CN115581766A - PD-L1/TGF beta combined bifunctional antibody fusion protein liquid preparation - Google Patents
PD-L1/TGF beta combined bifunctional antibody fusion protein liquid preparation Download PDFInfo
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- CN115581766A CN115581766A CN202110757800.8A CN202110757800A CN115581766A CN 115581766 A CN115581766 A CN 115581766A CN 202110757800 A CN202110757800 A CN 202110757800A CN 115581766 A CN115581766 A CN 115581766A
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- fusion protein
- tgf
- ser
- antibody fusion
- liquid formulation
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- A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a PD-L1/TGF beta combined bifunctional antibody fusion protein liquid preparation and a preparation process thereof. The PD-L1/TGF beta combined bifunctional antibody fusion protein liquid preparation provided by the invention effectively overcomes the problem that the antibody fusion protein is easy to break due to the molecular characteristics of the antibody fusion protein, ensures the stability of bioactive molecules in the production or storage process, and efficiently exerts the application of the liquid preparation in treating diseases. The invention provides a preparation method of a PD-L1/TGF beta bifunctional antibody fusion protein liquid preparation, which is simple, convenient and efficient, can effectively reduce the generation of small molecular substances in the liquid preparation, can effectively prevent molecules from being broken, and enables the liquid preparation to be more stable.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a PD-L1/TGF beta combined bifunctional antibody fusion protein liquid preparation and a preparation process thereof.
Background
Human programmed death factor ligand (PD-L1), also called B7-H1, full length cDNA 870bp, coded a segment of type I transmembrane protein containing 290 amino acids, belongs to B7 family members, widely distributed in peripheral tissues and hematopoietic cells. The main receptor of PD-L1 is programmed death factor 1 (pd1), and PD1 is an important immunosuppressive molecule that regulates the immune system and promotes self-tolerance by down-regulating the immune response and suppressing T-cell inflammatory activity. Activation of PD-1 may prevent not only autoimmune diseases, but also the immune system from killing cancer cells. In the process of tumor development, the expression of PD-L1 of cancer cells is up-regulated, and the PD-L1 is combined with PD-1 to inhibit immune response and induce apoptosis of T cells, thereby avoiding the elimination of cancer cells by an immune system and further causing the progress of diseases. In addition, the PD-1/PD-L1 pathway is related to some infectious diseases, and the PD-L1 related infectious diseases, such as HIV and intestinal mucositis, can be effectively improved by inhibiting the PD-1/PD-L1 pathway.
Transforming growth factor-beta (TGF-beta) is a TGF-beta superfamily that regulates cell growth and differentiation. There are five subtypes of TGF-beta, i.e., TGF-beta 1-5. Among them, TGF-beta 1, TGF-beta 2, TGF-beta 3 are present in mammals, and TGF-beta 4, TGF-beta 5 are present in birds and amphibians in many cases. There is 64% -82% sequence homology between subtypes of TGF-beta. TGF-. Beta.s are dimeric disulfide-linked structures of two structurally identical or closely related subunits of molecular weight 12.5 kDa. TGF-beta receptor (TGF-beta R) exists on the cell surface, and has high affinity with TGF-beta. Depending on the structure and function of the molecule, they can be classified as type I receptors (TGF-. Beta.RI) or activin receptor-like kinases, type II receptors (TGF-. Beta.RII) and type III receptors (TGF-. Beta.RIII).
Research shows that TGF-beta induces tumor immune escape, and the TGF-beta can reduce or even prevent interleukin-2 secretion, thereby inhibiting the proliferation of immune cells and monitoring the tumor. Moreover, TGF-beta derived from the tumor can stimulate regulatory T cells (Tregs) in a tumor microenvironment to proliferate, so that the tumor immune response is inhibited, and the growth of the tumor is promoted. Studies also indicate that TGF-beta can promote tumor angiogenesis, thereby promoting tumor metastasis and growth. Clinical experiments show that the inhibition of TGF-beta pathway plays a positive role in the disease progression and prognosis of patients.
On the other hand, researchers find that inhibiting TGF-beta/TGF-beta R and PD-L1 simultaneously can effectively inhibit the metastasis of mouse tumors and improve the survival rate of mice. Experiments prove that the TGF-beta inhibitor has unobvious performance when being used alone, but can obviously enhance the anti-tumor effect of the PD-L1 antibody when being used together with the PD-L1 antibody for treatment. Clinical trial data show that the response effectiveness of patients with metastatic urothelial cancer to the anti-PD-L1 treatment is inversely related to the secretion of TGF-beta by fibroblasts in a tumor microenvironment. This suggests that blocking both the PD-L1 and TGF- β signaling pathways may enhance the immunotherapy effect.
