CN1150388A - 免疫治疗剂及其应用 - Google Patents
免疫治疗剂及其应用 Download PDFInfo
- Publication number
- CN1150388A CN1150388A CN95193357A CN95193357A CN1150388A CN 1150388 A CN1150388 A CN 1150388A CN 95193357 A CN95193357 A CN 95193357A CN 95193357 A CN95193357 A CN 95193357A CN 1150388 A CN1150388 A CN 1150388A
- Authority
- CN
- China
- Prior art keywords
- mycobacterium vaccae
- tumor
- application
- diffusion
- mycobacterium
- 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.)
- Granted
Links
- 239000002955 immunomodulating agent Substances 0.000 title claims description 8
- 241000187644 Mycobacterium vaccae Species 0.000 claims abstract description 53
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 31
- 239000000463 material Substances 0.000 claims abstract description 10
- 244000005700 microbiome Species 0.000 claims description 15
- 238000009792 diffusion process Methods 0.000 claims description 12
- 230000004614 tumor growth Effects 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 229940124644 immune regulator Drugs 0.000 claims description 5
- 230000001934 delay Effects 0.000 claims description 3
- 210000005075 mammary gland Anatomy 0.000 claims description 3
- 201000005242 bronchial neoplasm Diseases 0.000 claims description 2
- 230000005180 public health Effects 0.000 claims description 2
- 230000001580 bacterial effect Effects 0.000 claims 2
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 230000012010 growth Effects 0.000 abstract description 5
- 230000000890 antigenic effect Effects 0.000 abstract description 2
- 230000004957 immunoregulator effect Effects 0.000 abstract 1
- 238000002347 injection Methods 0.000 description 24
- 239000007924 injection Substances 0.000 description 24
- 229960000190 bacillus calmette–guérin vaccine Drugs 0.000 description 13
- 241001467552 Mycobacterium bovis BCG Species 0.000 description 12
- 239000003085 diluting agent Substances 0.000 description 10
- 238000002649 immunization Methods 0.000 description 10
- 230000003053 immunization Effects 0.000 description 10
- 238000002560 therapeutic procedure Methods 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- 230000007246 mechanism Effects 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 4
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000000427 antigen Substances 0.000 description 4
- 108091007433 antigens Proteins 0.000 description 4
- 102000036639 antigens Human genes 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 230000000813 microbial effect Effects 0.000 description 4
- 231100000915 pathological change Toxicity 0.000 description 4
- 230000036285 pathological change Effects 0.000 description 4
