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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
  • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/38—Albumins
• • A—HUMAN NECESSITIES
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  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
  • A61K38/46—Hydrolases (3)
  • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
  • A61K9/7007—Drug-containing films, membranes or sheets
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
  • A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
  • A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
  • A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
  • A61M1/3687—Chemical treatment

Definitions

• the present invention relates to methods for the activation of macrophages and methods for treating cancer, bacterial pathogens and viral pathogens.
• Gc protein is converted to Gc-macrophage activating factor (GcMAF), in vivo or ex vivo.
• GcMAF Gc-macrophage activating factor
• the GcMAF activates macrophages which can then target cancer cells, bacterial pathogens and/or viral pathogens.
• macrophages are activated by contacting them, in vivo or ex vivo, with GcMAF.
• nagalase is inactivated in a patient receiving the present macrophage activating treatment by contacting the patient's blood with a nagalase binding ligand immobilized on an inert medium.
• metastases arise from the nonrandom spread of specialized malignant cells that preexist within a primary neoplasm. These metastases can be clonal in their origin, and different metastases can originate from different progenitor cells. In addition, metastatic cells can exhibit an increased rate of spontaneous mutation compared with benign nonmetastatic cells. This data provides an explanation for the clinical observation that multiple metastases can exhibit different sensitivities to the same therapeutic modalities.
• Macrophages can be activated to become tumoricidal by interaction with phospholipid vesicles (liposomes) containing immunomodulators.
• Tumoricidal macrophages can recognize and destroy neoplastic cells in vitro and in vivo, leaving non-neoplastic cells uninjured.
• the exact mechanism(s) by which macrophages discriminate between tumorigenic and normal cells is unknown, it is independent of tumor cell characteristics such as immunogenicity. metastatic potential, and sensitivity to cytotoxic drugs.
• macrophage destruction of tumor cells apparently is not associated with the development of tumor cell resistance.
• activated macrophages are essential for the immune response to form relati ve to bacterial and viral invasion. As the mechanism of activation is identical in the three responses (tumoricidal, bactericidal, viricidal), the activation of macrophages has applications across the host immune response, against tumor, bacteria and viral challenges.
• Vitamin D-binding protein also known as DBP or Gc Protein
• DBP Vitamin D-binding protein
• Gc Protein is an evolutionary conserved glycoprotein among animals (Cooke and Haddad, Endocrine Rev. 10:294 1989).
• DBP from animals serologically cross-reacts with human DBP (Ogata et al., Comp. Bioch. Physiol. 90B: 193, 1988).
• Animal DBP is a genetically polymorphic plasma protein in some species and has a relative molecular weight of about 52,000. It normally constitutes about 0.5% of the plasma proteins in animals.
• the plasma concentration is generally about 260 Polymorphism of the human DBP.
• Gc protein group specific component
• group specific component or "Gc protein” is demonstrable by gel electrophoretic analysis, which reveals two major phenotypes: Gel and Gc2 (Hirschfeld et al., Nature 185:931 , 1960). The entire nucleotide coding sequences of the Gel and Gc2 genes, and the predicted amino acid sequences, have been reported (Cooke, et al., J. Clin. Invest. 76:2420, 1985; Yang ct al., Proc. Natl. Acad. Sci. USA 82:7994, 1985). Gel is further divided into Gcl f and Gel s subtypes which migrate electrophoretically as two bands, “fast” and “slow", (Svasti et al, Biochem. 18: 161 1 , 1979).
• Activation of macrophages which is characterized by their consequent, enhanced phagocytic activity , is the first major step in a host's immune defense mechanism against cancer and bacterial and viral pathogens. Macrophage activation requires B and T lymphocyte functions, which modify DBP/Gc Protein in a step-wise fashion, to yield GcMAF.
• Reaction "a" in FIG. 1 shows how Gc protein reacts with beta-galactosidase expressed by B-cells to form an intermediary Gc protein product which then reacts with sialidase expressed by T-cclls resulting in the formation of GcMAF
• Nagalase alpha-N-acetylgalactosaminidase
• Gc-MAF a deglycosylated Gc protein product that prevents the formation of GcMAF and consequent activation of macrophages.
• Nagalase is produced by many cancer cells and some bacterial and viral pathogens and is a mechanism whereby cancer cells and other pathogens attempt to avoid the host's immune system. Nagalase measurements in blood are used as a diagnostic tool, such as, for example, to diagnose cancer and monitor tumor burden during cancer diagnosis and therapy.
• GcMAF should be distinguished from T-cell lymphokine macrophage activating factor, also known as ⁇ -interferon, which is generated by lymphokine-producing T-cells in small amounts, or is obtained by genetic engineering at pharmaceutical grade levels.
• T-cell lymphokine macrophage activating factor also known as ⁇ -interferon
• Yamamoto US 5,177,001 ; 5,177,002; 5,326,749 and 6,410,269 disclose methods for making GcMAF from Gc protein and smaller domains of the Gc protein resulting in the production of CdMAF.
