US20160152697A1 - Methods, compositions and apparatuses for facilitating regeneration - Google Patents

Methods, compositions and apparatuses for facilitating regeneration Download PDF

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US20160152697A1
US20160152697A1 US14/932,200 US201514932200A US2016152697A1 US 20160152697 A1 US20160152697 A1 US 20160152697A1 US 201514932200 A US201514932200 A US 201514932200A US 2016152697 A1 US2016152697 A1 US 2016152697A1
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cells
cell
amino acid
toxin
functional
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US20180111982A2 (en
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Lewis S. Gruber
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Siwa Corp
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Siwa Corp
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Priority to US15/720,912 priority patent/US11261241B2/en
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    • C07—ORGANIC CHEMISTRY
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    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
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    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
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    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6843—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a material from animals or humans
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
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    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A—HUMAN NECESSITIES
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    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00452—Skin
    • A61B2018/0047—Upper parts of the skin, e.g. skin peeling or treatment of wrinkles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
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    • A—HUMAN NECESSITIES
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    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N7/02—Localised ultrasound hyperthermia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Definitions

  • the present invention relates in general to methods, compositions and apparatus for promoting tissue and organ regeneration, and in particular to preventing cells from inhibiting regenerative processes to obtain the recognized benefits in health and function associated with the results of regeneration.
  • Tissue and organ regeneration research has focused on the need to stimulate regeneration by activating stem cells by soluble factors or treat partially- or non-functional cells to improve their function, e.g. by breaking damage-related crosslinks. Such research has overlooked the need to remove inhibitory effects.
  • the present invention provides apparatus, compositions and methods for removing cells that interfere with regenerative processes by blocking locations in a tissue where progeny of stem cells can improve function.
  • the present invention also reduces the proportion of partially- and non-functional cells without regard to location in a tissue.
  • Functionality according to the present invention is defined as the state of operation of a cell of the same type in a selected healthy individual.
  • the apparatuses, compositions and methods according to the present invention promote regenerative processes by differentially killing cells based inversely on the degree of functionality of the cells (i.e., the less functionality the more likely to be killed), and then applying that technique.
  • This cell killing technique preferentially preserves proliferating cells.
  • any of lipofuscin, glycarion end-products or cell stiffness can be selected as a proliferation-preserving marker of partial- or non-functionality.
  • Cell killing technologies directed against such markers can include, respectively, lasers/intense light, antibodies, and ultrasound.
  • Cells can be killed according to the present invention by physical, electromagnetic, chemical or biological techniques, for example. Physical techniques include without limitation ultrasound and other oscillatory methods for disrupting cell membranes or structures leading to cell death.
  • Electromagnetic techniques include without limitation and as targeted by sensitizers (such as absorbent nanoparticles, for example) EMF (see, e.g., Litovitz, U.S. Pat. No. 7,367,988 for EMF methods), high intensity light, radio waves microwaves, lasers, magnetism and ionizing radiation.
  • Chemical techniques include without limitation toxic nanoparticles, chemical toxins and structure removal compounds such as ⁇ -aminopropionitrile.
  • Biological techniques include without limitation antibodies against partially-functional or non-functional cells and variations and modifications thereof, such as toxin conjugates and natural killer cells modified to express target-specific antibodies. Techniques can be combined as determined to be effective (e.g. see McHale et al., U.S. Pat. No. 6,821,274 for sensitization to ultrasound by EMF treatment). Apparatuses, methods and compositions according to the present invention can be used sequentially or simultaneously in combination as monitoring determines to be effective for promoting regeneration.
  • the apparatuses, compositions and methods selectively kill partially and/or non-functional cells versus functional cells of the same cell type to the extent that, upon removal of the killed cells by disintegration or scavenging, functional cells replace them.
  • the cell killing apparatus, compositions and methods according to the present invention must preferentially preserve proliferating, functional cells and must be of a degree that avoids excessive inflammatory responses.
  • Evaluation of improvement or maintenance of a desired result can be used to direct the frequency of reapplication of the apparatus, compositions and methods according to the present invention.
  • the application and reapplication can be determined with the goal of gradual improvement to avoid overwhelming natural mechanisms, such as removal of cells/debris by scavenging cells.
  • the FIGURE illustrates apparatus according to the present invention.
  • Proliferating cells include both cells that are dividing and cells, such as stem cells, that divide normally when stimulated to do so.
  • stem cells participate in mundane tissue replacement, injury can also be an occasion for release of a factor or factors to stimulate stem cell proliferation and differentiation.
  • Stem cells give rise to cells which heal the injury, for example, healing a cut in an epithelium.
  • stem cell division and differentiation would be abnormal, even tumorigenic, in the presence of a normal complement of cells. Accordingly, there are mechanisms to prevent excessive proliferation. For example, the presence of a cell at a location in an epithelium prevents replacement at that position.
  • An example of this sort of phenomenon is contact inhibition where cells cease proliferating when they come in contact with other cells.
  • the phenomenon can be generalized to a rule that, to facilitate stem cell proliferation and differentiation for regeneration of cells at a location, there can not be a cell or structure at the location in the tissue.
  • the human body includes cells for tearing down a structure, such as osteoclasts in bone, as well as cells for building up a structure, such as osteoblasts in bone. It is the balance between the activities of the two types of cells that determines the extent of the resulting structure. To the extent that any intrinsic mechanisms do not remove cells/structure for periodic renewal, the present invention provides for removal to promote regeneration.
  • the cell at the location that inhibits stem cell action can be fully functional, partially functional, or non-functional.
  • Dead cells can be removed by scavenging macrophages, thus allowing for replacement, but a malfunctioning cell may remain despite deleterious effects on the subject (i.e., the organism of which they are a part).
  • a partially or non-functional cell i.e. a malfunctioning cell, can not be apoptotic, and, thus, can not stimulate clearance by macrophages on its own.
  • Such malfunctioning cells are killed according to the present invention for removal by the body's natural processes.
  • Therapeutic killing of cells in cancer therapy is targeted against proliferating cells, the exact opposite of the present invention.
  • action against cancer is provided by stimulating proliferation of stem cells so that error-correcting mechanisms that function during cell division can correct mutations that otherwise might accumulate in a non-dividing cell.
  • partially or non-functional cells according to the present invention can fail to be fully functional due to damage, such as free radical damage, or cross-linkage as a result of reaction with sugars, i.e. glycation.
  • Damage such as free radical damage, or cross-linkage as a result of reaction with sugars, i.e. glycation.
  • Cells that are partially or non-functional due to a genetic makeup that is shared by stem cells of a subject can be replaced by exogenous stem cells having a fully functional genetic makeup.
  • Non-cellular material such as scar tissue, can block such regeneration. This can explain failures in regeneration and in stem cell transplantation.
  • non-cellular blocking structures can be removed according to the present invention.
  • regenerative cells such as stem cells
  • transplantation With removal of blocking cellular and/or non-cellular materials, appropriate regenerative cells, such as stem cells, are retained or supplemented by transplantation in order to permit regeneration.
  • “Fully functional” is defined as the degree of a specified function for a particular cell type exhibited by an available progeny of a stem cell in a subject with or without stem cell transplantation, whichever is greater.
  • Effector 10 is a device for killing cells. Effector 10 can be, without limitation, ultrasound equipment or a device for antibody administration, such as a drip apparatus.
  • Control 20 is a device for regulating the operation of effector 10 according to preset parameters and/or as modified to ensure safety or effectiveness. Without limitation, control 20 can be a control panel of effector 10 .
