CN102037119B - 促进再生的方法、组合物及设备 - Google Patents

促进再生的方法、组合物及设备 Download PDF

Info

Publication number
CN102037119B
CN102037119B CN200980118817.6A CN200980118817A CN102037119B CN 102037119 B CN102037119 B CN 102037119B CN 200980118817 A CN200980118817 A CN 200980118817A CN 102037119 B CN102037119 B CN 102037119B
Authority
CN
China
Prior art keywords
cell
monoclonal antibodies
humanized monoclonal
functional
agep
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN200980118817.6A
Other languages
English (en)
Other versions
CN102037119A (zh
Inventor
刘易斯·S·格鲁伯
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Siwa Corp
Original Assignee
Siwa Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Siwa Corp filed Critical Siwa Corp
Priority to CN201510303227.8A priority Critical patent/CN104987416A/zh
Publication of CN102037119A publication Critical patent/CN102037119A/zh
Application granted granted Critical
Publication of CN102037119B publication Critical patent/CN102037119B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • 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
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • 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
    • 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
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • 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
    • 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
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—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
    • 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
    • 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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/1815—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 microwaves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • 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
    • A61N7/00—Ultrasound therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Surgery (AREA)
  • Physics & Mathematics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Electromagnetism (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Otolaryngology (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Physiology (AREA)
  • Food Science & Technology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)

Abstract

本发明涉及一种去除干扰再生过程的细胞的设备、组合物及方法。相对于功能细胞而言，所述设备、组合物及方法选择性地杀死具有部分功能和/或无功能的细胞，同时保护功能性增殖细胞达到下述程度：一旦通过破碎或清除来去除已经杀死的细胞，功能细胞就替换所述具有部分功能或无功能的细胞。

