CN117106033A - Maytansine-polypeptide conjugate, and preparation method and application thereof - Google Patents
Maytansine-polypeptide conjugate, and preparation method and application thereof Download PDFInfo
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- CN117106033A CN117106033A CN202311068854.9A CN202311068854A CN117106033A CN 117106033 A CN117106033 A CN 117106033A CN 202311068854 A CN202311068854 A CN 202311068854A CN 117106033 A CN117106033 A CN 117106033A
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- maytansine
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/537—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines spiro-condensed or forming part of bridged ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention relates to the technical field of biological pharmacy, in particular to a maytansine-polypeptide conjugate, a preparation method and application thereof. The maytansine-polypeptide conjugate provided by the invention has a molecular structural formula shown in a formula I, wherein R represents maytansine and L represents maytansineTable links. The invention also provides a preparation method of the conjugate, which comprises the following steps: (1) synthesizing an affinity polypeptide; (2) synthesizing an L-affibody polypeptide conjugate; (3) synthesizing a maytansine-affibody polypeptide conjugate. The maytansine-polypeptide conjugate provided by the invention has the advantages of low molecular weight, strong tissue penetrating capacity, low immunogenicity, relatively simple preparation process and low cost, and can be synthesized by a chemical method.
Description
Technical Field
The invention relates to the technical field of biological pharmacy, in particular to a maytansine-polypeptide conjugate, a preparation method and application thereof.
Background
Treatment of tumors includes surgical resection, radiation therapy, drug therapy, including chemotherapy and targeted therapy. Because of lack of targeting, the medicine for clinical chemotherapy kills normal tissue cells while killing tumor cells, has obvious toxic and side effects, causes great pain for patients, and greatly limits the clinical application of the chemotherapeutic medicine. Targeted therapies include small molecule targeted drugs, antibody targeted drugs, targeted ligand drug conjugates, and the like. Among them, small molecule targeting drugs mainly include imatinib, erlotinib, etc., but such drugs have a short half-life and are liable to cause drug resistance. Antibody drugs mainly target membrane receptors on the surface of tumor cells, such as EGFR, HER2/neu, VEGFR and the like, but the curative effect is often unsatisfactory when used alone, and the drug resistance of tumors and the like are also easily caused. In order to effectively clear tumor cells and overcome drug resistance, the development of conjugates of targeting ligands with anti-tumor drugs has been of great interest. Wherein the targeting ligand comprises an antibody, a polypeptide, a small molecule compound, a nucleic acid oligonucleotide aptamer and the like. After the coupling medicine enters the body, the target head can specifically identify the tumor cells over-expressed by the receptor, and the anti-tumor medicine enters the tumor cells to act by utilizing endocytosis, so that the tumor cells are killed, and the defects of low curative effect of the antibody medicine and large toxic and side effects of the anti-tumor medicine are overcome.
Currently, antibody drug conjugates (Antibody Drug Conjugate, ADC) are a hotspot in the development of conjugated drugs. 14 ADC drugs are marketed worldwide, and 70 ADC drugs are in different research and development stages in China. However, there are some difficulties in developing ADC drugs, including (1) large molecular weight of antibody, poor tissue penetration, strong immunogenicity, and large dosage; (2) Through liver metabolism, the internal residence time is long, the toxic and side effects are large, and the treatment window is narrow; (3) coupling only highly toxic compounds; (4) The medicine/antibody ratio (DAR) is different, the components are mixed, the preparation process is complex, and the cost is high. Therefore, the ligand which not only maintains the affinity of the receptor, but also has lower molecular weight is searched for as the target head of the coupled medicine, and has very important practical significance for reducing the immunogenicity of the coupled medicine, improving the tumor penetrating capacity of the coupled medicine and reducing the production cost.
Disclosure of Invention
The invention aims at the defects of the prior art and provides a maytansine-polypeptide conjugate, a preparation method and application thereof.
