Antibody-drug conjugate pharmaceutical compositions

Abstract

This invention provides a pharmaceutical composition of an antibody-drug conjugate, a method for producing the same, and its uses.

Claims

1. A pharmaceutical composition comprising an antibody-drug conjugate represented by formula I: 【Chemistry 1】 In the formula, Ab is an antibody or antigen-binding fragment that targets HER2, HER3, or EGFR, and R is C 1-6 Selected from alkyl groups, where n is selected from integers or decimals between 1 and 8, preferably n is 8; The pharmaceutical composition is an injectable preparation, preferably an injectable solution or a lyophilized injectable preparation; Preferably, the antibody-drug conjugate represented by formula I has structures represented by formula Ia and formula Ib. 【Chemistry 2】 More preferably, the antibody-drug conjugate represented by formula I has structures represented by formulas I-1, Ia-1, and Ib-1. 【Transformation 3】

2. A pharmaceutical composition according to claim 1, If Ab is an antibody or antigen-binding fragment targeting HER2, it comprises a heavy chain variable region (HV) and a light chain variable region (LV), where the heavy chain variable region sequence comprises heavy chain complementarity-determining region 1 (HCDR1), heavy chain complementarity-determining region 2 (HCDR2), and heavy chain complementarity-determining region 3 (HCDR3), and the light chain variable region comprises light chain complementarity-determining region 1 (LCDR1), light chain complementarity-determining region 2 (LCDR2), and light chain complementarity-determining region 3 (LCDR3), where the amino acid sequence of HCDR1 is as shown in SEQ ID NO:1, the amino acid sequence of HCDR2 is as shown in SEQ ID NO:2, the amino acid sequence of HCDR3 is as shown in SEQ ID NO:3, and / or the amino acid sequence of LCDR1 is as shown in SEQ ID NO:4, the amino acid sequence of LCDR2 is as shown in SEQ ID NO:5, and the amino acid sequence of LCDR3 is as shown in SEQ ID As shown in NO:6; More preferably, if Ab is an antibody targeting HER2 or an antigen-binding fragment thereof, it comprises a heavy chain variable region (HV) and a light chain variable region (LV), where the amino acid sequence of HV is as shown in SEQ ID NO:7 and the amino acid sequence of LV is as shown in SEQ ID NO:8; More preferably, if Ab is an antibody targeting HER2 or an antigen-binding fragment thereof, it comprises a heavy chain (HC) and a light chain (LC), where the amino acid sequence of HC is as shown in SEQ ID NO:9 and the amino acid sequence of LC is as shown in SEQ ID NO:10; If Ab is an antibody or antigen-binding fragment targeting HER3, it comprises a heavy chain variable region (HV) and a light chain variable region (LV), where the heavy chain variable region sequence comprises heavy chain complementarity-determining region 1 (HCDR1), heavy chain complementarity-determining region 2 (HCDR2), and heavy chain complementarity-determining region 3 (HCDR3), and the light chain variable region comprises light chain complementarity-determining region 1 (LCDR1), light chain complementarity-determining region 2 (LCDR2), and light chain complementarity-determining region 3 (LCDR3), where the amino acid sequence of HCDR1 is as shown in SEQ ID NO:11, the amino acid sequence of HCDR2 is as shown in SEQ ID NO:12, the amino acid sequence of HCDR3 is as shown in SEQ ID NO:13, and / or the amino acid sequence of LCDR1 is as shown in SEQ ID NO:14, and the amino acid sequence of LCDR2 is as shown in SEQ ID As shown in NO:15, the amino acid sequence of LCDR3 is as shown in SEQ ID NO:16; More preferably, if Ab is an antibody targeting HER3 or an antigen-binding fragment thereof, it comprises a heavy chain variable region (HV) and a light chain variable region (LV), where the amino acid sequence of HV is as