- 238000001959 radiotherapy Methods 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 201000008827 tuberculosis Diseases 0.000 description 4
- 229960005486 vaccine Drugs 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 241000101040 Pityriasis Species 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 201000008275 breast carcinoma Diseases 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 210000003716 mesoderm Anatomy 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 2
- 102100037850 Interferon gamma Human genes 0.000 description 2
- 108010074328 Interferon-gamma Proteins 0.000 description 2
- 102100030703 Interleukin-22 Human genes 0.000 description 2
- 206010024229 Leprosy Diseases 0.000 description 2
- 241000186359 Mycobacterium Species 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000007853 buffer solution Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000016784 immunoglobulin production Effects 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 108010074109 interleukin-22 Proteins 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 1
- 208000003322 Coinfection Diseases 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 206010016275 Fear Diseases 0.000 description 1
- 206010019375 Helicobacter infections Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910004844 Na2B4O7.10H2O Inorganic materials 0.000 description 1
- 206010057444 Oropharyngeal neoplasm Diseases 0.000 description 1
- 235000018259 Solanum vestissimum Nutrition 0.000 description 1
- 240000002825 Solanum vestissimum Species 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 206010043276 Teratoma Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 206010000269 abscess Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- -1 antiseptic Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 208000019804 backache Diseases 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical class OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 238000002619 cancer immunotherapy Methods 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 238000009104 chemotherapy regimen Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 108091036078 conserved sequence Proteins 0.000 description 1
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000003981 ectoderm Anatomy 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 230000003760 hair shine Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- 208000012285 hip pain Diseases 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 201000000289 malignant teratoma Diseases 0.000 description 1
