PL205786B1 - Nucleic acid, prokaryotic or eukaryotic host cell, mammalian anti-IL-12 antibodies and pharmaceutical compositions and uses thereof - Google Patents

Description

Description of the Invention The invention relates to nucleic acid encoding a mammalian anti-IL-12 antibody, a prokaryotic or eukaryotic host cell containing such nucleic acid, and a mammalian anti-IL-12 antibody, and pharmaceutical compositions containing such antibodies and their substances. used in diagnosis, prevention or treatment. BACKGROUND OF THE INVENTION Interleukin 12 (IL-12) is a heterodimeric cytokine containing 35 and 40 kD glycosylated polypeptide chains which are linked by a disulfide bridge. This cytokine is synthesized and secreted by antigen presenting cells, including dendritic cells, monocytes, macrophages, B cells, Langerhans cells and keratinocytes, as well as from NK cells. Natural killer). IL-12 mediates multiple biological processes and has been recognized as NK cell stimulating factor (NKSF), T cell stimulating factor, cytotoxic T cell maturation factor, and EBV transformed B cell line factor (Curfs, J. H. AND. J. , et al. , Clinical Microbiology Reviews, 10: 742-780 (1997)). Interleukin 12 can bind to the IL-12 receptor expressed on the plasma membrane of cells (e.g. T cells, NK cells), thus changing (e.g. by initiating, preventing) biological processes. For example, binding of IL-12 to the IL-12 receptor can stimulate the proliferation of previously activated T and NK cells, enhancing the cytolytic activity of cytotoxic T cells (CTL), NK cells and LAK cells (cytotoxic cells). of activated lymphokines a), inducing the production of interferon gamma (IFN GAMMA) by T cells and NK cells and inducing the differentiation of naive Th0 cells into Th1 cells that produce IFN GAMMA and IL-2 (Trinchieri, G. , Annual Review of Immunology, 13: 251-276 (1995)). In particular, IL-12 is important in the generation of cytolytic cells (e.g. NK, CTL) and in enhancing the cellular immune response (e.g. immune response mediated by Th1 cells). Thus, IL-12 is extremely important in generating and regulating both protective immunity (e.g. fighting infection) as well as pathological immune responses (e.g. autoimmunity) (Hendrzak, J. AND. and Brunda, M. J. , Laboratories Investigation, 72: 619-637 (1995)). Consequently, by manipulating the biological activity of IL-12 in vivo, e.g. protective or pathogenic). Non-human mammalian, chimeric, polyclonal (e.g. immune sera) and / or monoclonal antibodies (MAb) and fragments (e.g. proteolytic cuttings or protein fusion products) are potential therapeutic agents that are under investigation in some cases of treatment trials for certain diseases. However, such antibodies or fragments may elicit an immune response when administered to humans. Such an immune response may result in the removal of antibodies or fragments from the circulation by complexation by the immune system, making re-administration unsuitable for therapy, thereby reducing the therapeutic benefit for the patient and limiting the possibility of re-administration. antibody Ia or fragment. For example, the repeated administration of antibodies or fragments including fragments of non-human origin can lead to serum sickness and / or anaphylaxis. In order to avoid these and other problems, many approaches have been used to reduce the immunogenicity of such antibodies and fragments thereof, including chimera production and humanization, as well known in the art. However, these and other approaches may still result in some immunogenicity of the antibody fragments, their low affinity, low binding aspiration or problems with cell culture, upscaling, production and / or low yields. the process of receiving. Thus, such antibodies or fragments may be insufficiently adapted to be produced or used as therapeutic proteins. Hence, there is a need to provide 1 anti-IL-12 antibodies or fragments thereof that overcome at least one of these problems, as well as for improvement of known antibodies or fragments thereof. Summary of the Invention The present invention relates to a nucleic acid encoding a mammalian anti-IL-12 antibody having a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8. Preferably the antibody is a human antibody. Preferably the antibody has an affinity constant between 1 x 10 9 and 7 x 10 12. The invention further relates to a prokaryotic or eukaryotic host cell, characterized in that it comprises a nucleic acid as defined above. Preferably, the nucleic acid encodes human anti-IL-12 antibodies. Preferably the antibody has an affinity constant between 1 x 10 9 and 7 x 10 12. The invention also relates to mammalian anti-IL-12 antibodies having a heavy chain variable region with the sequence SEQ ID NO: 7 and a light chain variable region with the sequence SEQ ID NO: 8. Preferably it is a human antibody. Preferably, the antibody has an affinity constant between 1 x 10 9 and 7 x 10 12. The invention relates also to antibodies as defined above for use in diagnosis or treatment. The invention also relates to the antibodies as defined above for use in the treatment of psoriasis. The invention also relates to the antibodies as defined above for use in the treatment of psoriatic arthritis, sarcoidosis or Crohn's pathology. The invention further relates to a pharmaceutical composition, characterized in that it comprises: (a) the antibodies as defined above, and (b) a pharmaceutically acceptable carrier or diluent. The invention also relates to a pharmaceutical composition as defined above for use in diagnosis or treatment. The invention also relates to a pharmaceutical composition as defined above for use in the treatment of psoriasis. The invention also relates to a pharmaceutical composition as defined above for use in the treatment of psoriatic arthritis, sarcoidosis or Crohn's pathology. The present invention provides isolated anti-IL-12 Ia antibodies - human, primate, rodent, mammalian, chimeric, humanized and / or altered CDR? Domains, as well as compositions containing anti-IL-12 antibodies, encoding ace nucleic acids, host cells, pharmaceutical compositions and their uses as described and illustrated herein in conjunction with what is known in the art. The antibodies of the invention may be, but are not limited to, derived from a mammalian antibody including, but not limited to, human, mouse, rabbit, rat, rodent, primate, or combinations thereof, and the like. The present description discloses isolated nucleic acid molecules containing a complementary or hybridizing polynucleotide encoding at least one anti-idiotypic IL-12 antibody containing at least one specific sequence, domain, part or variant. . The present specification further discloses recombinant vectors containing nucleic acid molecules encoding the anti-idiotypic IL-12 antibodies, host cells containing such nucleic acids and / or recombinant vectors, as well as methods for their production and / or the use of such nucleic acids encoding anti-idiotype antibodies, vectors and / or host cells. The present specification also discloses that at least one method of expressing at least one anti-IL-12 1a antibody or anti-idiotypic IL-12 1a antibody in a host cell, comprising culturing the host cell described herein under conditions wherein the at least one antibody is anti-IL-12 is expressed in detectable and / or purifiable amounts. The present invention also provides that at least one composition comprising a (a) the isolated antibodies described herein and (b) a suitable carrier or diluent. The carrier or diluent may optionally be pharmaceutically acceptable according to known carriers and diluents. The composition may optionally contain at least one further ingredient, protein or composition. The present specification further discloses at least one method or composition with an anti-IL-12 antibody for administration in a therapeutically effective dose to modulate or treat at least one IL-12 related condition in a cell, tissue, organ, animal. or in a patient, before, after, or during the occurrence of the condition. The present specification also discloses that at least one composition, device, and / or method for delivering a therapeutically or prophylactically effective amount of at least one anti-IL-12 antibody of the present invention. The present specification further discloses at least one method or composition with an anti-IL-12 antibody for the diagnosis of at least one IL-12 related condition in a cell, tissue, organ, animal or patient, and / or before. , after or during this state. The present specification also discloses that at least one composition, device, and / or delivery method for the diagnosis of at least one anti-IL-12 antibody of the present invention. Description of the figures Fig. 1A and 1B are graphs showing the concentration-dependent binding of human anti-IL-12 mAbs to immobilized human IL-12. Anti-IL-12 la antibodies were serially diluted in 1% BSA / PBS and incubated for 1 hour at 37 ° C on rhIL-12 coated plates. Plates were washed twice with 0.02% Tween 20 (polyoxyethylene (20) sorbitan monolaurate), 0.15 M saline solution, and then hybridized at room temperature for 1 hour with probes in the form of a goat-specific antibody 1a against human IgG kappa labeled with horseradish peroxidase (HRP). Plates were washed again, developed with an o-phenylenediamine (OPD) substrate, and the optical gains (OD) of each well were measured at 490 nm. Fig. 2: Lines from left to right in Fig. A and B include human IL-12, human IL-12 p40, murine IL-12, and a stained size standard. Fig. 2A shows stained bands of the total white drug fraction. The strongest bands in each pathway are human IL-12 (75 kD), human IL-12 p40 (40 kD), and murine IL-12 (75 kD). Fig. 2B shows a Western filter prepared with a gel identical to that shown in Fig. 2A. The filter was reacted with C340 then HRP-labeled goat anti-human IgG and specifically detected only human IL-12 (monomer and multimers) and human IL-12 p40. A control filter (not shown) reacted with HRP labeled goat anti-human IgG will not reveal any bands. Fig. 3: PCR analysis with the step of reverse transcription of IFN gene expression? in human PBL treated with IL-2, IL-12, IL-2 + IL-12 with or without anti-IL-12 antibody Ia C340, isotype control Ia antibody 8. 6. 2. Total RNA was reverse transcribed, amplified by PCR using gene specific primers. The level of ß-actin mRNA in each sample was also determined, which is used as a control for the quality and composition of the mRNA. Fig. 4 is a histogram showing that human anti-IL-12 (C340) mAb inhibits interferon production? (IFNα) by the monocyte-depleted CD3 + peripheral blood mononuclear cells (PBMC) stimulated with IL-2 plus IL-12. PBMCs were cultured for five hours in control medium (no cytokines added), medium supplemented with IL-12 (0.1 ng / ml) plus IL-2 (50 IU / ml) (IL-12 / IL-2). ), control medium containing mAb C340 (10 µg / ml) and medium IL-12 / IL-2 containing mAb C340 (10 µg / ml). Intracellular IFN? was measured by two-color immunostaining with CD3-PE and IFNα-FITC. Data shown for one donor. Fig. 5 is a graph showing dose-dependent inhibition of IFN secretion? by stimulated IL-2 plus IL-12 peripheral blood lymphocytes in two different samples of human anti-IL-12 mAb (C340). Human PBL (8x10 6 / ml) were cultured for 24 hours with 10 U / ml IL-2, IL-2 plus 400 pg / ml IL-12 or IL-2 plus IL-12 and mAb C340 as stated checked. Cell culture supernatants were removed and tested for the presence of IFN? for help and the EIA. Fig. 6 is a histogram showing the dose-dependent inhibition of IL-12 plus IL-2 induced LAK cell cytotoxicity by the human anti-IL-12 mAb (C340). LAK effector cells (human PBL, 8x10 6 / ml) were cultured for 24 hours with IL-12 (400 pg / ml) plus IL-2 (10 U / ml) and mAb C340 (5000 ng / ml or 50 ng / ml). ml as indicated). LAK effector cells were washed and cultured for four hours with 51 Cr-labeled Raji target cells at an effector to target (E: T) ratio of 80: 1 and the amount of sc 51 Cr released into the medium after lysis of Raji cells was determined. The results are expressed as the standard error of the mean of three healthy donors. A positive control for IL-12 (IL-12) is effector cells incubated with and without IL-12 antibody. Tem (BKGD) are effector cells incubated without IL-12 or antibodies. Ia. Fig. 7A and 7B are histograms showing that IL-12 plus IL-2 induced CD95 expression on CD3 + peripheral blood mononuclear cells is inhibited by the human anti-IL-12 mAb (C340). PBMCs were cultured for 72 hours in medium containing 0.1 ng / ml IL-12 and a suboptimal dose of IL-2 (50 IU / ml) in the presence or absence of the C340 mAb (10 µg / ml). CD95 expression was measured by flow cytometry of anti-CD95-FITC stained cells. The gating was performed using two-color analysis (CD3 or CD56-PE versus CD95-FITC) and light scattering relative to perpendicular. Fig. 8 is a graph showing that recombinant human anti-human IL-12 antibodies (rC340) binds to immobilized IL-12 in a manner that is indistinguishable from purified mAb C340. The concentration of rC340 in the supernatant from the three rC340-producing recombinant cell lines was determined and the supernatants were assessed for IL-12 binding by ELISA. Plates were coated with 2 µg / ml human IL-12 and incubated with mAb C340 purified from the original hybridoma (standard) or from the supernatants of recombinant cell lines. IL-12 binding antibodies have been detected using goat anti-human IgG (heavy chain + light chain) conjugated to alkaline phosphatase. Fig. 9A-9C are graphs showing the growth kinetics and the amount of antibody Ia secreted by three independently derived subclones of a recombinant rC340 producing cell (Fig. 9A, subclone C379B; Fig. 9B, subclone C381A; Fig. 9C, subclone C389A). Recombinant cells were seeded in T75 flasks at an initial concentration of 2 x 105 cells / ml in standard media. At various points in time the cells were re-suspended and the number of viable cells and the amount (µg / ml) of rC340 in the medium were determined. Description of the Invention The present invention provides isolated, recombinant and / or synthetic anti-IL-12 antibodies - human, primate, rodent, mammalian, chimeric, humanized or altered CDRs, as well as compositions and encoding nucleic acid molecules containing ace at least one polynucleotide encoding at least one anti-IL-12 antibody of the invention. The present specification also discloses that, inter alia, the use of such l antibodies of the invention in diagnostic and therapeutic compositions, methods and devices. As used herein, the terms "anti-interleukin 12 antibody," "anti-IL-12 antibody," "anti-IL-12 antibody part" or "anti-IL-12 antibody fragment" and / or "antibody variant Ia." anti-IL-12 "and the like refer to any protein or peptide containing a molecule that consists of at least a portion of an immunoglobulin molecule, such as, but not limited to, a heavy complementarity determining region (CDR). or a light chain or ligand binding a fragment thereof, a heavy or light chain variable region, a heavy or light chain constant region, a framework region or any fragment thereof, or at least one fragment of the IL-12 receptor or a protein binding which may be included in the antibody of the present invention. Such an antibody may, moreover, optionally interact with a specific ligand, in such a way, without limiting it, that the antibody modulates, reduces, increases, acts in an antagonistic, agonistic, elevating, blocking, inhibiting, abolishing manner. and / or interferes with at least one activity or binding of IL-12 or with the activity or binding of IL-12 receptor, in vitro, in situ and / or in vivo. A non-limiting example is a suitable anti-IL-12 antibody, specific fragment or variant thereof, which may bind at least one IL-12, or specific fragments, variants or domains thereof. Suitable anti-IL-12 antibodies, specific fragment or variant thereof, may also optionally affect at least one activity or function of IL-12, other than the synthesis of RNA, DNA or protein in an unlimited manner. lka, IL-12 release, IL-12 receptor signaling, IL-12 membrane cut, sc activity of IL-12, production and / or synthesis of IL-12. In addition, it is suggested that the term "antibody 1" encompasses antibodies 1, digest fragments, specific fragments and variants thereof, including mimetics of antibody 1, or includes 1 fragments of antibody 1 which follow the structure and / or function of that the antibody or a specific fragment or portion thereof. Functional fragments include antigen-binding fragments that bind to mammalian IL-12. For example, IL-12 binding fragments or portions thereof include, but are not limited to, Fab fragments (e.g. by digestion of papain), Fab '(e.g. by digestion of pepsin and partial reduction of e) and F (ab ') 2 (e.g. by digestion of pepsin a), facb (e.g. by digestion of plasmin a), pFc '(e.g. by pepsin digestion or plasmin digestion), Fd (e.g. by digestion of pepsin, partial reduction and reaggregation), Fv or scFv (e.g. by molecular biology techniques), (see e.g. Colligan, Immunology, supra). Such fragments may be obtained by enzymatic cleavage, using synthetic or genetic recombination techniques which are known in the art and / or described herein. Antibodies 1a can be obtained in various truncated forms using the antibody 1 genes in which one or more stop codons have been introduced to the left of the natural end of translation site. For example, a gene combination encoding a heavy chain F (ab ') 2 fragment may be designed to contain DNA sequences encoding CH 1 domains and / or a heavy chain joining region. The various antibody fragments I can be chemically linked together using classical techniques or they can be obtained as a single protein fragment using genetic engineering techniques. The term "human antibody" as used herein refers to an antibody in which essentially every part of a protein (e.g. CDR, Framework Region, C L, CH domains (e.g. CH1, CH2, CH3), the acy junction region (V L, V H)) is essentially non-immunogenic for humans, with only slight sequence changes or deviations. Similarly, antibodies la designated as primate antibodies (ma lpa, baboon, chimpanzee, etc. ) rodents (mouse, rat, rabbit, guinea pig, hamster and the like) and other mammals indicate a given species, subgenus, genus, subfamilies and families. In addition, the chimeric antibodies contain combinations of the above. Such changes or deviations, optionally and preferably, suppress or reduce the immune response in humans or other species as compared to unmodified antibodies. Thus, a human antibody is different from a chimeric or humanized antibody. It should be emphasized that human antibodies may be produced by non-human animals or by a prokaryotic or eukaryotic cell that is capable of expressing functionally altered human immunoglobulin genes (e.g. heavy chain and / or light chain). In addition, if the human antibody is a single-chain antibody, it may contain a binding peptide that is not found in native human antibodies. For example, an Fv may contain a linking peptide, such as two to eight glycines or other amino acid residues that link a heavy chain variable region and a light chain variable region. Such linking peptides are considered to be of human origin. Bispecific, heterospecific, heteroconjugate or the like antibodies may also be used as monoclonal antibodies, especially human or humanized antibodies, which have binding specificities to at least two different antigens. In this case, one of the binding specificities is for at least one IL-12 protein, the other is for any other antigen. Methods for making specific antibodies I are known in the art. Traditionally, the recombinant production of bispecific I antibodies is based on the co-expression of two immunoglobulin pairs 1 heavy chain light chain, with the two heavy chains having different specificities (Milstein and Cuello, Nature 305: 537 (1983)). Due to the random assembly of heavy and light immunoglobulins, these hybridomas (quadromas) produce a potential mixture of 10 different antibody molecules, only one of which has the correct bispecific structure. Appropriate particle purification, which is usually done using affinity chromatography, is rather difficult and the yields are rather low. Similar procedures are disclosed in e.g. WO 93/08829, U.S. Patent Nos. 6210668, 6193967, 6132992, 6106833, 6060285, 6037453, 6010902, 5989530, 5959084, 5959083, 5932448, 5833985, 5821333, 5807706, 5643759, 5601819, 556582996, 549604976, 549604976, 549604976, , WO 92/00373, EP 03089, Traunecker et al. , EMBO J. 10: 3655 (1991), Suresh et al. , Methods in Enzymology 121: 210 (1986). Anti-IL-12 antibodies (also referred to as IL-12 antibodies) may be optionally characterized by high binding affinity to IL-12 and, optionally, low toxicity. In particular, the antibodies of the present invention are particularly useful in the present invention if their individual components, such as the variable region, constant region, framework region, each individually or all together in an optional and preferred manner have a low a immunogenno sc. The antibodies that may be used in the present invention are optionally characterized by their ability to be used in patients for an extended period of time with measurable improvement in disease symptoms and low and / or acceptable toxicity. Low or acceptable immunogenicity and / or high affinity, as well as other recommended properties, may contribute to the achievement of therapeutic results. "Low immunogenicity" is defined herein as significantly increasing HAHA, HACA or HAMA responses in less than about 75% or especially less than about 50% of treated patients and / or increasing low titer in treated patients (less than from about 300, especially less than about 100 when measured in a dual antigen enzymatic immunoassay) (Elliott et al. Lancet 344: 1125-1127 (1994). Use The isolated nucleic acids of the present invention may be viable to obtain at least one anti-IL-12 antibody or a specific variant thereof which