TWI329672B - Anti-il-12 sntibodies, compositions, method and uses - Google Patents

Description

1329672 A7 B7

K V. INSTRUCTIONS INSTRUCTIONS (汐 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明 发明U.S. Provisional Application Serial No. 60/236,827, the entire contents of each of which is incorporated herein by reference in its entirety in its entirety in the the the the the the the the the the the the the the the the the the the the the (IL-12) protein or fragment thereof, and nucleic acid, complementary nucleic acid, vector (medium), host cell, and preparation method thereof for such anti-IL-12 antibody type code, including treatment thereof Formulation, application and device. Related literature Interleukin-12 (IL-12) is a heterodivalent cytokine composed of disulfide-bonded polymorphisms with molecular weights of 35 and 40 Kd. The chain 'cytokine is synthesized and secreted by antigens present in the cell, including dendritic cells, single cells, giant cells, B cells, Langerhans cells and keratinocytes, and natural killers. ) cells, IL-12 media, a variety of biological procedures It is classified as Νκ cell-stimulated factor (NKSF), T-cell stimulating factor, cytotoxic τ·lymphogenic 20-factor and EBV-deformed B-cell strain factor (Curfs, JHAJ, et al., Clinical Microbiology Reviews, 10:742-780(1997)) ° Interleukin-12 can be expressed on the cytoplasmic membrane of cells (eg, T cells, NK cells) by binding to the IL-12 receptor, thereby changing (eg, initiation, Preventing biological processes 'for example, combining IL-12 to IL-12 -3 - 90374a This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) (please read the notes on the back and fill in the form)丨 · ! ! ! 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 91 Stimulates the proliferation of pre-activated tau cells and NK cells, enhances the cytolytic activity of cytotoxic tau cells (CTL), NK cells and LAK (lymphokine activated killer) cells, and induces T by T cells and NK cells. - interferon (IFN GAMMA) and induced natural 5 ThO cell division Adult Thl cells producing IFN GAMMA and 11^-2 (Trinchieri, G., Annual Review of Immunology, 13:251-276 (1995)), specifically, cells producing lysed cells (eg, NK, CTL) And the immune response of the cells (for example, an immune response mediated by Th1 cells), IL-12 is vital to life, 10 so IL-12 protects immunity (eg eradication of infection) and pathology Both immune responses (such as autoimmunity) are critically important in production and regulation (Hendrzak, JA and Brunda, MJ, Laboratory Investigation, 72: 619-637 (1995)). The response (e.g., protective or pathological) can be elevated, suppressed, or prevented by modulating the biological activity of 15 IL-2 in vivo (e.g., by an antibody). Non-human mammals, chimeric, polyclonal (eg, anti-serum) and/or monoclonal antibodies (Mabs) and fragments (eg, digestion of solubilized proteins or their fused protein products) Etc., is a potential therapeutic agent that is being explored in some cases for the treatment of a particular disease, however, such antibodies or fragments, when administered to humans, elicit an immune response that results in an antibody Immune complex _ media clearance and resulting in unsuitable administration of treatment, thus reducing the therapeutic benefit to patients and limiting the re-administration of antibodies or fragments, -4- This paper scale applies to China National Standard (CNS) A4^ (21〇X 297 公爱)------- , ,ς. 91. 1. 2.000 (Please read the notes on the back and fill out this page) .- Order! ·--Line —. 1329672 A7 B7 V. INSTRUCTIONS (i) Repeated administration of antibodies or fragments containing non-human parts can cause blood diseases and/or allergic reactions. To avoid these and other problems, many species have been adopted. Methods for reducing such antibodies and partial immunogenicity, including chimerization and humanization, and those already known in the literature, however, these and other methods can still result in antibodies or fragments having some Immunity, low affinity, low appetite, or problems in cell culture, scale, production, and/or low yield, so such antibodies or fragments are not ideally suited for use in manufacturing or as a therapeutic protein. . 10 Accordingly, there is a need to provide an anti-IL-12 antibody or fragment' that overcomes more than one of these problems and which is more known than the known antibodies or fragments thereof. BRIEF DESCRIPTION OF THE INVENTION The present invention provides for the isolation of human, primate, rodent, and lactating economic ministry intellectual property bureau employee consumption cooperatives (please read the back of the note before refilling this page) class, chimera, human And/or CDR-grafted anti-IL_12 antibodies, immunoglobulins, cleavage products and other specific proteins and variants thereof, and anti--11^12 antibody compositions, cryptographic or complement nucleic acids Classes, vectors, host cells, compositions, formulations, devices, 20 animals that have been transferred to foreign genes, plants that have been transferred to foreign genes, methods of preparation thereof, and uses thereof, as disclosed and in accordance with this property, The present invention also provides at least one isolated anti-IL_12 antibody. As disclosed herein, the antibody of the present invention comprises any protein or peptide which is applicable to the Chinese National Standard g (21〇x 297). PCT 3 ---------- 91. 1. 2.000 5 10 15 20 V. Description of invention (4) Globulin molecule, for example: (CDR) or its ligand binding site, gravity J Chain or light chain fixed range, basic knot The constitutive zone is added to the present invention, and the anti-suspension of the present invention::::: raw: any mammal, for example, but not limited to from the rat, the dentate, the primate, or any second-class exemption thereof The invention provides, in one aspect, a 'body' or a mixture to a specific anti-IL_;:::: part of a body or variant thereof, the invention further provides a recombinant medium; = 2 The anti-IL_12 antibody nucleic acid molecule, the host cell containing the nucleic acid and/or the heavy medium, and the at least one antibody of the at least one of the invention, the acid/medium and/or the eir antibody core. An IL-12 protein, a subunit, a fragment, a portion thereof or any heavy specific epitope (the epitope of the at least one) may comprise a range of binding to one antibody comprising at least two of the protein f such At least in part - preferably comprising at least 1 to 5 amino acids, extracellularly restricted, at least one functional, finely structured portion of the protein: soluble::::minute: a macromolecule, the at least one antibody optionally comprising at least one specific moiety The range of decisions for complement (CDR) (eg, the paper standard (CNS) A4 X 297 mm) 1329672 A7 ____B7 V. Description of the invention (5) 5 ο 5 Ministry of Economic Affairs Intellectual Property Bureau employees eliminate the cooperative printing 20 or CDR1, CDR2 or CDR3) of the light chain variable region and/or at least one fixed or variable basic structure or any portion thereof, the at least one antibody amino acid sequence may additionally comprise at least one specific substitution, Insertion or intermediate deletions are as described herein or in the literature. The invention also provides at least one isolated anti-IL-12 antibody, wherein the antibody has at least one activity, such as, but not limited to: (i) IL-12-induced inhibition of iFN-gamma secretion; (ii) inhibition of cytotoxicity of LAK cells; (iii) inhibition of IFN gamma mRNA transcription; (iv) inhibition of intracellular ifn gammaCD3+ cells; and/or (v) CD95 expression 'see, eg, chan, et al., (1992), J. Immunol. 148(1): 92-98; Chan, et al., (1991), J. Exp. Med. 173(4): 869-79; Chehimi, et al., (1992 J. Exp. Med. 175(3): 789-96; Medved, et al., (1997) Cytokine 9(6): 394-404, anti-IL-12 antibodies can then be screened out according to known methods Activity, such as, but not limited to, at least one activity against an organism of the IL-12 protein. The invention also provides at least one IL-12 anti-hereditary antibody to at least one IL-12 antibody of the invention, the anti-hereditary antibody comprising any protein or a bacterium comprising at least a portion of an immunoglobulin molecule, eg, but a region that is not limited to a complement of a heavy or light chain (CDR) or a site to which its ligand binds, a heavy or light chain variable region, a heavy bond or a light chain immobilization region, a basic structural region, or any portion thereof, Where it can be added to an antibody of the invention, the antibody of the invention may comprise or be derived from any

(Please read the notes on the back and fill out this page) Order: --Line. 1329672 A7 -------- B7 Ministry of Economic Affairs. Intellectual Property Bureau employee consumption cooperative printing 5, invention description (6) mammals' For example, but not limited to humans, mice, mice, white cockroaches V*, storage teeth, primates, and so on. The present invention provides, in one aspect, an isolated nucleic acid molecule comprising a complement, or a heterozygous to a polynucleotide encoding at least one IL12 anti-hereditary anti-5, comprising at least a specific sequence, large The present invention further provides a recombinant medium comprising the IL-12 anti-hereditary antibody of the nucleic acid molecule, and a host cell comprising the nucleic acid and/or the recombinant medium, wherein the molecule comprises a specific structural part, a part or a variant thereof, And 10 methods of preparing and/or using each anti-hereditary antibody nucleic acid, vehicle, and/or host cell. The present invention also provides at least one method for expressing at least one anti-IL-12 antibody, or IL_12 anti-hereditary antibody in a host cell, under the conditions of setting a host cell as described herein, wherein at least one of the antibodies The IL-12 antibody is shown to exhibit an amount that is detectable and/or recoverable. ▲ The invention also provides at least one composition comprising (8) an isolated k IL-12 antibody-encoded nucleic acid friend or antibody, as described; and (匕) a carrier or diluent, the stable vector or The diluent may alternatively be as acceptable as the known thief or dilution vessel, and the composition may alternatively comprise at least one other compound, protein or composition. The invention also provides at least one anti-pore 12 antibody method or combination that is not therapeutically effective (IV) for regulating or treating a condition associated with IU12 in a cell, tissue, organ, animal or patient and / 20 -8 - This paper size wipes @国标准(CNS)A4 «坆οιη X 公》" - 一> X ° \ - - - ! (Please read the back of the precautions again - 艮ί I page) Order. •line

Description of the Invention (10) Administration before, after or at the time of occurrence of the relevant condition. The invention also provides at least one composition, device and/or delivery of a therapeutic or prophylactically effective amount of at least one anti-IL_12 of the invention. The method of the invention also provides at least one anti-IL_12 antibody method or combination D. For at least one IL_12 related condition in a cell, tissue, state, animal or patient and/or prior to, then, or The relevant conditions are as described above. The invention also provides at least one composition, device and/or delivery method for diagnosing at least one anti-French antibody of the invention. (Please read the notes on the back and then fill out this form. Page)

5 IX Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20 详细 Detailed Description Figures 1A and 1B show the binding of human anti-mAbs to immobilized human IL_12 as a function of concentration, with 1〇/〇BSA/pBS Hole _12 Carcass was serially diluted and allowed to grow on rhIL-12 coated plates at 37 ° C for one hour to 〇·〇 2% Tween 20 (polyoxyethylene (2 〇) dehydrated sorbus Alcohol monolaurate), wash the plate twice with 0.15M saline and then probe with the goat anti-human IgG kappa-specific antibody, and then react at room temperature for one hour. The plates were washed, developed with o-phenylenediamine (〇PD) and the absorbance density (OD) of each cell was measured at 490 nm. Figure 2: From left to right in Figures A and B for human IL-12, human IL-12 p4〇, murine iL_12, and pre-stained molecular weight marker gene. Figure 2A shows band stained by total protein (band ), each path -9- -6· - Line 7 paper size timely (CNS) A4 specification (210 X 297 mm) 1329672 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description The basic band of (8) is human IL-12 (75 kd), p40 human and mouse IL-12 (75 kd) 'Figure 2B shows that Western blot analysis was obtained from the gel identical to that in Figure 2A, and the ink dots were Acting with C340, followed by the HRP effect of goat anti-human IgG, which is only used to detect human IL-12 (monomer and multiple) and human Jiang-丨2 p4〇 Control blots (not shown) for the HRP effect of the goat anti-human IgG were not shown to be any bands. Figure 3: IFNr gene expression in human PBL,s treated with IL_2, IL-12, IL-10 2+IL-12 with and without anti-IL_12 antibody C340, 8.6.2, isotype control antibody Reverse transcription-PCR analysis, reverse transcription of total RNA, proliferation using pCR using a specific primer: the value of cold-actin m-RNA in each sample was also determined as a comparison of mRNA integrity and content. group. Figure 4 is a frequency distribution diagram in which human anti-Jiang_j 2 15 mAb (C340) inhibits the production of interferon-r (IFNr) by single cell depleted CD3+ stimulated by IL-12+IL-12 Peripheral blood mononuclear cells (PBMC), PBMC were incubated for five hours in control medium (no cytokine) and supplemented with IL-12 (0.1 Ng/ml) + IL-2 (50 IU/ml) (IL-12/IL-2), control medium containing mAb C340 (10 μg / 20 ml) and IL-12/IL-2 medium containing mAb C340 (10 μg/ml), extracellular iFNr The data were determined for one donor with the two color immunostaining methods of CD3 and IFNr. FITC. Figure 5 shows the dose-related, horse-stimulated by IL-2+IL-12 (please read the back note on this page) ί "0 Τ , the paper scale applies to the Chinese national standard ( CNS) A4 specification (210 297 297 mm) A7

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 13296672 V. Description of invention (9) Peripheral lymphocytes and two different large numbers of human-anti-_il_12 mAb (C340) inhibit the secretion of iFNr, human pBL (8 x 10 /3⁄4 liters with lOU/ml IL-2, IL-2+400 pg/ml IL-12, or IL-2+IL-12 and mAb C340 together as shown, the cultured supernatant 5 was removed IFN γ was analyzed by EIA. Figure 6 is a frequency distribution diagram showing dose-dependent inhibition of IL-12+IL-2 by cytotoxicity of human anti-IL-12 mAb (C340-) LAK cells, LAK effector cells ( Human PBL, 8 x 106 ml) was used with IL-i (4 〇〇pg/ml) + IL_2 (i〇u/ml) with 10 mAb C340 (5000 Ng/ml or 5 〇Ng/ml as shown) Incubated together, the LAK effector cells were washed and incubated with 51Cr-labeled Raji target cells for four hours, the effector to target ratio (E:T) was 80:1, and the assay was released to the medium and The amount of 51Cr in the homogenate cell lysate was expressed as the average of the 15 normal donor standard lines, and the IL-12 positive control group (IL_12) was the effector cells incubated with IL_12 and without the antibody. Background (BKGD)s are effector cells incubated with no IL-12 and no antibodies. Figures 7A and 7B are frequency distribution diagrams showing that IL_12+IL_2 induced CD95 on CD3+ peripheral blood mononuclear cells is inhibited by human 20 anti-IL-12 mAb (C340), and PBMC is contained in 〇Nike/ The suboptimal dose of IL-12 and IL-2 (5〇IU/ml) in the medium, in the presence or absence of mAb C34〇 (l〇μg/ml), the same month, 72 hours, 0〇95 performance Cell assays stained with anti-CD95-FITC were counted by flow cytometry using two-color analysis (CD3)

Do not take the wave of people to avoid T圏 because of the 豕 flat specifications (21〇X 297 public) 1329672 A7 B7 five, invention description (λ or CD56-PE relative CD95-FITC) and forward vs. right angle of the light scan Got it. Figure 8 shows that recombinant human anti-human IL_12 antibody (rC34〇) binds to immobilized 5 IL-12 in a manner indistinguishable from purified mAb C340. Three rC340-produced recombinant cell lines were assayed in Shangcheng The rC340 concentration produced in the experiment, and the ELISA was used to evaluate the binding of the supernatant to the iL-12. The plate was coated with 2 μg/ml human IL_12 and with the supernatant obtained from the original hybridoma (standard) or recombinant cell strain. The purified mAb C340 was cultured and the IL-12-conjugated antibody was detected using alkaline phosphatase-conjugated goat 10 anti-human 1 gG (heavy chain + light chain). Figures 9A-9C show growth kinetics and amount of antibody secreted by three independent sub-clones (subcl〇ne) derived from rC340 (Figure 9A 'subclone C379B; map, subclone C381A; , subcloning C389A). Recombinant cells were seeded into T75 flask 15 to a density of 2 X 1〇5 cells/ml, placed in standard medium. 'Resuspend the cells at various times and determine the number of viable cells in the medium and rC340 Amount (μg/ml). DETAILED DESCRIPTION 20 The present invention provides isolated, recombinant and/or synthetic anti-IL-12 human, primate, rodent, mammalian, chimeric, humanized or CDR-grafted, antibody and IL -12 anti-hereditary antibody class 'and composition and encoded nucleic acid molecule include at least one polynucleotide encoding at least one anti-IL-12 antibody or anti-hereditary antibody, -12- paper size Applicable to China's national standard "CNS" A4 specification (21〇x 297 mm) (please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing II ^^^1 I-I n ·1 ϋ ϋ *1 91. 1. 2,000 1329672 A7 _______B7 ____ V. INSTRUCTION DESCRIPTION (η) The present invention further encompasses, but is not limited to, the preparation and use of such nucleic acids and antibodies and anti-hereditary antibodies The method comprises a composition, a method and a device for diagnosis and treatment. The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative is printed in the present specification, "anti-interleukin-12 antibody,,,,, anti-IL_丨2 anti-5 Body, anti-IL-12 antibody partial anti-IL-12 antibody fragment" and / or" Anti-IL-12 antibody variants" and the like, including any protein or peptide comprising a molecule comprising at least a portion of an immunoglobulin molecule, such as, but not limited to, at least one heavy or light bond or ligand thereof. The complement-determined range (CDR), heavy or light chain variable region, heavy or light chain 10 fixed range, basic structural range, or any portion thereof, or at least a portion of the IL-12 receptor or bound protein , which may be incorporated into an antibody of the invention, which antibody may alternatively affect an obligate ligand 'for example, but not limited to, at least one iL-12 active or binding, or an IL-12 receptor Activity or binding, affecting, reducing, enhancing, purging, stimulating, mitigating, alleviating, blocking, inhibiting, abolishing, and/or interfering with such antibodies in vitro, in vivo, and/or in vivo. In a limited example, a suitable anti-IL_12 antibody of the invention, a particular site or variant may bind at least one IL-12, or a specific site, a variant thereof or a macromolecular specific moiety, a suitable anti-IL_12 antibody, Special 20 The site, or variant, also optionally affects at least one of the IL-1 activity or function, such as, but not limited to, RNA, DNA or protein synthesis, IL-12 release, IL-12 receptor signaling, membrane IL-12 division, IL 12 Activity, IL-12 production and / or synthesis, the word "antibody" is used to encapsulate human antibodies, digested fragments, specific parts or variants, and the anti-^- 13- paper scale applies to China Standard (CNS) A4 specification (210 X 297 mm) 1329672 A7 B7 V. Description of invention (^ Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative prints mimetic or antibody-containing parts, which are mock antibodies or special fragments or Part of the structure and / or functional 'including single-chain antibody and its fragment' functional fragment includes an anti-binding fragment that binds to mammalian IL-12, for example, antibody fragments can bind to il_i2 or its 5 points 'Includes, but is not limited to, Fab (eg, 'Papaya Enzyme Digester'), Fab, (eg, pepsin digested and partially reduced) and F(ab')2 (eg, pepsin digested), facb Blood fibroin Lysozyme digestor), pFc' (eg, by pepsin or plasmin digester), Fd (eg 'pepsin digested, partially reduced 10 and reaggregated), Fv or scFv (eg 'borrowing molecule' Biotech producers) Fragments, which are encompassed by the present invention (see, for example, Colligan, Inununology ϊ supra) ° Such fragments can be cleaved and synthesized by enzymes by methods known and/or described herein. Or recombinant techniques, antibodies can also be produced into more than 15 truncated versions, using antibody genes in which one or more stop codons are introduced upstream of the natural termination site, eg, F(ab') The mixed gene of the 2 heavy chain portion can be designed to contain a stranded DNA sequence encoding a special structural portion of the Ch1 macromolecule and/or a heavy bond, and various parts of the antibody can be combined by chemical bonds or conventional techniques, or 20 can be utilized. Genetic engineering techniques are prepared as contiguous proteins. As used herein, "human antibody," refers to each part of the antibody that is actually a protein (eg, CDRs, basic structure, Cl, Ch macromolecular specific structural parts (eg, Ch1, Ch2, Ch3), stranded parts (乂B, VH)) is essentially non-immunogenic to humans, it only has a trace amount of sequence-14-wave scale over T solid group know: quasi (CNS>A4 specification X 297 public)

(Please read the following on the back of the note) _ ! ί _ 丨 丨丨 * * * * * * * * * * * * * * 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 The property bureau employee consumption cooperative printed 20 Γ文= variant, similar 'antibody class refers to primate (monkey-like white chimpanzee, etc.), rodent (white mouse, white rat, free child, both, hamster, etc.) And other antibodies classified as mammals, such as species, subgenus 'genus, subfamily, science, and in addition, chimeric antibodies include a mixture of any of the above antibodies, such changes or variations selectively And the face-to-face, compared with the anti-difficultness of silk money, in humans or its more persistent or less immunogenic, so human anti-systems are distinct /, Xin or humanized antibodies are distinguished, it points out that human antibodies can be Produced by non-human animals or prokaryotic or eukaryotic cells that have the ability to express functionally recombinant human immunoglobulin (eg, heavy and/or light chain) genes 'in addition' when human antibodies are When a single chain antibody is used, A segment-ligated (chi)-containing peptide that can be included in a synthetic DNA, which is not found in natural human antibody classes, for example, an Fv can contain n, such as from about 8 to about 8 glycine acids or other a silk-based group that binds a variable region of a stressed variable region to a light bond, such a peptide of synthetic DNA is considered to belong to the original human part. Double-specific, heterozygous, heteroconjugate or similar Antibodies can also be used, which are monoclonal, preferably human or humanized antibodies, which have binding specificity for at least two different antigens, in the context of the present invention, one of the specificities of binding A method for preparing at least one IL-12 protein and the other for use in any other antigen for preparing a bispecific antibody is a technique known in the literature. Traditionally, a bispecific antibody recombination method Based on two immunoglobulin heavy bonds - light -15 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 91. 1. 2,000 (Please read the notes on the back and fill in the form) Page) !—订------线—. nnn I— dnnn Nnnnn I < 1329672 A7 B7 V. INSTRUCTIONS (Η) The co-expression of chain pairing, in which the two chains have different specificities (Milstein and Cuello, Nature 305:537 (1983)) ' Due to immunoglobulin weight A random genetic arrangement of light chain pairings, these hybridomas (quadromas) produce a potential mixture of 10 different antibody molecules, of which only 5 have the correct bispecific structure, the purification of this correct molecule, usually The hydrazine affinity chromatography step is an extremely complicated hydrazine process, and the yield of the product is not high. A similar preparation method is disclosed, for example, in WO 93/08829, US Patent Nos, 6210668, 6193967, 6132992, 6106833, 6060285, 6037453. , 6010902, 10 5989530, 5959084, 5959083, 5932448, 5833985, 5821333, 5807706, 5643759, 5601819, 5582996, 5496549, 4676980, WO 91/00360, WO 92/00373, EP 03089 ' Traunecker et al., EMBO 1.10:3655 (1991) ' Suresh et al., Methods in Enzymology 121: 210 (1986), all of which are incorporated herein by reference. The anti-IL_12 antibody (also referred to as IL-12 antibody) of the method and the composition 'optionally selects the following characteristics: high affinity and selectivity to IL-12 and preferably low toxicity' Specifically, 'an antibody of the invention, a particular fragment or variant, an individual group of 20 minutes' such as a variable region, a fixed range and a basic structure, individually and/or collectively, selectively and suitably Those having low immunogenicity are those used in the present invention; and the antibodies used in the present invention are selectively selected to have the following traits for treating patients for a period of time and having the ability to reduce symptoms and have a low / or acceptable toxicity, low or acceptable -16- This paper scale applies to China's map standard iMCNS) A4 specifications;!;h;h; order···Line· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative 1321329672 V. Description of invention (ls) Immunity 1 · Birth and / or positive affinity, and other appropriate characteristics 'can contribute to the outcome of f to / alpha treatment of diseases, "low immunogenicity" in this context refers to its In the treatment of patients, it caused significant improvement in HAHA, HACA or HA=reaction Is less than about 75%, or preferably less than about 50%, and / 5 or ask for a low titer in a patient treated with a fork (less than about 300, preferably less than about 100' is a double antigenic enzyme Immunophenotyping assay X see, for example, Elliott et al., Lancet 344: 1125-1127 (1994), which is incorporated by reference in its entirety for reference herein. Anti-IL-12 antibodies or unique variants thereof, which can be used to determine or affect cells, tissues, organs or animals, including mammals and humans, for diagnosis, monitoring, adjustment, treatment, alleviation, help Prevent occurrence, or reduction! 5 less symptoms in 'at least one IL_12 condition, selected from, but not limited to, at least - _ immune discomfort or disease, palpitations discomfort or disease, infection, malignant properties, and / or nerve cells Discomfort or illness, or other known or specific conditions associated with IL-12. The method of printing 3G2 by the Intellectual Property Intelligence Bureau of the Ministry of Economic Affairs may include administering an effective amount of the composition or pharmaceutical composition 20 comprising at least one anti-poro 2 antibody to cells, tissues, organs, animals or Patients, who are in need of adjustment, treatment, alleviation, prevention, or reduction of signs, effects, or mechanisms, may be administered in amounts ranging from about 0.001 to 500 mg/kg per individual (eg, bolus), multiple or continuous The amount of application, or the concentration reached in the serum is -17 - the standard of the paper (CNS) A4 specification (210 X 297 mm) - 1329672 A7 __ B7 Printed by the Intellectual Property Office of the Ministry of Economic Affairs V. INSTRUCTIONS (I6) 0.01-5000 μg/ml concentration per individual, multiple or continuous application rate, or any effective range or valence, according to known methods (as known here or in the literature) Execute or decide to come out. 5 Citations Each of the publications or patents cited herein is hereby incorporated by reference in its entirety in its entirety herein in its entirety herein in its entirety in its entirety in Any other information available in any media format (including all recorded, electronic 10 or printed formats), the following references are hereby fully incorporated by reference: Ausubel, et al" ed" Current

Protocol in Molecular Biology, John Wiley & Sons, Inc., NY, NY (1987-2001); Sambrook, et al., Molecular Cloning: A Labobatory Mannual, 2nd Edition, Cold Spring Harbor, 15 NY (1989); Colligan , et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2001); Colligan et al., Current Protocols in Protein Science, John Wiley & Sons, Inc" NY, NY, (1997-2001). 20 The antibody of the present invention at least one of the anti-IL-12 antibodies of the present invention can be selected from a cell line, a mixed cell line, a perpetuated cell or an immortal cell clone. The population, as well known in the literature, for example, can be found in Ausubel, et al., ed., Current Protocols in Molecular -18- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm).

