Beta-glucans are known as "biological response modifiers" because of their ability to activate the immune system.Immunologists at the University of Louisville, discovered that a receptor on the surface of innate immune cells called Complement Receptor 3 (CR3 or CD11b/CD18) is responsible for binding to beta-glucans, allowing the immune cells to recognize them as "non-self." However, it should be noted that the activity of beta-glucans is different from some pharmaceutical drugs which have the ability to over-stimulate the immune system. Pharmaceutical drugs have the potential to push the immune system to over-stimulation, and hence are contraindicated in individuals with autoimmune diseases, allergies, or yeast infections. Beta-glucans seem to make the immune system work better without becoming overactive. In addition to enhancing the activity of the immune system, beta-glucans also reportedly lower elevated levels of LDL cholesterol, aid in wound healing, help prevent infections, and have potential as an adjuvant in the treatment of cancer.
Beta-glucans, like lentinan (derived from the Shiitake mushroom) and Polysaccharide-K, have been used as an immunoadjuvant therapy for cancer since 1980, primarily in Japan. There is a large collection of research which demonstrates beta-glucans have anti-tumor and anti-cancer activity. In a mouse model study, beta 1,3 glucan in conjunction with interferon gamma inhibited tumors and liver metastasis.[10] In some studies, beta-1,3 glucans enhanced the effects of chemotherapy. In a cancer experiment, using a mouse model, administration of cyclophosphamide, in conjunction with beta-1,3 glucans derived from yeast resulted in reduced mortality. In human patients with advanced gastric or colorectal cancer, the administration of beta-1,3 glucans derived from shiitake mushrooms, in conjunction with chemotherapy resulted in prolonged survival times.
Preclinical studies have shown that a soluble yeast β-glucan product, Imprime PGG, when used in combination with certain monoclonal antibodies or cancer vaccines, offers significant improvements in long-term survival versus monoclonal antibodies alone.This benefit, however, does not result from Betafectin enhancing the specific killing action of the antibody. The anti-tumor activity is caused by a unique killing mechanism that involves neutrophils that are primed with Betafectin and which are not normally involved in the fight against cancer. Recent research by Hong et al., demonstrates that this mechanism of action is effective against a broad range of cancers when used in combination with specific monoclonal antibodies that activate or cause complement to be bound to the tumor.The complement enables these primed neutrophils to find and bind to the tumor, which facilitates killing. Innate immune cells are the body’s first line of defense and circulate throughout the body engaging in an immune response against “foreign” challenges (bacteria, fungus, parasites). Typically, neutrophils are not involved in the destruction of cancerous tissue because these immune cells view cancer as "self" rather than foreign or "non-self." Current cancer immunotherapies involve monoclonal antibodies and vaccines, which stimulate the acquired immune response, but do nothing to change the innate immune system's view of cancer as "self." As a result the monoclonal antibodies alone do not engage or initiate the potential killing ability of the innate immune system, which is our primary mechanism of defense against bacteria and yeast (fungal) infections.
Dr. Gordon Ross and Dr. Vaclav Vetvicka, respected immunologists and cancer researchers at the University of Louisville, discovered that a receptor on the surface of these innate immune cells called Complement Receptor 3 (CR3 or CD11b/CD18) was responsible for binding to fungi or yeast, allowing the immune cells to recognize them as "non-self." This receptor is a dual occupancy receptor in that it has two binding sites. The first site is responsible for binding to a type of complement, a soluble blood protein, known as C3 (or iC3b). C3 becomes attached to pathogens that specific antibodies have targeted and opsonized. The second site of this receptor binds to a carbohydrate on yeast or fungal cells that allows the innate immune cell to recognize yeast and fungi as being "non-self ”.Both of these receptor sites must be simultaneously occupied to trigger the innate immune cell to destroy the yeast or fungi. Two obstacles prevent neutrophils from using this mechanism of action against cancer. First, the body usually does not generate enough natural antibodies to bind to the tumor, and this prevents the activation and attachment of (or “fixing”) complement to the surface of the cancer cell. Therefore, neutrophils don’t bind to cancer via the first receptor site of CR3. The second obstacle is that even when the natural antibody response is supplemented with monoclonal antibodies that fix complement and binding occurs at the first site, tumors do not contain a foreign carbohydrate serving as “second signal” on their surface that allows neutrophils to recognize the cancer as "non-self “.[13][16] Other human receptors have been identified as being able to receive signals from beta-glucans such as Dectin-1, lactosylceramide, and scavenger receptors.
Dr. Ross discovered that a bio-processed fragment of Imprime PGG specifically binds to the second CR3 receptor site on neutrophils. When neutrophils bind to tumors, the Betafectin allows them to “see” cancer as if it were a yeast or fungal pathogen and provide the “second signal” to trigger killing. In summary, Betafectin engages neutrophils in the fight against cancer, dramatically and synergistically enhancing the effectiveness of complement activating monoclonal antibodies and vaccines through a different killing mechanism.