may be viable to measure or affect a cell, tissue, organ or animal. e (including mammals and humans), for the diagnosis, monitoring, modulation, treatment, alleviation of suffering, as an aid in the prevention of the effects or the alleviation of disease symptoms of at least one IL-12 related disease state selected but not limited to an immune disorder or disease, a cardiovascular disorder or disease, an infectious, malignant or neurological tumor associated disorder or disease, or other known bug of the specified IL-12 related condition. Such a method may include administering an effective dose of a composition or pharmaceutical composition containing at least one anti-IL-12 antibody to a cell, tissue, organ, animal or patient in need of such modulation, treatment, alleviation from suffering, protecting or reducing symptoms, effects or mechanisms. An effective dose may be from about 0.001 to 500 mg / kg for single dose administration (e.g. as one large dose), multiple or continuous administration, or by single, multiple or continuous dosing, up to a concentration of 0.01-5000 µg / ml serum or any other range or value within therein, as done and determined using known methods as described herein or as known in the art. References All publications or patents cited herein show the state of the art at the time of the development of the present invention and / or provide a description and practice of the present invention. Publications relate to any scientific or patent publication or any other information in a media format, including recorded, electronic or printed format. The following references should be mentioned in particular: Ausubel et al. , ed. , Current Protocols in Molecular Biology, John Wiley & Sons, Inc. , NY, NY (1987-2001); Sambrook et al. , Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, NY (1989); Harlow and Lane, Antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989); Colligan, et al. , ed. , Current Protocols in Immunology, John Wiley & Sons, Inc. , NY (1994-2001); Colligan et al. , Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2001). Antibodies according to the present invention At least one anti-IL-12 antibody according to the present invention may optionally be produced by a cell line, a mixture of a cell line, an immortalized cell, or a clonal population of cells. mortal unions as is well known in the art. See e.g. Ausubel, et al. , pub. , Current Protocols in Molecular Biology, John Wiley & Sons, Inc. , NY, NY (1987-2001); Sambrook, et al. , Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor, NY (1989); Harlow and Lane, Antibodies, a Laboratory Manual, Cold Spring Harbor, NY (1989); Colligan, et al. , ed. , Current Protocols in Immunology, John Wiley & Sons, Inc. , NY (1994-2001); Colligan et al. , Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2001). Human antibodies, which are specific to the human IL-12 protein or fragments thereof, may be raised against a suitable immunogenic antigen, such as the isolated antigen and / or the IL-12 protein or fragment thereof (including synthetic drugs such as synthetic peptides). Other specific or general mammalian antibodies can be similarly elicited. The production of immunogenic antibodies and the production of monoclonal antibodies can be accomplished using any convenient technique. In one approach, a hybridoma is produced by fusing an appropriate immortalized cell line (e.g. a myeloma cell line such as, but not limited to, Sp2 / 0, Sp2 / 0-AG14, NSO, NS1, NS2, AE-1, L. 5, 243, P3X63Ag8. 653, Sp2 SA3, Sp2 MAI, Sp2 SS1, Sp2 SA5, U937, MLA 144, ACT IV, MOLT4, DA-1, JURKAT, WEHI, K-562, COS, RAJI, NIH 3T3, HL-60, MLA 144, NAMAIWA, NEURO 2A or the like, or hetero-myelomas, their fusion products, or any cell or cell fusion derived therefrom, or any suitable cell line known in the art. See e.g. www. atcc. org, www. lifetech. com and the like with antibody producing cells such as isolated or cloned cells of spleen, peripheral blood, lymph, tonsil, or other cells including cells of the immune system or B cells or any other cells expressing constant sequences or heavy or light chain variables or CDRs, both endogenous and heterologous nucleic acid, recombinant or endogenous, viral, bacterial, algae, prokaryotic, amphibian, insect, reptile , fish, mammalian, rodent, mono-hoof, goat, sheep, primate, eukaryotic, genomic DNA, cDNA, rDNA, mitochondrial DNA or RNA, chloroplast DNA or RNA, hnRNA, mRNA, tRNA, single-stranded, double-stranded, triple-stranded, hybridized and the like, or any combination thereof. See e.g. Ausubel, supra, and Colligan, Immunology, supra, chapter 2. Antibody-producing cells may also be obtained from peripheral blood or, more preferably, the spleen or lymph nodes of humans or other relevant animals that have been immunized with an antigen of interest. interests. Any other suitable host cell may be used for the expression of a heterologous or endogenous antibody-encoding nucleic acid, a specific fragment or variant thereof. Cell fusions (hybridomas) or recombinant cells can be isolated using selective culture conditions or other suitable known methods and cloned by dilution into single cells or by cell sorting or other known methods. Cells that produce antibodies with the desired specificity can be selected by using an appropriate label (e.g. ELISA test). Other suitable methods may be used to produce or isolate the antibody with the required specificity, including but not limited to methods for selecting a recombinant antibody from a peptide library or a protein library (for example, but not limited to, a bacteriophage library, ribozymes, oligonucleotides, RNA, cDNA or a similar display based library, e.g. available from Cambridge antibody Technologies, Cambridgeshire, UK; MorphoSys, Martinsreid / Planegg, DE; Biovation, Aberdeen, Scotland, UK; BioInvent, Lund, Sweden; Dyax Corp. , Enzon, Affymax / Biosite; Xoma, Berkeley, CA; Ixsys. See e.g. , EP 368,684, PCT / GB91 / 01134; PCT / GB92 / 01755; PCT / GB92 / 002240; PCT / GB92 / 00883; PCT / GB93 / 00605; US 08/350260 (5/12/94); PCT / GB94 / 01422; PCT / GB94 / 02662; PCT / GB97 / 01835; (CAT / MRC); WO90 / 14443; WO90 / 14424; WO90 / 14430; PCT / US94 / 1234; WO92 / 18619; WO96 / 07754; (Scripps); EP 614 989 (MorphoSys); WO95 / 16027 (BioInvent); WO88 / 06630; WO90 / 3809 (Dyax); USA 4,704,692 (Enzon); PCT / US91 / -02989 (Affymax); WO89 / 06283; EP 371 998; EP 550,400; (Xoma); EP 229 046; PCT / US91 / 07149 (Ixsys); or stochastically generated peptides or a drug - USA 5723323, 5763192, 5814476, 5817483, 5824514, 5976862, WO 86/05803, EP 590 689 (Ixsys, now Applied Molecular Evolution (AME), or which rely on the immunization of transgenic animals ( e.g. SCID mice, Nguyen et al. , Microbiol. Immunol. 41: 901-907 (1997); Sandhu et al. , Crit. Rev. Biotechnol. 16: 95-118 (1996); Eren et al. , Immunol. 93: 154-161 (1998), as well as related patents and uses that may result in the preparation of various human antibodies, as known in the art and / or described herein. Such techniques include, but are not limited to, ribosome display (Hanes et al. , Proc. Natl. Acad. Sci. USA, 94: 4937-4942 (May 1997); Hanes et al. , Proc. Natl. Acad. Sci. USA, 95: 14130-14135 (Nov. 1998)); technologies for obtaining antibodies from a single cell (e.g. a method of selecting an antibody from a selected lymphocyte ("SLAM") (US Patent No. 5627052, Wen et al. , J. Immunol. 17: 887-892 (1987); Babcook et al. , Proc. Natl. Acad. Sci. USA 93: 7843-7848 (1996)); Gel microdroplets and flow cytometry (Powell et al. , Biotechnol. 8: 333-337 (1990); One Cell Systems, Cambridge, MA; Gray et al. , J. Imm. Meth. 182: 155-163 (1995); Kennyetal. , Bio / Technol. 13: 787-790 (1995)); selection of B cells (Steenbakkers et al. , Molec. Biol. Reports 19: 125-134 (1994); Jonak et al. , Progress Biotech, Vol. 5, In vitro Immunization in Hybridoma Technology, Borrebaeck, ed. , Elsevier Science Publishers B. V. , Amsterdam, Netherlands (1988)). Methods for processing or humanizing non-human or human I antibodies may also be used and are well known in the art. Generally, a humanized or processed antibody has one or more amino acid residues from a source Ia that is non-human, e.g. but not limited to mice, rats, rabbits, non-human primates or other mammals. These human amino acid residues are often referred to as "import" residues, which are typically taken from an "import" variable, constant, or other domain of a known human sequence. Known human Ig sequences are disclosed, e.g. at www. ncbi. nlm. nih. gov / entrez / query. fcgi; www. atcc. org / phage / hdb. html; www. sciquest. com /; www. abcam. com /; www. antibodyresource. com / onlinecomp. html; www. public. iastate. edu / pedro / researchtools. html; www. mgen. uniheidelberg. de / SD / IT / IT. html; www. whfreeman. com / immunology / CH05 / kuby05. htm; www. library. thinkquest. org / 12429 / Immune / Antibody. html; www. hhmi. org / grants / lectures / 1996 / vlab /; www. path. cam. ac. uk / mrc7 / mikeimages. html; www. antibodyresource. com /; mcb. harvard. edu / BioLinks / Immunology. html. Www. immunologylink. com /; pathbox. wustl. edu / hcenter / index. html; www. biotech. ufl. edu / hcl /; www. pebio. com / pa / 340913/340913. html; www. nal. usda. gov / awic / pubs / antibody /; www. m. ehimeu. ac. jp / yasuhito / Elisa. html; www. biodesign. com / table. asp; www. icnet. uk / axp / facs / davies / links. html; www. biotech. ufl. edu / fccl / protocol. html; www. isacnet. org / sites ~ geo. html; aximtl. imt. unimarburg. de / rek / AEPStart. html; baserv. cut off. kunas. nl / jraats / linksl. html; www. recab. unihd. de / immuno. bme. nwu. edu /; www. mrccpe. cam. ac. uk / imt-doc / public / INTRO. html; www. ibt. unam. mx / vir / V ~ mice. html; imgt. cnusc. fr: 8104 /; www. biochem. ucl. ac. uk / martin / abs / index. html; antibody. bath. ac. uk /; abgen. cvm. tamu. edu / lab / www. abgen. html; www. unizh. ch / honegger / AH0seminar / Slide0l. html; www. cryst. bbk. ac. uW ~ ubog07s /; www. nimr. mrc. ac. uk / CC / ccaewg / ccaewg. htm; www. path. cam. ac. uk / mrc7 / humanisation / TAHHP. html; www. ibt. unam. mx / vir / structure / stataim. html; www. biosci. missouri. edu / smithgp / index. html; www. cryst. bioc. cam. ac. uk / fmolinaAVeb-pages / Pept / spottech. html; www. jerini. de / frproducts. htm; www. patents. ibm. com / ibm. html. Kabat et al. , Sequences of Proteins of Immunological Interest, U. NS. Dept. Health (1983), each of which are hereby incorporated by reference. Such imported sequences may be used to reduce immunogenicity or reduce, enhance or modify binding, affinity, binding rate, dissipation rate, binding avidity, half-life or any other suitable characteristic. as known in the art. In general, some or all of the human or non-human CDR sequences are conserved, while the variable or constant regions are replaced by amino acids in the human or other sequence. Antibodies can optionally be humanized while retaining a strong affinity for the antigen and other biological properties desired. To achieve this, humanized antibodies could be optionally prepared by a process of analyzing the starting sequences and the various humanized products developed using spatial starting sequence and humanized models. Sterile immunoglobulin models are widely available and are known to those skilled in the art. Computer programs are available which illustrate and represent the probable three-dimensional conformational structures of selected immunoglobulin sequences. A review of these representations allows for an analysis of the putative role of amino acid residues in the functioning of the selected immunoglobulin sequence, i.e. analyzes of amino acid residues that affect the ability of the selected immunoglobulin sequence to bind its antigen. In this way, the amino acid residues of the FR can be selected and linked to the consensus and imported sequences so that an appropriate antibody characteristic such as increased affinity for the antigen (s) is obtained. In general, the amino acid residues of the CDRs are directly and most significantly involved in influencing antigen binding. Humanizing or designing an antibody in accordance with the present invention may be performed using any known method, such as but not limited to that described in Winter (Jones et al. , Nature 321: 522 (1986); Riechmann et al. Nature 332: 323 (1988); Verhoeyen et al. , Science 239: 1534 (1988)), Sims et al. , J. Immunol. 151: 2296 (1993); Chothia and Lesk, J. Moth. Biol. 196: 901 (1987), Carter et al. , Proc. Natl. Acad. Sci. AT. NS. AND. 89: 4285 (1992); Presta et al. , J. Immune. 151: 2623 (1993), U.S. Patent Nos: 5,723,323, 5976862, 5,824,514, 5,817,483, 5,814,476, 5,763,192, 5,723,323, 5,766,886, 5,714,352, 6204023, 6,180,370, 5,693,762, 5,530,101, 5585089, 5,225,539; 4816567, PCT /: US98 / 16280, US96 / 18978, US91 / 09630, US91 / 05939, US94 / 01234, GB89 / 01334, GB91 / 01134, GB92 / 01755; WO90 / 14443, WO90 / 14424, WO90 / 14430, EP 229246. Anti-IL-12 antibodies may optionally be produced by immunizing a transgenic animal (e.g. mice, rat, hamster, non-human primates and the like) capable of producing a repertoire of human antibodies as described herein and / or as known in the art. Cells that produce human anti-IL-12 antibodies can be isolated from such animals and immortalized using suitable methods such as those described herein. Transgenic mice, which can produce the repertoire of human I antibodies that bind to human antigens, can be obtained by known methods (e.g. but not limited to U.S. Patent Nos .: 5,770,428, 5,569,825, 5,545,806, 5,625,126, 5,625,825, 5,633,425, 5,661,016, and 5,789,650 to Lonberg et al. ; Jakobovits et al. WO 98/50433, Jakobovits et al. WO 98/24893, Lonberg et al. WO 98/24884, Lonberg et al. WO 97/13852, Lonberg et al. WO 94/25585, Kucherlapate et al. WO 96/34096, Kucherlapate et al. EP 0463 151 B1, Kucherlapate et al. EP 0710 719 Al, Surani et al. U.S. Patent No. 5,545,807, Bruggemann et al. WO 90/04036, Bruggemann et al. EP 0438 474 B1, Lonberg et al. EP 0814 259 A2, Lonberg et al. GB 2 272 440 A, Lonberg et al. Nature 368: 856-859 (1994), Taylor et al. , Int. Immunol. 6 (4) 579-591 (1994), Green et al. Nature Genetics 7: 13-21 (1994), Mendez et al. , Nature Genetics 15: 146-156 (1997), Taylor et al. , Nucleic Acids Research 20 (23): 6287-6295 (1992), Tuaillon et al. , Proc Natl Acad Sci USA 90 (8) 3720-3724 (1993), Lonberg et al. , Int Rev Immuzlol 13 (l): 65-93 (1995) and Fishwald et al. , Nat Biotechnol 14 (7): 845-851 (1996). Generally, these mice contain at least one transgene containing DNA from at least one human immunoglobulin locus that has been functionally rearranged or that can undergo a functional rearrangement. Endogenous immunoglobulin loci in such a mouse can be damaged or removed to eliminate the animal's ability to produce antibodies from endogenous genes. Screening for 1 antibody to find specific binding to similar proteins or fragments can be performed using peptide display libraries. This method consists in searching large collections of peptides in order to find individual members of peptides having the desired function or structure. Antibody screening of such peptide display libraries is well known in the art. The presented peptide sequences may be 3 to 5,000 or more amino acids long, often 5 to 100 amino acids long, and most often about 8 to 25 amino acids long. In addition to methods for generating peptide libraries directly by chemical synthesis methods, several methods using recombinant DNA have been described. One type is the presentation of a peptide sequence on the surface of a bacteriophage or cell. Each bacteriophage or cell contains a nucleotide sequence that encodes the individual peptide sequences displayed. Such methods are described in PCT Patent Publication Nos. 91/17271, 91/18980, 91/19818, and 93/08278. Other systems for producing peptide libraries have aspects of both chemical synthesis and recombinant DNA methods. See Patent Publication Nos. 92/05258, 92/14843 and 96/19256. See also U.S. Patent Nos. 5,658,754 and 5,643,768. Peptide libraries, vectors, and screening kits are commercially available from suppliers such as Invitrogen (Carlsbad, CA) and Cambridge Antibody Technologies (Cambridgeshire, UK). See e.g. U.S. Patent Nos. 4,704,692, 4,939,666, 4,946,778, 5,260,203, 5,455,030, 5,518,889, 5,534,621, 5,656,730, 5,763,733, 5,766,260, 5,856,456 to Enzon; 5223409, 5403484, 5571698, 5837500 to Dyax, 5427908, 5580717 to Affymax; 5,885,793 to Cambridge Antibody Technologies; 5750373 to Genentech, 5618920, 5595898, 5576195, 5698435, 5693493, 5698417 to Xoma, Coligan, supra; Ausubel, as above; or Sambrook, supra. The antibodies of the present invention may be prepared using at least one anti-IL-12 antibody encoding nucleic acid for delivery to transgenic animals or mammals such as goats, cows, horses, sheep and the like that produce such antibodies in their milk. Such animals can be obtained using known methods. See e.g. but not limited to, U.S. Patent Nos. 5,827,690; 5,849,992; 4,873,316; 5,849,992; 5994616; 5,565,362; 5304489 and the like. The antibodies of the present invention may further be prepared using at least one anti-IL-12 antibody-encoding nucleic acid for delivery to transgenic plants and cultured plant cells (e.g. but not limited to tobacco and corn) which produce such antibodies, specific fragments or variants in cells or parts of plants grown therefrom. As a non-limiting example, leaves of transgenic tobacco expressing recombinant proteins have been successfully used to obtain large amounts of recombinant proteins, e.g. using an inducible promoter. See e.g. Cramer et al. , Curr. Top. Microbol. Immunol. 240: 95-118 (1999) and references cited therein. Thus, the transgenic maize has been used for the industrial expression of mammalian proteins whose biological activities are equivalent to proteins obtained in other recombinant systems or purified from natural sources. See, e.g. , Hood et al. , Adv. Exp. Med. Biol. 464: 127-147 (1999) and references cited therein. Antibodies have also been obtained in abundance from transgenic plant seeds, including antibody fragments of I, such as single chain antibodies (scFv's), including tobacco seeds and potato tubers. See e.g. Conrad et al. , Plant Mol. Biol. 38: 101-109 (1998) and references cited therein. Thus, the antibodies according to the present invention can also be obtained using transgenic plants according to known methods. See it with e.g. Fischer et al. , Biotechnol. Appl. Biochem. 30: 99-108 (Oct. , 1999), Ma et al. , Trends Biotechnol. 13: 522-7 (1995); Ma et al. , Plant Physiol. 109: 341-6 (1995); Whitelam et al. , Biochem. Soc. Trance. 22: 940-944 (1994) and references cited therein. The antibodies according to the present invention can bind to human IL-12 with a high affinity range (K D). In a preferred embodiment, at least one human mAb of the present invention may optionally bind to human IL-12 with high affinity. For example, a human mAb may bind human IL-12 with a K D equal to or less than 10 -7 M, such as but not limited to 0.1-9.9 (or any range or value sc of the following) X 10-7, 10-8, 10-9, 10-10, 10-11, 10-12, 10-13 or any range or value therein. The affinity or tendency of an antibody to bind an antibody for an antigen can be experimentally determined using an appropriate method. (See, for example, Berzofsky, et al. , "Anti-body-Antigen Interactions" in Fundamental Immunology, Paul, W. E. , Ed. , Raven Press: New York, NY (1984); Kuby, Janis Immunology, W. H. Freeman and Company: New York, NY (1992); and methods described here). The measured affinity of the individual antibody-antigen interactions may vary when measured under different conditions (e.g. salt concentration, pH). Thus, measurements of affinity and other antigen binding parameters (e.g. K D, K a, K d) are preferably made in standardized antibody Ia and antigen solutions, such as the buffer described herein. Nucleic Acid Molecules A nucleic acid molecule of the present invention that encodes at least one anti-IL-12 antibody can be obtained using methods described herein or known in the art. The nucleic acid molecules of the present invention may be in the form of RNA, such as mRNA, hnRNA, tRNA or any other form thereof, or in the form of DNA, including, but not limited to, cDNA, genomic DNA obtained by cloning or synthesized or any combination thereof. The DNA can be three-stranded, double-stranded, or single-stranded, or any combination thereof. Any fragment of at least one strand of DNA or RNA may be a coding strand, known to be a sense strand, or it may be a non-coding strand, also called an antisense strand. Isolated nucleic acid molecules disclosed herein may include nucleic acid molecules containing an open reading frame (ORF), optionally with one or more introns, e.g. but not limited to at least one specific fragment of at least one CDR region such as CDR1, CDR2 and / or CDR3 of at least one heavy chain (e.g. SEQ ID NO: 1-3) or a light chain (e.g. SEQ ID NO: 4-6); Nucleic acid molecules containing an anti-IL-12 antibody coding sequence or a variable region (e.g. SEQ ID NO: 7, 8) and a nucleic acid molecule that contains a nucleotide sequence substantially different from those described above, but which, due to the degeneracy of the genetic code, still encodes at least one anti-IL-12 antibody as described here and / or is known in the art. Of course, the genetic code is well known in the art. Thus, it is routine for one skilled in the art to generate degenerate nucleic acid variants that encode specific anti-IL-12 antibodies of the present invention. See e.g. Ausubel, et al. as above. Non-limiting examples of isolated nucleic acid molecules include the sequences SEQ ID NOs: 1-8 corresponding to the non-limiting examples of nucleic acid encoding HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, LC, respectively. CDR3, HC variable region and LC variable region. As described herein, nucleic acid molecules of the present invention that contain a nucleic acid encoding an anti-IL-12 