Globulin Component Macrophage Activating Factor (GcMAF), Immunotherapy, Globulin Component Macrophage Activating Factor, Cancer, Macrophages, Nagalase

Globulin Component

Macrophage Activating Factor (GcMAF) Immunotherapy

By James Odell, ND, OMD, LAc

At the turn of the 20th century, the emerging field of medical oncology chose a cytotoxic approach to cancer therapy over an immune-centered approach. In the intervening years, nearly 120 years of data have established that (a) even the best cytotoxic regimens only infrequently cure late-stage malignancy and (b) strategies that supplement and augment existing antitumor immune responses offer the greatest opportunities to potentiate durable cancer remission.

The immune system consists of a multitude of cells and cell lines that communicate with one another through specific messenger substances. Immunotherapy uses cells, messenger substances, and molecules to trigger a reaction in the immune system. It employs known antibodies, complement proteins, and cytokines – as well as metabolites of the vitamin D axis. The vitamin D3-binding protein (Gc protein)-derived macrophage activating factor (GcMAF) activates tumoricidal macrophages against a variety of cancers indiscriminately. This article outlines current immunotherapy practices using GcMAF.

Macrophage activating factor (MAF) is a lymphokine or other receptor-based signal that primes macrophages towards cytotoxicity to tumors, cytokine secretion, or clearance of pathogens. MAF is formed by dissociation of two sugar compounds from the vitamin D3-binding protein. This enzymatic transformation is significantly stimulated by T and B lymphocytes and results, among other things, in a striking increase in activity levels of the macrophages.

MAF specifically serves to activate macrophages triggering an immunomodulatory effect, by linking to the vitamin D receptor (VDR). However, to do so, the saturation of the protein with two further components is necessary: vitamin D and oleic acid. Hence, vitamin D and oleic acid must be present to activate the relevant macrophages and cause a targeted immunomodulation. The VDR functionally works as a transcription factor within the cell nucleus and modulates the expression of more than 900 known genes. VDR blockades play an important role in the pathogenesis of many chronic diseases.

Macrophages are specialized cells involved in the detection, phagocytosis and destruction of cancerous cells, bacteria and other harmful organisms. Macrophages act as a first line or primary defense against intruders; they migrate to and circulate within almost every tissue, patrolling for pathogens and eliminating dead cells. They also direct other types of white blood cells, especially lymphocytes. Macrophages readily infiltrate diseased and damaged tissues, including tumors. As such, macrophage-based cancer therapies have long been investigated.

Macrophages are released from the bone marrow as immature monocytes. After circulating in the blood, they are recruited by chemokines into the tissue and undergo differentiation into macrophages. They can exhibit different phenotypes and functions, depending on the physiologic or pathologic situation to which they are recruited. Moreover, macrophages can exhibit different responses depending on the type of stimuli they receive from the surrounding microenvironment, varying from pro-inflammatory to anti-inflammatory. There are several activated forms of macrophages. Based on their activation state, there are two main phenotypes designated M1 and M2. The differences displayed by macrophages in terms of receptor expression, cytokine production, and function, define these two populations. 

M1 (classically activated) macrophages can produce large amounts of proinflammatory cytokines and are involved in the killing of pathogens and tumor cells. In most tumors, the infiltrated macrophages are of the M2-phenotype, which provides an immunosuppressive microenvironment for tumor growth. Furthermore, these tumor-associated macrophages secrete many cytokines, chemokines, and proteases that promote tumor angiogenesis, growth, metastasis, and immunosuppression.

More than 25 years ago, the immunologist Dr. Nobuto Yamamoto isolated GcMAF as a specific immunotherapy. Since then, studies have demonstrated that GcMAF enhances the ability of the immune system to fight pathogens and cancer cells, by enhancing M1-macrophages as well as reducing the enzyme α-N-acetylgalactosaminidase (nagalase).^1-12 Accordingly, its administration has potential benefits in patients with a variety of conditions, ranging from cancer to HIV and other chronic viruses.^13-15

Dr. Yamamoto has authored or co-authored over 50 papers on immunology. In 2014, however, three of his articles were retracted,^16-18 giving rise to considerable negative media and controversy around GcMAF immunotherapy. Since then, numerous others have picked up the torch and continued this line of research, further demonstrating that GcMAF has wide application for use in many diseases by activating macrophages and stimulating the immune system.