Description

促进再生的方法、组合物及设备
相关申请的交叉引用
本申请要求2008年5月23日提交的申请号为No.61/055,846、标题为“METHODS，COMPOSITIONS AND APPARATUS FORFACILITATING REGENERATION”的美国临时申请的优先权，将上述申请通过引用的方式整体并入本文中。
关于联邦政府资助研发的声明
不适用。
通过引用将光盘上所提交的资料结合到本文中
不适用。
技术领域
总体而言，本发明涉及一种用于促进组织和器官再生的方法、组合物及设备。具体地说，本发明涉及阻止细胞抑制再生过程，从而获得健康方面公认的益处以及与再生结果相关的功能。
背景技术
组织和器官再生的研究集中于通过用可溶因子活化干细胞来刺激再生的需求，或通过破坏与损伤相关的交联来处理具有部分功能或无功能的细胞以改善其功能的需求。上述研究忽视了去除抑制效果的需求。
衰老由多种因素引起，但当且仅当再生干细胞是功能性干细胞的情况下，再生能够克服衰老的影响。干细胞在正常的损耗(normalwear-and-tear)后，对细胞进行替换、使机体结构重新生长并使机体组织更新，以生成替换细胞甚至替换结构(如毛囊)。事实上，如果机体内所有干细胞都被破坏，几天内机体就会死亡。
然而，在多种疾病、机能失常(如男性型秃发)及组织损伤中，当细胞受损或无功能时，并未观察到细胞类型被替换。对于上述情况，有人提出采取干细胞移植疗法，尽管该方法并不总能成功。
在本领域中留下了这样的疑问，即机体具有再生机制时，为何还会屈从于损伤及衰老。
发明内容
本发明提供了将干扰再生过程的细胞去除的设备、组合物及方法，所述细胞通过阻断组织中的某些位置(在这些位置，干细胞后代可改善功能)来干扰再生过程。本发明还降低了具有部分功能及无功能的细胞的比例，而不考虑其在组织中的位置。
本发明的功能性(functionality)被定义为在所选择的健康个体中，相同类型的细胞的运行状态(state of operation)。
本发明的设备、组合物及方法反向地(inversely)基于所述细胞的功能性程度(degree of functionality)，区别性地杀死细胞(即功能性越低，越可能被杀死)，以及采用该技术来促进再生过程。这一杀死细胞的技术优先保留增殖细胞。举例来说，可选取脂褐质(lipofuscin)、糖基化终产物或细胞硬度(cell stiffness)作为具有部分功能性或无功能性的增殖维持的标记物。针对上述标记物的杀死细胞的技术分别包括激光/强光、抗体及超声。依照本发明，可通过例如物理技术、电磁技术、化学技术或生物技术杀死细胞。所述物理技术包括但不限于用于扰乱细胞膜或结构从而引起细胞死亡的超声及其它振动(oscillatory)方法。所述电磁技术包括但不限于致敏剂(例如吸收剂纳米颗粒)EMF(参见例如Litovitz，美国专利No.7,367,988关于EMF方法的记载)、高强度光、无线电波微波(radio waves microwaves)、激光、磁以及电离辐射，并被上述技术作为目标。所述化学技术包括但不限于毒性纳米颗粒、化学毒素以及例如β-氨基丙腈等结构去除化合物(structure removal compounds)。所述生物技术包括但不限于针对具有部分功能或无功能的细胞的抗体及其变种或修饰物，如毒素缀合物(toxin conjugates)以及经过修饰以表达靶特异性抗体的天然杀伤细胞。经确认有效，可组合使用上述技术(如：见McHale等，美国专利No.6,821,274关于通过EMF处理的超声致敏的记载)。当监测确定对促进再生有效时，本发明的设备、方法及组合物可以顺序使用，或同时组合使用。
优选地，相对于相同细胞类型的功能细胞而言，所述设备、组合物及方法选择性地杀死具有部分功能和/或无功能的细胞，并达到下述程度：一旦通过破碎(disintegration)或清除(scavenging)将杀死的细胞去除，功能细胞就将部分功能和/或无功能的细胞替换。本发明的杀死细胞的设备、组合物及方法必须优先保留增殖的功能细胞，同时必须在一定程度上避免过度的炎性反应。
对于所需结果的改善或维持的评估，可用于指导再次应用本发明的设备、组合物及方法的频率。所述应用与再次应用可根据逐渐改善的目标来确定，从而避免无法抵抗的自然机制，比如通过清除性细胞(scavenging cell)去除细胞/碎片。
附图说明
附图表示依照本发明的设备。
具体实施方式
高等多细胞有机体表现为共同发挥作用的特化细胞的群体(community)，它们并不保护每个单独的细胞，而是将该有机体作为一个整体进行保护。在发育中的人体内，发育过程中的细胞通过程序性细胞死亡(即凋亡)去除，以使得组织、器官或整个有机体受益。即使当有机体已到达了成熟期，具有一定损伤的细胞(例如损伤的血细胞)也会被机体破坏，从而让步于替换作用。所述替换细胞源自于干细胞。因此，在成熟的有机体中，细胞更新(cell turnover)是维持年轻/有功能的整体的关键。