  • Monitor 30 provides information regarding the degree of inflammatory response and/or other important factors in the condition of the subject to which effector 10 is applied. Information from monitor 30 can be used to adjust control 20 and thereby to adjust or change the operation of effector 10 . Monitor 30 can be, without limitation, a thermometer connected to control 20 .
  • a technique according to the present invention is selected to preferentially kill partially functional or nonfunctional cells or to remove non-cellular compositions, as opposed to indiscriminate killing, which has as great an effect on functional cells.
  • a technique may be selected according to the present invention by exposing functional and partially functional and/or non-functional cells to the technique and choosing concentrations, intensities and characteristics such as wavelength, frequency, wave shape, continuity and treatment duration.
  • concentrations, intensities and characteristics such as wavelength, frequency, wave shape, continuity and treatment duration.
  • the technique to be applied to a particular subject can be chosen on the basis of identifying an acceptable selectivity for partially functional and/or non-functional cells versus functional cells.
  • selection methods and criteria are readily available to those skilled in the art. Such selection methods are routinely applied by those of skill in the relevant arts to select laser treatment levels for removing blemishes, treating cancers by radiation therapy, selecting monoclonal antibodies, selecting toxins to be used therapeutically, and selecting ultrasound properties for therapy, for example. According to the present invention, selected techniques discriminate functional versus non-functional and/or partially functional cells of the same cell type as the functional cells.
  • Techniques that act upon differences between functional and partially or non-functional cells can be based upon cellular properties associated with dysfunction, such as cross-linking, membrane stiffness and brown coloration associated with lipofuscin in aged or senescent cells as opposed to nascent, dividing or functional cells.
  • Techniques such as ultrasound, targeted to harmonic frequencies of cross-linked cell membranes or components, can be used according to the present invention.
  • techniques such as lasers or intense light of a wavelength preferentially absorbed by partially functional or non-functional cells can be used according to the present invention.
  • Techniques according to the present invention can be used to localize therapy where needed. Localization can be accomplished by, without limitation, computer assisted tomography, magnetic resonance imaging, and positron emission tomography. Most preferably, techniques according to the present invention can be applied to the whole organism without the need for localization.
  • the techniques can be applied periodically, particularly at a low intensity or concentration, to maintain or increase a positive balance between functional versus partially or non-functional cells. Gradual versus precipitate cell killing can aid in avoiding toxic effects from high levels of cellular breakdown products and/or deleterious effects of an inflammatory response.
  • non-therapeutic, non-human and industrial applications be included within the scope of the present invention.
  • Cosmetic applications, diagnostic applications and veterinary applications are also contemplated.
  • Repeatedly practicing the method according to the present invention at a low level can be coupled with monitoring to determine the degree of improvement as a diagnostic measure of the component of a condition due to damaged cells versus genetic factors.
  • destruction of blocking cells can permit the resulting dead cells and debris to be washed away. In this way, productivity of cell and tissue cultures can be increased by increasing the relative proportion of productive cells versus non-productive cells.
  • glycation end-products crosslinks created by sugars bonded to proteins, are selected as indicia of an accumulation of cellular damage correlated with partial- or non-functionality.
  • Antibodies against such glycation end-products can be raised according to methods well known to those skilled in the art (e.g. Abed et al., U.S. Pat. No. 6,380,165; Bucala, U.S. Pat. No. 5,702,704) and humanized monoclonal antibodies retaining constant regions which permit destruction of targeted cells by the immune system can be produced for injection, also according to well known methods (e.g. Basi et al., U.S. Pat. No. 7,256,273).
  • Antibodies can be screened for effectiveness according to the present invention by labeling them and applying them separately to untreated cells versus cells incubated with a sugar such as ribose used to induce formation of glycation end-products. Binding of the antibodies to a higher degree to the cells previously incubated with sugar as opposed to the cells not treated with sugar indicates preferential effect against the selected target.
  • a sugar such as ribose used to induce formation of glycation end-products.
  • Antibodies produced as described above can be administered to a subject intravenously with monitoring to determine that inflammatory responses such as fever or swelling do not exceed limits well known to be safe. This process can be repeated at intervals to maintain a level of regeneration. The process can be focused to remove partially- and/or non-functional cells a particular location (e.g. where stem cell transplantation is targeted).
  • Evaluation of improvement or maintenance of a desired result can be used to direct the frequency of reapplication of the antibodies according to the present invention.
  • the application and reapplication can be determined with the goal of gradual improvement to avoid overwhelming natural mechanisms, such as removal of cells/debris by scavenging cells.
  • glycation end-products are selected as indicia of an accumulation of cellular damage correlated with partial- or non-functionality. This crosslinking manifests itself in a stiffening of the cells. Those in the art understand stiffness to distinguish types of proliferating versus non-proliferating cells (e.g. Kas et al., U.S. Pat. No. 6,067,859).
  • Ultrasound apparatus can be used according to practices well known to those skilled in the art to destroy cells by vibrational techniques (e.g. Chapelon et al., U.S. Pat. No. 5,601,526).
  • Ultrasound parameters e.g. frequency, power, and pulsation
  • Vibrational versus thermal destruction by ultrasound is preferred according to the present invention. Parameters selected for preferential destruction of sugar-treated cells as opposed to the cells not previously treated with sugar indicates preferential effect against the selected target.
  • Ultrasound as described above can be applied to a subject with monitoring to determine that inflammatory responses such as fever or swelling do not exceed limits well known to be safe. This process can be repeated at intervals to maintain a level of regeneration. The process can be focused to remove partially- and/or non-functional cells a particular location (e.g. where stem cell transplantation is targeted).
  • Evaluation of improvement or maintenance of a desired result can be used to direct the frequency of reapplication of ultrasound according to the present invention.
  • the application and reapplication can be determined with the goal of gradual improvement to avoid overwhelming natural mechanisms, such as removal of cells/debris by scavenging cells.

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Abstract

A polypeptide having at least 70% homology, in particular 80%, 90% or 95% homology to the polypeptide of SEQ ID No 2 representing the wild-type of the protein insect metalloproteinase inhibitor IMPIa and having at least one mutation at position 35, 36 and/or 39 of the amino acid sequence of IMPIa and the polypeptide having an IC50 value to thermolysine of less than the IC50 value of IMPIa wherein—the nonpolar amino acid isoleucine at position 35 of IMPIα is replaced either by a nonpolar amino acid selected from the group consisting of leucine, methionine and phenylalanine or by polar amino acid selected from the group consisting of cysteine, asparagine, glutamine, histidine, lysine and arginine; and/or—the nonpolar amino acid isoleucine at position 36 of IMPIa is replaced either by a nonpolar amino acid selected from the group consisting of valine, phenylalanine and tryptophan or by polar amino acid selected from the group consisting of tyrosine, serine, threonine, asparagine, glutamine, histidine, lysine and arginine; and/or—the polar amino acid position 39 of IMPIa is replaced either by the nonpolar amino acid valine or by the polar amino acids histidine or lysine.

Description

    CROSS-REFERENCE TO RELATED APPLICATION
  • The present application claims priority to U.S. Provisional Application Ser. No. 61/055,846, METHODS, COMPOSITIONS AND APPARATUS FOR FACILITATING REGENERATION, filed on May 23, 2008, and is hereby incorporated in its entirety by reference.
    • STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
  • Not applicable.
    • INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A COMPACT DISC
  • Not applicable.
    • FIELD OF THE INVENTION
  • The present invention relates in general to methods, compositions and apparatus for promoting tissue and organ regeneration, and in particular to preventing cells from inhibiting regenerative processes to obtain the recognized benefits in health and function associated with the results of regeneration.
    • BACKGROUND OF THE INVENTION
  • Tissue and organ regeneration research has focused on the need to stimulate regeneration by activating stem cells by soluble factors or treat partially- or non-functional cells to improve their function, e.g. by breaking damage-related crosslinks. Such research has overlooked the need to remove inhibitory effects.
  • Aging results from a combination of factors, but regeneration can overcome aging effects, if and to the extent that regenerative stem cells are functional. The stem cells, which replace cells, re-grow structures and renew the tissues of the body after normal wear-and-tear, give rise to replacement cells, and even structures, like hair follicles. In fact, if all stem cells in the body were destroyed, death would follow in a matter of days.
  • However, in a variety of diseases, malfunctions (such as male pattern baldness) and tissue injuries, cell types are not observed to be replaced when damaged or nonfunctional. Stem cell transplant therapy is proposed for such conditions, although it is not always successful.
  • The art has been left with the question as to why, then, does the body succumb to injury and aging when it has a mechanism for regeneration.
    • SUMMARY OF THE INVENTION
  • The present invention provides apparatus, compositions and methods for removing cells that interfere with regenerative processes by blocking locations in a tissue where progeny of stem cells can improve function. The present invention also reduces the proportion of partially- and non-functional cells without regard to location in a tissue.
  • Functionality according to the present invention is defined as the state of operation of a cell of the same type in a selected healthy individual.
  • The apparatuses, compositions and methods according to the present invention promote regenerative processes by differentially killing cells based inversely on the degree of functionality of the cells (i.e., the less functionality the more likely to be killed), and then applying that technique. This cell killing technique preferentially preserves proliferating cells. For example, any of lipofuscin, glycarion end-products or cell stiffness can be selected as a proliferation-preserving marker of partial- or non-functionality. Cell killing technologies directed against such markers can include, respectively, lasers/intense light, antibodies, and ultrasound. Cells can be killed according to the present invention by physical, electromagnetic, chemical or biological techniques, for example. Physical techniques include without limitation ultrasound and other oscillatory methods for disrupting cell membranes or structures leading to cell death. Electromagnetic techniques include without limitation and as targeted by sensitizers (such as absorbent nanoparticles, for example) EMF (see, e.g., Litovitz, U.S. Pat. No. 7,367,988 for EMF methods), high intensity light, radio waves microwaves, lasers, magnetism and ionizing radiation. Chemical techniques include without limitation toxic nanoparticles, chemical toxins and structure removal compounds such as β-aminopropionitrile. Biological techniques include without limitation antibodies against partially-functional or non-functional cells and variations and modifications thereof, such as toxin conjugates and natural killer cells modified to express target-specific antibodies. Techniques can be combined as determined to be effective (e.g. see McHale et al., U.S. Pat. No. 6,821,274 for sensitization to ultrasound by EMF treatment). Apparatuses, methods and compositions according to the present invention can be used sequentially or simultaneously in combination as monitoring determines to be effective for promoting regeneration.
  • Preferably, the apparatuses, compositions and methods selectively kill partially and/or non-functional cells versus functional cells of the same cell type to the extent that, upon removal of the killed cells by disintegration or scavenging, functional cells replace them. The cell killing apparatus, compositions and methods according to the present invention must preferentially preserve proliferating, functional cells and must be of a degree that avoids excessive inflammatory responses.
  • Evaluation of improvement or maintenance of a desired result can be used to direct the frequency of reapplication of the apparatus, compositions and methods according to the present invention. The application and reapplication can be determined with the goal of gradual improvement to avoid overwhelming natural mechanisms, such as removal of cells/debris by scavenging cells.
    • BRIEF DESCRIPTION OF THE DRAWING
  • The FIGURE illustrates apparatus according to the present invention.
    •  DETAILED DESCRIPTION
  • Higher multicellular organisms behave as communities of specialized cells that work together not to preserve each individual cell, but to preserve the organism as a whole. In humans during development, cells that are “in the way” of development are removed by programmed cell death, apoptosis, to benefit tissues, organs or the organism as a whole. Even when an organism reaches maturity, certain damaged cells, such as damaged blood cells are destroyed by the body to make way for replacements. The replacement cells are derived from stem cells. Accordingly, in a mature organism, cell turnover is the key to maintenance of a youthful/functional whole.
  • This turnover can come at the expense of destruction of functional cells to the extent that the destruction does not degrade the function of the organism over time. Thus, such destruction must preferentially target non-proliferating cells that are partially- or non-functional, but it need not absolutely avoid killing functional and proliferating cells. The goal is to preserve the community of cells (e.g. organism) not individual cells. Proliferating cells include both cells that are dividing and cells, such as stem cells, that divide normally when stimulated to do so.
  • While stem cells participate in mundane tissue replacement, injury can also be an occasion for release of a factor or factors to stimulate stem cell proliferation and differentiation. Stem cells give rise to cells which heal the injury, for example, healing a cut in an epithelium.
  • However, stem cell division and differentiation would be abnormal, even tumorigenic, in the presence of a normal complement of cells. Accordingly, there are mechanisms to prevent excessive proliferation. For example, the presence of a cell at a location in an epithelium prevents replacement at that position. An example of this sort of phenomenon is contact inhibition where cells cease proliferating when they come in contact with other cells. The phenomenon can be generalized to a rule that, to facilitate stem cell proliferation and differentiation for regeneration of cells at a location, there can not be a cell or structure at the location in the tissue.
  • In some cases, the human body includes cells for tearing down a structure, such as osteoclasts in bone, as well as cells for building up a structure, such as osteoblasts in bone. It is the balance between the activities of the two types of cells that determines the extent of the resulting structure. To the extent that any intrinsic mechanisms do not remove cells/structure for periodic renewal, the present invention provides for removal to promote regeneration.
  • The cell at the location that inhibits stem cell action can be fully functional, partially functional, or non-functional. Dead cells can be removed by scavenging macrophages, thus allowing for replacement, but a malfunctioning cell may remain despite deleterious effects on the subject (i.e., the organism of which they are a part). A partially or non-functional cell, i.e. a malfunctioning cell, can not be apoptotic, and, thus, can not stimulate clearance by macrophages on its own. Such malfunctioning cells are killed according to the present invention for removal by the body's natural processes.
  • Therapeutic killing of cells in cancer therapy is targeted against proliferating cells, the exact opposite of the present invention. According to the present invention, action against cancer is provided by stimulating proliferation of stem cells so that error-correcting mechanisms that function during cell division can correct mutations that otherwise might accumulate in a non-dividing cell.
  • Without limitation, partially or non-functional cells according to the present invention can fail to be fully functional due to damage, such as free radical damage, or cross-linkage as a result of reaction with sugars, i.e. glycation. Cells that are partially or non-functional due to a genetic makeup that is shared by stem cells of a subject can be replaced by exogenous stem cells having a fully functional genetic makeup.
  • Blocking stem cell action by a cell or structure at a location in a tissue interferes with the action of endogenous and transplanted stem cells. A structure that blocks stem cell action need not be a cell. Non-cellular material, such as scar tissue, can block such regeneration. This can explain failures in regeneration and in stem cell transplantation. To the extent feasible under a given situation, non-cellular blocking structures can be removed according to the present invention.