Dr. Yamamoto patented the process of preparing GcMAF by treating glycosylated human group-specific component, also known as human vitamin D-binding protein, with glycosidases in 1990 and 2015.^{19, 20} The manufacturing process of GcMAF is very technical and an impurity can be introduced at any step. Hence, there is certainly risk of product contamination. Reputable manufacturers test the final product for purity and efficacy.

Function, Biological and Pharmacological Properties of Gc-Globulin and GcMAF

Macrophages play a principal role in the fight against cancer cells, but only following a complex activation mechanism. In the context of cancer, classically activated macrophages (M1-macrophages) play an important role in the recognition and destruction of cancer cells, and their presence usually indicates good prognosis. After recognition, malignant cells can be destroyed through several mechanisms, which include contact-dependent phagocytosis and cytotoxicity.

Vitamin D-binding protein (known as Gc) can be converted to the potent macrophage activating factor (GcMAF) by stepwise modification of Gc with beta-galactosidase of B cells and sialidase of T cells. Gc protein is synthesized in the liver and carries vitamin D and its metabolites through the circulation and mediates the response of tissue. Gc protein, in addition to the storage and transport of vitamin D, has an important physiological function as a scavenger of extracellular G-actin to increase neutrophil chemotaxis as well as macrophage activation. Gc protein, when modified, can affect the activation and fortification of immune cells exhibiting anticancer activity. Macrophages activated by GcMAF offer different properties that are effective against a variety of cancers in human and animal models.^21-23

GcMAF Indications and Associated Treatment Methods

Injectable GcMAF and oral forms of colostrum-derived MAF are not used as stand-alone therapies. Instead, in the world of bioregulatory medicine, this form of immunotherapy is used in concert with a comprehensive, multi-therapeutic modality approach. This involves incorporating individualized dietary approaches, nutritional supplementation, organ and extracellular matrix detoxification, improvement of acid-base balance, as well as all-important psycho-emotional supportive therapies. In relationship to cancer patients, it is important to know which patients and which types of cancers are the best candidates for GcMAF therapy. Prostate, breast, colon, liver, stomach, lung (including mesothelioma), kidney, bladder, uterus, ovarian, head/neck and brain cancers, fibrosarcomas and melanomas are the types of cancer tested thus far.²⁴ Although many types of cancer have been the focus for GcMAF therapy, it has not been used as a clinical treatment for lung and brain cancer.

Route of Administration

GcMAF therapy has been developed as an injectable and, in Germany, is usually administered by intravenous infusion (drip) or by IV “push.” Some doctors also administer GcMAF as an intratumoral injection together with oxidative therapy. Another option is to use a nebulizer to deliver the protein to activate macrophages in the bronchus-associated lymphoid tissue of the lungs.

Oral forms of GcMAF are ineffective because the protein, when orally consumed, is destroyed by stomach hydrochloric acid and pancreatic protease enzymes. However, there are now some oral colostrum forms that are viable in increasing bodily GcMAF. In fact, reports of these products are very promising. One German company has developed a colostrum-derived MAF (Cd-MAF) protein.²⁵ This proprietary product also contains vitamin D3 (cholecalciferol), Sango coral powder, oleic acid, and probiotic microorganisms.

A 2015 study showed that colostrum MAF greatly enhanced phagocytic activity in the peritoneal macrophages and intestinal macrophages of mice, in vitro and in vivo, respectively.²⁶ Colostrum-derived MAF has multiple positive attributes, including being a safe food, easy to obtain and use, and being a non-inducer of inflammatory cytokines. Colostrum-derived MAF is becoming more commonly used as an effective macrophage activator in various immunotherapy programs.

Doctors using oral colostrum-derived MAF in Europe often combine this therapy with intravenous vitamin C for maximum immune effects. Vitamin C contributes to immune defense by supporting various cellular functions of both the innate and adaptive immune system. Vitamin C accumulates in phagocytic cells, such as neutrophils, and can enhance chemotaxis and phagocytosis. It is also needed for apoptosis and clearance of the spent neutrophils from sites of infection by macrophages, thereby decreasing necrosis and potential tissue damage. The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene-regulating effects.

