CN101525385A - Screening and preparation method and application for antibody medicament for malignant lymphoma and autoimmune diseases - Google Patents
Screening and preparation method and application for antibody medicament for malignant lymphoma and autoimmune diseases Download PDFInfo
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Abstract
The invention relates to screening and a preparation method and application for an antibody medicament for malignant lymphoma and autoimmune diseases, and discloses a lymphoma specificity humanized antibody for resisting HLA-DR10, a person and whole person monoclonal antibodies and segments thereof, and a radioactive isotope labeling antibody thereof including a heavy chain and a light chain, wherein the heavy chain contains a constant region, a heavy chain variable region amino acid sequence is SEQID NO:1, the light chain contains a constant region, a light chain variable region amino acid sequence is SEQID NO:2, and the heavy chain is connected with the light chain through a disulfide bond. The invention obtains NSO and CHO engineering cell strains of stable high-level expression lymphoma specificity humanized, person and the whole person monoclonal antibodies (chlym-1 antibody) for resisting the HLA-DR10, adopts a serum-free high density culture technique so that the expression of the chlym-1 is more than 500 milligrams per liter, and discloses application of the monoclonal antibodies in treating the malignant lymphoma and the autoimmune diseases.
Description
Technical field
The present invention relates to the screening preparation and the application of monoclonal antibody drug.
Background technology
Malignant lymphoma (ML) is to come from lymphoglandula and the adenoid malignant tumour of outside lymph node, and why ML can divide outstanding golden lymphomas (HD) and non_hodgkin lymphoma (NHL) two big classes.In China, in the malignant lymphoma new cases, NHL patient accounts for 85～90%.In NHL, prognosis low potential malignancy lymphoma preferably is lower at the sickness rate of China, accounts for 5% of NHL; And the relatively poor high-grade malignant lymphoma sickness rate of prognosis is higher, accounts for about 30% of NHL.As time goes on and The development in society and economy investigation shows,, malignant lymphoma presents the trend of growth, and wherein HD is relatively stable, and the M ﹠ M of NHL is all rising.The cause and onset of disease mechanism of non_hodgkin lymphoma is not determined as yet, is thought relevant with sex, age, immunologic function disappearance, bacterium or multiple factor such as virus infection, environment at present.
The method for the treatment of NHL clinically has chemotherapy, radiotherapy, operative treatment, bone marrow transplantation etc.At present to the treatment of NHL based on chemotherapy, but the short-term side-effects of chemotherapy is clearly, and to recurrence patient effect uncertainly, general chemotherapy scheme for combining poor effect; The problem that radiotherapy exists is that range of application is less, and operation only plays diagnostic effect to NHL, and very easily recurrence need be in conjunction with chemotherapy; Then reason is difficult to carry out marrow transplant techniques may owing to joining type difficulty, rejection, cost an arm and a leg etc.
Along with the development of cytobiology, molecular biology and biotechnology, immunotherapy becomes one of main method of cancer therapy gradually in recent years.It directly or indirectly utilizes immunocyte in the human immune system and antibody to resist cancer or reduces because of cancer or its and treat caused side effect, and the monoclonal antibodies medicine of tumour-specific is the dominant direction of present immunotherapy.
If at present in the world research in order to the monoclonal antibody class drug main target of treatment NHL in the antigen of lymphocytic cell surface, have at several antigenic antibody products such as CD20, CD22, CD52, CD19, CD30 and HLA-DR in the result of study of having delivered.
Can act on normally and produce on a plurality of sites on the HLA-DR antigen β chain on malignant B surface the cell toxic action of antibody dependent by the humanization IgG1 monoclonal antibody Apolizumab (MoAb Hu1D10) of National Cancer Insititute development, in I clinical trial phase at recurrent or diffuse type CLL or ALL, after being arranged, 11% patient reaches PR, 67% patient is SD, and 22% patient is PD.1-2 degree infusion reaction (58% weak, 50% feel sick, 50% hyperglycemia, 42% heating, 42% rubella and 33% headache) has appearred in all patients.This medicine now is in II clinical trial phase conceptual phase.