antibody may include, but are not limited to, molecules alone encoding the amino acid sequence of an antibody fragment of 1a; coding sequences encoding all or part of the antibody; sequences encoding the antibody, a fragment or part thereof, as well as additional sequences, such as the sequence encoding at least one leader signal or fusion protein, with or without the above-mentioned additional coding sequences, such as at PL 205 786 B1 12 at least one intron, together with additional non-coding sequences, including, but not limited to, 5 'and 3' non-coding sequences, such as transcribed but untranslated sequences that play a role in transcription, mRNA processing, including intron excision and polyadenylation signals (for example, ribosome binding and mRNA sc stability); an additional coding sequence that codes for additional amino acids, such as those that provide additional functions. Thus, an antibody coding sequence may be fused to a tag sequence, as can a peptide coding sequence which facilitates purification of the fused antibody containing a fragment or part of the antibody. Polynucleotides Which Selectively Hybridize To A Polynucleotide As Described Here The present specification discloses isolated nucleic acids that hybridize under selectively hybridizing conditions to a polynucleotide disclosed herein. Thus, such polynucleotides may be used to isolate, detect and / or measure the quantity of nucleic acids containing such polynucleotides. For example, polynucleotides can be used to identify, isolate, or amplify partial or full-length clones in a deposited library. In some embodiments, the polynucleotides are isolated genomic or cDNA sequences, or on the contrary, complementary to cDNAs from a human or mammalian nucleic acid library. Preferably, the cDNA library contains at least 80% of the full-length sequences, in particular 85% or 90% of the full-length sequences, and in particular at least 95% of the full-length sequences. CDNA libraries can be normalized to increase the representation of rare sequences. Low or intermediate hybridization conditions are typically, but not limited to, applied to sequences having a reduced sequence identity with respect to the complementary sequences. Moderate or stringent hybridization conditions can be optionally used for sequences of higher identity. The mild hybridization conditions allow for the selective hybridization of sequences having about 70% identity and can be used to identify ortholog or paralog sequences. Optionally, the polynucleotides will encode at least a portion of the antibody encoded by the polynucleotides described herein. Polynucleotides include nucleic acid sequences that can be used for selectively hybridizing to a polynucleotide encoding an antibody of the present invention. See e.g. Ausubel, as above; Colligan, as above. Construction of Nucleic Acids The isolated nucleic acids of the present invention may be produced using (a) genetic recombination methods, (b) synthetic techniques, (c) purification techniques, or combinations thereof, as is well known in the art. Nucleic acids may conveniently include sequences additional to the polynucleotide of the present invention. For example, a multiple cloning site containing one or more endonuclease cut sites can be added to a nucleic acid to facilitate isolation of the polynucleotide. So that translated sequences may be added to facilitate the isolation of the translated polynucleotide of the present invention. For example, the tag with the sequence of six histidines provides a convenient method of protein purification according to the present invention. The nucleic acid of the present invention, excluding coding sequences, is optionally a vector, adapter or linker for the cloning and / or expression of a polynucletotide according to the present invention. Additional sequences may be added to the cloning and / or expression sequences to optimize their cloning and / or expression functions, to facilitate polynucleotide isolation, or to improve the introduction of the polynucleotide into the cell. The use of cloning vectors, expression vectors, adapters and linkers is well known in the art. (See e.g. Ausubel, as above; or Sambrook, supra). Genetic recombination methods used for the construction of nucleic acids. . In certain embodiments, oligonucleotide probes that hybridize selectively under stringent hybridization conditions to the polynucleotides of the present invention are used to identify a given sequence in a cDNA or genomic DNA library. RNA isolation and construction of cDNA and genomic libraries are well known to those skilled in the art. (See, e.g. Ausubel, as above; or Sambrook, supra). Methods for the Isolation and Screening of Nucleic Acids A cDNA or genomic library may be screened using a probe prepared on the basis of the polynucleotide sequence of the present invention, such as those disclosed herein. Probes may be used to hybridize with genomic DNA or cDNA sequences to isolate homologous genes in the same or different organisms. Those skilled in the art will appreciate that different levels of stringency of hybridization conditions can be used in this method; both the hybridization solution and the scavenging solution can be strong enough. As the stringency of hybridization conditions increases, the degree of complementarity must increase between the probe and its target for duplex formation to occur. The degree of stringency of the hybridization conditions may be controlled by one or more parameters such as temperature, ionic strength, pH, and the presence of a partially denaturing solvent such as formamide. For example, the stringency of sc hybridization is conveniently altered by changing the polarity of the reaction solution, manipulating the formamide concentrations ranging from 0 to 50%. The degree of complementarity (sequence identity) required for detectable binding will vary with changes in the stringency of the hybridization solution and / or the gap solution. The degree of complementarity will be optimally 100%, 70-100% or any range or value specified therein. However, it should be understood that minor sequence changes in the probes and primers can be compensated for by reducing the stringency of the hybridization solution and / or the gap. RNA or DNA amplification methods are well known in the art and can be used in the present invention without undue experimentation, based on the information and guidance provided herein. Known methods for amplifying DNA or RNA include, but are not limited to, chain polymerase reaction (PCR) and related amplification processes (see e.g. U.S. Patent Nos. 4,683,195, 4,683,202, 4,800,159, 4,965,188 to Mullis, et al. ; 4,795,699 and 4,921,794 to Tabor, et al; 5,142,033 to Innis; 5122464 for Wilson, et al. ; 5,091,310 to Innis; 5,066,584 to Gyllensten, et al; 4,889,818 to Gelfand, et al; 4,994,370 to Silver, et al; 4,766,067 to Biswas; 4,656,134 to Ringold) and RNA-mediated amplification, which uses antisense RNA to the target sequence as a template for the synthesis of double-stranded DNA (US Patent No. 5,130,238 to Ma Lek, et al., Under the trade name NASBA). (See e.g. Ausubel, as above; or Sambrook, supra. ) For example, polymerase chain reaction (PCR) technology can be used to amplify the polynucleotide sequences of the present invention and related genes directly from genomic DNA or cDNA libraries. PCR and other in vitro amplification methods may be useful, for example, to clone nucleic acid sequences that encode expressed proteins, to use nucleic acids as probes to detect the presence of a given mRNA in samples, for sequencing nucleic acids or for other purposes. Examples of techniques sufficient to introduce those skilled in the art to in vitro amplification methods can be found in Berger as above, Sambrook as above, and Ausubel as above, as well as in Mullis, and co. , US Patent No. 4,683,202 (1987); and Innis, et al. , PCR Protocols A Guide to Methods and Applications, Ed. , Academic Press Inc. , San Diego, CA (1990). Commercial kits for genomic DNA amplification by PCR techniques are known in the art. See, e.g. Advantage-GC Genome PCR Kit (Clontech). Moreover, the protein gene 32 T4 (Boehringer Mannheim) can be used to improve the yield of long PCR products. Synthetic methods for the construction of nucleic acids The isolated nucleic acids according to the present invention can also be prepared by known methods by direct chemical synthesis (see e.g. Ausubel, et al. , as above). Chemical synthesis generally produces a single-stranded oligonucleotide that can be converted to double-stranded DNA by hybridization with a complementary sequence, or by polymerization using DNA polymerase using a single nothing as templates. One skilled in the art will recognize that while chemical DNA synthesis may be limited to about a hundred or more nucleotides, longer sequences can be obtained by ligation of shorter sequences. Recombinant expression cassettes The present specification further discloses recombinant expression cassettes containing the nucleic acid of the present invention. A nucleic acid sequence according to the present invention, for example a cDNA or genomic sequence encoding an antibody according to the present invention, can be used to construct a recombinant expression cassette that can be introduced into at least one desired cell. the host. The recombinant expression cassette will typically contain the polynucleotide of the present invention operably linked to transcription initiation regulatory sequences that will control the transcription of the polynucleotide in the host cell used. Both heterologous and non-heterologous promoters (e.g. endogenous). In some embodiments, the isolated nucleic acids are loose as a promoter, transcription enhancer, or other elements that can be joined at an appropriate position (right, left, or intron) in a non-heterologous form of the polynucleotide of the present invention so as to enhance or by reducing the expression of a polynucleotide according to the present invention. For example, endogenous promoters can be altered in vivo or in vitro by mutations, deletions and / or substitutions. Vectors and Host Cells Also disclosed herein are vectors that contain isolated nucleic acid molecules of the present invention, host cells into which recombinant vectors are introduced, and the production of at least one anti-IL-12 antibody by recombi techniques. - genetic nation, as is well known in the art. See e.g. Sambrook, et al. , as above; Ausubel, et al. , as above. The polynucleotides may optionally be linked to a vector containing a selectable label expressed in a host. Generally, the plasmid vector is introduced in a precipitate, such as a calcium phosphate precipitate, or in a complex with a charged lipid. If the vector is a virus, it can be packaged in vitro using an appropriate packaging cell line and then transduced into host cells. The DNA insert should be operably linked to an appropriate promoter. The expression constructs will furthermore contain transcription initiation and termination sites and, in the transcription region, a ribosome binding site needed for translation. The coding part of the mature transcripts expressed from the constructs would be preferred to include a translation initiation codon at the beginning and a stop codon (e.g. UAA, UGA or UAG) suitably placed at the end of the translated mRNA, with the codons of the UAA and UAG being preferred when expressed in a mammalian or eukaryotic cell. Expression vectors will be preferred, but may optionally contain at least one selectable marker. Such tags include, for example, but not limited to, for eukaryotic cell culture, methotrexate resistance (MTX) resistance genes, dihydrofolate reductase (DHFR, U.S. Patent Nos. 4,399,216; 4,634,665; 4,656,134; 4,956,288; 5,149,636; 5,179,017), G418), mycophenolic acid, or glutamine synthetase (GS, US Pat. Nos. 5,122,464; 5,770,359; 5,827,739) and in the case of E. coli and other bacteria or prokaryotic cells resistance genes to tetracyclines or ampicillins. Suitable media and culture conditions for all host cells described above are known in the art. Suitable vectors can easily be identified by one skilled in the art. The introduction of a vector construct into the host cell may take place by calcium phosphate transfection, DEAE-dextran mediated transfection, cationic lipid mediated transfection, electroporation, transduction, infection or other known ways. Such methods are described in the art, e.g. Sambrook, supra, chapters 1-4 and 16-18; Ausubel, as above, chapters 1, 9, 13, 15, 16. At least one antibody according to the present invention may be expressed in an altered form, such as a fusion protein, and may contain not only secretion signals but additionally heterologous functional regions. For example, a region of additional amino acids, especially on charged amino acids, may be added to the N-terminus of an antibody to improve stability and stability in the host cell during purification or during subsequent processing and storage. . Peptide fragments could also be added to the antibody to facilitate purification. Such regions may be removed prior to the final preparation of the antibody or at least one fragment thereof. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, chapter 17. 29-17. 42 and 18. 1-18. 74; Ausubel, as above, chapters 16, 17 and 18. Those skilled in the art are familiar with the numerous expression systems capable of expressing the nucleic acid encoding the protein of the present invention. Alternatively, the nucleic acids of the present invention may be expressed in host cells by assembly (by manipulation) in a host cell that contains endogenous DNA encoding the antibodies of the present invention. Such methods are well known in the art, e.g. as described in US Patent Nos. 5,580,734, 5,641,670,5733746, and 5,733,761, all incorporated herein by reference. Mammalian cells are exemplary cell cultures useful for the production of antibodies, specific fragments or variants thereof. Mammalian cell systems are often used in the form of a monolayer of cells, although suspension or mammalian cell bioreactors are also used. A number of suitable host cell lines capable of expressing intact glycosylated proteins have been developed in the art, including COS-1 cell lines (e.g. ATCC CRL 1650), COS-7 (e.g. ATCC CRL1651), HEK293, BHK21 (e.g. ATCC CRL-10), CHO (e.g. ATCC CRL 1610) and BSC-1 (e.g. ATCC CRL-26), Cos-7 cells, CHO cells, hep G2 cells, P3X63Ag8 cells. 653, SP2 / 0-Agl4, 293, HeLa cells and the like which are readily available from, for example, the American Type Culture Collection, Manassas, Va (www. atcc. org). Preferred host cells include: cells of lymphoid origin, such as myeloma and lymphoma cells. P3X63Ag8 cells are particularly preferred host cells. 653 (ATCC Accession Number CRL-1580) and cells SP2 / 0-Agl4 (ATCC Accession Number CRL-1851). In a particularly preferred embodiment, the recombinant cell is a P3X63Ab8 cell. 653 or SP2 / 0-Agl4. Expression vectors for these cells may contain one or more of the following expression control sequences such as, inter alia, an origin of replication, a promoter (e.g. SV40 late or early promoters, CMV promoter (US Patent Nos. 5,168,062; 5,385,839), HSV tk promoter, pgk promoter (phosphoglycerol kinase), EF-1 alpha promoter (US Patent No. 5,266,491), at least one human immunoglobulin promoter; transcription enhancer, and / or sites containing mRNA processing information, such as ribosome binding sites, RNA intron excision sites, polyadenylation sites (e.g. poly (A) addition site from large Ag T) and transcription termination sequences. See, e.g. Ausubel et al. , as above; Sambrook, et al. , as above. Other cells useful in the production of the nucleic acids or protein of the present invention are known and / or available, for example, from the American Type Culture Collection of Cell Lines and Hybridomas (www. atcc. org) or other known or commercial sources. In the case of eukaryotic host cells, polyadenylation or transcription termination sequences are usually ligated into the vector. An example of a terminator sequence is the polyadenylation sequence from the bovine growth hormone gene. Sequences for the exact splicing of introns from the transcript so that they can be linked. An example of an intron excision sequence is the VP1 intron from SV40 (Sprague, et al. , J. Virol. 45: 773-781 (1983)). In addition to the vector, gene sequences that control replication in the host cell may be linked, as is known in the art. Purification of antibody IA anti-IL-12 antibody can be recovered and purified from recombinant cell culture by well-known methods, including, but not limited to, protein A purification, ammonium sulfate precipitation, or ethanol, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxyapatite chromatography and lectin chromatography. High performance liquid chromatography ("HPLC") can also be used for purification. See, e.g. Colligan, Current Protocols in Immunology or Current Protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2001), e.g. chapters 1, 4, 6, 8, 9, 10. Antibodies according to the present invention include: naturally purified products, products of chemical synthesis procedures, and products obtained by genetic recombination techniques from a eukaryotic host, including, for example, yeast cells, higher plants, insects, and mammals. cows. Depending on the host used in the production procedure using genetic recombination techniques, the antibodies of the present invention may or may not be glycosylated, with glycosylation being preferred. Such methods are described in many standard laboratory manuals, such as Sambrook, supra, section 17. 37-17. 42; Ausubel, as above, chapters 10, 12, 13, 16, 18, and 20, Colligan, Protein Science, as above, chapters 12-14. Anti-IL-12 Ia Antibodies The isolated Ia antibodies of the present invention include any antibodies encoded by any of the polynucleotides of the present invention, as further described herein, or any isolated or obtained antibodies. Preferably, human antibodies bind to human IL-12 and thus partially or substantially neutralize at least one biological activity of the protein. Antibodies that partially or advantageously substantially neutralize at least one biological activity of the at least one IL-12 protein or fragment thereof may bind the protein or fragment thereof and thus inhibit the activity of dependent from binding of IL-12 to the IL-12 receptor or by other IL-12 dependent mechanisms or mediated by IL-12. The term "neutralizing antibodies" as used herein refers to an antibody that can inhibit IL-12 dependent activity by about 20-120%, especially by at least about 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100% or more depending on the designation. The ability of sc anti-IL-12 anti-IL-12 to inhibit IL-12 dependent activity is preferably estimated from at least one appropriate IL-12 protein or receptor assay as described herein and / or as known herein. in the field. Human antibodies according to the present invention can be of any class (IgG, IgA, IgM, IgE, IgD, etc. ) or isotype and may contain the entire light chain kappa or lambda. In one embodiment, the human antibody comprises a heavy IgG chain or a defined fragment, for example at least one of the isotypes IgG1, IgG2, IgG3, or IgG4. Antibodies of this type may be obtained by using a transgenic mouse or other non-human transgenic mammal containing at least one transgene encoding a human light chain (e.g. IgG, IgA and IgM (e.g. Α1, β2, β3, β4) as described herein and / or known in the art. In another embodiment, human anti-human IL-12 antibodies comprise an IgG1 heavy chain and an IgG1 light chain. At least one antibody according to the present invention binds to at least one specific epitope specific for at least one IL-12 protein, subunit, fragment, portion, or any combination thereof. The at least one epitope may contain at least one antibody-binding region that contains at least one fragment of the protein, the epitope of which is preferably composed of at least one extracellular, soluble, hydrophilic, external or cytoplasmic fragment of this protein. The at least one specified epitope may contain any combination of at least one amino acid sequence of at least 1-3 amino acids appended to the entire specified fragment of the full amino acid sequence of SEQ ID NO: 9. Antibodies according to the invention can be obtained by chemically linking together different fragments of the antibody (e.g. CDR region, framework region) using conventional techniques, by producing and expressing a nucleic acid molecule (i.e. one or more) encoding an antibody by conventional recombinant DNA techniques or by the use of other suitable technique. The anti-IL-12 antibody comprises a heavy chain variable region, optionally with the amino acid sequence of SEQ ID NO: 7, and a light chain variable region with the amino acid sequence of SEQ ID NO: 8. Antibodies that bind to human IL-12 and that contain a defined heavy or light chain variable region can be obtained using suitable methods such as phage display (Katsube, Y. , et al. , Int J Mol Med, 1 (5): 863-868 (1998)) or methods using transgenic animals as known in the art and / or described herein. For example, a transgenic mouse containing a functionally rearranged human immunoglobulin heavy chain transgene and a transgene containing DNA from a human immunoglobulin light chain locus may be immunized with human IL-12 or a fragment thereof to induce the production of antibody. If desired, the antibody-producing cells can be isolated and hybrids or other immortalized antibody-producing cells can be created as described herein and / or known in the art. Alternatively, an antibody, a specific fragment or variant thereof may be expressed using an encoding nucleic acid or a fragment thereof in an appropriate host cell. Preserved amino acid substitutions involve the replacement of one amino acid by another amino acid that has chemical and / or physical properties (e.g. charge, structure, polarity, hydrophobic sc / hydrophilic sc), which are similar to those in the specificity of the first amino acid. Conserved substitutions include replacing one amino acid with another from the following groups: lysine (K), arginine (R), and histidine (H); aspartic acid (D) and glutamic acid (E); aspartine (N), glutamine (Q), serine (S), threonine (T), tyrosine (Y), K, R, H, D and E; alanine (A), valine (V), leucine (L), isoleucine (I), proline (P), phenylalanine (F), tryptophan (W), methionine (M), cysteine (C) and glycine (G); F, W and Y; C, S and T. Amino Acid Codes The amino acids that make up the anti-IL-12 antibodies in accordance with the present invention are often abbreviated. Amino acid names may be given by amino acid designation as one letter code, three letter code, full name, or three nucleotide codon (s) as is well understood in the art (see Alberts, p. B. , et al. , Molecular Biology of The Cell, Ed. third, Garland Publishing, Inc. , New York, 1994): One-letter code Three-letter code Name Trinucleotide codons A Ala Alanine GCA, GCC, GCG, GCU C Cys Cysteine UGC, UGU D Asp Aspartic acid GAC, GAU E Glu Glutamic acid GAA, GAG F Phe PhenyUUUU UUC, G Gly Glycine GGA, GGC, GGG, GGU H His Histidine CAC, CAU I Ile Isoleucine AUA, AUC, AW K Lys Lysine AAA, AAG L Leu Leucine UUA, WG, CUA, CUC, CUG, CUU M Met Methionine AUG N Asn Asparagine AAC, AAU P Pro Proline CCA, CCC, CCG, CCU Q Gln Glutamine CAA, CAG R Arg Arginine AGA, AGG, CGA, CGC, CGG, CGU S Cheese Serine AGC, AGU, UCA, UCC, UCG, UCU T Thr Threonine ACA, ACC, ACG, AC UV Val Valine GUA, GUC, GUG, GUU W Trp Tryptophan UGG Y Tyr Tyrosine UAC, UAU Anti-IL-12 antibodies according to the present invention may contain one or more e substitutions, deletions, or additions of amino acids derived from both natural mutations and human manipulation as recited herein. Of course, one skilled in the art would make the number of amino acid substitutions dependent on a number of factors, including those described above. Generally speaking, the number of amino acid substitutions, insertions or deletions for any given anti-IL-12 IgG derivative protein, fragment or variant thereof will be no greater than 40, 30, 20, 19, 18, 17. , 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, i.e. 1-30 or any range or value of sc mentioned herein. Amino acids in an anti-IL-12 antibody of the present invention that are essential for its function can be identified by methods known in the art, such as site directed mutagenesis or alanine scanning mutagenesis (e.g. Ausubel, as above, chapters 8, 15; Cunningham and Wells, Science 244: 1081-1085 (1989)). The second procedure introduces single mutations that introduce an alanine at every position in the molecule. The resulting mutant molecules are then tested for the presence of biological activity, such as but not limited to at least one IL-12 neutralizing activity. The sites that are critical for antibody binding can also be identified by structural analysis, as well as crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith, et al. , J. Moth. Biol. 224: 899-904 (1992) and de Vos, et al. , Science 255: 306-312 (1992)). One skilled in the art will appreciate that the present invention includes at least one biologically active antibody of the present invention. Biologically active antibodies have a specific activity of at least 20%, 30% or 40%, and more preferably of at least 50%, 60% or 70%, and most suitably at least 80%, 90% or 95% -1000 % activity of native (non-synthetic), endogenous, or a related and known antibody 1a. Methods for determining and quantifying the quantitative enzyme activity and substrate specificity are well known to those skilled in the art. In another aspect, the present invention relates to the human antibodies 1 described herein, which may be modified by covalently linking an organic moiety. Such modification may lead to the production of antibodies with improved pharmacokinetic properties (e.g. extended in vivo serum half-life). The organic moiety may be linear or branched from the a group of the polymer, the a group of fatty acid or the a group of fatty acid ester. In certain embodiments, the hydrophilic group of the polymer may have a molecular weight of from about 800 to about 120,000 Daltons and may be a polyalkene glycol (e.g. polyethylene glycol (PEG), polypropylene glycol (PPG), carbohydrate polymer, amino acid polymer, or polyvinylpyrrolidone, and the fatty acid or fatty acid ester group may contain from about eight to about forty carbon atoms . Modified antibodies of Ia according to the present invention may include one or more organic moieties that are covalently attached directly or indirectly to the antibody. Each organic moiety that is attached to the antibody in accordance with the present invention may independently be the a hydrophilic group of the polymer, the a group of fatty acid or the a group of the fatty acid ester. The term "fatty acid" as used herein includes monocarboxylic acids and dicarboxylic acids. The term "hydrophilic polymer group" as used herein refers to an organic polymer that is more soluble in water than in octane. Thus, antibodies altered by the covalent linkage of polylysine are encompassed by the present disclosure. Hydrophilic polymers suitable for modifying antibodies in accordance with the present invention may be linear or branched and include, for example, polyalactate glycols (e.g. monomethoxypolyethylene glycol (mPEG), PPG and the like), into carbohydrates (e.g. dextran, cellulose, oligosaccharides, polysaccharides and the like) polymers of hydrophilic amino acids (e.g. polylysine, polyarginine, polyaspartate and the like), polyalkane oxides (e.g. polyethylene oxide, polypropylene oxide and the like), polyvinylpyrrolidone. A preferred hydrophilic polymer that modifies antibodies in accordance with the present invention has a molecular weight of about 800 to about 150,000 Daltons as a separate molecule. For example, PEG 5000 and PEG 20000 can be used, the subscript being the average Daltone molecular weight of the polymer. The hydrophilic polymer groups can be substituted with one to about eight alkyl groups, fatty acids or fatty acid esters. Hydrophilic polymers which are substituted with the α group of fatty acid or fatty acid ester can be obtained by the use of suitable methods. For example, a polymer containing an amino group can be linked to the carboxyl group of a fatty acid or fatty acid ester and an activated carboxyl group (e.g. activated by N, N-carbonyldiimidazole) on the fatty acid or fatty acid ester can be linked to the hydroxyl group of the polymer. The fatty acids or fatty acid esters suitable for modification of the antibodies according to the present invention may be saturated or may contain one or more unsaturated n bonds. Fatty acids that are suitable for modifying antibodies in accordance with the present invention include, for example, n-dodecanoic acid (C 12, lauric acid), n-tetradecanoic acid (C 14, myristic acid), n-octadecanoic acid. (C 18, stearic acid), n-eicosanoic (C 20, arachidic acid), n-docosanoic (C 22, behenic acid), n-triacontanoic (C 30), n-tetracontanoic (C 40,), cis-? 9-octanoic acid (C 18, oleic acid), all cis-α 5,8,11,14-eicosatetraenoic acids (C 20, arachidonic acid), octanedioic acid, tetradecanedioic acid, octadecanedioic acid, docosanedioic acid and the like like. Suitable fatty acid esters include monoesters of dicarboxylic acids that contain a linear or branched lower alkyl group. The lower alkyl group may contain from one to about twelve, especially from one to about six, carbon atoms. Modified human antibodies may be obtained by any suitable means, such as by reaction with one or more modifying agents. The term "modifying agent" as used herein refers to a suitable organic group (e.g. hydrophilic polymer, fatty acid, fatty acid ester), which contains an activating group. An "activating group" means a chemical component or functional group which, under appropriate conditions, reacts with a second chemical group, thereby forming a covalent bond between the modifying agent and the other chemical group. For example, activating reactive amino groups include electrophilic groups such as tosylate, mesylate, halogen derivatives (chloro, bromo, fluoro, iodo), N-hydroxy-succinimide (NHS) esters, and the like. Activating groups that can react with thiols include, for example, maleimide, iodoacetyl, acrylolyl, pyridyl disulfide, 5-thio-2-nitrobenzoic acid (TNBthiol) thiol, and the like. The aldehyde functional group can be combined with molecules containing an amino or hydrazide group, and the azide group can react with a trivalent phosphorus group to form phosphoramidate or phosphorimide linkages. Suitable methods for introducing activating groups into molecules are known in the art (see, for example, Hermanson, G. T. , Bioconjugate Techniques. Academic Press: San Diego, CA (1996)). The activating group can be bound directly to an organic group (e.g. a hydrophilic polymer, fatty acid or fatty acid ester), or by a linkage aca, for example a di-valent group e C 1-12, in which one or more carbon atoms can be being replaced by heteroatoms such as oxygen, nitrogen or sulfur. Suitable linkers include, for example, tetraethylene glycol, - (CH 2) 3 -, -NH- (CH 2) 6 -NH-, - (CH 2) 2 -NH-, and -CH 2 -O- CH 2 -CH 2 -O-CH-CH 2 -O-CH-NH-. Modifying agents which contain the linking part ac a can be obtained, for example, by mono-Boc-alkyldiamine reactions (e.g. mono-Boc-ethylenediamine, mono-Boc-diaminohexane) with fatty acid in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) to obtain an amide bond between the free amine and the carboxyl group t fatty acid. The Boc protecting group can be removed from the product by treatment with trifluoroacetic acid (TFA) to liberate a primary amine which may be attached to another carboxyl group as described or may be removed from the product. reaction with maleic anhydride, and the resulting product can undergo cyclization to form an activated maleimide derivative of fatty acid. See, for example, Thompson, et al. , WO 92/16221. Modified antibodies described herein may be obtained by reacting a human antibody with a modifying agent. For example, organic moieties may be attached to an antibody in a non-site specific manner by using an amine-reactive modifying agent, for example, an NHS PEG ester. Modified human antibodies can also be obtained by reducing disulfide bonds (e.g. inside the n-disulfide chain) of the antibody or antigen-binding fragment. The reduced antibody may then be reacted with a thiol-reactive modifying agent to provide the modified antibody described herein. Modified human antibodies Ia containing an organic moiety that is attached to specific sites of the antibody Ia in accordance with the present invention can be obtained by suitable methods such as reverse proteolysis (Fisch et al. , Bioconjugate Chem. , 3: 147-153 (1992); Werlen et al. , Bioconjugate Chem. , 5: 411-417 (1994); Kumaran et al. , Protein Sci. 6 (10): 2233-2241 (1997); Itoh et al. , Bioorg. Chem. , 24 (1): 59-68 (1996); Capellas et al. , Biotechnol. Bioeng. , 56 (4): 456-463 (1997)), and the methods described in Hermanson, G. T. , Bioconjugate Techniques, Academic Press: San Diego, CA (1996). Protein Compositions of Anti-Idiotypic I Antibodies Anti-IL-12 Antibodies In addition to monoclonal or chimeric anti-IL-12 I antibodies, the present specification also discloses anti-idiotypic (anti-Id) antibodies specific for such anti-IL-12 antibodies according to the present invention. invention. An anti-Id antibody is an antibody that recognizes specific determinants that are typically associated with the antigen-binding region of another antibody. Anti-Id can be obtained by immunizing animals of the same species and genetic type (e.g. mouse strain) as a source of the Ia Id antibody using an antibody Ia or CDR containing part of it. The immunized animals will recognize and respond to the idiotypic determinants of the immunizing antibody by producing anti-Id antibodies. The anti-Id antibody can also be used as an "immunogen" to elicit an immune response in yet another animal by obtaining so-called anti-anti-Id antibodies. Anti-IL-12 Antibody Protein Compositions The present invention also provides at least one anti-IL-12 antibody composition comprising at least one, at least two, at least three, at least four, at least one anti-IL-12 antibody composition. thereafter, five, at least six, or more 1 anti-IL-12 antibodies of this invention, as described herein and / or known in the art, are provided in a composition, mixture, or form not found in nature. The anti-IL-12 antibody compositions of the present invention may furthermore comprise an appropriate and effective amount of at least one TNF antagonist (e.g. but not limited to TNF la antibodies or fragment, soluble TNF receptor or fragment, fusion proteins thereof or low molecular weight TNF antagonist), anti-rheumatic drug (e.g. methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, lotus sodium thioate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxant, narcotic, non-steroidal anti-inflammatory drug, anti-painkiller (NSAID) a sedative, a local anesthetic, a neuromuscular blocker, an antimicrobial drug (e.g. aminoglycoside, antifungal drug, antiparasitic drug, antiviral drug, carbapenem, cephalosporin, fluoroquinoline, macrolide, penicillin, sulfonamide, tetracycline, other anti-microbial drug), anti-psoriasis drug, anabolic corticosteroid, anabolic steroid , mineral, nutrient, thyroid factor, vitamin, calcium hormone, anti-diarrheal drug, antitussive, anti-emetic, anti-ulcer, laxative, anticoagulant, erythropoietin (e.g. epoetin alfa), filgrastim (e.g. G-CSF, Neupogen), Sargramostim (GM-CSF, Leukine), Vaccine, Immunoglobulins, Immunosuppressant (e.g. basiliximab, cyclosporin, daclizumab), growth hormone, hormone replacement therapy drug, estrogen receptor modulator, cerebral dilator, cycloplegic agent, alkylating agent, antimetabolite, mitosis inhibitor, radiotherapy agent, antidepressant agent, antidepressant agent, anti-psychosis, anti-drug, hypnotic, sympathomimetic, stimulant, donepezil, tacrine, asthma drug, beta agonist, inhaled steroid, leukotriene inhibitor, methylxanthine, cromoline, epinephrine or its analogue, dornzyme alpha ), cytokines or cytokine antagonists. Non-limiting examples of such cytokines include IL-1 through IL-23. Appropriate dosages are well known in the art. See e.g. Wells et al. , pub. , Pharmacotherapists Handbook, 2nd Edition, Appleton and Lange, Stamford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000). Such anti-cancer or anti-cancer agents may also contain toxin molecules which are associated with, bound, are part of the same composition or are co-administered with at least one antibody of the present invention. The toxin may possibly serve to kill pathological cells or tissues. The pathological cell may be a cancer cell or other cell. Such toxins may include, but are not limited to, purified or recombinant toxins or fragments of toxins containing at least one functional cytotoxic domain of the toxin, e.g. selected from at least one of ricin, gallbladder toxin, venom toxin, or bacterial toxin. The term toxin also includes endotoxins and exotoxins produced by any naturally occurring mutant or recombinant bacteria or viruses that can cause human and other mammals any pathological condition, including toxic shock that can with the end of death. Such toxins may include, but are not limited to, the heat-sensitive enterotoxins from enterotoxin-producing E. coli (LT), heat insensitive enterotoxins (ST), Shigella cytotoxins, Aeromonas enterotoxins, toxic shock syndrome toxin-1 (TSST-1), enterotoxins A (SEA), B ( SEB) or C (SEC) Staphylococcus, Streptococcus enterotoxins and the like. Such bacteria include, but are not limited to, strains producing E. coli (ETEC), entero-haemorrhagic E. coli (e.g. strains of serotype 0157: H7), Staphylococcus species (e.g. Staphylococcus aureus, Staphylococcus pyogenes), Shigella species (e.g. Shigella dysenteriae, Shigella flexneri, Slaigella boydii and Shigella sonnei), Salmonella species (e.g. Salmonella typhi, Salmonella cholerasuis, Salmonella enteritidis), Clostridium species (e.g. Clostridium perfringens, Clostridium dificile, Clostridiuna botulinum), Camphlobacter species (e.g. Camphlobacter jejuni, Camphlobacter fetus), Heliobacter species (e.g. Heliobacter pylori), Aeromonas species (e.g. Aeromonas sobria, Aeromonas hydrophila, Aeromonas caviae), Pleisomonas shigelloides, Yersina enterocolitica, Vibrios species (e.g. Vibrios cholerae, Vibrios parahemolyticus), Klebsiella species, Pseudomonas aeruginosa and Streptococci. See e.g. Stein, pub. , INTERNAL MEDICINE, ed. 3, p. 1-13, Little, Brown and Co. , Boston, (1990); Evans et al. , pub. , Bacterial Infections of Humans: Epidemiology and Control, ed. 2, p. 239-254, Plenum Medical Book Co. , New York (1991); Mandell et al. , Principles and Prac- tice of Infectious Diseases, ed. 3. , Churchill Livingstone, New York (1990); Berkow et al. , pub. , The Merck Manual, 16th Edition, Merck and Co. , Rahway, N. J. , 1992; Wood et al. , FEMS Microbiology Immunology, 76: 121-134 (1991); Marrack et al. , Science, 248: 705-711 (1990). The compounds, compositions and combinations of anti-IL-12 antibodies of the present invention may further contain at least one of any suitable excipients such as diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives. - brooms, adjuvants and the like. Pharmaceutically acceptable excipients are preferred. Non-limiting examples and methods of preparing such sterile solutions are well known in the art, such as, but not limited to, those described in Gennaro, 2nd ed. , Remington's Pharmaceutical Sciences, ed. 18, Mack Publishing Co. (Easton, PA) 1990. It is possible to routinely select pharmaceutically acceptable carriers that are compatible with the mode of administration, the solubility, and / or stability of the anti-IL-12 antibody composition, fragment or variant that are well known in the art or described herein. Pharmaceutical excipients and additives useful in the present composition include, but are not limited to, proteins, peptides, amino acids, lipids, and carbohydrates (e.g. sugars, including monosaccharides, di-, tri-, tetra- and oligosaccharides, sugar derivatives such as alditols, aldonic acids, esterified sugars and the like, and polysaccharides or sugar polymers) that may be present alone or in combination , acting alone or in combination from 1-99.99% by weight or volume. Examples of protein excipients include plasma albumin such as human plasma albumin (HSA), recombinant human albumin (rHA), gelatin, casein and the like. Representative antibody amino acids / components that may also act as buffers include alanine, glycine, arginine, betaine, histidines, glutamic acid, aspartic acid, cysteines, lysines, leucines, isoleucines, valines, methionines, phenylalanines, aspartame, and the like. One of the recommended amino acids is glycine. Carbohydrate excipients suitable for use in this invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose and the like; disaccharides such as lactose, sucrose, trehalose, cellobiose and the like, polysaccharides such as raffinose, melesitose, maltodextrins, dextrans, starches and the like, and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol ( glucitol), myo-inositol and the like. Hydrocarbon excipients recommended for use in the present invention are mannitol, trehalose and raffinose. Anti-IL-12 antibody compositions may also include a buffer or a pH adjuster, typically the buffer is a salt formed from an acid or an organic base. Representative buffers include organic acid salts such as salts of citric acid, ascorbic acid, gluconic acid, egolic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid; Tris, tromethamine hydrochloride or phosphate buffers. Buffers recommended for use in the present invention are organic acid salts such as citrate. Additionally, the anti-IL-12 antibody compositions of the invention may contain polymeric excipients / additives such as polyvinylpyrrolidones, phycols (polymeric sugar), dextrans (e.g. cyclodextrins, such as 2-hydroxypropyl- (3-cyclodextrin), polyethylene glycols, flavoring agents, antibacterial agents, sweetening agents, antioxidants, antistatic agents, surfactants (e.g. polysorbates such as "TWEEN 20" and "TWEEN 80"), lipids (e.g. phospholipids, fatty acids), steroids (e.g. cholesterol), and chelating agents (e.g. EDTA). These and additional known excipients and / or pharmaceutical additives suitable for use in the anti-IL-12 antibody compositions of the invention are known in the art, e.g. mentioned in "Remington: The Science & Practice of Pharmacy", ed. 19, Williams & Williams, (1995), and in "Physician's Desk Reference", eds. 52, Medical Economics, Montvale, NJ (1998). The recommended carrier or excipient materials are carbohydrates (e.g. saccharides and alditols) and buffers (e.g. citrate) or polymeric agents. Compositions As noted above, the present invention provides stable compositions, that is, in particular with phosphate buffered saline or a selected salt, and also from preserved solutions and compositions containing a preservative and preserved compositions for multiple use. for use suitable for pharmaceutical or veterinary use, comprising at least one anti-IL-12 antibody in a pharmaceutically acceptable composition. Preserved compositions contain at least one preservative known or optionally selected from the group consisting of at least one of phenol, m-cresol, p-cresol, o-cresol, chlorocreosol, benzyl alcohol, nitrite, phenylether ecological, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride (e.g. hexahydrate), alkyl paraben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof in an aqueous solvent. Any suitable concentration known in the art can be used, such as 0.001-5%, or any range or value therein, such as, but not limited to, 0.001, 0.003, 0.005, 0.009, 0.01, 0 .02, 0.03, 0.05, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9 , 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2 , 2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4 , 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.3, 4.5, 4.6, 4.7, 4.8, 4.9, or any ranges or values within this range. Non-limiting examples include no preservative, 0.1-2% m-cresol (e.g. 0.2, 0.3, 0.4, 0.5, 0.9, 1.0%), 0.1-3% benzyl alcohol (e.g. 0.5, 0.9, 1.1, 1.5, 1.9, 2.0, 2.5%), 0.001-0.5% thimerosal (e.g. 0.005, 0.01), 0.001-2.0% phenol (e.g. 0.05, 0.25, 0.28, 0.5, 0.9, 1.0%), 0.0005-1.0% of the alkyl paraben (s) (e.g. 0.00075, 0.0009, 0.001, 0.002, 0.005, 0.0075, 0.009, 0.01, 0.02, 0.05, 0.075, 0.09, 0.1, 0.2, 0.3, 0.5, 0.75, 0.9, 1.0%) and the like. As described above, the invention describes a product comprising a package and at least one vial containing a solution of at least one anti-IL-12 antibody with prescribed buffers and / or preservatives, optionally in an aqueous diluent, wherein the package contains a label, which indicates that this solution can be stored for a period of 1, 2, 3, 4, 5, 6, 9, 12, 18, 20, 24, 30, 36, 40, 48, 54, 60, 66, 72 hours or more. The present invention further describes a product comprising a package, a first vial containing a lyophilized at least one anti-IL-12 antibody and a second vial containing an aqueous diluent of a prescribed buffer or preservative, the latter being the package includes a label that instructs the patient to dissolve at least one anti-IL-12 antibody in an aqueous diluent to form a solution that can be stored for twenty-four hours or more. The at least one anti-IL-12 antibody used in the present invention may be produced by recombinant means, including transgenic preparations and mammalian cells, or may be purified from other biological sources. as described herein or as known in the art. The range of at least one anti-IL-12 antibody in the product described herein includes amounts which, when dissolved, in a dry substance / solution system, result in concentrations of from about 1.0 µg / ml to about 1000 mg / ml. although lower and higher concentrations may be used, depending on the intended administration vehicle, e.g. Solution formulations will be distinct from transdermal patches and methods of pleural delivery, either via mucosal or osmotic or micropump. Preferably, the aqueous diluent comprises and further comprises an optionally pharmaceutically acceptable preservative. Recommended preservatives include those selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, alkyl paraben (methyl, ethyl, propyl, butyl and the like), chloride benzalkonium, benzethonium chloride, sodium dehydroacetate and thimerosal or mixtures thereof. The concentration of the preservative used in the composition is a concentration sufficient to obtain the antimicrobial effect. Such concentrations depend on the selected preservative and can be easily determined by a trained contractor. Other excipients, e.g. isotonic agents, buffers, antioxidants, preservative enhancers. An isotonic agent such as glycerin at known concentrations is commonly used. The addition of a physiologically tolerable buffer is recommended to improve pH control. The compositions may have a wide pH range, such as from about pH 4 to about pH 10, preferably from about pH 5 to about pH 9, and most preferably from about pH 6.0 to about pH 9. about 8.0. The preferred pH of the compositions of the present invention is from about 6.8 to about 7.8. Preferred buffers include phosphate buffers, sodium phosphate is most preferred and in particular phosphate buffered saline (PBS). Optionally, other additives can be added to the composition to reduce aggregation, such as pharmaceutically acceptable solubilizers such as Tween 20 (polyoxyethylene (20) sorbitan monolaurate), Tween 40 (polyoxyethyl monopalmitate). - sorbitan (20), Tween 80 (polyoxyethylene (20) sorbitan monooleate), Pluronic F68 (polyoxyethylene polyoxypropylene block copolymers) and PEG (polyethylene glycol) or non-ionic surfactants such as polysorbate 20 or 80 or poloxamer 184 or 188, Pluric® polyols, other block copolymers and chelators such as EDTA and EGTA. These additives are especially useful when a pump or a plastic container is used to administer the composition. The presence of a pharmaceutically acceptable surfactant weakens the protein's tendency to aggregate. The compositions of the present invention can be prepared by a process that comprises mixing at least one anti-IL-12 antibody and a preservative selected from the group consisting of phenol, m-cresol, p-cresol, o-cresol , chlorocresol, benzyl alcohol, alkyl paraben (methyl, ethyl, propyl, butyl and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof in an aqueous solvent. Mixing the at least one anti-IL-12 antibody and preservative in an aqueous diluent is performed using conventional dissolution and mixing procedures. To obtain a suitable composition, for example, a measured amount of at least one anti-IL-12 antibody in a buffered solution is combined with the prescribed preservative in the buffered solution in sufficient amounts to provide the protein and the preservative. at the given concentrations. Modifications to this process will be clear to those with ordinary knowledge of the field. For example, the sequence in which the ingredients are added, whether any further additives are used, the temperature and the pH at which the composition is made, are factors that can be optimized for the concentration and agents used. administration. Compositions may be provided to patients as pure solutions or as pairs of vials that include a vial containing lyophilized at least one anti-IL-12 antibody, which is dissolved with a second vial containing water. , preservative and / or excipients, preferably a phosphate buffer and / or saline and a selected salt, in an aqueous diluent. Both a single solution vial and a pair of vials requiring reconstitution can be used multiple times and may be sufficient for a single or multiple patient treatment cycles, thus providing a treatment regimen that is more convenient than currently available. The products described herein are suitable for administration periods ranging from immediately to twenty-four hours or more. Accordingly, the products described herein provide significant benefits to the patient. The compositions according to the invention can optionally be safely stored at temperatures from about 2 to about 40 ° C, while maintaining the biological activity of the protein for a longer period of time, which allows it to be stated on the package label that the solution can be used and / or stored for 6, 12, 18, 24, 36, 48, 72 or 96 hours or less. If a preservative diluent is used, such a label may indicate use up to 1-12 months, a half, a half, a half and / or two years. The solutions of at least one anti-IL-12 antibody of the invention can be prepared by a process that comprises mixing at least one antibody with an aqueous diluent. Mixing is performed using conventional dissolution and mixing procedures. In order to obtain a suitable diluent, for example, a measured amount of at least one antibody is combined in the water or buffer in amounts sufficient to provide the protein and possibly a preservative or buffer at the desired concentrations. Modifications to this process will be clear to those with ordinary knowledge of the field. For example, the sequence in which the ingredients are added, whether further additives are used, the temperature and pH at which the composition is made, are factors that can be optimized for the concentration and means of administration used. The products described herein may be provided to patients as pure solutions or as pairs of vials that include a lyophilized vial with at least one anti-IL-12 antibody that is dissolved with a second vial containing an aqueous diluent. Both a single solution vial and a pair of vials requiring reconstitution can be used multiple times and may be sufficient for a single or multiple patient treatment cycles, thus providing a treatment regimen better than currently available. The products described herein can be delivered to patients indirectly by delivering to pharmacies, clinics, or other institutions and establishments clean solutions or vial pairs, which include a vial with lyophilized at least one anti-IL-12 antibody that is is dissolved with a second vial containing a diluent in water. The pure solution in this case may be one liter or even more, in the form of a large reservoir from which one or more times smaller aliquots of the solution of at least one antibody Ia can be obtained for transfer to smaller vials and delivery by pharmacies eb ad from clinics to customers and / or patients. Recognized devices that include these single vial systems include injection devices that deliver solutions such as the BD Pen, BD Autojector®, Humaject®, NovoPen®, BD®Pen, AutoPen® , and OptiPen®, GenotropinPen®, Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®, iject®, J-tip Needle-Free Injector®, Intraject®, Medi-Ject®, e.g. such as made or enhanced by Becton Dickenson (Franklin Lakes, NJ, www. bectondickenson. com), Disetro-PL 205 786 B1 24 nic (Burgdorf, Switzerland, www. disetronic. com; Bioject, Portland, Oregon (www. bioject. com); National Medical Products, Weston Medical (Peterborough, UK, www. weston-medical. com), Medi-Ject Corp (Minneapolis, MN, www. mediject. com). Recognized devices that include a pair of vial systems include those injection devices that dissolve the lyophilized drug in a cartridge to deliver the resultant solution, such as HumatroPen®. The products described herein include a packaging. The packaging provides, in addition to the information required by the administrative authorities, the conditions in which the product can be used. This type of package provides instructions for the patient to dissolve at least one anti-IL-12 antibody in an aqueous diluent to obtain a solution and apply the solution over a period of 2 to 24 hours or more. for a two-vial product, dry substance / solution system. For a single vial and solution product, the label indicates that the solution can be used over a period of 2-24 hours or more. The products described herein can be used in accordance with human pharmaceutical applications. The compositions of the present invention may be prepared by a process that comprises mixing at least one anti-IL-12 antibody and a selected buffer, in particular a phosphate buffer containing saline or a selected salt. Mixing of the at least one antibody and buffer is performed using conventional dissolution and mixing procedures. In order to obtain a suitable composition, for example, a measured amount of at least one antibody in water or buffer is combined with a given buffering factor in water in amounts sufficient to provide the protein and buffer in desired concentrations. Modifications to this process will be clear to those skilled in the art. For example, the sequence in which the ingredients are added, whether further additives are used, the temperature and pH at which the composition is made, are factors that can be optimized for the concentration and means of administration used. Permanent or preserved compositions described herein can be provided to patients as neat solutions or as pairs of vials that include a lyophilized vial of at least one anti-IL-12 antibody that is dissolved with the aid of the other. a vial containing either a preservative or a buffer and excipients in a dilution of water. Both a single solution vial and a pair of vials, requiring reconstitution, can be used multiple times and can be sufficient for a single or multiple patient treatment cycles, thus providing a treatment regimen that is more convenient than currently available. At least one anti-IL-12 antibody, in both the stable and preserved compositions described herein, may be administered to a patient in accordance with the present invention by a variety of delivery methods, including subcutaneous or intramuscular injection. transdermal, pulmonary, transmucosal, implant, osmotic pump, cassette, micro-pump and other means known to the skilled practitioner as is well known in the art. Therapeutic Uses An antibody or pharmaceutical composition of the invention may be intended to modulate or treat at least one immune related disease in a cell, tissue, organ, animal or patient, but not limited to at least one among patients with chronic progressive disease, juvenile rheumatoid arthritis, systemic adolescent rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, gastric ulcer, serous-negative arthritis, osteoarthritis and arthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosus, antiphospholipid syndrome, iritis and salivitis / uveitis / optic neuritis, spontaneous pulmonary fibrosis, systemic inflammation - vessel vessel n / Wegener's granulomatosis, sarcoidosis, testicular inflammation, reverse procedure vasectomy, allergic / atopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplantation, organ transplant rejection, graft versus host disease , systemic inflammatory reaction syndrome, sepsis syndrome, gram-positive sepsis, gram-negative sepsis, culture-absent sepsis, mycotic sepsis, febrile neutropenia, diuretic sepsis, meningococcal infection, trauma / haemorrhage, burns n, exposure to ionizing radiation, acute pancreatitis, adult respiratory distress syndrome, chronic progressive disease, alcoholic atheritis, chronic inflammation, sarcoidosis, Crohn's disease, sickle cell anemia, diabetes , nephrosis, atopic diseases, hypersensitivity reactions, allergic rhinitis, hay fever, all-year rhinitis, inflammation conjunctivitis, endometriosis, asthma, urticaria, systemic anaphylaxis, dermatitis, lymphocytic anemia, haemolytic disease, thrombocytopenia, any organ or tissue transplant rejection, kidney transplant rejection, heart transplant rejection, transplant rejection for atherosclerosis, pancreatic transplant rejection, lung transplant rejection, bone marrow transplant rejection (BMT), skin allograft rejection, cartilage rejection, bone graft rejection, small intestine transplant rejection, ice thymus transplant rejection , parathyroid transplant rejection, transplant rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reactions, Graves' disease, Raynoud's disease, B-type insulin-resistant diabetes, asthma, muscle wasting, antibody-1 dependent cytotoxicity, hypersensitivity reaction Type III anger, generalized impetigo Erythematosus, POEMS syndrome (polyneuropathy syndrome, organomegaly, endocrinopathy, monoclonal gammopathy and skin lesions) polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin lesion syndrome, antiphospholipid syndrome, mixed skin disease , idiopathic Addison's disease, diabetes mellitus, chronic active inflammation of the liver, biliary primary cirrhosis in atoms, vitiligo, vasculitis, post-valgus opening syndrome, type IV hypersensitivity reaction, contact dermatitis, inflammation of the pectoris hypersensitive luc, allograft rejection, endocellular granulomas, drug susceptibility, metabolic / idiopathic, Wilson's disease, haemochromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, Hashimoto's thyroiditis, osteoporosis assessment of the hypothalamus-pituitary-adrenal axis, cirrhosis in primary biliary atoms, inflammation enia of the thyroid gland, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial hematophagocytic lymphohistiocytosis, dermatological conditions, psoriasis, alopecia, nephrotic syndrome, nephritis , keratoconjunctivitis, acute renal failure, hemodialysis, uremia, poisoning, pre-eclampsia, oct3 therapy, anti-cd3 therapy, cytokine therapy, chemotherapy, radiotherapy (e.g. not limiting asthenia, anemia, cachexia and the like), chronic salicylate poisoning and the like. See e.g. Merck Manual, Issue 12-17, Merck & Company, Rahway, NJ (1972, 1977, 1982, 1987, 1992, 1999), Pharmacotherapy Handbook, Wells et al. , pub. , Second Edition, Appleton and Lange, Stamford, Conn. (1998, 2000). An antibody or pharmaceutical composition according to the invention may be for modulating or treating at least one cardiovascular disease in a cell, tissue, organ, animal or patient. An antibody or pharmaceutical composition of the invention may be administered prior to, concurrently with, or subsequent to the administration of at least one agent selected from at least one TNF antagonist (e.g. but not limited to TNF antibody or fragment thereof, soluble TNF receptor or fragment thereof, fusion proteins thereof or low molecular weight TNF antagonist), anti-rheumatic drug (e.g. methotrexate, auranofin, aurothioglucose, azathioprine, etanercept, lotava sodium thioate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxant, narcotic, non-steroidal anti-inflammatory drug, analgesic (NSAID) a sedative, a local anesthetic, a neuromuscular blocker, an antibacterial agent (e.g. aminoglycoside, antifungal drug, antiparasitic drug, antiviral drug, carbapenem, cephalosporin, fluoroquinoline, macrolide, penicillin, sulfonamide, tetracycline, other antibacterial drug), anti-psoriatic drug, corticosteroid, diabetic anabolic steroid, anabolic steroid , nutrient, thyroid factor, vitamin, calcium hormone, anti-diarrheal drug, antitussive, anti-emetic, anti-ulcer, laxative, anti-coagulant, erythropoietin (e.g. epoetin alfa), filgrastim (e.g. G-CSF, Neupogen), Sargramostim (GM-CSF, Leukine), vaccine, immunoglobulins, immunosuppressant (e.g. basiliximab, cyclosporine, daclizumab), growth hormone, hormone replacement therapy drug, estrogen receptor modulator, cerebral dilator, cycloplegic agent, alkylating agent, antimetabolite, mitosis inhibitor, radiotherapy agent, antidepressant, anti-mania agent, , anti-drug, hypnotic, sympathomimetic, stimulant, donepezil, tacrine, asthma drug, beta agonist, inhaled steroid, leukotriene inhibitor, methylxanthine, cromoline, epinephrine or its analogue, dornzyme alpha ( ), cytokines or cytokine antagonists. Non-limiting examples of such cytokines include, but are not limited to, IL-1 through IL-23. Appropriate dosages are well known in the art. See e.g. Wells et al. , pub. , Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange, Stam-Ford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition, Tarascon Publishing, Loma Linda, CA (2000). Anti-TNF antagonists suitable for the present invention include, but are not limited to, anti-TNF antibodies, antigen-binding fragments thereof, and receptor molecules that bind specifically to TNF; compounds that prevent and / or inhibit TNF synthesis, TNF secretion or its action on target cells, such as thalidomide, tenidap, phosphodiesterase inhibitors (e.g. pentoxifylline and rolipram), A2b adenosine receptor agonism and A2b adenosine receptor stimulating compounds, compounds that prevent and / or inhibit TNF receptor signaling, such as mitogen-activated protein kinase (MAP) inhibitors ); compounds that block and / or inhibit the cut of TNF in the membrane, such as metalloprotease inhibitors, compounds that block and / or inhibit the activity of TNF, such as angiotensin converting enzyme (ACE) inhibitors (e.g. captopril) and compounds that block and / or inhibit TNF production and / or synthesis, such as MAP kinase inhibitors. As used herein, "tumor necrosis factor antibody", "TNF antibody", "TNF antibody", or fragment thereof, reduces, blocks, inhibits, abolishes or interferes with TNF activity in vitro, in situ. and / or, in particular, in vivo. For example, suitable human TNF antibodies described herein can bind to TNFα, and include anti-TNF antibodies, antigen-binding fragments thereof, and specific mutants or domains thereof that bind specifically to TNFα. A suitable TNF a antibody or fragment can also reduce, block, inhibit, suppress or interfere with the synthesis of TNF RNA, DNA or protein, TNF secretion, TNF signaling, TNF cut in the lung , TNF activity, production and / or synthesis of TNF. The cA2 chimeric antibodies consist of an antigen-binding variable region neutralizing a murine IgG1 anti-TNF antibody, a high affinity human A2, and human IgG1 constant regions, kappa. The Fc region of human IgG1 improves the allogeneic effector function of the antibody, lengthens the plasma half-life, and lowers the immunogenicity of the antibody. The sc activity and epitope specificity for the chimeric antibody cA2 are derived from the variable region of the antibody la A2 of the mouse. In a particular embodiment, a preferred source for nucleic acids encoding the variable region of the mouse antibody Ia A2 is the A2 hybridoma cell line. Chimeric A2 (cA2) neutralizes the cytotoxic effect of human TNFα, both natural and recombinant, in a dose dependent manner. From the binding assays of the chimeric antibody cA2 and recombinant human TNF a, the affinity constant of the chimeric antibody cA2 was calculated as 1.04 x 10 -10 M -1. Recommended methods for determining the specificity and affinity of monoclonal antibodies by competitive inhibition can be found in Harlow, et al. , Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1988; Colligan et al. , pub. , Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, New York, (1992-2000); Kozbor et al. , Immunol. Today, 4: 72-79 (1983); Ausubel et al. , pub. Current Protocols in Molecular Biology, Wiley Interscience, New York (1987-2000) and Muller, Meth. Enzymol. , 92: 589-601 (1983). In a specific embodiment, the murine monoclonal antibody A2 is produced by a cell line designated a c134A. The cA2 chimeric antibodies are produced by a cell line designated a c168A. Additional examples of anti-TNF monoclonal antibodies that can be used in the present invention are described in the art (see, e.g. U.S. Patent No. 5,231,024; Moller, A. et al. , Cytokine 2 (3): 162-169 (1990); U.S. Application No. 07/943852 (filed September 11, 1992); Rathjen et al. , International Publication No. WO 91/02078 (published February 21, 1991); Rubin et al. , EPO Patent Publication No. 0218868 (published April 22, 1987); Yone et al. EPO Patent Publication No. 0288088 (October 26, 1988); Liang et al. , Biochem. Biophys. Res. Comm. 137: 847-854 (1986); Meager et al. , Hybridoma 6: 305-311 (1987); Fendly et al. Hybridoma 6: 359-369 (1987); Bringman et al. , Hybridoma 6: 489-507 (1987) and Hirai et al. , J. Immunol. Meth. 96: 57-62 (1987). TNF Receptor Molecules Preferred TNF receptor molecules which may be useful in the present invention are those which bind TNF with high affinity (see, e.g. Feldmann et al. , International Publication No. WO 92/07076 (published April 30, 1992); Schall et al. , Cell 61: 361-370 (1990) and Loetscher et al. , Cell 61: 351-359 (1990) and possibly having a low immunogenicity sc. Cell surface TNF receptors are especially useful in the present invention. Truncated forms of these receptors, containing extracellular domains (ECD) or functional parts thereof (see, e.g. Corcoran et al. , Eur. J. Biochem. 223: 831-840 (1994)) may also be useful in the present invention. Truncated forms of TNF receptors containing ECD, detected in urine and blood plasma as inhibitory TNF-binding proteins of 30 kDa and 40 kDa (Engelmann, H. et al. , J. Biol. Chem. 265: 1531-1536 (1990)), multimeric receptor proteins and TNF immunoreceptor fusion molecules, derivatives and fragments or portions thereof, are additional examples of TNF receptor molecules that may be useful herein. invention. The TNF receptor molecules that can be used in the invention can be used to treat patients for extended periods of time, with good or excellent symptom relief and low toxicity. The achieved therapeutic results may include low immunogenicity and / or high affinity, as well as other undefined properties. TNF receptor multimeric molecules useful in the present invention consist of all or a functional part of the ECD of two or more TNF receptors linked by one or more polypeptide linkers or other non-peptide linkers such as polyethylene glycol (PEG). The multimeric molecules may in addition contain the signal peptide of a secreted protein to direct the expression of the multimeric molecule. These multimeric molecules and methods of making them are described in US Application No. 08/437533 (filed May 9, 1995). TNF immunoreceptor fusion molecules that may be useful in the present invention comprise at least one portion of one or more immunoglobulin molecules and all or a functional portion of one or more TNF receptors. These immunoreceptor fusion molecules can be assembled as monomers, or hetero- or homomultimers. TNF immunoreceptor fusion molecules can also be monovalent or multivalent. An example of such a TNF immunoreceptor fusion molecule is the TNF receptor / IgG fusion protein. TNF immunoreceptor fusion molecules and methods of making them have been described in the art (Lesslauer et al. , Eur. J. Immunol. 21: 2883-2886 (1991); Ashkenazi et al. , Proc. Natl. Acad. Sci. USA 88: 10535-10539 (1991); Peppel et al. , J. Exp. Med. 174: 1483-1489 (1991); Kolls et al. , Proc. Natl. Acad. Sci. USA 91: 215-219 (1994); Butler et al. , Cytokine 6 (6): 616-623 (1994); Baker et al. , Eur. J. Immunol. 24: 2040-2048 (1994); Beutler et al. , US Patent No. 5,447,851 and US Application No. 08/442133 (filed May 16, 1995). Methods of making immunoreceptor fusion molecules may also be found in Capon et al. , US Patent No. 5,116,964; Capon et al. , U.S. Patent No. 5,225,538, and Capon et al. , Nature 337: 525-531 (1989). A functional equivalent, derivative, fragment or region of a TNF receptor molecule refers to the portion of the TNF receptor molecule or sequence portion of the TNF receptor molecule that encodes a TNF receptor molecule that has a size and sequence sufficient to To be functionally similar to TNF receptor molecules which can be used in the present invention (e.g. binds TNF with high affinity and has a low immunogenicity). The functional equivalent of a TNF receptor molecule also includes modified TNF receptor molecules that functionally resemble the TNF receptor molecules that can be used in the present invention (e.g. binds TNF with high affinity and has low immunogenicity). For example, a functional equivalent of a TNF receptor molecule may include a "MUTE" codon or one or more based on n amino acids, deletions, or additions (e.g. substitution of one acidic amino acid with another acidic amino acid or substitution of a codon encoding the same or a different hydrophobic amino acid with another codon encoding a hydrophobic amino acid. See Ausubel et al. , Current Protocols in Molecular Biology, Greene Publishing Assoc. and Wiley-Interscience, New York (1987-2000). Cytokines include all known cytokines. See e.g. CopewithCytokines. com. Cytokine antagonists include, but are not limited to, any antibodies, fragments or mimetics, any soluble receptors, fragments or mimetics, any low molecular weight antagonists, or any combination thereof. Treatment An antibody or a pharmaceutical composition according to the present invention may be used in the treatment of an IL-12 mediated disorder, comprising administering an effective amount of an anti-IL-12 antibody or pharmaceutical composition to a cell, tissue, organ, animal or patient in need of it. Such a method can also optionally include co-administration or combination therapy for the treatment of such immune diseases, wherein the administration of said anti-IL-12 antibody or pharmaceutical composition comprises administration before, concurrently with, or after at least one selected route. among at least one TNF antagonist (e.g. but not limited to TNF antibodies or fragment thereof, soluble TNF receptor or fragment thereof, fusion proteins thereof, or low molecular weight TNF antagonist), anti-rheumatic drug (e.g. methotrexate, auranic acid, aurothioglucose, azathioprine, etanercept, lotava sodium thioate, hydroxychloroquine sulfate, leflunomide, sulfasalazine), muscle relaxant, drug, non-steroidal anti-inflammatory drug (NSAID) , pain reliever, anesthetic, sedative, local anesthetic, neuromuscular blocker, antimicrobial drug (e.g. aminoglycoside, antifungal drug, antiparasitic drug, antiviral drug, carbapenem, cephalosporin, fluoroquinoline, macrolide, penicillin, sulfonamide, tetracycline, other antimicrobial drug), anti-psoriatic drug, corticosteroid, diabetic steroid, anabolic steroid a mineral, a nutrient, a thyroid factor, a vitamin, a calcium hormone, an anti-diarrheal drug, an antitussive, an anti-emetic, an anti-ulcer, a laxative, an anti-coagulant, erythropoietin (e.g. epoetin alfa), filgrastim (e.g. G-CSF, Neupogen), Sargramostim (GM-CSF, Leukine), Vaccine, Immunoglobulins, Immunosuppressant (e.g. basiliximab, cyclosporine, daclizumab), growth hormone, hormone replacement therapy drug, estrogen receptor modulator, cerebral dilator, cycloplegic agent, alkylating agent, antimetabolite, mitosis inhibitor, radiotherapy agent, antidepressant drug, anti-manic agent , anti-psychotic agent, anxiety factor, hypnotic, sympathomimetic agent, stimulant, donepezil, tacrine, asthma drug, beta agonist, inhalation steroid, leukotriene inhibitor, methylxanthine, cromoline, epinephrine or its alpha analogue (dornase Pulmozyme), cytokines or cytokine antagonists. Typically, treatment of a pathological condition is accomplished by administering an effective amount or dose of at least one anti-IL-12 composition that has an average amount of SC ranging from at least about 0.01 to 500 milligrams of at least one anti-IL-12 antibody. -IL-12 per kilogram of body weight per patient - per dose, in the case recommended from about 0.1 to 100 milligrams per kilogram of body weight per patient - per dose administered once or repeatedly, depending on the specific activity contained in the composition. Alternatively, the effective plasma concentration can be 0.1 - 5000 µg / ml plasma per single or multiple administration. Appropriate dosages are known to the practicing physician, of course, depending on the particular disease state, the activity of the specific composition administered, and the particular patient to be treated. In some cases, it may be necessary to repeat the administration to achieve the desired therapeutic amount, i.e. repeated individual administration of a specific monitored or metered dose, and continued administration to the individual until the desired daily dose or effect is reached. Recommended doses are optionally 0.1; 0.2; 0.3; 0.4; 0.5; 0.6; 0.7; 0.8; 0.9; 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; thirty; 31; 32; 33; 34; 35; 36; 37; 38; 39; 40; 41; 42; 43; 44; 45; 46; 47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59; 60; 62; 63; 64; 65; 66; 67; 68; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99 and / or 100-500 mg / kg / administration, or any range, sc value or part thereof, or until a plasma concentration of 0.1 is reached; 0.5; 0.9; 1.0; 1.1; 1.2; 1.5; 1.9; 2.0; 2.5; 2.9; 3.0; 3, 5; 3, 9; 4.0; 4.5; 4.9; 5.0; 5.5; 5.9; 6.0; 6.5, 6.9; 7.0; 7.5; 7.9; 8.0; 8.5; 8.9; 9.0; 9.5; 9.9; 10; 10.5; 10.9; 11; 11.5; 11.9; 20; 12.5; 12.9; 13.0; 13.5; 13.9; 14.0; 14.5; 4.9; 5.0; 5.5; 5.9; 6.0; 6.5; 6.9; 7.0; 7.5; 7.9; 8.0; 8.5; 8.9; 9.0; 9.5; 9.9; 10; 10.5; 10.9; 11; 11.5; 11.9; 12; 12.5; 12.9; 13.0; 13.5; 13.9; 14; 14.5; 15; 15.5; 15.9; 16; 16.5; 16.9; 17; 17.5; 17.9; 18; 18.5; 18.9; 19; 19.5; 19.9; 20; 20.5; 21; 22; 23; 24; 25; 26; 27; 28; 29; thirty; 35; 40; 45; 50; 55; 60; 65; 70; 75; 80; 85; 90; 96; 100; 200; 300; 400; 500; 600; 700; 800; 900; 1000; 1500; 2000; 2500; 3000; 3500; 4000; 4,500 and / or 5,000 µg / ml of plasma per single or multiple dose administration or any range, value or part thereof. Alternatively, the dose administered may vary depending upon known factors, such as the pharmacodynamic characteristics of the agent, the way and route of administration, the patient's age, health, and weight, nature and severity of symptoms, type of concurrent therapy, frequency of administration, and frequency of administration. sc treatment and after the desired effect. Typically, the dose of the active ingredient may be in the range of about 0.1 to 100 milligrams per kilogram of body weight. Typically, 0.1 to 50 is sufficient to achieve the desired results, preferably 0.1 to 10 milligrams per kilogram at a time or in the case of pre-slow release form. As a non-limiting example, administration can be performed in humans or animals by single or periodic administration of at least one antibody of the present invention at a dose of 0.1 to 100 mg / kg, such as 0.5; 0.9; 1.0; 1.1; 1.5; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; thirty; 40; 45; 50; 60; 70; 80; 90 or 100 mg / kg, per day n, at least once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 days or alternatively or additionally at least once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 , 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 , 48, 49, 50, 51 or 52 weeks or alternatively or additionally at least once every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 years of age, or any combination thereof, using single dose, infusion or repeated doses. Dosage forms (composition) suitable for topical administration will generally contain from about 0.1 milligrams to about 500 milligrams of active ingredient per unit or package. In these pharmaceutical compositions, the active ingredient is usually present in an amount of about 0.5-99.999% by weight, based on the total weight of the composition. For parenteral administration, the antibody may be formulated as a solution, suspension, emulsion, or lyophilized powder, supplied separately or with a pharmaceutically acceptable parenteral carrier. Examples of such carriers are water, saline, Ringer's solution, dextrose solution and 1 - 10% human serum albumin. Liposomes or non-aqueous vehicles such as solidified oils may also be used. A carrier or freeze-dried powder may contain additives that make it isotonic (e.g. sodium chloride, mannitol) and chemical stability (e.g. buffers and preservatives). The composition is sterilized by known or appropriate techniques. Suitable pharmaceutical carriers are described in the latest edition of Remington's Pharmaceutical Sciences, A. Donkey, the standard textbook in the field. Alternative Administration Many of the known and improved modes described herein may be used to administer a pharmaceutically effective amount of at least one anti-IL-12 antibody of the present invention. Pulmonary administration is used in the following description, but other modes of administration can be used in accordance with the invention with appropriate results. The IL-12 antibodies of the present invention can be administered in a carrier, as a solution, emulsion, colloid, suspension, or as a dry powder using any of a number of methods and devices suitable for administration by inhalation or other modes as described herein or known in the art. Compositions and Parenteral Administration Compositions for parenteral administration may contain, as conventional excipients, sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. Injectable aqueous or oily suspensions may be made with a suitable emulsifier or wetting agent and a suspending agent in accordance with known methods. The injection agents can be non-toxic diluting agents which are not suitable for oral administration, such as an aqueous solution or sterile injection solution or a suspension in a solvent. Acceptable carriers or solvents are water, Ringer's solution, isotonic saline, etc. ; sterile fixed oil can be used as an ordinary solvent or suspending solvent. For these purposes, any type of fixed oil or fatty acid may be used, including natural or synthetic or semi-synthetic fatty oils or fatty acids, natural or synthetic or semi-synthetic mono- or di- or triglycerides. Parenteral administration is known in the art and includes, but is not limited to, conventional injection methods, a needle-free injection device using pressurized gas as described in US Patent No. 5,851,198, and a laser perforation device as described in the patent. U.S. No. 5,839,446. Alternative Delivery ventricles of the brain, intra-cervical, intra-gastric, atrophic, intra-myocardial, intraosseous, intravenous, intra-pericardial, intraperitoneal, intopulmonary, prostatic, inhaled, rectal, intraretinal, intraretinal, medullary, intrasynovial , intra-thoracic, intrauterine, intra-epidermal, single dose, vaginal, rectal, buccal, sublingual, intranasal or transdermal. The composition of at least one anti-IL-12 antibody may be prepared for use for parenteral (subcutaneous, intramammary or intravenous) administration or any other application, particularly as a liquid solution or suspension; for use for vaginal or rectal administration, particularly in semi-solid forms such as, but not limited to, creams and suppositories; for buccal or sublingual administration, such as, but not limited to, in tablet or capsule form; or intranasally, such as but not limited to powders, nasal drops or aerosols or certain agents; or transdermal, such as in the form of gels, ointments, lotions, suspensions, or patch modes of administration, with chemical adjuvants such as dimethylsulfoxide to either modify the skin structure or increase the concentration of the drug in the transdermal patch (Junginger et al. in "Drug Permeation En- hancement"; Hsieh, D. NS. , pub. , p. 59-90 (Marcel Dekker, Inc. New York 1994, either with the help of oxidizing agents that allow the administration of compositions containing proteins and peptides to the skin (WO 98/53847), or the use of electric fields to create transient transport pathways, such as electroporation, or to increase the motility of sc on the transdermal laden drugs, such as iontophoresis, or the use of ultrasound compounds, such as sonophoresis (US Pat. Nos. 4,309,989 and 4,767,402). Pulmonary / intranasal administration For pulmonary administration, it is recommended that at least one anti-IL-12 antibody composition provide a particle size effective to achieve the lower respiratory tract, lungs or sinuses. The at least one anti-IL-12 antibody according to the invention can be delivered by any of a variety of inhalation or intranasal devices known in the art that relieves the administration of therapeutic agents by inhalation. These devices capable of delivering aerosol compositions into the sinuses or pulmonary alveoli include metered dose inhalers, nebulizers, dry powder generators, nebulizers and the like. Other devices are also known in the art suitable for effecting pulmonary or intranasal administration of 1 antibody. All these devices may use compositions suitable for the administration of an aerosolized antibody. Such aerosols can contain either solutions (both aqueous and non-aqueous) or solid particles. Metered dose inhalers, such as the Ventolin® metered dose inhaler, typically use propellant gas and require activation during inspiration (see e.g. WO 94/16970, WO 98/35888). In dry powder inhalers such as Turbuhaler ™ (Astra), Rotahalere® (Glaxo), Diskus® (Glaxo), Spiros ™ inhaler (Dura), devices sold by Inhale Therapeutics and the Spinhaler® powder inhaler (Fisons), used is breath activation of the mixed powder (US 4,668,218 Astra, EP 237507 Astra, WO 97/25086 Glaxo, WO 94/08552 Dura, US 5458135 Inhale, WO 94/06498 Fiscons). In nebulizers such as AERx ™ Aradigm, Ultravent® nebulizer (Mallinckrodt) and Acorn II® nebulizer (Marquest Medical Products) (US 5404871 Aradigm, WO 97/22376), aerosols are made from solutions, while metered dose inhalers, dry powder inhalers e.t.c. produce aerosols of small particles. These particular examples of commercially available inhalation devices are intended to be representative of specific devices suitable for the practice of this invention, but are not intended to be limiting in scope. Preferably, a composition comprising at least one anti-IL-12 antibody is delivered via a dry powder inhaler or nebulizer. There are several desirable features of an inhalation device for administering at least one antibody in accordance with the present invention. For example, in a preferred situation, delivery by an inhalation device is reliable, reproducible and accurate. The inhalation device may optionally provide some dry particles, e.g. less than approximately 10 µm, with approximately 1-5 µm recommended for good inhalation. Administration of the IL-12 antibody composition in a nebulized form. A spray of the anti-IL-12 antibody protein composition can be prepared by forcing a suspension or solution of at least one anti-IL-12 antibody through a nozzle under pressure. The size and pattern of the nozzles, the applied pressure and the fluid delivery rate can be selected to obtain the desired outflow and particle size. For example, it is possible to generate an electrospray by means of an electric field in conjunction with a capillary or by feeding to a nozzle. In the case of the recommended particle size of the protein composition, the IL-12 antibodies administered by a nebulizer have a particle size smaller than about 10 µm, in the case of the recommended particle size from about 1 µm to about 5 µm, and in particular approx. 2 µm to approx. 3 µm. Compositions with at least one anti-IL-12 antibody protein composition suitable for use in a nebulizer generally comprise a protein composition of the antibody Ia in an aqueous solution at a concentration of about 0.1 mg per eye 100 mg of at least one anti-IL-12 antibody 1a protein composition per mL of solution, or mg / gm or any range or value therefrom, e.g. not limiting acoPL 205 786 B1 31 0.1; 0.2; 0.3; 0.4; 0.5; 0.6; 0.7; 0.8; 0.9; 1; 2; 3; 4; 5; 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17; 18; 19; 20; 21; 22; 23; 24; 25; 26; 27; 28; 29; thirty; 40; 45; 50; 60; 70; 80; 90 or 100 mg / ml or mg / gm. The composition may contain agents such as an excipient, buffer, isotonic agent, preservative, surfactant and, preferably, zinc. The composition may also contain an excipient or an agent to stabilize the protein composition of an antibody, such as a buffer, a reducing agent, a filler protein, or a carbohydrate. For white filler drugs useful for the preparation of protein compositions of antibodies, include albumin, protamine and the like. Typical carbohydrates useful in formulating antibody 1 protein compositions include sucrose, mannitol, lactose, trehalose, glucose, and the like. The preparation of the antibody Ia protein composition may also contain a surfactant which can reduce or prevent surface contact induced aggregation of the antibody Ia protein composition caused by atomization of the solution during aerosol formation. Various conventional surfactants can be employed, such as fatty acid polyoxyethylene alcohol esters and polyoxyethylene sorbitan fatty acid esters. Amounts will typically range from 0.001 to 14% by weight of the composition. Especially preferred surfactants for the purposes of this invention are polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20 or the like. Additional factors known in the art of formulating protein compositions such as IL-12 antibodies, or specific portions or variants, may also be included in the composition. Administration of IL-12 antibody composition with a nebulizer The protein antibody composition 1a may be administered with a nebulizer, such as jet nebulizer or ultrasonic nebulizer. As a rule, a nebulizer uses a stream of compressed air to generate a high velocity air stream flowing out of the orifice. As the gas expands beyond the nozzles, a low pressure region is created which draws the solution of the antibody protein composition Ia through a capillary tube connected to the liquid reservoir. The stream of n liquid from the capillary tube breaks down into unstable filaments and droplets as it leaves the tube, generating an aerosol. A variety of configurations, flow rates, and deflector types can be used to achieve a given performance characteristic for a given jet nebulizer. In an ultrasonic nebulizer, high frequency electrical energy is used to generate vibrational mechanical energy, generally using a piezoelectric transducer. This energy is transferred to the protein composition of the antibody composition either directly or via the coupling fluid, producing an aerosol containing the antibody protein composition. In the case of the recommended particle size of the protein composition, the antibodies Ia administered through the nebulizer have a particle size smaller than about 10 µm, in the case of the recommended particle size from about 1 µm to about 5 µm, especially about 2 µm up to approx. 