  • With removal of blocking cellular and/or non-cellular materials, appropriate regenerative cells, such as stem cells, are retained or supplemented by transplantation in order to permit regeneration. “Fully functional” is defined as the degree of a specified function for a particular cell type exhibited by an available progeny of a stem cell in a subject with or without stem cell transplantation, whichever is greater.
  • An example of an apparatus according to the present invention is illustrated in FIG. 1. Effector 10 is a device for killing cells. Effector 10 can be, without limitation, ultrasound equipment or a device for antibody administration, such as a drip apparatus. Control 20 is a device for regulating the operation of effector 10 according to preset parameters and/or as modified to ensure safety or effectiveness. Without limitation, control 20 can be a control panel of effector 10. Monitor 30 provides information regarding the degree of inflammatory response and/or other important factors in the condition of the subject to which effector 10 is applied. Information from monitor 30 can be used to adjust control 20 and thereby to adjust or change the operation of effector 10. Monitor 30 can be, without limitation, a thermometer connected to control 20.
  • A technique according to the present invention is selected to preferentially kill partially functional or nonfunctional cells or to remove non-cellular compositions, as opposed to indiscriminate killing, which has as great an effect on functional cells. A technique may be selected according to the present invention by exposing functional and partially functional and/or non-functional cells to the technique and choosing concentrations, intensities and characteristics such as wavelength, frequency, wave shape, continuity and treatment duration. The technique to be applied to a particular subject can be chosen on the basis of identifying an acceptable selectivity for partially functional and/or non-functional cells versus functional cells.
  • Suitable selection methods and criteria are readily available to those skilled in the art. Such selection methods are routinely applied by those of skill in the relevant arts to select laser treatment levels for removing blemishes, treating cancers by radiation therapy, selecting monoclonal antibodies, selecting toxins to be used therapeutically, and selecting ultrasound properties for therapy, for example. According to the present invention, selected techniques discriminate functional versus non-functional and/or partially functional cells of the same cell type as the functional cells.
  • Techniques that act upon differences between functional and partially or non-functional cells can be based upon cellular properties associated with dysfunction, such as cross-linking, membrane stiffness and brown coloration associated with lipofuscin in aged or senescent cells as opposed to nascent, dividing or functional cells. Techniques such as ultrasound, targeted to harmonic frequencies of cross-linked cell membranes or components, can be used according to the present invention. Likewise, techniques such as lasers or intense light of a wavelength preferentially absorbed by partially functional or non-functional cells can be used according to the present invention.
  • Techniques according to the present invention can be used to localize therapy where needed. Localization can be accomplished by, without limitation, computer assisted tomography, magnetic resonance imaging, and positron emission tomography. Most preferably, techniques according to the present invention can be applied to the whole organism without the need for localization.
  • Once techniques are chosen for one or more targets, the techniques can be applied periodically, particularly at a low intensity or concentration, to maintain or increase a positive balance between functional versus partially or non-functional cells. Gradual versus precipitate cell killing can aid in avoiding toxic effects from high levels of cellular breakdown products and/or deleterious effects of an inflammatory response.
  • In addition to therapeutic applications, it is intended that non-therapeutic, non-human and industrial applications be included within the scope of the present invention. Cosmetic applications, diagnostic applications and veterinary applications are also contemplated. Repeatedly practicing the method according to the present invention at a low level can be coupled with monitoring to determine the degree of improvement as a diagnostic measure of the component of a condition due to damaged cells versus genetic factors. With respect to tissue and cell culture applications, for example, destruction of blocking cells can permit the resulting dead cells and debris to be washed away. In this way, productivity of cell and tissue cultures can be increased by increasing the relative proportion of productive cells versus non-productive cells.
    • EXAMPLES
  • The following examples are for illustrative purposes only and should not be interpreted as limitations of the claimed invention. There are a variety of alternative techniques and procedures available to those of skill in the art that would similarly permit one to successfully perform the intended invention.
    • Example 1
  • In an embodiment of the present invention glycation end-products, crosslinks created by sugars bonded to proteins, are selected as indicia of an accumulation of cellular damage correlated with partial- or non-functionality. Antibodies against such glycation end-products can be raised according to methods well known to those skilled in the art (e.g. Abed et al., U.S. Pat. No. 6,380,165; Bucala, U.S. Pat. No. 5,702,704) and humanized monoclonal antibodies retaining constant regions which permit destruction of targeted cells by the immune system can be produced for injection, also according to well known methods (e.g. Basi et al., U.S. Pat. No. 7,256,273). Antibodies can be screened for effectiveness according to the present invention by labeling them and applying them separately to untreated cells versus cells incubated with a sugar such as ribose used to induce formation of glycation end-products. Binding of the antibodies to a higher degree to the cells previously incubated with sugar as opposed to the cells not treated with sugar indicates preferential effect against the selected target.
  • Antibodies produced as described above can be administered to a subject intravenously with monitoring to determine that inflammatory responses such as fever or swelling do not exceed limits well known to be safe. This process can be repeated at intervals to maintain a level of regeneration. The process can be focused to remove partially- and/or non-functional cells a particular location (e.g. where stem cell transplantation is targeted).
  • Evaluation of improvement or maintenance of a desired result can be used to direct the frequency of reapplication of the antibodies according to the present invention. The application and reapplication can be determined with the goal of gradual improvement to avoid overwhelming natural mechanisms, such as removal of cells/debris by scavenging cells.
    • Example 2
  • In another embodiment of the present invention, glycation end-products, crosslinks created by sugars bonded to proteins, are selected as indicia of an accumulation of cellular damage correlated with partial- or non-functionality. This crosslinking manifests itself in a stiffening of the cells. Those in the art understand stiffness to distinguish types of proliferating versus non-proliferating cells (e.g. Kas et al., U.S. Pat. No. 6,067,859).
  • Ultrasound apparatus can be used according to practices well known to those skilled in the art to destroy cells by vibrational techniques (e.g. Chapelon et al., U.S. Pat. No. 5,601,526). Ultrasound parameters (e.g. frequency, power, and pulsation) can be screened for effectiveness in selectively destroying stiffer cells according to the present invention by application to untreated cells versus cells incubated with a sugar such as ribose used to induce formation of glycation end-products. Vibrational versus thermal destruction by ultrasound is preferred according to the present invention. Parameters selected for preferential destruction of sugar-treated cells as opposed to the cells not previously treated with sugar indicates preferential effect against the selected target.
  • Ultrasound as described above can be applied to a subject with monitoring to determine that inflammatory responses such as fever or swelling do not exceed limits well known to be safe. This process can be repeated at intervals to maintain a level of regeneration. The process can be focused to remove partially- and/or non-functional cells a particular location (e.g. where stem cell transplantation is targeted).
  • Evaluation of improvement or maintenance of a desired result can be used to direct the frequency of reapplication of ultrasound according to the present invention. The application and reapplication can be determined with the goal of gradual improvement to avoid overwhelming natural mechanisms, such as removal of cells/debris by scavenging cells.
  • While the present invention has been described in terms of preferred embodiments, it is not intended that the present invention be limited to the embodiments described herein, but, rather, that the present invention include all embodiments within the scope of die appended claims as properly construed.