By the mouse source type monoclonal antibody Lym-1 (Oncolym) of Peregrine Pharmaceuticals company development be a kind of can the antigenic mouse of specific recognition HLA-DR10 source property IgG2a monoclonal antibody, this antigen all has expression at 80% malignant lymphoma B cell surface.The binding ability of it and lymphoma cell apparently higher than with the binding ability of normal bone-marrow-derived lymphocyte.Confirm that in to the radioactivity video picture of 125I-Lym-1 research Lym-1 has the selective binding of height to known lymphoma tissue position, and at normal tissue in conjunction with less.
Lym-1 is carried out in the I clinical trial phase, have 3 examples occur to alleviate among the 10 routine patients.IgM HAMA reaction all is negative.Main toxic reaction shows as: have 8 routine patients to occur in injection during near terminal point or the heating of injection after finishing, wherein the high fever of 4 examples remains on below 38 ℃, in addition the high fever of 4 examples remains between 38～40 ℃, and this heating is easy to medication control, and only continues 2～4 hours usually; There are 4 routine patients rubella after injection, to occur; In research process, do not find heart, liver kidney or lung's toxic reaction; And aspect the hematology index, significantly do not change yet; The peripheral blood lymphocyte of most patient does not reduce, and the level of immunoglobulin (Ig) also finds no obvious change.
Radioimmunotherapy (Radioimmunotherapy, RIT) then be the treatment means that a kind of immunotherapy and radiotherapy combine, it be with can with tumour antigen bonded material as targeting vector, the coupling radionuclide as the anti-tumor medicine of " bullet " (therapeutical agent) inject in the body with tumor by local due to the tumour cell correlation antigen specific combines than other healthy tissues dosage height, reach tumor-killing and a kind of methods of treatment little to normal tissue injury exempted from the monoclonal antibody that targeting vector the most frequently used in the therapy is the tumour cell related antigen and put.
At present the monoclonal antibody class radioimmunity medicine of getting permission the treatment tumour of list marketing in the U.S. mainly contains: Zevalin and Bexxar, infusion reaction and bone marrow toxicity are its main toxic side effecties.3 degree or 4 degree oligoleukocythemia and thrombopenia are comparatively common, and often betide treatment back 5-7 week, and recover after week at 2-4.The patient that about 5-7% accepts Zevalin and Bexxar treatment needs hospital care because of infection.Myelodysplastic syndrome and acute leukemia can appear in the patient that small part is accepted Zevalin and Bexxar treatment, but these patients had often before accepted the alkylating agent treatment.Research finds that also serious more if patient's marrow is invaded by lymphoma, then more radio isotope is assembled marrow, thereby bigger to the damage of normal bone marrow.Therefore, before using Zevalin or Bexxar treatment, must careful evaluate patient marrow situation.Lymphoma marrow is invaded above 25% or is found that the bad person of marrow function should not accept Zevalin or Bexxar treatment.
Mouse source type monoclonal antibody Lym-1 (Oncolym) by the development of U.S. Peregrine Pharmaceuticals company both can guide radionuclide to be targeted to tumor by local kill tumor cell, also had ADCC, CDC and induced the apoptotic effect killing tumor cell of Raji.Lym-1 is through radionuclide
131Form behind the I mark
131I-Lym-1 with can guide radionuclide 131I to be targeted to tumor by local kill tumor cell after the HLA-DR10 antigen of most of Malignant B cell surfaces combines.
Chinese patent ZL200410053872.0 discloses the variable region gene of Lym-1 and human IgG1's γ 1 and κ constant region gene fusion, the chimeric monoclonal antibody of people mouse (chLym-1) of a reduced immunogenicity that obtains wherein humanized's sequence is 65%, and mouse source property sequence accounts for 35%.Studies show that chLym-1 has the avidity similar with Lym-1, and the hold-up of chLym-1 on tumour is close to Lym-1 in the 24-72 after picked-up hour identical.In addition, chLym-1 has the ability of inducing ADCC, CDC effect and inducing the next direct kill tumor cell of lymphoma cell apoptosis effect equally.It induces the level of ADCC effect is the twice of mouse source type Lym-1, even and if also can induce maximum ADCC effect under the condition of lower antibody concentration.Therefore the people mouse resistant chimeric monoclonal antibody chLym-1 of a new generation with respect to mouse source type Lym-1 have expression rate height, stable performance, tumor uptake rate height, healthy tissues uptake ratio low, can increase effector functions, be difficult for that HAMA reacts and advantage such as reduction immunogenicity and self killing tumor cell ability be outstanding, optimized to put and exempted from result of treatment.But the present research of this medicine only limits to the application in the oncotherapy, is still waiting exploitation and expands for the application of other disease.
