CN107619442A - One kind recombinates the anti-full human monoclonal antibody preparations of TNF α - Google Patents

Abstract

The invention discloses a kind of stabilization formulations for the new anti-full human monoclonal antibodies of TNF α of restructuring.The invention provides a kind of new anti-TNF Alpha antibodies, its light chain has SEQ ID NO：1 amino acid sequence, and heavy chain have SEQ ID NO：3 amino acid sequences.The present invention also bag aqueous medicament preparations, include the antibody for the treatment effective dose being present in buffer solution, and the pharmaceutical preparation enhances the stability of antibody pharmaceutical formulation.

Description

One kind restructuring full human monoclonal antibody preparation of anti-tnf-alpha

The application is Application No. " 201610554636X ", entitled " the full people source Dan Ke of one kind restructuring anti-tnf-alpha The divisional application of the patent application of grand antibody preparation ".

Technical field

The invention belongs to biological technical field, more specifically, the invention discloses the full people source Dan Ke of one kind restructuring anti-tnf-alpha The pharmaceutical formulation of grand antibody.

Background technology

TNF (TNF-α) is the cell factor as caused by polytype cell, including monocyte and huge Phagocyte, be initially according to they induce that the ability of some murine tumor necrosis identifies (referring to Old, L. (1985) Science 230:630-632).Then, it was confirmed that the factor for being referred to as malignant disease albumen with malignant disease qualitative correlation is and TNF-α identical is divided Son.Have proven to that TNF-α is related to mediating shock, it is related to the Pathological Physiology of various other human diseases and imbalance, including Pyemia, infection, autoimmune disease, graft rejection and graft versus host disease(GVH disease) etc..

TNF-α is a kind of important inflammatory cytokine, in normal immunologic function and causes the cascade of inflammatory process anti- Played an important role in answering.In Patients With Rheumatoid Arthritis knuckle synovia, TNF-α and other inflammatory factor great expressions. TNF-α is as the key inflammatory factor, the effect in inflammatory process cascade reaction and the possible mechanism in rheumatoid arthritis Including：(1) IL-1, IL-6, IL-8, the synthesis of other inflammatory factors such as TGF, GM-CSF are induced；(2) stimulate prostaglandin E2 and The generation of the inflammatory mediators such as leukotriene B4；(3) by raising E-Selectin, vascular cell adhesion molecule and intercellular adhesion molecule Activated leukocyte cell simultaneously assists it to be oozed out to inflammation part；(4) neutrophil leucocyte and fibroblast is stimulated to produce clostridiopetidase A and base Matter metalloproteinases.In addition, TNF-α also can induce Apoptosis and produce Acute-phase protein.Therefore block TNF-α generation and Effect, compared with blocking other cell factors (such as IL-1), more can fully and effectively suppress the development of rheumatoid arthritis.

TNF-α inhibitor is the current treatment maximally effective treatment means of rheumatoid arthritis, rapid-action, curative for effect, especially It is anti-tnf-alpha monoclonal antibody.But what is initially prepared is mouse source anti-tnf-alpha monoclonal antibody, neutralized for rheumatoid arthritis The treatment of TNF-α.But research finds that mouse source monoclonal antibody has many defects as medicine, and mouse source monoclonal antibody, which is used for human body, to be had by force Strong immunogenicity, eliminate soon in vivo, half-life short, cause clinical efficacy limited, side effect is big.Humanization monoclonal antibody technology segment The defects of overcoming anti-tnf-alpha mouse source monoclonal antibody.Wherein the full people source anti-tnf-alpha monoclonal antibody of people mouse (Infliximab,) profit Prepared with genetic engineering upstream constructing technology, its variable region is still derived from mouse source TNF-α monoclonal antibody, remains and tumor necrosis factor The specificity and affinity (Ka=1010M-1) that sub- soluble fragments and transmembrane region combine, constant region are the constant region of human IgG1 Substituted, Half-life in vivo greatly prolongs.

Infliximab is a kind of people's mouse resistant chimeric monoclonal antibody of specific inhibition TNF-α, its by with it is solvable and The combination of cross-film form TNF-α high-affinity, the biological activity of TNF-α is neutralized, block TNF-α and the combination of its acceptor.Together When Infliximab expression TNF-α is further killed by the CDCC of antibody-dependant and the CDCC of Complement Dependent Cell.But Infliximab does not neutralize the cytokine TNF β (also known as lymphotoxin) that same receptor is shared with TNF-α Effect.