1329672 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 _B7 _ V. Invention description (1>7

Biology, John Wiley & Sons, Inc., NY, NY (1987-2000); Sambrook, et al" Molecular Cloning: A Labobatory Mannual, 2nd Edition, Cold Spring Harbor, NY (1989);

Harlow and Lane, antibodies, a Laboratory Manual, Cold 5 Spring Harbor, NY (1989); Colligan, et al., eds., Current Protocols in Immunology, John Wiley & Sons, Inc., NY (1994-2001); Colligan et al., Current Protocols in Protein. Science, John Wiley & Sons, Inc., NY, NY, (1997-2001) > each is hereby incorporated by reference in its entirety. 10 Human antibodies that are specific to human IL-12 proteins or fragments thereof can thus be raised against a suitable immunogenic antigen, such as isolated and/or IL-12 proteins or a portion thereof (including synthetic molecules, such as synthetic The peptides), other specific or general mammalian antibodies can be similarly enhanced, and the preparation of immunogenic antigens and the production of monoclonal antibodies can be accomplished using any suitable technique. One method consists in fusing an appropriate permanent cell line (eg, a myeloma cell line such as, but not limited to, Sp2/0, Sp2/0-AG14, NSO, NS1, NS2, AE-1, L.5, >;243, P3X63 Ag8.653, Sp2 SA3, Sp2 MAI, Sp2 SSI, Sp2 SA5, 20 U937, MLA 144, ACT IV, M0LT4, DA-l, JURKAT, WEHI, K-562, COS, RAJI, NIH3T3, HL 60, MLA 144, NAMAIWA, NEURO 2A, etc.) to produce hybridoma, or xenogeneic myeloma, fusion products thereof, or any cells or fusion cells derived therefrom, or any other suitable fine known in the literature -19- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page). Order --------- Line!

-n ϋ nnnnnnnn I 91. 1. 2,000 1329672 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Invention Description (ύ8 cell line, see for example, www.atcc.org 'ww.lifetech.com. etc.' A heavy or light chain that is expressed by cells that produce antibodies, such as, but not limited to, isolated or vegetatively spleen, peripheral blood, lymph, tonsils, or other cells containing immune or sputum cells, or any other cell. Fixed or variable or basic or CDR sequence range, endogenous or foreign nucleic acid, recombinant or endogenous, viral, bacterial, algal, prokaryotic, amphibian, insect, reptilian, Fish, mammals, rodents, equines, aries, goats, sheep, primates, eukaryotic cells, genomic DNA, cDNA, rDNA, mitochondrial 10 DNA or RNA, chloroplast DNA or RNA, hnRNA , mRNA, tRNA, single, double, triple, standard, hybrid, etc. or any combination thereof see 'eg Ausubel, supra, and

Colligan, Immunology, supra, chapter 2, which is hereby incorporated by reference in its entirety. 15 The antibody-producing cell line may also be obtained from the peripheral blood of a human or other appropriate animal that has been immunized with a related antigen or, preferably, from its spleen or lymph nodes, and any other suitable host cell may also be used. Used to represent exogenous or endogenous nucleic acids, which are to be arranged for antibodies, special fragments or variants thereof, fusion cell types (hybrid 20 tumors) or recombinant cells using selective culture conditions or Other suitable methods for isolation, and vegetative propagation by limiting dilution or cell sorting, or other known methods, may be selected by appropriate assays (eg, ELISA) to produce cell types with desired specificity. . Other appropriate methods for producing or isolating antibodies with the necessary specificity-20- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) 91. 1. 2,000 (Please read the back note first) Please fill out this page again.,··--------Book n ad nn I Line 1·------------------„---- 1329672 A7 B7 V. INSTRUCTIONS (19) The method may be used, including, but not limited to, methods for selecting recombinant antibodies from a peptide or protein gene bank (eg, but not limited to phage, ribosomes, oligonucleotides, RNA, cDNA, etc., display base; for example, available from Cambridge antibody Technologies, Cambridgeshire, UK; 5 MorphoSys, Martinsreid/Planegg, DE; Biovation, Aberdeen, Scotland, UK; Biolvent, Lund, Sweden; Dyax Corp., Enzon, Affymax/Biosite; Xoma, Berkeley, CA; Ixsys see, for example, EP 368,684, PCT/GB91/01134, PCT/GB92/01755, PCT/GB92/002240, PCT/GB92/00883, PCT/GB93/00605, us 08 /350260 10 (5/12/94), PCT/GB94/01422, PCT/GB94/02662, PCT/GB97/ 01835, (CAT/MRC), WO90/14443, WO90/14424, WO90/14430, P CT/US94/1234, W092/18619, WO96/07754, (Scripps) 'EP 614 989 (MorphoSys) > WO95/16027 (Bioinvent), W088/06630, WO90/3809 (Dyax), US 15 4,704,692 (Enzon) , PCT/US91/02989 (Affymax), Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed WO89/06283, EP 371 998, EP 550 400, (Xoma), EP 229 046, PCT/US91/07149 (Ixsys), or Stoichiometrically produced peptides or proteins - US 5723323, 5763192, 5814476, 5817483, 5824514, 5976862, WO86/ 05803, EP 590 20 689 (Ixsys, now Applied Molecular Evolution (ΑΜΕ), each of which is fully incorporated herein As a reference), or rely on the immunization of genetically transferred animals (eg, SCID mice, Nguyen et al., Microbiol. Immunol. 41:901-907 (1997); Sandhu et al., Crit. Rev Biotechnol. 16:95-118 (1996); Eren et al., -21- ....... This paper scale applies to National Standard (CNS) A4 (210 x 297 mm) 1329672 A7 B7 V. Description of invention (20)

Immunol. 93: 154-161 (1998), each fully incorporated by reference, and to the entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire disclosure Such techniques, _ / include, but not limited to, nuclear brewing (Hanes et al., Proc. Natl. 5 Acad. Sci. USA, 94: 4937-4942 (May 1997); Hanes et al., Proc. Natl. Acad. Sci. USA, 95: 14130-14135 (Nov. 1998)); Cellular antibody production technology alone (eg, selected lymphocyte antibody method ("SLAM,') (US Patent No. 5,627,052 » Wen et al., J. Immunol. 17:887-892 (1987); Babcook et al., Proc. Natl. 10 Acad. Sci. USA, 93:7843-7848 (1996); gel droplets and flow cells Counting method (Powell et al., Biotechnol. 8: 333-337 (1990); One Cell Systems, Cambridge, MA; Gray et al., J. Imm. Meth. 182: 155-163 (1995); Kenny et al . Bio/Technol. 13:787-790 (1995)); B-cell selection Steenbakkers et al., Molec·Biol. Reports 15 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 of engineering or human production of non-human or human class 20 antibodies can also be used, which are known in the art. Typically, humanized or engineered antibodies have one from a non-human or Multiple amino acid residues, such as, but not limited to, mice, rats, exons, non-human primates, or other mammals, these human amino acid residues are often referred to as ''foreign ( Import) ''Residue, which is typically taken from a ', -22- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) <Please read the notes on the back before this page ) -5J- - Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printed 13296672, Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed A7 B7

V. Description of the invention (A foreign), a variable, fixed or other macromolecular specific structural part of a known human sequence, known human Ig sequences are disclosed, for example, at www.ncbi.nlm.nih.gov /entrez/query.fcgi; ' 5 www.atcc.org/phage/hdb.html; www.sciquest.com/; www.abcam.com/; www.antibodyresource.com/onlinecomp.html; www.public.iastate .edu/~pedro/research_tools.html;www.mgen.uni- 10 heidelberg.de/SD/IT/IT.html; www.whfreeman.com/immunology/CH05/kuby05.htm; www.library.thinkquest.org /12429/lmmune/Antibody.html; 15 www.hhmi.org/grants/lectures/1996/vlab/; www.path.cam.ac.uk/~mrc7/mikeimages.html; www.antibodyresource.com/; 20 mcb.harvard.edu/BioLinks/lmmunology.html.www.immunologylink.com/; pathbox.wustl.edu/~hcenter/index.html; www.biotech.ufl.edu/~hd/; -23- paper scale Applicable to China National Standard (CNS) A4 specification (210 297 297 mm) 91. i. 2,000 (please read the notes on the back and fill out this page) -丨·丨丨丨丨丨丨丨定··丨丨· Line — 1329672 A7 B7 Ministry of Economics Intellectual Property Printed by the Employees' Cooperatives. V. Description of the invention (2^ www.pebio.com/pa/340913/340913.html; www.nal.usda.gov/awic/pubs/antibody/; www.rn.ehime-u.ac .jp/~yasuhito/Elisa.html; 5 www.biodesign.com/table.asp; www.icnet.uk/axp/facs/davies/links.html; wvsrw.biotech.ufl.edu/~fccl/protocol. Html; www.isac- 10 net.org/sites_geo.html; aximtl.imt.uni-marburg.de/~rek/AEPStart.html; baserv.uci.kun.nl/~jraats, /lmks I .html; www .recab.uni-hd.de/immuno.bme.nwu.edu/; 15 www.mrc-cpe.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; 20 antibody.bath.ac.uk/; abgen.cvm.tamu.edu /lab/vsrwwabgen.html; www.unizh.ch/~honegger/AHOseminar/SlideO I .html; -24- (Please read the notes on the back and fill out this page) ··-------- I-line ------------------------ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 91. 2,000 1329672 A7 B7 ____ V. Description of the invention (full www.cryst.bbk.ac.uk/~ubcg07s/; www.nimr. mrc.ac.uk/CC/ccaewg/ccaewg.htm; 5 www.path.cam.ac.uk/~mrc7/humanisation/TAHHP.html; www.ibt.unam.mx/vir/structure/stat_aim.html; Www.biosci.missouri.edu/smithgp/index.html; 10 www.cryst.bioc.cam.ac.uk/~finolina/web-pages/Pept/spottech.html; www.jerini.de/fr_products.htm; The Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Association, prints www.patents.ibm.com/ibm.html.Kabat et al., Sequences of Proteins of Immunological Interest, US Dept. Health (1983), each being completely and 15 As a reference, such foreign sequences can be used to reduce immunogenicity or reduce, enhance or modify binding, affinity, yield (〇n-rate), out-rate, desire, specificity Sex, half-life, or any other suitable trait, as is known in the art, typically, a non-human sequence or part or all of a human CDR sequence is maintained and the non-human sequence variable with the fixed region 20 is Substituted into human or other amino acids, antibodies are also optionally humanized to maintain high affinity for antigens and other beneficial biological properties, To achieve this goal, humanized antibodies can be selectively induced by three-dimensional spatial patterns of parental and humanized sequences to analyze parental sequences and various conceptual humanized products, three-dimensional immunity. -25-

2.00Π <Please read the notes on the back and fill out this page.) This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 丄329672 A7

V. INSTRUCTIONS (24) The globulin pattern is generally achievable and is familiar to the practitioner, and the computer program for the possible three-dimensional configuration can be used to analyze and select the selected immunoglobulin sequence. Examination of the displayed map allows for the possible role analysis of the residues in the selected immunoglobulin sequence, ie, the ability to separate the residues to affect the binding of the selected immunoglobulin to its antigen, in this manner, FR residues The base may be selected and mixed by a desired and foreign sequence such that it has the desired properties, for example, an increased affinity for the antigen of interest (typically), typically, this CDR residue is directly and largely Humanization or engineering of antibodies that affect antigen binding 'the invention can be performed using any known method, for example, but not limited to those described in the literature: 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. Mol. Biol. 196:901 (1987), 15 Carter et al., Proc. Natl. Acad. Sci. USA 89:4285 (1992) 'Priesta et al., J. Immunol. 151:2623 (1993), US patent Nos : 5723323 , 5976862 , 5824514 , 5817483 , 5814476 , 5763192 , 5723323 , 5766886 , 5714352 , 6204023 , 6180370 , 5693762 , 5530101 , 5585089 , 5225539 , 20 4816567 , PCT / : US98/16280 , US96/18978 , US91/09630 , US91 /05939, US94/01234, GB89/01334, GB91/01134, GB92/01755, WO90/14443, WO90/14424, W090/14430, EP 229246, each fully incorporated herein by reference, including References. -26- (Please read the note on the back and then on this page) «Good Editor--Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm) 1329672 A7 B7 V. INSTRUCTIONS (25) Anti-IL-12 antibodies may also be selected by animals that have been transfected into foreign genes (eg, mice, rats, hamsters, non-human primates) Immunization of, etc., which have the ability to produce human antibodies at any time, as described herein and/or known in the art, can produce human anti-IL-12 5 antibodies from such cells. The animals are isolated and made permanent using appropriate methods, such as the methods described herein. Gene-transferred mice, which are capable of producing human antibodies that bind to human antigens at any time, can be produced by known methods (for example, but not limited to, US Pat. Nos: 5,770,428, 5,569,825, 5,545,806, 10 5,625 , 126, 5, 625, 825, 5, 633, 425, 5, 661, 016 and 5, 786, 650 assigned 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, 15 Kucherlapate et al. EP 0463 151 B1, Kucherlapate et al. EP 0710 719 Al ' Surani et al. US. Pat. 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 20 (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) 'Tayl et al. Nucleic Acids Research 20(23):6287-6295 (1992) 'Tuaillon Et al. Proc Natl Acad Sci USA 90(8) 3720-3724 (1993), Lonberg -27-, this paper scale applies to Chinese national standards (CNS> A4 specifications (210 x 297 public)) (please read the back first) Note: Please fill out this page again) 'SJ. --Line. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1329672 A7 B7

V. Description of invention (26) 5 ο 11

5 IX Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 et al. im Rev Immunol 13(1): 65-93 (0995) and Fishwald et al. Nat Biotechnol 14(7): 845-851 (1996), Each of these mice is fully incorporated by reference.) Typically, these mice contain at least one transferred foreign gene, including from at least one human immunoglobulin site 'which is functionally recombined' or which can be functionally recombined DNA, such endogenous immunoglobulin sites in mice can be disrupted or deleted to remove the ability of an animal to produce antibodies encoded by endogenous genes. Screening antibodies for specific binding to similar proteins or fragments can be conveniently obtained using a peptide display gene bank, which involves screening a large number of individual members from a desired class or structure, peptide display Antibody screening of gene banks is a technique well known in the art, and the displayed peptide sequences may comprise from 3 to 5000 or more amino acid lengths, often from 5 to 100 amino acids, and often from Approximately 8 to 25 amino acids are long. In addition to direct chemical synthesis to generate a peptide peptide gene library, many recombinant DNA methods have also been revealed. One type includes the display of peptide sequences on the surface of phage or cells. . Each bacterium or cell contains a nucleotide sequence which can be assigned a specially displayed peptide sequence code. Such a method is disclosed in the following number of PCT patent publications: 91/1727, 91/18980, 91/19818 and 93/. 08278, other systems used to generate peptide gene libraries are in vitro from both chemical synthesis and recombinant methods. See, PCT Patent Publication Specification Series: 92/05258, 92/14843, and 96/19256, see also, ! ^ Patent Nos. 5,658,754 and 5,643,768, Peptide Display Gene Bank, Medium-28- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and then --- .II This page) - Line 13269672 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 37- A7 B7 V. Description of Invention (27) Quality, and screening kits are available from such suppliers: Invitrogen (Carlsbad, CA), and Cambridge Antibody Technology (Cambridgeshire, UK), see, for example, US Pat Nos. 4704692, 4939666, 4946778, 5260203, 5455030, 5518889, 5534621, 5 5656730, 5673733, 5767260, 5856456, assigned to Enzon; 5223409 , 5403484, 5571698, 5837500, assigned to Dyax; 5427908, 5580717, assigned to Affymax; 5885793, assigned to Cambridge antibody Technologies; 5750373, assigned to Genentech; 5618920, 5559896, 5576195, 5698435, 10 5693493, 5698417, assigned to Xoma, Colligan, supra; Ausubel, supra; or Sambrook, supra, the above-identified patents and disclosures are hereby incorporated by reference. The antibodies of the invention may also be prepared from 'an animal or mammal that uses at least one anti-IL-12 antibody-encoding nucleic acid to provide gene transfer, such as 15 goats, cows, horses, sheep, etc., to produce antibodies in their milk, such The animal can be prepared by known methods, for example, but not limited to US Patent Nos. 5,827,690, 5,849,992, 4,873,316, 5'849,992, 5,994,616, 5,565,362, 5,304,489, etc. each of which is hereby incorporated by reference in its entirety The antibody class can be further prepared by using at least one thief encoded by an anti-IL_12 antibody to provide a substrate-transferred plant and a cultured plant cell (eg, but not limited to tobacco and corn), which can be in the plant part or The cultured cells scream for 'special parts or variants' of such antibodies. In a non-limiting example, 'gene transfer squama leaves show heavy -29-^ paper scales apply to the Chinese National Standard (CNS) A4 specification (21Q) x 297 g g 1329672 A7 B7 V. INSTRUCTIONS (28) The assemblage protein has been successfully used to provide a large amount of recombinant protein, for example, using a promoter that can be uttered 'E.g., Gramer et al.,

Curr·Top. Microbol. Immunol·240:95-118 (1999) and the references mentioned in the 'other' gene transfer of corn have been used to table 5 mammalian proteins to achieve commercial production values, which have organisms The activity is equivalent to those produced from other recombinant systems or purified from natural sources 'see, for example, Hood et al., Adv. Exp. Med. Bio. 464: 127-147 (1999)) and references cited therein Antibodies can also be produced from a large number of plant-derived plant seeds, including antibody fragments, such as single-chain antibodies (scFv's), including tobacco seeds and potato tubers, see, for example, Conrad et Spit, Plant Mol. Biol. 38: 101-109 (1998)) and the references mentioned therein, the antibodies of the invention may also be produced using plants which have been genetically transferred according to known methods, see also, for example, Fisher et al., Biotechnol. Appl. Biochem. 15 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. Trans. 22: 940-944 (1994); Test data, see also generally for plant performance antibody class, non-limited to, the above references entirely 20 each is incorporated herein by reference. The antibodies of the present invention bind to human IL-12 in a wide range of affinity (KD). In preferred embodiments, at least one human mAb of the present invention optionally binds human il-12 with very high affinity, for example, The human mAb can have a KD equivalent to or less than about 1〇_7 Μ affinity combined with -30-. The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) (Jing Xian read the back of the note) Fill in this page again) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed-*T-«»J· nn 1 n I ϋ nn D nnnn III nn - n ϋ I nn Ί — n ϋ n 91. 1. 2,000 1329672 Economy Ministry of Intellectual Property Bureau employee consumption cooperative printed A7 _B7__ V. Description of invention (29) Human IL-12, for example but not limited to, 0.1-9.9 (or any range or value thereof) X10_7,1 (Γ8,10·9 , 10·10, 10·", 10·12, 1〇·13 or any range or value thereof. Such affinity or desirability of an antibody to an antigen can be determined experimentally using an appropriate method 5 (see, For example, Berzofsky, et al., "Antibody-Antigen Interaction," In Fundamental mmunology, Paul, W. E., Ed., Raven Press: New York, NY (1984); Kuby, Janis Immunology, WH Freeman and Company: New York, NY (1992); and the methods described therein), 10 specific The antibody-antigen interaction may have different affinities measured under different conditions (eg, salt concentration, pH). Therefore, the determination of affinity and other antigen-binding parameters (eg, KD, Ka, Kd) should be made. Standardized solutions of antibodies and antigens, and standardized buffers, for example, buffers as described herein. 15 Nucleic acid molecules use information provided in the description, such as nucleotide sequences, which can be given a cryptogram to generate at least one SEQ ID NOS At least 70-100% contiguous amino acid of one of l, 2, 3, 4, 5, 6, 7, 8 or a particular 20 fragment, variant or a desirable sequence thereof, or a deposited medium , comprising at least one of these sequences, the nucleic acid molecules of the present invention encoding at least one anti-IL l2 antibody can be prepared using methods described herein or known in the art. The nucleic acid molecules of the invention can be in the form of RNA , for example (please read first Note on the back of the page and fill in this page) Order --------- Line! -31-

91. 1. 2,000 1329672 A7 ____^B7__ V. INSTRUCTIONS (30) mRNA, hnRNA, tRNA or any other type 'either in DNA form, including 'but not limited to cDNA and from colonization or synthesis a group of genes DN A ' or any mixture thereof, which may be three-stranded, double-stranded or single-stranded, or any mixture thereof, and any part of at least one strand of DNA 5 or RNA may be a coded strand, Also known as a sense strand, or it can be a non-coded stock (also known as an anti-sense strand). An isolated nucleic acid molecule of the invention can comprise a nucleic acid molecule comprising an open reading frame (ORF), optionally with one or more introns, such as, but not limited to, at least one of at least one CDR A specific part, such as at least one heavy chain (eg, SEQ IDNOS: 1-Ministry of Economics, Intellectual Property Office, Staff Consumer Cooperative, Print 3) or light chain (eg, 'SEQ ID NOS: 4-6), CDR1, CDR2, and/or CDR3 a nucleic acid comprising a coding sequence comprising an anti-IL-12 antibody or a variable region (eg, SEQ ID NOS: 7, 8); and the nucleic acid molecule comprising a 15 nucleotide sequence substantially different from the above description, but due to the gene Degradation of the password can still dictate at least one anti-IL-12 antibody as described herein and/or known in the art. Of course, the code for this gene is well known in the art, so The Bank is skilled in the routine production of such degenerate nucleic acid variants, encoding a specific anti-IL-12 antibody 2 〇 class for the present invention 'see' such as ' Ausubel, et al' supra, and such nucleic acid variants The body is included in the present invention, the isolated core of the present invention Non-limiting examples of molecules include SEQ ID NOS: 10-15, corresponding to, without limitation, encoding HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, LC CDR3, HC variable region and LC variable region, respectively -32- 9l* I. 2,000 This paper size is applicable to China National Standard (CNS) A4 (21G X 297 public) υΖ^Ό/Ζ Α7 Β7 Invention Description (31 Nucleic Acid 5 10 15 Miscellaneous ^ I Surface 'This The invention provides a spacer for the anti-IL12 antibody, a lambda acid molecule, the antibody having an amino acid sequence such as oxime given by a nucleic acid, the nucleic acid molecule of the present invention, which comprises an anti-chemical_ The nucleic acid of the hexadecimal cipher may include, but is not limited to, those from the amino acid sequence of the contiguous; the entire antibody or a part thereof; the phase of the antibody; the antibody, the fragment or the moiety, and the sequence of the additional sequence 'eg at least one signal leader or fused pattern, small column, with or without the additional coded sequence described above, eg one less embedded sequence, with additional, non-coded sequences, including Guided to, non-coded 5, and 3, sequences, such as transcribed, non-split translation , which plays a role in transcription and mRNA manipulation, including the splicing of adenosine (eg, cell binding and mRNA stability); another additional encoded sequence which can be incorporated into the amine group Acids, such as those that provide additional functionality, can be fused to the phase of the antibody, such as the sequence of the 肷 code, which facilitates fusion of the antibody, including fragmentation or purity of the antibody (please read the back first) Precautions for re-filling this page) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed 20 Polynucleotides selectively hybridized into polynucleotides as described herein. The present invention provides isolated nucleic acids which are selected Polynucleotides revealed at the cost of hybridization under hybridization conditions, therefore, the polynucleotides of this specific example can be used for isolation, speculation, and/or quantification of polynuclear inclusions of this type. Applicable to China National Standard (CNS) A4 specification (21〇X 297 public love) 91. I. 2,000 --------^» — 1 —--I--^ I -------- ---------------- 1329672 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 five Description of the Invention (32) Nucleic acids of nucleotides, for example, the polynucleotides of the present invention can be used to identify, isolate, or propagate a portion or full-length clone of a registered gene bank, in some specific examples. In this case, the polynucleotide is a complete set of gene or cDNA sequences isolated, or a complement of cDNA derived from a human or mammalian, 5 acid gene bank. Preferably, the cDNA gene bank comprises at least a full length sequence, preferably at least 85% or 90% of the full length sequence, and preferably at least 95% of the full length sequence, and the cDNA gene pool can be normalized to increase the representation of the rare sequence Typically, in low or moderate stringency hybridization conditions, 10 but not completely exclusive, the sequences used in comparison to complement are sequences with reduced sequence identity, moderate and high stringency conditions are optionally selected Using sequences with higher consistency, low stringency conditions allow for hybridization of selected sequences with about 70% sequence identity and can be used to identify orthologus or paralogus sequences. 15 Alternatively, the polynucleotide of the present invention will give at least a portion of the antibody code, and the latter will be given to the crypton by the polynucleotides herein, and the polynucleotide of the present invention comprises a nucleic acid sequence which can be applied. For selective hybridization to a polynucleic acid encoding an antibody of the invention, see, for example, Ausube Bu supra; Colligan ' supra, each of which is incorporated by reference in its entirety. Establishment of Nucleic Acids The isolated nucleic acids of the present invention can be prepared by: (a) recombinant methods, (b) synthetic techniques, (c) purification techniques, or mixtures thereof - 34- Read the notes on the back and fill out this page>

-I ϋ ϋ I · n I n ϋ I nnnn It nnnnnnnn I This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 91. 1. 2,000 1329672 A7 B7 V. Description of invention (33 method The Ministry of Economic Affairs is a well-known person in the art of consumer cooperatives. Nucleic acids may conveniently contain other sequences in addition to the polynucleotides of the present invention, for example, comprising one or more endonuclease restriction The position of the clonal-reproductive lineage can be inserted into the nucleic acid to aid in the isolation of the polynucleotide 'in addition to a translatable sequence, which can be inserted to aid in the isolation of the translated polynucleotide of the invention, for example, A six histidine labeling gene sequence provides a convenient method for purifying the protein of the invention, except for the nucleic acid-encoding sequence of the invention, optionally for the selection of the polynucleotide of the invention and/or Or a segment of a medium, adapter, or synthetic DNA. Additional sequences may be added to such selected and/or expressed sequences to best suit their selection and/or performance. Isolation of the helper polynucleotide, or improved introduction of the polynucleotide into the cell; the use of the selected medium, expression medium, adapter, and synthetic DNA is well known in the art. See, for example, Ausubel, supra; or Sambrook, supra) Recombinant Methods for Establishing Nucleic Acids The isolated nucleic acid compositions of the invention, such as RNA, dDNA, DNA of a whole set of genes, or any recombinant thereof, As far as the Bank is well aware, 'any number of colonization methods can be used to extract from the source of the organism' in certain specific cases' in the strict strips of the glucosinolate probes to selectively hybridize to the polynucleotides of the present invention. Determine the phase of the CD or the whole set of genes in the surface of the library; the isolation of the ship, -35-degree of wealth and wealth (CNS) A4 specifications (210 X 297 ^5 Ding 10 15 20 (please Read the notes on the back and fill out this page. -3⁄4 Order·Line· 1329672