只要随时间推移，该破坏作用不降低有机体的功能，所述更新便能以破坏功能细胞为代价而进行。因此，上述破坏作用必须优先靶向具有部分功能或无功能的非增殖细胞，但并不需要完全避免杀死功能细胞和增殖细胞。目标在于保护细胞的群体(如有机体)，而不是单独的细胞。增殖的细胞包括两种：正在分裂的细胞；以及在刺激下正常分裂的细胞(例如干细胞)。
当干细胞参与通常的组织替换时，损伤也可成为诱因从而释放刺激干细胞增殖和分化的一个或多个因子。干细胞可以生成治愈损伤(例如，治愈上皮中的伤口)的细胞。
然而，在正常的细胞补充作用的存在下，干细胞的分裂和分化是不正常的，甚至可引起肿瘤。因此，存在着阻止过度增殖的机制。例如，上皮中某位置存在细胞便阻止了在该处的替换。该种现象的实例是接触抑制(contact inhibition)，即当细胞与其它细胞接触时便停止增殖。所述现象可以归纳为如下规律，即，为了促进干细胞的增殖和分化以使细胞在某位置再生，组织中在此位置不能存在细胞或结构。
在某些情况下，人体既包括破坏结构的细胞(如骨中的破骨细胞)，也包括构建结构的细胞(如骨中的成骨细胞)。两类细胞的活性之间的平衡决定了所得结构的程度。在这个意义上，如果任何内在的机制均未去除细胞/结构以实现周期性的更新，本发明提供了去除作用以促进再生。
处于抑制干细胞作用位置的细胞可以是全功能的、部分功能的或无功能的。死细胞可被清除性巨噬细胞去除，从而使替换成为可能，但机能失常的细胞(malfunctioning cells)仍可能被保留，尽管这会对受试者(即，其是有机体的一部分)产生不良影响。具有部分功能或无功能的细胞，即机能失常的细胞不能发生凋亡，因此也无法自发刺激巨噬细胞的清除作用。可依照本发明杀死这种机能失常的细胞，从而实现利用机体的自然进程清除所述细胞。
癌症治疗中治疗性地杀死细胞的目的是针对增殖的细胞，与本发明刚好相反。依照本发明，通过刺激干细胞增殖使得在细胞分裂中发挥功能的纠错(error-correcting)机制可纠正突变，否则所述突变可在非分裂的细胞中发生累积，由此提供了抗癌作用。
不加限制地，依照本发明的具有部分功能或无功能的细胞由于损伤(如自由基损伤)或与糖反应(即糖基化)引起的交联不是全功能的。由于与受试者的干细胞享有相同遗传组成(genetic makeup)而具有部分功能或无功能的细胞，可被具有全功能遗传组成的外源干细胞替换。
通过组织中某位置的细胞或结构阻断干细胞的作用，干扰了内源干细胞及移植干细胞的作用。阻断干细胞作用的结构不需要是细胞。非细胞的物质(如瘢痕组织)也可以阻断这种再生作用。这一点便可解释再生及干细胞移植中的失败。只要在给定情况下可行，便可依照本发明去除非细胞的阻断结构。
去除阻断的细胞物质和/或非细胞物质后，合适的再生细胞(如干细胞)被保留或通过移植进行补充，从而使再生成为可能。“全功能的(fullyfunctional)”定义如下：在进行干细胞移植或未进行干细胞移植的受试者体内，可获得的干细胞后代所展现出的特定细胞类型的指定功能的程度中，程度更高的那种情况。
依照本发明的设备的实例如图1所示。效应器10是杀死细胞的装置。效应器10可以是超声仪器或抗体给予装置(例如滴注设备)，但不限于此。控制器20是依照预设的参数和/或为保证安全性或有效性而修改的参数，调控效应器10运行的装置。控制器20可以是效应器10的控制面板，但不限于此。在效应器10应用于受试者的条件下，监测器30提供关于炎性反应的程度和/或其他重要因子的信息。来自监测器30的信息可用于调节控制器20，由此调节或改变效应器10的运行。监测器30可以是与控制器20相连的温度计，但不限于此。
与对功能细胞有很大影响的无差别杀灭作用(indiscriminate killing)相反，选择依照本发明的技术，用以优先杀死具有部分功能或无功能的细胞，或去除非细胞的组成部分。通过对功能细胞和具有部分功能的细胞和/或无功能的细胞使用本发明的技术，选择浓度、强度以及例如波长、频率、波形、连续性及处理的持续时间等特征，可选定这一技术。相对于功能细胞，对具有部分功能和/或无功能的细胞可接受的选择性的识别为基础，可选择应用于特定受试者的技术。
本领域技术人员很容易获取适当的选择方法及标准。所述选择方法是相关领域技术人员常规采用的方法，如选择用于去除瘢痕(blemish)的激光治疗水平、通过放射疗法治疗癌症、选择单克隆抗体、选择治疗性使用的毒素及选择用于治疗的超声波性质。依照本发明，所选择的技术可以区分功能细胞以及与所述功能细胞的细胞类型相同的无功能的细胞和/或具有部分功能的细胞。
