CN109776684A - A kind of bispecific antibody - Google Patents

A kind of bispecific antibody Download PDF

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Publication number
CN109776684A
CN109776684A CN201910219509.8A CN201910219509A CN109776684A CN 109776684 A CN109776684 A CN 109776684A CN 201910219509 A CN201910219509 A CN 201910219509A CN 109776684 A CN109776684 A CN 109776684A
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CN
China
Prior art keywords
bispecific antibody
antigen
chain
binding site
amino acid
Prior art date
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Pending
Application number
CN201910219509.8A
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Chinese (zh)
Inventor
蔡毓旻
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Individual
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Individual
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Publication of CN109776684A publication Critical patent/CN109776684A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/241—Tumor Necrosis Factors
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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/55—Glands not provided for in groups A61K35/22 - A61K35/545, e.g. thyroids, parathyroids or pineal glands
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Abstract

The present invention provides a kind of bispecific antibody, specifically, the bispecific antibody is anti-TNF/IL23 bispecific antibody, the bispecific antibody is humanization lgG type antibody, the bispecific antibody includes the first antigen-binding site with tumor necrosis factor TNF-alpha specific binding, it further include the second antigen-binding site with interleukins IL-23 specific binding, wherein the bispecific antibody also includes the first Fc chain and the 2nd Fc chain connected by one or more disulfide bond interchains, first Fc chain and the 2nd Fc chain are connected respectively on the first antigen-binding site and the second antigen-binding site by covalent bond or connector.

Description

A kind of bispecific antibody
Technical field
The present invention relates to antibody art more particularly to a kind of bispecific antibodies.
Background technique
Monoclonal antibody is the high degree of specificity antibody for acting only on single epitope, has been widely used for many diseases Treatment, for example, cancer, inflammation and autoimmune disease, infectious diseases.But if such treatment molecule individually makes With, it can show that enough drug effects without one kind, this is because the complexity of disease, as cancer or diseases associated with inflammation usually relate to And the mutually fork effect between the molecular pathway and signal path of a variety of diseases mediations.In these cases, single point is targeted Son cannot provide optimal therapeutic effect, and block the molecule in multiple sites of multiple target spots or same target spot that can change simultaneously Kind therapeutic effect.Meanwhile can simplify new drug development process using double targeted therapies of polyspecific such as bispecific molecule, because It is single molecule for it.With use the drug combination of multiple single special moleculars to compare, be all more for patient and medical worker Easily.
Rheumatoid arthritis (RA) is a kind of unknown systemic disease chronic, based on inflammatory synovitis of cause of disease.Its It is characterized in hand, the multi-joint of sufficient Minor articulus, symmetry, aggressive arthritis, is often accompanied by organ outside joint and is involved serum Rheumatoid factor positive can cause joint deformity and function to be lost.The morbidity of RA may have with heredity, infection, sex hormone etc. It closes.The arthritic pathology of RA mainly has the new of synovial membrane stave cell hyperplasia, interstitial massive inflammatory cells infiltrated and capilary The raw, formation of pannus and cartilage and the destruction of bone tissue etc..
The main purpose for the treatment of rheumatoid arthritis is to mitigate arthritis reaction, inhibition pathological development and irreversible bone Matter is destroyed, as far as possible the function of Saving cortilage and muscle, is finally reached the target of state of an illness complete incidence graph.The present invention provides a kind of double Specific antibody, it is multiple to waist-leg arthralgia caused by rheumatoid, osteoproliferation, cervical vertebra pain, sciatica, leg joint pain Oedema is swollen, the therapeutic effect of extremity numbness is significant.
Summary of the invention
In order to solve the above technical problem, the present invention provides a kind of bispecific antibodies.
The present invention is realized with following technical solution:
A kind of bispecific antibody, the bispecific antibody are anti-TNF/IL23 bispecific antibody, described double special Property antibody be humanization lgG type antibody.
Further, the bispecific antibody includes the first antigen with tumor necrosis factor TNF-alpha specific binding Binding site further includes the second antigen-binding site with interleukins IL-23 specific binding, wherein described double special anti- Body also includes the first Fc chain and the 2nd Fc chain connected by one or more disulfide bond interchains, the first Fc chain and the 2nd Fc chain It is connected respectively on the first antigen-binding site and the second antigen-binding site by covalent bond or connector.
Further, the first Fc chain includes the replacement of 2 amino acid in following position, 356 on the first Fc chain And 379 amino acids replacement.
Further, the 2nd Fc chain includes the replacement of 3 amino acid in following position, 321 on the 2nd Fc chain, 407 and the replacement of 409 amino acids.
Further, it is more likely to form heterologous two mutually comprising the first Fc chain of the amino acid substitution and the 2nd Fc chain Aggressiveness and be not inclined to respectively formed homodimer.
Further, the first antigen-binding site chain variable region amino acid sequence is as shown in SEQ ID NO:1；Institute The first antigen-binding site chain constant region amino acid sequence is stated as shown in SEQ ID NO:2.
Further, the first antigen-binding site heavy chain variable amino acid sequence is as shown in SEQ ID NO:3；Institute The first antigen-binding site light chain constant region amino acid sequence is stated as shown in SEQ ID NO:4.
Further, the second antigen-binding site chain variable region amino acid sequence is as shown in SEQ ID NO:5；Institute The second antigen-binding site chain constant region amino acid sequence is stated as shown in SEQ ID NO:6.
Further, the second antigen-binding site heavy chain variable amino acid sequence is as shown in SEQ ID NO:7；Institute The second antigen-binding site light chain constant region amino acid sequence is stated as shown in SEQ ID NO:8.
The beneficial effects of the present invention are:
Monoclonal antibody is the high degree of specificity antibody for acting only on single epitope, has been widely used for many diseases Treatment, for example, cancer, inflammation and autoimmune disease, infectious diseases.But if such treatment molecule individually makes With, it can show that enough drug effects without one kind, this is because the complexity of disease, as cancer or diseases associated with inflammation usually relate to And the mutually fork effect between the molecular pathway and signal path of a variety of diseases mediations.In these cases, single point is targeted Son cannot provide optimal therapeutic effect, and block the molecule in multiple sites of multiple target spots or same target spot that can change simultaneously Kind therapeutic effect.Meanwhile can simplify new drug development process using double targeted therapies of polyspecific such as bispecific molecule, because It is single molecule for it.With use the drug combination of multiple single special moleculars to compare, be all more for patient and medical worker Easily.
The present invention also provides a kind of equipment comprising the bispecific antibody, slow release layer that the equipment provides can be Sustained release drugs in long period after medication, long-acting, blood concentration is constant for a long time to maintain effective concentration, reduces " peak valley " phenomenon；Administration number of times is reduced, to half-life short or the drug of frequent drug administration is needed, the compliance of patient can be improved；It adopts Can be without " first pass effect " of liver and the destruction of gastrointestinal tract with percutaneous dosing, and skin interbed makes there are also storage effect Drug concentration profile is gentle, avoids " peak valley phenomenon ", provide can scheduled and longer action time, it is lasting to maintain to stablize Blood concentration, toxicity and adverse reaction are small, easy to use.
Detailed description of the invention
Fig. 1 is a kind of schematic diagram of bispecific antibody provided in this embodiment；
Fig. 2 is the schematic diagram of extraordinary administration device provided in this embodiment
Fig. 3 is the top view of extraordinary administration device provided in this embodiment.
Wherein: 1- apparatus body, 2- immune substance nitride layer, 3- Chinese medicine layer, 4- slow release layer, 5- sticky region.
Specific embodiment
To make the object, technical solutions and advantages of the present invention clearer, the present invention will be made below further detailed Description.Test method as used in the following examples is conventional method unless otherwise specified；Used equipment, raw material, Reagent etc. is unless otherwise specified the equipment that can be commercially available from routine business approach, raw material, reagent.
Embodiment 1:
A kind of special type administration device, as shown in Fig. 2, the equipment includes apparatus body 1, immune substance nitride layer 2, Chinese medicine Layer 3 and slow release layer 4, the apparatus body 1 be it is U-shaped, outer edge protrusion, outer edge is provided with sticky region 5, can affix to people Body any position, the apparatus body 1 are made of waterproof material, are provided between the immune substance nitride layer and Chinese medicine layer anti- Water supporting layer is immune substance nitride layer 2 in dotted line, is Chinese medicine layer 3 outside dotted line as shown by dotted lines in figure 3, the apparatus body 1 Diameter is 4-10cm, can specifically be customized according to affected part area.
Embodiment 2:
Slow release layer of the present invention the preparation method is as follows: the chitosan solution of 0.5% (w/v) intermediate molecular weight is dissolved in To final concentration of 0.1% in 1% (w/v) acetic acid, the first dispersion liquid is obtained.Dry powder quality is added into the first dispersion liquid to be equivalent to 30% 3,4-dihydroxycinnamic acid of chitosan dry powder quality in chitosan solution, it is the first dispersion liquid that mass ratio is added later The second dispersion liquid is obtained after 0.01% hard amine, curing agent is added in the second dispersion liquid of Xiang Suoshu, and the curing agent is sweet hydroxyl Aluminium, mass ratio are the 5.7% of the second dispersion liquid, and curing substrate is added, and the curing substrate is poly- for incomplete neutralization type NP-700 Sodium acrylate, mass ratio are the 26% of the second dispersion liquid, and solidification regulator is added, and the solidification regulator is tartaric acid, quality Than 12.1% for the second dispersion liquid, thickener and complexing agent is added, the tackifier are 60% polyvinylpyrrolidone The mixture of PVPK90 and 40% sodium cellulose glycolate CMC-Na composition, the mixture quality is than for the second dispersion liquid 5.8%, complexing agent is disodium ethylene diamine tetraacetate, and mass ratio is the 2.2% of the second dispersion liquid.The above process at 65 DEG C into All the components are poured into mold by row after mixing evenly, and slow release layer is made after cooling, and the slow release layer is in gel, with a thickness of 2mm can fit closely human skin, have large biological molecule penetration capacity, but it is stagnant to play certain large biological molecule simultaneously Effect is stayed, so that there is slow release layer stronger drug to penetrate effect and slow release effect, 3,4-dihydroxycinnamic acid has stronger Skin permeability can penetrate cuticula and transport a effective amount of medical fluid to subcutaneous, make medical fluid in subcutaneous Dispersed precipitate, effectively make Long with the time, drug absorption rate is higher.
Percutaneous dosing can be without " first pass effect " of liver and the destruction of gastrointestinal tract, and skin interbed also stores work With, keep drug concentration profile gentle, avoid " peak valley phenomenon ", provide can scheduled and longer action time, maintain stablize Lasting blood concentration, toxicity and adverse reaction are small, easy to use.
Embodiment 3:
A kind of present invention method that heterodimer bispecific antibody is mass produced with reference to described in WO2013060867, This method first restores the homodimer form antibody of two kinds of mixing, then by the area Fc of both homodimer antibody Asymmetric amino acid mutation is introduced to promote the Fab arm of different antibodies to exchange, finally by the interchain of oxidation hinge area The stable bispecific antibody of disulfide bond formation.
Anti- TNF/IL23 bispecific antibody is placed in immune substance nitride layer of the present invention, the bispecific antibody is Humanization lgG type antibody, the bispecific antibody include the first antigen knot with tumor necrosis factor TNF-alpha specific binding Position is closed, further includes the second antigen-binding site with interleukins IL-23 specific binding, wherein the bispecific antibody Comprising the first Fc chain and the 2nd Fc chain by one or more disulfide bond interchain connections, the first Fc chain and the 2nd Fc chain pass through Covalent bond or connector are connected respectively on the first antigen-binding site and the second antigen-binding site, and the first Fc chain and Two Fc chains are in the replacement that following position includes 5 amino acid:
Heavy chain constant region is human IgG1,356 and the replacement of 379 amino acids on the first Fc chain, 321 on the 2nd Fc chain The replacement of position, 407 and 409 amino acids, is more likely to mutually comprising the first Fc chain of above-mentioned amino acid substitution and the 2nd Fc chain It mutually forms heterodimer and is not inclined to and respectively forms homodimer, specifically, the first Fc chain T356L and D379Q replacement, 2nd Fc chain L321E, Y407K and I409V replacement.
Further, the first antigen-binding site chain variable region amino acid sequence is as shown in SEQ ID NO:1；Gently Chain amino acid constant region sequence is as shown in SEQ ID NO:2；Heavy chain variable amino acid sequence is as shown in SEQ ID NO:3；Weight Chain amino acid constant region sequence is as shown in SEQ ID NO:4.The second antigen-binding site chain variable region amino acid sequence As shown in SEQ ID NO:5；Chain constant region amino acid sequence is as shown in SEQ ID NO:6；Heavy chain variable amino acid sequence As shown in SEQ ID NO:7；Light chain constant region amino acid sequence is as shown in SEQ ID NO:8.It is expanded respectively by the method for PCR Light chain variable region and constant region of light chain, heavy chain variable region and heavy chain constant region.All PCR reactions use in the application The super fidelity dna polymerase (F-530L) of the Phusion of NEB company.PCR primer is according to base complementrity principle and restriction enzyme site Need to carry out conventional design, bispecific antibody is synthesized with reference to conventional method, and above-mentioned antibody is injected into immune substance nitride layer.
Embodiment 4:
It is as follows that drug matching is placed in Chinese medicine layer of the present invention:
30 parts of Radix Astragali, 15 parts of Radix Codonopsis, 8 parts of Rhizoma Atractylodis Macrocephalae, 15 parts of Radix Angelicae Sinensis, 6 parts of Radix Paeoniae Alba, 6 parts of Cortex Eucommiae, 6 parts of herba taxilli, radix cyathulae 10 Part, 9 parts of Radix Angelicae Pubescentis, 7.5 parts of radix saposhnikoviae, 15 parts of Caulis Spatholobi, 10 parts of rhizoma homalonemae, 10 parts of scabrousstem greenbrier rhizome, 32 parts of fructus lycii, 25 parts of smilax, Bi revives 19 parts, and 12 parts of dandelion, 25 parts of viola mandshurica, 25 parts of oldenlandia diffusa, 5 parts of Cortex Phellodendri, 8 parts of radix rehmanniae recen, 20 parts of Radix Salviae Miltiorrhizae, the heart of a lotus seed 30 parts of the seed of jog's tears, 15 parts of peach kernel, 10 parts of safflower, 10 parts of Rehmannia glutinosa, 15 parts of Rhizoma Chuanxiong, 6 parts of radix paeoniae rubra, 6 parts of Rhizoma Arisaematis (processed), 6 parts of semen brassicae, system It is 10 parts of bombyx batryticatus, 10 parts of pheretima, 10 parts of nidus vespae, 19 parts of the root of Chinese clematis, 15 parts of Fructus Liquidambaris, 23 parts of Semen Strychni, 15 parts of Radix Aconiti Kusnezoffii, raw 25 parts of Southern Star, 2 parts of borneol, woods musk deer Moschus is a.
By Radix Astragali, Radix Codonopsis, Rhizoma Atractylodis Macrocephalae, Radix Angelicae Sinensis, Radix Paeoniae Alba, Cortex Eucommiae, herba taxilli, radix cyathulae, Radix Angelicae Pubescentis is windproof, Caulis Spatholobi, and thousand It is good for, scabrousstem greenbrier rhizome, fructus lycii, smilax, Bi Soviet Union, dandelion, viola mandshurica chopping, residual components are ground to 80 mesh, sesame oil is put Enter heating in pot, by Radix Astragali, Radix Codonopsis, Rhizoma Atractylodis Macrocephalae, Radix Angelicae Sinensis, Radix Paeoniae Alba, Cortex Eucommiae, herba taxilli, radix cyathulae, Radix Angelicae Pubescentis is windproof, Caulis Spatholobi, and thousand Nian Jian, scabrousstem greenbrier rhizome, fructus lycii, smilax, Bi Soviet Union, dandelion, viola mandshurica enter pot, mild fire frying simultaneously, and spice is fried to yellowish-brown When color, spice is taken out, removes slag and filters clear medicine oil；Medicine oil is put into clean copper pot, is heated to 120 DEG C or so, by residue at Divide in addition pot and stir, aqueous vapor disperses, loose to spend, anxious firmly fire, takes supernatant after precipitating, is injected into Chinese medicine layer.
Embodiment 5:
The therapeutic effect of the equipment of adjuvant therapy rheumatoid arthritis
(1) waist-leg arthralgia caused by rheumatism
Diagnostic criteria: the waist-leg arthralgia as caused by rheumatism, cardinal symptom be waist-leg local joint have it is apparent it is red, Swollen, heat, pain and tenderness, ache migratory pain, in migrans.
The standard of recovery from illness are as follows: the main performance symptom of waist-leg arthralgia caused by rheumatism completely disappears.
Effective standard are as follows: the main performance symptom of waist-leg arthralgia caused by rheumatism mitigates.
Invalid standard are as follows: the main performance symptom of waist-leg arthralgia caused by rheumatism does not change.
(2) osteoproliferation
Diagnostic criteria: by orthopaedics inspection, hyperplasia sclerotin on the Bones and joints edge of patient is in great pain.
The standard of recovery from illness are as follows: hyperplasia sclerotin completely disappears on the Bones and joints edge of patient, without pain.
Effective standard are as follows: hyperplasia sclerotin reduces on the Bones and joints edge of patient, pain relief.
Invalid standard are as follows: hyperplasia sclerotin does not change on the Bones and joints edge of patient, and pain is without improvement.
(3) cervical vertebra pain
Diagnostic criteria: cervical vertebra pain cardinal symptom is ached for cervical vertebra, shoulder aches or harden, dizziness, tinnitus, four limbs it is numb.
The standard of recovery from illness are as follows: cervical vertebra pain mainly shows symptom and completely disappears.
Effective standard are as follows: cervical vertebra pain mainly shows symptom mitigation.
Invalid standard are as follows: cervical vertebra pain mainly shows symptom and do not change.
(4) sciatica
Diagnostic criteria: the sciatica as caused by prolapse of nucleus pulposus of lumbar spine, cardinal symptom be sciatic nerve access and its Pain in distributed area is radiated along thigh rear side, small leg outer side to distal end from buttocks.
The standard of recovery from illness are as follows: sciatica mainly shows symptom and completely disappears.
Effective standard are as follows: sciatica mainly shows symptom mitigation.
Invalid standard are as follows: sciatica mainly shows symptom and do not change.
(5) leg joint rehydration swelling
Diagnostic criteria: the leg joint rehydration swelling as caused by rheumatism, rheumatoid, cardinal symptom are swollen for leg joint pain rehydration It is swollen.
The standard of recovery from illness are as follows: leg joint pain rehydration swelling symptom completely disappears.
Effective standard are as follows: leg joint pain rehydration swelling symptom mitigates.
Invalid standard are as follows: leg joint pain rehydration swelling symptom does not change.
(6) extremity numbness
Diagnostic criteria: the extremity numbness as caused by rheumatism, rheumatoid, cardinal symptom are extremity numbness.
The standard of recovery from illness are as follows: extremity numbness symptom completely disappears.
Effective standard are as follows: extremity numbness symptom mitigates.
Invalid standard are as follows: extremity numbness symptom does not change.
By the clinical use of 998 patients, wherein 472 patients are waist-leg arthralgia caused by rheumatism, 115 are Osteoproliferation, 98 are cervical vertebra pain, there is 101 sciatica, and 116 are the rehydration swelling of leg joint pain, and 96 are limbs It is numb.Oldest 84 years old, the smallest age was 23 years old, and male patient 347, women is 651, and every patch is replaced for 48 hours Once, 30 days it is as a treatment course.After 850 patches, 2 courses for the treatment of effectively；Have and is fully recovered after 578 patches, 13 courses for the treatment of after the period；Remaining is not fullyed recover from an illness More, but symptom has mitigation trend；Total cure rate is 57.9%.
The above disclosure is only the preferred embodiments of the present invention, cannot limit the right model of the present invention with this certainly It encloses, therefore equivalent changes made in accordance with the claims of the present invention, is still within the scope of the present invention.
Sequence table
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325 330

Claims (9)

1. a kind of bispecific antibody, which is characterized in that the bispecific antibody is anti-TNF/IL23 bispecific antibody, institute Stating bispecific antibody is humanization lgG type antibody.
2. bispecific antibody according to claim 1, which is characterized in that the bispecific antibody includes and neoplasm necrosis First antigen-binding site of factor TNF-α specific binding further includes second with interleukins IL-23 specific binding Antigen-binding site, wherein the bispecific antibody also include by one or more disulfide bond interchains connect the first Fc chain and 2nd Fc chain, the first Fc chain and the 2nd Fc chain are connected respectively to the first antigen-binding site and by covalent bond or connector On two antigen-binding sites.
3. bispecific antibody according to claim 1 to 2, which is characterized in that the first Fc chain is in following position Replacement comprising 2 amino acid, 356 and the replacement of 379 amino acids on the first Fc chain.
4. bispecific antibody according to claim 1 to 3, which is characterized in that the 2nd Fc chain is in following position Replacement comprising 3 amino acid, 321,407 and the replacement of 409 amino acids on the 2nd Fc chain.
5. bispecific antibody described in -4 according to claim 1, which is characterized in that the first Fc comprising the amino acid substitution Chain and the 2nd Fc chain are more likely to form heterodimer mutually and be not inclined to and respectively form homodimer.
6. bispecific antibody according to claim 5, which is characterized in that the first antigen-binding site light chain variable region Amino acid sequence is as shown in SEQ ID NO:1；The first antigen-binding site chain constant region amino acid sequence such as SEQ ID Shown in NO:2.
7. bispecific antibody according to claim 6, which is characterized in that the first antigen-binding site heavy chain variable region Amino acid sequence is as shown in SEQ ID NO:3；The first antigen-binding site light chain constant region amino acid sequence such as SEQ ID Shown in NO:4.
8. bispecific antibody according to claim 7, which is characterized in that the second antigen-binding site light chain variable region Amino acid sequence is as shown in SEQ ID NO:5；The second antigen-binding site chain constant region amino acid sequence such as SEQ ID Shown in NO:6.
9. bispecific antibody according to claim 8, which is characterized in that the second antigen-binding site heavy chain variable region Amino acid sequence is as shown in SEQ ID NO:7；The second antigen-binding site light chain constant region amino acid sequence such as SEQ ID Shown in NO:8.
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Application publication date: 20190521