It is Infliximab trade name, its product is sterile, the white, freeze-dried powder of venoclysis, often Bottle contains 100 milligrams of Infliximab, 500 milligrams of sucrose, 0.5 milligram of polyoxyethylene sorbitan monoleate, 2.2 milligrams of sodium dihydrogen phosphate and phosphoric acid 6.1 milligrams of disodium hydrogen, without preservative.Dissolved using preceding with 10 milliliters of USP sterile water for injection, pH7.2, then use physiological saline Drip-feed after dilution.

Antibody, all it is complicated molecule as other protein therapeutic agents, and due in mammal particularly people Treatment effective dose in class, substantial amounts of antibody must not be generally used in pharmaceutical preparation.The liquid preparation of protein therapeutic agent Should retaining protein therapeutic agent full biological activity and protected protein matter therapeutic agent functional group in production and shelf life From degraded, the degradation pathway of protein can be related to chemical instability or physical instability.

Antibody pharmaceutical formulation should be pharmaceutical preparation steady in a long-term, containing safe and effective amount, by the special of antibody Structure and property determine that antibody class medicine is required to the environment stabilized it in preparation, preservation, transportation.For not Congener protein, different types of antibody, its physicochemical property and degradation reaction etc. are all different, therefore, antibody class medicine system The Formulation Buffer composite formula of agent is also not quite similar.

In order to solve the stability problem of antibody drug, it is set to transport and still ensure that validity in storage, very Multispecific antibody class pharmaceutical preparation is to supply patient in the form of powder-injection to use.But powder-injection need to use when in use it is sterile Water for injection or the liquid preparation for being used in lytic antibody by preparing, unnecessary fiber crops can be brought to patient by so using It is tired.

It is a kind of preferred embodiment of mab treatment chronic disease by subcutaneous (SC) injection at present, by antibody Medicine preparation greatly facilitates patient to carry and use into the liquid preparation of preliminary filling pin type.But the content of preparation of traditional Chinese medicine, The factors such as the physical property of medicine, chemical property can all influence the validity of preparation, it is necessary to which suitable buffer system ensures medicine While thing curative properties, the stability of high concentration antibody preparation is improved.Different preparaton strategies has been had attempted to reduce The viscosity of high-concentration monoclonal antibody liquid solution, prepared with salt, amino acid or sugar.Sugar and polyalcohol belong to non-specific Property protein stabilizing agent, wherein sucrose, trehalose, glycerine, mannitol, sorbierite etc. are the most commonly used.

Commercially available TNF-α antibody preparation Humira, its pharmaceutical formulation are：Antibody 50mg/ml, sodium chloride 6.16mg/ml, phosphorus Acid dihydride sodium dihydrate 0.86mg/ml, disodium phosphate dihydrate 1.53mg/ml, sodium citrate 0.3mg/ml, citric acid Monohydrate 1.3mg/ml, Tween80 1mg/ml, mannitol 12mg/ml, pH 5.2.

The content of the invention

In order to solve the above problems, anti-TNF-α antibody pharmaceutical preparation stable, that immunogenicity is low is obtained, the present invention carries A kind of new anti-TNF-α antibody is supplied, its light chain has SEQ ID NO：1 amino acid sequence, and heavy chain have SEQ ID NO：3 amino acid sequences.The invention also discloses a kind of for the new full human monoclonal antibody of restructuring anti-tnf-alpha Stabilization formulations.

The present invention also bag aqueous medicament preparations, include the antibody for the treatment effective dose being present in buffer solution, form The preparation that pH is about 4-8, and the shelf-life in a liquid state be at least 24 months.

Stabilization formulations provided by the invention, in one embodiment, the pharmaceutical preparation have the stability enhanced, In another embodiment pass through freezing and thawing test after be it is stable, in other embodiments by high temperature, vibration, It is stable after illumination and long term test.Contain anti-TNF-α antibody in the preparation of stabilization of the present invention, wherein institute The anti-TNF-α antibody stated is CMAB815.

The invention discloses：

One kind restructuring full human monoclonal antibody preparation of anti-tnf-alpha, it is characterised in that liquid pharmaceutical formulation, including exist The antibody for the treatment of effective dose in buffer solution, the pH of said preparation are about 4-8, at least 24 months shelf-life.