Frequency and Dosage

As with any immunotherapy

,

it is important to determine the dosage of GcMAF, the frequency of administration, and the length of time required for response to therapy before decisions about its administration can be made. In his early published human studies, Dr. Yamamoto always used the same dose: 100 nanograms (ng) per week in a single injection. (Equivalent to 100 billionths of a gram, this is an extremely small amount.) Dr. Yamamoto determined that the half-life of the activation effect in an activated macrophage is approximately six days. Therefore, he chose a once per week interval between GcMAF doses. Following this protocol, Saisei Mirai clinics in Japan inject their GcMAF product intramuscularly at 1500 ng/0.5 ml, two to three times per week. Together with this immunotherapy, they also incorporate an integrative approach to treating cancer and other illnesses. They further recommend that more frequent dosing (daily or every second day) may be safely used with more advanced stage of disease, or initially in the treatment course. In certain cases, as in many German clinics, Saisei Mirai doctors administer their GcMAF by intravenous injection, 0.5-1.0 ml two to three times per week in 20 ml or more saline.

Moreover, the frequency of administration depends upon the individual responsiveness associated with any vitamin D receptor (VDR) polymorphism. The association between polymorphisms of gene coding for VDR should always be considered. Additionally, blood levels of 25-hydroxyvitamin D should be periodically monitored. Insufficient vitamin D is linked to virtually every age-related disorder including cancer, vascular disease, and chronic inflammation. Generally, many doctors consider the ideal ranges for 25-hydroxyvitamin D are between 50-80 ng/mL. For some individuals, to maintain that ideal level, it may be necessary to take vitamin D3 doses of up to 5,000 IU to 10,000 IU daily.

Duration and Maintenance of Treatment

The duration of GcMAF therapy depends on the individual’s condition. Usually, with most cancer patients or those with chronic viral infections, four to six months is necessary to fully activate the immunity. Maintenance is often continued with oral colostrum MAF, together with vitamin D3, oleic acid supplementation, and intravenous vitamin C.

Monitoring GcMAF Treatment

GcMAF administration must always be monitored by a physician trained in its use. Aside from the usual cancer tests (monitoring the effectiveness of treatments), there are two additional tests that are often used. The first is the monocyte count of a white blood cell differential. As previously discussed, monocytes produced in the bone marrow enter the blood, then migrate to organs and tissues where they mature into macrophages. Low monocyte count, low phagocytic activity of monocytes, low lymphocyte count, low NK cell activity, and depressed TNF-α are often observed following standard external beam radiation therapy or cytotoxic chemotherapy for cancer. This has consequences for anticancer immune competence in the weeks and months following completion of cytotoxic chemotherapy and radiotherapy and is one reason why immunotherapy is so important. GcMAF therapy increases the number of monocytes as it activates macrophages. A patient’s monocyte count will generally rise in the early stages of GcMAF treatment and indicates a response to GcMAF. Normal monocyte levels are between 2% and 10% of the total differential. Upward of 6% or more is considered an optimum response to GcMAF treatment.

Cancers and viruses both make the enzyme α-N-acetylgalactosaminidase (nagalase) and increased serum levels of nagalase have been reported in many cancer patients. It has been suggested that this enzyme is responsible for the inactivation, or specifically deglycosylation of GcMAF.^27-29 Even though the intracellular (lysosomal) form of nagalase is vital for proper hepatic cell function, the extracellular form (secreted by cancer cells) seems only to benefit the progression of cancer.³⁰

Specialized laboratories can now measure the level of nagalase in the blood. An elevated nagalase test result reveals that either cancer or a virus (or both) could be present. It has been established that nagalase activity is directly proportional to viable tumor burden, whereas decreased nagalase activity is associated with improved clinical conditions. Hence, some doctors using GcMAF employ nagalase testing to determine the efficacy of the therapy.