• the MAF products made by Yamamoto are then injected into patients to treat cancers and other pathogenic diseases.
• the present invention provides a novel treatment of activating a patient's own macrophages by in vivo or ex vivo treatments where the macrophages are contacted with MAF or the Gc protein is contacted with enzymes that produce GcMAF.
• a leukocyte rich fraction of the patient's blood is contacted with the MAF and/or the enzymes which are immobilized on an inert support/medium such as polymer beads or membranes within an aphoretic device or a micro fluidic device.
• nagalase can be removed from the patient's blood by immobilizing a. nagalase ligand to a solid support and contacting the blood with the immobilized Nagalase ligand.
• the GcMAF made and used in accordance with the present invention is created therapeutically in-vivo and/or ex-vivo and from DBP/Gc Protein which is circulating in the plasma of mammalian blood. Additionally, nagalase can be removed from a patient's blood in accordance with the present invention thereby reducing the inhibitory effects of nagal ase on the production of GcMAF in the body.
• the present invention includes an extracorporeal process where a patient's blood and/or plasma are treated outside of the body and returned to the patient's vascular system.
• a microfluidic device could be implanted in the body to treat macrophages and/or plasma.
• Strategy #1 Standard leukapheresis is performed removing at least 500 cc of plasma rich in leukocytes from a mammal.
• the leukocyte-rich plasma is then passed over a surface containing immobilized GcMAF or Nagalase-binding ligands or both.
• immobilized GcMAF the macrophages will activate. Any longer-term inhibitory effects from Nagalase on macrophage activation will be mitigated by removal of Nagalase from the plasma by Nagalase-binding ligands.
• the thus treated leukocyte-rich plasma is then re- transfused back into the mammal to treat a bacterial infection, a viral infection such as hepatitis C or a malignancy.
• a mammal's blood is passed through an apheretic filter containing a fluidized-bed of (a) beads bound with Nagalase-binding ligands, (b) beads bound with beta- galactosidase, (c) beads bound with sialidase or alpha-mannidase, or combinations of (a), (b) and (c).
• Immune-suppressing Nagalase will be bound in the filter reducing its systemic effect while the beads bound with beta-galactosidase and sialidase, will convert the mammal' s own GcProtein into GcMAF for activation of macrophages.
• the thus treated blood is then re-transfused back into the mammal (patient) to treat a bacterial infection, a viral infection such as hepatitis C or a malignancy.
• FIG. 1 shows (a) the reaction whereby iVlAF is made by reactions of GcProtein with enzymes produced by B-cells and T-cells, (b) the deglycosylation reaction of GcProtein by nagalase and (c) the reaction of GcProtein with immobilized enzymes.
• FIG. 2 is a flow diagram depicting various treatments made to a mammal's blood by a microfluidic device.
• CJt AF ta Factor
• the present invention differentiates itself by performing either direct in-vivo or ex-vivo but real-time exposure of leukocytes to GcMAF or, direct in-vivo or ex-vivo but real-time generation of endogenous GcMAF from circulating GcProtein.
• extracorporeal device means any device that is used in a procedure in which blood is taken from a patient's circulation to have a process applied to it before it is returned to the patient's circulation wherein the process can add or subtract either compounds or cells or both in the blood.
• Suitable extracorporeal devices include, but are not limited to. mierofluidic devices, apheresis devices, leukopheresis devices and plasmapheresis devices.
• a patient is subjected to in-vivo or ex-vivo treatments where the patient's macrophages are activated and optionally the inhibitory effects of Nagalase are reduced.
• the patient's macrophages can be activated by (a) contacting a macrophage rich fraction of the patient's blood with GcMAF immobilized to an inert medium or solid support whereby the GcMAF reacts with the macrophages resulting in activation of the macrophages and (b) contacting the patient's plasma that is rich in Gc protein with enzymes that convert Gc protein into GcMAF which can then activate macrophages when the treated plasma is re-introduced back into the patient's vascular system.
• a Nagalase- binding ligand immobilized to an inert medium can also be employed to reduce the inhibitory ef ect that nagalase has on the immune system and in particular the deglycosylation of Gc protein.
• Mierofluidic and mierofluidic devices refer to a laminar flow device that either cell sorts or provides plasma over a biocompatible surface with immobilized binding or catalytic agents.
• Mierofluidic devices may be external to the body with a small pump, or implantable without a pump using pressure drops to drive it.
• Mierofluidic devices are well known and are commercially available from Micronics, Inc., Seattle. WA, USA.
• leukopheresis and plasmapheresis systems are well known to one of ordinary skill in the art and commercially available from multiple sources.
• macrophages are activated in a leukophoretic process where a leukocyte fraction (macrophage rich) of the blood is separated and contacted with immobilized MAF on a biocompatible surface.
• macrophages in the leukocyte fraction are returned to the patient where the macrophages can perform their immune function in controlling cancers, viral pathogens and bacterial pathogens.