3 µm. Compositions of at least one anti-IL-12 antibody, Ia, suitable for use in a jet or ultrasonic nebulizer, typically contain as much as about 0.1 mg to about 100 mg of at least one anti-IL-12 antibody protein Ia per ml of solution. The composition may contain c agents such as an excipient, buffer, isotonic agent, preservative, surfactant and, preferably, zinc. The composition may also contain an excipient or an agent to stabilize the protein composition of an antibody, such as a buffer, a reducing agent, a filler protein, or a carbohydrate. Protein fillers useful in the preparation of protein compositions of antibodies include albumin, protamine and the like. Typical carbohydrate antibodies useful in formulating protein compositions include sucrose, mannitol, lactose, trehalose, glucose, and the like. The at least one anti-IL-12 antibody composition may also include a surfactant that can reduce or prevent surface-induced aggregation of the antibody protein composition caused by atomization of the solution during formation. aerosol. Various conventional surfactants can be employed, such as fatty acid polyoxyethylene alcohol esters and polyoxyethylene sorbitan fatty acid esters. Amounts will generally range from 0.001 to 4% by weight of the composition. Particularly preferred surfactants in the invention are polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20 or the like. The compositions may also include additional factors known in the art of formulating protein compositions such as antibody proteins. Administration of IL-12 antibody composition by means of a metered dose inhaler a mixture containing a compressed liquid gas. Activation of the measuring valve releases the mixture in the form of an aerosol, in the recommended case containing particles from the size range smaller than about 10 µm, especially about 1 µm to about 5 µm and in particular about 2 µm to about 3 µm. The desired size of the aerosol particles can be obtained by using an anti-Ia protein composition preparation obtained by a variety of methods known to those skilled in the art, including pulverization, spray drying, critical point condensation or the like. . The recommended metered dose inhalers are those that make 3M or Glaxo that use hydrofluoric propellant gas. Compositions of at least one anti-IL-12 antibody for use in a metered dose inhaler include, in general a fine powder, containing at least one anti-IL-12 antibody suspended in a non-aqueous medium, for example a suspension in a non-aqueous medium. in propellant gas with a surfactant. The propellant gas can be any conventional material used for this purpose, such as a hydroclorofluorocarbon compound, a hydroclorofluorocarbon compound, a hydrofluorocarbon compound, or a hydrocarbon compound including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoro, and 1,1,2-tetrafluoroethane, HFA-134a (hydrofluoroalkane-134a), HFA-227 (hydrofluoroalkane-227) or the like. The recommended propellant gas is the hydrofluorocarbon compound. A surfactant can be used to protect the at least one anti-IL-12 antibody from chemical degradation and the like. Suitable surfactants include sorbitan trioleate, soy lecithin, oleic acid, and the like. In some cases, aerosols containing solutions using solvents such as ethanol are recommended. The composition may also contain additional agents known in the art of protein formulation, such as protein. It will be appreciated by one of skill in the art that the methods described herein can be accomplished by inhaling a composition of at least one anti-IL-12 antibody using devices not described herein. Oral Compositions and Administration Compositions for oral administration are based on the co-administration of adjuvants (e.g. resorcinol and non-ionic surfactants such as polyoxyethylene oleic ether and polyethylene n-hexadecyl ether) to artificially increase the permeability of the intestinal walls, as well as co-administration of enzyme inhibitors (e.g. pancreatic trypsin inhibitors, diisopropyl fluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation. The compound, which is the active ingredient of a solid dosage form for oral administration, may be mixed with at least one additive, including sucrose, lactose, cellulose, mannitol, trehalose, raffinose. , maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, gum tragacanth, arabic gum, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer and glyceride. These dosage forms may also contain other type (s) of additives, e.g. inactive diluting agents, lubricant such as magnesium stearate, paraben, preservative such as sorbic acid, ascorbic acid, alpha tocopherol, antioxidant such as cysteine, dispersant, binders a, a thickening agent, a buffering agent, a sweetening agent, a flavoring agent, a flavoring agent, etc. Tablets and pills can be transformed further into coated preparations, protecting against the action of gastric juice. Liquid preparations for oral administration include medicinally acceptable emulsion, syrup, elixir, suspension and solution. These preparations may contain inactive diluting agents conventionally used in this field, e.g. water e. Liposomes have also been described as drug delivery systems for insulin and heparin (US Pat. No. 4,239,754). Recently, microspheres of artificial polymers of mixtures of amino acids (proteinoids (U.S. Pat. No. 4,925,673). In addition, carrier compounds described in US Pat. U.S. Patent No. 5,879,681 and U.S. Pat. No. 5,587,1753. Compositions and Intra-mucosal Administration For absorption by the surface of the mucosa of the mucosa, compositions and methods for administering at least one anti-IL-12 antibody include a multi-submicron emulsion, a mucoadhesive macromolecule, a bioactive peptide, and an anti-IL-12 antibody. The water phase facilitates the absorption by the surface of the mucous membranes by obtaining mucoadhesion of the emulsion particles (pat. No. 5,514,670). Mucous membranes suitable for applying the emulsions described herein include: the corneal, conjunctival, buccal, sublingual, nasal, vaginal, pulmonary, gastric, enteral, and rectal routes of administration. Compositions for vaginal or rectal administration, e.g. suppositories, which may contain excipients, for example, polyalkylene glycols, petroleum jelly, cocoa butter and the like. Compositions for nasal administration may be solid and contain, for example, lactose as excipients, or they may be aqueous solutions or oily nasal drops. Excipients for buccal delivery include sugars, calcium stearate, magnesium stearate, gelatinized starches, and the like (U.S. Pat. No. 5,849,695). Transdermal Compositions and Administration For transdermal administration, at least one anti-IL-12 antibody described is encapsulated in a delivery device, such as a liposome or polymer nanoparticles, microparticles, microcapsules, or microspheres (collectively referred to as microspheres, unless otherwise stated). A number of suitable devices are known including microparticles made of synthetic polymers such as polyhydroxy acids such as polylactic acid, polyglycolic acid and their copolymers, orthopolyesters, polyanhydrides and polyphosphazenes, and natural polymers such as collagen, polyamino acids, albumin and other proteins, alginate and other polysaccharides, and combinations thereof (U.S. Pat. U.S. No. 5,814,599). Compositions and Prolonged Administration At times, it may be desirable to deliver the compounds described herein to a patient for an extended period of time, for example, from one week to one year, after the first administration. Various slow release, depot or implant dosage forms can be used. For example, the dosage form may contain a pharmaceutically acceptable non-toxic salt of a compound that dissolves only to a low degree in the body fluids, for example, (a) an acid addition salt with a polybasic acid such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannin, para-amino acid, alginic acid, polyglutamic acid, naphthalenemono- or disulfonic acids, polygalacturonic acid and the like; (b) a salt with a polyvalent metal ion such as zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium and the like, or with an organic cation resulting from e.g. N, N'-dibenzylethylenediamines or ethylenediamines; or (c) a combination of (a) and (b), e.g. zinc-tannin salt. Additionally, the compounds described herein or, preferably, a relatively insoluble salt such as those described herein may be formulated as a gel, e.g. aluminum monostearate gel with e.g. sesame oil, suitable for injection. Zinc salts, zinc tannin salts, pamic acid salts and the like are particularly preferred. Another type of slow release depot composition for injection may include a dispersion of a compound or salt to be encapsulated in a slowly decomposing, non-toxic, non-antigenic polymer such as a polylactic acid / polyglycolic acid polymer on an example as described in US Pat. U.S. No. 3,773,919. The compounds or, preferably, relatively insoluble salts, such as those described above, can also be formulated in silastic granules with a cholesterol matrix, particularly for use in animals. Other slow release, depot or implant compositions are known in the literature, e.g. gas or liquid liposomes (Pat. No. 5,770,222 and "Sustained and Controlled Release Drug Delivery Systems", J. R. Robinson, ed. , Marcel Dekker, Inc. , N. Y. , 1978). Upon general description of the invention, the invention can be understood more readily by reference to the following examples, which are given by way of illustration and not by way of limitation. Example 1: Cloning and expression of an anti-IL-12 antibody in mammalian cells A typical mammalian expression vector contains at least one promoter element mediating the initiation of mRNA transcription, the antibody coding sequence, and the signals required for ter - transcription mination and transcript polyadenylation. Additional elements include enhancers, Kozak sequences, and intron sequences flanked by donor and acceptor sites for RNA assembly. High throughput transcription can be achieved from the SV40 early and late promoters, the long terminal long repeat n repeats (LTRs) from retroviruses e.g. RSV, HTLVI, HIVI and cytomegalovirus early promoter (CMV). However, it is also possible to use cellular elements (e.g. promoter of the human actin gene). Suitable expression vectors for use in the invention include, e.g. vectors such as pIRESlneo, pRetro-Off, pRetro-On, PLXSN or pLNCX (Clonetech Labs, Palo Alto, CA), pcDNA3. 1 (+ /), pcDNA / Zeo (+ / -) or pcDNA3. 1 / Hygro (+ / -) (Invitrogen), PSVL and PMSG (Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 37152), pSV2dhfr (ATCC 37146) and pBC12MI (ATCC 67109). Mammalian host cells that may be used include human Hela 293, H9 and Jurkat cells, mouse NIH3T3 and C127 cells, Cos 1, Cos 7 and CV 1 cells, QC1-3 quail cells, mouse L cells, and chi hamster ovary cells. nski (CHO). Alternatively, the gene can be expressed in stable cell lines containing the gene integrated on a chromosome. Co-transfection with a selectable marker such as sc resistance to dhfr, gpt, neomycin or hygromycin allows the identification and isolation of transfected cells. The gene that is transfected can also be duplicated to express large amounts of the encoded antibody. The DHFR (dihydrofolate reductase) marker is useful in obtaining cell lines carrying up to several thousand copies of the relevant gene. Another useful selectable marker is the enzyme glutamine synthase (GS) (Murphy et al. , Biochem. J. 227: 277279 (1991); Bebbington et al. , Bio / Technology 10: 169-175 (1992)). Using these markers, mammalian cells are grown on a selective medium and cells with higher resistance are selected. Such cell lines contain a duplicated (duplicated) gene (s) integrated on a chromosome. Chinese hamster ovary (CHO) cells and NSO cells are often used for the production of the antibody. The expression vectors pC1 and pC4 contain a strong promoter (LTR) of the Mi Esaka Rous virus (Cullen et al. , Molec. Cell. Biol. 5: 438-447 (1985)), additionally contain a fragment of the CMV enhancer (Boshart et al. , Cell 41: 521-530 (1985)). Multiple cloning sites, e.g. The cut-off sites for the restriction enzymes BamHI, Xbal and Asp718 allow for the cloning of the corresponding gene. The vectors contain, in addition, the 3 'intron, the polyadenylation and termination signal of the rat preproinsulin gene. Cloning and Expression in CHO Cells The vector pC4 is used to express anti-IL-12 antibody. The plasmid pC4 is derived from the plasmid pSV2-dhfr (ATCC Accession No. 37146). The plasmid contains the murine DHFR gene under the control of the SV40 early promoter. Chinese hamster ovary cells or other cells lacking dihydrofolate reductase activity transfected with these plasmids can be selected by growing on a selective medium (e.g. alpha minus MEM, Life Technologies, Gaithersburg, MD) supplemented with methotrexate, a chemotherapeutic agent. The duplication of DHFR genes in methotrexate (MTX) resistant cells has been well documented (see e.g. F. IN. Alt et al. , J. Biol. Chem. 253: 1357-1370 (1978); J. NS. Hamlin and C. Ma, Biochem. et Biophys. Acta 1097: 107-143 (1990); them. J. Page and M. AND. Sydenham, Biotechnology 9: 64-68 (1991)). Cells cultured in increasing concentrations of MTX develop SC drug resistance by overproducing the target enzyme DHFR, achieved by amplifying the DHFR gene. If another gene is linked to the DHFR gene, it is usually duplicated and overexpressed along with it. It is known that this approach can be used to create cell lines carrying more than 1000 copies of the duplicated gene (s). Then, when methotrexate is withdrawn, cell lines are obtained containing the amplified gene integrated into one or more of the host cell chromosomes. The plasmid pC4 for expression of a given gene contains the strong promoter of the long terminal repeat (LTR) of the Rous virus (Cullen et al. , Molec. Cell. Biol. 5: 438-447 (1985)), it additionally contains a fragment isolated from the enhancer of the human cytomegalovirus (CMV) earliest genes (Boshart et al. , Cell 41: 521-530 (1985)). Downstream from the promoter are the cut sites for the restriction enzymes BamHI, Xbal and Asp718 allowing gene splicing. Downstream of these cloning sites, the plasmid contains the 3 'intron and the polyadenylation site of the rat preproinsulin gene. For expression, other, highly efficient promoters, e.g. human ß-actin promoter, SV40 early or late promoters or long terminal repeats (LTRS) from retro viruses e.g. HIV and HTLVI. Regulated expression of IL-12 in mammalian cells can be done using the Tet-Off and Tet-On gene expression systems from Clontech or similar systems (M. Gossen and H. Bujard, Proc. Natl. Acad. Sci. USA 89: 5547-5551 (1992)). Other signal sequences, e.g. from the human growth hormone or globin genes. Stable cell lines carrying the appropriate gene integrated into chromosomes can also be selected by co-transfection with a selectable marker such as gpt, G418 and methotrexate. Plasmid pC4 is digested with restriction enzymes and then dephosphorylated with calf intestinal phosphatase in a standard manner. The vector is then isolated from a 1% agarose gel. The DNA sequence that encodes all of the IL-2 antibody is used, e.g. as shown in SEQ ID NOS: 7 and 8, corresponding to the HC and LC variable regions of the antibody IL-12 according to the invention, according to known methods. The isolated DNA encoding the corresponding variable and constant region (i.e. HC and LC regions) is also used in this construct (as provided in the p1351 vector). The isolated DNA encoding the variable and constant region and the dephosphorylated vector are then ligated and the DNA of T4 phage. E cells are transformed. coli HB101 or XL-1 Blue, and bacteria are identified that contain the pC4 plasmid with the insert, e.g. by restriction enzyme analysis. Chinese hamster ovary (CHO) cells that do not have an active DHFR gene are used for transfection. Cotransfections are performed with 5 µg of the pC4 expression plasmid and 0.5 µg of the pSV2-neo plasmid with lipofectin. The pSV2neo plasmid contains the dominant selection marker the neo gene from the Tn5 transposon, which encodes the enzyme responsible for sc resistance to antibiotics from the group to which G418 belongs. Cells are seeded on the alpha minus MEM medium supplemented with G418 at 1 µg / ml. After two days, cells are trypsinized and plated on hybridoma cloning dishes (Greiner, Germany) on alpha minus MEM medium supplemented with 10, 25 or 50 ng / ml methotrexate and 1 µg / ml G418. . After approximately 10-14 days individual clones are trypsinized and then seeded in 6-well petri dishes or 10 ml bottles at different concentrations of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM). Clones grown at a higher concentration of methotrexate are transferred to new 6-well petri dishes with an even higher concentration of methotrexate (1 mM, 2 mM, 5 mM, 10 mM, 20 mM). This procedure was repeated to obtain clones growing at 100-200 mM concentrations. The expression of the products of the relevant genes is checked by e.g. SDS-PAGE and Western blot or reverse phase HPLC chromatography. Example 2: Production of high affinity human monoclonal IgG antibodies reactive with human IL-2 using transgenic mice Summary Transgenic mice containing human heavy and light immunoglobulin genes were used to produce full human flax monoclonal monoclonal antibodies that can be used to inhibit the action of IL-12 in the treatment of one or more IL-12 related diseases. F2 hybrid mice (CBA / J x C57 / BL6 / J) containing human variable and constant region transgenes for both heavy and light antibody l chains are immunized with human recombinant IL -12 (Taylor et al. , Intl. Immunol. 6: 579-591 (1993); Lonberg et al. , Nature 368: 856-859 (1994); Neuberger, M. , Nature Biotech. 14: 826 (1996); Fishwild et al. , Nature Biotechnology 14: 845-851 (1996)). Several fusions generated one or more sets of fully human monoclonal IgG antibodies reactive with IL-12. Fully human anti-IL-12 antibodies were further characterized. They all belong to the IgG1 class. These antibodies have been shown to have constant affinity in the range of approximately 1x10 9 and 9x10 12. The surprisingly high affinity of these fully human monoclonal I antibodies makes them suitable for therapeutic applications in IL-12 related diseases, pathologies or disorders. Abbreviations BSA - bovine serum albumin CO 2 - carbon dioxide DMSO - dimethyl sulfoxide EIA - enzyme immunoassay FBS - ice bovine serum H 2 O 2 - hydrogen peroxide HRP - horseradish peroxidase ID - intradermal Ig - immunoglobulin IL-12 - interleukin 12 IP - intraperitoneal IV - intravenous Mab - monoclonal antibodies OD - g esto sc optical OPD - o-phenylenediamine dihydrochloride PEG - polyethylene glycol PSA - penicillin, streptomycin, amphotericin RT - room temperature SQ - subcutaneous v / v - vol eto sc / vol etosc w / v - mass / vol. sc Materials and Methods Animal eta Transgenic mice capable of expressing human lsa antibodies known in the art (are available (e.g. with GenPharm International, San Jose, CA; Abgenix, Freemont, CA, and others) and express human immunoglobulins, but not murine IgM or Ig. For example, such transgenic mice possess V (D) J-linkage human transgene sequences, heavy chain class alterations, and somatic mutations, allowing the generation of a wide repertoire of human immunoglobulin sequences ( Lonberg et al. , Nature 368: 856-859 (1994)). The light chain transgene may be derived from e.g. Partly from yeast clones with an artificial pathway chromosome containing nearly half of the human V region encoded in the germ cell line. Additionally, the heavy chain transgene can encode both the human µ and 1 regions (Fishwild et al. , Nature Biotechnology 14: 845-851 (1996)) and / or 3 constant regions. In order to obtain fully human, monoclonal anti-IL-12 antibodies, mice derived from genotypically appropriate lines can be used for the immunization and fusion process. Immunization One or more immunization regimens can be used to generate human anti-IL-12 hybridomas. The first few fusions may be performed according to the following exemplary immunization protocol, and other known similar protocols may also be used. Several 14-20 week old females and / or surgically castrated transgenic male mice are immunized with IP and / or ID 1 - 10,000 µg of recombinant human IL-12, emulsified in an equal volume of TITERMAX or Freund's complete adjuvant in the total volume of 100-400 µl (eg. 200). Each mouse can optionally be administered SQ 1-10 µg of saline for each of the 2 injection sites. Mice can then be immunized c 1-7, 5-12, 10-18, 17-25 and / or 21-34 days later by administration of IP (1-400 µg) and SQ (1-400 µg x 2) IL-12 emulsified in equal volume with TITERMAX or incomplete Freund's adjuvant. Mice can be exsanguinated 12-25 and 25-45 days later by orbital puncture without the use of anticoagulants. The blood clots for hours at RT, then serum is collected and the antibody titer of IL-12 is determined by the EIA test for IL-12 according to known methods. Mergers are performed when repeated injections do not result in a titer increase. The mice can then be given a final booster injection in the form of 1-400 µg IL-12 dissolved in 100 µl physiological saline. Three days later the mice are put to sleep by disrupting the spinal cord, the spleen is taken sterile, then flooded with 10 ml of cold saline solution in phosphate buffer (PBS), containing 100 U / ml of penicillin, 100 µg / ml of streptomycin and 0.25 µg / ml of amphotericin B (PSA). The splenocytes are harvested sterile by half of the spleen PSA-PBS. Cells are then pooled once with cold PSA-PBS, counted by elimination of dead cells in the trypan protein test and