- 238000009607 mammography Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 201000006958 oropharynx cancer Diseases 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000005549 size reduction Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000012899 standard injection Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000037816 tissue injury Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000004804 winding Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
-
- 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
- A61K39/02—Bacterial antigens
- A61K39/04—Mycobacterium, e.g. Mycobacterium tuberculosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Microbiology (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Mycology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Pulmonology (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Materials For Medical Uses (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明涉及得自牝牛分枝杆菌供延缓或防止肿瘤的生长或扩散的抗原性和/或免疫调节物质的应用。
Description
本发明涉及在延缓或防止肿瘤生长中有用的免疫治疗剂。
已有人提出至少在一些病例中免疫系统能防止或延缓肿瘤生长，并且尝试进行一些研究以支持此观点。因此柯雷(W.B.1894“利用丹毒毒素及灵杆菌治疗不可手术的恶性肿瘤”)描述了一种显示对中胚层来源的限制性范围肿瘤有效的免疫治疗方法，通过诱导类似于郭霍氏免疫治疗对结核所诱导的坏死机制。从那时起，多种对癌症免疫治疗的尝试以诱导类似于在柯雷的一些病例中获得的快速组织坏死为目标。
己知至少有两型成熟辅助T细胞，称为TH1和TH2。前者与白介素2(IL2)，γ干扰素(IFN-γ)， 细胞毒性T细胞(CTLs)的产生，降低的抗体产生和TH2细胞产生的下调有关。后者产生IL4，IL5，增加抗体产生并降调节TH1细胞。郭霍现象，很可能由柯雷氏毒素诱导，被认为是TH1+TH2成熟细胞混合物的结果。
已发现至少2组免疫反应可用于控制肿瘤，且两者均可由卡介苗(BCG)引起。一种机制是组织破坏，如由郭霍的和柯雷的免疫治疗和用TNFα的肿瘤免疫治疗所举例说明，并可能涉及在通过T细胞依赖性郭霍现象适当制备的炎症位点中的细胞因子介导的组织损伤。这种机制显示对中胚层起源的肿瘤有效。第2种机制，基于肿瘤细胞本身的免疫识别，可能对任何起源的肿瘤有效。存在基于非特异性TH1的抗肿瘤机制的间接证据来自重组白介素，即一种强大的TH1诱导物，在实验癌症中的成功。
据信，如果以避免诱导郭霍现象的方式应用，分枝杆菌能通过热休克蛋白(HSP)表位和具有高度保守序列的其它蛋白的表位激活应激的自体细胞的识别，并从而导致选择性肿瘤细胞破坏。我们得出结论，过去BCG免疫治疗的多变的有效性是因为未认识到BCG趋向于促进已用抗原激活的反应类型，如在对结核和麻风的保护中BCG有效性研究中所出现的。
BCG作为针对分枝杆菌疾病(结核和麻风)的疫苗非常多变，在不同研究中保护作用可为80％至0％。因此出生时给予BCG似乎通常只保护BCG被用于预防结核的那些地理位置的儿童免于白血病，这是颇具意味的(Grange JM，Stanford JL.BCG vaccination and cancer.Tubercle.(1990)；71：61-64)。也就是说，在BCG引起对分枝杆菌抗原的非组织坏死性及非郭霍现象的反应的那些地区，BCG对两种疾病有保护作用。
很多肿瘤细胞在它们的表面呈递细菌模仿物，碳水化合物，应激蛋白和其它与1类和2类主要组织相容性复合物(MHC)相关的高度保守蛋白的抗原和表位。在高抗体产量环境下，原来针对细菌糖产生的抗碳水化合物抗体，可能为IgA类型，可覆盖肿瘤细胞并阻断它们的表面成分免受细胞免疫攻击。
如我们已在我们的国际申请PCT/GB 93 00643中所示，用牝牛分枝杆菌的免疫治疗诱导主要是TH1类型反应伴随巨噬细胞被IFN-γ激活和少量抗体产生。已知这种TH1反应驱动CTLs的产生。显著的抗体产量下降，与CTLs数量增加一起将引起肿瘤细胞变得对攻击开放，既可通过结合于肿瘤细胞表面上细菌模仿的糖后激活的巨噬细胞，也可通过识别由1类MHC呈递的应激蛋白或其它高度保守蛋白表位的CTLs。一般认为通过郭霍现象的组织坏死机制，可通过使用牝牛分枝杆菌衍生的制剂的应用被极大地抑制。
因此可以期待应用牝牛分枝杆菌的免疫治疗通过防止或延缓肿瘤细胞的生长或扩散，可有效对抗中胚层，内胚层和外胚层来源的肿瘤，包括乳腺和支气管肿瘤。
本发明相应地提供应用来自牝牛分枝杆菌的抗原性和/或免疫调节性物质用于制造延缓或防止肿瘤生长和扩散有用的药物。这种物质可以以至少足够延缓或防止肿瘤生长或扩散的剂量试用于受治疗者。
本发明的治疗学制剂方便地，因而是优选，包含牝牛分枝杆菌的死细胞，最优选经高压热灭菌杀死的细胞。该免疫治疗学制剂通常包含每毫升稀释液108以上个微生物，优选每毫升稀释液108至1011杀死的牝牛分枝杆菌微生物。本发明的范围包含供在延缓或防止肿瘤的生长或扩散的治疗中使用的得自牝牛分枝杆菌的抗原性和/或免疫调节性物质。
稀释液可单为注射用的无热原盐水，或pH8.0的硼酸盐缓冲液。该稀释液应被灭菌。一种适当的硼酸盐缓冲液是：