The technical scheme for solving the technical problems is as follows:
a maytansine-affibody polypeptide conjugate having the molecular structural formula shown in formula I:
wherein R represents maytansine and L represents a linker.
Each symbol in structural formula I represents an amino acid as follows:
asn asparagine, arg arginine, lle isoleucine, glu glutamic acid, trp tryptophan, ala alanine, met methionine, lys lysine, asn asparagine, phe phenylalanine, asp aspartic acid, val valine, gly glycine, cys cysteine, leu leucine, pro proline, leu leucine, gin glutamine, ser serine.
The technical scheme has the following technical effects: the maytansine-polypeptide conjugate structure takes the affinity body polypeptide as a target head, so that the receptor affinity is reserved, and a ligand with lower molecular weight is used as the target head of the conjugated medicine, so that the immunogenicity of the conjugated medicine can be reduced, and the tumor penetrating capacity of the conjugated medicine can be improved.
Based on the technical scheme, the invention can also make the following improvements:
further, the linker comprises the structure-S-S-.
Further, the maytansine-affibody polypeptide conjugate has a molecular structural formula shown in formula II:
wherein, maytansine has a structural formula shown in formula III:
the thiol (-SH) group in the maytansinoid structure bonds with S in the 2,2' -dithiodipyridine structure to form-S-.
The invention also relates to a preparation method of the maytansine-polypeptide conjugate, which comprises the following steps:
(1) Synthesizing an affinity polypeptide;
(2) Synthesizing an L-affibody polypeptide conjugate: taking 2,2 '-dithiodipyridine and an affinity body polypeptide as raw materials, stirring and reacting for 24-48 hours at room temperature in the presence of a DMSO solvent, wherein the molar ratio of the 2,2' -dithiodipyridine to the affinity body polypeptide is (1-4): 1, after the reaction is finished, preparing a liquid phase for purification, concentrating and freeze-drying to obtain an L-affibody polypeptide conjugate;
(3) Synthesis of maytansine-affibody polypeptide conjugates: maytansine and the L-affinity body polypeptide conjugate are mixed according to the molar ratio (1-4): 1 is dissolved in an organic solvent, stirred and reacted for 24 to 36 hours at room temperature to obtain a reaction solution, the reaction solution is purified by a preparation liquid phase, and the purified liquid containing the product is combined, concentrated and freeze-dried to obtain the maytansine-affibody polypeptide conjugate.
The technical scheme has the following technical effects: the maytansine-affibody polypeptide conjugate is synthesized by a chemical method, the preparation process is simple, and the cost is low.
Based on the technical scheme, the invention can also make the following improvements:
further, in the step (1), the method specifically includes the steps of:
s1, adopting a solid-phase polypeptide synthesis method, and reacting 9-fluorenylmethoxycarbonyl-protected amino lysine (Fmoc-Lys (Boc) -OH) with Rink Amide-MBHA resin in the presence of N, N' -Diisopropylethylamine (DIEA) to obtain Fmoc-Lys-Rink Amide-MBHA resin;
s2, removing Fmoc protecting groups from the Fmoc-Lys-Rink Amide-MBHA resin by using a mixed solution of piperidine and N, N' -Dimethylformamide (DMF) with the volume concentration of 20% -40%, and then gradually coupling amino acid (Fmoc-amino acid) of 9-fluorenylmethoxycarbonyl-protecting amino group from the C end to the N end by using O-benzotriazole-tetramethylurea Hexafluorophosphate (HBTU) as a condensing reagent according to a peptide sequence to obtain a full-protection peptide resin;
s3, adding a lysate into the fully protected peptide resin, performing room temperature pyrolysis for 30-60 min, filtering to obtain filtrate, adopting 50mL of diethyl ether for sedimentation, performing centrifugal separation at 8000rpm for 10min after sedimentation, removing supernatant, adding 50mL of diethyl ether, uniformly mixing lower-layer sediments for washing, repeatedly performing centrifugal separation operation (8000 rpm for 10 min), removing supernatant after centrifugation, and drying in a vacuum drying oven to obtain an affinity body crude peptide;
s4, purifying the crude peptide through a preparation liquid phase, and freeze-drying to obtain an affinity body polypeptide pure product.