In order to realize immunotherapy for simultaneously blocking PD-L1 and TGF-beta, besides the combined use of two different inhibitors, the construction of a bifunctional molecule capable of simultaneously combining PD-L1 and TGF-beta is another effective method, which not only can reduce the production cost, but also can reduce the side effect generated by a single target molecule. For example, the M7824 bifunctional fusion protein simultaneously blocks PD-1/PD-L1 and TGF-beta RII/TGF-beta signal pathways, and preliminary clinical data show that the bifunctional fusion protein has clinical benefits superior to the traditional PD-1/PD-L1 monoclonal antibody. Therefore, the research of bifunctional antibody drugs aiming at PD-1/PD-L1 and TGF-beta RII/TGF-beta signal pathways and related preparations thereof also have important significance.
Disclosure of Invention
The invention aims to provide a liquid preparation combined with PD-L1/TGF beta bifunctional antibody fusion protein, which can reduce the degradation of bioactive substances in the storage process of a finished product to the greatest extent, ensure the stability of the finished product during production or storage, has simple preparation process, is more convenient and efficient to administer by using the liquid preparation, and can better exert the treatment effect of a medicament.
The technical scheme of the invention is as follows:
in one aspect, the invention provides a liquid formulation that binds to a PD-L1/TGF-beta bifunctional antibody fusion protein, comprising a binding PD-L1/TGF-beta bifunctional antibody fusion protein, a buffer system, a stabilizer, and a surfactant.
Preferably, the bifunctional antibody fusion protein comprises:
a PD-L1 antibody heavy chain-Linker-TGF-beta RII ECD with an amino acid sequence of SEQ ID NO. 1 and a PD-L1 antibody light chain with an amino acid sequence of SEQ ID NO. 2;
wherein, SEQ ID NO:1 (amino acid sequence of PD-L1 antibody heavy chain-Linker-TGF-beta RII ECD):
EVQLQESGPGLVKPSQTLSLTCTVSGDSFSSGYWNWIRQHPGKGLEYIGYVSYTGSTYYIPSLKSRVTISRDTSKNQFSLKLSSVTAADTAVYYCAGYRDWLHGYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAGGGGSGGGGSGGGGSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNT
2 (amino acid sequence of PD-L1 antibody light chain):
DIQMTQSPSSLSASVGDRVTITCKASQNVMDNVAWYQQKPGKAPKRLIYSASYRFSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYNGYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
preferably, the content of the bifunctional antibody fusion protein in a liquid preparation is 5mg/ml-100mg/ml; preferably 5mg/ml to 45mg/ml; more preferably 5mg/ml to 25mg/ml.
Preferably, the buffer system is selected from acetic acid/sodium acetate, citric acid/sodium citrate, succinic acid/sodium succinate, histidine/histidine hydrochloric acid, sodium dihydrogen phosphate/disodium hydrogen phosphate; the preferable buffer system is acetic acid/sodium acetate or citric acid/sodium citrate.
Preferably, the content of the buffer system in the liquid preparation is 10-50mM; preferably 10-20mM.
Preferably, the stabilizer is selected from trehalose, sucrose, sorbitol, maltose, methionine, lysine, disodium edetate, proline, mannitol, arginine; preferably sucrose, trehalose, proline, lysine or a combination thereof.
Preferably, the stabilizer is present in the liquid formulation in an amount of 10mM to 290mM.
Further preferably, the stabilizer is trehalose, sucrose or maltose, and the content of the trehalose, sucrose or maltose is 180mM-290mM; preferably 200mM to 220mM.
Further preferably, the stabilizing agent is proline or lysine in an amount of 10mM-50mM; preferably 20-30mM.
Preferably, the surfactant is selected from polysorbate 80 or polysorbate 20, a poloxamer; preferably polysorbate 80 or polysorbate 20.
Preferably, the content of the surfactant in the liquid preparation is 0.01-0.1% (mass-volume ratio W/V); preferably 0.02% to 0.06% (W/V).
Preferably, in an embodiment said bifunctional antibody fusion protein comprises the following components:
preferably, the bifunctional antibody fusion protein comprises the following components:
in another aspect, the invention further provides a preparation method of the liquid preparation of the fusion protein of the bifunctional antibody binding to PD-L1/TGF β, the method comprising the following specific steps:
preparing a buffer solution according to the prescription amount, sampling and detecting the pH value of the buffer solution to be qualified, then accurately weighing the stabilizer, the surfactant and the bifunctional antibody fusion protein stock solution according to the prescription amount, adding the stabilizer, the surfactant and the bifunctional antibody fusion protein stock solution into the buffer solution, uniformly mixing to obtain a semi-finished product solution, performing sterile filtration on the semi-finished product solution by using a 0.22 mu m filter membrane, and subpackaging after the endotoxin is detected to be qualified.