依据具有部分功能或无功能的细胞与功能细胞间的差异发挥作用的技术，可以基于与功能异常相关的细胞特性，例如，与新生细胞、分裂细胞或功能细胞相反，在老化细胞或衰老细胞中的交联、膜硬度和与脂褐质相关的褐色着色。依照本发明，可以采用如超声的技术，其目标是交联的细胞膜或组分的谐振频率。同样地，依照本发明，也可采用如激光或强光的技术，所述激光或强光具有可优先被具有部分功能或无功能的细胞吸收的波长。
依照本发明的技术可用于在需要的地方进行定点治疗(localizetherapy)。可以通过计算机辅助断层成像术、磁共振成像及正电子发射断层成像术实现定位，但不限于这些成像技术。更优选地，依照本发明的技术可应用于整个有机体而无需定位。
一旦选定了针对一个或多个靶的技术，所述技术可以周期性地使用，尤其可在低强度或低浓度的条件下周期性使用，以维持或提高功能细胞与具有部分功能或无功能的细胞间的正平衡。与急促的细胞杀伤相比，逐步的细胞杀伤能够避免来自高水平的细胞破坏产品的毒性影响和/或炎性反应的有害影响。
除治疗性的应用之外，非治疗性应用、非人类应用及工业化应用也包括在本发明的范围内。化妆品的应用、诊断的应用及兽医的应用也在本发明的范围内。在低水平下重复实施本发明的方法可与监测相结合，以确定改善的程度，作为比较受损细胞与遗传因子引起的疾病的组分的诊断测量。就组织和细胞培养物的应用而言，例如，对阻断细胞的破坏可使得所得死细胞及碎片能够被冲洗掉。以这种方式，可通过提高生产性细胞相对于非生产性细胞的相对比例，来提高细胞及组织培养物的生产能力。
实施例
以下实施例仅用于说明的目的，不应被理解为对所要求保护的发明的限制。对本领域技术人员而言，还存在多种可替代的技术和方法，所述技术和方法也可类似地使得本领域的技术人员成功完成预期的发明。
实施例1
在本发明一个实施方式中，糖基化终产物、由糖与蛋白结合而产生的交联被选作与部分功能性或无功能性相关的细胞损伤累积的指标。依照本领域技术人员公知的方法，可产生针对上述糖基化终产物的抗体(如：Abed等，美国专利No 6,380,165；Bucala，美国专利No 5,702,704)，还可依照公知的方法，制备注射用的保留了恒定区的人源化单克隆抗体，所述人源化单克隆抗体使得通过免疫系统破坏靶细胞成为可能(如：Basi等，美国专利No.7,256,273)。依照本发明，通过对抗体进行标记并分别应用于未处理的细胞以及用糖(如核糖)培养的细胞(用于诱导形成糖基化终产物)，可对抗体的有效性进行筛选。与未经糖处理的细胞相反，抗体与事先用糖培养的细胞的结合性更高，表明优先针对所选的靶标发挥作用。
如上所述产生的抗体可通过静脉给予受试者，通过监测来确定例如发烧或肿胀等的炎性反应并未超过公认的安全极限。该过程可每隔一定时间重复进行，以维持再生的水平。该过程可关注于去除特定位置的具有部分功能和/或无功能的细胞(如：干细胞移植靶向的位置)。
对于改善或维持的所需结果的评估，可用于指导依照本发明的抗体再次应用的频率。所述应用与再次应用可根据逐渐改善的目标来确定，从而避免无法抵抗的自然机制，比如通过清除性细胞去除细胞/碎片。
实施例2
在本发明另一个实施方式中，糖基化终产物、由糖与蛋白结合而产生的交联被选作与具有部分功能性或无功能性相关的细胞损伤的累积的指标。所述交联以细胞的硬化显现出来。本领域技术人员了解可以通过硬度将增殖细胞及非增殖细胞进行类型区分(如：Kas等，美国专利No.6,067,859)。
依照本领域技术人员公知的实践，可利用超声装置通过振动技术破坏细胞(如：Chapelon等，美国专利No.5,601,526)。依照本发明，可通过将超声应用于未处理的细胞以及用糖(如核糖)孵育的细胞(用于诱导形成糖基化终产物)，针对选择性破坏更硬的细胞(stiffer cells)方面的有效性，对超声参数(如频率、功率和脉冲)进行筛选。依照本发明，相比超声引起的热破坏，优选超声引起的振动破坏。所选的参数用于优先破坏经糖处理的细胞，而不是事先未经糖处理的细胞，表明本发明优先针对所选的靶标发挥作用。
如上所述的超声可应用于受试者，通过监测确定例如发烧或肿胀等的炎性反应并未超过公认的安全极限。该过程可每隔一定时间重复进行，以维持再生的水平。该过程可关注于去除特定位置的具有部分功能或无功能的细胞(如：干细胞移植靶向的位置)。
对于所需结果的改善或维持的评估，可用于指导依照本发明的超声再次应用的频率。所述应用与再次应用可根据逐渐改善的目标来确定，从而避免无法抵抗的自然机制，比如通过清除性细胞去除细胞/碎片。
本发明从优选实施方式的方面进行了描述，并不意味着本发明局限于此处所记载的实施方式，相反，在合理解释的情况下，本发明包括所附权利要求书范围内的所有实施方式。

Claims (8)

1.一种结合至糖基化终产物的人源化单克隆抗体，所述人源化单克隆抗体用于通过对受试者给予所述人源化单克隆抗体来结合并杀死含有所述糖基化终产物的、具有部分功能或无功能的细胞，促进所述受试者体内组织和器官再生。
2.如权利要求1所述的人源化单克隆抗体，其中，所述人源化单克隆抗体与毒素缀合。
3.结合至糖基化终产物的人源化单克隆抗体在制备药剂方面的用途，所述药剂用于通过对受试者给予所述人源化单克隆抗体来结合并杀死含有所述糖基化终产物的、具有部分功能或无功能的细胞，促进所述受试者体内组织和器官再生。
4.如权利要求3所述的用途，其中，所述人源化单克隆抗体与毒素缀合。
5.一种用于促进再生过程的组合物，其中，对受试者给予所述组合物从而选择性地杀死衰老细胞，其中，通过糖基化终产物的存在选择所述衰老细胞，其中，所述组合物包含结合并杀死衰老细胞的人源化单克隆抗体。
6.一种用于克服衰老影响的组合物，其中，对受试者给予所述组合物从而选择性地杀死衰老细胞，其中，通过糖基化终产物的存在选择所述衰老细胞，其中，所述组合物包含结合并杀死衰老细胞的人源化单克隆抗体。
7.如权利要求5或6所述的组合物，其中，所述组合物包含缀合至所述人源化单克隆抗体的毒素。
8.如权利要求7所述的组合物，其中，所述人源化单克隆抗体结合至靶细胞上的糖基化终产物。 
CN200980118817.6A 2008-05-23 2009-05-22 促进再生的方法、组合物及设备 Active CN102037119B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510303227.8A CN104987416A (zh) 2008-05-23 2009-05-22 促进再生的方法、组合物及设备

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US5584608P 2008-05-23 2008-05-23
US61/055,846 2008-05-23
PCT/US2009/044951 WO2009143411A2 (en) 2008-05-23 2009-05-22 Methods, compositions and apparatus for facilitating regeneration

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN201510303227.8A Division CN104987416A (zh) 2008-05-23 2009-05-22 促进再生的方法、组合物及设备

Publications (2)

Publication Number Publication Date
CN102037119A CN102037119A (zh) 2011-04-27
CN102037119B true CN102037119B (zh) 2015-06-24

Family

ID=41340916

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201510303227.8A Pending CN104987416A (zh) 2008-05-23 2009-05-22 促进再生的方法、组合物及设备
CN200980118817.6A Active CN102037119B (zh) 2008-05-23 2009-05-22 促进再生的方法、组合物及设备

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201510303227.8A Pending CN104987416A (zh) 2008-05-23 2009-05-22 促进再生的方法、组合物及设备

Country Status (19)

Country Link
US (4) US20110105961A1 (zh)
EP (3) EP2294178B1 (zh)
JP (6) JP2011521009A (zh)
KR (4) KR20110000585A (zh)
CN (2) CN104987416A (zh)
AU (1) AU2009248945B2 (zh)
BR (1) BRPI0913047A2 (zh)
CA (1) CA2724886C (zh)
DK (1) DK2789684T3 (zh)
ES (2) ES2616728T3 (zh)
HK (2) HK1150628A1 (zh)
HU (1) HUE031902T2 (zh)
IL (3) IL209513A (zh)
MX (2) MX342994B (zh)
PL (1) PL2789684T3 (zh)
PT (1) PT2789684T (zh)
RU (2) RU2640249C2 (zh)
WO (1) WO2009143411A2 (zh)
ZA (1) ZA201008209B (zh)

Families Citing this family (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2294178B1 (en) 2008-05-23 2014-07-16 Siwa Corporation Methods for facilitating regeneration
WO2012047629A2 (en) 2010-09-27 2012-04-12 Siwa Corporation Selective removal of age-modified cells for treatment of ather0sclerosis
US8721571B2 (en) 2010-11-22 2014-05-13 Siwa Corporation Selective removal of cells having accumulated agents
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 (ru) 2011-12-13 2016-02-10 Бак Инститьют Фо Рисерч Он Эйджин Способы улучшения средств консервативной терапии
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 (ko) 2013-03-24 2016-01-08 오이신 바이오테크놀로지스 표적 세포 내에서 치료적 단백질의 표적화된 생산을 위한 시스템 및 방법
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
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
BR112017005517A2 (pt) 2014-09-19 2017-12-05 Siwa Corp anticorpos antiage para o tratamento de inflama-ção e de transtornos autoimunes
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 (ja) 2015-10-13 2018-12-06 シワ コーポレーション 抗ａｇｅ抗体およびその使用方法
US10889634B2 (en) 2015-10-13 2021-01-12 Siwa Corporation Anti-age antibodies and methods of use thereof
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)
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
US10961321B1 (en) 2017-01-06 2021-03-30 Siwa Corporation Methods and compositions for treating pain associated with inflammation
US10995151B1 (en) 2017-01-06 2021-05-04 Siwa Corporation Methods and compositions for treating disease-related cachexia
CA3047140A1 (en) 2017-01-09 2018-07-12 Oisin Biotechnologies Constructs for expression of therapeutic proteins in target cells
EP3609923A1 (en) 2017-04-13 2020-02-19 Siwa Corporation Humanized monoclonal advanced glycation end-product antibody
JP2020521117A (ja) 2017-05-04 2020-07-16 シワ コーポレーション 診断用終末糖化産物抗体
US11518801B1 (en) 2017-12-22 2022-12-06 Siwa Corporation Methods and compositions for treating diabetes and diabetic complications
JP2021526505A (ja) 2018-04-18 2021-10-07 オイシン バイオテクノロジーズ，インク． 治療用タンパク質の標的細胞に特異的な産生のための、および、標的細胞に関連する疾患、疾病、または障害の処置のための、融合性脂質ナノ粒子、および、融合性脂質ナノ粒子の製造方法と使用方法
EP3826670A1 (en) 2018-07-23 2021-06-02 Siwa Corporation Methods and compositions for treating chronic effects of radiation and chemical exposure
US20210253739A1 (en) 2018-08-23 2021-08-19 Siwa Corporation Anticarboxymethyl lysine antibodies and ultrasound for removing age-modified cells
KR20210101481A (ko) * 2020-02-10 2021-08-19 한국과학기술연구원 초음파 출력부를 포함하는 노화세포 제거 장치
IL297799A (en) 2020-05-01 2022-12-01 Siwa Corp Methods for treating infections
WO2022093195A1 (en) 2020-10-27 2022-05-05 Siwa Corporation Methods and compositions for treating osteoarthritis using anti-age antibodies or age antigens
US20240000930A1 (en) 2020-12-09 2024-01-04 Siwa Corporation Methods and compositions for treating kidney diseases
KR102650316B1 (ko) * 2021-06-18 2024-03-25 재단법인대구경북과학기술원 초음파 자극이 가능한 자성 패치 및 그 제작 방법
WO2023023654A1 (en) 2021-08-20 2023-02-23 Siwa Corporation Methods and compositions for treating fibrotic diseases
WO2024102157A1 (en) 2022-11-09 2024-05-16 Siwa Corporation Methods and compositions for treating diabetes and diabetic complications