Claims (21)

What is claimed is:
1-9. (canceled)
10. A humanized antibody that binds to a glycation end-product of a cell, wherein the antibody is conjugated to a toxin.
11. The antibody of claim 10, wherein the antibody is monoclonal.
12. The antibody of claim 10, wherein the toxin is a toxic nanoparticle.
13. The antibody of claim 10, wherein the toxin is a chemical toxin.
14. The antibody of claim 10, wherein the toxin is p-aminopropionitrile.
15. The antibody of claim 10, wherein the cell is a senescent cell.
16. The antibody of claim 10, wherein the antibody is monoclonal,
the toxin is a chemical toxin, and
the cell is a senescent cell.
17. A composition comprising a humanized antibody that binds to a glycation end-product of a cell,
wherein the antibody is conjugated to a toxin.
18. The composition of claim 17, wherein the antibody is monoclonal.
19. The composition of claim 17, wherein the toxin is a toxic nanoparticle.
20. The composition of claim 17, wherein the toxin is a chemical toxin.
21. The composition of claim 17, wherein the toxin is p-aminopropionitrile.
22. The composition of claim 17, wherein the cell is a senescent cell.
23. The composition of claim 17, wherein the antibody is monoclonal,
the toxin is a chemical toxin, and
the cell is a senescent cell.
24. A method of making an antibody-toxin conjugate, comprising:
conjugating a toxin to a humanized antibody that binds to a glycation end-product of a cell.
25. The method of claim 24, wherein the antibody is monoclonal.
26. The method of claim 24, wherein the toxin is a toxic nanoparticle.
27. The method of claim 24, wherein the toxin is a chemical toxin.
28. The method of claim 24, wherein the cell is a senescent cell.
29. The method of claim 24, wherein the antibody is monoclonal,
the toxin is a chemical toxin, and
the cell is a senescent cell.
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US9649376B2 (en) 2010-09-27 2017-05-16 Siwa Corporation Selective removal of age-modified cells for treatment of atherosclerosis
US9993535B2 (en) 2014-12-18 2018-06-12 Siwa Corporation Method and composition for treating sarcopenia
US10358502B2 (en) 2014-12-18 2019-07-23 Siwa Corporation Product and method for treating sarcopenia
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US10858449B1 (en) 2017-01-06 2020-12-08 Siwa Corporation Methods and compositions for treating osteoarthritis
US10919957B2 (en) 2017-04-13 2021-02-16 Siwa Corporation Humanized monoclonal advanced glycation end-product antibody
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Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140189897A1 (en) 2011-06-21 2014-07-03 Mayo Foundation For Medical Education And Research Transgenic animals capable of being induced to delete senescent cells
RU2014128010A (en) 2011-12-13 2016-02-10 Бак Инститьют Фо Рисерч Он Эйджин WAYS OF IMPROVEMENT OF CONSERVATIVE THERAPY
WO2013158664A2 (en) 2012-04-17 2013-10-24 Kythera Biopharmaceuticals, Inc. Use of engineered viruses to specifically kill senescent cells
US9901080B2 (en) 2012-08-23 2018-02-27 Buck Institute For Research On Aging Transgenic mouse having a transgene that converts a prodrug into a cytotoxic compound in senescent cells
US9901081B2 (en) 2012-08-23 2018-02-27 Buck Institute For Research On Aging Transgenic mouse for determining the role of senescent cells in cancer
US10279018B2 (en) 2012-12-03 2019-05-07 Unity Biotechnology, Inc. Immunogenic compositions for inducing an immune response for elimination of senescent cells
KR20160002848A (en) 2013-03-24 2016-01-08 오이신 바이오테크놀로지스 Systems and methods for the targeted production of a therapeutic protein within a target cell
US10328058B2 (en) 2014-01-28 2019-06-25 Mayo Foundation For Medical Education And Research Treating atherosclerosis by removing senescent foam cell macrophages from atherosclerotic plaques
WO2015116735A1 (en) 2014-01-28 2015-08-06 Mayo Foundation For Medical Education And Research Methods and combinations for killing senescent cells and for treating senescence-associated diseases and disorders
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JP2021526505A (en) 2018-04-18 2021-10-07 オイシン バイオテクノロジーズ，インク． Methods for Producing Fused Lipid Nanoparticles and Fused Lipid Nanoparticles for Target Cell-Specific Production of Therapeutic Proteins and for the Treatment of Target Cell-Related Diseases, Diseases, or Disorders And how to use
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KR20210101481A (en) * 2020-02-10 2021-08-19 한국과학기술연구원 A device for removing senescent cells comprising an ultrasound output unit
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KR102650316B1 (en) * 2021-06-18 2024-03-25 재단법인대구경북과학기술원 magnetic patch capable of ultrasonic stimulation and its manufacturing method
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WO2024102157A1 (en) 2022-11-09 2024-05-16 Siwa Corporation Methods and compositions for treating diabetes and diabetic complications

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0259893A2 (en) * 1986-09-12 1988-03-16 The Rockefeller University Agents for removing advanced glycosylation endproducts
US4965288A (en) * 1988-02-25 1990-10-23 Merrell Dow Pharmaceuticals Inc. Inhibitors of lysyl oxidase
US5518720A (en) * 1992-12-30 1996-05-21 Exocell, Inc. Treatment of complications of diabetes with substances reactive with the fructosyl-lysine structure in glycated albumin
US5702704A (en) * 1991-12-20 1997-12-30 The Rockefeller University Antibodies to in vivo advanced glycosylation endproducts
US5766590A (en) * 1994-12-30 1998-06-16 Alteon Inc. Therapeutic methods and pharmaceutical compositions
US5817771A (en) * 1993-04-28 1998-10-06 Worcester Foundation For Experimental Biology Cell-targeted lytic pore-forming agents
US6380165B1 (en) * 1997-09-19 2002-04-30 The Picower Institute For Medical Research Immunological advanced glycation endproduct crosslink
US20030073138A1 (en) * 2001-03-22 2003-04-17 Rosemarie Kientsch-Engel Reagents and solid phase components in specific binding assays free of advanced glycosylation endproducts
US6821274B2 (en) * 2001-03-07 2004-11-23 Gendel Ltd. Ultrasound therapy for selective cell ablation
US20070065443A1 (en) * 2004-02-17 2007-03-22 Annette Tobia Fructoseamine 3 kinase and the formation of collagen and elastin
US20070225242A1 (en) * 2005-06-21 2007-09-27 The Board Of Trustees Of The Leland Stanford Junior University Method and composition for treating and preventing tumor metastasis in vivo
US9649376B2 (en) * 2010-09-27 2017-05-16 Siwa Corporation Selective removal of age-modified cells for treatment of atherosclerosis

Family Cites Families (138)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4217344A (en) * 1976-06-23 1980-08-12 L'oreal Compositions containing aqueous dispersions of lipid spheres
US4900747A (en) * 1984-03-19 1990-02-13 The Rockefeller University Method and agents for removing advanced glycosylation endproducts
US5811075A (en) 1984-03-19 1998-09-22 The Rockefeller University Method and agents for removing advanced glycosylation endproducts
US4917951A (en) * 1987-07-28 1990-04-17 Micro-Pak, Inc. Lipid vesicles formed of surfactants and steroids
US4911928A (en) * 1987-03-13 1990-03-27 Micro-Pak, Inc. Paucilamellar lipid vesicles
US5530101A (en) * 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
IN172208B (en) * 1990-04-02 1993-05-01 Sint Sa
US20080063603A1 (en) * 1990-04-02 2008-03-13 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
US20040208826A1 (en) * 1990-04-02 2004-10-21 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
US6372249B1 (en) * 1991-12-16 2002-04-16 Baylor College Of Medicine Senscent cell-derived inhibitors of DNA synthesis
US5601526A (en) 1991-12-20 1997-02-11 Technomed Medical Systems Ultrasound therapy apparatus delivering ultrasound waves having thermal and cavitation effects
WO1994000592A1 (en) * 1992-06-26 1994-01-06 Exocell, Inc. Monoclonal antibodies against glycated low density lipoprotein
US5620479A (en) * 1992-11-13 1997-04-15 The Regents Of The University Of California Method and apparatus for thermal therapy of tumors
US6387373B1 (en) * 1993-01-15 2002-05-14 Novavax, Inc. Vaccines containing paucilsmellar lipid vesicles as immunological adjuvants
CA2182731A1 (en) 1994-02-03 1995-08-10 Michael P. Vitek Compositions and methods for advanced glycosylation endproduct-mediated modulation of amyloidosis
US6410598B1 (en) 1994-02-03 2002-06-25 Michael P. Vitek Compositions and methods for advanced glycosylation endproduct-mediated modulation of amyloidosis
ES2203651T3 (en) * 1994-12-30 2004-04-16 Alteon, Inc. SPECIFIC MONOCLONAL ANTIBODIES FOR FINAL PRODUCTS OF ADVANCED GLYCOSILATION IN SAMPLES.