Na2B4O7.10H2O 3.63g
H3BO3 5.25g
NaCl 6.19g
吐温 0.0005％
蒸馏水 至1升
优选的牝牛分枝杆菌株是从中部乌干达Lango区泥样分离的一种命名为R877R者(J.L.斯坦福和R.C.保尔，Ann.Soc.Belge Med，Trop.1973，53，141-389)。该株是稳定的粗糙型变异株并且按生物化学和抗原标准可鉴定为属于牝牛分枝杆菌(R.勃尼克，S.E.朱哈兹.，Zentr albl.Bakteriol.Parasitenkd Infectionskr.Hgy，Abt.1.Orig.，1964，192，133)。
命名为R887的此株保存于国立典型培养物保藏中心(NCTC)中心公共卫生实验室，Colindale街，伦敦NW9 5HT，英国，于1984年2月13日，保藏号为NCTC 11659。
为制备该免疫治疗学制剂，微生物牝牛分枝杆菌可在适当的固体培养基上培养。优选改良的Sauton氏液体培养液(S.V.勃登和E.索金.，免疫学杂志，1955，75，15)用琼脂固化。优选该固体培养基含1.3％琼脂。
对接种该微生物的培养基进行有氧保温以使微生物的生长能够发生，通常在32C培养10天。收获微生物，然后称重并悬溶于稀释液中。稀释液可为未缓冲的盐水但优选硼酸盐缓冲的并含有如上面所述吐温80的表面活性剂。将该悬溶液稀释以得到100mg微生物/ml。对于进一步稀释，优选使用硼酸盐缓冲盐水以使悬溶液含10mg湿重的微生物/ml稀释液。该悬溶液随后可悬溶于5ml多次剂量瓶。虽然剂量瓶中的微生物可使用放射如得自60钴，剂量为2.5兆拉德，或通过任何其它方法，如化学法，但优选通过高压热灭菌杀死微生物，例如在10psi持续10分钟(115-125℃)。已发现压热灭菌产生的制剂比放射产生的更有效。
该免疫治疗剂通常以0.1～0.2ml，优选0.1ml的体积通过皮内注射给药。单个剂量通常含107至1010个杀死的牝牛分枝杆菌微生物。优选以含108至109个杀死的牝牛分枝杆菌的单个剂量给病人用药。但是，根据病人的病情该剂量可以重复。
虽然该免疫治疗剂通常通过皮内注射给药，但其它途径，例如口服，也可被应用。
在本方法范围内包含一种延缓或防止肿瘤生长或扩散的方法，它包含向肿瘤患者施用来自牝牛分枝杆菌的剂量足以引起有效地延缓或防止肿瘤生长或扩散的免疫反应的抗原性和/或免疫调节物质。
在本发明范围内并且有利的是，可以使用多于一株牝牛分枝杆菌，和/或在治疗学制剂中包括其它分枝杆菌抗原。结核菌素也可包括在内。
该治疗学制剂也可包含BCG(卡介苗)疫苗，特别是该疫苗的冻干形式，以促进其作用。
该治疗学制剂还可包含其它成分如佐剂，防腐剂，稳定剂等。可以灭菌的可注射液体形式提供或为在使用前再重配的冻干形式。
牝牛分枝杆菌可如此应用或作为该生物本的提取物或分级级分以按照本发明制备治疗学制剂。
本发明通过下列实施例进一步说明。实施例1
牝牛分枝杆菌在包含用1.3％琼脂固化的改良的Sauton’s培养基的固态培养基上培养。用该微生物接种此培养基并在32C保温10天以使微生物的生长能够发生。然后收获微生物并称重和在稀释液中悬溶以得到100mg微生物/ml稀释液。该悬液随后被进一步用缓冲盐水稀释以得到含10mg湿重微生物/ml稀释液的悬液并配制为5ml多剂量瓶。然后将含有活微生物的剂量瓶在10psi压热灭菌10分钟以杀死该微生物并得到本发明的免疫治疗剂，它可(如果需要的话)被进一步稀释以供应用。
这种免疫治疗剂可以已经描述的方式经皮内注射给药。实施例2
已给予几个肿瘤病人牝牛分枝杆菌注射。获得的一些结果报告如下：乳腺癌
1)在越南河内的卫生和流行病学国立研究院，正在使用牝牛分枝杆菌作为免疫治疗进行几项研究，工作人员之一患了乳腺癌并且已有腋窝转移。在手术去除肿瘤后她被劝告进行BCG免疫治疗。由于已见到在其它病人中这种治疗方案，该病人不愿接受BCG，并要求用牝牛分枝杆菌治疗。该病人接受了109杀死的牝牛分枝杆菌的标准注射，至少3年情况很好，没有肿瘤复发的迹象。
2)在为治疗持续性糠疹接受牝牛分枝杆菌注射数周后，一名年龄50岁的妇女在常规乳腺X线摄影术检查时发现有一个乳腺包块。活检显示肿物为恶性的并通过包块切除而去除。组织病理学显示围绕腋窝淋巴结有无肿瘤的显著窦组织细胞增多病。约9个月后糠疹复发并再次给予一剂牝牛分枝杆菌，糠疹几乎立即减轻。在去除肿瘤后21个月没有继发的迹象。
3)一名刚过70岁的妇女在数年前切除过一个乳腺肿瘤。她由于关节炎而有背痛多年的病史，并接受牝牛分枝杆菌以图缓解。不久后脊柱X线显示数个考虑为肿瘤继发灶的病变，并要求她进行放射治疗。在延迟8周后她来进行放射治疗，并且再次放射摄影检查发现没有继发灶的迹象；因而未给予放射治疗。2年半后她情况很好，没有肿瘤复发。
4)一名55岁的普通医生呈现被认为是急性乳腺脓肿的2天病史。切除显示该包块为一种非常快速生长的癌，在腋窝中已出现继发灶。立即进行了切除，并且在出院后立即给予了牝牛分枝杆菌注射。以3个月为间隔又进行了2次注射。手术伤口愈合良好，并且一年后在这个害怕疾病迅速转移的病人中，没有继发灶的证据。
5)一名主诉髋部疼痛1年的年龄50岁的护士被诊断为已有来自一个小的乳腺肿瘤的骨继发。在初次注射牝牛分枝杆菌疫苗后她病情好转，对化疗耐受良好并进行了第2次牝牛分枝杆菌注射。她情况很好。肺肿瘤
1)一名55岁的妇女在1993年10出现气短，发现是由于肺中数个不可手术的肿瘤所致。这些肿瘤被认为是来自不明原发肿瘤的继发灶。在得到肿瘤学家的同意后，给予了牝牛分枝杆菌注射并开始了1个疗程的化疗和放射治疗。病人耐受良好，很少有副作用，并且当6个月后向她提出进行第2次牝牛分枝杆菌注射时不愿接受。在发病后10个月她的病情恶化了，改变了化疗方案，但病人预后不好。在1994年10月始给予了牝牛分枝杆菌的第2次注射，随后病人的病情改善并且她已经又接受了2次注射，1次在1994年12月，别一次在1995年3月1日。此病人不但比预期情况良好，而且她还耐受了20个疗程的化疗而无不便。其它恶性肿瘤
1)一名因恶性畸胎瘤而处于疾病终末期的30岁的牙医在被送回家等死前接受了一次牝牛分枝杆菌注射。在一两天之内他已显示好转的迹象，3周后显示可见的肿瘤大小缩小并在数周以来第一次开始吃饭。