The PD-L1/TGF beta combined bifunctional antibody fusion protein liquid preparation prepared by the invention has the following technical advantages:
firstly, the invention provides a liquid preparation of PD-L1/TGF beta bifunctional antibody fusion protein, which effectively solves the problem that the antibody fusion protein is easy to break due to the molecular characteristics of the antibody fusion protein, ensures the stability of bioactive molecules in the production or storage process, and efficiently exerts the application of the liquid preparation in treating diseases.
Secondly, the invention provides a preparation method of the PD-L1/TGF beta bifunctional antibody fusion protein liquid preparation, the method is simple, convenient and efficient, the generation of small molecular substances in the liquid preparation can be effectively reduced, the molecular breakage can be effectively prevented, and the liquid preparation is more stable.
Detailed Description
While the technical solutions of the present invention are further illustrated and described below by means of specific embodiments, it should be understood that the following examples are for illustrative purposes only and are not intended to limit the present invention, and that some obvious alternatives in the art are also within the scope of the present invention.
The following examples are experimental methods without specifying specific conditions, and are selected in accordance with conventional methods and conditions, or in accordance with commercial instructions. In the embodiment, the stability test and the related biological test are carried out according to the specifications of Chinese pharmacopoeia. In the embodiment, the reagents are all medicinal grade and are all sold in the market.
Example 1
1. Prescription
2. Preparation method
Weighing sodium acetate according to the prescription amount, dissolving the sodium acetate with a proper amount of water for injection, adjusting the pH value with acetic acid, sampling, detecting the qualified pH value to obtain an acetic acid/sodium acetate buffer solution, accurately weighing sucrose, proline, polysorbate 80 and bifunctional antibody fusion protein stock solution according to the prescription amount, adding the sucrose, proline, polysorbate 80 and bifunctional antibody fusion protein stock solution into the acetic acid/sodium acetate buffer solution, uniformly mixing to obtain a semi-finished product solution, performing sterile filtration on the semi-finished product solution by using a 0.22 mu m filter membrane, and filling after the qualified endotoxin is detected.
Example 2
1. Prescription
2. Preparation method
Weighing sodium acetate according to the prescription, dissolving the sodium acetate with a proper amount of water for injection, adjusting the pH value with acetic acid, sampling and detecting the qualified pH value to obtain an acetic acid/sodium acetate buffer solution, accurately weighing sucrose, polysorbate 80 and the bifunctional antibody fusion protein stock solution according to the prescription, adding the sucrose, polysorbate 80 and the bifunctional antibody fusion protein stock solution into the acetic acid/sodium acetate buffer solution, uniformly mixing to obtain a semi-finished product solution, performing sterile filtration on the semi-finished product solution by using a 0.22 mu m filter membrane, and filling after the qualified endotoxin is detected to obtain the finished product.
Example 3
1. Prescription
2. Preparation method
Weighing sodium acetate with a prescription amount, dissolving the sodium acetate with a proper amount of water for injection, adjusting the pH value with acetic acid, sampling, detecting the qualified pH value to obtain an acetic acid/sodium acetate buffer solution, accurately weighing trehalose, polysorbate 80 and bifunctional antibody fusion protein stock solution with the prescription amount, adding the trehalose, polysorbate 80 and bifunctional antibody fusion protein stock solution into the acetic acid/sodium acetate buffer solution, uniformly mixing to obtain a semi-finished product solution, performing sterile filtration on the semi-finished product solution with a 0.22 mu m filter membrane, detecting the qualified endotoxin, and filling to obtain the finished product.
Example 4
1. Prescription
2. Preparation method
Weighing sodium citrate in a prescription amount, dissolving the sodium citrate in a proper amount of water for injection, adjusting the pH value by using citric acid, sampling and detecting the qualified pH value to obtain a citric acid/sodium citrate buffer solution, accurately weighing sucrose, polysorbate 80 and bifunctional antibody fusion protein stock solution in the prescription amount, adding the sucrose, polysorbate 80 and bifunctional antibody fusion protein stock solution into the citric acid/sodium citrate buffer solution, uniformly mixing to obtain a semi-finished product solution, performing sterile filtration on the semi-finished product solution by using a 0.22 mu m filter membrane, and filling after the qualified endotoxin is detected.