Multinational research has successfully demonstrated that the oral form of yeast Beta 1,3-D glucan has similar protective effects as the injected version, including defense against infectious diseases and cancer.Recently, orally-delivered glucan was found to significantly increase proliferation and activation of monocytes in peripheral blood of patients with advanced breast cancer.
The technology has wide applicability for cancer therapy. Each form of cancerous tumor cell has specific antigens on the cell surface, some of which are common to other types of cancer. (Example: Mucin 1 is present on about 70% of all types of cancer cells) Different immunotherapies target different antigens for binding monoclonal antibodies to tumor cells. This has resulted in the development of hundreds of monoclonal antibodies, many targeting a different specific antigen on cancer cells. In research studies, Betafectin has improved the effectiveness of all complement-activating monoclonal antibodies tested including breast, liver and lung cancer (company data). The magnitude of success varies based on the specific monoclonal antibody used and the type of cancer.
Prevention of infection
To date there have been numerous studies and clinical trials conducted with the soluble yeast β-glucan and the whole glucan particulate. These studies have ranged from the impact of β-glucan on post-surgical nosocomial infections to the role of yeast β-glucans in treating anthrax infections.
Post-surgical infections are a serious challenge following major surgery with estimates of 25-27% infection rates post-surgery.Alpha-Beta Technologies conducted a series of human clinical trials in the 1990’s to evaluate the impact of β-glucan therapy for controlling infections in high-risk surgical patients. In the initial trial 34 patients were randomly (double-blind, placebo-controlled) assigned to treatment or placebo groups. Patients that received the PGG-glucan had significantly fewer infectious complications than the placebo group (1.4 infections per infected patient for PGG-glucan group vs. 3.4 infections per infected patient for the placebo group). Additional data from the clinical trial revealed that there was decreased use of intravenous antibiotics and shorter stays in the intensive care unit for the patients receiving PGG-glucan vs. patients receiving the placebo.
A subsequent human clinical trial further studied the impact of β-glucan for reducing the incidence of infection with high-risk surgical patients. The authors found a similar result with a dose-response trend (higher dose provided greater reduction in infectious occurrences than low doses). In the human clinical trial 67 patients were randomized and received either a placebo or a dose of 0.1, 0.5, 1.0 or 2.0 mg PGG-Glucan per kilogram of body weight. Serious infections occurred in four patients that received the placebo, three patients that received the low dose (0.1 mg/kg) of PGG-Glucan and only one infection was observed at the highest dose of 2.0 mg/kg of PGG-Glucan.
The results of a phase III human clinical trial showed that PGG-Glucan therapy reduced serious post-operative infections by 39% after high-risk noncolorectal operations. This study was conducted in patients that were already as high-risk because of the type of surgery and were more susceptible to infections and other complications.
At this point in the development of an injectable form of b-glucan (Betafectin PGG-glucan) most scientists already concluded that yeast-derived b-glucan promoted phagocytosis and subsequent killing of pathogenic bacteria. A phase III clinical trial was proposed and conducted at thirty-nine medical centers in the U.S. involving 1,249 subjects stratified according to colorectal or non-colorectal surgical patients. The PGG-glucan was given once pre-operatively and three times post-operative at 0, 0.5 or 1.0 mg/kg body weight. The measured outcome was serious infection or death of the subjects within 30 days post-surgery. The results of the phase III human clinical trial showed that injectable PGG-Glucan therapy reduced serious post-operative infections by 39% after high-risk noncolorectal operations.
There have been studies with humans and animal models that further support the efficacy of β-glucan in combating various infectious diseases. One human study demonstrated that consumption of oral whole glucan particles increased the ability of immune cells to consume a bacterial challenge (phagocytosis). The total number of phagocytic cells and the efficiency of phagocytosis in healthy human study participants increased while consuming a commercial particulate yeast β-glucan. This study demonstrated the potential for yeast β-glucan to increase the reaction rate of the immune system to infectious challenges. The study concluded that oral consumption of whole glucan particles represented a good enhancer of natural immunity.
Anthrax is a disease that cannot be tested in human studies for obvious reasons. In a study conducted by the Canadian Department of Defense, Dr. Kournikakis showed that orally administered yeast β-glucan given with or without antibiotics protected mice against anthrax infection. A dose of antibiotics along with oral whole glucan particles (2 mg/KG body weight or 20 mg/KG body weight) for eight days prior to infection with Bacillus anthracis protected mice against anthrax infection over the 10-day post-exposure test period. Mice treated with antibiotic alone did not survive.
A second experiment was conducted to investigate the effect of yeast β-glucan orally consumed after exposure of mice to B. anthracis. The results were similar to the previous experiment with an 80-90% survival rate for mice treated with β-glucan, but only 30% for the control group after 10-days of exposure. The hopeful inference is that similar results would be observed with humans.