Rheumatosis comprises because the autoimmune disorder of many organs that immunologic derangement causes and osteoarthropathy two big class diseases etc. more than 100 are planted sick the kind.Its sickness rate height, the World Health Organization in 1999 classifies rheumatosis and cardiovascular disorder and cancer as threaten human health three big killers.Nearly 3.55 hundred million people in the whole world suffer from various rheumatosis at present.In China, rheumatoid arthritis (RA), ankylosing spondylitis (AS), sjogren syndrome (SS) morbidity are respectively up to 0.3%～0.5%, 0.2%～0.4% and 0.29%～0.77%.Rheumatosis is the morbidity height not only, and hazardness is big, and untreated RA patient 2-3 disability rate is 70%, and the disability rate of AS is also up to 37%.In China, 2000 so far the medication total charge in rheumatisant every year surpassed 20,000,000,000 yuan.For a long time, rheumatosis does not have specific treatment, and only biotechnological formulation has just obtained immense success over past ten years in rheumatism treatment is used, and this class drug main will comprise anti-TNF-alpha monoclonal antibodies and similar biological product.Existing some in the world at present monoclonal antibody listings, its curative effect is outstanding, side effect is little, and a few years has promptly been established its market position.But big because of its dosage, manufacturing process is complicated, make its price high, and injection interval is shorter, brings a lot of inconvenience to patient.Therefore, how to reduce the manufacturing cost of monoclonal antibody medicine, further improve its curative effect, prolongation medication cycle, become the task of top priority of international biological medicine circle.The present invention has further studied its application on autoimmune disease according to the mechanism of action of development monoclonal antibody.
Summary of the invention
The present invention improves it on the basis of existing chLym-1, has not only optimized its preparation method, has also further expanded its application simultaneously.
One aspect of the present invention discloses the lymphoma-specific humanized antibody of a kind of anti-HLA-DR10, the lymphoma-specific humanized antibody of above-mentioned anti-HLA-DR10 comprises heavy chain and light chain, wherein, heavy chain contains constant region, the weight chain variable region amino acid sequence is SEQ ID NO:1, light chain contains constant region, and the light chain variable region amino acid sequence is SEQ ID NO:2, and heavy chain and light chain link to each other by disulfide linkage.Preferable, above-mentioned radio isotope is selected from
131I,
188Re,
90Y or
67Cu, preferred
131I.
In a preference, described heavy chain of antibody constant region is the γ type; And antibody light chain constant region is the κ type.
In another preference, described antibody is to be produced by NSO or CHO engineering cell strain.
Second aspect present invention discloses the preparation method of the lymphoma-specific humanized antibody of above-mentioned anti-HLA-DR10, comprises the following steps:
Under the condition of expressing described antibody, cultivate above-mentioned host cell, thereby give expression to described antibody; With separate described antibody.
In the culturing process, in order to improve the expression amount of monoclonal antibody, the present invention is again further from determining to be fit to substratum and other nutritive ingredient of scale operation demand, determine the additional way of nutritive ingredient, determine suitable culture cycle, determine aspects such as process control parameters such as dissolved oxygen, pH, optimized its expression process condition.Adopt serum-free high-density culture technology, make the expression amount of product chlym-1 greater than 500mg/L.
Third aspect present invention discloses a kind of antibody of labelled with radioisotope, for the lymphoma-specific humanized antibody of aforementioned anti-HLA-DR10 obtains through labelled with radioisotope.
Fourth aspect present invention, the lymphoma-specific humanized antibody that discloses above-mentioned anti-HLA-DR10 are used to prepare the medicine for the treatment of malignant lymphoma or are used to prepare the reagent of diagnosing malignant lymphoma.Be particularly useful for preparation treatment Fei Hejiejinshi B cell lymphoma.
Fifth aspect present invention, the lymphoma-specific humanized antibody that discloses above-mentioned anti-HLA-DR10 is used to prepare the medicine for the treatment of autoimmune disorder.Above-mentioned autoimmune disorder comprises rheumatoid arthritis etc.
Sixth aspect present invention provides a kind of pharmaceutical composition, comprises the lymphoma-specific humanized antibody of the anti-HLA-DR10 of the present invention of safe and effective amount, and pharmaceutically acceptable carrier or vehicle or thinner.This class carrier comprises (but being not limited to): salt solution, damping fluid, glucose, water, glycerine, ethanol and combination thereof.Pharmaceutical preparation should be complementary with administering mode.Pharmaceutical composition of the present invention can be made into the injection form, for example is prepared by ordinary method with the physiological saline or the aqueous solution that contains glucose and other assistant agents.Pharmaceutical composition such as tablet and capsule can be prepared by ordinary method.Pharmaceutical composition such as injection, solution, tablet and capsule should be made under aseptic condition.The dosage of activeconstituents is the treatment significant quantity.For example every day about 1 microgram/kg body weight one about 10 mg/kg body weight.In addition, polypeptide of the present invention also can use with the other treatment agent.
The present invention has obtained the NSO engineering cell strain of the lymphoma-specific humanized antibody (chlym-1 monoclonal antibody) of the anti-HLA-DR10 of stable high expression level, serum-free high-density culture technology, make the chlym-1 expression amount greater than 500mg/L, finish radio-labeling smoothly to this antibody, and radiolabeled antibody has been carried out it is used as targeted drug the clinical application research of malignant lymphoma and autoimmune disorder, radiolabeled antibody of the present invention, target is good, good effect, part has been eliminated the immune response that human antimouse antibody produces, reduced the HAMA positive reaction, safe and effective, can repeatedly use, can not be widely used in clinical problem thereby solved radioimmunotherapy, and improve T/NT ratio.
Embodiment
Further set forth the present invention below in conjunction with embodiment.Should be understood that these embodiment only are used to illustrate the present invention, but not limit the scope of the invention.
The preparation of the lymphoma-specific humanized antibody of embodiment 1 anti-HLA-DR10
(patent No.: the method for embodiment prepares the NSO engineering cell strain 200410053872.0) to adopt Chinese patent.Mainly comprise the following steps:
1. mouse source property lymphoma MONOCLONAL ANTIBODIES SPECIFIC FOR:
2. the specificity embedding of anti-HLA-DR10 and the preparation of monoclonal antibody comprise the preparation of variable region of heavy chain and variable region of light chain; Variable region gene and constant region gene Fusion; The foundation and the evaluation thereof of the strain of express cell seed cell.
3. after obtaining the NSO engineering cell strain, adopt following processing condition to prepare the lymphoma-specific humanized antibody of anti-HLA-DR10
Expression process condition: by determining to be fit to substratum and other nutritive ingredient of scale operation demand, determine the additional way of nutritive ingredient, determine suitable culture cycle, determine process control parameters such as dissolved oxygen, pH.Make expression amount greater than 500mg/L.
With the FineLINE post that sample on the acellular supernatant after filtering is filled to MabSelect, the concentration of last sample is 30mg/ml.Behind the wash-out, elutriant immediately with in the potassiumphosphate and the pH value to 6.8-7.0.Detect with gel-filtration, the result shows that purity is more than 95% again.
With product order-checking, the result is, the weight chain variable region amino acid sequence of antibody is SEQ ID NO:1, and the light chain variable region amino acid sequence is SEQ ID NO:2.
Embodiment 2
131The preparation of the lymphoma-specific humanized antibody of the anti-HLA-DR10 of I mark
Adopt chloramine-T iodate labelling method, will
131The I mark is to the lymphoma-specific humanized antibody of the anti-HLA-DR10 of embodiment 1 acquisition, and the specific radioactivity that makes product is 11mCi/mg.
Embodiment 3
131The lymphoma-specific humanized antibody affinity costant of the anti-HLA-DR10 of I mark is measured
(patent No.: the method for embodiment mensuration embodiment 2 obtains 200410053872.0) to adopt Chinese patent
131The lymphoma-specific humanized antibody of the anti-HLA-DR10 of I mark, the affinity costant Ka=3.40 of this monoclonal antibody * 10
8Mol
-1
Embodiment 4
131The pharmacodynamic study of the lymphoma-specific humanized antibody treatment tumour of the anti-HLA-DR10 of I mark
(patent No.: the method for embodiment 6 detects the drug action of the monoclonal antibody of embodiment 2 acquisitions to lotus human lymphoma nude mice animal model 200410053872.0) to adopt Chinese patent.
The result confirms that the anti-lotus lymphoma of the monoclonal antibody effect of adopting method of the present invention to obtain is definite, and for nude mice, the tumor control rate of the above dosage of 350uCi is greater than 30%.
Embodiment 5
131Human safety, tolerance, pharmacokinetic and the effectiveness study of the lymphoma-specific humanized antibody treatment tumour of the anti-HLA-DR10 of I mark
The human research comprises following content: (1) research iodine [
131I] the chimeric monoclonal antibody of malignant lymphoma (
131I-chLym-1) injection liquid is to the security and the tolerance of malignant lymphoma patient single intravenous applications; (2) carry out
131The human pharmacokinetics research of I-chLym-1 injection liquid; (3) observe
131The I-chLym-1 injection liquid is to malignant lymphoma patient's preliminary curative effect; (4) explore
131The safe dose of I-chLym-1 injection liquid is for its later stage research provides dosage regimen safely and effectively.
Test method: this experiment for multicenter, at random, open I clinical trial phase, have 2 centers and participate in test.This test amount to be drawn and to be included 28 routine Malignant B cell NHL patients in and accept the single-dose tolerance test, 14 routine Malignant B cell NHL patients accept pharmacokinetic, wherein 9 examples are carried out the single-dose pharmacokinetic, and 5 examples are carried out the successive administration pharmacokinetic.The tolerance test medication once; The single-dose pharmacokinetics is tested shared medicine 3 times, each 6 weeks at interval; Successive administration pharmacokinetics test medication twice, two weeks at interval.Select and the eliminating experimenter according to standard of formulating of including in and exclusion standard.This programme and experimenter's letter of consent thereof are implemented after SFDA and Ethics Committee (EC) approval.
The therapeutic evaluation index comprises the variation of improvement, focus size and the number of KPS scoring, sings and symptoms, index evaluation this product curative effects such as variation of tumor marker; The safety evaluation index comprises the incidence of adverse events and the WHO anticarcinogen is acute and there is the unusual incidence of clinical meaning in subacute toxicity reaction, health check-up, laboratory.To all demography data, number of times that comprises age, sex, neoplasm staging and accept chemotherapy and/or radiotherapy in the past etc. is analyzed and is summed up with descriptive statistics in this experiment.Method in accordance with regulations and program are calculated pharmacokinetic parameter, the data that obtain are carried out chi square test, and the F value is provided as far as possible.Lab test results will be used and describe the row statistical analysis, and give expression to its mean value and standard deviation.
Test-results shows,
131The lymphoma-specific humanized antibody of the anti-HLA-DR10 of I mark has certain curative effect to malignant lymphoma.
Embodiment 6
131The lymphoma-specific humanized antibody of the anti-HLA-DR10 of I mark is to arthritic therapeutic action
Animal experiment comprises following content: (1) research iodine [
131I] the chimeric monoclonal antibody of malignant lymphoma (
131I-chLym-1) injection liquid is to the arthritic therapeutic action of rat formaldehyde; (2) observe [
131I] the chimeric monoclonal antibody of malignant lymphoma (
131I-chLym-1) injection liquid is to the restraining effect of mouse writhing reaction; (3) observe
131The I-chLym-1 injection liquid is to the influence of mouse swimming time, serum urea nitrogen and blood lactic acid content, thus evaluation
131The I-chLym-1 injection liquid is for the therapeutic action of rheumatoid arthritis.
Experimental animal: Wistar rat, each 16 of male and female, body weight 180 ± 20g.
Test method: the Wistar rat is all adopted in every kind of test, is divided into 4 groups at random, (placebo, positive controls, small dose drug group, heavy dose of medicine group), half and half, 10/group of every group of male and female.Each test group subcutaneous injection administration 1 time, detect index of correlation after six days, comprise the paw swelling of formaldehyde mouse, the swimming time of turning round body number of times, mouse, serum urea nitrogen and the blood lactic acid content behind the injection acetic acid solution, and lab test results carried out statistical analysis, and calculate its mean value and standard deviation.