Example 5
1. Prescription
2. Preparation method
Weighing sodium acetate according to the prescription amount, dissolving the sodium acetate with a proper amount of water for injection, adjusting the pH value with acetic acid, sampling, detecting the qualified pH value to obtain an acetic acid/sodium acetate buffer solution, accurately weighing sucrose, proline, polysorbate 80 and bifunctional antibody fusion protein stock solution according to the prescription amount, adding the sucrose, the proline, the polysorbate 80 and the bifunctional antibody fusion protein stock solution into the acetic acid/sodium acetate buffer solution, uniformly mixing to obtain a semi-finished product solution, performing sterile filtration on the semi-finished product solution by using a 0.22 mu m filter membrane, and filling after the qualified endotoxin is detected.
Example 6
1. Prescription
2. Preparation method
Weighing sodium citrate in a prescription amount, dissolving the sodium citrate in a proper amount of water for injection, adjusting the pH value by using citric acid, sampling and detecting the qualified pH value to obtain a citric acid/sodium citrate buffer solution, accurately weighing sucrose, lysine, polysorbate 80 and bifunctional antibody fusion protein stock solution in the prescription amount, adding the sucrose, the lysine, the polysorbate 80 and the bifunctional antibody fusion protein stock solution into the citric acid/sodium citrate buffer solution, uniformly mixing to obtain a semi-finished product solution, performing sterile filtration on the semi-finished product solution by using a 0.22 mu m filter membrane, and filling after the qualified endotoxin detection to obtain the product.
Example 7
1. Prescription
2. Preparation method
Weighing sodium acetate according to the prescription, dissolving the sodium acetate with a proper amount of water for injection, adjusting the pH value with acetic acid, sampling and detecting the qualified pH value to obtain an acetic acid/sodium acetate buffer solution, accurately weighing sucrose, polysorbate 80 and the bifunctional antibody fusion protein stock solution according to the prescription, adding the sucrose, polysorbate 80 and the bifunctional antibody fusion protein stock solution into the acetic acid/sodium acetate buffer solution, uniformly mixing to obtain a semi-finished product solution, performing sterile filtration on the semi-finished product solution by using a 0.22 mu m filter membrane, and filling after the qualified endotoxin is detected to obtain the finished product.
Example 8
1. Prescription
2. Preparation method
Weighing sodium citrate in a prescription amount, dissolving the sodium citrate in an appropriate amount of water for injection, adjusting the pH value by using citric acid, sampling and detecting the qualified pH value to obtain a citric acid/sodium citrate buffer solution, accurately weighing sucrose, polysorbate 20 and bifunctional antibody fusion protein stock solution in the prescription amount, adding the sucrose, polysorbate 20 and bifunctional antibody fusion protein stock solution into the citric acid/sodium citrate buffer solution, uniformly mixing to obtain a semi-finished product solution, performing sterile filtration on the semi-finished product solution by using a 0.22 mu m filter membrane, and filling after the qualified endotoxin detection.
Example 9
1. Prescription
2. Preparation method
Weighing sodium dihydrogen phosphate according to a prescription amount, dissolving the sodium dihydrogen phosphate with a proper amount of water for injection, adjusting the pH value with disodium hydrogen phosphate, sampling and detecting the qualified pH value to obtain a sodium dihydrogen phosphate/disodium hydrogen phosphate buffer solution, accurately weighing sucrose, polysorbate 80 and bifunctional antibody fusion protein stock solution according to the prescription amount, adding the sucrose, polysorbate 80 and bifunctional antibody fusion protein stock solution into the sodium dihydrogen phosphate/disodium hydrogen phosphate buffer solution, uniformly mixing to obtain a semi-finished product solution, performing sterile filtration on the semi-finished product solution by using a 0.22 mu m filter membrane, and filling after the qualified endotoxin is detected.
Verification examples
1、SEC-HPLC
The experimental method comprises the following steps: purity (SEC-HPLC) was determined by size exclusion chromatography according to the Chinese pharmacopoeia 2020 edition (general rules 0512).
TABLE 1 SEC-HPLC results for PD-L1/TGF β dual-resistant liquid formulations
SEC results show that the prepared sample is colorless microemulsion light liquid after 4 weeks at 40 ℃ and 3 months at 25 ℃, has no visible particles, and has no obvious change in pH and protein content. The results of the small molecules and the polymers show that the stability of the protein is well maintained after 3 months of investigation at 25 +/-2 ℃ and 4 weeks of investigation at 40 +/-2 ℃.