US6176842B1 (en) * 1995-03-08 2001-01-23 Ekos Corporation Ultrasound assembly for use with light activated drugs
AU6907496A (en) 1995-08-25 1997-03-19 Case Western Reserve University Process for detecting pentosidine and for assessing the biological age of a biological sample
JP3579549B2 (en) 1995-10-24 2004-10-20 株式会社トクヤマ Use as a marker for diabetes or diabetic complications
US6090382A (en) 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα
US5664570A (en) 1996-02-20 1997-09-09 Svc Apparatus for applying high-intensity ultrasonic waves to a target volume within a human or animal body
US5908925A (en) * 1996-06-27 1999-06-01 Exocell, Inc. Genetically engineered immunoglobulins with specificity for glycated albumin
US5984882A (en) * 1996-08-19 1999-11-16 Angiosonics Inc. Methods for prevention and treatment of cancer and other proliferative diseases with ultrasonic energy
US6261537B1 (en) * 1996-10-28 2001-07-17 Nycomed Imaging As Diagnostic/therapeutic agents having microbubbles coupled to one or more vectors
US7258857B2 (en) 1996-11-22 2007-08-21 The Trustees Of Columbia University In The City Of New York Rage-related methods for treating inflammation
US6245318B1 (en) * 1997-05-27 2001-06-12 Mallinckrodt Inc. Selectively binding ultrasound contrast agents
US7101838B2 (en) * 1997-08-05 2006-09-05 The Trustees Of Columbia University In The City Of New York Method to prevent accelerated atherosclerosis using (sRAGE) soluble receptor for advanced glycation endproducts
TR200000331T2 (en) 1997-08-08 2000-05-22 University Of Washington Isolation of the new aging factor gene P23.
US6896659B2 (en) * 1998-02-06 2005-05-24 Point Biomedical Corporation Method for ultrasound triggered drug delivery using hollow microbubbles with controlled fragility
JP4016304B2 (en) 1998-02-26 2007-12-05 日本油脂株式会社 Monoclonal antibody, hybrid cell, and method for producing monoclonal antibody
JP2002517224A (en) * 1998-06-09 2002-06-18 アルテオン インコーポレーテッド Monoclonal antibodies specific for advanced glycosylation end products from guanidino groups in biological samples
US6753150B2 (en) 1998-10-05 2004-06-22 The Trustees Of Columbia University In The City Of New York Method for determining whether a compound is capable of inhibiting the interaction of a peptide with rage
JP2002526117A (en) * 1998-10-06 2002-08-20 ザ・トラスティーズ・オブ・コランビア・ユニバーシティー・イン・ザ・シティー・オブ・ニューヨーク Extracellular new RAGE binding protein (EN-RAGE) and use thereof
US6309355B1 (en) * 1998-12-22 2001-10-30 The Regents Of The University Of Michigan Method and assembly for performing ultrasound surgery using cavitation
DE60045240D1 (en) 1999-03-02 2010-12-30 Centocor Inc ANTIBODIES TO TNF ALPHA FOR THE THERAPY OF STEROID-RESISTANT ASTHMA
US6067859A (en) * 1999-03-04 2000-05-30 The Board Of Regents, The University Of Texas System Optical stretcher
EP2112167A3 (en) 1999-06-25 2010-12-22 Genentech, Inc. Humanized ANTI-ERBB2 antibodies and treatment with ANTI-ERBB2 antibodies
JP2003507013A (en) * 1999-08-13 2003-02-25 ザ・トラスティーズ・オブ・コランビア・ユニバーシティー・イン・ザ・シティー・オブ・ニューヨーク Method for inhibiting the binding of β-sheet fibril to RAGE and its result
EP1219639A4 (en) 1999-09-08 2009-03-25 Toray Industries Materials for extracorporeal circulation, adsorbents for diabetic complication factors, containers for eliminating diabetic complication factors and method of eliminating diabetic complication factors
US6853864B2 (en) 2000-02-02 2005-02-08 Catholic University Of America, The Use of electromagnetic fields in cancer and other therapies
WO2001089584A2 (en) * 2000-05-23 2001-11-29 Amersham Health As Contrast agents
NO312338B1 (en) * 2000-08-25 2002-04-29 Gunnar Myhr Device for selective cell or virus destruction in a living organism
CN2445326Y (en) * 2000-10-09 2001-08-29 刘永详 Immune analysis device for assaying saccharified protein
US6676963B1 (en) * 2000-10-27 2004-01-13 Barnes-Jewish Hospital Ligand-targeted emulsions carrying bioactive agents
US7481781B2 (en) * 2000-11-17 2009-01-27 Gendel Limited Ultrasound therapy
AU2002217412B2 (en) 2001-01-03 2006-09-14 Ultrashape Ltd. Non-invasive ultrasonic body contouring
US7347855B2 (en) 2001-10-29 2008-03-25 Ultrashape Ltd. Non-invasive ultrasonic body contouring
US20040210042A1 (en) 2001-07-19 2004-10-21 Tsuchida Jun-Ichi Polypeptides relating to signal transfer of advanced glycation end product receptor
JP4012722B2 (en) 2001-11-22 2007-11-21 株式会社トランスジェニック Antibodies against carboxymethylated peptides
MY139983A (en) 2002-03-12 2009-11-30 Janssen Alzheimer Immunotherap Humanized antibodies that recognize beta amyloid peptide
EP1542997B1 (en) 2002-07-24 2012-02-29 Dermira (Canada), Inc. Pyrazolylbenzothiazole derivatives and their use as therapeutic agents
CN1774445A (en) 2002-08-16 2006-05-17 惠氏公司 Compositions and methods for treating RAGE-associated disorders
US20070128117A1 (en) * 2003-02-04 2007-06-07 Bracco International B.V. Ultrasound contrast agents and process for the preparation thereof
EP1597280B2 (en) 2003-02-26 2016-08-24 Institute for Research in Biomedicine Monoclonal antibody production by ebv transformation of b cells
US7700307B2 (en) * 2003-03-08 2010-04-20 Auvation Limited Mitochondrial stress-70 protein markers for colorectal cancer
WO2005009256A2 (en) * 2003-07-31 2005-02-03 Woodwelding Ag Method and device for promotion of tissue regeneration on wound surfaces
US7358226B2 (en) * 2003-08-27 2008-04-15 The Regents Of The University Of California Ultrasonic concentration of drug delivery capsules
CA2554239C (en) * 2004-01-20 2015-05-12 Sunnybrook And Women's College Health Sciences Centre High frequency ultrasound imaging using contrast agents
US7470521B2 (en) 2004-07-20 2008-12-30 Critical Therapeutics, Inc. RAGE protein derivatives
EP1781700B1 (en) 2004-08-03 2014-03-19 TransTech Pharma, LLC Rage fusion proteins and methods of use
GB0422525D0 (en) * 2004-10-11 2004-11-10 Luebcke Peter Dermatological compositions and methods
GT200600031A (en) 2005-01-28 2006-08-29 ANTI-BETA ANTIBODY FORMULATION