V. INSTRUCTIONS (34) The construction of a database of cDNA and the entire set of genes is well known to those skilled in the Bank. (See 'eg Ausubel, supra; or Sambr〇〇k, supra) 5 ο 5 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Print 20 Nucleic Acid Association and Isolation Methods A database of cDNA or entire set of genes can be utilized with the present invention. Probes with a predominantly polynucleotide sequence (as disclosed herein) are screened and probes can be used to hybridize to the DNA or cDNA sequence of the entire set of genes to isolate homologous genes in the same or different microorganisms' The skilled hands of the Bank can understand that various degrees of hybrid stringency can be used for this analysis; and the parent or wash medium can be used strictly, and when the conditions of hybridization become stricter, the investigation is There is a greater degree of complementarity between the needle and the target for the formation of a double helix. The degree of stringency can be determined by the presence of one or more temperatures, ionic strength, pH and partially denatured solvents such as guanamine. Control, for example, the stringency of hybridization can be conveniently altered by altering the polarity of the reagent bath, for example, operating at the concentration of methamine in the range of 〇〇4 to, the degree of complementarity required to detect binding ( Column consistency) will vary with the stringency of the hybridization medium and/or wash medium, with an optimal complementarity of 100%, or 7〇1%, or any range or value in between, however, it should be understood Smaller sequence variations in probes and primers can be compensated for by reducing the stringency of hybridization and/or wash media. The method of colonization of RNA or DNA is well known in the art and can be guided by the guidance and guidance of the present invention to avoid undue experiment-36- (Jing Xian read the back of the pan 4 matter again? ^ This page) Order - • Line · • 3gS paper size applicable to China National Standard (CNS) A4 x 297 public Chu) Ministry of Economic Affairs Intellectual Property Bureau staff consumption cooperatives India Purple 13296672 A7 B7 V. Invention Description (35). Known methods of proliferation of RNA or DNA include, but are not limited to, polymerase chain reaction (PCR) and related proliferation methods (see, for example, US Patent Nos. 4,683,195 ' 4,683,202 ' 4,800,159 ' 5 4,965,188, to Mullis, et 4,795,699 and 44,921,794 to Tabor, et al; 5,142,033 to Innis; 5,122,464 to 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, 4,766,067 to Biswas; 4,656,134 to Ringogen) and RNA Vector 10 for proliferation, using antisense RNA to the target sequence as a template for double-stranded DNA synthesis (US Patent No. 5,130,238 to Malek, The et al 'trade name is NASBA), the entire contents of which are incorporated herein by reference. (See, for example, Ausubel, supra; or Sambrook, supra) 15 For example, polymerase chain reaction (PCR) technology can be used to propagate the sequence of the polynucleotides of the present invention with DNA or cDNA genes taken directly from the entire set of genes. The library-related genes, PCR and other in vitro proliferation methods can also be used to select the nucleic acid sequence of the protein to be expressed, and use the nucleic acid as a probe to detect the desired 20 mRNA in the sample. The existence of a technique for nucleic acid sequencing, or other purposes, is sufficient to guide a well-known method of proliferation in vitro, in Berger, supra,

Sambrook, supra, and Ausubel, supra, and Mullis, et al., U.S. Patent No. 4,683,202 (1987); and Innis, et al., PCR

Protocols A Guide to Methods and Applications, Eds., -37- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public). (Please read the notes on the back and fill out this page) Ή. -Line·1329672 A7 B7 V. Description of invention (36)

Academic Press Inc" San Diego, CA (1990), a commercially available kit for PCR propagation of a whole set of genes is known in the art, see, for example, the PCR Kit (Clontech) of the Advantage-GC set of genes, In addition, for example, the T4 gene 32 protein (Boehringer 5 Mannheim) can be used to enhance the yield of long PCR products. Synthesis of nucleic acids for the structure The preparation method of the isolated nucleic acid of the present invention can be carried out directly according to known methods. Chemical synthesizers (see, for example, Ausubel, et al., 10 supra) 'Chemical synthesis usually produces single-stranded nucleotides that can be hybridized to complementary strands into double stranded DNA, or using single strands As a template for polymerization by DNA polymerase, skilled in the art will recognize that, on the one hand, chemical synthesis of DNA can be limited to about 1 or more bases. 'Longer sequences can be linked by shorter sequences. 15 Recombinant Expression Box Economics Department Intellectual Property Office Staff Consumer Cooperative Printed The present invention further provides a recombinant expression cassette comprising the nucleic acid of the present invention, a nucleic acid sequence of the present invention, such as cDNA or given to the present invention The sequence cryptome of the entire set of antibodies can be used to create a recombinant expression cassette that can be introduced into at least 20 desired host cells, which will typically comprise a polynucleotide operably manipulated by the present invention. Linking to a sequence that initiates transcriptional regulation 'which will direct transcription of the polynuclear acid in a desired host cell, both heterologous and non-heterologous (endogenous) promoting substances can be applied to guide the expression of the invention Nucleic Acids -38- >3-02 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 1329672

V. INSTRUCTIONS (37) In some embodiments, nucleic acids that promote isolation of a substance, enhancer, or other element can be introduced into the appropriate position of the non-heterologous form of the polynucleotide of the present invention ( Upstream, downstream or in the embedded sequence), the expression of the polynucleotide of the invention is adjusted upwards or downwards, for example, 'endogenous promoters can be altered by mutation, intermediate deletion and/or substitution In or outside the body. ο 5 11 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 Vectors and Host Cells The present invention also relates to a medium comprising the isolated nucleic acid molecule of the present invention, a host cell genetically engineered with a recombinant medium, and a borrowed Recombinant techniques produce at least one anti-IL-12 antibody, as is well known in the art, 'see, for example, Sambrook et al. supra; Ausubel, et al. supra, each fully incorporated herein by reference. . The polynucleotides are optionally conjugated to a medium containing a selectable marker gene for propagation in a host, typically, the plasmid medium is in a precipitate (eg, calcium phosphate precipitate), or in a complex The charged lipid shell is introduced into 'if the medium is a virus' which can be packaged into the virus in vitro using a suitable packaging cell line and then transduced into the host cell. The DNA insert should be operably linked to the appropriate promoter, the expression construct will additionally contain a site for transcription initiation, termination, and translation will be provided at the ribo-binding site in the transcribed region, and the coding site for the mature transcription expressed by the construct will be Preferably, the translation starts with the start and end of the cryptogram (eg, UAA, UGA, or UAG) appropriately located at the end of the mRNA to be translated, and the performance of the mammalian or eukaryotic cell is applied to the UAA and -39- paper scales in China. National Standard (CNS) A4 Specification C210 X 297 mm) (Please read the notes on the back and fill out this page) *SJ. .线·1329672 A7 B7 V. Invention Description (38) UAG is better. Preferably, the expression medium comprises, but is selected to include, at least one selectable marker gene, including but not limited to, for example, amino thioglycolic acid (MTX), dihydrofolate, which is resistant to eukaryotic cell culture. Reductase 5 (DHFR > US Pat. Nos. 4,399,216; 4,634,655; 4,656,134; 4,956,288; 5,149,636; 5,179,017), ampicillin, neomycin (G418), mycophenolic acid, Or glutamine-enzyme synthase (GS, US Pat. Nos. 5, 122, 464; 5, 770, 359; 5, 827, 739), and resistance to tetracycline 10 or ampicillin which is resistant to coliforms and other bacteria or prokaryotic cells. Genes (the above-identified patents are hereby incorporated by reference in their entirety in their entireties in each of the the the the the the the the the the the the the the the the the the the the the the The host cell can be obtained by calcium discotransport infection, DEAE-glucan-mediated metastatic infection, cation 15 lipid-mediated transfer infection, electroporation, conduction, infection or other known Method, such methods are described in the present art, for example, Sambrook, Supra, first μ Chapters 16_18; Ausubd, Qing Yang, Chapter 1,9,13,15,16. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Infected At least one antibody of the present invention may be expressed in a modified (e.g., 20 fusion protein), and may include not only a secretion signal but also a heterologous functional range, for example, A range of additional amino acids, particularly charged amino acids, can be added to the oxime-terminator of the antibody to improve its stability in the host (4), in purification, or during subsequent processing and storage. Miscellaneous, in addition, can be read to the present invention -40-

1329672

V. INSTRUCTIONS (μ) 5 ο tl 5 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives print 20 bodies to make purification easy, such a range can be removed before preparing the antibody or at least the final step of the fragment Such methods are described in Xu Xi's 'Quarter's Laboratory Guide, such as Sambrook, supra, pp. 42 and 18.1-18.74; Ausubel, supra, Chapters 16, 17 and 18. A person skilled in the art is well acquainted with the numerous expression systems of the proteins of the invention that are cryptic from nucleic acids. Or 'the nucleic acid of the present invention can be expressed in a host cell, in a host cell containing an antibody of the present invention containing endogenous DNA to a codon, by opening (or operating) a switch, such a method being It is disclosed in U.S. Patent Nos. 5,58, 734, 5, 641, 670, 5, 733, 746, and 5, 733, 761, which are incorporated herein by reference. Descriptions of cell cultures for the production of antibodies, specific parts or variants thereof are exemplified by mammalian cells, which are often in the form of monolayers of cells, although mammalian cell suspensions or bioreactants may also be used. Many suitable host cell lines with the ability to express intact glycosylated proteins have been developed in the art, and include COS-1 (eg, ATCC CRL 1650), COS-7 (eg, ATCC CRL 1651), HEK293, BHK21. (eg, ATCC CRL-10), CHO_WATCCCRL1610; ^BSC-1GMWATCCCRL-26) cell line, Cos-7 cell, CHO cell, hep G2 cell, P3X63Ag8.653, SP2/0-Agl4, 293 cells, Hela cells, etc., It can be easily obtained, for example, American Type Culture -41- This paper size is applicable to China National Standard (CNS) A4 specification (210 297 297 mm) {Please read the note on the back and fill out this page) Order: -Line · 1329672 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description Uo )

Collection, Manassas, Va (www.atcc.org), preferred host cell types include those derived from lymphoid origin, such as myeloma and lymphoma cells, and the preferred host cell is P3X63Ag8.653 cell r ( ATCC Accession Number CRL-1580) and SP2/0-Agl4 cells 5 (ATCC Accession Nmber CRL-1851). In a particularly preferred embodiment, the recombinant cells are P3X63Ag8.653 or SP2/0-Agl4 cells.

The expression vector for these cells may include one or more of the following expression control sequences, such as, but not limited to, the origin of replication, a promoting substance (eg, late-type or early-type SV40 promoting substance), CMV promoting substance (US 10) Pat. Nos. 5,168,062; 5,385,839), HSV tk promotes cytoplasmic, pgk (phosphoglycerate kinase) promoting cytoplasm, EF-1 alpha promoting substance (US Pat. No. 5,266,491), at least one human immunoglobulin promoting substance , an increasing agent, and/or processing information location, such as ribosome binding position, RNA splicing position, polyadenylation formation position (eg, sV large T Ag multiple A 15 addition position), and terminator sequence of transcription, see, E.g,

Aausubel et al" supra; Sambrook, et al., supra. Others are known and/or available for use in the production of nucleic acids or proteins. For example, from the American Type Culture Collection

Catalogue of Cell Lines and Hybridomas (www.atcc.org) or 20 other known or commercial sources. When a eukaryotic host cell is used, the polyadenylation or transcription terminator sequence is typically incorporated into the mediator. An example of a terminator sequence is the polyadenylation sequence derived from the growth hormone gene of the bovine. A sequence that can be correctly spliced for transcription, an example of a splicing sequence is taken

-42-

1329672 A7 ____B7____ V. INSTRUCTIONS () (Please read the note on the back and fill out this page) From the VP1 embedding sequence of SV40 (Sprague, et al., J. Virol. 45:773-781 (1983)), In addition, gene sequences for controlling replication in a host cell can be incorporated into a medium, as is known in the art. 5 Purification of antibodies Anti-IL-12 antibodies can be recovered and purified from recombinant cell culture by known methods including, for example, but not limited to, protein A purification, ammonium sulfate or ethanol precipitation, acid extraction, anions Or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity 10 chromatography, hydroxyapatite chromatography and lectin chromatography, high performance liquid chromatography ("HPLC") can also be used for purification, see, for example, Colligan, Current Protocols in Immunology, or Current protocols in Protein Science, John Wiley & Sons, NY, NY, (1997-2001), for example , i, 4, 6, 8, 9, 10, 15 '' are each fully incorporated herein by reference. The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperatives print antibodies of the present invention including natural purified products, products obtained by chemical synthesis, and products obtained from a host of eukaryotic nucleus by recombinant techniques, including, for example, yeast, Higher plant, insect and mammalian cells, depending on the host used in the recombinant production step, the antibody of the present invention 20 may be saccharified or non-saccharified, preferably in a saccharified form. Methods are disclosed in many standard laboratory manuals such as Sambrook, supra, Sections 17.37-17.42; Ausubel, supra, Chapters 1, 12, 13, 16, 18 and 2, c〇mgan, Protein Science , supra, Chapters 12-14, all fully incorporated -43- This paper scale applies to the Central Standards (CNS) A4 specification (210 X 297 mm) - A7 B7 V. Description of invention (42) This is used as a reference 5 ο 5 11 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

S 20 anti-IL-12 antibody class = antibody class comprises an antibody or any isolated or prepared anti-human antibody or antigen-binding fragment bound by any of the antibodies detailed in the present invention. = at least one organism that neutralizes the protein in the texture is preferably a di-dimer, or a specific part or a variant thereof, which is partially or relatively == and at least - a 1 L·12 protein or at least one of the fragments: a living person' Binding to this protein or fragment and thus inhibiting the activity via the mediator mt2 receptor or via other mediators/mediators, here, neutralizing antibody " means an anti-, (iv) effect of activity About 2〇1 to > about: 2, 3, 4, 5, 55, 6, 65, 7, 75, 8, 85, 90, 91, 92, 93, 94, 95, 96 97, 98 99, more 'depending on the analytical method, the ability of the anti-cutting antibody to inhibit an affected activity is derived from at least an appropriate IL- or X-body analysis, as described here and/or As known in the art, the human antibody of the present invention may be of any class (IgG, IgA, IgM, IgE, IgD #) or the same type and may contain "or lighter" In particular, the human antibody comprises an IgG heavy chain or a definitive fragment 'eg at least one isoform' IgG1, IgG2 igG3 or IgG4, which may be a base-transferred mouse or other gene transfer Preparation of non-human mammals, which contain at least 44- of this paper scale applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) species 13296672

Description of the Invention (43) 5 ο Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives prints 20 human light chain (eg IgG, IgA and IgM) (eg γ丨, γ 2 r4) transgenic genes, as disclosed herein and/or This two, η, 'in another-specific examples' this anti-human IL_12 human anti-spoon: known IgGl heavy chain and an IgGl light chain. ^ 3 - at least one antibody of the invention binds to at least - a protein, a subunit, a fragment, a site or any of its specific epitopes, the at least one of which may comprise at least one species The range of antibody binding comprising at least one portion, wherein the epitope is preferably composed of at least one species = extracellular, soluble, hydrophilic, external to the protein or sputum. At least one specific epitope may comprise any combination of at least one to three amino acid sequences of contiguous amino acids of SEQ ID Ν0:9 to a particular portion thereof. Typically, a human antibody or an antigen-binding fragment of the invention will comprise an antigen-binding region comprising at least one human complementarity determining region (CDR1, CDR2 and CDR3) or at least one heavy chain variable region variant A variant of a decision region (CDR1, CDR2 and CDR3) or at least one light chain variable region that is complementary to at least one human, and a non-limiting example 'antibody or antigen-binding site or variant may comprise at least one SEQ. The heavy chain CDR3 of the amino acid sequence of ID Ν0:3, and/or the light chain CDR3 of the amino acid sequence of SEQ ID Ν0:6; as a specific example, the antibody or antigen-binding fragment may have The antigen-binding region' is a heavy chain -45- (containing at least one amino acid sequence having an associated CDRs 1, 2 and/or 3 (eg, SEQ ID NOS: 1, 2, and/or 3) Please read the notes on the back and fill out this page. 幻·线. This paper scale applies to China National Standard (CNS) A4 specification (210 * 297 mm) 1329672 A7 B7 V. Invention Description (44) CDR (CDR1) At least one of CDR2 and/or CDR3), in another specific entity, antibody or The pro-binding site or variant may have an antigen-binding region comprising at least one associated CDRs 1, 2 and/or 3 (eg, SEQ ID NOS: 4, 5, and/or 6) At least a portion of a light chain CDR of an amino acid sequence (ie, CDR1, CDR2, and/or CDR3), in a preferred embodiment, three heavy chain CDRs of an antibody or antigen-binding fragment and three light chain CDRs An amino acid sequence having at least one of mAb 12B75, C340, or any of the related CDRs described herein, which can be prepared by using conventional techniques of 10 proteins (eg, CDRs, basic structure) of the antibody. Chemically linked, by one or more nucleic acid molecules that give the antibody code, using conventional techniques of recombinant DNA technology or by using any other suitable method for preparation and performance. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives The IL-12 antibody may comprise at least one of 15 heavy or light chain variable regions with a defined amino acid sequence, for example, in a preferred embodiment, the anti-IL-12 antibody comprises at least one heavy Chain variable region, optionally with SEQ ID ΝΟ: an amino acid sequence of 7 and/or at least one light chain variable region 'optionally an amino acid sequence having SEQ ID NO: 8, an antibody class that binds to human IL-12 and which comprises a definite heavy or light chain The variable region 20 can be prepared using an appropriate method, such as phage display (Katsube, Y" et al., lnt j Mol. Med, 1 (5): 863-868 (1998)) or an animal using gene transfer. Methods, such as those known in the art and/or described herein, such as 'gene-transferred mice, include a functionally rearranged human immunoglobulin heavy chain transgene and DNA contained in the transgene-46- This paper scale applies to the Chinese national standard <CNS) A4 specification C210 X 297 mm> 1329672 Α7 Β7

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (45) Human immunoglobulin light chain sites that can be functionally recombined, which can be immunized with human IL-12 or its fragments to induce antibody production. If desired, the cells produced by the antibody can be isolated and the hybridoma or other permanent antibody producing cells can be prepared according to the methods described herein and/or known in the art, or antibodies, specific sites or variants. The encoded nucleic acid or a portion thereof can be expressed in a suitable host cell. The invention also relates to antibody, antigen-binding fragment, immunoglobulin chain and CDRs comprising the amino acid sequence substantially identical to the amino acid sequence, preferably such antibody or antigen-binding fragments And an antibody comprising 10 such chains or CDRs, which can bind to human IL-12 with high affinity (e.g., less KD or equal to about 10-9 M), substantially identical to the amino group of the amino acid sequence. The acid sequence includes a sequence comprising a conservative amino acid substitution, and an intermediate amino acid deletion and/or insertion, and a conservative amino acid substitution means having similar chemical and/or physical properties (eg, Substituting a second amino acid for the charge, structure, polarity, hydrophobicity/hydrophilicity of the first amino acid's conservative substitution includes substituting an amino acid for another amino acid between the following groups: Aminic acid (K), arginine (R) and histidine (H); aspartic acid (D) and glutamic acid (E); aspartame (N), glutamic acid (Q), Serine (S), threonine (T), tyrosine (γ), 20 K, R, Η, D and E; alanine (A), valine (V), leucine (L) ), isoleucine (1), 脯Acid (Ρ), phenylalanine (F), tryptophan (W), methionine (Μ), cysteine (C) and glycine (G); F 'W and Υ; C, S With Τ. -47- The paper size applies to the Chinese National Standard <CNS) A4 Specification C210 X 297 mm) (Please read the note on the back and fill out this page), 3⁄4 lsi· --Line—』 1329672 A7 B7 V. Invention Description (46) Amino acid code construction The amino acid of the anti-IL-12 antibody of the present invention is often represented by an abbreviation, and the name of the amino acid can be a single letter code, a three letter code, a common name, or three. Nucleotide codon representation, as is known in the art (see Alberts, B., et al., Molecular Biology of The Cell, Third Ed., Garland Publishing, Inc., New York, 1994). ):

Alone letter code Three letter code Commonly known as three nucleotide codons A Ala Alanine GCA ' GCC ' GCG ' GCU C Cys Cysteine UGC, UGU D Asp Aspartic acid GAC, GAU E Glu Glutamate GAA ' GAG F Phe phenylalanine UUC 'UUU G Gly Glycine GGA, GGC, GGG, GGU Η His histidine CAC > CAU I lie Isoleucine AUA, AUC, AUU K Lys amic acid AAA ' AAG L Leu leucine UUA ' UUG > CTJA ' CUC ' CUG ' CUU Μ Met 曱 thioacetic acid AUG Ν Asn aspartate AAC ' AAU Ρ Pro proline CCA, CCC ' CCG ' CCU Q Gin glutamine CAA ' CAG R Arg arginine AGA ' AGG ' CGA ' CGC ' CGG ' CGU S Ser Serine AGC ' AGU ' UCA ' UCC ' UCG ' UCU Τ Thr sulphonic acid ACA , ACC ' ACG , ACU V Val 缬Amino acid GUA ' GUC ' GUG ' GUU -48- 3 This paper size applies to China National Standard (CNS) A4 specification (210 * 297 mm) -II — ! — — — ! — — — — · II (Please read first Precautions on the back side, please fill out this page) Order.· -- Line. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 13296672 A7 ------- B7 V. Invention (47)

W Trp Tryptophan UGG Y Tyr tyrosine UAC ' UAU Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed The anti-IL-12 antibody of the present invention may comprise one or more amino acid substituents, intermediate deletions or additions , or from natural mutations or human manipulation, as indicated herein. 5 Of course, the number of 'amino acid substituents' will be determined by the skilled artisan, including those already disclosed, in general, for any given anti-IL-12 Ig-derived protein, fragment or variant. Will not exceed 40 ' 30 ' 20 ' ' 18 ' 17 ' 16 ' 15 ' 14 > 13 ' 12 ' 11 ' '9, 8, 7, 6'5, 4, 3, 2, Bu, for example 1-30 Or any range or value of 10, as defined herein. Functionally essential amino acids in the anti-IL-12 antibodies of the invention can be identified by methods known in the art, such as position-directed mutagenesis or alanine-sweeping mutagenesis (eg, Ausubel, supra, Chapters 8,15; Cunningham and Wells, Science 244:1081-1085 (1989)) » The latter method is the biological activity of a mutant molecule obtained by introducing a separate alanine mutation at each residue in the molecule. For example, but not limited to, at least one IL-12 neutralizing activity, the critical position for antibody binding can also be identified by structural analysis, for example using crystallization, nuclear magnetic resonance or photoaffinity labeling (Smith, et al. J. Mol. Biol. 224: 899-904 20 (1992) and de Vos, et al., Science 255: 306-312 (1992)). The anti-IL-12 antibodies of the invention may include, but are not limited to, at least one site, sequence or combination selected from 5 to all numbers of contiguous amino acids' which belong to at least SEQ ID NOS: -49- <4,5,6 - Please read the note on the back and fill out this page) -,3⁄4 .SJ· --Line paper size applies to China National Standard (CNS) A4 specification C210 X 297 PCT> 1329672 A7 ___ B7 V. Description of invention (48) One. The IL-12 antibodies or particular sites or variants of the invention may include, but are not limited to, at least one site, sequence or composition selected from at least 3-5 contiguous amino acids belonging to SEQ ID NOS: 5_17 genus 5 contiguous amino acids of SEQ ID NOS: 2, 5-1 contiguous amino acids belonging to SEQ ID NOS: 3, 5-11 contiguous amines belonging to SEQ ID NOS: a base acid '5-7 contiguous amino acids belonging to SEQ ID NOS: 5' 5-9 contiguous amino acids belonging to SEQ ID NOS: 6; Leu21, Lys76, Met83, Ser85 belonging to SEQ ID NO: 7 Amino acid.

The anti-IL-12 antibody may alternatively comprise 5, 17 '10, 11 ' 7 ' belonging to at least one of SEQ ID NOS: 1, 2, 3 ' 4 ' 5 ' 6 ' 7 or 8 9,119, or 108 is more than one of 70-100% of the amino acid. In one embodiment, the amino acid 15 sequence (eg, variable region, CDR) of the immunoglobulin chain, or a portion thereof, has a cis-100% (eg, 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 Or a range or value between 100 or any of the amino acid sequence of the related chain of at least one of SEQ ID NOS: 7,8, for example, the amino acid sequence of the light chain variable region can be SEQ ID NO The sequence of :8 is compared, or the amino acid sequence of the heavy chain CDR3 is comparable to the sequence of SEQ ID NO: 3, preferably 70-100% amino acid identity (ie, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 or any range or value between them) is performed using appropriate computer operations. -50 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 * 297 mm) Love) (Please read the note on the back and fill out this page) ·% --Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 13296672 A7 _______ B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperatives Ming (49) have, as is known in the art are. Examples of heavy and light chain variable region sequences are SEQ ID NOs: 7 and 8 'the antibodies of the invention, or unique variants thereof, which may comprise any number of contiguous amino acid residues from an antibody of the invention. Wherein the number 5 is selected from 10-100% of the number of residues contiguous in the anti-IL-12 antibody. 'Selectively' the sequence of the contiguous amino acid is at least about 10, 20' 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220 '230 ' 240, 250 or more amino acid length Or any range or value of 10 'In addition, the number of such sequences may be selected to include an integer number of 1 to 1 〇 (eg, at least 2, 3, 4, or 5). As known to those skilled in the art, the present invention encompasses at least one active antibody of the organism of the present invention, the biologically active antibody having a unique activity at least equivalent to natural (non-synthetic), endogenous or related and known. 15 of that. 20%, 30%, or 4%, and preferably at least 5%, 6 〇/〇, or 70%, and preferably at least 8%, 9%, or 95% of the antibody. Activity, enzyme activity and analysis and quantification of the specificity of the f, are well known to those skilled in the art. In another aspect, the invention relates to a human antibody-like fish snapper' as disclosed, which is covalently attached to the organic moiety: modification, such modification can result in improved pharmaceutical kinetics such as ' The antibody or antigen-binding sheet of the increased in vivo mound phase can be a linear or branched hydrophilic polymerized base group or a fat (tetra) group. In particular, this hydrophilic ^51 - This paper size 剌 National Standard (CNS) A4 297 mm) (Please read the notes on the back and fill out this page)

1329672 A7 B7 V. INSTRUCTION DESCRIPTION (50) The polymerized group may have a molecular weight of from about 800 to about 12 Å, and may be a polyalkylglycol (eg, polyethylene glycol (PEG), polypropylene glycol). (PPG)), a saccharide polymer, an amino acid polymer or a polyvinylpyrrolidone, and the fatty acid or fatty acid ester group may comprise from about 8 to about 40 carbon atoms. The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative prints the modified antibody of the present invention and the antigen-binding fragment, which may comprise one or more organic parts directly or indirectly covalently bonded to the antibody, and is bonded to The antibody or antigen-binding fragment of the present invention may independently be a hydrophilic polymeric group, a fatty acid group or a 10-fatty acid ester group, as used in the specification, "fatty acid," Acids and dicarboxylic acids, the term "hydrophilic polymeric radicals" means organic polymers which are more soluble in water than in octane. For example, polylysine is easier in water than in octane. Soluble, therefore, an antibody modified by covalent attachment of polyamino acid is also included in the present invention, and the hydrophilic polymer suitable for modification 15 of the antibody of the present invention may be linear or branched and Including, for example, polyglycols (such as PEG, monodecyloxy-polyethylene glycol glycol (mPEG), PPG, etc.), sugars (such as dextran, cellulose 'oligosaccharides, polysaccharides) Etc.) Polymerization of hydrophilic amino acids (eg, 'polyaminic acid, polyarginine, polyaspartic acid, etc.), polyalkane oxide 20 species (eg, polyethylene oxide, polypropylene oxide, etc.) and polyvinylpyrrole bite - preferably, The polymer used to modify the hydrophilicity of the antibody of the present invention has an intrinsic molecular weight of from about 800 to about 15 Å, respectively, and that 〇〇〇 dalton can be used, for example, PEG 5 〇 00 and PEG 2 〇, 〇 00, wherein the subscript For this purpose, the average molecular weight of the polymer, in Daltons; hydrophilic polymeric base-52-this paper scale applies to Chinese national standards (CNS> A4 specifications (210 X 297 mm) 1329672 A7