2)一名36岁的妇女在幽门产气螺旋杆菌感染所致溃疡周围的胃部发生了腺癌。虽然进行了化疗她还是出现了多个扩散转移灶。她已接受了第1次牝牛分枝杆菌注射并且还准备以2个月为间隔继续注射。HIV相关肿瘤
1)一名有多发Kaposi氏肉瘤的AIDS病早期病人在1993年11月接受了1次牝牛分枝杆菌注射。他未发展新的肿瘤，并且已存在的肿瘤显示消退的迹象。在他出现HLI相关的继发感染后在1994年12月给予了第2次牝牛分枝杆菌注射。他准备每隔2个月接受1次牝牛分枝杆菌重复注射。
2)一名几乎无CD4+细胞，但无明显AIDS病体征的患者在1994年6月接受了一次牝牛分枝杆菌注射，数周后发现在一侧股部有一处约0.5cm直径的小KS病变。以2个月为间隔造一步给予病人牝牛分枝杆菌注射，在1995年3月该病人显示没有新的病变并且他的首发病变大小未增加。
3)一名患有多发性复发性口咽癌的48岁病人在1994年6月被给予牝牛分枝杆菌注射，并以2个月为间隔被给予进一步的注射。到1995年3月没有肿瘤复发。
以上提供的逸事为牝牛分枝杆菌治疗肿瘤提供支持。未发现使用牝牛分枝杆菌与任何副作用相关，事实上至少在2名病人中它可帮助减轻化疗的毒性副作用。这些早期实践观察结果支持理论预期并提供了有价值抗肿瘤活性的最早迹象。实施例3
使用用小鼠乳癌株MM3攻击的Balb/c小鼠已进行了初步实验。
将3组10只小鼠用107MM3细胞攻击。1周后第一组用107牝牛分枝杆菌注射，第2组接受109牝牛分枝杆菌而第3组作为对照。在攻击40天后处死动物并检查肿瘤的出现。
第1组 第2组 第3组
107牝牛分枝杆 109牝牛分枝杆 对照
菌 菌出现肿瘤 1 2 5
p＝0.056无肿瘤 9 8 5
Claims (13)
1.来源于牝牛分枝杆菌的抗原性和/或免疫调节物质的应用，用于制造可用于延缓或防止肿瘤生长或扩散的药物。
2.按照权利要求1的应用，其中来自牝牛分枝杆菌的抗原性和/或免疫调节物质包含牝牛分枝杆菌的死细胞。
3.按照权利要求2的应用，其中牝牛分枝杆菌细胞通过高压灭菌被杀死。
4.按照前述任一项权利要求的应用，其中来自牝牛分枝杆菌的物质得自保藏号为NCTC11659的菌株，该菌株于1984年2月13日保藏于英国，伦敦NW9 5HT，Colindale街，中心公共卫生实验室，国立典型培养物保藏中心(NCTC)。
5.按照前述权利要求的任意一个的应用，其中来自牝牛分枝杆菌的材料被包含在一种药物中，该药物含每剂量107-1010个微生物。
6.按前述权利要求的任意一个的应用，其中肿瘤为乳腺或支气管肿瘤。
7.一种延缓或防止肿瘤生长或扩散的方法，它包括向受治疗者施予剂量至少足以延缓或防止所述肿瘤生长或扩散的来自牝牛分枝杆菌的抗原性和/或免疫调节物质。
8.按照权利要求7的方法，其中该肿瘤是乳腺肿瘤。
9.按照权利要求7或8的方法，其中来自牝牛分枝杆菌的该物质按照权利要求2至5中任意一项所定义。
10.包含来自牝牛分枝杆菌用于延缓或防止肿瘤生长或扩散的物质的产品。
11.按照权利要求10的产品，其中来自牝牛分枝杆菌的物质按照权利要求2至5中任意一项所定义。
12.一种包含来自牝牛分枝杆菌的抗原性和/或免疫调节物质的用于延缓或防止肿瘤生长或扩散治疗的免疫治疗剂。
13.按照权利要求12的治疗剂，其中所述来自牝牛分枝杆菌的物质按照权利要求2至5中任意一项所定义。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9406301A GB9406301D0 (en) | 1994-03-30 | 1994-03-30 | Immunotherapeutic agent and its use |
| GB9406301.3 | 1994-03-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1150388A true CN1150388A (zh) | 1997-05-21 |
| CN1121874C CN1121874C (zh) | 2003-09-24 |
Family
ID=10752750
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95193357A Expired - Fee Related CN1121874C (zh) | 1994-03-30 | 1995-03-29 | 免疫治疗剂及其应用 |
Country Status (22)
| Country | Link |
|---|---|
| EP (1) | EP0752870B1 (zh) |
| JP (1) | JP4135190B2 (zh) |
| KR (1) | KR100392582B1 (zh) |
| CN (1) | CN1121874C (zh) |
| AP (1) | AP9600861A0 (zh) |
| AT (1) | ATE218355T1 (zh) |
| AU (1) | AU699081B2 (zh) |
| BR (1) | BR9507338A (zh) |
| CA (1) | CA2186851C (zh) |
| CZ (1) | CZ280196A3 (zh) |
| DE (1) | DE69526935T2 (zh) |
| DK (1) | DK0752870T3 (zh) |
| ES (1) | ES2177638T3 (zh) |
| FI (1) | FI111223B (zh) |
| GB (1) | GB9406301D0 (zh) |
| HU (1) | HU220858B1 (zh) |
| NO (1) | NO964075L (zh) |
| NZ (1) | NZ282863A (zh) |
| PT (1) | PT752870E (zh) |
| RU (1) | RU2139728C1 (zh) |
| WO (1) | WO1995026742A1 (zh) |
| ZA (1) | ZA952644B (zh) |