A kind of restructuring full human monoclonal antibody preparation of anti-tnf-alpha as described above, it is characterised in that the antibody concentration is about For 1-100mg/ml.

A kind of restructuring full human monoclonal antibody preparation of anti-tnf-alpha as described above, it is characterised in that the antibody concentration is about For 50mg/ml.

A kind of restructuring full human monoclonal antibody preparation of anti-tnf-alpha as described above, it is characterised in that the antibody is CMAB815, light chain have SEQ ID NO：1 nucleotide sequence, and heavy chain have SEQ ID NO：3 nucleotides sequences Row.

A kind of restructuring full human monoclonal antibody preparation of anti-tnf-alpha as described above, it is characterised in that including 1-100mg/ml CMAB815；0.1-10mg/ml polyoxyethylene sorbitan monoleates；5-20mg/ml mannitols；With contain citrate and/or phosphatic Buffer system, pH 4-8.

A kind of restructuring full human monoclonal antibody preparation of anti-tnf-alpha as described above, it is characterised in that the buffer solution pH4.9-5.5。

A kind of restructuring full human monoclonal antibody preparation of anti-tnf-alpha as described above, it is characterised in that pH of buffer 5.2 is wrapped Include 50mg/ml CMAB815；1.0mg/ml polyoxyethylene sorbitan monoleate；12.0mg/ml mannitols；6.16mg/ml sodium chloride； 1.19mg/ml anhydrous citric acid；0.3mg/ml citric acid dihydrates；0.86mg/ml sodium dihydrogen phosphate dihydrates； 1.53mg/ml disodium phosphate dihydrate.

A kind of purposes for recombinating the full human monoclonal antibody preparation of anti-tnf-alpha as described above, it is characterised in that for preparing Treatment wherein TNF-α activity is the medicine of harmful illness.

A kind of purposes for recombinating the full human monoclonal antibody preparation of anti-tnf-alpha as described above, it is characterised in that prepare rheumatoid The medicines such as property arthritis, ankylosing spondylitis, psoriasis arthropathica, plaque psoriasis.

The present invention is studied the preparation of CMAB815 antibody, described in a preferred embodiment of the present invention scheme Liquid pharmaceutical formulation includes：CMAB815 including 50mg/ml；1.0mg/ml polyoxyethylene sorbitan monoleate；12.0mg/ml mannitols； 6.16mg/ml sodium chloride；1.19mg/ml anhydrous citric acid；0.3mg/ml citric acid dihydrates；0.86mg/ml biphosphates Sodium dihydrate；1.53mg/ml disodium phosphate dihydrates, pH 5.2.

Brief description of the drawings

Fig. 1, CMAB815 preparation heat endurance routine collection of illustrative plates

Fig. 2, CMAB815 preparation heat endurance derive collection of illustrative plates

PH change collection of illustrative plates in Fig. 3, vibration, high temperature, illumination, strong destruction experiment

Protein content change collection of illustrative plates in Fig. 4, vibration, high temperature, illumination, strong destruction experiment

Protein reduction electrophoresis purity change collection of illustrative plates in Fig. 5, vibration, high temperature, illumination, strong destruction experiment

Macromolecule impurity change collection of illustrative plates in Fig. 6, vibration, high temperature, illumination, strong destruction experiment

Electric charge heteroplasmon change collection of illustrative plates in Fig. 7, vibration, high temperature, illumination, strong destruction experiment

Proteins biological activity change collection of illustrative plates in Fig. 8, vibration, high temperature, illumination, strong destruction experiment

Protein content changes collection of illustrative plates in Fig. 9, freezing-thawing test

Protein reduction electrophoresis purity change collection of illustrative plates in Figure 10, freezing-thawing test

HMW impurity changes collection of illustrative plates in Figure 11, freezing-thawing test

Proteins biological activity changes collection of illustrative plates in Figure 12, freezing-thawing test

Figure 13, different batches long-term stable experiment protein content detection collection of illustrative plates

Figure 14, different batches long-term stable experiment bioactivity detection collection of illustrative plates

Figure 15, different batches long-term stable experiment reduction electrophoresis purity detection collection of illustrative plates

Figure 16, different batches long-term stable experiment SEC-HPLC/UPLC HMW defects inspecting collection of illustrative plates

Figure 17, different batches long-term stable experiment electric charge heteroplasmon distribution detection collection of illustrative plates.