Wherein the C-terminal refers to the carboxyl group (-COOH) terminal of the polypeptide peptide chain, and the N-terminal refers to the amino group (-NH) of the polypeptide peptide chain 2 ) And a terminal end.
Further, in S1, the substitution degree of the Rink Amide-MBHA resin is 0.337mmol/g;
the Rink Amide-MBHA resin comprises the following components in terms of molar ratio: DIEA: the Fmoc-Lys (Boc) -OH molar ratio was 1:2 to 6:4 to 8.
Further, in S2, the molar ratio of Fmoc-Lys-Rink Amide-MBHA, HBTU, fmoc-amino acid is 1:2 to 6: 4-8, and the coupling time is 30 min-3 h.
Further, in S3, the total protective peptide resin: the cracking liquid is 1 g:5-10 mL;
the lysate comprises trifluoroacetic acid (TFA), 1, 2-Ethanedithiol (EDI), triisopropylsilane (TIS) and purified water (H) 2 O) the TFA: EDI: TIS: h 2 O is 94:2:2:2.
The invention also relates to application of the maytansine-affibody polypeptide conjugate in preparing a medicine for preventing or treating tumor, wherein the tumor is lung cancer.
Compared with the prior art, the invention has the following technical effects:
the maytansine-affibody polypeptide conjugate provided by the invention has the advantages of low molecular weight, strong tissue penetrating capacity, low immunogenicity, relatively simple preparation process and low cost, and can be synthesized by a chemical method.
Drawings
FIG. 1 shows a mass spectrum of a maytansinoid-affibody polypeptide conjugate of an embodiment of the present invention;
fig. 2 shows the volume change trend of human lung cancer H460 nude mice subcutaneous transplants according to the present invention (TV plot, ×p < 0.01, vs Control): control is Control group, PTX is paclitaxel solution group, BX-105 is maytansine-affibody polypeptide conjugate group;
FIG. 3 shows a graph of relative tumor volume change trend of human lung cancer H460 nude mice subcutaneous transplants according to the present invention (RTV graph, < 0.01, vs Control);
FIG. 4 shows a graph (T/C graph) showing the relative tumor proliferation rate trend of human lung cancer H460 nude mice subcutaneous transplants of the present invention;
figure 5 shows a schematic size of human lung cancer H460 nude mice subcutaneous transplantable tumor of the present invention.
Detailed Description
Further advantages and effects of the present invention will become apparent to those skilled in the art from the disclosure of the present specification, by describing the embodiments of the present invention with specific examples. While the description of the invention will be described in connection with the preferred embodiments, it is not intended to limit the inventive features to the implementation. Rather, the purpose of the invention described in connection with the embodiments is to cover other alternatives or modifications, which may be extended by the claims based on the invention. The following description contains many specific details for the purpose of providing a thorough understanding of the present invention. The invention may be practiced without these specific details. Furthermore, some specific details are omitted from the description in order to avoid obscuring the invention. It should be noted that, without conflict, the embodiments of the present invention and features of the embodiments may be combined with each other.
Example 1: preparation method of maytansine-affibody polypeptide conjugate
The maytansine-affibody polypeptide conjugate is prepared by the following steps:
(1) Synthesis of the affibody polypeptide:
and (3) sequentially synthesizing amino acid sequences by using a solid-phase polypeptide synthesis method of Fmoc strategy to obtain polypeptide fragments. Starting the reaction with 2.225g Rink Amide-MBHA Resin, and obtaining 3.41g crude polypeptide after cleavage. The crude product is dissolved in acetonitrile: purification was performed in water (1:1) with a C18 prep column, detection wavelength: 214nm, mobile phase a: acetonitrile (0.1% trifluoroacetic acid), mobile phase B: water (containing 0.1% trifluoroacetic acid). MS determines the molecular weight of the obtained pure product, and freeze-dries to obtain 1.26g of target polypeptide intermediate.