Families Citing this family (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6284255B1 (en) * | 1996-08-29 | 2001-09-04 | Genesis Research & Development Corporation Limited | Compounds and methods for treatment and diagnosis of mycobacterial infections |
| US6160093A (en) * | 1996-08-29 | 2000-12-12 | Genesis Researth And Development Corporation Limited | Compounds and methods for treatment and diagnosis of mycobacterial infections |
| US5985287A (en) * | 1996-08-29 | 1999-11-16 | Genesis Research And Development Corporation Limited | Compounds and methods for treatment and diagnosis of mycobacterial infections |
| US6406704B1 (en) | 1996-08-29 | 2002-06-18 | Genesis Research And Development Corporation Limited | Compounds and methods for treatment and diagnosis of mycobacterial infections |
| US6878377B2 (en) | 1996-12-18 | 2005-04-12 | Stanford Rook Limited | Mycobacterium vaccae for down-regulation of the Th2 activity of the immune system |
| AU730548B2 (en) * | 1996-12-18 | 2001-03-08 | Stanford Rook Limited | Mycobacterium vaccae for down-regulation of the TH2 activity of the immune system |
| US6328978B1 (en) | 1997-12-23 | 2001-12-11 | Genesis Research & Development Corp. Ltd. | Methods for the treatment of immunologically-mediated skin disorders |
| US5968524A (en) * | 1997-12-23 | 1999-10-19 | Genesis Research & Development Corp. | Methods and compounds for the treatment of immunologically-mediated psoriasis |
| US6350457B1 (en) | 1999-06-02 | 2002-02-26 | Genesis Research & Development Corporation Limited | Methods and compounds for the treatment of immunologically-mediated diseases using mycobacterium vaccae |
| UA79952C2 (en) * | 2001-12-10 | 2007-08-10 | Kabulesh Mafatlal Khamar | MYCOBACTERIUM w APPLICATIONS FOR CANCER TREATMENT |
| WO2003063896A1 (en) * | 2002-01-29 | 2003-08-07 | Modi, Rajiv, Indravadan | Process of preparing a pharmaceutical composition for immunity against tuberculosis in hiv positive individuals |
| US8501198B2 (en) | 2004-06-07 | 2013-08-06 | Qu Biologics Inc. | Tissue targeted antigenic activation of the immune response to treat cancers |
| NZ581806A (en) * | 2004-06-07 | 2011-10-28 | Qu Biolog Inc | Bacterial compositions for the treatment of cancer |
| US8034359B2 (en) | 2004-06-07 | 2011-10-11 | Qu Biologics Inc. | Tissue targeted antigenic activation of the immune response to cancers |
| US9107864B2 (en) | 2004-06-07 | 2015-08-18 | Qu Biologics Inc. | Tissue targeted antigenic activation of the immune response to treat cancers |
| BG66067B1 (bg) * | 2005-05-18 | 2011-01-31 | Спартак ХАДЖИЕВ | Средство с антитуморна активност на база бцж ваксина, метод за неговото получаване и използването му |