suspended in RPMI 1640 containing 25 mM Hepes. Cell fusions Fusions can be performed according to well known methods at a ratio of 1: 1 to 1:10 murine myeloma cells to viable spleen cells. In the non-limiting example, spleen cells are deposited together with the myeloma cells. The pellet is then slowly suspended for more than 30 seconds in 1 ml of 50% (w / v) PEG / PBS solution (1450 molecular weight PEG, Sigma) at 37 ° C. The fusion can then be stopped by slowly adding 10.5 ml of RPMI 1640 medium containing 25 mM Hepes (37 ° C) over 1 minute. The combined cells are then centrifuged for 5 minutes at 500-1500 rpm. Then the cells are suspended in HAT medium (after RPMI 1640 medium containing 25 mM Hepes, 10% Fetal Clone I (Hyclone) serum, 1 mM sodium pyruvate, 4 mM L-glutamine, 10 µg / ml gentamicin, 2, 5% Origen (Fisher) culture supplement, 10% conditioned media RPMI 1640 / Hepes 653, 50 µM 2-mercaptoethanol, 100 µM hypoxanthine, 0.4 µM aminopterin and 16 µM thymidine) and seeded at 200 µL / well on five 96-well, flat-bottomed cell culture plates. Plates are placed for 7-10 days in a humidified incubator at 37 ° C, 5% CO 2 and 95% air. Detection of Human IgG Anti-IL-12 Antibodies in Mouse Serum Solid-phase EIA assays are used to check for the presence of human IL-12 specific human IgG antibodies in mouse serum. Briefly, plates are coated with IL-12 by incubation overnight in PBS plus IL-12 at 2 µg / ml. After washing in 0.15 M sodium chloride solution containing 0.02% (v / v) Tween 20, plates are blocked with 1% (w / v) BSA in PBS, 200 µl / well for 1 hour at RT . Plates are immediately frozen at -20 ° C before further use. 50 µl / well of dilution of mouse serum are incubated on IL-12 coated plates for 1 hour at RT. Plates are washed and then incubated with goat anti-human IgG, Fc-specific, diluted 1: 30,000 in 1% BSA-PBS for 1 hour at RT. The plates are washed again and added for 15 minutes at RT 100 µl / well of citrate-phosphate substrate solution (0.1 M citric acid, 0.2 M sodium phosphate, 0.01% H 2 O 2 1 mg / ml OPD). Add 25 µl / well ePL 205 786 B1 37 stop solution (4N sulfuric acid) and read the OD at 490 nm using an automated pan spectrophotometer. Detection of Fully Human Immunoglobulins in Hybridoma Supernatants Growing hybridomas secreting fully human immunoglobulins are detected in the appropriate EIA assay. Briefly, 96-well pop-out plates (VWR, 610744) are coated with human Fc IgG by incubating in a 10 µg / ml solution of this antibody in sodium carbonate buffer overnight at 4 ° C. Plates are rinsed and blocked with 1% BSA-PBS for 1 hour at 37 ° C and used immediately or frozen at -20 ° C. The plates are incubated with undiluted hybridoma supernatants for 1 hour at 37 ° C. Plates are washed and then incubated with HRP-labeled goat anti-human kappa antibody diluted 1: 10,000 in 1% BSA-PBS for 1 hour at 37 ° C. The plates are then incubated with the substrate solution as described above. Determination of Fully Human Anti-IL-12 Reactivity The above hybridomas can be simultaneously tested for IL-12 reactivity using an appropriate RIA or other assay. For example, supernatants are incubated on plates coated with goat anti-human IgG Fc as described above, the plates are washed and incubated with radiolabeled IL-12 at an appropriate number of counts. per well for 1 hour at RT. The wells are rinsed twice with PBS and bound radiolabelled IL-12 is counted using an appropriate counter. Human IgG1 anti-IL-12 secreting hybridomas are amplified in cell culture and gradually subcloned by appropriate dilutions. The resulting clonal populations will be expanded and preserved by freezing in liquid nitrogen in freezing medium (95% FBS, 5% DMSO). Isotyping Determination of the isotype of antibody I can be done using EIA in a manner similar to that used to screen immunized mouse sera for specific titers. 96-well plates are coated with IL-12 as described above and incubated with purified antibody at 2 µg / ml for one hour at RT. The plate is washed and incubated with HRP labeled goat anti-human IgG 1 or HRP labeled goat anti-human IgG 3 diluted 1: 4000 in 1% BSA-PBS for one hour at RT. The plates are then washed and incubated with the substrate solution as described above. Binding kinetics of human anti-human IL-12 antibodies to human IL-12 The binding characteristics of anti-human I antibodies can be appropriately determined using e.g. retention of IL-12 in EIA and BIAcore technology. In the assays described above, various concentrations of purified human IL-12 antibodies can be assessed for binding to EIA plates coated with 2 µg / ml IL-12. The OD is presented as semi-logarithmic plots showing the relative bonding efficiencies. The constant quantitative constraint can be determined c, e.g. as shown below or another suitable known method a. The BIAcore CM-5 microarray (carboxymethylated) is placed in the BIAcore 2000 instrument. The matrix flow cell is flushed with HBS buffer (0.01 M HEPES, 0.15 M NaCl, 3 mM EDTA, 0.005% v / v P20 surfactant, pH 7.4) at a rate of 5 µl / min. to achieve a stable baseline reading. A solution (100 µl) of 15 mg EDC (N-ethyl-N '- (3-dimethyl-aminopropyl) carbodiimide hydrochloride) in 200 µl of water is added to 100 µl of a solution of 2.3 mg of NHS (N-hydroxysuccinimide) in 200 µl of water. Forty (40) µL of the resulting solution is injected onto the matrix. The matrix is injected with 6 µl of human IL-12 solution (15 µg / ml in 10 mM sodium acetate, pH 4.8), which causes an increase of approx. 500 RU. Buffer is changed to TBS / Ca / Mg / BSA working buffer (20 mM Tris, 0.15 M sodium chloride, 2 mM calcium chloride, 2 mM magnesium acetate, 0.5% Triton X-100, 25 µg / ml BSA , pH 7.4) and pooled overnight to equilibrate the matrix and achieve hydrolysis or protection of all unformed succinimide esters. Antibodies Ia are dissolved in the running buffer at concentrations of 33.33, 16.67, 8.33, and 4.17 nM. The flow rate is set to 30 µl / min and the operating temperature of the device to 25 ° C. Two flow chambers are used for the kinetics tests, one of which binds IL-12 (the test sample) and the other is the unmodified flow chamber (blank test). 120 µl of each concentration of 1 antibody is injected into the flow chamber at a rate of 30 µl / min (association phase), followed by an uninterrupted flow of buffer for 360 seconds (dissociation phase). The surface of the matrix is regenerated (dissociates the IL-12 / antibody complex) by injecting twice with 30 µl of 2M guanidine radical. Data analysis is normally performed using BIA version 3. 0 or CLAMP 2. 0. For each of the antibody concentrations, the blind sensogram is subtracted from the sample sensogram. A global fit for both dissociation (k d, sec -1) and association (k a, mol -1, sec -1) is performed and the dissociation constant (K D, mol) is calculated (k d / k a). If the affinity of antibody 1 is high such that the RU of the retained antibody 1a is 100, a test is performed with additional dilutions of the antibody 1a. Results and discussion Obtaining anti-human IL-12 monoclonal I antibodies Several fusions were performed and each fusion was plated on 15 plates (1440 wells / fusions), resulting in several dozen types of l antibodies specific for human IL-12. Some of them have been found to be composed of a combination of human and mouse Ig chains. The remaining poor hybridomas secrete anti-IL-12 antibodies consisting exclusively of human heavy and light chains. All human hybridomas are presumed to be of the IgG1 class. Binding kinetics of human anti-human IL-12 antibodies ELISA analyzes confirmed that the purified antibodies bind IL-12 to most hybridomas in a concentration-dependent manner. Fig. 1-2 show a relative binding efficiency of these antibodies l. In this case, the binding susceptibility of antibody 1 to its antigen (epitope) was measured. It should be noted that binding of IL-12 directly to the EIA plate may induce denaturation of the protein and the observed binding affinity may not reflect binding to the undenatured protein. At different concentrations, fifty percent efficiency is observed. The constant quantitative binding of human I antibodies is determined by BIAcore analysis and shows that several human I monoclonal antibodies have a very high affinity with K D ranging from 1x10-9 to 7x10-12. Conclusions Several fusions are performed using splenocytes from hybrid mice carrying human variable and constant antibody I transgenes immunized with human IL-12. A panel of several fully human IL-12 reactive monoclonal antibodies of IgG isotype IgG1 is being prepared. It is then characterized by fully human anti-IL-12 antibodies. The few produced opposites I have affinity constants between 1x10 -9 and 9x10 -12. The unexpectedly high affinity of these fully human monoclonal I antibodies makes them suitable for therapeutic applications in IL-12 related diseases, pathologies or disorders. Example 3: C340 is a neutralizing human monoclonal antibody It has been shown that the biological activity of IL-12 is neutralized by C340 in various IL-12 dependent activity assays. Since IL-12 enhances the production of IFN GAMMA by NK cells and T cells, the effect of the C340 antibody on the elevation of IFN GAMMA mRNA and the effect of C340 on the production of IFN GAMMA protein (Trinchieri, G. , Current Opinion in Immunology, 9: 17-23 (1997), Morris, S. C, et al. , Journal of Immunology, 152: 1047-1056 (1994)). The ability of C340 to induce IL-12-mediated neutralization to induce killer activated lymphokine (LAK) cell activity has also been investigated (Kutza, J. and Murasko, D. M. , Mechanisms of Aging and Development, 90: 209-222 (1996), Stem, A. NS. , et al. , Proceedings of the National Academy of Sciences of the U. NS. AND. , 87: 6808-6812 (1990)). Finally, the effect of C340 on the IL-12 mediated elevation of the level of CD95 expression on the surface of T and NK cells was tested (Medvedev, A. E. , et al. , Cytokine, 9: 394404 (1997)). Inhibition of mRNA transcription for IFN gamma A reverse transcription and PCR based assay was performed to determine whether C340 inhibits IL-12 and IL-2 induced IFN GAMMA gene transcription in human PBL. Specific primers for ß-actin (as controls for sci quality and quantity of mRNA) and for IFN GAMMA were used to amplify the cDNA obtained from stimulated human PBL. Fig. 3 shows that C340 negatively regulates IFN GAMMA mRNA in activated IL-12 / IL-2 PBMC (hour 2). Inhibition of intra-atracellular IFN GAMMA as measured by flow cytometry In response to a variety of signals and as an activation medium, T and NK cells can be stimulated to secrete cytokines. More precisely, PBLs treated with IL-2 and IL-12 begin, 4 to 8 hours after stimulation, with intensive IFN GAMMA synthesis. This production can be detected in the cytoplasm of PBLs treated with Brefeld a-A by flow cytometry. In Fig. 4 shows a 60% decrease in IFN GAMMA production in cultures to which C340 was added for five hours for IL-12 when combined with IL-12. Inhibition of IL-12 induced IFN GAMMA secretion Fig. 5 clearly shows that the two different C340 formulations inhibited the secretion of IFN GAMMA by peripheral blood lymphocytes in a dose dependent manner. Four hundred picograms of IL-12 were pre-mixed with various amounts of C340 and then added to IL-2 stimulated PBL cultures. When IFN GAMMA was measured by the EIA test after 18-24 hours of incubation, a noticeable reduction in the amount of GAMMA IFN was detected already with as little as 1 pg / ml of the Ia C340 antibody as 1 pg / ml in the culture. Inhibition of IL-12-induced cytotoxicity of LAK cells Raji cells, a cell line derived from Burkitt's IL-12 sensitive lymphoma, are resistant to NK cells and sensitive to LAK cells. Raji cells were grown in triplicate for four hours with LAK cells activated with 400 pg / ml IL-12 and 10 U / ml IL-2 in the presence or absence of human monoclonal Ia C340 antibody (5000 ng / ml). ml or 50 ng / ml). Fig. 6 shows the results for three normal, healthy donors. As a result of activation of IL-12 + IL-2 effector cells, an increase in cytotoxic activity was observed in comparison to cells activated only by IL-2. Antibodies Io C340 inhibited the IL-12 dependent effect. The increase in inhibition depends on the concentration of antibody Ia, and at the highest tested concentrations, a reduction in cytotoxicity to the levels of background Ia was observed. Inhibition of upregulation of CD95 Results are shown describing an IL-12-induced increase in the amount of CD95 on the surface of highly purified CD56 + PBL. As can be seen from Fig. 7A and 7B, analysis by distributed flow cytometry showed that CD95 expression was significantly enhanced on CD3 + T cells and CD56 + NK cells after treatment with IL-12 plus IL-2 for 72 hours. Treatment of the anti-IL-12? Mixtures inhibited CD95 expression in both the CD3 + and CD56 + populations. CD3 + cells were inhibited by ~ 50% (Fig. 7A) and CD56 + cells were inhibited by ~ 85% (Fig. 7B), inhibition was determined by the reduction of the MFI index (percentage greater than that of the unstimulated control). Example 4: Cloning and characterization of genes Fragments of genomic DNA containing either the C340 heavy chain or the C340 light chain genes were cloned and purified. Genomic DNA isolated from the C340 hybridoma cells was partially digested with the restriction enzyme Sau3A and separated by mass by centrifugation with a 10-40% sucrose gradient. DNA fragments of 15-23 kb in size were cloned on the EMBL3 vector, a derivative of bacteriophage [commercially available, and packaged into phage particles. Several packaging reactions resulted in a library of 1 million bacteriophage clones. About 600,000 clones from the library were screened by lysin hybridization using 32 P-labeled genomic DNA fragments as probes containing either human IgG1 heavy chain constant region sequences or human kappa light chain constant region sequences. Thirteen heavy chain clones and nine light chain clones were detected. Of these clones, three heavy chain clones and four light chain clones were purified after two additional rounds of screening. PCR analysis of bacteriophage DNA showed that one of the heavy chain clones and two of the light chain clones contained 5 'and 3' ends of the coding sequences. The DNA insert in the H4 1a heavy chain (HC) clone was 16 kb in size and contained a 3.6 kb fragment of the 5 'flanking sequence and at least 2 kb of the 3' flanking sequence. The DNA insert in the LC1 1a light chain (LC) clone was 15 kb in size and contained a 4.4 kb fragment of the 5 'flanking sequence and 6.0 kb of the 3' flanking sequence. Complete inserts were cut from the bacteriophage vector as SalI fragments and cloned between the XhoI and Sal sites of the plasmid expression vector p1351, which would provide I as a selection marker for the gpt gene. Since within the sequence coding the variable region of the heavy chain there was an internal SalI site, two SalI fragments from bacteriophage H4 had to be transferred to the p1351 expression vector. The obtained expression plasmids for the heavy and light chains were named p1560 and p1558, respectively. The orientations of the heavy and light chain genes in these two plasmids with respect to the sequence of the p1351 vector were determined using restriction enzyme analysis and PCR, respectively. In both cases the orientation was such that the 5 'end of the Ab gene was 1 proximal to the 3' end of the gpt gene. Both strands of the coding regions of the cloned genes were sequenced. The sequences of the plasmids p1560 and p1558 are shown in Fig. 11A-11K and Fig. 13A-13J. Example 5: Production of Recombinant Cell Lines The heavy chain plasmid p1560 was linearized by digestion with the restriction enzyme Pvul and the light chain plasmid p1558 was linearized by digestion with the restriction enzyme Sall. P3X63Ag8 cells. 653 (653) and SP2 / 0-Ag14 (SP2 / 0) cells were separately transformed with pre-mixed linearized plasmids by electroporation, the cells were further cultured and the mycophenolic acid transfectants selected as described earlier (Knght et al. , Molecular Immunology 30: 1443 (1993)). Cell supernatants from mycophenolic acid resistant colonies were tested two weeks later for the presence of human IgG (e.g. recombinant C340 (rC340)). For this, the supernatants were incubated in 96-well ELISA plates coated with goat antibodies specific for the Fc portion of human IgG. Human IgG bound to the coated plate was detected using goat anti-human IgG (heavy chain + light chain) conjugate with alkaline phosphatase and alkaline phosphatase substrates as described (Knight, et al. . , Molecular Immunology 30: 1443 (1993)). High production clone cells were transferred to 24-well culture plates in standard medium and expanded (IMDM, 5% FBS, 2 mM glutamine, selection mix with mycophenolic acid). Amount of produced antibodies l (i.e. secreted into the medium in cultures grown to the end) was accurately determined by an ELISA test using purified mAb C340 as standard. The selected clones were then expanded in T75 flasks and the production of human IgG by these clones was determined by ELISA. Based on these values, six independent 653 transfectants and three independent SP2 / 0 transfectants (sowing an average of one cell per well on 96-well plates) were subcloned, and the amount produced by these subclones was determined the opponent by testing (ELISA) supernatants from the colonies of individual subclones. Three subclones were selected for further investigation, transfectants 653 19-20 (C379B) and transfectants SP2 / 0 84-81 (C381A) and 22-56 (C389A). Antigen Binding Assay by rC340 Earlier, before subcloning selected cell lines as described above, supernatants from three parental lines (transfectants 653 clone 2 and clone 18 and the SP2 / 0 transfectant clone 1) were used to define the binding characteristics antigen by rC340. First, the rC340 concentration was determined for the three cell supernatant samples by ELISA. Supernatant samples with titers of antibody I sc or purified C340 as positive control were then incubated in 96-well plates coated with 2 µg / ml of human IL-12. The bound mAb was then detected using a goat anti-human IgG antibody (heavy chain + light chain) conjugate with alkaline phosphatase and appropriate alkaline phosphatase substrates. As shown in Fig. 8, rC340 bound specifically to human IL-12 in a manner indistinguishable from the original mAb C340. Characteristics of selected cell lines Growth curve analyzes for C379B, C381A and C389A were performed by seeding cells in T75 flasks at an initial cell concentration of 2 X 10 5 cells / ml in standard medium or SFM-5 serum-free medium and monitored sc cells daily and rC340 concentration until the end of culture. The results for the cultures grown in standard medium are shown in Fig. 9A - 9C. The maximum production levels of the C340 mAb for C379B, C381A and C389A are 135 µg / ml, 150 µg / ml and 110 µg / ml, respectively. Attempts to adapt C379B cells to SFM-5 medium have failed. C381A cells produced the same amount of rC340 in SFM-5 medium as in standard medium, while C398A cells only produced low amounts of rC340 in SFM-5 medium compared to standard medium. The stability of rC340 production over time for the three subclones was determined by growing cells in 24-well plates with standard medium or with standard medium without mycophenolic acid selection for different time intervals. It was observed that lines C379B and C381A stably produced rC340 with or without selection for 30 days (maximum time tested) and 75 days, respectively. The C389A line was unstable, and after 43 days of culture, it only produced 20% 1 antibody relative to the start of the study. It is clear that the invention can be practiced in ways other than those described in the description and examples provided. GB 205 786 B1 41GB 42GB 205 786 B1 205 B1 786 B1 786 205 43GB 44GB 45GB 205 786 B1 205 B1 786 B1 46GB 205 786 47 EN EN

Claims (16)

1. Claims 1. Nucleic acid encoding mammalian anti-IL-12 antibodies having a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8. 2. A nucleic acid according to claim 1 The method of claim 1, wherein the antibody is a human antibody. 3. A nucleic acid according to claim 1 The method of claim 1 or 2, characterized in that the antibody has an affinity constant of between 1x109 and 7x1012. 4. A prokaryotic or eukaryotic host cell which comprises a nucleic acid according to claim 1. 1. 5. Cell according to claim according to claim 1, The method of claim 4, wherein the nucleic acid encodes a human anti-IL-12 antibody. 6. The cell according to claim The method of claim 4 or 5, characterized in that the antibodies have an affinity constant of between 1x109 to 7x1012. 7. Mammalian anti-IL-12 antibodies having a heavy chain variable region of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8. 8. The antibodies according to claim 1 The method of claim 7, characterized in that it is a human antibody. 9. The antibodies according to claim 1 7 or 8, characterized in that it has an affinity constant between 1x10 9 to 7x10 12. 10. The antibodies as defined in any one of claims 1 to 10. 7 to 9, for use in diagnosis or treatment. 11. The antibodies as defined in any one of claims 1 to 11. 7 to 9, for use in the treatment of psoriasis. 12. The antibodies as defined in any one of claims 1 to 12. 7 to 9, for use in treating psoriatic arthritis, sarcoidosis or Crohn's pathology. 13. A pharmaceutical composition comprising: (a) the antibodies according to any one of claims 1 to 13; 7 to 9, and (b) a pharmaceutically acceptable carrier or diluent. 14. A pharmaceutical composition as defined in claim 1 13, for use in diagnosis or treatment. 15. A pharmaceutical composition as defined in claim 1, 13, for use in the treatment of psoriasis. 16. A pharmaceutical composition as defined in Claim 13, for use in the treatment of psoriatic arthritis, sarcoidosis, or Crohn's pathology. 55PL 205 786 B1 56PL 205 786 B1 57PL 205 786 B1 58 Publishing Department of the Polish Patent Office of the Republic of Poland