° Hydrophilic polymers substituted with one to six alkyl, fatty acid or fatty acid ester groups = fatty acid succinyl groups can be suitably used: a fatty acid: a polymer such as an acid can be coupled to a fatty acid or a lipid 5 η A fatty acid or a fatty acid-activated slow acid 1 M-based secondary activator can be coupled to an interesting group located on the polymerization. Suitably, the fat- or fatty acid vinegar for modifying the antibody of the present invention may be saturated or may contain one or more unsaturated units, and the fatty acid suitable for modifying the antibody of the present invention includes, for example, a positive twelve Sour burning acid (C!2, lauric acid), n-tetradecanoic acid (C", myristic acid), n-octadecanoic acid (Cu, stearic acid), n-decanoic acid (C2Q, arachidic acid), 廿Dicalcinous acid (C22, behenic acid), n-tridecanoic acid (c3〇), positive forty burned acid (C4〇), cis-Δ9-octadecanoic acid (Cls, oleic acid), all cis Formula _Δ5,8,1114_ 廿tetradecenoic acid (C2 〇, arachidonic acid), octanoic acid, tetradecanedioic acid, 15 octyl succinic acid, decanedioic acid, etc., suitable fatty acid esters The class includes a mono- vinegar of a di-lowering acid comprising a linear or branched lower alkyl group, and the lower alkyl group may comprise from 1 to about 12, preferably from 1 to about 6 carbon atoms. The modified human antibody-antigen-bound fragment may be prepared by a suitable method, for example, by reacting with one or more modifying agents, and the "modifying agent in the specification means a substrate containing activation. Suitable organic groups (for example, hydrophilic polymers, fatty acids, fatty acid esters), the group for activation refers to a chemical moiety or functional group which can react with a second chemical group under appropriate conditions. This is the group that forms a covalent bond between the modifier and the second group, for example, the group for activation of the reaction with the amine, -53- This paper scale applies to the China National Standard (CNS) A4 specification (210 X 297 PCT) (Please read the notes on the back and fill out this page) --!! Printed by the Department of Intellectual Property of the Intellectual Property Department of the Ministry of Economic Affairs 91. 1. 2,000 1329672 A7 B7 Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs - V. Description of the Invention (52) Includes electrophilic groups such as anthracenesulfonate , an anthracene sulfonate group, a halogen group (chloro 'bromo 'fluorine' iodine), N-hydroxy amber succinimide (NHS), etc., and an activation group reactive with a thiol includes, for example, maleic amine, Broken B. · mercapto, propenol, pyridyl disulfide, 5-thiol-2-nitro alum 5 acid thiol (TNB-thiol), etc., aldehyde functional group can be coupled to amine-containing Or a molecule of the moon - and the azide group can react with a trivalent phosphorus-containing group to form a phosphoniumamine or a phosphoniumamine linkage, and a suitable method for introducing an activation group into the molecule is a technique Known (see, for example, Hermanson, GT) Bioconjugate Techniques, Academic Press: 10 San Diego, CA (1996), activated groups can be directly attached to organic groups (eg hydrophilic polymers, fatty acids, fatty acids) Ester), or via a linker moiety 'eg bivalent <: 1-(: 12 base, One or more carbon atoms may be substituted with a hetero atom such as oxygen, nitrogen or sulfur, and suitable couplings include, for example, tetraethylene glycol, -(CH2)3-, -NH-(CH2)6-NH-, -15 (CH2)2-NH- and -CH2-0-CH2-CH2-0-CH2-CH2-0-CH-NH-, the modifier comprising a linker can be, for example, at 1 ethyl In the presence of -3-(3-dimethylaminopropyl)carbodiimide (EDC), mono-Boc-alkyl diamines (eg, mono-Boc-ethylenediamine, mono-Boc-diamine) The alkane is reacted with a fatty acid to form a guanamine bond between the free amine and the fatty carboxylic acid group. The Boc protecting group in the 2 oxime product can be removed by treatment with trifluoroacetic acid (TFA), and the exposed primary amine can be Coupling with other buffer acids as described or 'can be reacted with maleic anhydride and the resulting product is cyclized to produce a maleic amine derivative of the activated fatty acid. (See, for example, Thompson, et Al" WO 92/1622, all of which is incorporated herein as -54- This paper scale applies to Chinese national standards (CNS > A4 specifications (210 * 297 mm) > nn ϋ I ϋ n _1 I · 1· 1_1 I nn 1 a δπ 9 ln If (please read the note on the back first) Items and then Complete this page) fe i n tl t line 1329672 Ministry of Economic Affairs Intellectual Property Office employees consumer cooperatives printed A7 B7 V. invention is described in (53) reference). The modified antibodies of the present invention can be utilized, and an antibody-like or antigen-binding fragment is reacted with a modifier, for example, the organic moiety can be used in a non-position specific manner by applying a modifier reactive with an amine (Example 5). For example, an NHS ester of pEG is bound to an antibody, and a modified human antibody or antigen-binding fragment can also be used to reduce the disulfide bond of an antibody or antigen-binding fragment (eg, a disulfide bond between chains). Prepared, then the reduced antibody or antigen-binding fragment can be reacted with a thiol-reactive modifier to produce a modified antibody of the invention comprising an organic moiety that binds to a particular position of the 10 antibody of the invention. Modified human antibodies and anti-proto-binding fragments can be prepared using suitable methods, such as reverse phase 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 15 (1997); Itoh et al" Bioorg. Chem., 24(1): 59 -68 (1996); Capellas et al., Biotechnol. Bioeng·, 56(4): 456- 463 (1997)), and disclosed in Hermanson, G. T., Bioconjugate Techniques, Academic Press: San Diego, CA (1996). 20 Anti-genetic antibody against anti-IL-12 IG-derived protein composition In addition to monoclonal or chimeric anti-IL-12 antibodies, the invention also targets antibodies against such antibodies specific to the invention - Hereditary (anti-Id) antibody 'anti-Id antibody is identifiable antigen that is usually attached to another antibody_knot-55-001 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 〉> ----------------- — — — — — ^» — — — — 1 — 11^ <Please read the notes on the back and fill out this page) 1329672 A7 B7 V. Description of the invention (54) An antibody of the unique determinant of the region, the anti-I (j can use the same species and isotype (for example, mouse strain) as the source of the Id antibody, with antibodies Or immunization with its CDR regions, the immunized animal will recognize and react with the genotype of the immunogenic antibody and produce an anti-Id antibody, which may also be Use as an "immunogen" to induce an immune response to another animal, producing a so-called anti-anti-Id antibody.

5 IX Hydrocarbon Ministry Intellectual Property Office Staff Consumer Cooperative Printed 20 Anti-IL-12IG Derived Protein Compositions The present invention also provides at least one anti-IL_12 antibody composition comprising at least one, at least two, at least two , at least three, at least four, at least five, at least six or more of the anti-IL_12 antibodies, as disclosed herein and/or as known in the art, are provided in a non-naturally occurring composition, For mixtures or the like, such compositions comprise non-naturally occurring variants containing at least one or two full length, C- and/or N-terminally truncated variants, macromolecular specific moieties, fragments, or unique Variants' are selected from 70-100% contiguous amino acids belonging to SEQ ID NOS: 1, 2, 3, 4, 5, 6, 7 or 8, or unique fragment macromolecular specific moieties Or a variant thereof, preferably an anti-IL12 derived protein, fragment or variant composition comprising at least one or two full length, fragmented large knife specific structural portions or variants, as at least one of which contains a SEQ ID NOS: 1, 2, 3, 4, 5, 6 of 7〇• Just % of anti-IL-12 Parts of the sequences, or unique fragments, special macromolecules, m configuration. For a minute or a variant thereof, a better composition comprises 40-99% of

1329672

Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed M A7 B7 V. Description of Invention (55) One less 70-100% sequence belonging to one of SEQ ID NOS:i, 2, 3, 4, 5, 6 or a unique fragment , a special structural part of a macromolecule or a variant thereof, the percentage measurement of such a composition, which can be calculated according to weight, volume, concentration, volume molar concentration, or weight molar concentration, to make 5 liquid or dry solutions, mixtures, Suspensions, emulsions or gels, as known in the art or as described herein. The anti-IL-12 antibody composition of the present invention may further comprise at least one suitable and effective amount of the composition or pharmaceutical composition comprising the need to adjust, treat the cells, tissues, organs, animals or patients. 10 or at least one anti-IL-12 antibody at the time of treatment, optionally comprising at least one member selected from the group consisting of at least one TNF antagonist (eg, but not limited to, a TNF antibody or fragment, a soluble TNF receptor or fragment, fusion thereof) Protein, or small molecule TNF antagonist), antirheumatic drugs (such as 4-amino-10-decyl folate, auranofm, aurothioglucose, sulfur ° ° ° vote, Iraq Tannercept, sodium sulphate, hydroxy quinine sulfate, leflunomide, sulfasalzine, muscle relaxants, anesthetics, non-steroidal anti-inflammatory drugs ( NSAID), analgesics, anesthetics, sedatives, local anesthetics, neuromuscular blockers, antimicrobials 2 (eg aglycone's antifungal, parasitic, antiviral, kababen ( Carbapenem), head bud Cyclosporine, flurorquinolone, macrolide, penicillin, sulfonamide, tetracycline, other antimicrobials, peony, corticosteroids, steroids that promote metabolism, and diabetes Related pharmaceuticals, minerals, -57- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -nnnn ϋ nnnn ϋ · nn ϋ n — ϋ I ϋ n ϋ nn III ^ n I 1 ϋ II nnnn II nn ϋ n 1· n < (Please read the notes on the back and fill out this page)

DO 1329672 A7 B7 V. INSTRUCTIONS (56) Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives print nutrients, thyroid agents, vitamins, calcium-related hormones, anti-through drugs, antitussives, antiemetics, anti-cancer drugs, Banqiao, anticoagulant, erythropoietin (eg 'epoetin alpha), filgrastim (eg G-CSF, Neupogen), granulocyte-like macrophage colony-stimulating factor 5 (GM-CSF, white pigment), immunoassay, Immunoglobulins, immunosuppressive agents (eg ' basilimimab, circumcision, daclizumab), growth hormones, hormone replacement drugs, estrogen receptor modulators, mydriatics, ciliary muscle numbness, alkylating agents, antimetabolites Medicines, mitotic inhibitors, radiopharmaceuticals, antidepressants, manicides, antipsychotics, anti-anxiety 10 drugs, sleeping pills, mimicking sympathetic drugs, stimulants, Dominicans, donepezil, anti-biliary Alkali vinegar, asthma medication, beta agonist, inhaled steroids, leukotrienes, sulfhydryl xanthine, cromolyn, adrenaline or congeners, deoxyribonucleic acid Alpha (Puliriozyme), cytokine or cytokine antagonists, non-limiting examples of such 15 cytokines include, but are not limited to, any of IL-1 to IL-23, and the appropriate dosage is sufficient in the art. See, for example, 'Wells et al., eds., Handbook of Pharmaceutical Therapy, 2nd Edition, Appleton and Lange, Stamford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, 20 Duluxe Edition, Tarascon Publishing, Loma Linda, CA (2000), these references are hereby incorporated by reference in entirety. Such anti-malignant or anti-infective agents may also comprise a toxin molecule that is concomitant, co-formulated or co-administered with at least one antibody of the invention, which selectively acts to kill the pathogen Fine -58- This paper scale applies to China National Standard (CNS) A4 specification C210 X 297 mm)

,-V»^ A Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 13296672 A7 ---B7 V. Description of invention (57) Cell or tissue, the cells of this pathogen can be malignant tumors or other cells, such toxins can Is a 'but not limited to a purified or recombinant toxin or toxin fragment containing at least one functional cytotoxic macromolecular moiety, for example, selected from at least one of ricinine, diphtheria toxin, worm 5 venom, or one Bacterial toxins, the term "toxins" also includes endotoxins and exotoxins, which are produced by any naturally occurring, mutated or recombinant bacteria or viruses that cause disease in humans and other mammals, including death. Toxic shock, such toxins may include, but are not limited to, enterotoxin-producing coliforms to heat-sensitive enterotoxin (LT), heat-tolerant enterotoxin (ST), Shigella cytotoxin, production Aeromonas enterotoxin, toxic shock syndrome (TSST4), staphylococcal enterotoxin A (SEA), B (SEB), or C (SEC), enterotoxin of streptococcus, etc., such bacteria include, but Not limited to, producing sausage Various strains of Escherichia coli (ETEC), coliforms that cause intestinal bleeding (such as strains of serotype 〇157:H7 15), Staphylococcus species (for example, Staphylococcus aureus, Staphylococcus aureus ( Staphylococcus

Py〇genes)], Shigella species [eg, Shigella dysenteriae, Shigella flexneri, Shigella boydii ' and Shigella sonnei'), Salmonella species [Example 2〇 Such as 'Salmonella typhi, Salmonella cholera-suis, Salmonella enteritidis', Clostridium species [eg ' Clostridium perfringens, Clostridium dificile, Clostridium botulinum, Camphlobacter species (eg, Camphlobacter jejuni, Camphlobacter fetus), Heliobacter eyebrows-59- This paper scale applies to the Chinese National Standard (CNS) A4 specification C210 x 297 mm) r C -nn I a·— I n I ϋ I · n I kn II - δ, · 1 n ϋ nn I sfl (please read the notes on the back and fill out this page) rt Vt 1329672 A7 B7 V. Description of invention (58) Species (eg Heliobacter pylori), Aeromonas Various species (for example, Aeromonas sobria, Aeromonas hydrophila, Aeromonas caviae, Pleisomonas shigelloides, Yersina enterocolitica, Vibrio Vibrios [eg 'Vibrios cholerae, 5 Vibrios parahemolyticus'), Klebsiella genus, Pseudomonas aeruginosa and Streptococci, see For example, Stein, ed., INTERNAL MEDICINE, 3rd ed., pp 1-13, Little, Brown and Co., Boston, (1990); Evans et al., eds., Bacterial Infections of 10 Humans: Epidemiology and Control , 2nd. Ed. » pp 239-254, Plenum Medical Book Co., New York (1991); Mandell et al, Principles and Practice of Infectious Diseases, 3d. Ed., Churchill Livingstone, New York (1990); Berkow et Al, eds., The Merck Manual, 16th edition, Merck and Co., 15 Rahway, NJ, 1992; Wood et al, FEMS Microbiology Immunology, 76: 121-134 (1991); Marrack et al, Science, 248:705 -711 (1990), the entire disclosure of which is hereby incorporated by reference. The Anti-IL-12 antibody compound, composition or mixture of the invention may comprise at least one suitable adjuvant, such as, but not limited to, a diluent or a binder. , tranquilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc., preferably as pharmaceutically acceptable adjuvants, non-limiting examples and methods for preparing such sterile solutions have been Knower 'for example, but not limited to, Gennaro, Ed., -60- This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) 1329672 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Α7 Β7 V. Description of invention (59)

Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (aston 'PA) 1990, a pharmaceutically acceptable carrier can be conventionally selected for the mode of administration, the anti-IL-12 antibody, fragment or variant composition Solubility and/or stability, and is well known in the art or as disclosed herein. Pharmaceutical excipients useful in the compositions of the present invention include, but are not limited to, proteins, peptides, amino acids, lipids, and sugars (eg, sugars, including monosaccharides, di-, tri-, tetra-, And oligosaccharides; derivatized saccharides, such as sugar alcohols, sugar acids, esterified saccharides, etc.; and polysaccharides, 10 saccharide polymers, which may be present alone or in combination, including separate or mixed The amount of the protein excipient comprises 1 to 99.99% by weight or volume. The exemplary protein excipient comprises serum albumin, such as human serum albumin (HSA), recombinant human albumin (rHA), animal glue, casein, etc. Amino acid/antibody component, which also functions as a buffering capacity, 15 includes alanine, glycine, arginine, betaine, histamine, hub acid, aspartic acid, cysteamine Acid, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, etc. The preferred amino acid is glycine. The saccharide excipients suitable for use in the present invention include, for example, monoterpenoids, such as sugar, maltose, galactose, glucose, D-mannose, sorbose, etc.; disaccharides such as lactose, sucrose, Trehalose, cellobiose, etc.; polysaccharides, such as cottonseed sugar 'Songsanying sugar, maltodextrin, dextrin, starch, etc.; and sugar alcohols, such as mannitol, xylitol, maltitol, Lactitol, xylitol sorbitol (ghjCit〇1), cretinol-61 - This paper scale applies to China National Cobalt (CNS) A4 specification (21〇X 297 mm) Λ lid 91· 1· 2,000 (please read the notes on the back and fill out this page) ϋ n ί ϋ nnn · I n I n I n < 1329672 A7 B7 V. Inventive Note (60) etc. 'Preferred saccharides for use in the present invention The sputum type agents are mannitol, sea bath sugar, and cotton xanthose. The anti-IL-12 antibody composition may also contain a buffer or a pH agent; typically the 'buffer agent is made from an organic acid or a base. Salts, representative 5 buffers include organic acid salts such as bar acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, Salts of peric acid, acetic acid, or citric acid; Tris, tromethamine hydrochloride, or phosphate buffer, preferred buffers for use in the compositions of the present invention are organic acid salts such as citrate 0 10 The anti-IL-12 antibody composition of the invention may comprise a polymerized.

Formulations/additives such as polyvinylpyrrolidone, ficolls (a polymeric saccharide), polydextrin (eg cyclodextrin, eg 2-propyl-β-cyclic paste) Fine), polyethylene glycols, flavoring agents, microbicides, sweeteners, antioxidants, antistatic agents, surfactants 15 (eg 'polysorbate esters, eg "TWEEN 20", "TWEEN 8〇") 'Lipids (such as phospholipids, fatty acids), sterols (such as cholesterol), and chelating agents (for example, EDTA). These and other known pharmaceutical excipients and/or additives suitable for use in the anti-IL-12 antibodies, sites or variant compositions of the invention are those known in the art of the '20' as listed in &quot Remington: The Science & Practice of Pharmacy", 19th ed., Williams & Williams, (1995), and in the "Physician's Desk Reference*', 52th ed., Medical Economics, Montvale, NJ (1998) ' These disclosures are fully incorporated herein by reference. The preferred carrier or shaping material is carbon hydrate-62- This paper scale applies to the Chinese national standard (CNS > A4 specification C210 X 297 public) (please first « Read the back of the note and fill out this page) on δ · Line _ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1329672 A7

Compounds (such as sugars and sugar alcohols) and buffers (for example, citrate) or polymeric reagents. 5 10 15 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printing 20 Formulations As mentioned above, the present invention provides a stable formulation which is preferably a phosphate-reducing and __preservative solution and formulation and suitable for pharmacy Or a versatile preservative formulation of the veterinary route comprising at least one anti-IL_12 antibody in a pharmaceutically acceptable formulation. The formulation of the P-Pesticide contains at least one known preservative or is selected from at least - Materials: phenol, m-cresol, p-cresol, o-nonylphenol, chlorinated phenol, benzoyl alcohol, phenylmercuric iodate, phenoxyethanol, formaldehyde, gas butanol, gasification Magnesium (for example, its hexahydrate), alkyl parabens (methyl, ethyl, propyl, butyl, etc.), methyl ammonium, gasified benzinone, sodium dehydrated sodium acetate Sodium ethylmercury salicylate, or a mixture thereof in an aqueous diluent, may be employed in any suitable concentration or mixture, as is known in the art, for example, 〇〇〇15%, or any range thereof or The value 'for example, but not limited to 〇〇〇 1, 〇 (8) 3, 0.005, 0.0Q9, 〇. 1. 〇.02, 〇〇3, 〇〇5, 〇〇9, 〇1, 0.2, 0.3, 0.4, 0.5, 〇.6, 〇.7, 〇.8, 〇.9, [ο, 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 range or value therein, non-limiting examples include, preservative-free, containing 12% bismuth Cresol (Example-63- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 male cages) (Please read the back note for $ items and then fill out this page) - -SJ. --Line · 1329672 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing & 5. Inventions (62) 5

ο 1X 5 11 20 A7 B7

For example, '0·2, 0·3 'Μ, 〇·5, 〇·9, h0%), 〇1_35 of benzyl alcohol (for example, 0 5, 0 9, 11, L5, 1.9, 2.0, 2· 5〇/0), 〇〇〇1_ 〇.5 / 〇ethyl water sulphuric acid sulphate (丨himer〇sal) (for example, 〇〇〇5, 〇.〇1), 0.01-2.0% phenol (for example , 〇〇5, 〇25, 〇28, 〇.9, p-mercaptobenzoic acid base s (for example, 0 00075, 0·0009, 0.001, 0.001, 0.005, 〇〇〇75, 0 009 , 0 01, 0 02, 0.05, 0.075, 0.09, Oj, 〇 2, 〇·3, 0.5, 0.75, 〇.9, i 〇%), etc. As indicated above, the present invention provides an article preparation, A vial containing at least one solution comprising at least one anti-IL_12 antibody = prescribed buffer and/or preservative, optionally placed in an aqueous thin towel, the packaged material of the towel comprising - a label indicating that the solution can be maintained for 1, 2, 3, 4, 5, 6, 7, 8 9 .12 18 20, 24, 30, 36, 40, 48, 54, 60, 66 72 The invention also includes a re-prepared item, including the packaged material, the first bottle, for an hour or more. The vial contains at least one anti-IL_12 antibody that is lyophilized, and the second vial contains a pre-formed aqueous buffer or preservative, wherein the packaging material comprises a method for indicating how the patient reconstitutes the at least one The anti-IL_12 antibody to the aqueous diluent t, so that the formed solution can be stored for a period of more than 24 hours or longer. The method for producing at least one anti-IL-12 antibody used in the present invention can be by recombinant means. Produces 'a preparation that includes cells from a milk cell or a gene for transfer, or a source that can be purified from other organisms, as described above. 64- The paper size applies to the Chinese National Standard (CNS) A4 specification C210 X 297 mm > 1329672 A7

5 ο 11 5 1* Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Staff Consumer Cooperatives 20 or known in the art. The range of anti-IL_12 antibodies of at least one of the products of the present invention comprises the amount produced after reconstitution, in a wet/dry state, at a concentration of from about 10 micrograms/ml to about 1000 mg/liter, although it is also possible To a lower or heavier concentration and depending on the carrier to be delivered, for example, the solution formulation will be different from the transdermal patch, transpulmonary, transmucosal, or osmotic or micropump or applicator. Preferably, the aqueous diluent optionally further comprises a pharmaceutically acceptable preservative, and preferred preservatives include those selected from the group consisting of phenol, m-phenol, p-cresol, o-cresol, Chlorocresol 'benzoyl alcohol, p-hydroxy benzoic acid 'pestyl ester (mercapto, ethyl, propyl, butyl, etc.), benzoquinone ammonium chloride, phenyl chlorinated chlorinated, dehydrated sodium acetate and Sodium sulphate, or a mixture thereof, has a preservative concentration sufficient to produce an antimicrobial effect. Such concentrations depend on the preservative selected and can be readily determined by a skilled technician. Other shaped vanilloids such as isotonic agents, buffers, antioxidants, preservative enhancers, may be selected and preferably added to the diluent; isotonic agents, such as glycerol, typically use known concentrations, Physiologically acceptable buffers are added and added to provide improved pH control, and the formulation can be used to a wide range of temperatures, for example, between about 4 and 10 pH, and preferably from about pH 5 to about pH 9, and preferably Preferably, the pH of the formulation of the present invention is between about 6.8 and 67.8 between about pH 6 and about pH 8. Preferred buffers include phosphate buffers, preferably sodium phosphate, especially dish acid. Buffered saline (PBS). -65- This paper size is applicable to China National Standard (CNS) A4 specification (210 * 297 mm) <Please read the notes on the back and fill out this page.) Order··--------Line— « 1329672 A7 ------ B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (64) "his additions" such as pharmaceutically acceptable solubilization, such as TWEEN 20 (polyoxyethylene) (10) Sorbitol monolauric acid vinegar), TWEEN 40 (polyoxyethylene (2〇) sorbitol single palm vinegar), top een 80 (polyoxyethylene (20) sorbitol monooleate), decay (four) f ton polyoxyethylene 5-diene polyoxypropylene money copolymer)' with peg (polyethylene glycol) or nonionic surfactants, such as polysorbate _ 20 or 8 〇 or ρ - 184 or 188, Plur 〇 Other block copolymers of mc8 polyols, and chelating agents such as EDTA and egta may be optionally added to the formulation or composition to reduce agglomeration, when the secret or _ container is used in a 10 formula. The presence of these additives is particularly useful in the presence of pharmaceutically acceptable surfactants to alleviate the tendency of protein aggregation. The formulation of the present invention can be prepared by The method comprises the steps of: mixing at least one anti-porous 12 antibody with a preservative selected from the group consisting of: expectant, meta-A, _ 甲甲, 甲甲, 氯甲酴, phenyl decyl alcohol, acetonitrile (methyl, ethyl, propyl butyl, etc.) 经 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基 甲基Sodium thiosulfate, or a mixture thereof; mixing the at least one anti-cardiac 12 antibody and preservative in an aqueous diluent, using conventional dissolution and mixing methods, when formulating an appropriate formulation, Example 20 a predetermined amount of at least one anti-IL_12 antibody to be placed in a buffer solution, mixing the preservative dissolved in the buffer solution, the amount of preservative should be sufficient to provide the protein and preservative at the desired concentration, and the senior technician can also Choose a variety of variations of this method, for example, the order of component addition, whether to use additional additives, temperature and pH during preparation, etc. - (Please read the back of the precautions and then install I---uSf this page ) -10· - Line · This paper scale applies to China National Standard (C NS>A4 specification (210 X 297 public affair) 1329672 A7 V. Inventive Note (65), the most appropriate adjustment can be made for the concentration and the application method used. The claimed formula can be provided to the patient as a clarified solution or A double small glass bottle containing a bottle of lyophilized at least one of the above-mentioned 12 antibodies and a bottle containing water, a preservative and/or a reconstituting agent for reconstituting the former, preferably a disc salt buffer And/or saline and, optionally, placed in an aqueous diluent, whether it is a single solution single bottle or a double bottle that needs to be reconstituted, can be reused multiple times and can be used for a single time for the patient Or multiple uses and thus provide convenience for ingestion. The processed article claimed by the present invention is useful for providing administration from immediately to 24 J or longer, and therefore, the processed article claimed herein provides significant benefits to the patient, and the formulation of the present invention can be selectively stored safely. At about 2 to about 4 inches. The underarm and still retain the biological activity of the protein to the slave time 'so' allows the package label to indicate that the solution can be maintained and/or used for 6, 12, 18, 24, 36, 48, 72, or 96 hours or longer 15 During the period 'if using a preservative thinner', such labels may include use for up to 1] February, half year, one and a half years, and/or two years. The preparation method of the solution of at least one anti-IL-12 antibody in the present invention may include mixing at least one type of antibody in an aqueous dilution solution by using a conventional dissolution and mixing step, for preparing a suitable formulation, for example. ' Mixing a solution of at least one anti-IL 12 antibody in water or buffer into a sufficient amount to provide a protein and a selected preservative or buffer to the desired concentration. Known, for example, can change the order of component addition, whether to use additional additives, temperature and pH during preparation, etc., can be applied to China (CNS>A4 specification (10)χ297 public) -- ______________^--- (Please read the note on the back and fill out this page) '«J. --Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 13296672 A7 ___ B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative Printing " V. Invention Description (66) Degrees and the application method used to make the most appropriate adjustment. The claimed product can be provided to a patient in a clarified solution or a double small glass bottle containing a bottle of lyophilized at least one k-IL-12 antibody and a second bottle containing an aqueous dilution that reconstitutes the former. Agent 5, whether it is a single solution single bottle or a double bottle that needs to be reconstituted, can be reused multiple times and can be used for single or multiple use of patients and thus providing patients with more convenient use than current usage. Taking medicine. The claimed product can be provided to the patient indirectly via a pharmacy, clinic, or other such institution and location, with a clarified solution or a double small glass bottle containing a bottle that is cold-dried at least one bottle. An anti-IL-.12 antibody and a second bottle contain an aqueous diluent for recombining the former, in which case the clear solution can be made up to one liter or more, and is provided in a large storage device. A small portion of the at least one antibody solution is extracted into the vial one or more times and transferred to the 15th customer and/or patient for use by the pharmacy or clinic. The approved devices containing these individual glass vials include those for delivery of solutions, such as BD Pens, BD Autojector® 'Humaject®, NovoPen®, BD® Pen 'AutoPen®, OptiPen®, GenotropinPen®, Genotronorm 20 Pen® 'Humatro Pen®, Reco-Pen®, Roferon Pen® ., Biojctor®, iject®, J-tip Needle-Free Injector®, Intraject®, Medi-Ject®, eg manufactured or developed from Becton Dickensen (Franklin Lakes, NJ, www.bectondickenson.com). Disetronic (Burgdorf, Switzerland, www.disetronic.com; Bioject, Portland, -68- This paper scale applies to the Chinese S standard (CNS) A4 specification C210 x 297 MM)

1329672 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 _ B7_ V. Invention description (67)

Oregon (www.bioiect.com): National Medical Products, Weston Medical (Peterborough, UK, www.weston-medical com) Medi-ject Corp (Minneapolis, MN. www.mediiect.com), containing double glass vials The device includes a pen-type injection device for reconstituting a cold-dried 5 drug in a cassette for delivery of a recombinant solution, for example,

HumatroPen®. The claimed product includes packaged materials, and the packaged materials provide the information required by the management agent to indicate that the product can be used. The packaged materials of the present invention provide knowledge to 10 The patient is capable of reconstituting two bottles of wet/dry product, forming at least one anti-IL-12 antibody with an aqueous diluent and providing a period of use of 2-24 hours or longer, A small glassy solution product alone, the label indicates that such a solution can be used for 2-24 hours or longer, and the claimed product is useful for use in human pharmaceutical products. 15 The formulation of the invention may be prepared by a method comprising mixing at least one anti-IL-12 antibody with a selected buffer, preferably a phosphate buffered saline or a selected salt, mixing the at least one antibody with a buffer The aqueous diluent is carried out using conventional dissolution and mixing steps. To prepare a suitable formulation, for example, a solution of a predetermined amount of at least one anti-IL-12 antibody in water or buffer is mixed enough to provide The protein and the selected preservative or buffer are added to the desired concentration. The method is modified by those skilled in the art, for example, the order in which the components are added, whether additional additives are used, temperature and pH during formulation, etc. 'The most appropriate adjustment can be made regarding the concentration and the method of application used. -69- Zhang scale applies Chinese national standard (CNS>A4 specification (2)Q χ 297 public love> - ,I 1 -ϋ nnnn I nnn I » nnn 1 n一· n I 1 It ϋ ϋ n I (Please read the back Precautions Please fill out this page. ) 1 SI ϋ I na — ϋ n · 1 n 1 ii - 1329672 A7 B7 V. INSTRUCTIONS (68) The claimed stable or preservable formula can be provided to the patient for clarification. a solution or a double small glass bottle containing a bottle of lyophilized at least one anti-IL-12 antibody and a second bottle containing a preservative-containing preservative or buffer and excipient in aqueous dilution Agents, whether 5 is a single solution single bottle or a double bottle that needs to be reconstituted, can be reused multiple times and can be used for single or multiple use of the patient and thus providing patients with more convenient use than current usage. The formulation or solution of at least one anti-IL-12 antibody described herein, which may be stabilized or preserved, may be administered to a patient via a variety of routes of delivery, including SC or IM injection, transdermally, in conjunction with the present invention. , transpulmonary, meridian, implant, osmotic pump, cartridge, micropump , or other methods recognized by senior technicians and known techniques. Therapeutic application 15 The present invention also provides a method for regulating or treating at least one of the diseases associated with the Ministry of Economic Affairs, the Intellectual Property Office, and the consumer cooperatives, which occur in cells, tissues, Organ, animal, or patient disease, including, but not limited to, at least one of the following diseases: rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid joints, psoriatic arthritis, joint stiffness Spondylitis, gastric ulcer 2 ulcer, arthritis negative for blood and clear reaction, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosus, antiphospholipid syndrome, iridocyclitis / uveitis / ocular neuritis, primary pulmonary fibrosis, systemic vasculitis / Wegener's granulomatosis, sarcoma-like disease, testicular inflammation, vasectomy, allergic / atopic disease, gas -70- This paper scale applies to China National Standard (CNS) A4 specification C210 X 297 mm) 1329672 A7 B7 Jade, invention description (69 10 15 Ministry of Economic Affairs wisdom Department of staff consumption cooperatives printed 20 asthma, allergic rhinitis 'eczema, allergic contact dermatitis, allergic conjunctivitis, allergic pneumonia, grafts, organ transplant rejection, transplanted two pairs of host disease, systemic inflammatory response symptoms Cluster, septicemia syndrome, gram (+) sepsis, gram (a) sepsis, culture-negative abortion, fungal sepsis, neutrophilic fever, urinary sepsis, meningococcal disease Sore/ash, burn, free light exposure, acute pancreatitis, adult respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory disease, sarcoma-like disease, local ileitis, wart Cellular anemia, diabetes, nephropathy, atopic disease, allergic reaction, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometrial tissue ectopic, urticaria diagnosis: systemic absence: allergic, Dermatitis, pernicious anemia, hemolysis disease, thrombocytopenia, transplant rejection of any organ or tissue, kidney transplant rejection, heart transplant rejection, liver transplantation row , pancreas transplantation rejection, lung transplant rejection, bone marrow transplantation (ΒΜΤ) rejection, skin allograft rejection, fetal chest line implantation rejection, accessory verrucous transplant rejection, xenograft rejection of any organ or tissue, same type of fluid transplantation Exfoliation, anti-receptor allergic reaction, Graves' disease, symmetry, sputum-type diabetes, resistance to diabetes, asthma, rapid deterioration of muscle strength, antibody-mediated cytotoxicity, type III allergic reaction, Systemic lupus erythematosus, p〇EMS syndrome (multiple neuropathy, giant organ, endocrine disease) immunoglobulin disease in a single plant, and skin change syndrome), multiple neuropathy, giant organ, endocrine disease, immunity from a single plant Globulin disease and skin change syndrome, antiphospholipid syndrome eight clusters, acne, scleroderma, mixed knot-t-nn ϋ ϋ na-i> II * ·1 n amme if St ϋ 1· -or I n 1 ·1 nnn II (Please read the note on the back of the M and then fill out this page) -71- 1329672 A7 B7 V. Description of invention (70 5

5 IX Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20 Organized diseases, primary Edison's disease, diabetes, chronic active hepatitis, primary biliary cirrhosis, leukoplakia, vasculitis, MI heart incision, posterior (4) Type IV allergy, contact dermatitis, allergic pneumonia, allograft rejection, granuloma of extracellular organs, drug sensitivity, metabolic/primary disease, Wilson's disease, hemochromatosis , alpha-ι-anti-trypsin deficiency, diabetic retinopathy, chronic thyroiditis, osteoporosis, hypothalamic _ pituitary _ cyst fibrosis, neonatal chronic lung disease, chronic lung obstructive disease (COPD), family Lymphatic tissue cells, skin condition, psoriasis, alopecia, nephrotic syndrome, nephritis, renal glomerular nephritis, acute renal failure, hemodialysis, uremia, toxicity, toxemia in late pregnancy , 〇kt3 therapy, anti-Cd3 therapy, cytokine therapy, chemotherapy, radiotherapy (eg, including but not limited to, weak 'anemia, Qualitative fluids, etc., chronic salicylic acid poisoning, etc., see, for example, the Merck Manual, 12th-17th Editions, Merck & Company, Rahway, NJ (1972, 1977, 1982, 1987, 1992 '1999), Pharmacotherapy Handbook, Wells et al eds., Second Edition, Appleton and Lange, Stamford, Conn. (1998, 2000), each fully incorporated by reference. The invention also provides a method for modulating or treating at least one cardiovascular disease occurring in a cell, tissue, organ, animal, or patient, including, but not limited to, at least one cardiac stun syndrome, Myocardial infarction, congestive heart failure 'stroke, ischemic stroke, hemorrhage, arteriosclerosis' atherosclerosis, restenosis, diabetic arterial hard-72- This paper scale applies Chinese National Standard (CNS) A4 specification C210 x 297 (million) .% t fy 1329672 A7 B7 V. Description of invention (71 faint 10 15 Ministry of Economic Affairs Intellectual Property Bureau Bayer Consumer Cooperative Printed 20 diseases, hypertension, arterial pressure, renal vascular pressure too high, 厥, Shock, cardiovascular system syphilis, heart failure, cardiopulmonary bypass, primary lung hypertension, arrhythmia, atrial ectopic agitation, atrial agitation, atrial fibrillation (continuous or burst), then After the perfusion, the family, the cardiopulmonary shunt inflammatory reaction, the multi-focal atrial tachycardia, the regular narrow QRS heartbeat rapid, the rhythm irregularity, the ventricular fibrillation, the histidine nerve bundle rhythm Incomplete, atrial and ventricular block, nerve bundle branch block, myocardial ash deficiency disease, coronary artery disease, narrow heart disease, myocardial infarction, myocardial disease, diastolic congestive cardiomyopathy, restricted cardiomyopathy, valve heart Disease, endocarditis, pericardial disease, cardiac tumor, aortic and peripheral aneurysm, division of aorta, inflammation of the aorta, closure of the abdominal aorta and its branches, peripheral vascular disease, closed arterial disease, surrounding Gray tube sclerosing disease, thrombotic vasculitis occlusion, g peripheral arterial disease, Raynaud's phenomenon and disease, hand and foot cyanosis, limb red pain, venous disease, venous embolism, varicose veins, arterial and venous catheter, lymphatic Edema, lipoma, restless colic disease, reperfusion injury, post-pressurization syndrome, ischemia reperfusion injury, etc., such methods may optionally include such adjustments, treatments, or The treated cells, tissue 'organs or patients are administered an effective dose of a composition comprising at least one anti-IL 12 antibody = a pharmaceutical composition. Ming also provides a method for regulating or treating at least a salty hole in a cell, tissue, organ or patient's disease 'including, but not at least 'in the following cases: acute or chronic bacterial infection, acute-73- This paper scale applies to the Chinese national standard <CNS) A4 specification (210 X 297 mm) -------- order---------line/-·黹 first read the back Μ note Fill in this page) 1329672 A7 B7 V. INSTRUCTIONS (72 10 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives print 20 or k parasitic or infectious processes, including bacterial, viral and fungal infections , HIV infection / HIV neuropathy, encephalomyelitis, liver fire (A, sputum or C, etc.) 'toxic toxic arthritis, peritonitis, lung Β Β 乂, 知 〇 〇 l57: h7, hemolytic urethra blood syndrome Cluster / thrombotic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, leprosy, toxic shock syndrome, streptococcal disease, myositis, gas gangrene, tuberculosis, avian tuberculosis Pneumonia of pulmonary cysts, = inflammatory disease of the basin, testicular inflammation, paratypitis, aerobic Gram-negative bacilli, lymphatic disease, influenza, EB virus, (iv) levy sigh enterprises and life and death of cells' life Yau _ enteritis / septic cerebrospinal go far. The invention also provides a method for modulating or treating at least a malignant disease occurring in a cell, tissue, organ or patient, including, but not limited to, at least the following conditions: white disease, acute leukemia, acute lymphoid Embryonic leukemia (ALL), B' cells, tau's cells or (10) cells, acute myeloid leukemia (AML), chronic osteoblastic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, Myelosynthesis syndrome 襄S), lymphoma, Hodgkin's disease, sub-sex = lymphoma, "Kinsen's lymphoma" Bukter's gamma nodules, multiple myeloma, Kaposi's tumor, knot Rectal cancer, visceral sputum, pain, malignant histiocytic carcinoma, signs of paraneoplastic neoplasms/malignant hemorrhagic disease, solid tumor, gland tumor, sarcoma, % melanoma, hemangioma, migration Sexual diseases, bones associated with cancer, bone pain associated with cancer, etc. Cluster -74-

(Please read the note on the back of the item and then fill out this page) Order — I ί ^1 ϋ i 1 ϋ I n In nnn 1 n ακ) V. Description of the invention ( 73 A7 B7 5 ο ri 5 Intellectual Property Office of the Ministry of Economic Affairs Consumer Cooperatives 20 The invention also provides a means for regulating or treating at least one neuropathic disease occurring in a cell, tissue, organ or patient, including, but not limited to, at least the following: neurodegenerative, multiple Sclerosing disorder, partial occupation, AIDS dementia complex, observing disease, such as 'multiple sclerosis and acute transverse sclerotherapy, extrapyramidal and cerebellar diseases', for example, brain skin f and (four) systemic damage , basal god, "two, .., disease or cerebellar disease, excessively active diseases such as Huntington's disease and senile chorea" drug-induced action diseases, for example, can be blocked by CNS Dobaan Drug-induced, motion-reducing motor diseases such as Parkinson's disease, progressive nuclear paralysis, structural damage to the cerebellum, degeneration of the spinal cord and cerebellum, such as spinal coordination, hereditary ataxia, Degeneration of the cerebral cortex, multi-system degeneration (Mencel, Dejerine-Thomas, Shi-Drager, and Machado- Joseph); systemic disease (Refsum, s disease), blood/monthly sputum protein deficiency (abetalipoprotemia), ataxia, telangiectasia, multi-system disease with mitochondria, core disease with myelin loss, such as multiple scleroderma, acute transverse myelitis, diseases with motor units, such as Neuromuscular muscle atrophy (degeneration of anterior horn cells such as lateral sclerosis of muscular atrophy, atrophy of juvenile spinal muscles and atrophy of adolescent spinal muscles), Alzheimer's disease, middle-aged Mongolian disease, Diffuse Lewy body Disease, Lewy body type dementia, Wooke's micro-honey cluster, chronic alcoholism, Kjelda's disease, subacute sclerosing encephalitis, Hass' disease, and Dementia pugilistica, etc. Including the application of an effective amount of -75- paper size applicable to China National Standard (CNS) A4 ^ " (210 X 297 < Please read the back of the note first, then fill this page > order -------- ----Line 丨j 13 29672

Ministry of Economic Affairs Intellectual Property Office Staff Consumption Cooperatives Printed M A7 B7 V. Description of Invention (74) There are at least one TNF antibody or unique site or variant for cells, tissues, organs, animals or animals in need of such adjustment, treatment or treatment. For patients, see, for example, the Merck Manual, 16th Edition, Merk & Company, Rahway, Nj (1992). 5 Any method of the invention may comprise administering to a cell, tissue, organ or patient in need of such modulation, treatment or treatment an effective amount of a composition or pharmaceutical composition comprising at least one anti-IL-12 antibody, For the treatment of such immune diseases, the method optionally further comprises a co-administration or combination therapy wherein, in addition to administering said at least one anti-IL-12 anti-10 body, its unique site or variant, is further included Prior to, simultaneously with, and/or after, administration of at least one protein selected from at least one TNF antagonist (eg, but not limited to TNF antibodies or fragments, soluble TNF receptors or fragments, fusions thereof, or small molecules) TNF antagonists), anti-rheumatic drugs (eg 4-amino-10-methylfolate, auranofin 15 (auranofin), aurothioglucose, sulfur 0 sputum, etanercept , gold sulfur malate, chlorhexidine sulfate, leflunomide, sulfasalzine, muscle relaxants, anesthetics, non-steroidal anti-inflammatory drugs (NSAIDs), painkillers, Narcotics, town Medicine, local anesthetic, 2 〇 neuromuscular blocker 'antimicrobial drugs (eg, aminoglycoside, antifungal, parasitic, antiviral, carbapenem, cephalosporin, Fluororquinolone, macrocyclosporine, penicillin, sulfonamides, tetracycline, other antimicrobials), peony, corticosteroids, steroids that promote metabolism, and diabetes-76- This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) i — — — — — —— — — i IIIIII ^ « — — — — — — I — (Please read the back first Note on this page)

1329672 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 ----2Z---- V. Description of invention (75) Closed pharmacy, minerals, nutrients, sputum glands, vitamins, calcium-related hormones, Antidiarrheal, antitussive, antiemetic, antiulcer, thirst, anticoagulant, erythropoietin (eg, epoetin alpha), filgrastim (eg, G-CSF, Neupogen), granular giant 5 phagocytes Colony stimulating factor (GM-CSF, white pigment), immunoassay, immunoglobulin, immunosuppressant (eg, basiliximab, cyclosporine, daclizumab), growth hormone, hormone replacement, estrogen receptor modulator, mydriasis Drugs, ciliary muscle paralysis agents, alkylating agents, anti-metabolite drugs, mitotic inhibitors, radiopharmaceuticals, antidepressants, treatment of mania 10, antipsychotics, anti-anxiety drugs, sleeping pills, mimicking sympathetic nerves. Medication, stimulant, donepezil, anti-cholestasis enzyme, asthma medication, beta agonist, inhaled steroid, leukotriene, sulfhydryl scutellaria, crocetin (crom〇lyn) Adrenaline And analogs, deoxyribonuclease alpha (Pulmozyme) 'cytokine or cytokine antagonist, suitable dosages are well known in the art, see, for example, Wells et al., eds_, pharmaceutical treatment Manual, 2nd Edition, Appleton and Lange, Stamford, CT (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Duluxe Edition » Tarascon Publishing » Loma Linda » CA 20 (2000), these references are fully incorporated herein reference. TNF antagonists suitable for use in the compositions of the invention (additionally comprising at least one antibody of the invention, a particular site and variants thereof), combination therapies, co-administered devices and/or methods include, but are not limited to, 'Anti-TNF antibody, antigen-binding fragment, and specific combination-77- This paper scale is applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) ---I---丨丨丨丨丨—丨丨丨丨—Book· I丨丨丨丨丨丨丨- {Please read the notes on the back and fill out this page) 1329672 A7

10 to TNF t receptor molecule, a compound that prevents and/or inhibits the synthesis of TNF, a release of lysine or a target cell thereof, such as sedap, temdap, and a phospho-enzyme inhibitor (for example, Pem〇X1fymne and adenosine receptors promote A2b adenine enhancer, prevent and/or inhibit the receptor signal, such as mitogen-activated protein f (MAp), inhibiting and blocking / or compounds that inhibit membrane TNF cleavage, such as a tube of angiotensin-converting enzyme (ACE) inhibitors (such as captopnl), and compounds that block and/or inhibit TNF production and/or synthesis Classes, such as MAP kinase inhibitors. 15 As referred to herein, a "tumor necrosis factor antibody", "tnf antibody", "TNF antibody", or fragmentation can be used in test tubes, on the spot, and / or preferably in vivo, which reduces, blocks, inhibits, eliminates or interferes with tnf activity. For example, a suitable TNF human antibody of the invention may bind to TNFct and include anti-TNF antibodies, antigen-binding fragments thereof, Use a specific mutation or its macromolecular region for specific integration In TNFa, appropriate TNF can also reduce blocking, elimination, interference, prevention and/or inhibition of TNF RNA, DNA or protein synthesis, TNF release, Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative, TNF receptor signal, membrane TNF division , TNF activity, TNF production, and/or synthesis. The medium-to-human grafted chimeric antibody cA2 is conjugated to the human IgG1 by the high-affinity labeled A2 and the antigen binding of the mouse anti-human TNFa IgG1 antibody. The fixed region of kappa immunoglobulin, the 1gG1 Fc region improves the function of the allogeneic antibody, and increases the -78- paper size. The Common Chinese National Standard (CNS) A4 specification (21〇x 297 mm) A1% -·* 1329672 A7 B7 V. INSTRUCTIONS (77) Circulating serum half-life and reducing the immunogenicity of the antibody, the affinity of the chimeric antibody CA2 and the epitope are derived from the variable region of the antibody A2 of the mouse, In a specific embodiment, a preferred source of variable region cryptonucleotides for administration of antibody A2 to a mouse is an A2 hybridoma cell line. 5 Chimeric A2 (cA2) neutralizes natural and recombinant in a dose-dependent manner body The cytotoxic effect of TNF-like, from the binding analysis of the chimeric antibody cA2 and recombinant human TNFct, the affinity constant of the chimeric antibody can be calculated as Ι.ίΜχΙΟ10]^·1, and the monoclonal antibody is determined by competitive inhibition. Preferred methods for specificity and affinity can be found in: Harlow, et al., 10 antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1988; Colligan et al., eds., Current Protocol in Immnology, Greene Publishing Assoc, and Wiley Interscience, New York, (1992-2000); Kozbor et al., Immunol. Today, 4:72-15 79 (1983); Ausubel et al., eds. Current Protocols in

Molecular Biology, Wiley Interscience, New York (1987-2000); and Muller, Meth. Enzymol., 92: 589-601 (1983) » These references are hereby incorporated by reference. In a specific embodiment, a mouse monoclonal antibody A2 is produced using a cell line 20 designated C134A, and a chimeric antibody CA2 is produced using a cell line designated C168A. The monoclonal anti-TNF antibody can be used in the present invention. Additional examples of the classes are described in the art (see, for example, U.S. Patent No. 5,231,024 > Moller, A. et al., Cytokine 2(3): 162-169 -79- This paper scale applies to China Standard (CNS) A4 specification (210 x 297 mm) -I____--------I (Please read the note on the back and fill out this page) Order---------Line* Ministry of Economic Affairs Printed by the Intellectual Property Office Staff Consumer Cooperative, ^1 ^1 ϋ H ϋ ϋ Mi ninnn I ϋ ϋ nn · 1 < 1329672 A7 B7 V. Inventions (78) (1990), US Application No. 07/943,852 ( September 11, 1992, 曰建棺), Rathjen et al., International Publication No. WO 91/02078 (published on February 21, 1991), Rubin et al., EPO Patent Publication No. 0 218 868 (1987 4 On the 22nd of the month, 5th), Yone et al., EPO Patent Publication No. 0 288 088 (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 10. (1987) ' and Hirai, et al., J Immunol. Meth. 96:57-62 (1987), whose data is completely Included herein as a reference) TNF Receptor Molecules Preferred TNF receptor molecules in the present invention are those which bind TNF with high affinity (see, for example, Feldmann et al., International Publication No. WO 92/07076). (published on April 30, 1992), Schall et al., Cell 61: 361-370 (1990), and Loetscher et al., Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives Printed ---------- ------mi (please read the notes on the back and then fill out this page) Order · - Crab.

Cell 61: 35l-359 (1990), the entire disclosure of which is hereby incorporated by reference in its entirety in its entirety, in its entirety, in its entirety, in the s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s TNF-R) TNF cell surface receptors are those of the present invention that have a truncated version of these receptors, including the extracellular domain of the receptor (ECD) or a site of its function (see, for example, 'Corcoran et Al., Eur. J. Biochem. 223:831-840 (1994)) 'also for the inventors, truncated version of TNF receptor, -80- This paper scale applies to Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) 1329672 A7 ------ B7 V. INSTRUCTIONS (79) Contains ECD, which has been detected in the urine and serum to be combined with 3〇kDa and 4〇kDa TNF inhibition. Protein (Engeim_, H ^, then 〇 1 Chem. 265: 1531-1530 (1990)), TNF receptor multimeric molecules and TNF immunoreceptor fusion molecules, as well as derivatives and fragments or parts thereof, '5 is Further examples of TNF receptor molecules useful in the methods of the invention and compositions of the invention can be used in the TNF receptor molecules of the invention = 'A disease process in its long-term availability symptomatic benign disease (iv) the ability to ease and have low toxicity, low immunogenicity and / or high affinity, as well as other undefined properties, so to achieve therapeutic results. 10 Molecules having a TNF receptor multimer for use in the present invention comprise two or more TNF linked via one or more multi-linkers or other non-peptide linkers such as polyethylene glycol (PEG). The site of all or a kind of function of the receptor, the multi-component molecule may further comprise a mono(tetra)peptide of the secreted protein to guide the expression of the multi-element molecule, and the multi-i5 element molecule and its production method are revealed in Jiangyi. The application sequence is detailed, 533 (accepted on March 9th of the year of measurement), the content of which is completely: as a reference here. # 经济部Intelligent Property Bureau employee consumption cooperative printed with methods and compositions for use in the present invention The TNF immunoreceptor co-synthesis molecule comprises at least a part--one immunoglobulin molecule and all or one functional part of the fused 20 or more TNF receptors, and the EGFR fusion molecule can be combined into a monomer. Or a heterozygous or homozygous immunoglobulin fusion molecule may also be in a monovalent or multivalent form, and an example of a TNF-like immunoreceptor fusion molecule is the TNF receptor 々 fusion protein 'TNF-free Money bulk molecules and their preparation method are =

-8 K This paper scale applies to China National Standard (CNS) A4 Specification C210 X 297^17 1329672 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Invention Description (80) In this technique (Lasslaueretal.,Eur · J. Jmmunol 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. 5 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. 08/442,133 (field May 16, 1995), each of which is incorporated by reference. The entire disclosure of the disclosure of the entire disclosure of the entire disclosure of the entire disclosure of the entire disclosure of the disclosure of the entire disclosure of the disclosure of the entire disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of the disclosure of Capon et al., Nature 337: 525-531 (1989) 'These references are hereby incorporated by reference in entirety. A substitute for the function of the TNF receptor molecule, a derivative, a fragment, or a region of the TNF receptor molecule, or a portion of the TNF receptor molecule sequence that encodes the TNF receptor molecule, with sufficient size and sequence In order to have a function similar to that which can be applied to the TNF receptor molecule of the present invention (for example, a molecule which binds TNF with high affinity and has low immunogenicity), the function of the TNF receptor molecule and the like also includes a modification 20 a TNF receptor molecule which functions similarly to those which can be used in the TNF receptor molecule of the present invention (for example, a molecule which binds TNF with high affinity and has low immunogenicity), for example, a function of a TNF receptor molecule, etc., Substituting a "codon" or one or more amino acids for substitution, deletion or addition (for example, replacing one acid amino acid with another acid amino acid; or using -82- this paper size for Chinese national standards (CNS) )A4 size (210 X 297 mm) ------------丨!丨* Order·!------Line (please read the notes on the back and fill out this page) 1329672 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative System 5, invention description (81) Compilation of one or the same hydrophobic amino acid of a dense mother is replaced by another codon with a hydrophobic amino acid, see, Ausubel et al, Current Protocols in Molecular Biology, Greene Publishing

Assoc, and Wiley-Interscience, New York (1987-2000). 5 Cytokines include any known cytokines, see, for example, w_wwX:opewithCvtokines.com, cytokine antagonists include, but are not limited to, any antibodies, fragments or variants, any soluble receptor 'Slice or variant, antagonist of any small molecule' or any combination thereof. 10 Treatment of Treatment Any method of the invention may comprise an uncomfortable method of treating an IL-12 media, comprising administering to a cell, tissue, organ or patient in need of such modulation, treatment or treatment, an effective amount comprising at least An anti-antibody composition or pharmaceutical composition, which method optionally further comprises a co-administration or combination therapy to treat such an immune disease, wherein in addition to administration of said at least one anti-IL-12 antibody, unique The site or variant thereof, before, and/or after, is administered at least one member selected from the group consisting of at least one TNF antagonist (eg, but not limited to 20 TNF antibodies or fragments, soluble TNF receptors or fragments) , its fused protein, or small molecule TNF antagonist), anti-rheumatic drugs (such as 4-amino-10-indolyl folate 'auran〇nn (auran〇nn), aurothioglucose, sulfur ° Sitting on sputum, etanercept, sodium sulphate, hydroxy quinine sulphate, refractory ------------ I I---- — — — — <Please read the notes on the back first Complete this page) -83-

1329672 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Description of invention (82) (leflunomide) 'Safifasaizine', muscle relaxant' anesthetic, non-steroidal anti-inflammatory drug (NSAID), analgesic Medicines, anesthetics, sedatives, local anesthetics, neuromuscular blockers, antimicrobials (eg, aminoglycoside, antifungal, parasitic, antiviral 5, carbapenem, head) Spores, flurorquinolone, macrolides, penicillin, sulfonamides, tetracyclines, other antimicrobials), peony, corticosteroids, steroids that promote metabolism, and diabetes Related agents, minerals, nutrients, sputum glands, vitamins, calcium-related hormones, antidiarrheal agents 10, antitussives, antiemetics, antiulcer drugs, laxatives, anticoagulants, erythropoietin (eg 'epoetin alpha), filgrastim (eg 'G-CSF, Neupogen'), granulocyte-like macrophage colony stimulating factor (GM-CSF, white pigment), immunoassay, immunoglobulin, immunosuppressant (eg Basiliximab, cyclosporine, daclizumab), growth hormone, 15 hormone replacement, estrogen receptor modulator, mydriatic, ciliary muscle itch, alkylating agent, antimetabolite, mitotic inhibitor, radioactive Medicine, antidepressants, madness, antipsychotics, anxiolytics, hypnotics, mimicking sympathetic drugs, stimulants, donepezil, anticholinergic enzymes, asthma medication, beta 20 drugs, inhaled steroids 'white tris, sulfhydryl xanthine, cromolyn, adrenaline or similar 'deoxyribonuclease alpha (Pulmozyme), cytokines or cytokine antagonists. Typically, the treatment of a morbid condition can be effected by administering an effective amount or a dose of at least one anti-IL-12 antibody composition, for example, a total amount, -84- the paper size applies to the Chinese National Standard (CNS) A4 specification ( 210 * 297 mm) Λ

Kyj c1' — —III1III — — — — — — — III — · 11111111 (Please read the note on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 13296672 A7 " -_ B7 V. Invention Illustrating (S3) an average or range of at least about 0.01 to 500 mg of at least one anti-porous _ U antibody/kg body weight/dose, and preferably at least about 〇丨 to 1 〇〇 mg antibody/kg body weight/single or multiple Administration, depending on the particular activity contained in the composition, or effective serum concentration may comprise 〇丄5 5 00 micrograms per milliliter of supernatant concentration / single or multiple administrations, the appropriate dose may be determined by the physician And depending on the particular disease state, the specific activity of the composition to be administered; and in the case of the patient to be treated, in some cases it may be necessary to provide repeated administration in order to achieve the desired therapeutic effect, That is, individual administration is repeated under special monitoring or metered measurement until 10 times the daily dose or effect is achieved. Preferred dosages may optionally include 0 丨, 0 2, 〇 3, 〇 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, 30 '31, 32, 15 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 , 61, 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, 20 93 ' 94 '95, 96, 97, 98 '99 and / or 100-500 mg / kg / medication ' or any range, value or part of it Amount, or to achieve a concentration of 0.1, 0.5, 〇·9, 1.0, 1.1, 1.2, 1.5, 1.9, 2·〇, 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, -85- This paper scale applies to national standard (CNS) A4 specification C210 x 297 mm) -I! _ II ! II t · I! $ {Please Read the notes on the back and fill out this page> 1329672 A7 B7 V. INSTRUCTIONS (84 10 15 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print 20 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, 20, 12.5, 12.9, 13..0, 13.5, 13.9, 14.0, 14.5, 15, 15.5, 15.9, 16 , 16.5, 16.9, 17, 17.5, Π.9, 18, 18.5, 18.9, 19, 19.5, 19.9, 20, 20.5, 20.9, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 , 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 96, 1〇〇, 200, 300, 400, 500, 600, 700, 800, 900, 1〇〇 〇, 1500, 2000, 2500, 3000, 3500, 4000, 4500, and/or 5000 μg/ml serum concentration / single or multiple administrations, or any range, value or any fraction thereof. Or 'the dose to be administered may vary depending on known factors, such as the pharmacokinetic properties of the particular agent, its mode of administration and application, the age of the patient, health, weight and the nature and extent of the disease, and simultaneous treatment. The type, the frequency of treatment, and the desired effect, usually the dose of the active ingredient may be from about 丨.丨 to 1〇〇mg/kg body weight, and the hanging weight is from 0.1 to 50, and preferably from 〇丨 to 1〇mg/kg body weight. / Each application or sustained release to achieve the desired result. In a non-limiting example, the human or animal treatment may provide one or more of the at least one antibody of the invention at a dose of from 0.1 to 100 mg/kg, such as 0.5, 0.9, 1.0, 1.1. , 1-5, 2'3^4; 5^6>7^8^9M0M1M2M3> 14M5^ **86- x 297 mm) nnn ϋ ϋ n · i «I I- *· one"_ * ϋ ϋ 1« m fi ί I (Please read the note on the back and fill out this page) 1329672 A7 _Β7_ V. Description of invention (85) 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 40, 45, 50, 60, 70, 80, 90 or 100 millimeters (please read the notes on the back and fill out this page) g/kg, daily, at least the following days One: 1, 2, 3, 4, « 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 5, 18, 19, 20, 21, 22, 23 , 24, 25, 26, 27 ' 28 ' 29 ' 30, 3 32, 33, 34, 34, 36, 37, 38, 39, or 40, or additionally or additionally, at least 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, 10 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 Or one of 52 weeks, or alternatively, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 A single, injectable or repeated dose of 19, or 20 years, or any combination thereof. 15 Dosage forms (compositions) suitable for internal administration usually contain about 0.1 mg per unit or container. To about 500 mg of the active ingredient, the active ingredient in these pharmaceutical compositions is usually present in an amount of from about 0.5 to 99.999% by weight, based on the total weight of the composition. The antibody may be formulated into a solution 20, a suspension, an emulsion or a lyophilized powder, or a pharmaceutically acceptable excipient without digestive tract, respectively, without the administration of the digestive tract. Examples of such excipients are water, saline, Lin's solution, dextrose solution, and 1-10% human serum albumin, lipid granules and non-aqueous hydrates. Agents, for example, given © oils may also be used, the excipient or the drug frozen powder may contain additives that maintain isotonicity -87- applies the present paper China National Standard Scale (CNS) A4 size C210 X 297 mm)

Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumer Cooperatives, M 1329672 A7 V. INSTRUCTIONS (86) (eg, gasified sodium, mannitol) and chemical stability (eg, buffers and preservatives) additives, this formula is Known or appropriate techniques for killing bacteria. Suitable pharmaceutical carriers are disclosed in the most recent edition of Remington's 5 Pharmaceutical Sciences, A. 〇s〇l, which is a standard reference in the art. Alternative Modes of Administration Many well-known and developed modes can be applied to administer a 10 effective amount of at least one anti-IL-12 antibody of the present invention, on the one hand, to the application of the application to the lungs, Other modes of application may also be applied to the present invention to achieve appropriate results. The IL-12 antibodies of the present invention can be delivered in a carrier, which is formulated into a solution of glutinous rice, an emulsion, a colloid, or a suspension, or as a dry powder, 15 using any suitable inhalation or other skill. A device and method for administering a known mode is achieved. Formulations without digestive tract and formulations for administration of the drug without digestive tract may contain general excipient sterilized water 20 or saline 'polyalkylene glycols such as polyethylene glycol, natural vegetable oils, hydrogenated naphthalenes, etc. 'Aqueous or oleaginous suspensions for injection may be prepared according to known methods using suitable emulsifiers or moisturizers and suspending agents, and the agents for injection may be non-toxic, non-orally applicable. An agent, such as an aqueous solution in a solvent or a sterilized injectable -88-paper size, meets the National Standard for T (CNS) A4 specification (21〇x 297 mm) -------- ------------Book---------Line··. (Please read the notes on the back and fill out this page) -41329672 A7 B7 V. Description of invention (87) A solution or suspension, as a usable excipient or solvent, may be allowed to use water, Lin's solution, isotonic saline, etc.; as for a common solvent or suspension solvent, 'sterilized non-volatile oil may be used, For these purposes, any type of non-volatile oil and fatty acid may be used, including natural or 5 synthetic or semi-synthetic. Lipid oils or fatty acids, natural or synthetic or semi-synthetic mono- or di- or tri-glycerides, parenteral administration is known and included in the art, but not only Zhang Yu, a conventional injection method, such as a gas-pressed needle-free injection device disclosed in US Pat. No. 5,851,198, and a 10 laser perforation device as disclosed in US Pat. No. 5,839,446, which is completely It is incorporated herein by reference. Another kind of delivery method is printed by the Ministry of Economic Affairs, Intellectual Property Bureau, and the employee consumption cooperative (please read the note on the back and fill out this page) - Line - The present invention is still concerned with at least one anti-IL- 12 antibody administration, which is through the digestive tract, subcutaneous, intramuscular, intravenous 15, intra-articular, intrabronchial, lower abdomen, intracapsular, intra-cartilage, cavity In the cavity, in the body cavity, in the cerebellum, in the ventricles, in the colon, in the neck, in the stomach, in the liver, in the myocardium, in the bone, in the pelvis, in the pericardium, in the peritoneum , intrapleural, intraprostatic, intrapulmonary, rectal, intrarenal , in the 20 omentum, intraspinal, synovial, intrathoracic, intrauterine, intravesical, bolus, vaginal, rectal, buccal, sublingual, intranasal, or transdermal Device; at least one anti-IL_12 antibody composition can be formulated for administration to the digestive tract (subcutaneous, intramuscular or intravenous) or any other mode of administration, in particular as a liquid solution or suspension -89- η ^ Κ>\: 91. 1. 2,000 1329672 A7 B7 V. Invention Description (88 10 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 20; for vaginal or rectal use 'especially semi-solid type, for example, But not limited to emulsions or suppositories; for buccal or sublingual administration, for example, but not limited to tablets or capsules; or intranasally, for example, but not limited to 'powder or intranasal drops Or a gas solution or a specific agent; or when administered subcutaneously, for example, but not limited to a knee, ointment, lotion, suspension or patch delivery system, with a dimethyl sulfoxide or the like Chemical synergists to improve the structure of the skin or increase the The fun of the skin patch; Jinginger, et al. In "Drug Permeation Enhancement"; Hsieh, DS, Eds., pp. 59090 (Marcel Dekker, Inc. New York 1994, which is completely As a reference here, 'or add an oxidizing agent to apply a protein and peptide-containing formulation to the skin (W〇98/53847), or an electric field application to create a temporary electrical penetration method. The route of transmission, or the mobility of a charged drug through the skin, such as iontophoresis, or the application of ultrasound, such as sound penetration (US Pat. Nos. 4, 309, 989 and 4, 767, 402) (publication of the above) The patent is hereby incorporated by reference in its entirety. Pulmonary/nasal administration For pulmonary administration, at least one anti-IL_12 antibody composition is delivered in a small particle size to facilitate the lower airway of the lung or sinus, according to the invention, at least one anti-IL For delivery of the -12 antibody, any of a variety of inhaled or nasal devices for administering a therapeutic agent by inhalation may be used, having the ability to deposit an aerosolized formulation to the patient's sinus cavity 90-, paper scale Applicable to China National Standard (CNS) A4 Specification (10) 297 297 public interest) 91. 1. 2,000 (Please read the note on the back and fill out this page) *δ* - --线· 1329672 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative System f / 3 A7 B7 V, invention instructions (89) or alveolar devices include metered dose inhalers, nebulizers, dry powder generators, sprayers, etc., other suitable for pulmonary or intranasal administration of antibodies Also known in the literature, all such devices may employ a formulation suitable for dispersing the antibody in a gas solution which may be comprised of both solution 5 (aqueous and non-aqueous) or solid particles, metered Dose inhaler' Inhalers such as Ventoiln® metering typically use a propellant gas and require agitation when inhaling (see, for example, WO 94/16970, WO 98/35888), dry powder inhalers such as TurbuhalerTM (Astra). , Rotahaler® (Glaxo), Diskus® (Glaxo), SpirosTM Inhaler 10 (Dura), various devices sold by Inhale Therapeutics, and Spinhaler® powder inhalers (Fisons), mixed with breath-absorbed powder ( US 4668218 Astra, EP 237507 Astra, WO 97/25086 Glaxo, WO 94/08552 Dura, US 5458135 Inhale, WO 94/06498 Ficons » fully incorporated herein by reference), sprayers, such as AERxtm

15 Aradigm 'Ultravent® Sprayer (Mallinckrodt), and Acomll® Sprayer (Marquest Medical Products) (US 5,404,871 Ardigm, WO 97/22376), the above references are hereby incorporated by reference in entirety The solution, on the one hand, a metered dose inhaler, a dry powder inhaler, etc., produces a small amount of particulate gas solution, and a specific example of these commercially available inhalation devices 20 is exemplified as a representative special for the practice of the present invention. The present invention is not limited thereto, and preferably, the composition containing at least one anti-IL-12 antibody is administered by dry powder inhaler or spray for administration of at least one inhalation device of the present invention. Many of the necessary features, for example, must be trusted by the delivery of the inhalation device, -91- This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇x 297 public love)--------- -------------Ψ--------Book--------------Line· (Jing Xian read the back note *Ϋ item again Fill in this page) 1329672 A7 B7 V. INSTRUCTIONS (90) Reproducible and correct, this inhalation device can be selectively delivered Small dry particles, for example less than about 10 microns, preferably about 1-5 microns, facilitate good breathing. 5 Application of an IL-12 antibody composition formulated as a spray comprising an IL-12 antibody composition The spray of protein can be generated by pressure to force a suspension or solution containing at least one anti-IL-12 antibody through the nozzle. The size and structure of the nozzle, the applied pressure, and the liquid feed rate can be selected to obtain The desired output and particle size may also be applied by electrospraying, such as by means of an electric field connecting a capillary or a feed nozzle. Advantageously, the particles of the protein comprising at least one anti-IL-12 antibody composition delivered by the nebulizer are preferably less than about 10 microns, preferably in the range of from about 1 micron to about 5 microns, and most preferably from about 2 microns to about 3 microns. Suitable for administration by a nebulizer comprising at least one anti-IL-12 antibody combination 15 protein Formulations, typically comprising an aqueous solution of an antibody combination protein dissolved in water at a concentration of from about 0.1 mg to about 100 mg of at least one anti-IL-12 antibody composition protein per ml of solution or per gram of composition, or of Any range or value, such as, but not limited to, .1, .2, .3, .4, .5, .6, _7, .8, .9, 1, 2, 3, 4, 20 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, 40 45, 50, 60, 70, 80, 90 or 100 mg/ml or mg/g, the formulation may contain reagents such as excipients, buffers, isotonic agents, surfactants, and, preferably, , zinc, this formula can also be packaged -92- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------------% (Please read the back Note: Please fill out this page) Order---------Line 1 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 13296672 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 _B7_ V. Invention Description (9i) An excipient or reagent for attenuating the antibody composition protein, such as a buffer, a reducing agent, a bulk protein, or a carbohydrate, and a bulk protein for formulating the protein of the antibody composition, including albumin, protamine, etc. , used for formulation Typical carbohydrate complexes of antibody composition proteins include sucrose, mannitol, lactose, trehalose, glucose, etc., and the antibody composition protein formulation may also comprise a surfactant which reduces or prevents surface-induced solution Spraying to form agglutination of antibody composition proteins caused by aerosol droplets, a variety of surfactants can be used, such as polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbitol 10 alcohol fatty acid esters, the amount can be Between 0.001 and 14%, based on the weight of the formula, the surfactants which are particularly suitable for use herein are polyoxyethylene sorbitan monooleate, polysorbate 80, polysorbate 20 and the like. Additional protein-providing agents known in the art, such as IL-12 antibodies, or specific sites or variants, may also be included in the formulation. IL-12 Antibody Composition Application by Sprayer Antibody Composition Protein can be administered by a nebulizer (such as a jet nebulizer) or an ultrasonic nebulizer. In the jet nebulizer, a pressurized air source is used to generate a high velocity air jet through the mouth, and when the gas expands on the nozzle, a low pressure region is created, which is then pumped through a capillary connected to the liquid reservoir. A solution of the antibody composition protein, which is cut into unstable filaments and droplets when it is in the tube, resulting in a gas-soluble paper scale applicable to Chinese national standards (CNS > A4) Specifications C210 X 297 mm) --------------------tx--------- (Please read the notes on the back and fill out this page) 1329672

Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed by M A7 B7_ V. Inventive Note (92) Liquid, can use the structure range, flow rate, and baffle type to achieve the desired performance characteristics from the given spray atomizer; In a nebulizer, high frequency electrical energy is used to generate vibrating, mechanical energy, typically using a piezoelectric transducer that is conducted directly or through a coupled stream 5 to the antibody composition protein formulation. An aerosol solution comprising a protein of the antibody composition is produced, advantageously, the particles of the antibody composition protein delivered via the nebulizer have a particle size of less than about 10 microns, preferably from about 1 micron to about 5 Between microns, and preferably between about 2 microns and about 3 microns. 10 Formulations suitable for use in a nebulizer, whether jet or supersonic, for administration of at least one anti-IL-12 antibody, typically comprising at least a concentration of from about 0.1 mg to about 100 mg per ml of solution. An anti-IL-12 antibody protein, which may comprise an agent, such as an excipient, a buffer, an isotonic agent, a preservative, a surfactant, and preferably, preferably, the formula may also be used. An excipient or a substance for stabilizing at least one anti-IL-12 antibody composition protein, such as a buffer, a reducing agent, a bulk protein, or a carbohydrate, for formulating at least one anti-IL-12 antibody The bulk proteinaceous class of the composition protein includes albumin, protamine, etc., and typical carbohydrates used to formulate at least one anti-20 IL-12 antibody composition include sucrose, mannitol, lactose, trehalose, glucose. Etc., the at least one anti-IL-12 antibody formulation may also comprise a surfactant which reduces or prevents surface-induced at least one anti-IL-12 antibody caused by aerosolization of the solution to form aerosol droplets. Aggregation, a variety of surfactants can be applied, for example -94- This paper scale applies to China National Standard (CNS) A4 specification C210 X 297 mm) ----------------- ---Book----------Korean<Please read the notes on the back and fill out this page.) 1329672 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Print A7 B7 V. Invention Description (93) Polyoxyethylene fatty acid esters and alcohols, and polyoxyethylene sorbitan fatty acid esters, the amount may be between 0.001 and 4%, based on the weight of the formula, especially suitable for the surfactant used in the field is polyoxygen Ethylene sorbitan monooleate, polysorbate 80, polysorbate 20, etc., 5 additional reagents for protein formulation known in the art, such as antibody proteins, may also be included in In the recipe. Administration of the IL-12 antibody composition by metered dose inhaler In a metered dose inhaler (MDI), the propellant, at least one 10 anti-IL-12 antibody, together with any excipients or other additives, comprises liquefaction The pressurized gas mixture is contained in a metal can, and the agitated metering valve releases a mixture of gaseous solutions, preferably having a particle size of less than about 10 microns, preferably from about 1 micron to about 5 particles. Between micrometers, and preferably between about 2 micrometers and about 3 micrometers, the desired particle size of the 15 gas solution can be prepared by a skilled technician using various known methods for application to the antibody composition, including spray-grinding, spraying. Froth drying, critical point concentration, etc., preferred metered dose inhalers include those manufactured and applied by 3M or Glaxo. A formulation of at least one anti-20 IL-12 antibody suitable for administration by a metered-dose inhaler device, typically comprising a very finely ground powder containing at least one anti-IL-12 antibody protein, as placed in a non-aqueous state a suspension of a medium, such as by suspending a surfactant in a propellant, which may be any user skilled in the art, such as CFCs, hydrofluorocarbons, hydrofluorocarbons, or Hydrocarbons, including trichlorofluorodecane, two gas two-95- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) --------------- -----til--- (Please read the notes on the back and fill out this page) 1329672 A7 B7 94 10 V. Description of the invention (Fluorine Court, Yifeng Tetrafluoroethanol and 1,1,1,2_ Tetrafluoroethylene, hfa_134a (hydrofluoroalkane-134a), HFA-227 (hydrofluorocarbon_227), etc., the preferred propellant is a hydrofluorocarbon, and the surfactant can be selected to stabilize at least one anti- -IL-12 antibody is made into a suspension placed in a propellant to protect the active agent against chemical degradation, etc. Suitable surfactants include sorbitol triolein, soy eggs Lipid, oleic acid, etc., in some cases, the solution of the solution should use a solvent such as ethanol, or a formula containing the protein known in the art for use in the formulation of the protein. The skilled hands of the bank will be able to recognize The method of the present invention can achieve administration of at least one anti-IL12 antibody composition via the lung by means of a device not disclosed herein. « — —ml —----·丨I (Please read the notes on the back first) Fill in this page) The Ministry of Economic Affairs' Intellectual Property Office employees' consumption cooperatives print oral formulations and medications for oral administration depending on the co-administration (eg, meta-phenylene 15 _ with nonionic surfactants, such as polyoxyethylene oil base) Mystery and n-?? Alkyl polyvinyl ether) to increase the penetration of artificial intestinal wall, as well as inhibitors of co-administered enzymes (such as trypsin inhibitor; diisopropyl fluorophosphate (^^qiao and trasyl 〇l) In order to inhibit the degradation of enzymes, the active ingredient component of the m-state (IV) for oral administration can be mixed with 'additives, including sucrose, lactose, cellobiose, sugar, trehalose, and raffinose. ,malt , glucose, starch, Chinese cabbage 4 butyl, several brews, preserved fruit, huangqisheng, Arabian knee, = gum, bone riding, road protein, * protein, synthetic or semi-synthetic σ, and diglycerides, these Dosage type can also contain other classes 20 de-96-

91. 1. 2,000 Order--Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 13296672 A7 _ B7 V. Additives of type (95), for example, non-active diluents, lubricants such as stearin Magnesium, para-hydroxy hydroxy acid alkyl esters, preservatives, such as sorbic acid, ascorbic acid, alpha-tocopherol, antioxidants, such as cysteine, disintegrating agents, binders, thickeners, slow Granules, sweeteners, flavoring agents, flavoring agents, etc. The tablet and the pill can be further processed into an enteric-coated preparation, and the liquid preparation for oral administration comprises an emulsion, a concentrate, a stimulating agent, a suspending agent and a solution preparation, etc., and the preparation can be used in the preparation. Inactive diluents such as water, liposomes have also been disclosed for use in drug delivery systems for pancreatic 10 and heparin (uS Pat. No. 4, 239, 754), and more recently, mixed amine groups have been used. A disclosure of a microsphere-delivered pharmaceutical product of an artificial polymer of a protein (proteoids) (US Pat. No. 4,925,673), and further disclosed by us Pat. No. 5,879,681 and US Pat. No. 5, Carrier agents of 5,871,753 are useful agents for the delivery of orally administered organisms as are known in the art. The composition of the dry film and the composition absorbed by the drug through the surface of the drill film and the method of applying the at least one anti-IL_2〇12 antibody include an emulsion comprising a plurality of submicron particles, a giant molecule with a dead film, and a biological activity. The peptide, and the aqueous continuous phase, which enhance absorption through the mucosal surface by making the emulsion particles into adhesion to the mucosa (US Pat. No. 5,514,670), the mucosal surface suitable for administration of the emulsion of the present invention includes the cornea and conjunctiva , vaginal, lung, stomach, small-97- This paper scale applies to China National Standard (CNS) A4 specification (210 * 297 mm) .-V Α Λ

U-4 J I---------------- _i Book·! — · Line (please read the notes on the back and then fill out this page) 1329672 A7 B7_ V. Inventions (96) (Please read the notes on the back and fill out this page) Intestines, rectum and other routes of administration for the vagina Or when administered rectally, for example, a suppository may contain an excipient such as polyglycerol, petrolatum, cocoa butter, etc., and the formulation for intranasal administration may be solid or contain an excipient such as lactose or may be aqueous. Or nasal drops for oily solutions, excipients for buccal use 5 include sugars, calcium stearate, magnesium stearate, pregelatinized starch, etc. (US Pat. No. 5,849,695). When administered via the skin via a formulation and administration via the skin, at least one anti-IL-12 antibody is encapsulated 10 in a delivery device, such as a vesicle or polymeric nanoparticle, microparticle, microcapsule, or microsphere ( As a collection of microparticles, unless otherwise stated, many suitable devices are known, including those made from synthetic polymers, such as polyhydroxy acids, such as polyacetic acid, polyglycolic acid and its copolymers, polyorthoesters, poly Anhydrides, polybutoxides, and 15 natural polymers such as collagen, polyamino acids, albumin and other proteins, alginates and other polysaccharides, and mixtures thereof ( US Pat. Nos. 5,814,599). Department of Economics, Intellectual Property Office, Staff and Consumer Cooperatives, Printing Extended Formulations and Formulations 20 Sometimes it is necessary to deliver the compounds of the present invention to the patient for an extended period of time, such as a single application for one week or one year. A variety of slow release, accumulation or implant dosage forms, for example, a dosage form which may contain a salt of a pharmaceutically acceptable non-toxic compound having a low solubility in body fluids, for example, (a) with a polybasic acid - 98- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1^29672 A7

V. INSTRUCTIONS INSTRUCTIONS (97) 5 ο 5 tl Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, India 20 , such as phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid, palmitic acid, alginic acid, polyglutamine, naphthalene Acid addition salts formed by mono- or di-sulfonic acid, galacturonic acid, etc.; (b) with multivalent metal cations, such as ^ dance '铋, 钡, magnesium, aluminum, copper 'cobalt, nickel, a salt formed by cadmium or the like, or a salt formed with an organic cation such as N,N,-diphenylfluorenyl-ethylenediamine or ethylene dimer; or (c), a combination of (a) and (b), for example Zinc tannins, in addition, the compounds of the invention or, preferably, the relatively less complex salts, as described, may be formulated into a gel, such as an aluminum monostearate gel such as sesame oil. It is suitable for injection. Particularly preferred salts are zinc salts, zinc tannins, palmitates, etc. Other types of slow-release I" for injection are formulated to disperse the compound or salt. Slowly degradable, non-toxic, antigen-free polymers (eg, polyacetic acid/polyglycolic acid 1 &) are disclosed, for example, in US P The compound, or preferably a relatively less soluble salt, such as those disclosed above, may also be formulated in a cholesterol-based ruthenium rubber pellet, particularly for use in animals. In terms of use, other slow release, accumulation or implant formulations, such as gaseous or liquid liposomes, are also known in the literature (US·Nos. 5,770,222 and "Continuous and Controlled Drug Delivery Systems", JR Robinson Ed., Marcel Dekker, Inc. Ny, 1978. After a general disclosure of the present invention, reference will be made to the following examples, which will provide a further understanding, and the invention is not limited thereto. Example 1: IL- Purification and performance of 12 antibodies in mammalian cells -99- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ---------------- ----Book---I-----Line (please read the note on the back and then fill out this page) 1329672 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 Β7 5, invention description (98) typical Mammalian expression medium contains at least one promoter element' The vector begins to transcribe mRNA, the sequence encoded by the antibody, and the signal required for the formation of polyadenylation that ends transcription and transcription. Additional elements include enhancers, Kozak sequences and donors (d〇n〇r), and 5 RNA splicing Inserted sequences surrounded by receptor positions, utilizing early and late promoters from SV40, long terminal resurfacing from retroviruses (LTRS), such as RSV, HTLVI, early stages of HIVI and cytomegalovirus (CMV) The promoting substance can achieve efficient transcription, however, elements of the cell (e.g., human actin promoting substance) can also be used, and 10 suitable expression mediums for practical application of the present invention include, for example, pIRESlneo, pRetro-〇. Ff, pRetr〇0n, 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), 15 ? 8 ¥ 2 this & (Bading: 37146) and? 6(:12]^(八1'(^ 67109), mammalian host cells that can be used include human Hela 293, H9 and Jurkat cells, mouse NIH3T3 and C127 cells, Cos 1, Cos 7 and CV 1, quail QC1-3 cells, mouse L cells and Chinese hamster ovary (CHO) cells. 20 Alternatively, the gene can be expressed in a stable cell line containing genes integrated into the chromosome, with selectable marker genes (eg dhfr, gpt , neomycin, or hygromycin) together to do a common-transfer infection, allowing the identification and isolation of infected cells. Transfer-infected genes can also be proliferated to express a large number of given passwords -100- This paper scale applies China National Standard (CNS) A4 Specification (210 X 297 mm) .% A r 91. 1. 2,000 (Please read the notes on the back and fill out this page)

1329672 A7 B7 5. The antibody of the invention (99), the DHFR (dihydrofolate reductase) marker gene is used to develop a replica of a gene with hundreds or even thousands of desired genes, and other useful selectable marker genes are Enzymes of glutamine-synthase (GS) (Murphy, et al., Biochem. J. 227:277-279 (1991); Bebbington, et al., 5 Bio/Technology 10:169-175 (1992)) Using these marker genes, mammalian cells are raised in selected media and selected for the highest resistance. These cell lines contain genes (classes) that are integrated into the chromosome, and Chinese hamster ovary (CHO) and NSO cells are often Used for the production of antibodies. 10 The expression mediators pCl and pC4 contain the strong promoting substance (LTR) of Rous sarcoma virus (Cullen, et al., Molec. Cell. Biol. 5: 438-447 (1985)) plus fragments of CMV·enhancer (Boshart, Et al., Cell 41:521-530 (1985)), the location of most asexual reproduction lines, for example, to limit the position of enzyme splitting BamHI, Xbal and Asp 718, to facilitate the selection of beneficial genes 15 in addition to this medium In addition to the 3* intron, it also contains a multi-adenophyte formation and a termination signal of the pro-insulin gene before synthesis of the mouse. In Chinese hamster ovary (CHO) cells for clonal selection and expression using the mediator pC4 for IL-12 antibody expression, plasmid PC4 is a derivative of 20 pSV2-dhfr (ATCC Accessi〇I1 No. 37146), This plasmid contains the mouse DHFR gene, the Chinese hamster ovary- or other cells lacking dihydrofolate activity, which can be placed in selected matrices by transfer of these plasmids under the early promotion of SV40. (eg 'α-MEN, Life, Technologies, -101- This paper scale applies to Chinese national standards (CNS> A4 specifications (210 297 297 g) (please read the notes on the back and fill out this page) Τ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 9i. 1. 2,000 1329672 A7 B7 V. Invention description (100) (Please read the note on the back and fill out this page)

In Gaithersburg, MD), the proliferation of the DHFR gene, which is selected by the chemotherapeutic agent of aminomethyl folate, to be selected for growth, and which is resistant to aminomercapto folate (MTX) in cells has been made. Documented (see, for example, FWAlt, et al., J. Biol. Chem. 253:1357-1370 5 (1978); JL Hamlin and C. Ma, Biochem. Et Biophys. Acta 1097:107-143 (1990) And MJ Page and MA Sydenham, Biotechnology 9:64-68 (1991)), cells that grow at increased MTX concentration produce target enzymes, DHFR, to develop resistance to antibiotics, and proliferate DHFR genes, If the second gene is ligated to the DHFR gene, it is usually co-proliferated and co-expressed, as is known in the art. This technique can be applied to developing cell lines carrying copies of more than 1,000 proliferating genes. Then, when the aminomethyl decanoic acid is withdrawn, a cell strain containing the proliferating gene integrated into one or more chromosomes of the host cell can be obtained. 15 Plasmid PC4 contains an interesting strong promoter gene for the expression of long terminal repeat (LTR) of Rous sarcoma virus (Cullen, et al, M〇lec. Cell. Biol. 5: 438-447 (1985)) Fragments isolated from enhancers of human cytomegalovirus (CMV) immediate early genes (B〇shart, et Department of Economics, Intellectual Property Bureau, Bayer Consumers Cooperative, G4 al., Cell 41:521-530 (1985)) 'The downstream of the promoting substance is BamHI, 20 Xbal and Asp 718 restriction enzyme cleavage position' which allows integration of genes. After these cloning sites, the plasmid contains the 3' intron and the polyadenosine of the pre-synthesis insulin precursor gene in mice. Formation location, others can also be used for performance-enhancing quality promotion, such as human b_actin promoting substance, early or late promotion of SV40 or other reverse transcription diseases -102- This paper scale applies to Chinese national standards ( CNS) A4 Specification (210 X 297 mm) 1329672 A7 B7 V. INSTRUCTIONS (1〇1) Toxic Long End Gathering (LTRS), such as HIV and HTLIVI, Clontech's Tet-Off and Tet-On Gene Expression System With similar systems can be used, in feeding In mammalian cells, a few -12 are expressed in a regulated manner (M. Gossen, and H. Bujard, Proc. Natl. Acad. Sci. USA 5 89: 5547-5551 (1992)), and multiple glands of other mRNA signals. Glycoside formation, for example, can be used from human growth hormone or globin genes. A stable cell line with a gene of interest integrated into the chromosome can also be selected with a selectable marker gene (eg gpt, G418 or wet). Co-mycins are common-transfer infections, and it is advantageous to use more than one selectable marker gene 10 (eg, G418 plus aminomethylfolate). Plasmid pC4 is digested with restriction enzymes and then carbonated using calf intestinal phosphatase by methods known in the art, and then the medium is isolated from a 1% agarose gel. The DNA sequence for the complete code of the IL-12 antibody is used, as in Example 15 as presented in SEQ ID NOS: INSERT MAB AA SEQ ID 1, and INSERT MAB AA SEQ ID 2, which is equivalent to the HC-12 of the IL-12 antibody of the present invention. The LC variable region, according to known method steps, the appropriate human immobilization region (ie, HC and LC regions) encoded by the isolated nucleic acid is also used in this structure (eg, as provided in the medium pl351: INSERT ATCC 20 ACCESSION NUMBER AND ADDITIONAL HC /LC plasmid). The isolated variable and fixed region encodes the DNA and ligates the dephosphorylated medium with T4 DNA ligase, then converts E. coli HB101 or XL-1 blue cells' and uses, for example, restriction enzyme analysis to determine bacteria-103 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210 297 297 public affair) (please read the note on the back and fill out this page first) The Ministry of Economic Affairs Intellectual Property Office staff consumption ^ one company print

91. 1. 2,000 1329672

102> V. Description of the invention (including fragments inserted into plasmid pC4. — — — — — — — — — — — -11 (Please read the notes on the back and fill out this page) - Employees of the Intellectual Property Office of the Ministry of Economic Affairs Cooperatives of Chinese hamster ovary (CH〇) cells lacking the active DHFR gene were used for metastatic infection, and 5 μg of expression plasmid PC4, using lipofectin 'is together with ps.5 μg of psV2-new plasmid Transfer 5 to infect 'this plasmid PSV2 new, containing a dominant selectable marker gene' The new gene from Tn5 encodes an enzyme that is resistant to a population of antibiotics including G418, which is sown in supplements with 1 μg/ In mL-G418 in α-MEM, 2 days later, cells were trypsinized and seeded onto a plate formed by hybridoma clones (Greiner, Germany), and 10 lines were placed in supplemented with 25, or 50 Ng/ml of amine. After about 10-14 days, the individual clones were trypsinized and then sown to 6 tanks containing different concentrations of aminomethyl folate (50 ηΜ). , 100 ηΜ, 2 00 η Μ, 400 η Μ, 800 η Μ) glass dish or 10 ml glass bottle was grown in the highest concentration of 15 amino fluorenyl folate clones, and then transferred to a higher concentration of aminomethyl folate (1 mM, The same procedure was repeated in a new 6-well plate of 2 mM, 5 mM, 10 mM, 20 mM) until the resulting clone grew to a concentration of ι〇〇 2 〇〇 mM, and the expression product of the desired gene was analyzed, for example , by sds-PAG and western blotting method or using reversed phase HPLC analysis. 20 Example 2: High-affinity human IgG monoclonal antibody class which can react with human iL_12 in mice using transfer gene Abstract -104- Zhang scale applies China National Standard (CNS) A4 specification (210 X 297 mm) λ r λ UJ^· 1329672 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (103) Use contains human heavy and light Chain-immunized globulin-transferred mice to produce high-affinity, fully human, monoclonal antibodies that can be used therapeutically to inhibit the effects of IL-12 and to treat one or more IL-12 mediators Disease 'variable region and solid with both human heavy and light bonds The region 5 antibody-transferred gene (CBA/JX C57/BL6/J) F2 hybrid mouse was immunized with human recombinant IL-12 (Ding 3丫1〇16131.,1!11;1.11111111111〇1·6: 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)), many fusions produce 10 one or more boxes of fully human IL-12-reactive IgG monoclonal antibodies, and this complete human anti-IL-12 antibody class is further characterized All IgG1, these antibodies were found to have an affinity constant between 1χ1〇9 and 9xl〇12, all of which are unanticipated high affinity for human monoclonal antibodies, making them suitable for treatment and IL -12 related diseases, pathology or not comfortable. Abbreviation BSA-Bovine Serum Albumin C〇2 - Carbon Dioxide DMS0 - Diterpenoid Stone 20 EIA-Enzyme Immunoassay EBS-Fetal Bovine Serum H2O2-Nitrogen Oxide HRP-Drosophila Peroxidase ID - Intradermal-105 - Words (please read the notes on the back and fill out this page)

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public interest) 91. 1. 2,000 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1329672 A7 V. Invention description (104)

Ig-immunoglobulin IL-12-interleukin _12 IP _ intraperitoneal IV-intravenous 5 Mab-monoclonal antibody OD-optical density o-p-diamine dihydrochloride PEG-polyethylene glycol PSA - Penicillin's bond, bismuth auxin 1 〇 RT - room temperature SQ - subcutaneous v / v - volume / volume w / v - weight / volume 15 Materials and Methods Animals can express human antibody class transfer gene mice Those known in the art and commercially available (e.g., from GenPharm International, San, A, Abgenix, Freemont, CA, and others), which exhibit human 20 class immunoglobulins, but not the mouse. For example, such transfer gene-bearing mice contain human-sequence-transferred genes that undergo ah-/linking, heavy-chain switching' and somatic cell mutations to produce human-ordered 免疫J immunoglobulins at any time (Lonberg, et & 1 , Nature 368: 856-859 (1994)) Light chain transfer genes can be derived, for example - partly from yeast -106 - this paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇X 297 public) - -------------------- Order --------- Line · (Please read the note on the back of the 4th and then fill out this page) 1329672 Hui Property Bureau employee consumption cooperative printed A7 B7 V. Invention Description (105) Artificial chromosome clone, which contains almost half of the germline human v range, in addition, the heavy-chain transfer gene can give both human V and human 密码 password (fishwild, et al., Nature Biotechnology 14: 845-851 (1996)) and/or 3 fixed regions, small mouse 5 derived from the appropriate gene lineage can be used in the immunogenic and fusion processes to produce a counter-il -12 of a fully human monoclonal antibody. The immunization method may use one or more immunization schedules to generate anti-IL-12 human 10 hybridomas. The first fusions may be completed according to the immunization plan exemplified below, but other similar known operations may be used. The manual is done, many 14-20 weeks old female and/or surgical castrated metastatic male mice are injected with M000 micrograms of recombinant human il-12 with an equal volume of TITERMAX or with complete IP via IP and/or ID. Freund's (FreuncTs) 15 adjuvant is made into a final volume of 100-400 microliters (for example, 200) of the emulsion to be immunized, each mouse can also choose to obtain 1-10 micrograms in each 2SQ position dissolved in 100 micro For liter of saline, use IL-12 emulsified with an equal volume of TITERMAX or incomplete Fround's adjuvant, administered with sputum (1-400 μg) and sQ (1-400 μg X 2) After 1-20 7, 5-10, 10-18, 17-25 and/or 21-34 days, the mouse can be immunized, and the mice can be bred for 12-25 and 25-40 days without using a clotting agent. Next, puncture the blood from the posterior hernia, then let it stand at room temperature for one hour and collect the serum according to the known IL-1. 2 EIA analysis titration, when repeated injections no longer increase the titer, start to melt -107- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----- ---Order---------Line (Please read the note on the back of the M and then fill in this page) 1329672 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention Description (106) At that time, the mice can be given a dose of 1-400 micrograms diluted in 100 microliters of physiological saline solution to the final IV supplement. After three days, the mice can be euthanized by cervical dislocation, and the spleen is removed under sterile treatment and immersed in 1 〇ml, containing 100 U/ml penicillin, 100 μg/ml streptavidin, and 0.25 μg/ml amphotericin B (PSA) in cold acid buffered saline (PBS), using PSA-PBS sterile The spleen was perfused to collect spleen cells, and the cells were washed once in cooled PSA-PBS, counted using Trypan blue dye separation and resuspended in RPMI 1640 medium containing 25 mM Hepes buffer. 10 cell fusion fusions can be carried out using known methods (such as those known in the art) at a ratio of 1:1 to 1:10, murine myeloma cells: viable spleen cells, by way of non-limiting example. In other words, the spleen cells and the myeloma cells can be pelleted together, and then the pellet can be slowly resuspended in 50 ml of 1 ml at 37 ° C for more than 30 seconds (w/v In PEG/PBS solution (PEG molecular weight 1,450, Sigma), this fusion can be terminated by adding 10.5 ml of RPMI 1640 medium containing 25 mM Hepes (37 ° C) for more than one minute. The fused cells are at 500. After centrifugation at 1500 rpm for five minutes, the cells were resuspended in HAT medium (RPMI 1640 medium containing 25 mM Hepes, 10% fetal clone I serum (Hyclone), 1 mM sodium pyruvate, 4 mM L-guanamine Acid, 10 μg/ml gentamicin, 2.5% original culture supplement (Fisher), 10% 653-adjusted RPMI 1640/Hepes medium, 50 -108- This paper scale applies to Chinese national standards (CNS>A4 Specifications (210 X 297 mm) -------------------- Order-!-----Line (please read the notes on the back first) Fill in this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 13296672 A7 ___________ B7 V. Invention Description (107) 2-Hydroxythioethanol, 100//Μ of the jaundice, 〇4^M amine butterfly Fin, with 16#M thymine), and then placed in 15 96-well flat-bottomed tissue culture plates at 200 μl/well, then placed under 37 with 5% carbon dioxide In a humidified incubator with 95% air 5, for 7-10 days. Detection of human IgG anti-IL-12 antibodies in serum of small mice can be performed using solid phase EIA, which is used to screen human serum in humans. IL-12-specific human IgG antibodies, in short, can be coated with 10 IL-12 at a concentration of 2 μg/ml in PSB overnight, over 0-02% (v/v) Tween 20 After washing in 0.15M saline solution, it can be blocked by using 1〇/〇(w/v) BSA in PBS, 200 μl/well, and treated at room temperature for one hour to block. The plate is used immediately or frozen. _ 2 ° ° C for further use, mouse serum dilution, in an amount of 50 μl / trough 15 placed on the IL-12 coated plate, incubated at room temperature After the plate was washed, the probe was washed and 50 μl/well of HRP-labeled goat anti-human IgG, pc, diluted to 1:30,000 with 1% BSA-PBS, and allowed to stand at room temperature for one hour. The plate can be washed again, and then add 1 〇〇 microliter/tank of citrate-phosphate 2 〇 substrate solution at room temperature (〇·1Μ falling acid and 〇.2M acid, 0.01% The ruthenium oxide and 1 mg/ml OPD were added to the reaction solution (4 Ν sulfuric acid) at 25 μl/well over 15 minutes, and the 〇D, s at 490 nm was read using an automatic plate spectrometer. -109- This paper size applies to China National Standard (CNS) A4 specifications (10) x 297 public love 〉 ------------------- order -------- line &lt Please read the note on the back and fill out this page. 1329672 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 _______B7____ V. INSTRUCTIONS (108) Extract the complete human immunoglobulin in the hybrid tumor supernatant A fully human immunoglobulin secreted by a growing hybridoma can be detected using an appropriate sputum, in short, a 96-well pop-out plate (VWR ' 610744) can be coated with 1 〇 micro The goat anti-human IgG Fc was placed in sodium carbonate buffer 5, and the plate was washed at 4 ° C overnight, and the plate was washed with 1 hour BSA-PBS at 37 ° C for one hour to block, use immediately or After freezing at -20 ° C, the undiluted hybridoma supernatant was incubated on the plate 'washed at 37 ° C for one hour, using HRP-labeled goat anti-human κ, 1 :1〇, diluted in ι〇/〇10 BSA-PBS, probed at 37 ° C for one hour, and then the plate was incubated with the above-mentioned substrate. Determination of intact human anti-IL-12 reactivity, such as the hybridoma described above, can be analyzed for its reactivity to IL-12 using appropriate RIA or other analytical methods, for example, the supernatant is as described above Incubate on goat anti-human IgG Fc plate, wash, and then, at room temperature for one hour, perform appropriate counting on each well with radiolabeled IL-12. Wash the small well twice with PBS and use appropriate The counter will be counted by the radiolabeled IL-12. 20 Human IgG anti-IL-12 secreted hybridomas can be expanded in cell culture and subjected to a series of secondary clones with limited dilution, and the resulting clone population can be expanded and stored in cold bead culture medium. Medium (95°/〇FBS, 5% DMS0) and stored in liquid nitrogen. -110- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -------------------111 - I (Please read the back Please fill out this page again) 1329672

Description of the Invention (109) Isoty ping of the Intellectual Property Office of the Ministry of Finance and Intellectual Property. The isotype determination of antibodies can be performed using EIA, which can be achieved using a format similar to the specific titer used to screen mouse immune sera. IL_12 can be applied to a 96-well plate as described above, and 2 μg/ml of purified 5 antibody is introduced on the plate and incubated at room temperature for one hour, and the plate is washed and HRP-labeled goat anti-- Human IgGi or HRp-labeled goat anti-human IgGs, diluted 1:4000 in 1% BSA-PBS, probed at room temperature for one hour, washed the plate again and together with the substrate solution as described above Cultivate. 10 Kinetics of binding of human anti-human IL-12 antibody to human IL_12 The binding properties of the antibody can be appropriately evaluated by using the IL_i2 capture EIA and BIA core techniques, for example, as described above, EIA plates coated with 2 micrograms/ml of il-12 can be used to assess the gradient concentration of pure 15 human IL-12 antibodies, and OD, S can be plotted as a semi-logarithmic representation showing the efficiency of relative binding. The quantitative binding constant can be obtained by, for example, the following method or any known suitable method, placing BIA core CM-5 (carboxymethyl) fragments in BIA core 2000 units in HBS buffer (0.01 Μ 20 HEPES, OM M NaCl, 3 mM EDTA, 0.005% ν/ν Ρ20 Surfactant, pH 7.4) Flow through the fragmented flow cells at a rate of 5 μl/min until a stable baseline is reached, 1 〇〇 microliter, dissolve Add 15 mg of EDC (N-ethyl-N,-(3-didecyl-aminopropyl)-carbodiimide hydrochloride) to 2 μl of microliters in 2 μL of water. Dissolved in 200 -111- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 91. 1. 2,000 (please read the note on the back and fill out this page) Order. Line - 1329672 Ministry of Economic Affairs, Intellectual Property Bureau, Bayer Consumers Cooperative, Printed A7 B7 V. Invention Description (110) 2.3 liters of NHS (N-based basal acetaminophen) solution of microliters of water, 40 μl of the solution is injected into the debris Six microliters of human il_i2 solution (15 μg/ml dissolved in 10 mM sodium sulphate, ΡΗ4·8) was injected into the debris, resulting in an increase of approximately 500 RU, buffered Change liquid to TBS/Ca/Mg/BSA 5 flow buffer (2 mM Tris, 0.15 Μ gasified sodium '.2 mM calcium chloride, 2 Mm ethyl magnesium' 〇.5% Triton X-100, 25 μg /ml BSA, pH 7.4) and the debris flowed overnight to reach equilibrium and any unreacted amber sulphate esters were taken away by water. The antibody was dissolved in a flowing buffer to 33.33, 16.67, 10 8.33, and 4.17 nM, the flow rate was adjusted to 30 μl/min and the temperature was adjusted to 25 C. Two flow cells were used for The kinetic operation, one on which IL-12 has been immobilized (sample set)' and the second on underivatized flow cells (blank group), the concentration of various antibodies taken at 120 μl was injected at a flow rate of 30 μl/ On the flow cells of the minute (combined phase), a 360-second buffer stream (dissociation phase) was injected without interruption, and the surface of the fragment was successively injected by two 30 μl of 2 M guanidine thiocyanate. And to regenerate. Analysis of the data can be performed using BIA Evaluate 3.0 or CLAMP 2.0 as known in the art. For each antibody concentration, the blank sensing map is subtracted from the sample sensing map by 20, for dissociation (kd.sec-1) and The binding (ka, m〇r hec·1) and the calculated (kd/ka) dissociation constant (KD, mol) are approximated to a global fit in which the antibody affinity is high enough for antibody capture. The RUs is >100 and additional antibody dilutions are required. -112- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ------Ill — — ----IIII I----II (Please read the note on the back first) 4th matter, please fill out this page> 1329672 Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Cooperative, Printed A7 B7 V. Description of Invention (1U) Results and Discussion Anti-human IL-12 monoclonal antibody production Many fusions were made And each fusion line was sown in 15 plates (1440 troughs/fusion), which produced a number of 5 antibodies specific to human IL-12, some of which were found to contain a combination of human and mouse Ig chains. The remaining hybridomas secreted anti-IL12 antibodies containing only human heavy and light bonds, belonging to human hybridomas, all of which showed IgQ1 ^ binding kinetics of human anti-human IL-12 antibodies. Purified anti-systems of most or all of these hybridomas bind to IL12 in a concentration-dependent manner. Figure 1_2 shows the results of the relative binding effectiveness of these antibodies, in which case the antibody is homologous to its antigen (antigen) The affinity of the determinant, epitope) was determined It is noted that when IL-12 is directly bound to the eia plate, 15% protein is denatured and the binding affinity of this surface is not reflected to the undenatured protein, and a concentration of 5% is found between the large concentration ranges. BIA core analysis of human antibodies gives quantitative binding constants and reveals that many human monoclonal antibodies have a very high affinity and 20 KDs range from 1 X 1〇·9 to 7x 10·12. Conclusion Many fusions The spleen cells can be obtained from a mixture of human variable and fixed region antibody-transferred genes, and the Chinese National Standard (CNS) A4 specification (210 x) is applied to the human-113-this paper scale. Four 7 mm) 91. 1- 2,000 (Please read the notes on the back and fill out this page again >

1329672 A7 V. INSTRUCTIONS (112) IL-12-immunized individuals' groups are produced with a number of intact human IL-12-reactive IgG monoclonal antibodies of the same type as IgG1, this complete human-anti-IL 12 antibody It has been further identified that many of the produced antibodies have an affinity constant between 1 X 1〇9 and 9 x 10〗 2 'The unanticipated high affinity of these intact human shell 5 monoclonal antibodies makes them suitable It is used as a 'therapeutic agent' for diseases, conditions, or related conditions associated with IL-12. 10 15 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

¢--G 20 Example 3: C34〇 is a neutralized human monoclonal antibody IL-12 biological activity is demonstrated by C340 in various IL_12-dependent activity assays, due to IL-12 enhancing NK cell and T lymphocyte production IFN GAMMA, so the effect of C340 antibody on the up-regulation of IFN GAMMA mRNA and the effect of C340 on the production of IFN GAMMA protein were examined (Trinchieri, G., Current Opinion in Immunology,. 9:17-23 (1997), Morris, SC , et al. 5 Journal of Immunology, 152: 1047-1056 (1994)), the ability of C340 to neutralize IL-12 to drive lymphokine activation of killer (LAK) cell activity was also explored in this study (Kutza , J. and Murasko, DM·, Mechanisms of Ageing and Development, 90:209-222 (1996), Stem, AS, et al., Proceedings of the National Academy of sciences of the UU.SA, 87:6808-6812 ( 1990)) Finally, the effect of C340 on the up-regulation of IL-12-mediated T and NK cells on CD95 cells was also tested (Medvedev, AE, et al., Cytokine, 9:394-404 (1997) ) ° 114- This paper scale applies to Chinese National Standard (CNS) A4 specification C210 x 297 mm ------------------- set i__ Shu-line ^ read the back of the front first heard 'no longer matters% Complete this page >! 1329672

V. INSTRUCTIONS INSTRUCTIONS (113) 5 11 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed 20 IFN gamma mRNA transcriptional inhibition] To determine whether C340 inhibits induction in human pBL, GAMMA __, conducts - thief transcription _pcR Analysis of the use of the pair of actin (controlling the integrity of the mRNA integrity plate) - a primer with IFN GAMMA to proliferate from the stimulated human PBL cDNA, ® 3 shows that in the heart of the heart to activate 2 Within hours of PBMC, C340 down-regulates IFN Gamma Mrna. Inhibition of extracellular IFN GAMMA is based on flow cytometry to estimate various signals in response and as an estimate of activation, tau cells and NK cells can be induced to secrete cytokines, more specifically, treated with IL-12. With pbl initiated with IL-12, substantial IFN gamma synthesis occurs 4-8 hours after stimulation, which can be detected by flow cytometry in the cytoplasm of Brefeldm-A treated PBL. It is known that Figure 4 demonstrates that in such cultures, when C340 is added to IL-12 for five hours, the production of IFN GAMMA can be reduced by 60%. Inhibition of IL-12-induced secretion of ifn GAMMA Figure 5 clearly shows that peripheral blood lymphocytes were placed in a dose-dependent mode of experiment, two different batches of C340 inhibited the secretion of IFN GAMMA, 400 pg IL-12 is pre-mixed with various amounts of C340 and then added to IL-2-stimulated PBL's culture-115- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) --- ---------- I------Book _丨_ _丨·丨! Line (please read the precautions on the back and fill out this page) 1329672 A7 B7 V. Invention Description (10 15 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printing 20, 'After 18-24 hours of cultivation', when measured by EIA In the case of IFN GAMMA, a significant reduction in the amount of IFN GAMMA was detected, and only as low as 1 μg/ml of C340 antibody was used. The cytotoxicity of IL-12-induced LAK cells inhibited Raji cells, a sensitivity to IL_12. The Birch's lymphoma-derived cell line is a cell line that is resistant to cells, sensitive to LAK cells, Raji cells, triple-coated, and has been used for 4 〇〇 picograms of IL-12 and 1〇u /ml IL_2 was incubated for four hours in the presence of human monoclonal antibody C34(R) (5000 ng/ml or 5 〇g/ml) or in the absence of pre-activated LAK cells, Figure 6 shows from three normal, Results from healthy donors (d〇n〇rs) 'IL_12+IL-2 activation of effector cells resulted in increased cytotoxic toxic activity over the toxicity of cells activated by 1L_2 alone, and C340 antibodies inhibited this IL- 12-dependent effect Size is related to antibody concentration, and the most tested concentration can attenuate cytotoxicity back to background values. Multiple reports of CD95 up-regulation inhibition have been revealed on the surface of highly purified CD56+PBL' CD95-party IL-12-induced up-regulation Adjustment, as shown in Figures 7a and 7B, the analysis of the flow cell count by the distribution revealed that CD95 expression on CD3+ τ cells and CD56+ NK cells after 72 hours of treatment with IL-l2+IL-2 It is clearly up-regulated with the accompanying anti-IL-12 treatment, inhibiting CD95 expression in cD3+ and CD56+ 116-

9L 1. 2,000 (please read the note on the back and fill out this page) •-Installation-δ. -Line 13296672 A7 _B7__ V. Description of invention (115) (Please read the note on the back and fill out this page) In contrast, CD3+ cells were inhibited by approximately 50% (Fig. 7A), while CD56+ cells were inhibited by approximately 85% (Fig. 7B), which was evidenced by a reduced MFI index (percentage greater than unstimulated controls). 5 Example 4: Gene replication and identification • Line

DNA fragments of the genome containing the C340 heavy chain gene or C340 light chain are replicated and purified, and the genomic DNA purified from C340 hybridoma cells is partially digested with Sau3A restriction enzyme and centrifuged, and centrifuged through a 10-40% sucrose gradient. Divide to size-selection, select a large 10 small range of 15-23 kb DNA fragments to replicate reproduction in phage medium, EMBL3, [available? And packaged into phage particles, many packaged reactants result in one million colonies of sputum, and approximately 600,000 clones from the cloning library are screened 'by hybridization with platelets, using 32P-labeled genomic DNA Fragments containing human igG1 heavy chain 15 fixed region sequences or human/c light chain fixed region sequences as probes, thirteen heavy chains and nine light chain clones were detected, among which three heavy chain clones Four light-key clones were purified using more than two rounds of screening (tw〇m〇re rounds of screening), and the DNA of the phage was printed using the PCR Department of Intellectual Property's Intellectual Property Agency's Consumer Cooperative, showing one of the heavy chain clones. Both the light chain clone and the 5' and 3' ends encoding the 20 sequence, the DNA inserted into the heavy chain (HC) clone H4 is 16 kb in size, and contains 3.6 kb of 5, flanking and At least 2 kb of the 3' flanking sequence, inserted in the light bond (l〇 clone LC1 DNA is 15 kb in size, and contains 4.4 kb of 5, flanking and 6.0 kb of 3, flanking sequence 'complete inserts Removed from phage media, as -117- 91. 1. 2,000 paper scales apply National Standard (CNS) A4 Specification (210 X 297 public) --- 1329672 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (116) Sail fragment 'and colonization in the plasmid expression medium pl351 Between the xh〇i and Sail positions, it provides a gpt-selectable marker gene, due to an internal Sail position in the sequence encoded by the heavy chain variable region. Two Sail fragments must be transferred from phage H4 to pl351 Table 5 shows that the obtained heavy and light chain expression plasmids are called P1560 and pl558, respectively. In the two plasmids relative to the pl35i vector sequence, the direction of the heavy and light chain genes is determined by restriction enzyme analysis and PCR, respectively. In both cases, the 'direction' decision is such that the 5' end of the Ab gene fragment is the closest to the gpt gene, and the two strands of the coding region of the selected gene are sequenced. Plasmids pl560 and pl558 The sequences are presented in Figures 11A-11K and Figures 13A-13J, respectively. Example 5: Preparation of Recombinant Cell Lines The heavy chain plasmid pl560 was digested with Pvul restriction enzyme to make the linear form 15 ' and the Sail restriction enzyme was used to make the light chain plasmid 1558 becomes , p3X63Ag8.653 (653) and SP2/0-Agl4 (SP2/0) cells were separately transfected with pre-mixed linearized plasmids, by electroporation and cultured cells with the use of mycophenolate as described Acid-selective metastatic infectious agents (Knight, et al., Molecular Immunology 30:1443 (1993)) » 20 After about two weeks, analysis of human IgG from supernatants of mycophenolic acid-resistant communities (ie 'Recombinant C340 (rC340)), for which the cell supernatant was incubated on a 96-well ELISA plate coated with a goat antibody specific for human IgG, using a confirmatory ligase-conjugate Combined goat anti-human IgG (heavy bond + light chain) antibody and the above-mentioned test fill-118- (please read the back of the note before filling this page) • - install lej,. - line · paper Zhang scale applies Chinese National Standard (CNS) A4 specification (21〇X 297 public) 91. 1. 2,000 1329672 / A7 B7 V. Description of invention (117) Acidase substrate (Knight, et al^Molecular Immunology 30:1443 (1993)), detection of human igG bound to the coated plate, propagation lines producing more cells were transferred to 24-well containing standard medium Propagation in nourishment (IMDM, 5% FBS, 2 mM glutamate, mycophenolic acid selected 5 mixture) 'The amount of antibody produced (ie, the culture that was secreted into the culture medium)' was carefully treated by ELISA Quantification, using the purified C340 mAb as a standard, the selected clones were then propagated in T75 flasks and the human IgG lines produced by these clones were quantified by ELISA. Based on these values, six separate 653 metastatic infections were transduced with three 10 independent SP2/0 metastatic infections were seeded again (each cell was evenly distributed on 96-well plates) 'analyzed by ELISA for antibodies produced from supernatants from individual clones Volume, three sub-selection lines, 653 metastatic infectious agents 19-20 (C379B) and SP2/0 metastatic infections 84-81 (C381A) and 22-56 (C389A) were selected for further analysis. Analysis of cell supernatants from three parental cell lines (653 transfer of infectious clone 2 and clone π and sp2/〇20 transfected infectious clone 1) prior to binding of the rC340 antigen to the cell line selected as described above. The concentration of rC34〇 used to test the antigen binding of rC340, the concentration of rC34〇 in the three cell supernatant samples was first determined by ELISA to determine the titration of the supernatant sample or the purified C340 positive control group, and then incubated. The 96-slot has been coated with a 2 μg/ml human IL-12 96-well plate, and then the alkaline acid-119- paper scale applies to the Chinese National Standard (CNS) A4 specification C210 X 297 public ---- ------I------------ order _丨_ 丨丨·! line (please read the back of the Wang Yi matter and then fill out this page) Ministry of Economics wisdom Property Bureau employee consumption cooperative printing

GG 1329672 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed S5 A7 B7___ V. INSTRUCTIONS (m) Enzyme-conjugated goat anti-human IgG (heavy chain + light chain) antibody and appropriate ELISA The tethered mAb was examined by mass spectrometry. As shown in Figure 8, rC340 was specifically bound to human IL-12 in an almost indistinguishable manner from the original C340 mAb. 5 Identification of selected cell lines The growth curve analysis was performed with C379B, C381A, and C389A. The initial cell density was 2×105 cells/ml, seeded in T75 flasks, using standard medium or SFM-5 serum-free medium, then 10 The number of cells and the concentration of rC340 were monitored daily until the culture was consumed. The results of the cultures in the standard medium are shown in Figures 9A-9C, C379B, C381A, and the largest C340 mAb produced by C389A, respectively, at 135 μg/ ML, 150 μg/ml, and 110 μg/ml, C379B cells could not be adapted to grow 15 times in SFM-5 medium, and C381 cells produced rC340 in SFM-5 medium in the same amount as in standard medium, while C389A The amount of cells producing rC340 in SFM-5 medium is only equivalent to one-half of its amount in standard medium. For the three subclonal lines, the stability of the rC34〇20 mAb produced over a period of time is evaluated, and the cells are selected in a standard medium or a standard medium without sulphuric acid for a period of time. The C398B and C381A cell lines were observed to be stably produced in a 24-well culture dish for 3 days (test time maximum) and 75 days, respectively, in the presence or absence of the selection. - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) ------nllll^w^------I — —------ (Read first Precautions on the back side of this page) 1329672 A7 B7_ V. Inventive Note (119) rC340, while the C389 cell line is not stable and the culture produced after 43 days is only 20% of the amount of antibody at the start of the study. . It will be apparent that the present invention may be practiced in other ways, in addition to the following detailed description and examples, and that many modifications and variations of the present invention are made in accordance with the above teachings, and are therefore also included in the attached application. In the scope of patents. ------------i ------Book -------Line {Please read the notes on the back and fill in this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative system

yG -121- This paper size applies to Chinese National Standard (CNS) A4 specification C210 X 297 mm) 1329672 C£N 24 8 Sequence Listing <110> Shealy, David; Knight, David; Scall〇n, Bemie; Giles- Komar, Jill; Peritt, David <i2〇> IL-12 antibody, composition, method and use thereof<I30> CEN248 <160> 15 <170> Patentln Ver 2.0

<210> 1 <211> 5 <212> PRT

<21> Homo sapiens (modern people) <400> 1

Thr Tyr Tip Leu Gly 1 5 <210 2 <211> 17 <212> PRT <213> Homo sapiens <4〇0> 2 lie Met Ser Pro Val Asp Ser Asp lie Axg Tyr Ser Pro Ser Phe Gin 1.5 10 15 .

Gly

<210> 3 <211> 10 <212> PRT

<213> Homo sapiens I <400> 3

Pro Arg Pro Gly Gin Gly Tyr Phe Asp Phe 1 5 10

<210 4 <2ll> 11 <212> PRT

<213> Homo sapiens I <400> 4

Aig Ala Ser Gin Gly lie Ser Ser Trp Leu Ala 1 5 10 <210> 5 <211> 7 <212> PRT <2I3> Homo sapiens <400> 5 1 2 1329672 C£N 248

Ala Ala Ser Ser Leu Gin Ser l 5 <210> 6 <211> 9 <212> PRT <213> Homo sapiens <400> 6

Gin Gin Tyr Asn lie Tyr Pro Tyr Thr 1 5

<210> 7 <211> 119 <212> PRT Homo sapiens <400> 7

Glu Val Gin Leu Val Gin Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 15 10 15

Ser Leu Lys lie Ser Cys Lys Gly Ser Gly Tyr Ser Phe Thr Thr Tyr 20 25 30

Trp Leu Gly Trp Val Arg Gin Met Pro Gly Lys Gly Leu Asp Tip lie 35 40 45

Gly Ue Met Ser Pro Val Asp Ser Asp De Arg Tyr Ser Pro Ser Phe 50 55 60

Gin Gly Gin Val Thr Met Set Val Asp Lys Ser lie Thr Thr AJa Tyr 65 70 75 80

Leu Gin Tip Asa Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 8S 90 95

Ala

Aig Arg Arg Pro Gly Gin Gly Tyr Phe Asp Phe Trp Gly Gin Gly 100 105 110

Thr Leu Val Tht Val Ser Ser 115 <210 8 <211> 108 <212> PRT <2D> Homo sapiens <400> g

Asp lie Gin Met Thr Gin Ser Pro Ser ser Leu ser Ala ser Val Gly 15 10 15

Asp Arg Val Thr He Thr Cys Arg Ala Ser Gin Gly lie Ser Ser Trp 20 25 30

Leu Ala Trp Tyr Gin Gin Lys Pro Glu Lys Ala Pro Lys Ser Leu lie 35 40 45

Tyr Ala Ala Ser Ser Leu Gin Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 2 3 1329672 CEN 248

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr He Ser Ser Leu Gin Pro 65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Gin Gin Tyr Asn lie Tyr Pro Tyr

85 90 9S

Tlir Phe Gly Gin Gly Thr Lys Leu Glu He Lys Axg 100 105 <210 9 <211> 503 <212> PRT <213> Homo sapiens <400>

Arg ksn Leu Pro val Ala Thr Pro Asp Pro Gly Mec Phe Pro Cya Leu 15 10 IS

His His Ser Gin Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gin Lys 20 25 30

Ala Arg Gin Thr Leu Glu Phe Tyr Pro Cy3 Thr Ser Glu Glu lie Asp 35 40 4S

His Glu Asp lie Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys Leu 50 55 60

Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu Thr 65 70 75 80

Ser Phe lie Thr Asn Gly ser Cys Leu Ala Ser Arg Lys Thr Ser Phe 85 90 95

Met Met Ala Leu Cys Leu Ser Ser lie Tyr Glu Asp Leu Lys Mec Tyr 100 105 110

Gin Val Glu Phe Lys Thr Mec Aen Ala Lys Leu Leu Mec Asp Pro Lys 115 120 125

Arg Glrx lie Phe Leu Asp Gin Asn Met Leu Ala Val lie Asp Glu Leu 130 135 140

Met Gin Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gin Lys Ser Ser 145 150 155 160

Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys lie Lys Leu Cys lie Leu

165 170 17S

Leu His Ala Phe Arg lie Arg Ala Val Thr lie Asp Arg Val Mec Ser 180 185 190

Leu Asn Ala Ser lie Trp Glu Leu Lys Lys Asp Val

Val Val 195 200 205

Glu Leu Asp Trp 210

Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr 215 220

Cys Asp Thr Pro Glu Glu Asp Gly lie Thr Trp Thr Leu Asp Gin Ser 225 230 235 240

Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr lie Gin Val Lys Glu 3 1329672 CEN 248 4 245 250 255

Phe Gly Asp Ala Gly Gin Tyr Thr Cys His Lys Gly Gly Clu Val Leu 260 265 270

Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Oly lie Trp Ser 275 2Θ0 2S5

Thr Asp lie Leu Lys Asp Gin Lys Glu Pro Lys ΑΘΠ Lys Thr Phe Leu 290 295 300

Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp lieu 305 310 315 320

Thr Thr lie Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly 325 330 335

Ser Ser Asp Pro Gin Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala 340 345 350

Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys 355 160 365

Gin Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro lie Glu 370 375 380

Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser 385 390 395 400

Ser Phe Phe lie Arg Asp lie lie Lys Pro Asp Pro Pro Lys Aen Leu 405 410 415

Gin Leu Lys Pro Leu Lys Asn Ser Arg Gin Val Glu Val Ser Trp Glu 420 425 430

Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe 435 440 445

Cys Val Gin Val Gin Gly Lys Ser Lys Arg Glu Lye Lys Asp Arg Val 450 455 460

Phe Thr Aep Lys Thr Ser Ala Thr Val He Cys Arg Lys Asn Ala Ser 465 470 475 480 lie Ser Val Arg Ala Gin Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu 4BS 490 495

Trp Ala Ser Val Pro Cy3 Ser 500 <210> 10 <2I1> 15 <212> DNA <213> Homo sapiens <400 10 agatatacta tgcac 15

<210 11 <2U> 51 <212> DNA 4 AO r 1329672 CEN 248 5 <213> Homo sapiens <400> 11 gttatatcat ttgaxggaag caataaatac tacgtagact ccgtgaaggg c 51 <210> 12 <211> 30 &lt ;212> DNA <2u> Homo sapiens <400> 12 gaggcccggg gaicgiatgc ttttgatatc 30 <210> 13 <211> 33 <2I2> DNA <213> Homo sapiens <400>

Ctctcctgca gggccagtca gagtgttagc agctacuag cc 33 <210> 14 <211> 21 <212> DNA <213> Homo sapiens <4〇〇> 14 gatgcatcca acagggcc 18 <210> 15 <211> 27 <212> DNA <213> Homo sapiens <400> 15 cagcagcgta gcaaetggce t 21

S

Claims (1)

Patent Application No. 91110319 ROC Patent Appln No.91110319 The text of the patent application scope without amendments after the amendment - Annex (II) Amended Claims in Chinese - Enel. (ID (April 22, 1999, submitted) (Submitted on April 22, 2010) Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative 1. An isolated anti-IL-12 antibody comprising the heavy chain variable region (VH) of the amino acid sequence of SEQ ID NO: 7 and The light chain variable region (VL) of the amino acid sequence of SEQ ID NO: 8. 2. The anti-IL-12 antibody according to the scope of claim 1 wherein the antibody has an affinity of at least 1 〇 12 与 with IL- 12. The anti-IL-12 antibody according to claim 2, wherein the antibody binds to IL-12 with an affinity of at least 10 η Μ. According to the anti-IL-12 antibody of claim 3, wherein the antibody Affinity of at least 10·10 结合 binds to IL-12. According to the anti-IL-12 antibody of claim 4, wherein the antibody binds to IL-12 with an affinity of at least 1 (Τ9Μ). An anti-IL-12 antibody, wherein the antibody neutralizes the activity of the IL-12 protein. A pharmaceutical composition for diagnosing or treating IL-12-related symptoms in a cell, tissue, organ or animal, comprising an isolated anti-IL-12 antibody having the amino acid sequence of SEQ ID NO: a heavy chain variable region (VH) and a light chain variable region (VL) of the amino acid sequence of SEQ ID: 8; and at least one pharmaceutically acceptable carrier or diluent. -IL-12 antibody comprising the heavy chain complementarity determining region 1 (CDR1) of the amino acid sequence of SEQ ID NO: 1, SEQ 3. 4. 5. The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 90374B-connected 1 1329672 A8 B8 C8 D8 force, patent application range ID NO: 2 amino acid sequence heavy chain complementarity determining region 2 (CDR2), SEQ ID NO: 3 amino acid The heavy chain complementarity determining region 3 (CDR3) of the sequence, the light chain complementarity determining region 1 (CDR1) of the amino acid sequence of SEQ ID NO: 4, and the light chain complementarity determining region 2 of the amino acid sequence of SEQ ID NO: 5 (CDR2) and the light chain complementarity determining region 3 (CDR3) of the amino acid sequence of SEQ ID NO: 6. The anti-IL-12 antibody according to claim 8 wherein the antibody is at least -12M affinity of binding of IL-12. 10. An anti-IL-12 antibody according to claim 9 wherein the antibody binds to IL-12 with an affinity of at least 10<">. U. The anti-IL-12 antibody according to claim 10, wherein the antibody binds to IL-12 with an affinity of at least 1 (T1 gM. 12. An anti-IL-12 antibody according to claim 11 of the patent application, wherein The antibody binds to IL-12 with an affinity of at least 10-9 M. 13. The IL-12 antibody according to claim 8 of the patent application, wherein the antibody neutralizes the activity of the IL-12 protein. Printing 14. A pharmaceutical composition for diagnosing or treating IL-12-related symptoms in a cell, tissue, organ or animal, comprising an isolated anti-Jiang-12 antibody comprising SEQ ID NO: 1 The heavy chain complementarity determining region 1 (CDR1) of the amino acid sequence, the heavy chain complementarity determining region 2 (CDR2) of the amino acid sequence of SEQ ID NO: 2, and the amino acid sequence of SEQ ID N: 3 The chain complementarity determining region 3 (CDR3), the light chain complementarity determining region 1 (CDR1) of the amino acid sequence of SEQ ID NO: 4, and the light chain of the amino acid sequence of SEQ ID NO: 5 - 1329672 A8 B8 C8 DX 6. The light chain complementarity determining region 3 (CDR3) of the amino acid sequence of the claim region 2 (CDR2) and the amino acid sequence of SEQ ID NO: 6; At least one pharmaceutically acceptable carrier or diluent p 15. An isolated nucleic acid molecule encoding a primary antibody _IL_12 comprising a heavy chain variable region of the amino acid sequence of SEQ ID NO: 7. (VH) and the light chain variable region (VL) of the amino acid sequence of SEQ ID NO: 8. 16. An isolated nucleic acid vector comprising the isolated nucleic acid molecule according to item 15 of the patent application. 17. An isolated host cell comprising a vector isolated according to claim 16 wherein the host cell is prokaryotic or eukaryotic. 18. According to the host cell of claim 17 of the patent application, Wherein the host cell is at least one selected from the group consisting of COS-1, COS-7, HEK293, BHK21, CHO, BSC-1, Hep G2, 653, SP2/0, 293, HeLa, myeloma, or lymphoma cells. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives 19. A method for producing anti-IL-12 antibodies is included in the process of cultivating and recovering IL-12 antibodies, according to Article 17 of the scope of the patent application. Host cell 20. An isolated nucleic acid molecule encoding An anti-IL-12 antibody comprising the heavy chain complementarity determining region 1 (CDR1) of the amino acid sequence of SEQ ID NO: 1, and the heavy chain complementarity determining region 2 of the amino acid sequence of SEQ ID NO: 2 (CDR2) , heavy chain complementarity determining region 3 (CDR3), SEQ ID NO: 4 of the amino acid sequence of SEQ ID NO: 3 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) 1329672. A8 B8 C8 D8 , the light chain complementarity determining region 1 (CDR1) of the amino acid sequence of the patent application, the light chain complementarity determining region 2 (CDR2) of the amino acid sequence of SEQ ID NO: 5, and the amino acid of SEQ ID NO: 6. The light chain complement of the sequence determines region 3 (CDR3). 21. A nucleic acid vector comprising an isolated nucleic acid molecule according to claim 20 of the scope of the patent application. 22. An isolated host cell comprising the nucleic acid vector according to claim 21, wherein the host cell is prokaryotic or eukaryotic. 23. The isolated host cell according to claim 22, wherein the host cell is at least one selected from the group consisting of COS-1, COS-7, HEK293, BHK21, CHO, BSC-1, Hep G2 '653 , SP2/0, 293, HeLa, myeloma, or lymphoma cells, or any of them that are permanent or transformed. 24_ a method for producing an anti-IL-12 antibody, which comprises translating in vitro, in vivo or on the spot to express IL-12 antibodies in a detectable or recoverable amount according to the scope of the patent application. The nucleic acid molecule of the item. The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed 25. An isolated nucleic acid molecule encoding the primary antibody _IL_12, which contains an amine having SEQ ID NOS: Bu 2, 3, 4, 5, and 6. The antibodies of the heavy and light chain CDRs of the base acid sequence bind to the same region of the IL-12 protein. 26. A nucleic acid vector comprising an isolated nucleic acid molecule according to the scope of the patent application. -4 - 1329672 A8 B8 C8 D8 VI. Scope of Application 27. An isolated host cell comprising a nucleic acid vector according to claim 26 of the patent application, which is prokaryotic or eukaryotic. 28. The isolated host cell according to claim 27, wherein the host cell is selected from the group consisting of COS-1, COS-7, HEK293, BHK21, CHO, BSC-1, Hep G2, 653,, SP2/ 0,293, HeLa, myeloma, or lymphoma cell line, or any of its perpetuated or transformed cells. 29. A method of producing an anti-IL-12 antibody, which comprises translating under conditions in which the IL-12 antibody is detectable or recoverable in vitro, in vivo or on the spot. 25 nucleic acid molecules. 30. A pharmaceutical composition for the diagnosis or treatment of dryness in an animal comprising an effective amount of an isolated anti-IL-12 antibody comprising a heavy chain variable of the amino acid sequence of SEQ ID NO: 7. Region (VH) and the light chain variable region (VL) of the amino acid sequence of SEQ ID NO: 8. 31. The pharmaceutical composition according to claim 30, wherein the effective amount is from 0.001 to 50 mg per kg of animal. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative 32. The pharmaceutical composition according to claim 30, which is administered by at least one of the following modes: non-digestive, subcutaneous, intramuscular, intravenous Internal, intra-articular, intrabronchial, intra-abdominal, intracapsular 'in the cartilage, in the cavity, in the body cavity, in the ventricle, in the colon, in the cervix, in the stomach, in the liver Internal, intramyocardial, intraosseous, pelvic, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, and rectal paper scales applicable to the Chinese National Standard (CNS) A4 specification (210 X 297) PCT) 1329672. A8 - B8 C8 _D8_ VI. Patented, intrathecal, intrasynovial, rectal, buccal, sublingual, intranasal or transdermal. 33. The pharmaceutical composition according to claim 30, which further comprises an effective amount of at least one compound or at least one protein selected from the group consisting of: detectable labels or reporters, TNF antagonists, antibodies Rheumatoid drugs, muscle relaxants, anesthetics, non-steroidal anti-inflammatory drugs (NASAID), analgesics, anesthetics, sedatives, local anesthetics, muscle neurobes, microbicide, antispasmodic, steroid cortisol, synthesis Metabolic steroids, immunizing agents, immunoglobulins, immunosuppressants, growth hormones, hormone replacement drugs, radiotherapeutics, stimulants,/5 stimulants, inhaled steroids, adrenaline or its analogs, cytokines, or cells Hormone antagonists. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. This paper scale applies the Chinese National Standard (CNS) A4 specification (210x297 mm).