diverse structures.•Extensive studies of β-glucan have been carried out to demonstrate its adjuvant activity on anti-infection vaccination and anti-tumor therapy.•The immunoadjuvant effects of β-glucans are mainly depending on the recognition of specific receptors such as dectin-1 and CR3. β-glucans, a group of polysaccharides exist in many organism species such as mushrooms, yeasts, oats, barley, seaweed, but not mammalians, have a variety of biological activities and applications in drugs and other healthcare products. In recent years, β-glucans have been studied as adjuvants in anti-infection vaccines as well as immunomodulators in anti-cancer immunotherapy. β-glucans can regulate immune responses when administered alone and can connect innate and adaptive immunity to improve immunogenicity of vaccines. When β-glucans act as immunostimulants or adjuvants, a set of receptors have been revealed to recognize β-glucans, including dectin-1, complement receptor 3 (CR3), CD5, lactosylceramide, and so on. Therefore, this review is mainly focused on the application of β-glucans as immune adjuvants, the receptors of β-glucans, as well as their structure and activity relationship which will benefit future research of β-glucans.

Abstract Vast efforts have been devoted to the development of antifungal drugs targeting the cell wall, but the supramolecular architecture of this carbohydrate-rich composite remains insufficiently understood. Here we compare the cell wall structure of a fungal pathogen Aspergillus fumigatus and four mutants depleted of major structural polysaccharides. High-resolution solid-state NMR spectroscopy of intact cells reveals a rigid core formed by chitin, β-1,3-glucan, and α-1,3-glucan, with galactosaminogalactan and galactomannan present in the mobile phase. Gene deletion reshuffles the composition and spatial organization of polysaccharides, with significant changes in their dynamics and water accessibility. The distribution of α-1,3-glucan in chemically isolated and dynamically distinct domains supports its functional diversity. Identification of valines in the alkali-insoluble carbohydrate core suggests a putative function in stabilizing macromolecular complexes. We propose a revised model of cell wall architecture which will improve our understanding of the structural response of fungal pathogens to stresses.

β-Glucans are a heterogeneous group of glucose polymers with a common structure comprising a main chain of β-(1,3) and/or β-(1,4)-glucopyranosyl units, along with side chains with various branches and lengths. β-Glucans initiate immune responses via immune cells, which become activated by the binding of the polymer to specific receptors. However, β-glucans from different sources also differ in their structure, conformation, physical properties, binding affinity to receptors, and thus biological functions. The mechanisms behind this are not fully understood. This mini-review provides a comprehensive and up-to-date commentary on the relationship between β-glucans' structure and function in relation to their use for immunomodulation.

Pancreatic cancers involve several challenges from difficulty in early diagnosis to high recurrence and mortality even after therapeutic interventions. Patients who undergo a surgical resection have several postoperative complications besides recurrence. Immunosuppression in the peri-operative period is a major challenge to overcome and in this study we investigated the effects of AFO-202 strain Aureobasidium-pullulans produced β-glucan (Nichi BRITE) in patients who underwent subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) for pancreatic, bile duct and duodenal malignancies. Thirty patients undergoing SSPPD were randomly assigned to a control (n = 15) group. A placebo was given, and the treatment arm (n = 15), administered Nichi BRITE 250 mg (Glucan) in 3 divided doses per day, starting from 1 d prior to the day of surgery up to the 21st postoperative day, either by oral intake or feeding gastrostomy. Parameters of relevance to immune system and biomarkers of cancer pathology were evaluated. Among the 22 patients who completed the study, the Nichi BRITE group showed notable increases in BG-IgA (+109.09%), CD209 (+54.68%, P = 0.034), and SAA (+800.70%, P = 0.050), while CA 19-9 decreased significantly (−5.86 U/mL, P < 0.001). Decrease in CD44 levels was greater in Nichi BRITE (−35.51%) than in the Placebo group (−14.05%). Disease-free survival (DFS) was longer in the Nichi BRITE group (16.1 mo) compared to the Placebo group (12.4 mo), with a lower recurrence rate (50% versus 71.4%) for pancreatic cancers. Administration of Nichi BRITE β-glucan during the perioperative period in patients undergoing surgery for pancreatic, bile duct and duodenal malignancies has been safe, and it has yielded immune enhancement and improvement in biomarkers of better prognosis. Reduction in circulating cancer stem cells and pancreatic cancer marker CA19-9 inclines us to recommend this Nichi BRITE β-glucan be included in onco-nutrition guidelines for patients undergoing surgical removal of malignant tumors. [Display omitted] •Nichi BRITE β-glucan was supplemented in peri-operative period of patients undergoing surgery for pancreas, bile duct and duodenal malignancies.•Nichi BRITE β-glucan supplementation was safe and there was increase in immune markers such as BG-IgA and CD209.•Decrease in cancer stem cell marker CD44 and significant decrease in cancer biomarker CA 19-9 proves Nichi BRITE’s efficacy.•Nichi BRITE β-glucan is worth consideration as a routine adjuvant in guidelines of onco-nutrition.

Fermentation of β-glucan fractions from barley [average molecular mass (MM), of 243, 172, and 137 kDa] and oats (average MM of 230 and 150 kDa) by the human faecal microbiota was investigated. Fractions were supplemented to pH-controlled anaerobic batch culture fermenters inoculated with human faecal samples from three donors, in triplicate, for each substrate. Microbiota changes were monitored by fluorescent in situ hybridization; groups enumerated were: Bifidobacterium genus, Bacteroides and Prevotella group, Clostridium histolyticum subgroup, Ruminococcus-Eubacterium-Clostridium (REC) cluster, Lactobacillus-Enterococcus group, Atopobium cluster, and clostridial cluster IX. Short-chain fatty acids and lactic acid were measured by HPLC. The C. histolyticum subgroup increased significantly in all vessels and clostridial cluster IX maintained high populations with all fractions. The Bacteroides-Prevotella group increased with all but the 243-kDa barley and 230-kDa oat substrates. In general β-glucans displayed no apparent prebiotic potential. The SCFA profile (51 : 32 : 17; acetate : propionate : butyrate) was considered propionate-rich. In a further study a β-glucan oligosaccharide fraction was produced with a degree of polymerization of 3-4. This fraction was supplemented to small-scale faecal batch cultures and gave significant increases in the Lactobacillus-Enterococcus group; however, the prebiotic potential of this fraction was marginal compared with that of inulin.

Beta-glucans comprise a group of polysaccharides of natural origin found in bacteria, algae, and plants, e.g., cereal seeds, as well as microfungi and macrofungi (mushrooms), which are characterized by diverse structures and functions. They are known for their metabolic and immunomodulatory properties, including anticancer, antibacterial, and antiviral. Recent reports suggest a potential of beta-glucans in the prevention and treatment of COVID-19. In contrast to β-glucans from other sources, β-glucans from mushrooms are characterized by β-1,3-glucans with short β-1,6-side chains. This structure is recognized by receptors located on the surface of immune cells; thus, mushroom β-glucans have specific immunomodulatory properties and gained BRM (biological response modifier) status. Moreover, mushroom beta-glucans also owe their properties to the formation of triple helix conformation, which is one of the key factors influencing the bioactivity of mushroom beta-glucans. This review summarizes the latest findings on biological and health-promoting potential of mushroom beta-glucans for the treatment of civilization and viral diseases, with particular emphasis on COVID-19.