shown in SEQ ID NO:17 and the amino acid sequence of LV is as shown in SEQ ID NO:18; More preferably, if Ab is an antibody targeting HER3 or an antigen-binding fragment thereof, it comprises a heavy chain (HC) and a light chain (LC), where the amino acid sequence of HC is as shown in SEQ ID NO:19 and the amino acid sequence of LC is as shown in SEQ ID NO:20; If Ab is an antibody or antigen-binding fragment targeting EGFR, it comprises a heavy chain variable region (HV) and a light chain variable region (LV), where the heavy chain variable region sequence comprises heavy chain complementarity-determining region 1 (HCDR1), heavy chain complementarity-determining region 2 (HCDR2), and heavy chain complementarity-determining region 3 (HCDR3), and the light chain variable region comprises light chain complementarity-determining region 1 (LCDR1), light chain complementarity-determining region 2 (LCDR2), and light chain complementarity-determining region 3 (LCDR3), where the amino acid sequence of HCDR1 is as shown in SEQ ID NO:21, the amino acid sequence of HCDR2 is as shown in SEQ ID NO:22, the amino acid sequence of HCDR3 is as shown in SEQ ID NO:23, and / or the amino acid sequence of LCDR1 is as shown in SEQ ID NO:24, and the amino acid sequence of LCDR2 is as shown in SEQ ID As shown in NO:25, the amino acid sequence of LCDR3 is as shown in SEQ ID NO:26; If Ab is an antibody targeting EGFR or an antigen-binding fragment thereof, it comprises a variable heavy chain region (HV) and a variable light chain region (LV), where the amino acid sequence of HCDR1 is as shown in SEQ ID NO:31, SEQ ID NO:35, or SEQ ID NO:38, the amino acid sequence of HCDR2 is as shown in SEQ ID NO:22, the amino acid sequence of HCDR3 is as shown in SEQ ID NO:23 or SEQ ID NO:32, and / or the amino acid sequence of LCDR1 is as shown in SEQ ID NO:24, the amino acid sequence of LCDR2 is as shown in SEQ ID NO:25, and the amino acid sequence of LCDR3 is as shown in SEQ ID NO:26; If Ab is an antibody targeting EGFR or an antigen-binding fragment thereof, it comprises a variable region of the heavy chain (HV) and a variable region of the light chain (LV), where the amino acid sequence of HCDR1 is as shown in SEQ ID NO:31, SEQ ID NO:35, or SEQ ID NO:38, the amino acid sequence of HCDR2 is as shown in SEQ ID NO:22, the amino acid sequence of HCDR3 is as shown in SEQ ID NO:32, and the amino acid sequence of LCDR1 is as shown in SEQ ID NO:24, the amino acid sequence of LCDR2 is as shown in SEQ ID NO:25, and the amino acid sequence of LCDR3 is as shown in SEQ ID NO:26; More preferably, if Ab is an antibody targeting EGFR or an antigen-binding fragment thereof, it comprises a heavy chain variable region (HV) and a light chain variable region (LV), where the amino acid sequence of HV is as shown in SEQ ID NO:27 and the amino acid sequence of LV is as shown in SEQ ID NO:28; More preferably, if Ab is an antibody targeting EGFR or an antigen-binding fragment thereof, it comprises a heavy chain variable region (HV) and a light chain variable region (LV), where the amino acid sequence of HV is as shown in SEQ ID NO:33, SEQ ID NO:36, or SEQ ID NO:39, and the amino acid sequence of LV is as shown in SEQ ID NO:28; More preferably, if Ab is an antibody targeting EGFR or an antigen-binding fragment thereof, it comprises a heavy chain (HC) and a light chain (LC), where the amino acid sequence of HC is as shown in SEQ ID NO:29 and the amino acid sequence of LC is as shown in SEQ ID NO:30; More preferably, if Ab is an antibody targeting EGFR or an antigen-binding fragment thereof, it comprises a heavy chain (HC) and a light chain (LC), where the amino acid sequence of HC is as shown in SEQ ID NO:34, SEQ ID NO:37, or SEQ ID NO:40, and the amino acid sequence of LC is as shown in SEQ ID NO:30, a pharmaceutical composition.