| US8557257B2 (en) | 2006-03-24 | 2013-10-15 | Oncovac Inc. | Mycobacterial immunotherapy for cancer treatment |
| EP3235506B1 (en) | 2010-07-26 | 2023-12-06 | Qu Biologics Inc. | Immunogenic anti-inflammatory compositions |
| US8980279B2 (en) | 2010-07-26 | 2015-03-17 | Qu Biologics | Personalized site-specific immunomodulation |
| CN106456740B (zh) | 2014-05-02 | 2021-06-08 | Qu生物制药公司 | 抗微生物免疫调节 |
| EP3319635B1 (en) * | 2015-06-24 | 2021-04-21 | Immodulon Therapeutics Limited | A checkpoint inhibitor and a whole cell mycobacterium for use in cancer therapy |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8919321D0 (en) * | 1989-08-25 | 1989-10-11 | Univ London | Treatment of chronic inflammatory conditions |
| GB9203814D0 (en) * | 1992-02-21 | 1992-04-08 | Univ London | Treatment of long term auto-immune conditions |
-
1994
- 1994-03-30 GB GB9406301A patent/GB9406301D0/en active Pending
-
1995
- 1995-03-29 AU AU20785/95A patent/AU699081B2/en not_active Ceased
- 1995-03-29 CA CA002186851A patent/CA2186851C/en not_active Expired - Fee Related
- 1995-03-29 BR BR9507338A patent/BR9507338A/pt not_active Application Discontinuation
- 1995-03-29 AP APAP/P/1996/000861A patent/AP9600861A0/en unknown
- 1995-03-29 KR KR1019960705485A patent/KR100392582B1/ko not_active IP Right Cessation
- 1995-03-29 DE DE69526935T patent/DE69526935T2/de not_active Expired - Lifetime
- 1995-03-29 DK DK95913247T patent/DK0752870T3/da active
- 1995-03-29 ES ES95913247T patent/ES2177638T3/es not_active Expired - Lifetime
- 1995-03-29 WO PCT/GB1995/000715 patent/WO1995026742A1/en active IP Right Grant
- 1995-03-29 RU RU96119793A patent/RU2139728C1/ru not_active IP Right Cessation
- 1995-03-29 CZ CZ962801A patent/CZ280196A3/cs unknown
- 1995-03-29 EP EP95913247A patent/EP0752870B1/en not_active Expired - Lifetime
- 1995-03-29 NZ NZ282863A patent/NZ282863A/en not_active IP Right Cessation
- 1995-03-29 AT AT95913247T patent/ATE218355T1/de not_active IP Right Cessation
- 1995-03-29 JP JP52549795A patent/JP4135190B2/ja not_active Expired - Fee Related
- 1995-03-29 CN CN95193357A patent/CN1121874C/zh not_active Expired - Fee Related
- 1995-03-29 PT PT95913247T patent/PT752870E/pt unknown
- 1995-03-29 HU HU9602661A patent/HU220858B1/hu not_active IP Right Cessation
- 1995-03-30 ZA ZA952644A patent/ZA952644B/xx unknown
-
1996
- 1996-09-27 NO NO964075A patent/NO964075L/no not_active Application Discontinuation
- 1996-09-27 FI FI963866A patent/FI111223B/fi not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ATE218355T1 (de) | 2002-06-15 |
| AU2078595A (en) | 1995-10-23 |
| PT752870E (pt) | 2002-09-30 |
| ES2177638T3 (es) | 2002-12-16 |
| FI963866A (fi) | 1996-09-27 |