According to some articles and research centers, the recommended reference range of nagalase in the serum of healthy people is between 0.32 and 0.95 nM/min/mg of substrate, although in some articles the normal range is slightly lower (up to 0.65 nM/min/mg).³¹ Be advised that reference ranges differ slightly depending on the laboratory.

Additional research is required to ascertain a universal and reliable normal threshold. Because the measurement of this enzyme can diagnose the presence of cancerous lesions below levels detectable by other diagnostic means, nagalase testing may eventually become a standard biomarker for early cancer detection.

GcMAF Side Effects

No harmful side effects from GcMAF treatment have been reported, even when it was successfully administered to autistic children.³² The primary reason being that its molecular structure is bioidentical (identical to the GcMAF made by the body). So long as the GcMAF is pure, there is no reason to expect any side effects.

A pure GcMAF protein contains only molecules of a single protein (no other molecules of any kind). Impurities cause compromised effectiveness, adverse reactions, and symptoms of toxicity. Beware because there are “bootleg” or phony versions of GcMAF being manufactured that are impure, contaminated, and consequently potentially toxic. These products are often sold over the internet, and their packaging may look identical to the real product. It is best to purchase GcMAF directly from the clinics in Japan³³ or Europe. These clinics usually require the patient to undergo GcMAF treatment at the clinic, and then dismiss the patient with enough injectable product or oral colostrum MAF product to follow up at home.

Current Global Status of GcMAF Therapy and Oral Colostrum-Derived MAF

Accumulated evidence suggests that GcMAF is a potent factor that activates tumoricidal macrophages, resulting in tumor regression. Thousands of cancer patients over the last two decades have been treated with injectable GcMAF in the United Kingdom, Europe and Asia. But many of its practitioners have faced adversity from government authorities. In short, GcMAF therapy is no stranger to controversy nor even to conspiracy theory. Some time ago a UK factory where GcMAF was being manufactured was closed under claims that the product “might be contaminated.” Importation of injectable GcMAF into the UK and the US has been halted. To date, oral Cd-MAF (colostrum-derived) can still be purchased and imported into the U.S. for personal use.

It is estimated that more than 300 doctors in 80 countries are now using both injectable GcMAF and oral CdMAF. The laboratory and clinical study of cancer immunotherapy is rapidly advancing; but unfortunately, current research of GcMAF is limited to Japan and selective parts of Europe. Several large pharmaceutical companies and their partner regulatory agencies have done much to discredit – and make unavailable – the product. The internet is full of quackery websites discrediting GcMAF and the doctors who advocate its use. It is tragic that this harmless body protein, studied for over 25 years as a promising immunotherapy agent, is not given more consideration for further research in the US.

Despite the doubts raised as a result of three retracted clinical studies, the efficacy and safety of this product has been endorsed in numerous other studies. Because GcMAF is produced by the human body, it is non-toxic (provided the manufacturing process is pure). At present, it appears non-scientific reasons are preventing FDA approval. With so many lives at risk and no real cures at hand, the FDA would be wise to allow GcMAF therapy to proceed with the requirement of real-time adverse event reporting to ensure patient safety.

References

1. Dr. Nobuto Yamamoto was born in Japan on April 25, 1925. Dr. Yamamoto, who holds a PhD in biochemistry from Gifu University in Japan, has been a US-based researcher since 1959, when he was invited to be a visiting associate researcher at the Fox Chase Cancer Center in Philadelphia. He was later hired as a biophysics and biochemistry researcher at the National Institute of Health in Maryland before becoming associated, in multiple capacities, with Temple University in Philadelphia until 1980. In 1980, Dr. Yamamoto was appointed Professor of Microbiology and Immunology at Hahnemann University School of Medicine, where he continued his research in viral evolution. His immunological studies focused on the mechanism of macrophage activation and GcMAF. When Dr. Yamamoto retired from Hahnemann University in 1990, he returned to Temple University Medical School as a Research Professor of Biochemistry and studied the tumoricidal capacity of macrophages activated by GcMAF and cancer therapy with GcMAF. In 1994, Dr. Yamamoto founded the Socrates Institute for Therapeutic Immunology, from which he continues to study the therapeutic efficacy of GcMAF for a variety of cancers and HIV.

2. Yamamoto N, Kumashiro R. Conversion of vitamin D3 binding protein (group specific component) to a macrophage activating factor by the stepwise action of ß-galactosidase of B cells and sialidase of T cells. J lmmunol. 1993;151: 2794–2802.

3. Yamamoto N, et al. Vitamin D3 binding protein required for in vitro activation of macrophages after alkylglycerol treatment of mouse peritoneal cells. Immunology. 1991;74:420–424.

4. Yamamoto N, Homma S Vitamin D3 binding protein (group specific component) is a precursor for the macrophage-activating signal. Proc Natl Acad Sci USA. 1991;88:8539–8543.

5. Corbeled M, Narayana VR, Yamamoto N. The value of serum alpha-N-acetylgalactosaminidase measurement for the assessment of tumour response to radio- and photodynamic therapy. Br J Cancer. 1998 Mar; 77(6):1009-14.

6. Naraparaju VR, Yamamoto N. Roles of b-galactosidase of B lymphocytes and sialidase of T lymphocytes in inflammation primed activation of macrophages. Immunol Lett. 1994;43:143–148.

7. Yamamoto N, Homma S. Vitamin D3 binding protein (group-specific component, Gc) is a precursor for the macrophage activating signal factor from lysophosphatidylcholine-treated lymphocytes. Proc. Natl. Acad. Sci. USA. 1991;88:8539-8543.

8. Yamamoto N, Ueda M, Benson CE. Treatment of HIV-infected patients with Gc protein-derived macrophage activating factor (GcMAF) eradicates HIV-infection. Proc 13th Int Cong Immunol. Italy: Medimond, Bologna. 2007; 35–38.

9. Yamamoto N, Kumashiro R.. Conversion of vitamin D3 binding protein (Group specific component) to a macrophage activating factor by the stepwise action of b-galactosidase of B cells and sialidase of T cells. J Immunol. 1993;151:2794–2802.

10. Yamamoto N, Homma S, Millman I. Identification of the serum factor required for in vitro activation of macrophages: Role of vitamin D3 binding protein (Group specific component, Gc) in lysophospholipid activation of mouse peritoneal macrophages. J Immunol. 1991;147:273–280.

11. Yamamoto N, et al. Macrophages Activated By GCMAF Develop Enormous Variation of Receptors That Recognize and Eradicate Adenocarcinomas. Clinical Immunology, Volume 119, Supplement 1, 2006, Page S96. FOCIS 2006 Abstract Supplement – 6th Annual Meeting.

12. Yamamoto N, et al. Macrophages Activated By GCMAF Develop Enormous Variation of Receptors That Recognize and Eradicate Adenocarcinomas. Clinical Immunology. 2006.

13. Thyer L, et al. GC protein-derived macrophage-activating factor decreases α-N-acetylgalactosaminidase levels in advanced cancer patients. Oncoimmunology. 2013;2(8): e25769.

14. Yamamoto N, Suyama H, Yamamoto N. Immunotherapy for prostate cancer with Gc protein-derived macrophage-activating factor, GcMAF. Transl Oncol. 2008;1: 65-72.

15. Gregory KJ, et al. Vitamin D Binding Protein-Macrophage Activating Factor Directly Inhibits Proliferation, Migration, and uPAR Expression of Prostate Cancer Cells. PLoS ONE. 2010;5(10): e13428.

16. Yamamoto N, Suyama H, Yamamoto N, Ushijima N: Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF). Int J Cancer. 2008;122: 461-467. –

Retraction

: Immunotherapy of metastatic breast cancer patients with vitamin D-binding protein-derived macrophage activating factor (GcMAF). [Int J Cancer. 2014]

17. Yamamoto N, Ushijima N, Koga Y: Immunotherapy of HIV infected patients with Gc protein-derived macrophage activating factor (GcMAF). J Med Virol. 2009;81:16-21.