3. A pharmaceutical composition according to claim 1 or 2, wherein the antibody-drug conjugate represented by formula I has the following structure: 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 Here: DP001 is an antibody having two heavy chains with the amino acid sequence shown in SEQ ID NO:9 and two light chains with the amino acid sequence shown in SEQ ID NO:10; Patritumab is an antibody having two heavy chains with the amino acid sequence shown in SEQ ID NO:19 and two light chains with the amino acid sequence shown in SEQ ID NO:20; SWY2110 is an antibody having two heavy chains with the amino acid sequence shown in SEQ ID NO:29 and two light chains with the amino acid sequence shown in SEQ ID NO:30; SWY2111 is an antibody having two heavy chains with the amino acid sequence shown in SEQ ID NO:34 and two light chains with the amino acid sequence shown in SEQ ID NO:30; SWY2112 is an antibody having two heavy chains with the amino acid sequence shown in SEQ ID NO:37 and two light chains with the amino acid sequence shown in SEQ ID NO:30; SWY2113 is an antibody having two heavy chains with the amino acid sequence shown in SEQ ID NO:40 and two light chains with the amino acid sequence shown in SEQ ID NO:30; A pharmaceutical composition in which n is selected from an integer or decimal number between 1 and 8, preferably n is 8.

4. A pharmaceutical composition according to any one of claims 1 to 3, The mass percentage content of the antibody-drug conjugate represented by Formula I is 1-30% (for example, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 8.5%, about 9%, about 9.5%, about 10%, about 10.5%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%), preferably 5-25%, 8-20%, 8-15%, 8-10%, 15-25%, where 100 wt% is based on the total amount of the pharmaceutical composition; Alternatively, the antibody-drug conjugate content represented by formula I is 1-30 mg / ml (for example, approximately 1 mg / ml, 2 mg / ml, 3 mg / ml, 4 mg / ml, 5 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 8.5 mg / ml, 9 mg / ml, 9.5 mg / ml, 10 mg / ml, 10.5 mg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml). A pharmaceutical composition having a concentration of g / ml, approximately 17 mg / ml, approximately 18 mg / ml, approximately 19 mg / ml, approximately 20 mg / ml, approximately 21 mg / ml, approximately 22 mg / ml, approximately 23 mg / ml, approximately 24 mg / ml, approximately 25 mg / ml, approximately 26 mg / ml, approximately 27 mg / ml, approximately 28 mg / ml, approximately 29 mg / ml, and approximately 30 mg / ml, preferably 5-25 mg / ml, more preferably 5-20 mg / ml, 5-15 mg / ml, and 15-25 mg / ml.