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6380165B1 (en) * 1997-09-19 2002-04-30 The Picower Institute For Medical Research Immunological advanced glycation endproduct crosslink
US20020193784A1 (en) * 2001-03-07 2002-12-19 Mchale Anthony Patrick Ultrasound therapy for selective cell ablation
US20060122543A1 (en) * 2003-07-31 2006-06-08 Woodwelding Ag Method for promoting tissue regeneration on wound surfaces as device and treatment instrument or implant for carrying out method

Family Cites Families (147)

* 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
JP2644767B2 (ja) * 1986-09-12 1997-08-25 ザ ロックフェラー ユニバーシティ 後生的なグリコシル化最終産物を除去する為の方法及び薬剤
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
US4965288A (en) * 1988-02-25 1990-10-23 Merrell Dow Pharmaceuticals Inc. Inhibitors of lysyl oxidase
US5530101A (en) * 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
IN172208B (zh) * 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
US5624804A (en) 1991-12-20 1997-04-29 The Rockefeller University Immunochemical detection of In vivo advanced glycosylation end products
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
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
US6387373B1 (en) * 1993-01-15 2002-05-14 Novavax, Inc. Vaccines containing paucilsmellar lipid vesicles as immunological adjuvants
CA2160909A1 (en) * 1993-04-28 1994-11-10 Hagan Bayley Cell-targeted lytic pore-forming agents
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
US5744318A (en) * 1994-12-30 1998-04-28 Alteon Inc. Monoclonal antibody for the detection of advanced glycosylation endproducts in biological samples
ES2203651T3 (es) * 1994-12-30 2004-04-16 Alteon, Inc. Anticuerpos monoclonales especificos para productos finales de glicosilacion avanzada en muestras.
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 (ja) 1995-10-24 2004-10-20 株式会社トクヤマ 糖尿病または糖尿病合併症用マーカーとしての使用
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 (tr) 1997-08-08 2000-05-22 University Of Washington Yeni yaşlanma faktörü geni P23'ün izolasyonu.
US6896659B2 (en) * 1998-02-06 2005-05-24 Point Biomedical Corporation Method for ultrasound triggered drug delivery using hollow microbubbles with controlled fragility
JP4016304B2 (ja) 1998-02-26 2007-12-05 日本油脂株式会社 モノクローナル抗体、ハイブリッド細胞、およびモノクローナル抗体の製造方法
JP2002517224A (ja) * 1998-06-09 2002-06-18 アルテオン インコーポレーテッド 生体サンプル内におけるグアニジノ基由来進行グリコシル化最終生成物に特異的なモノクローナル抗体
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 (ja) * 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 細胞外新規ｒａｇｅ結合タンパク質（ｅｎ−ｒａｇｅ）及びその使用
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 (de) 1999-03-02 2010-12-30 Centocor Inc Antikörper gegen tnf alpha zur therapie von steroidresistentem 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 (ja) * 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 βシートフィブリルのＲＡＧＥへの結合を阻害する方法及びその結果
EP1219639A4 (en) 1999-09-08 2009-03-25 Toray Industries CIPO - Patent
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 (no) * 2000-08-25 2002-04-29 Gunnar Myhr Anordning for selektiv celle- eller virusödeleggelse hos en levende organisme
CN2445326Y (zh) * 2000-10-09 2001-08-29 刘永详 测定被糖化蛋白的免疫分析装置
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
ATE283481T1 (de) * 2001-03-22 2004-12-15 Hoffmann La Roche Verfahren zum auffinden von reagenzien und festphasenkomponenten in spezifischen bindungsassays, frei von fortgeschrittenen glykosylierungsendprodukten
US20040210042A1 (en) 2001-07-19 2004-10-21 Tsuchida Jun-Ichi Polypeptides relating to signal transfer of advanced glycation end product receptor
JP4012722B2 (ja) 2001-11-22 2007-11-21 株式会社トランスジェニック カルボキシメチル化ペプチドに対する抗体
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 (zh) 2002-08-16 2006-05-17 惠氏公司 用于治疗rage相关病症的组合物和方法
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
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
AU2005214971A1 (en) * 2004-02-17 2005-09-01 Dynamis Therapeutics, Inc. Fructoseamine 3 kinase and the formation of collagen and elastin
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 (es) 2005-01-28 2006-08-29 Formulacion anticuerpo anti a beta
EP1866663A1 (en) * 2005-03-03 2007-12-19 Bracco Research S.A. Medical imaging system based on a targeted contrast agent
JP2006249015A (ja) * 2005-03-11 2006-09-21 Mochida Pharmaceut Co Ltd 細胞老化抑制剤
KR20070094950A (ko) 2005-04-05 2007-09-27 가부시끼가이샤 제이엠에스 3,4-ｄｇｅ에서 유래하는 ａｇｅ에 특이적으로 반응하는항체
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
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 (ja) 2005-12-16 2011-09-28 国立大学法人東北大学 早期肺癌の術後予後検査方法
EP1988918A4 (en) * 2006-02-22 2010-04-28 Novavax Inc ADJUVANZ 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 (ja) 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融合タンパク質
JP2007277263A (ja) 2007-07-13 2007-10-25 Transgenic Inc カルボキシメチル化タンパク質に対する抗体
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 (de) 2008-02-15 2009-08-20 Beiersdorf Ag Verfahren zur Reduzierung der Zeichen der Hautalterung
ES2579554T3 (es) * 2008-05-09 2016-08-12 Abbvie Deutschland Gmbh & Co Kg Anticuerpos para el receptor de productos terminales de glicación avanzada (RAGE) y usos de los mismos
EP2294178B1 (en) * 2008-05-23 2014-07-16 Siwa Corporation Methods for facilitating regeneration
JP5229473B2 (ja) * 2008-06-04 2013-07-03 財団法人ヒューマンサイエンス振興財団 超音波医療装置
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
WO2012047629A2 (en) 2010-09-27 2012-04-12 Siwa Corporation Selective removal of age-modified cells for treatment of ather0sclerosis
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 (uk) 2011-05-27 2016-09-12 Ґлаксо Ґруп Лімітед Антигензв'язувальний білок, який специфічно зв'язується з всма
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 (ko) 2011-11-10 2019-01-16 가천대학교 산학협력단 단핵식세포계 세포의 ａｇｅ-알부민 합성 또는 분비 저해제를 유효성분으로 포함하는 허혈성 심장질환 예방 또는 치료용 조성물
SG11201404354UA (en) 2012-02-17 2014-10-30 Seattle Genetics Inc ANTIBODIES TO INTEGRIN αVβ6 AND USE OF SAME TO TREAT CANCER
TWI557112B (zh) 2012-03-05 2016-11-11 百靈佳殷格翰國際股份有限公司 β－分泌酶抑制劑
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 (ko) 2012-11-30 2015-05-14 전남대학교산학협력단 패혈증 비브리오균의 편모 구성성분인 플라젤린과 병원체의 항원 단백을 융합시킨 재조합 단백을 포함하는 노화 예방, 개선 또는 치료용 조성물
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 (ko) 2013-03-12 2019-06-19 몰레큘러 템플레이츠, 인코퍼레이션. 세포 내재화를 유도하기 위한 ｃｄ20-결합 면역독소 및 이의 사용 방법
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 (de) 2014-05-20 2015-08-13 Ecs Engineered Control Systems Ag Schaltvorrichtung
US10238742B2 (en) 2014-06-25 2019-03-26 Yale University Cell penetrating nucleolytic antibody based cancer therapy
BR112017005517A2 (pt) 2014-09-19 2017-12-05 Siwa Corp anticorpos antiage para o tratamento de inflama-ção e de transtornos autoimunes
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 (ja) 2015-10-13 2018-12-06 シワ コーポレーション 抗ａｇｅ抗体およびその使用方法
US10889634B2 (en) 2015-10-13 2021-01-12 Siwa Corporation Anti-age antibodies and methods of use thereof
KR102503910B1 (ko) 2015-11-09 2023-02-27 삼성전자주식회사 기립 보조 방법 및 장치
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 (ja) 2017-05-04 2020-07-16 シワ コーポレーション 診断用終末糖化産物抗体
EP3826670A1 (en) 2018-07-23 2021-06-02 Siwa Corporation Methods and compositions for treating chronic effects of radiation and chemical exposure
KR20210045435A (ko) 2018-08-14 2021-04-26 이멜 바이오테라퓨틱스, 인코포레이티드. 미토콘드리아 질환 또는 장애 및 헤테로플라스미를 치료하기 위한 방법 및 조성물
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 for treating infections
WO2021247397A2 (en) 2020-06-04 2021-12-09 Siwa Corporation Methods and compositions for enhancing the immune system