• the macrophage activation can also be conducted in a microfluidic sorting construct that is intravascular that results in passing macrophages and monocytes over an MAF-immobilized surface at rates of a few ml/minutes, which will result in almost 100% exposure of all known macrophage precursors to the MAF in no more than a 7-day period.
• the macrophages can then perform their immune function in controlling cancers, viral pathogens and bacterial pathogens.
• Nagalase is removed from plasma by subjecting a patient's blood to plasmapheresis and contacting the plasma with immobilized Nagalase-binding ligands where the Nagalase is bound to the ligand and trapped in the electrophoresis apparatus.
• the treated plasma is returned to the patient minus the bound Nagalase which reduces the immune inhibition that Nagalase normally induces when circulating in the blood.
• a similar approach is done with a microfluidic device where the plasma is contacted with a Nagalase-binding ligand immobilized within the microfluidic device.
• the GcMAF is made by an apherctic or plasmapheretic process where plasma is separated from whole blood and passed over or contacted with beta- galactosidase and sialidase enzymes that are immobilized on a biocompatible solid support such as beads or a membrane.
• the beta-gal actosidase and sialidase convert the Gc protein into GcMAF. See FIG. 1.
• the resulting GcMAF produced in the plasma is then reintroduced back into the patient where the GcMAF can activate circulating macrophages.
• the plasma is also contacted with a Nagalase-binding ligand to decrease the concentration of Nagalase. This lowered concentration of Nagalase allows the GcMAF to interact better in the activation of macrophages when introduced back into the patient's vascular system.
• FIG. 1 is a flow diagram showing various treatments made to a mammal's blood by a microfluidic device.
• a patient's blood flows into a microfluidic device where a separator 10 separates the plasma from the blood cells (RBC, WBC, platelets),
• a portion of the plasma is analyzed for diagnostic purposes 11 by measuring the presence/absence of electrolytes 11a, cytokines l ib, cytokine receptors 11c, cancer specific biomarkers l id, gangliosides l ie, nagalase l lf, GcProtein l lg, total flow lib. or other desired compounds that are indicative of disease or lack thereof.
• the balance of the plasma, or all of the plasma in the case where no diagnostic tests are run, is then contacted with immobilized ligands to remove specifically targeted compounds from the plasma 12, 13, such as, for example, a Nagalase-binding ligand 12a to remove nagalase and ligands of soluble inhibitors 13a to remove specific soluble inhibitors of the immune system.
• immobilized ligands to remove specifically targeted compounds from the plasma 12, 13, such as, for example, a Nagalase-binding ligand 12a to remove nagalase and ligands of soluble inhibitors 13a to remove specific soluble inhibitors of the immune system.
• a list of soluble inhibitors of the immune system 13b include gangliosides; all known growth factors most notably TNF-alpha, TGF-beta and variants, PDGF, EGF, IGF and variants, FGF and variants and VEGF; all known inflammatory cytokine receptors most notably the TNF-alpha family -TNF-R1 ,TNF- R2,CD40L,NGFR,TRAIT and variants, FAST, IT-1R1 ,IT 1 R2, IL-2R, IL-31UL-5 R.1L-6R.IL- 7R.GM-CSFR, IL-9R.IL-12R, and erythropoietin receptor.
• the plasma can also be contacted with immobilized enzymes 14 to create new compounds in the plasma such as, for example, the enzymes (beta-gal actosidase, sialidase, alpha-mannidase) required to convert GcProtein into Gc-macrophage activating factor (GcMAF) 14a.
• the enzymes beta-gal actosidase, sialidase, alpha-mannidase
• GcMAF Gc-macrophage activating factor
• precursor compounds biological or recombinant
• GcProtein is added 14b to the plasma prior to contacting the plasma with the immobilized enzymes 14.
• a portion can be analyzed in a post-plasma treatment diagnostic test 15 to measure the effectiveness of the plasma treatment. Thereafter , the treated plasma is returned to the patient's vascular system with or without combining the plasma with the blood cells separated in 10.
• the red blood cells (RBCs). white blood cells (WBCs) and platelets separated in 10 can also be treated.
• WBCs are separated from the RBCs and platelets 17 to form a stream having a high concentration of WBCs 18.
• Further separation of macrophages 19 allows macrophages to be activated by contacting the macrophages with a macrophage activating surface 20 such as immobilized GcMAF or by contacting the macrophages with an antigen to induce a vaccine 21.
• the treated macrophages can be isolated 22 and administered to the patient or combined back with the patients' plasma 23 and other blood cells for return to the patient's vascular system 2.
• the vaccine induced macrophages 23 can be optionally retained in a reservoir 24 before being combined back with the WBC fraction that is rich in T cells, B cells and. granulocytes 25 and thereafter being retimed to the patient's vascular system 26.
• the present invention may be embodied in other specific forms without departing from its spirit or essential characteristics.
• the described embodiments are to be considered in all respects only as illustrative and not restrictive.
• the scope of the invention is, therefore, indicated by the appended claims rather than by the foregoing description. All changes which come within the meaning and range of equivalency of the claims are to be embraced within their scope.

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