| KR100392582B1 (ko) | 2003-10-30 |
| GB9406301D0 (en) | 1994-05-25 |
| EP0752870A1 (en) | 1997-01-15 |
| AP9600861A0 (en) | 1996-10-31 |
| MX9604401A (es) | 1997-12-31 |
| FI963866A0 (fi) | 1996-09-27 |
| AU699081B2 (en) | 1998-11-19 |
| HU9602661D0 (en) | 1996-11-28 |
| DE69526935T2 (de) | 2002-09-19 |
| CZ280196A3 (en) | 1997-02-12 |
| DE69526935D1 (de) | 2002-07-11 |
| HUT75835A (en) | 1997-05-28 |
| JPH09511737A (ja) | 1997-11-25 |
| JP4135190B2 (ja) | 2008-08-20 |
| CA2186851A1 (en) | 1995-10-12 |
| CN1121874C (zh) | 2003-09-24 |
| RU2139728C1 (ru) | 1999-10-20 |
| NZ282863A (en) | 2001-06-29 |
| FI111223B (fi) | 2003-06-30 |
| KR970702057A (ko) | 1997-05-13 |
| ZA952644B (en) | 1996-01-11 |
| WO1995026742A1 (en) | 1995-10-12 |
| HU220858B1 (en) | 2002-06-29 |
| DK0752870T3 (da) | 2002-07-15 |
| NO964075L (no) | 1996-11-25 |
| EP0752870B1 (en) | 2002-06-05 |
| CA2186851C (en) | 2008-11-18 |
| NO964075D0 (no) | 1996-09-27 |
| BR9507338A (pt) | 1997-09-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1121874C (zh) | 免疫治疗剂及其应用 | |
| Matsuzaki et al. | Modulating immune responses with probiotic bacteria | |
| DE60032622T2 (de) | Zusammensetzung und verfahren zur krebs-antigen-immuntherapie | |
| JP3107568B2 (ja) | ブドウ膜炎の処置 | |
| EP0489072B1 (en) | Treatment of chronic inflammatory conditions | |
| GB2156673A (en) | Immunotherapeutic agents for treating mycobacterial disease | |
| JPH08508976A (ja) | 改善化免疫療法用組成物 | |
| CA2064029C (en) | Use of mycobacterium vaccae in the prevention of aids | |
| Yoon et al. | Vaccines against coccidioides | |
| US6056964A (en) | Immunotherapeutic agent and its use | |
| US6726913B1 (en) | Treatment of dermal tumors, warts, and viral infections of the respiratory tract in humans using heat-killed P. acnes | |
| Ryu et al. | Immunologic reactivity of a lipopolysaccharide-protein complex of type A Pasteurella multocida in mice | |
| CA2383626A1 (en) | Treatment of dermal tumors, warts, and viral infections using heat-killed p. acnes | |
| US6806253B2 (en) | Immunodulatory complex and use thereof in helicobacter diseases | |
| MXPA96004401A (es) | Agente inmunoterapeutico y su uso | |
| KR20010113691A (ko) | Ｍ．배키를 이용한 만성 바이러스 감염의 치료 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent of invention or patent application | ||
| CB02 | Change of applicant information |
Applicant after: Standord Rook Ltd. Applicant before: Univ. College London |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: LONDON UNIV. TO: STANFORD LOOK CORP. |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C19 | Lapse of patent right due to non-payment of the annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |