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Methods for making tumor specific antibodies and also methods of making gene products encoded by the microorganism as well as antibodies reactive therewith are provided. The recombinant vaccinia virus according to any one of the preceding claims, wherein the heterologous nucleic acid encodes a detectable protein or capable of inducing a detectable signal protein. An animal cells of the immune privilege eliminate, comprising administering to the animal a pharmaceutical composition of claim 18 or 19, whereby the virus accumulates in immune privilege of the cells, thereby mediating autoimmunity, resulting in elimination of the cell or reduce the number. The method of claim 20, wherein: the pharmaceutical composition comprises a vaccinia virus Lister strain, the Lister strain comprising a modified TK and HA gene and optionally F3 gene or locus containing modifications thereof; and the resulting virus in non-targeted organs do not accumulate to toxic levels. A method of treatment to eliminate the exemption animal immune cells or tissue, comprising: administering to the animal a microorganism, wherein: the microbial cells accumulate in immune privilege; the microbes in the animal's organs and tissues unaffected in does not accumulate and has a low toxicity; immune privilege of the microbial cell membrane resulting in leakage of the cell, so that the animals against the cells or cell products of autoantibodies. A microorganism used in pharmaceutical formulations for the elimination of animal immune privilege in the cells or tissues, wherein: the microbial cells accumulate in immune privilege; the microorganism is not included in the exemption immune cells or tissues organs and tissues does not accumulate to toxic levels. Microorganism of the present invention is provided with respect to the wild-type and typical modified to present one or more characteristics such as reduced pathogenicity, reduced toxicity, relative to normal tissues and organs and preferentially accumulate in tumors, increasing the immunogen resistance, increased ability to stimulate or enhance the immune response to tumor cells, an increased ability to dissolve or kill tumor cells, decreased ability to dissolve or kill tumor cells.1-14 and 32 according to any one of the recombinant virus, or (b) 33. Usually given a microorganism will stimulate an immune response to clear the microorganism, but immunologically privileged site is shielded or isolated with the immune system, such that the microorganisms survive and replicate normally.
020,794, filed January 28, entitled "the process for the diagnosis and treatment of tumors and microbial cells" ;. 02 012 552.2,2002 application on June 5, invented the name "for the diagnosis and treatment of inflammatory tissue associated with trauma or disease-emitting microorganisms and cells" When enabled, the full text of these applications and the reference. The present invention also includes other viruses corresponding loci, leading to when it is modified to reduce or eliminate toxicity when and / or enhanced accumulation in tumors (and non-tumor cells, tissues and organs relative ratio).与LIVP中F3基因相等同的其他病毒中的相应基因座可以通过病毒基因组中基因的结构定位确定：LIVP F3基因位于痘苗病毒的Hind III-F片段上，在开放读框F14L和F15L之间，由Goebel et al.，Virology(1990)179：247-266阐明，并且与ORFs F14L和F15L的方向相反；因此本发明包括其他病毒如痘病毒包括正痘病毒(orthopoxvirus)中的相应基因座。 With LIVP F3 gene in other viruses equivalent to the corresponding locus by the viral genome structural gene location determination: LIVP F3 gene is located on the Hind III-F fragment of vaccinia virus between open reading frames F14L and F15L, by .For example, in a study to carry non-metastatic colon cancer in nude mice injected systemically modified vaccinia virus WR strain, the modified vaccinia virus growth factor is a deletion and insertion of the thymidine kinase locus enhanced green fluorescent protein . As used herein, a microorganism with low toxicity means that on the basis of the given microorganism, the microorganism in the organs and tissues of the host does not accumulate to the extent that cause organ damage or injury or survival of the host is higher than the disease being treated degree of influence on the survival of the host.The treatment of the disease is one of the target tissue and / or cells are immune disease exemption (immunoprivileged), and the target tissue and / or cells, and usually their local environment to some extent, it is difficult to escape the immune system or close to the immune system. As used herein, animals include any animal, such as, but not limited to, primates, including humans, apes and monkeys; rodents, such as mice and rats; poultry, such as chickens; ruminants, such as goats, cattle, deer, sheep; and other animals, including pigs, horses, cats, dogs and rabbits.The microorganism is an attenuated bacterium, an attenuated viruses and mammalian cells, such as poxviruses (pox virus), and other cytoplasmic viruses, bacteria such as Vibrio (vibrio), Escherichia coli (E.coli), Salmonella (salmonella ), Streptococcus (streptococcus) and Listeria (listeria), and mammalian cells such as immune cells, including B cells and lymphocytes, such as TIL cells, and stem cells. In another class of marine arthropods found in the sea firefly luciferase catalyzed (Cypridina) (Vargula) luciferin oxidation, and the other luciferase catalytic Coleoptera (Coleoptera) luciferin oxidation.The method of recombinant vaccinia virus as follows: (a) generating vaccinia virus (i) contains a restriction site inserted at x modified F3 gene shuttle plasmid and (ii) in a dephosphorylated restriction sites digested wt VV (VGL ) DNA; (b) the construct of step a (i) mixtures and (ii) are transfected with psoralen -UV (PUV) - inactivated helper virus VV (VGL) infected host cell; (c ) separated from the transfectants described recombinant vaccinia virus. Luciferase is different in nature having one or more proteins with a naturally occurring protein naturally occurring in an organism or a variant or mutant thereof, said variant or mutant thereof, for example, by mutagenesis The variant of the thermal stability.Said method comprising administering (typically for systemic administration) A microorganism, the microorganisms preferentially accumulate in cells such as immune privilege of tumor cells, leading to proteins and other compounds such as tumor antigen leakage, resulting in a host, such as a tumor antigen against non-host proteins immunity, thereby eliminating the exemption immune cells such as tumor cells through the immune system of the host. For example, the compounds produced in the tumor can be, for example metabolite, or a polypeptide encoded by RNA, or a compound represented by the recombinant polypeptide (e.g., an enzyme), and tumor cell or immune system cells or tissues exemption produced.
The microorganism is not selected according to their ability to rapidly lyse the cells, but according to their accumulation in tumor cells such as immune privilege in an amount sufficient to cause leakage of the antigen for a sufficient length of time to stimulate an immune response and the ability to choose. As used herein, a delivery vehicle for administration refers to a lipid-based composition or other polymers, such as liposomes, micelles or reverse micelles, a microorganism associated with active substances such as the present invention provides for delivery to the host animal.
In particular, the present invention provides a recombinant vaccinia virus, comprising a modified TK and HA gene and optionally containing a modified F3 gene or locus, wherein the resulting virus in non-targeted organs not accumulate to toxic levels. Generally, for the practice of the method of the invention and when using the microorganisms provided herein, the original tumor is not excised, but is given for accumulating microorganisms, and become an antigen or other product or when the cells become dissolved when leakage factor. Percent homology or identity of proteins and / or nucleic acid molecules can be determined by comparing sequence information (e.g., Needleman et al, for example using the GAP computer program (1970) J. This difference can be interpreted as point mutations in the full length amino acid sequence randomly distributed, or they may be clustered in various lengths in one or more locations, the length may be up to the maximum allowable, e.g., 10/100 amino acid difference (approximately 90% identity).
In an exemplary embodiment, the Lister strain of vaccinia virus is a virus, especially LIVP strain virus (LIVP refers Lister virus from Moscow Institute of Viral Preparations, which is the origin of this now widely spread strains ). As used herein, angiogenesis refers to the overall process covers directly or indirectly involved in the establishment and maintenance of new blood vessels (neovascularization), including but not limited to, neovascularization associated with tumor formation and neovascularization associated with the trauma is formed.一般地，对序列(蛋白质或核酸)加以排列以便获得最高等级的匹配(见例如Computational Molecular Biology，Lesk，AM，ed.，Oxford University Press，New York，1988；Biocomputing：Informatics and Genome Projects，Smith，DW，ed.，Academic Press，New York，1993；Computer Analysis of Sequence Data，Part I，Griffin，AM，and Griffin，HG，eds.，Humana Press，New Jersey，1994；Sequence Analysis in Molecular Biology，von Heinje，G.，Academic Press，1987；及Sequence Analysis Primer，Gribskov，Devereux，J.，eds.，M Stockton Press，New York，1991；Carillo et al.(1988)SIAM JApplied Math 48：1073)。 In general, sequences (protein or nucleic acid) to be arranged in order to obtain the highest degree of matching (see e.g. In approximately 85-90% higher than the same level of homology or the results should not depend on the program and gap parameters series; this high level of homology generally do not rely on software and can be easily determined.
Thus the present invention also provides an animal by administering (generally non-human animals) the microorganism to produce a gene product, and harvesting the tumors to isolate the product of the method. Thus, relative to normal tissues or organs of immune privilege preferentially accumulate in tumor tissue as in the microorganism refers to higher than normal tissue or organ accumulation levels accumulate in tissues such as tumors in immune privilege microorganisms.
The present invention also provides a selection of proteins or producing anti-cellular products (e.g., metabolites or intermediates) antibody method, expression or produce a protein or other product of the microorganism by administering to the host (typically a non-human host), and harvesting and separating the serum or the antibody that specifically binds the protein product from a host other performed. As used herein, "compound" in a tumor or other immunologically privileged site refers to any compound produced in the tumor due to the presence of microorganisms introduced produced, the microorganism is generally a recombinant microorganism expressing one or more genes.
The present invention further provides elimination of animal immune cells such as tumor cells process (and the application of the microorganism) exemption, the method of the pharmaceutical composition is administered to an animal, whereby the virus accumulates in immune privilege of the cells, by This mediated autoimmunity, resulting in the elimination or reduction of the cell number. Computer Analysis of Sequence Data, Part I, Griffin, AM, and Griffin, HG, eds, Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, Devereux, J., eds, M Stockton Press, New York, 1991; Carillo et al (1988) SIAM JApplied Math 48:. Nucleic acid molecule is typically substantially homologous full-length sequences under moderately stringent or highly stringent conditions to a nucleic acid of interest, or at least about 70%, 80% or 90% sequence hybridize.任两个核酸分子是否具有至少80％、85％、90％、95％、96％、97％、98％或99％的核苷酸序列“相同性”，可以使用已知计算机算法如FASTA程序使用例如默认参数确定，如Pearson et al.(1988)Proc. As used herein, refers to the light emitting detectable EM radiation, generally when the UV energy of the excited state product release chemical processes generated when accompanied by light emission and restore its ground state, IR or visible EM radiation.