2、CEX-HPLC
The experimental method comprises the following steps: the determination is made according to the law, china pharmacopoeia 2020 edition (general rules 0512).
TABLE 2 CEX-HPLC results for PD-L1/TGF β dual-resistant liquid formulation
The formulations are placed at 40 ℃ and 25 ℃, and the SEC-HPLC polymers and the charge heteroplasmons are comprehensively considered, so that the double-antibody liquid preparation prepared by the formula has better stability.
3. Biological activity
The experimental method comprises the following steps: the test is carried out according to the specifications of Chinese pharmacopoeia, and is determined according to a reporter gene method based on bioluminescence, and the test materials are as follows: TGF beta/SMAD cells, GS-C2/PD-L1 (CHO-PDL 1) cells.
TABLE 3 biological Activity results of PD-L1/TGF beta double-resistant liquid formulations
4. Freeze-thaw and oscillation test
The products of the examples were subjected to freeze-thaw tests for 5 cycles, shaking for 3 days, and illumination for 5 days at 4500lux, respectively, and the results are shown in Table 4.
Table 4. Test results of freeze-thaw and oscillation of PD-L1/TGF beta double-resistant liquid preparation
The results of oscillation (300rpm, 25 ℃) and repeated freeze thawing (-80 ℃ to room temperature thawing) show that after oscillation for 3 days and repeated freeze thawing for 5 rounds and illumination for 5 days, the detection results of appearance, concentration, pH (25 ℃), insoluble particles (pharmacopoeia standard is more than or equal to 10 microns and less than or equal to 6000 particles/bottle; more than or equal to 25 microns and less than or equal to 600 particles/bottle), particle size, purity (SEC-HPLC) and activity of DLS show that the PD-L1/TGF beta bispecific antibody preparation has better stability.
Sequence listing
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420 425 430
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450 455 460
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Claims (10)
1. A liquid formulation that binds to a PD-L1/TGF β bifunctional antibody fusion protein, comprising a binding PD-L1/TGF β bifunctional antibody fusion protein, a buffer system, a stabilizer, and a surfactant.
2. The liquid formulation of claim 1, wherein the binding PD-L1/TGF β bifunctional antibody fusion protein comprises: a PD-L1 antibody heavy chain-Linker-TGF-beta RIIECD with an amino acid sequence of SEQ ID NO. 1 and a PD-L1 antibody light chain with an amino acid sequence of SEQ ID NO. 2.
3. The liquid formulation of claim 2, wherein the PD-L1 antibody heavy chain-Linker-TGF- β RII ECD has an amino acid sequence of SEQ ID No. 1:
EVQLQESGPGLVKPSQTLSLTCTVSGDSFSSGYWNWIRQHPGKGLEYIGYVSYTGSTYYIPSLKSRVTISRDTSKNQFSLKLSSVTAADTAVYYCAGYRDWLHGYFDYWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGAGGGGSGGGGSGGGGSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNT
4. the liquid formulation of claim 2, wherein the light chain of the PD-L1 antibody has the amino acid sequence of SEQ ID No. 2:
DIQMTQSPSSLSASVGDRVTITCKASQNVMDNVAWYQQKPGKAPKRLIYSASYRFSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYNGYPLTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
5. the liquid formulation of claim 1, wherein the amount of the fusion protein that binds PD-L1/TGF β bifunctional antibody in the liquid formulation is from 5mg/ml to 100mg/ml.
6. The liquid formulation of claim 1, wherein the buffer system is selected from the group consisting of acetic acid/sodium acetate, citric acid/sodium citrate, succinic acid/sodium succinate, histidine/histidine hydrochloride, sodium dihydrogen phosphate/disodium hydrogen phosphate.
7. The liquid formulation of claim 1, wherein the stabilizer is one or a combination of trehalose, sucrose, sorbitol, maltose, methionine, lysine, disodium edetate, proline, mannitol, arginine.
8. The liquid formulation of claim 1, wherein the surfactant is selected from the group consisting of polysorbate 80, polysorbate 20, and poloxamer.
9. The liquid formulation of claim 1, wherein the liquid formulation of a PD-L1/TGF bifunctional antibody fusion protein comprises the following components:
10. the liquid formulation of claim 1, wherein the liquid formulation of a PD-L1/TGF bifunctional antibody fusion protein comprises the following components:
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| CN116688115B (en) * | 2022-03-18 | 2024-02-06 | 上海齐鲁制药研究中心有限公司 | PD-L1/TGF-beta double-function fusion protein preparation and application thereof |
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