5. A pharmaceutical composition according to any one of claims 1 to 4, further comprising a buffering agent; Preferably, the buffer is selected from acetate, succinate, gluconate, histidine salt, oxalate, lactate, phosphate, citrate, tartrate, fumarate, glycylglycine, trometamol (Tris), morpholinoethanesulfonic acid (MES), and other organic acid buffers, preferably a histidine salt buffer, and more preferably a histidine-histidine hydrochloride buffer; More preferably, the mass percentage content of the buffering agent is 1-10% (for example, about 1%, about 2%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about 6%, about 6.5%, about 7%, about 8%, about 9%, about 9.9%, about 10%), preferably 1-9.9%, 2-6%, 2-5%, and 4-6%, where 100 wt% is based on the total amount of the pharmaceutical composition; Alternatively, the buffering agent content is 1-10 mg / ml (for example, about 1 mg / ml, about 2 mg / ml, about 3 mg / ml, about 4 mg / ml, about 4.5 mg / ml, about 4.6 mg / ml, about 4.7 mg / ml, about 4.8 mg / ml, about 4.9 mg / ml, about 5 mg / ml, about 5.1 mg / ml, about 5.2 mg / ml, about 5.3 mg / ml, about 5.4 mg / ml, about 5.5 mg / ml, about 6 mg / ml, about 6.5 mg / ml, about 7 mg / ml, about 8 mg / ml, about 9 mg / ml, about 10 mg / ml), preferably 2-6 mg / ml, 2-4 mg / ml, 3-6 mg / ml, 4-6 mg / ml; Most preferably, the buffer is a histidine-histidine hydrochloride buffer, where the mass percentage content of histidine is 0.1-1% (e.g., about 0.1%, about 0.2%, about 0.25%, about 0.26%, about 0.27%, about 0.28%, about 0.29%, about 0.3%, about 0.31%, about 0.32%, about 0.33%, about 0.34%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%), preferably 0.1-0.5%, 0.2-0.4%, where 100 wt% is based on the total amount of the pharmaceutical composition; Alternatively, the histidine content is 0.1-1 mg / ml (for example, approximately 0.1 mg / ml, approximately 0.2 mg / ml, approximately 0.21 mg / ml, approximately 0.22 mg / ml, approximately 0.23 mg / ml, approximately 0.24 mg / ml, approximately 0.25 mg / ml, approximately 0.26 mg / ml, approximately 0.27 mg / ml, approximately 0.28 mg / ml, approximately 0.29 mg / ml, approximately 0.3 mg / ml, approximately 0.31 mg / ml, approximately 0.32 mg / ml, approximately 0.33 mg / ml, approximately 0.34 mg / ml, approximately 0.35 mg / ml, approximately 0.4 mg / ml, approximately 0.45 mg / ml, approximately 0.5 mg / ml, approximately 0.55 mg / ml, approximately 0.6 mg / ml, approximately 0.7 mg / ml, approximately 0.8 mg / ml, approximately 0.9 mg / ml, The histidine hydrochloride content is approximately 1 mg / ml, preferably 0.1-0.5 mg / ml, 0.1-0.3 mg / ml, or 0.2-0.4 mg / ml; where the mass percentage content of histidine hydrochloride is 1-10% (e.g., approximately 1%, approximately 2%, approximately 2.5%, approximately 2.6%, approximately 2.7%, approximately 2.8%, approximately 2.9%, approximately 3%, approximately 3.5%, approximately 4%, approximately 4%). The percentages are approximately 0.5%, 4.6%, 4.7%, 4.8%, 4.9%, 5%, 5.1%, 5.2%, 5.3%, 5.4%, 5.5%, 6%, 6.5%, 7%, 8%, 9%, 9.9%, and 10%, preferably 1-9.9%, 2-6%, 2-4%, 3-6%, 3.5-5.5%, and 4-5%, where 100 wt% is based on the total amount of the pharmaceutical composition; Alternatively, the histidine hydrochloride content is 1-10 mg / ml (for example, approximately 1 mg / ml, approximately 2 mg / ml, approximately 2.5 mg / ml, approximately 2.6 mg / ml, approximately 2.7 mg / ml, approximately 2.8 mg / ml, approximately 2.9 mg / ml, approximately 3 mg / ml, approximately 3.5 mg / ml, approximately 4 mg / ml, approximately 4.5 mg / ml, approximately 4.6 mg / ml, approximately 4.7 mg / ml, approximately 4.8 mg / ml, approximately 4.9 mg / ml, approximately A pharmaceutical composition having a concentration of 5 mg / ml, approximately 5.1 mg / ml, approximately 5.2 mg / ml, approximately 5.3 mg / ml, approximately 5.4 mg / ml, approximately 5.5 mg / ml, approximately 6 mg / ml, approximately 6.5 mg / ml, approximately 7 mg / ml, approximately 8 mg / ml, approximately 9 mg / ml, and approximately 10 mg / ml, preferably 2-6 mg / ml, 2-4 mg / ml, 3-6 mg / ml, 4-5.5 mg / ml, and 4.5-5 mg / ml.

6. A pharmaceutical composition according to any one of claims 1 to 5, further comprising a stabilizer; Preferably, the stabilizer is selected from sugars (e.g., sucrose, trehalose), polyhydric alcohols (e.g., mannitol, sorbitol), and amino acids (L-serine, sodium glutamate, alanine, glycine, sarcosine, etc.), preferably sugars, and more preferably sucrose and / or trehalose; More preferably, the mass percentage content of the stabilizer is 50-90% (for example, about 50%, about 60%, about 70%, about 75%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%), preferably 60-90%, 70-90%, and 80-90%, where 100 wt% is based on the total amount of the pharmaceutical composition; Alternatively, a pharmaceutical composition wherein the content of the stabilizer is 50-110 mg / ml (for example, about 50 mg / ml, about 60 mg / ml, about 70 mg / ml, about 75 mg / ml, about 80 mg / ml, about 81 mg / ml, about 82 mg / ml, about 83 mg / ml, about 84 mg / ml, about 85 mg / ml, about 86 mg / ml, about 87 mg / ml, about 88 mg / ml, about 89 mg / ml, about 90 mg / ml, about 91 mg / ml, about 92 mg / ml, about 93 mg / ml, about 94 mg / ml, about 95 mg / ml, about 100 mg / ml, about 105 mg / ml, about 110 mg / ml), preferably 70-100 mg / ml, 80-100 mg / ml, 75-95 mg / ml.

7. A pharmaceutical composition according to any one of claims 1 to 6, further comprising a surfactant; Preferably, the surfactant is selected from polysorbates, preferably polysorbate 20 and / or polysorbate 80; More preferably, the mass percentage content of the surfactant is 0.1-1% (for example, about 0.1%, about 0.15%, about 0.16%, about 0.17%, about 0.18%, about 0.19%, about 0.2%, about 0.25%, about 0.26%, about 0.27%, about 0.28%, about 0.29%, about 0.3%, about 0.31%, about 0.32%, about 0.33%, about 0.34%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.55%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%), preferably 0.2-0.4%, more preferably 0.15-0.4%, 0.15-0.35%, 0.25-0.35%, where 100 wt% is expressed based on the total amount of the aforementioned pharmaceutical composition; Alternatively, a pharmaceutical composition wherein the surfactant content is 0.1-1 mg / ml (for example, about 0.1 mg / ml, about 0.15 mg / ml, about 0.16 mg / ml, about 0.17 mg / ml, about 0.18 mg / ml, about 0.19 mg / ml, about 0.2 mg / ml, about 0.25 mg / ml, about 0.3 mg / ml, about 0.35 mg / ml, about 0.4 mg / ml, about 0.45 mg / ml, about 0.5 mg / ml, about 0.55 mg / ml, about 0.6 mg / ml, about 0.7 mg / ml, about 0.8 mg / ml, about 0.9 mg / ml, about 1 mg / ml), and preferably 0.1-0.4 mg / ml, 0.15-0.25 mg / ml, 0.2-0.4 mg / ml, 0.25-0.35 mg / ml.

8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the pH of the pharmaceutical composition is 4.0-7.5 (for example, about 4.0, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.5, about 7.0), preferably 4.5-7.0, more preferably 4.5-5.5, even more preferably 5.0-5.5, and most preferably about 5.

0.

9. A pharmaceutical composition according to any one of claims 1 to 8, The pharmaceutical composition is a lyophilized injectable preparation, and when the lyophilized injectable preparation is diluted with water for injection, the diluted pharmaceutical composition, based on the total volume of the diluted pharmaceutical composition, contains approximately 10 mg / ml of an antibody-drug conjugate represented by formula I, approximately 0.33 mg / ml of histidine, approximately 4.79 mg / ml of histidine hydrochloride, approximately 0.3 mg / ml of polysorbate 80, and approximately 90 mg / ml of trehalose, and the pH of the diluted pharmaceutical composition is approximately 5.