Retraction

. Immunotherapy of HIV-infected patients with Gc protein-derived macrophage activating factor. [J Med Virol. 2014]

18. Yamamoto N, Suyama H, Nakazato H, Yamamoto N and Koga Y: Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage activating factor, GcMAF. Cancer Immunol Immunother. 2008;57: 1007-1016. –

Retraction

: Immunotherapy of metastatic colorectal cancer with vitamin D-binding protein-derived macrophage-activating factor, GcMAF. [Cancer Immunol Immunother. 2014]

19. http://patents.com/us-5177002.html – In vitro enzymatic conversion of glycosylated human vitamin D binding protein to a potent macrophage activating factor: Abstract: A novel, potent macrophage activating factor is prepared in vitro by treating glycosylated human group-specific component, also known as human vitamin D-binding protein, with glycosidases. Group-specific component, which is isolated from retired blood by known procedures, is thus readily converted to a highly potent macrophage activating factor.

20. http://www.freepatentsonline.com/20150361151.pdf

21. Mohamad SB, Nagasawa H, Uto Y, Hori H. Preparation of Gc protein-derived macrophage activating factor (GcMAF) and its structural characterization and biological activities. Anticancer Res. 2002;22:4297–300. 

22. Pacini S, et al. Effects of vitamin D-binding protein-derived macrophage-activating factor on human breast cancer cells. Anticancer Res. 2012;32:45–52. 

23. Homma S, Yamamoto N. Activation process of macrophages after in vitro treatment of mouse lymphocytes with dodecylglycerol. Clin Exp Immunol. 1990;79:307–13.

24. Thyer L, Ward E, Smith R, et al. GC protein-derived macrophage-activating factor decreases alpha–acetylgalactosaminidase levels in advanced cancer patients. Oncoimmunology. 2013;2:e25769.

25. MITOcare GmbH & Co.KG; Firmensitz: Lindenschmitstr. 44; 81371 München; https://www.gesundheitsfundament.de/shop/mitocare-big-harmony-activator-540-kps/. Accessed January 28, 2018.

26. Uto Y, et al. Degalactosylated/Desialylated Bovine Colostrum Induces Macrophage Phagocytic Activity Independently of Inflammatory Cytokine Production. Anticancer Res. 2015;35(8), 4487-4492.

27. Yamamoto N, et al. Deglycosylation of serum vitamin D3-binding protein by alpha-N-acetylgalactosaminidase detected in the plasma of patients with systemic lupus erythematosus. Clin Immunol Immunopathol. 1997;82:290-8.

28. Reddi AL, et al. Serum alpha-N-acetylgalactosaminidase is associated with diagnosis/prognosis of patients with squamous cell carcinoma of the uterine cervix. Cancer Lett. 2000;158:61-4.

29. Korbelik M, Naraparaju VR, Yamamoto N. The value of serum alpha-N-acetylgalactosaminidase measurement for the assessment of tumour response to radio- and photodynamic therapy. Br J Cancer. 1998;77:1009-14.

30. Mohamad SB, et al. Tumor cell alpha-N-acetylgalactosaminidase activity and its involvement in GcMAF-related macrophage activation. Comp Biochem Physiol A Mol Integr Physiol. 2002;132:1-8.

31. Saburi, Ehsan, et al. Is α-N-acetylgalactosaminidase the key to curing cancer? A mini-review and hypothesis. Journal of BU ON.: official journal of the Balkan Union of Oncology. 2017;22.6: 1372.

32. Bradstreet J, Vogelaar E, Thyer L. Initial observations of elevated Alpha-N-acetylgalactosaminidase activity associated with autism and observed reductions from GC protein-macrophage activating factor injections. Autism Insights. 2012;4:31–8.

33. Saisei Mirai is a medical organization in Osaka, Japan, whose purpose is to treat patients and develop and produce therapies, in particular immunotherapies such as GcMAF and colostrum MAF.

Disclaimer:

The information in this monograph is intended for informational purposes only and does not constitute medical advice. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Its aim is to help Townsend Letter readers better understand current topics related to immunotherapy. Information is based on review of scientific research data, historical practice patterns, and clinical experience. Users should always consult with a qualified healthcare provider for specific questions regarding therapies, diagnosis and/or health conditions, prior to making therapeutic decisions.

©2017 James Odell, OMD, ND, L.Ac.

Dr. Odell currently serves as the Medical Director of the Bioregulatory Medicine Institute (BRMI). For more information on Bioregulatory Medicine and BRMI, visit www.BRMI.online.