The result shows, compares with placebo,
131The lymphoma-specific humanized antibody medicine group of the anti-HLA-DR10 of I mark has certain mitigation to arthritic symptom.
Sequence table
＜110〉Suzhou Industrial Park Chenjian Antibody Drug Development Co., Ltd.
＜120〉screening of malignant lymphoma, autoimmune disorder antibody drug and its production and use
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100 105
Claims (10)
1. the lymphoma-specific humanized antibody of an anti-HLA-DR10, comprise heavy chain and light chain, wherein, heavy chain contains constant region, the weight chain variable region amino acid sequence is SEQ ID NO:1, light chain contains constant region, and the light chain variable region amino acid sequence is SEQID NO:2, and heavy chain and light chain link to each other by disulfide linkage.
2. the lymphoma-specific humanized antibody of anti-HLA-DR10 according to claim 1 is characterized in that the lymphoma-specific humanized antibody of described anti-HLA-DR10 is selected from the part humanization, perhaps people and total man's monoclonal antibody, or its fragment.
3. the preparation method of the lymphoma-specific humanized antibody of claim 1 or 2 described anti-HLA-DR10 comprises the following steps:
A) under the condition of expressing described antibody, cultivate host cell, thereby give expression to described antibody;
B) separate described antibody.
4. as the preparation method of the lymphoma-specific humanized antibody of anti-HLA-DR10 as described in the claim 3, it is characterized in that described host cell is NSO or CHO engineering cell strain.
5. as the preparation method of the lymphoma-specific humanized antibody of anti-HLA-DR10 as described in the claim 3, it is characterized in that step a adopts serum-free high-density culture technology, the expression amount of product chlym-1 is greater than 500mg/L.
6. the antibody of a labelled with radioisotope is for the lymphoma-specific humanized antibody of claim 1 or 2 described anti-HLA-DR10 obtains through labelled with radioisotope.
7. the lymphoma-specific humanized antibody of claim 1 or 2 described anti-HLA-DR10 is used to prepare the medicine for the treatment of malignant lymphoma or is used to prepare the reagent of diagnosing malignant lymphoma.
8. as the purposes of the lymphoma-specific humanized antibody of anti-HLA-DR10 as described in the claim 7, it is characterized in that described malignant lymphoma is the Fei Hejiejinshi B cell lymphoma.
9. the lymphoma-specific humanized antibody of claim 1 or 2 described anti-HLA-DR10 is used to prepare the medicine for the treatment of autoimmune disorder.
10. a pharmaceutical composition comprises the claim 1 of safe and effective amount or the lymphoma-specific humanized antibody of 2 described anti-HLA-DR10, and pharmaceutically acceptable carrier or vehicle or thinner.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103041387A (en) * | 2011-10-11 | 2013-04-17 | 苏州工业园区晨健抗体组药物开发有限公司 | New application of malignant B-cell lymphoma antibody medicament |
| CN108713027A (en) * | 2015-12-17 | 2018-10-26 | 詹森生物科技公司 | Specifically bind the antibody and application thereof of HLA-DR |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1737011A (en) * | 2004-08-20 | 2006-02-22 | 上海美恩生物技术有限公司 | Lymphoma specific chimeric monoclonal antibody against HLA-DR10 |
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2008
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1737011A (en) * | 2004-08-20 | 2006-02-22 | 上海美恩生物技术有限公司 | Lymphoma specific chimeric monoclonal antibody against HLA-DR10 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103041387A (en) * | 2011-10-11 | 2013-04-17 | 苏州工业园区晨健抗体组药物开发有限公司 | New application of malignant B-cell lymphoma antibody medicament |
| CN103041387B (en) * | 2011-10-11 | 2014-12-10 | 苏州工业园区晨健抗体组药物开发有限公司 | New application of malignant B-cell lymphoma antibody medicament |
| CN108713027A (en) * | 2015-12-17 | 2018-10-26 | 詹森生物科技公司 | Specifically bind the antibody and application thereof of HLA-DR |
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