The preparation method comprises the steps of adopting a solid-phase polypeptide synthesis method, and reacting 9-fluorenylmethoxycarbonyl-protected amino lysine (Fmoc-Lys (Boc) -OH) with Rink Amide-MBHA Resin with a substitution degree of 0.337mmol/g in the presence of N, N' -Diisopropylethylamine (DIEA), wherein the addition amount of Rink Amide-MBHA Resin is 2.225g, and the addition amounts of DIEA and Fmoc-Lys (Boc) -OH are 77.55g and 1.406g respectively; the Fmoc-Lys-Rink Amide-MBHA resin obtained was subjected to a piperidine/N, N' -Dimethylformamide (DMF) solution with a volume concentration of 20%(volume ratio: piperidine: dmf=1:4) after removal of Fmoc protecting group, amino acids were coupled stepwise from C-terminal to N-terminal according to peptide sequence using O-benzotriazole-tetramethyluronium Hexafluorophosphate (HBTU) as a condensing agent to obtain a fully protected peptide resin, wherein the molar ratio of Fmoc-Lys-Rink Amide-MBHA resin, condensing agent HBTU and Fmoc-amino acid was 1:4:4, the coupling time is 40min; adding a lysate to the fully protected peptide resin according to the mass-volume ratio of 1g to 10mL to cut peptide, wherein the lysate comprises trifluoroacetic acid (TFA), 1, 2-Ethanedithiol (EDI), triisopropylsilane (TIS) and purified water (H) 2 O) =94:2:2:2 (volume ratio), after 50min of room temperature cleavage, filtering to obtain filtrate, adopting 50mL of diethyl ether for sedimentation, carrying out centrifugal separation (8000 rpm for 10 min) after sedimentation, removing supernatant, adding 50mL of diethyl ether, uniformly mixing the lower sediment for washing, repeatedly carrying out centrifugal separation operation (8000 rpm for 10 min), removing supernatant after centrifugation, and drying in a vacuum drying oven to obtain 3.41g of the affinity body crude peptide. The crude product is dissolved in acetonitrile: purification was performed in a C18 preparative column in water (v: v=1:1), detection wavelength: 214nm, mobile phase a: acetonitrile (0.1% trifluoroacetic acid), mobile phase B: water (containing 0.1% trifluoroacetic acid). MS determines the molecular weight of the obtained pure product, and freeze-drying to obtain 1.26g of target affibody polypeptide.
(2) Synthesis of L-affibody polypeptide conjugates:
2,2' -dithiodipyridine (42 mg,0.192mmol,1.02 eq), 1.26g of the affinity polypeptide obtained in the step (1) were dissolved in 30mL of DMSO, reacted at room temperature for 26 hours, after the reaction was completed, the reaction solution was diluted with acetonitrile, purified by a C18 column, and the detection wavelength was measured: 214nm, mobile phase a: acetonitrile (0.1% trifluoroacetic acid), mobile phase B: water (containing 0.1% trifluoroacetic acid). MS determines the molecular weight of the obtained pure product, HPLC determines the purity of the sample, and the L-affinity polypeptide conjugate 718mg is obtained by freeze drying, and the yield is 56%.
(3) Synthesis of maytansine-affibody polypeptide conjugates:
maytansine (27.1 mg,0.037mmol,1.25 eq), L-affinity polypeptide conjugate (200 mg,0.029 mmol) were dissolved in 10mL DMSO and the reaction stirred at room temperature and HPLC showed completion of the reaction for about 8 hours. The reaction solution was directly subjected to preparative liquid phase purification, and fractions containing the product were combined, concentrated and lyophilized to give 112mg of solid in 52% yield.
MS test shows that the target conjugate (maytansine-affibody polypeptide conjugate) is obtained.