Embodiment

The preparation of embodiment 1, the full human monoclonal antibody CMAB815 of restructuring anti-tnf-alpha

The artificial synthesized restructuring full human monoclonal antibody CMAB815 nucleotide sequences of anti-tnf-alpha, its nucleotide sequence is passed through It is attached after crossing digestion with plasmid pcDNA3.1 (+) (Invitrogen companies), structure helps people's endogenous light chain, heavy chain eucaryon table Up to carrier, SEQ ID NO:1 and SEQ ID NO:3 respectively illustrate full human monoclonal antibody CMAB815 heavy chain nucleotide Sequence；SEQ ID NO:2 and SEQ ID NO:4 respectively illustrate full human monoclonal antibody CMAB815 amino acid sequence.In 3 × 10 are inoculated with 3.5cm tissue culture dishes⁵CHO-K1 cells (ATCC CRL-9618), cell culture to 90%-95% are merged Shi Jinhang is transfected.

Obtained high-expression clone serum free medium expansion culture will be screened：For free serum culture by comparing repeatedly Compared with optimization, the culture medium (CHOM-B08) and benefit suitable for the full human monoclonal antibody CMAB815 of restructuring anti-tnf-alpha is finally determined Culture medium (CHOM-S08) is filled, engineering cell expression quantity in optimized culture medium is more than 30pg/cell.day, utilizes Fed- Batch training modes, in the culture supernatant of 2 weeks cultivation cycles harvest, the yield of purpose antibody can be in more than 3g/L.

Full human monoclonal antibody CMAB815 is isolated and purified with Protein A affinity columns (GE Products).

The CMAB815 obtained using above-mentioned preparation method has the sugar-type different from existing procucts.

The preparation of embodiment 2, preparation

According to the preparation method of the CMAB815 described in embodiment 1, CMAB815 antibody is obtained.In CMAB815 purifying In step, using molecular exclusion chromatography, CMAB815 antibody purifications are dissolved in containing 1.0mg/ml polyoxyethylene sorbitan monoleates；0mg/ml Or 12.0mg/ml mannitols；6.16mg/ml sodium chloride；1.19mg/ml anhydrous citric acid；0.3mg/ml citric acids two are hydrated Thing；0.86mg/ml sodium dihydrogen phosphate dihydrates；In the buffer solution of 1.53mg/ml disodium phosphate dihydrates.

After obtaining above-mentioned CMAB815 antibody-solutions, the sucrose of various concentrations is added in said preparation solution, is grouped, is carried out Stability test detects.Packet situation such as table 1.

Table 1, the packet of different formulations buffer solution

Test example 1, heat stabilization test analysis

Take the buffer solution of different pharmaceutical formulations to carry out heat stabilization test, released using Life Technologies Protein Thermal Shift Dye Kit (4461146) reagents and software, real-time quantitative PCR are steady to analyze the heat of antibody It is qualitative.Choose more excellent pharmaceutical formulation.

Heat stabilization test is carried out according to test procedure described in kit：

1), test specimen is mixed with Protein Thermal Shift dyestuffs

2), run solubility curve on real-time PCR to test, unfolding when albumen is heated, dyestuff is hydrophobic with exposure Region combines and sends fluorescence.

3), analyzed using Protein Thermal Shift softwares, obtain thermal stability analysis result, see Fig. 1, Fig. 2 and table 2.

Table 2, the result of the test of different formulations buffer solution are as follows：

Extreme difference wherein between 70.91 DEG C of maximum temperature, 70.32 DEG C of minimum temperature is 0.59 DEG C, and not up to kit provides 1 DEG C of significant difference index；

Therefore above-mentioned all formulas are investigated without significant difference from TmB angle.

Comprehensive various result of the tests, from pH 5.2, sucrose 20.0g/L, polysorbate 1.0g/L, sodium chloride 6.16g/L, Anhydrous citric acid 1.19g/L, Trisodium citrate dihydrate 0.3g/L, sodium dihydrogen phosphate dihydrate 0.86g/L, disodium hydrogen phosphate Dihydrate 1.53g/L pharmaceutical formulation.

Test example 2, stability test

Choose from pH 5.2, sucrose 20.0g/L, polysorbate 1.0g/L, sodium chloride 6.16g/L, anhydrous citric acid 1.19g/L, Trisodium citrate dihydrate 0.3g/L, sodium dihydrogen phosphate dihydrate 0.86g/L, disodium phosphate dihydrate 1.53g/L pharmaceutical formulation, shaking test, hot test, exposure experiments to light, freezing-thawing test, strong destruction experiment are carried out, further Verify preparation stability.Experimental design is shown in Table 3 and table 4.