0. Preferably, the antibody-drug conjugate represented by formula I is selected from SWY2110-JSSW-001, SWY2111-JSSW-001, and SWY2113-JSSW-001, and preferably SWY2110-JSSW-001; or The pharmaceutical composition is an injection solution containing approximately 10 mg / ml of an antibody-drug conjugate represented by formula I, approximately 0.33 mg / ml of histidine, approximately 4.79 mg / ml of histidine hydrochloride, approximately 0.3 mg / ml of polysorbate 80, and approximately 90 mg / ml of trehalose, the pH of the injection solution being approximately 5.0, and preferably the antibody-drug conjugate represented by formula I is selected from SWY2110-JSSW-001, SWY2111-JSSW-001, and SWY2113-JSSW-001, preferably SWY2110-JSSW-001; or The pharmaceutical composition comprises approximately 10 mg / ml of an antibody-drug conjugate represented by formula I, approximately 0.33 mg / ml of histidine, approximately 4.79 mg / ml of histidine hydrochloride, approximately 0.3 mg / ml of polysorbate 80, approximately 90 mg / ml of trehalose, and the remainder being water, and the pH of the pharmaceutical composition is approximately 5.0, and preferably the antibody-drug conjugate represented by formula I is selected from SWY2110-JSSW-001, SWY2111-JSSW-001, and SWY2113-JSSW-001, and preferably SWY2110-JSSW-001; or The pharmaceutical composition comprises or consists of about 10 parts by weight of an antibody-drug conjugate represented by formula I, about 0.33 parts by weight of histidine, about 4.79 parts by weight of histidine hydrochloride, about 0.3 parts by weight of polysorbate 80, and about 90 parts by weight of trehalose; preferably, the antibody-drug conjugate represented by formula I is selected from SWY2110-JSSW-001, SWY2111-JSSW-001, and SWY2113-JSSW-001, and preferably SWY2110-JSSW-001; or The pharmaceutical composition is a lyophilized injectable preparation, and when the lyophilized injectable preparation is diluted with water for injection, the diluted pharmaceutical composition, based on the total volume of the diluted pharmaceutical composition, contains approximately 20 mg / ml of an antibody-drug conjugate represented by formula I, approximately 0.21 mg / ml of histidine, approximately 2.86 mg / ml of histidine hydrochloride, approximately 0.2 mg / ml of polysorbate 80, and approximately 80 mg / ml of sucrose, and the pH of the diluted pharmaceutical composition is approximately 5.0, and preferably the antibody-drug conjugate represented by formula I is Patritumab-JSSW-001; or The pharmaceutical composition is an injectable solution containing approximately 20 mg / ml of an antibody-drug conjugate represented by formula I, approximately 0.21 mg / ml of histidine, approximately 2.86 mg / ml of histidine hydrochloride, approximately 0.2 mg / ml of polysorbate 80, and approximately 80 mg / ml of sucrose, the pH of the injectable solution being approximately 5.0, and preferably the antibody-drug conjugate represented by formula I being Patritumab-JSSW-001; or The pharmaceutical composition comprises approximately 20 mg / ml of an antibody-drug conjugate represented by formula I, approximately 0.21 mg / ml of histidine, approximately 2.86 mg / ml of histidine hydrochloride, approximately 0.2 mg / ml of polysorbate 80, approximately 80 mg / ml of sucrose, and the remainder being water, and the pH of the pharmaceutical composition is approximately 5.0, preferably the antibody-drug conjugate represented by formula I is Patritumab-JSSW-001; or The pharmaceutical composition comprises or consists of about 20 parts by weight of an antibody-drug conjugate represented by formula I, about 0.21 parts by weight of histidine, about 2.86 parts by weight of histidine hydrochloride, about 0.2 parts by weight of polysorbate 80, and about 80 parts by weight of sucrose; preferably, the antibody-drug conjugate represented by formula I is Patritumab-JSSW-001.

10. A method for producing the pharmaceutical composition according to any one of claims 1 to 9, comprising the following steps: S1) A step in producing an antibody-drug conjugate represented by formula I; S2) Step of preparing ultrafiltration replacement buffer; S3) A step in which the antibody-drug conjugate obtained in S1 is replaced by the buffer obtained in S2); Preferably, step S2) includes weighing the buffer and stabilizer according to the formulation amount, adding sterile water for injection and diluting to the target preparation volume, stirring and mixing to homogenize, and obtaining an ultrafiltration displacement buffer; The S3) step involves employing an ultrafiltration membrane and ultrafiltration-displacing the antibody-drug conjugate obtained in S1 into the ultrafiltration-displacing buffer obtained in S2) according to a certain volume, diluting the antibody-drug conjugate to the target concentration with water for injection, adding a surfactant according to the mass fraction or volume fraction to obtain the stock solution; optionally, the stock solution is freeze-dried, preferably including (1) pre-freezing, (2) primary drying, and (3) secondary drying. Here (1) The conditions for pre-freezing are: -60 to -30°C for 18-1800 minutes, for example -45°C for 180 minutes; (2) The conditions for primary drying are: -25 to 0°C, pressure of 0.02-0.5 mbar (absolute pressure), and time of 300 to 40000 minutes, for example -5°C, 0.06 mbar, 3000 minutes, or -20°C, 0.20 mbar, 4000 minutes; (3) The conditions for secondary drying are: 15-45°C, pressure of 0.1-0.5 mbar (absolute pressure), time of 90-12000 minutes, for example, 30°C, 0.20 mbar, 1200 minutes, or 35°C, 0.25 mbar, 900 minutes, manufacturing method.

11. Uses of the pharmaceutical composition according to any one of claims 1 to 9 in the manufacture of a drug for treating proliferative disorders, wherein the proliferative disorder is preferably a disease associated with abnormal expression of HER2, HER3 or EGFR, and includes cancer; preferably, the cancer is breast cancer, ovarian cancer, cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, gastric cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), and colon cancer. , selected from rectal cancer, colorectal cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, pancreatic cancer, or lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, or relapsed anaplastic large cell lymphoma); optionally, the cancers further include triple-negative breast cancer, esophageal cancer, pancreatic cancer, biliary tract cancer, HR-positive breast cancer, squamous cell carcinoma of the lung, non-squamous non-small cell lung cancer, squamous cell carcinoma of the head and neck (including nasopharyngeal cancer), and urothelial carcinoma.

12. Uses of the pharmaceutical composition according to any one of claims 1 to 9 in the manufacture of a drug for treating a proliferative disorder that has developed drug resistance, wherein the proliferative disorder that has developed drug resistance is a disease related to the abnormal expression of HER2, HER3 or EGFR that has developed drug resistance, and includes cancer; more preferably, the cancer that has developed drug resistance is a drug-resistant cancer caused by a HER2, HER3 or EGFR gene mutation, wherein the cancer is preferably breast cancer, ovarian cancer, or pediatric cancer. Cervical cancer, uterine cancer, prostate cancer, kidney cancer, urethral cancer, bladder cancer, liver cancer, stomach cancer, endometrial cancer, salivary gland cancer, esophageal cancer, melanoma, glioma, neuroblastoma, sarcoma, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), colon cancer, rectal cancer, colorectal cancer, leukemia (e.g., acute lymphoblastic leukemia, acute myeloid leukemia, acute promyelocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), bone cancer, skin cancer, thyroid cancer, pancreatic cancer or lymphoma (e.g. The cancer is selected from Hodgkin lymphoma, non-Hodgkin lymphoma, or relapsed anaplastic large cell lymphoma, and optionally, the cancer further includes triple-negative breast cancer, esophageal cancer, pancreatic cancer, biliary tract cancer, HR-positive breast cancer, lung squamous cell carcinoma, non-squamous non-small cell lung cancer, head and neck squamous cell carcinoma (including nasopharyngeal cancer), and urothelial carcinoma; more preferably, the cancer is colon cancer, rectal cancer, lung cancer, or pancreatic cancer; where the drug resistance is preferably receptor tyrosine The resistance is to kinase inhibitors, more preferably to first-generation, second-generation, or third-generation EGFR inhibitors, and even more preferably to gefitinib, erlotinib, icotinib, afatinib, dacomitinib, osimertinib, or ametinib, particularly to gefitinib, afatinib, osimertinib, or ametinib, and more preferably to gefitinib or osimertinib.

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