EP1866663A1 (en) * 2005-03-03 2007-12-19 Bracco Research S.A. Medical imaging system based on a targeted contrast agent
JP2006249015A (en) * 2005-03-11 2006-09-21 Mochida Pharmaceut Co Ltd Cellular senescence inhibitor
KR20070094950A (en) 2005-04-05 2007-09-27 가부시끼가이샤 제이엠에스 Antibody reactive specifically to age derived from 3,4-dge
WO2007027584A2 (en) * 2005-08-30 2007-03-08 University Of Virginia Patent Foundation Deposit contrast agents and related methods thereof
US20070065415A1 (en) * 2005-09-16 2007-03-22 Kleinsek Donald A Compositions and methods for the augmentation and repair of defects in tissue
US20070083120A1 (en) * 2005-09-22 2007-04-12 Cain Charles A Pulsed cavitational ultrasound therapy
US20070078290A1 (en) * 2005-09-30 2007-04-05 Esenaliev Rinat O Ultrasound-based treatment methods for therapeutic treatment of skin and subcutaneous tissues
US7766833B2 (en) * 2005-11-23 2010-08-03 General Electric Company Ablation array having independently activated ablation elements
JP4779115B2 (en) 2005-12-16 2011-09-28 国立大学法人東北大学 Postoperative prognostic method for early lung cancer
EP1988918A4 (en) * 2006-02-22 2010-04-28 Novavax Inc Adjuvant and vaccine compositions
US20070207141A1 (en) 2006-02-28 2007-09-06 Ivan Lieberburg Methods of treating inflammatory and autoimmune diseases with natalizumab
US9056905B2 (en) 2007-05-21 2015-06-16 Alderbio Holdings Llc Antibodies to TNF-α and use thereof
US20100249038A1 (en) 2007-06-12 2010-09-30 Board Of Regents, University Of Texas System Antagonists of the receptor for advanced glycation end-products (rage)
JP5706688B2 (en) 2007-06-14 2015-04-22 ギャラクティカ ファーマシューティカルズ， インク． RAGE fusion protein
JP2007277263A (en) 2007-07-13 2007-10-25 Transgenic Inc Antibody to carboxymethylated protein
WO2009085216A2 (en) * 2007-12-20 2009-07-09 Squicor Compositions and methods for detecting or elimninating senescent cells to diagnose or treat disease
US7751057B2 (en) * 2008-01-18 2010-07-06 The Board Of Trustees Of The University Of Illinois Magnetomotive optical coherence tomography
DE102008009461A1 (en) 2008-02-15 2009-08-20 Beiersdorf Ag Reducing the wrinkle, comprises applying a cosmetic preparation on the skin to be treated and subsequently working up by means of an ultrasonic applicator
ES2579554T3 (en) * 2008-05-09 2016-08-12 Abbvie Deutschland Gmbh & Co Kg Antibodies for the recipient of advanced glycation terminal products (RAGE) and uses thereof
EP2294178B1 (en) * 2008-05-23 2014-07-16 Siwa Corporation Methods for facilitating regeneration
JP5229473B2 (en) * 2008-06-04 2013-07-03 財団法人ヒューマンサイエンス振興財団 Ultrasound medical equipment
WO2010005531A2 (en) 2008-06-30 2010-01-14 The Johns Hopkins University Methods for the detection of advanced glycation endproducts and markers for disease
US9155805B2 (en) 2009-02-20 2015-10-13 Perseus Proteomics Inc. Monoclonal antibody, and use thereof
WO2011035104A1 (en) * 2009-09-17 2011-03-24 Sanuwave, Inc. Methods and devices for cleaning and sterilization with shock waves
US20110070227A1 (en) 2009-09-18 2011-03-24 Anna-Marie Novotney-Barry Treatment of Autoimmune and Inflammatory Diseases
EP2493486A1 (en) 2009-10-30 2012-09-05 University Of Arkansas For Medical Science Use of autologous effector cells and antibodies for treatment of multiple myeloma
WO2011101039A1 (en) 2010-02-22 2011-08-25 Universite Pierre Et Marie Curie (Paris 6) Apparatus for the treatment of brain affections and method implementing thereof
US9662347B2 (en) 2010-05-11 2017-05-30 Gachon University Of Industry-Academic Cooperation Foundation Method for inhibiting the induction of cell death by inhibiting the synthesis or secretion of age-albumin in cells of the mononuclear phagocyte system
US8721571B2 (en) 2010-11-22 2014-05-13 Siwa Corporation Selective removal of cells having accumulated agents
WO2012135616A1 (en) 2011-03-31 2012-10-04 Siwa Corporation Vaccination against advanced glycation end-products
UA112434C2 (en) 2011-05-27 2016-09-12 Ґлаксо Ґруп Лімітед ANTIGENCY BINDING SPECIFICALLY Binds to ALL
WO2013009785A2 (en) 2011-07-10 2013-01-17 Guided Therapy Systems, Llc. Systems and methods for improving an outside appearance of skin using ultrasound as an energy source
US8954155B2 (en) 2011-09-19 2015-02-10 Biotalk Technologies Inc Apparatus and method for rejuvenating skin
US9422365B2 (en) 2011-09-23 2016-08-23 Julius-Maximilians-Universität Würzburg Peptide or arrangement of peptides forming a Staphylococcus aureus epitope binding site
WO2013070468A1 (en) 2011-11-08 2013-05-16 The Trustees Of The University Of Pennsylvania Glypican-3-specific antibody and uses thereof
KR101939401B1 (en) 2011-11-10 2019-01-16 가천대학교 산학협력단 Composition for preventing or treating ischemic cardiac diseases comprising inhibiting agent for synthesis or secretion of AGE-albumin of mononuclear phagocyte as active ingredient
SG11201404354UA (en) 2012-02-17 2014-10-30 Seattle Genetics Inc ANTIBODIES TO INTEGRIN αVβ6 AND USE OF SAME TO TREAT CANCER
TWI557112B (en) 2012-03-05 2016-11-11 百靈佳殷格翰國際股份有限公司 Inhibitors of beta-secretase
US20130288980A1 (en) 2012-04-02 2013-10-31 Buck Institute For Research On Aging Targeting senescent and cancer cells for selective killing by interference with foxo4
US10379026B2 (en) 2012-08-29 2019-08-13 Inguran, Llc Cell processing using magnetic particles
KR101520336B1 (en) 2012-11-30 2015-05-14 전남대학교산학협력단 Compositions for prevention, improvement and treatment of Aging Phenotypes Comprising Recombinant Fusion Protein with Vibrio vulnificus Flagellin and Pathogenic Antigen
EP2742935A1 (en) 2012-12-14 2014-06-18 Tissue Med Biosciences Forschungs- und Entwicklungsgesellschaft mbH SERF2 for the treatment of atrophy and for increasing cell growth
AU2014224171B2 (en) 2013-03-06 2018-02-01 Protalix Ltd. Tnf alpha inhibitor polypeptides, polynucleotides encoding same, cells expressing same and methods of producing same
US20140257262A1 (en) 2013-03-11 2014-09-11 Alexandre Carpentier Interstitial ultrasonic disposable applicator and method for tissue thermal conformal volume ablation and monitoring the same
KR101990341B1 (en) 2013-03-12 2019-06-19 몰레큘러 템플레이츠, 인코퍼레이션. Cd20-binding immunotoxins for inducing cellular internalization and methods using same
CA2933557A1 (en) 2013-12-16 2015-06-25 Genentech, Inc. Peptidomimetic compounds and antibody-drug conjugates thereof
EP3087101B1 (en) 2013-12-20 2024-06-05 Novartis AG Regulatable chimeric antigen receptor
US10323083B2 (en) 2014-01-15 2019-06-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Agents that specifically bind matrilin-3 and their use
US10099027B2 (en) 2014-01-24 2018-10-16 Cole Research & Design Oral suction device
CA3100140C (en) 2014-01-28 2023-10-24 Buck Institute For Research On Aging Methods and compositions for killing senescent cells and for treating senescence-associated diseases and disorders
WO2015116735A1 (en) 2014-01-28 2015-08-06 Mayo Foundation For Medical Education And Research Methods and combinations for killing senescent cells and for treating senescence-associated diseases and disorders
DE102014107077B3 (en) 2014-05-20 2015-08-13 Ecs Engineered Control Systems Ag switching device
US10238742B2 (en) 2014-06-25 2019-03-26 Yale University Cell penetrating nucleolytic antibody based cancer therapy
BR112017005517A2 (en) 2014-09-19 2017-12-05 Siwa Corp antiage antibodies for the treatment of inflammation and autoimmune disorders
WO2016061532A1 (en) 2014-10-16 2016-04-21 The Broad Institute Inc. Compositions and methods for identifying and treating cachexia or pre-cachexia
US10358502B2 (en) 2014-12-18 2019-07-23 Siwa Corporation Product and method for treating sarcopenia
US9993535B2 (en) 2014-12-18 2018-06-12 Siwa Corporation Method and composition for treating sarcopenia
JP2018535953A (en) 2015-10-13 2018-12-06 シワ コーポレーション Anti-AGE antibody and method of use thereof
US10889634B2 (en) 2015-10-13 2021-01-12 Siwa Corporation Anti-age antibodies and methods of use thereof
KR102503910B1 (en) 2015-11-09 2023-02-27 삼성전자주식회사 Method and apparatus of standing assistance
EP3337829B1 (en) 2016-02-19 2020-01-08 Siwa Corporation Method and composition for treating cancer, killing metastatic cancer cells and preventing cancer metastasis using antibody to advanced glycation end products (age)
US10981021B2 (en) 2016-03-11 2021-04-20 Carthera Method for transiently disrupting a region of the blood-brain barrier of a human
WO2017181116A1 (en) 2016-04-15 2017-10-19 Siwa Corporation Anti-age antibodies for treating neurodegenerative disorders
US11213585B2 (en) 2016-06-23 2022-01-04 Siwa Corporation Vaccines for use in treating various diseases and disorders
US10925937B1 (en) 2017-01-06 2021-02-23 Siwa Corporation Vaccines for use in treating juvenile disorders associated with inflammation
US10858449B1 (en) * 2017-01-06 2020-12-08 Siwa Corporation Methods and compositions for treating osteoarthritis
US10995151B1 (en) 2017-01-06 2021-05-04 Siwa Corporation Methods and compositions for treating disease-related cachexia
US10961321B1 (en) 2017-01-06 2021-03-30 Siwa Corporation Methods and compositions for treating pain associated with inflammation
EP3609923A1 (en) 2017-04-13 2020-02-19 Siwa Corporation Humanized monoclonal advanced glycation end-product antibody
JP2020521117A (en) 2017-05-04 2020-07-16 シワ コーポレーション Antibody for advanced glycation end products
EP3826670A1 (en) 2018-07-23 2021-06-02 Siwa Corporation Methods and compositions for treating chronic effects of radiation and chemical exposure
KR20210045435A (en) 2018-08-14 2021-04-26 이멜 바이오테라퓨틱스, 인코포레이티드. Methods and compositions for treating mitochondrial diseases or disorders and heteroplasmy
US20210253739A1 (en) 2018-08-23 2021-08-19 Siwa Corporation Anticarboxymethyl lysine antibodies and ultrasound for removing age-modified cells
IL297799A (en) 2020-05-01 2022-12-01 Siwa Corp Methods of treating infections
WO2021247397A2 (en) 2020-06-04 2021-12-09 Siwa Corporation Methods and compositions for enhancing the immune system

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0259893A2 (en) * 1986-09-12 1988-03-16 The Rockefeller University Agents for removing advanced glycosylation endproducts
US4965288A (en) * 1988-02-25 1990-10-23 Merrell Dow Pharmaceuticals Inc. Inhibitors of lysyl oxidase
US5702704A (en) * 1991-12-20 1997-12-30 The Rockefeller University Antibodies to in vivo advanced glycosylation endproducts
US5518720A (en) * 1992-12-30 1996-05-21 Exocell, Inc. Treatment of complications of diabetes with substances reactive with the fructosyl-lysine structure in glycated albumin
US5817771A (en) * 1993-04-28 1998-10-06 Worcester Foundation For Experimental Biology Cell-targeted lytic pore-forming agents
US5766590A (en) * 1994-12-30 1998-06-16 Alteon Inc. Therapeutic methods and pharmaceutical compositions
US6380165B1 (en) * 1997-09-19 2002-04-30 The Picower Institute For Medical Research Immunological advanced glycation endproduct crosslink
US6821274B2 (en) * 2001-03-07 2004-11-23 Gendel Ltd. Ultrasound therapy for selective cell ablation
US20030073138A1 (en) * 2001-03-22 2003-04-17 Rosemarie Kientsch-Engel Reagents and solid phase components in specific binding assays free of advanced glycosylation endproducts
US20070065443A1 (en) * 2004-02-17 2007-03-22 Annette Tobia Fructoseamine 3 kinase and the formation of collagen and elastin
US20070225242A1 (en) * 2005-06-21 2007-09-27 The Board Of Trustees Of The Leland Stanford Junior University Method and composition for treating and preventing tumor metastasis in vivo
US9649376B2 (en) * 2010-09-27 2017-05-16 Siwa Corporation Selective removal of age-modified cells for treatment of atherosclerosis

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
Golay et al., Archives of Biochemistry and Biophysics 526: 146-153, 2012. *
Paul et al., Fundamental Immunology, (textbook), 1993, pp. 292-295 *
Rudikoff et al., Proc. Natl. Acad. Sci. USA 1982 Vol. 79 page 1979. *
Saito et al., The Journal of Biological Chemistry 272(13):8157-60, March 28, 1997. *
Tang et al., J Biol Bhem 258(7): 4331-4338, April 10, 1983. *
Wu et al., J. Mol. Biol. 294: 151-162, 1999. *

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