Condition is tested and placed to the influence factor of table 3

The stoste influence factor experiment investigation time point of table 4 and investigation project

Result of study：

Strong destruction result of the test shows that the restructuring full human monoclonal antibody stoste of anti-TNF alpha is relatively wet in 40 DEG C and 60% Under the conditions of degree, HMW impurity shows a rising trend with standing time, and to the 10th day, HMW impurity exceeded stock solution quality mark Quasi- bound requirements (1.0%)；Electric charge heteroplasmon (K0+K1+K2) ratio is on a declining curve with standing time, observes the end of term, still accords with Close quality standard.

Shaking test result shows that the restructuring full human monoclonal antibody stoste of anti-TNF alpha is at 2~8 DEG C, under the conditions of 300rpm, HMW impurity slightly raises with standing time, but change is not notable, to the end of term is observed, still conforms to quality standard.

Hot test result shows that the restructuring full human monoclonal antibody stoste of anti-TNF alpha is in 25 DEG C and 60% relative humidity bar Under part, HMW impurity slightly raises with standing time, but change is not notable, to the end of term is observed, still conforms to quality standard.

Exposure experiments to light result is shown, recombinates the full human monoclonal antibody stoste of anti-TNF alpha under 2~8 DEG C, 4500Lx illumination, It is laterally located, HMW impurity shows a rising trend with standing time, and to the 3rd day, HMW impurity exceeded stock solution quality Standard limits require (1.0%), observe the end of term, and HMW impurity reaches 1.7%；Electric charge heteroplasmon (K0+K1+K2) ratio with Standing time is on a declining curve, and observation end of term ratio is 63.9%, beyond quality standard.

Freezing-thawing test result shows that the full human monoclonal antibody stoste of restructuring anti-TNF alpha undergoes -80 DEG C~25 DEG C and frozen repeatedly Melt, 10 circulations or -20 DEG C~25 DEG C multigelations, 10 circulations, every quality index is not observed and significantly affected.

Result above is prompted, and the restructuring full human monoclonal antibody stoste of anti-TNF alpha should be kept in dark place at low temperature, avoid shaking Swing.In technical process whenever necessary, freeze thawing can be carried out in limited scope, does not interfere with the quality of stoste.

Vibration, high temperature, illumination, strong destruction experiment in pH change collection of illustrative plates see Fig. 3, protein content change collection of illustrative plates see Fig. 4, Protein reduction electrophoresis purity change collection of illustrative plates is shown in that Fig. 5, macromolecule impurity change collection of illustrative plates are shown in that Fig. 6, electric charge heteroplasmon change collection of illustrative plates are shown in Fig. 7, proteins biological activity change collection of illustrative plates are shown in Fig. 8.Protein content change collection of illustrative plates is shown in Fig. 9, protein reduction in freezing-thawing test Electrophoresis purity change collection of illustrative plates is shown in that Figure 10, HMW impurity change collection of illustrative plates are shown in that Figure 11, proteins biological activity change collection of illustrative plates are shown in figure 12。

According to above-mentioned experimental result, preferably pH 5.2, sucrose 20.0g/L, polysorbate 1.0g/L, sodium chloride 6.16g/L, Anhydrous citric acid 1.19g/L, Trisodium citrate dihydrate 0.3g/L, sodium dihydrogen phosphate dihydrate 0.86g/L, disodium hydrogen phosphate Dihydrate 1.53g/L pharmaceutical formulation.

Test example 3, long-term stable experiment

Choose from pH 5.2, sucrose 20.0g/L, polysorbate 1.0g/L, sodium chloride 6.16g/L, anhydrous citric acid 1.19g/L, Trisodium citrate dihydrate 0.3g/L, sodium dihydrogen phosphate dihydrate 0.86g/L, disodium phosphate dihydrate 1.53g/L pharmaceutical formulation, carry out the long-term stable experiment of pharmaceutical formulation.

Above-mentioned antibody pharmaceutical formulation is positioned over less than -18 DEG C, takes 1402 batches, 1403 batches, the antibody drug of 1404 batches Preparation, sample is periodically taken to carry out study on the stability index determining.The time and project that wherein long term test is investigated are shown in Table 5.

Table 5, long term test investigate time point and project

1402 batches, 1403 batches, the antibody pharmaceutical formulation of 1404 batches are taken, carries out Journal of Sex Research steady in a long-term, 1402 batches of medicines The long-term stable experiment that the long-term stable experiment of preparation the results are shown in Table 6,1403 batches of pharmaceutical preparations the results are shown in Table 7,1404 batches The long-term stable experiment of pharmaceutical preparation the results are shown in Table 8.

6,1402 batches of long-term test results of table

7,1403 batches of long-term test results of table

8,1404 batches of long-term test results of table

Long-term stable experiment result shows that the restructuring full human monoclonal antibody stoste of anti-TNF alpha is placed in less than -18 DEG C, Analysis result shows that protein content, bioactivity, reduction electrophoresis purity, SEC-HPLC/UPLC HMWs impurity, electric charge are different Significant changes do not occur for every quality index such as plastid distribution.Protein content result of the test collection of illustrative plates is shown in Figure 13, bioactivity examination Test result and see that Figure 14, reduction electrophoresis purity result of the test are shown in that Figure 15, SEC-HPLC/UPLC HMW impurity result of the test are shown in figure 16th, electric charge heteroplasmon distribution result of the test is shown in Figure 17.

Result above is prompted, and the restructuring full human monoclonal antibody stoste of anti-TNF alpha is stored in less than -18 DEG C, certain time In the range of do not interfere with the quality of stoste.

Stoste long-term stable experiment will continue observation to 36 months.

SEQUENCE LISTING

<110>Taizhou Mai Botaike pharmaceutcal corporation, Ltds

<120>One kind restructuring full human monoclonal antibody preparation of anti-tnf-alpha

<130> 2016

<160> 4

<170> PatentIn version 3.5

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Claims (9)

1. one kind restructuring full human monoclonal antibody preparation of anti-tnf-alpha, it is characterised in that liquid pharmaceutical formulation, including be present in The antibody for the treatment of effective dose in buffer solution, the pH of said preparation are about 4-8, at least 24 months shelf-life.

2. a kind of restructuring full human monoclonal antibody preparation of anti-tnf-alpha according to claim 1, it is characterised in that described anti- Bulk concentration is about 1-100mg/ml.

3. a kind of restructuring full human monoclonal antibody preparation of anti-tnf-alpha according to claim 1, it is characterised in that described anti- Bulk concentration is about 50mg/ml.

4. a kind of restructuring full human monoclonal antibody preparation of anti-tnf-alpha according to claim 1, it is characterised in that described anti- Body is CMAB815, and light chain has SEQ ID NO：1 nucleotide sequence, and heavy chain have SEQ ID NO：3 nucleosides Acid sequence.

A kind of 5. restructuring full human monoclonal antibody preparation of anti-tnf-alpha according to claim 1, it is characterised in that including

a）1-100mg/ml CMAB815,

b）0.1-10mg/ml polyoxyethylene sorbitan monoleates,

c）5-20mg/ml mannitols, and

Contain citrate and/or phosphatic buffer system, pH 4-8.

6. a kind of restructuring full human monoclonal antibody preparation of anti-tnf-alpha according to claim 5, it is characterised in that described slow Fliud flushing pH4.9-5.5.

7. according to claim 5, a kind of 6 restructuring full human monoclonal antibody preparations of anti-tnf-alpha, it is characterised in that buffering Liquid pH5.2, including

a）50mg/ml CMAB815,

b）1.0mg/ml polyoxyethylene sorbitan monoleates,

c）12.0mg/ml mannitol,

d）6.16mg/ml sodium chloride,

e）1.19mg/ml anhydrous citric acid,

f）0.3mg/ml citric acid dihydrates,

g）0.86mg/ml sodium dihydrogen phosphate dihydrates,

h）1.53mg/ml disodium phosphate dihydrate.

8. a kind of 1 purposes for recombinating the full human monoclonal antibody preparation of anti-tnf-alpha is required according to power, it is characterised in that use The medicine that wherein TNF-α activity is harmful illness is treated in preparing.

A kind of 9. purposes for recombinating the full human monoclonal antibody preparation of anti-tnf-alpha according to claim 9, it is characterised in that Prepare the medicines such as rheumatoid arthritis, ankylosing spondylitis, psoriasis arthropathica, plaque psoriasis.