Example 2: anti-tumor cell proliferation assay for maytansine-affibody polypeptide conjugates
Human lung cancer H460 cells were grown in 1640+10% FBS+1% double antibody expansion, the cell density was adjusted to 1.5X107 cells/mL before inoculation, and 200. Mu.L of cell suspension was inoculated on the right underarm back of nude mice under aseptic conditions. The diameter of the transplanted tumor is measured by a vernier caliper, and the tumor grows to an average volume of 200mm 3 Animals were randomly grouped into Control (10 ml/kg, i.v., q2 w/21), PTX (20 mg/kg, i.v., q2 w/21), BX-105 (10 mg/kg, i.v., q2 w/21) groups. PTX (20 mg/kg, i.v., q2 w/21) and BX-105 (10 mg/kg, i.v., q2 w/21) groups were given by continuous tail intravenous injection for 3 weeks, respectively, and Control (10 ml/kg, i.v., q2 w/21) groups were given by continuous tail intravenous injection for 3 weeks with 5% glucose of 10ml/kg, each group was given 2 times per week. Wherein the Control group is a negative Control group, the PTX group is a taxol solution group, and the BX-105 group is a maytansine-affibody polypeptide conjugate group; PTX is a paclitaxel solution and BX-105 is a maytansine-affibody polypeptide conjugate.
Throughout the experiment, the diameter of the transplanted tumor was measured 3 times per week while weighing the mice. The calculation formula of Tumor Volume (TV) is: tv=1/2×a×b 2 Wherein a and b respectively represent length and width. Based on the measured results, the relative tumor volume (Relative tumor volume, RTV) is calculated as: rtv=v t /V 1 Wherein V is 1 For measuring the volume of the tumor obtained at the time of divided administration (i.e. d 1), V t Tumor volume at each measurement.
The evaluation indexes of the antitumor activity are as follows:
1) Relative tumor proliferation rate T/C (%), the calculation formula is as follows: T/C (%) = (TRTV/CRTV) ×100%, TRTV: treatment group RTV; CRTV: negative control RTV;
2) Tumor weight inhibition rate IR (%), calculated as follows: IR (%) = (Wc-WT)/wc×100%, wc: tumor weight of control group, WT: treating the tumor weight of the group.
The Tumor Volume (TV) trend of each group is shown in fig. 2, the Relative Tumor Volume (RTV) trend of each group is shown in fig. 3, the relative tumor proliferation rate (T/C) trend of each group is shown in fig. 4, the tumor weight and tumor weight inhibition rate (tumor weight and IR, P < 0.01, vs Control) data of animals in which human lung cancer H460 nude mice were subcutaneously transplanted with tumors of each group are shown in table 1, wherein each group in the figures and tables represents the following meanings: control is Control, PTX is paclitaxel solution, BX-105 is maytansine-affibody polypeptide conjugate.
Table 1 comparison of tumor weights and IR for animals of each group
The evaluation index standard of the antitumor activity is as follows: T/C (%) >40% is not effective; T/C (%) is less than or equal to 40%, and P is less than or equal to 0.05 after being subjected to statistical T test. IR% >60% is an effective auxiliary index.
Statistics: and (5) analyzing and processing the experimental result by adopting SPSS17.0 statistical software. The data are expressed as mean ± standard deviation, the mean comparison of samples among multiple groups adopts single factor analysis of variance, and the double multiple comparison adopts LSD-t test. P < 0.01 indicates that the difference is statistically significant.
Experiments prove that the maytansine-affibody polypeptide coupling drug has strong proliferation inhibition effect on human lung cancer H460 nude mice subcutaneous transplantation tumor, has obvious anti-tumor effect, has far smaller molecular weight of affibody polypeptide serving as a target head than an antibody, is not easy to cause immune reaction, is completely synthesized by a chemical method, has higher efficiency and reduces the preparation cost. Therefore, the affinity body polypeptide coupling medicine can improve the targeting of the coupling medicine to tumor cells and reduce the toxic and side effects to normal tissues.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.
Claims (9)
1. A maytansine-polypeptide conjugate having the molecular structural formula of formula I:
wherein R represents maytansine and L represents a linker.
2. Maytansine-polypeptide conjugate according to claim 1, characterized in that the linker comprises the structure-S-.
3. The maytansine-polypeptide conjugate according to claim 2, characterized in that the maytansine-affibody polypeptide conjugate has the molecular structural formula shown in formula II:
4. a method of preparing a maytansinoid-polypeptide conjugate according to any one of claims 1 to 3, characterized by comprising the steps of:
(1) Synthesizing an affinity polypeptide;
(2) Synthesizing an L-affibody polypeptide conjugate: taking 2,2 '-dithiodipyridine and an affibody polypeptide as raw materials, stirring and reacting for 24-48 hours at room temperature in the presence of a dimethyl sulfoxide (DMSO) solvent, wherein the molar ratio of the 2,2' -dithiodipyridine to the affibody polypeptide is (1-4): 1, after the reaction is finished, preparing a liquid phase for purification, concentrating and freeze-drying to obtain an L-affibody polypeptide conjugate;
(3) Synthesis of maytansine-affibody polypeptide conjugates: maytansine and the L-affinity body polypeptide conjugate are mixed according to the molar ratio (1-4): 1 is dissolved in an organic solvent, stirred and reacted for 24 to 36 hours at room temperature to obtain a reaction solution, the reaction solution is purified by a preparation liquid phase, and the purified liquid containing the product is combined, concentrated and freeze-dried to obtain the maytansine-affibody polypeptide conjugate.
5. The method of claim 4, wherein in step (1), the method comprises the steps of:
s1, adopting a solid-phase polypeptide synthesis method, and reacting 9-fluorenylmethoxycarbonyl-protected amino lysine (Fmoc-Lys (Boc) -OH) with Rink Amide-MBHA resin in the presence of N, N' -Diisopropylethylamine (DIEA) to obtain Fmoc-Lys-Rink Amide-MBHA resin;
s2, removing Fmoc protecting groups from the Fmoc-Lys-Rink Amide-MBHA resin through a mixed solution of piperidine and N, N' -Dimethylformamide (DMF), and gradually coupling amino acid (Fmoc-amino acid) of 9-fluorenylmethoxycarbonyl-protected amino group from the C end to the N end by using O-benzotriazol-tetramethylurea Hexafluorophosphate (HBTU) as a condensing reagent according to a peptide sequence to obtain a full-protected peptide resin;
s3, adding a lysate into the full-protection peptide resin for cracking, filtering to obtain filtrate, and obtaining an affinity body crude peptide through sedimentation, centrifugal separation and drying;
s4, purifying and freeze-drying the crude peptide to obtain the affinity body polypeptide.
6. The method for preparing a maytansine-polypeptide conjugate according to claim 5, wherein in S1, the Rink Amide-MBHA resin has a degree of substitution of 0.337mmol/g;
the Rink Amide-MBHA resin comprises the following components in terms of molar ratio: DIEA: the Fmoc-Lys (Boc) -OH molar ratio was 1:2 to 6:4 to 8.
7. The method of claim 5, wherein in S2, the molar ratio of Fmoc-Lys-Rink Amide-MBHA, HBTU, fmoc-amino acid is 1:2 to 6:4 to 8.
8. The method for preparing a maytansine-polypeptide conjugate according to claim 5, wherein in S3, the fully protected peptide resin: the cracking liquid is 1 g:5-10 mL;
the lysate comprises trifluoroacetic acid (TFA), 1, 2-Ethanedithiol (EDI), triisopropylsilane (TIS) and purified water (H) 2 O) the TFA: EDI: TIS: h 2 O is 94:2:2:2.
9. Use of a maytansinoid-affibody polypeptide conjugate according to any one of claims 1 to 3, characterized in that the tumor is lung cancer, for the preparation of a medicament for the prevention or treatment of tumors.
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