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6380165B1 (en) * 1997-09-19 2002-04-30 The Picower Institute For Medical Research Immunological advanced glycation endproduct crosslink
US20020193784A1 (en) * 2001-03-07 2002-12-19 Mchale Anthony Patrick Ultrasound therapy for selective cell ablation
US20060122543A1 (en) * 2003-07-31 2006-06-08 Woodwelding Ag Method for promoting tissue regeneration on wound surfaces as device and treatment instrument or implant for carrying out method

Also Published As

Publication number Publication date
KR20150041158A (ko) 2015-04-15
MX342994B (es) 2016-10-21
HK1200485A1 (zh) 2015-08-07
KR101592156B1 (ko) 2016-02-04
CA2724886C (en) 2017-11-14
RU2015114990A (ru) 2015-11-27
KR101537460B1 (ko) 2015-07-16
ZA201008209B (en) 2012-04-25
CN104987416A (zh) 2015-10-21
JP6359051B2 (ja) 2018-07-18
EP2294178B1 (en) 2014-07-16
CA2724886A1 (en) 2009-11-26
KR20130132658A (ko) 2013-12-04
EP3170888A1 (en) 2017-05-24
US20160152697A1 (en) 2016-06-02
MX2010012473A (es) 2011-02-23
JP2016152815A (ja) 2016-08-25
PT2789684T (pt) 2017-02-14
IL240242A0 (en) 2015-09-24
EP2789684A1 (en) 2014-10-15
AU2009248945B2 (en) 2014-02-13
AU2009248945A1 (en) 2009-11-26
WO2009143411A2 (en) 2009-11-26
JP6637465B2 (ja) 2020-01-29
IL209513A (en) 2015-08-31
KR20120127543A (ko) 2012-11-21
US20180044411A1 (en) 2018-02-15
BRPI0913047A2 (pt) 2013-03-05
JP2017125073A (ja) 2017-07-20
JP2020050666A (ja) 2020-04-02
HK1150628A1 (zh) 2012-01-06
RU2010152693A (ru) 2012-06-27
EP2294178A2 (en) 2011-03-16
US20110105961A1 (en) 2011-05-05
HUE031902T2 (en) 2017-08-28
ES2499395T3 (es) 2014-09-29
IL248652A0 (en) 2016-12-29
RU2640249C2 (ru) 2017-12-27
ES2616728T3 (es) 2017-06-14
RU2553225C2 (ru) 2015-06-10
US20180111982A2 (en) 2018-04-26
JP2011521009A (ja) 2011-07-21
JP2022089873A (ja) 2022-06-16
DK2789684T3 (en) 2017-02-20
WO2009143411A3 (en) 2010-01-14
US20120183534A1 (en) 2012-07-19
PL2789684T3 (pl) 2017-06-30
IL209513A0 (en) 2011-01-31
JP2015131846A (ja) 2015-07-23
EP2789684B1 (en) 2016-12-21
US11261241B2 (en) 2022-03-01
CN102037119A (zh) 2011-04-27
KR20110000585A (ko) 2011-01-03
US9161810B2 (en) 2015-10-20
EP2294178A4 (en) 2011-12-07

Similar Documents

Publication Publication Date Title
CN102037119B (zh) 促进再生的方法、组合物及设备
AU2014202548A1 (en) Methods, compositions and apparatuses for facilitating regeneration
Dannenberg et al. The firing rate speed code of entorhinal speed cells differs across behaviorally relevant time scales and does not depend on medial septum inputs
Ragozzino et al. Rundown of GABA type A receptors is a dysfunction associated with human drug-resistant mesial temporal lobe epilepsy
Gasull et al. Evidence that long-term hyperexcitability of the sensory neuron soma induced by nerve injury in Aplysia is adaptive
Jarzebowski et al. Cholinergic suppression of sharp wave-ripples impairs hippocampus-dependent spatial memory
Zhu Synaptic excitability changes within the hippocampal formation of 3xTgAD mice
Ghaith et al. Proton versus photon adjuvant radiotherapy: a multicenter comparative evaluation of recurrence following spinal chordoma resection
Makwana et al. The role of Ras and dominant-negative MEK as mediators of intracellular sprouting in vivo

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant