Use of a composition targeting the erbb3 signaling pathway in the preparation of a medicament for treating lung adenocarcinoma

Abstract

The present application relates to the technical field of pharmaceutical compositions, and particularly relates to application of a composition targeting ERBB3 signal pathway in preparation of a drug for treating lung adenocarcinoma. The drug composition comprises Seribantumab, neratinib, TX1-85-1, procyanidin C1 and vilmorine D. The drug composition provided by the present application exhibits multidimensional anti-lung adenocarcinoma activity in in-vitro pharmacodynamic evaluation. The composition can significantly inhibit the proliferation activity of lung adenocarcinoma cells, and there is a clear dose-effect relationship between the action intensity and the concentration of the composition, and the composition also shows a good inhibitory effect on the clone formation which is an index reflecting the self-renewal and long-term survival ability of tumor cells, which indicates that the composition not only has an instant cytotoxic effect, but also can have a lasting impact on the tumor stemness characteristics, thereby reducing the risk of recurrence, and has a wide application prospect.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical composition technology, and more particularly to the application of a composition targeting the ERBB3 signaling pathway in the preparation of a drug for treating lung adenocarcinoma. Background Technology

[0002] Lung adenocarcinoma (LUAD) is one of the most common pathological types of non-small cell lung cancer and a major cause of cancer-related deaths worldwide. In recent years, with the deepening of precision medicine, targeted therapies targeting mutations in driver genes such as EGFR, ALK, and ROS1, as well as immune checkpoint inhibitors such as PD-1 / PD-L1, have made significant progress, significantly prolonging the survival of some patients. However, targeted therapies inevitably face the challenge of acquired resistance. For example, in patients with EGFR mutations, most develop resistance after 1-2 years of using EGFR-TKIs. The resistance mechanism involves multiple complex factors, including intratarget mutations (such as C797S) and bypass activation (such as MET amplification). Meanwhile, the efficacy of immunotherapy in lung adenocarcinoma is also limited by the inhibitory state of the tumor immune microenvironment, and many patients still experience insufficient treatment response and disease progression. Therefore, in-depth analysis of the key regulatory mechanisms in the development and progression of lung adenocarcinoma, the discovery of new therapeutic targets, and the development of treatment strategies based on new mechanisms are of significant clinical importance for improving the precision treatment of lung adenocarcinoma.

[0003] The tumor microenvironment (TME) plays a crucial role in the progression, metastasis, and treatment resistance of lung adenocarcinoma. Tumor-associated macrophages (TAMs) are one of the most abundant immune cell populations in the lung adenocarcinoma microenvironment. Based on their functional state, they can be divided into M1-like macrophages with pro-inflammatory and anti-tumor activities and M2-like macrophages with immunosuppressive and pro-tumor properties. Numerous studies have shown that M2-like macrophages infiltrate extensively in lung adenocarcinoma tissues and can promote tumor cell proliferation, angiogenesis, immune escape, and distant metastasis by secreting various cytokines, growth factors, and immunomodulatory molecules. Their enrichment is closely related to poor prognosis in lung adenocarcinoma patients. However, current intervention strategies targeting TAMs mainly focus on regulating macrophage recruitment, blocking related chemokines, or directly altering macrophage polarization states, and there is still a lack of clearly defined and effective regulatory targets derived from tumor cells. Our understanding of how lung adenocarcinoma cells actively regulate the functional state and polarization direction of macrophages through specific molecular signals is still insufficient, which has become a key bottleneck restricting the development of targeted tumor immune microenvironment therapy strategies.

[0004] ERBB3 (Erb-B2 receptor tyrosine kinase 3, also known as HER3) belongs to the epidermal growth factor receptor (EGFR) family and is a transmembrane receptor tyrosine kinase with defective kinase activity. In various malignant tumors, ERBB3, by forming heterodimers with its family members (such as HER2 and EGFR), activates classical signaling pathways such as PI3K / AKT, participating in the proliferation, survival, invasion, and treatment resistance of tumor cells. In recent years, ERBB3 has become an important research target for targeted cancer therapy, with related targeting strategies mainly focusing on inhibiting ERBB3 receptor activity or blocking its downstream signaling pathways. However, existing research mainly focuses on the endogenous signaling function of ERBB3 in tumor cell proliferation and survival. Whether ERBB3 participates in signal communication between tumor cells and the immune microenvironment, especially whether it can regulate the functional state and polarization direction of tumor-associated macrophages through paracrine mechanisms, remains a subject lacking in systematic and in-depth research.

[0005] In recent years, advancements in single-cell transcriptome sequencing and intercellular communication analysis have provided new technical means to elucidate the complex signaling networks among different cell types in the tumor microenvironment. A comprehensive analysis of single-cell data from lung adenocarcinoma and clinical databases revealed that ERBB3 exhibits significant expression enrichment in malignant epithelial cells and shows enhanced cell-cell communication associations with M2-like macrophage subsets. Notably, ERBB3 exists not only as a membrane-bound receptor on the cell surface but also in a soluble subtype—some ERBB3 subtypes, lacking an intercellular region, can be secreted extracellularly. This finding suggests that the extracellular domain (ECD) of ERBB3 may participate in intercellular communication as a releaseable paracrine signaling molecule. This evidence suggests that ERBB3 may play a novel role beyond traditional understanding in regulating the immune microenvironment remodeling in lung adenocarcinoma, namely, mediating signaling communication between tumor cells and tumor-associated macrophages through the paracrine pathway, thereby influencing macrophage polarization and function.

[0006] However, current research on ERBB3 mainly focuses on its role as a tumor cell membrane surface receptor in intracellular signal transduction, and there is no application to the specific mechanism by which the extracellular domain of ERBB3 mediates the interaction between tumor cells and immune cells as a paracrine signaling molecule. Existing technologies still lack a novel therapeutic strategy that uses ERBB3 as the core target to improve the immune microenvironment of lung adenocarcinoma by regulating the polarization state of tumor-associated macrophages. This technological gap not only limits the in-depth understanding of the regulatory mechanisms of the immune microenvironment in lung adenocarcinoma, but also restricts the development of novel therapeutic regimens based on tumor cell-immune cell communication networks. Therefore, clarifying the regulatory role of ERBB3 in the communication between lung adenocarcinoma tumor cells and tumor-associated macrophages, and developing ERBB3-mediated macrophage polarization regulation strategies, is expected to provide new molecular targets and technical solutions for the treatment of lung adenocarcinoma. This has significant scientific value and clinical application prospects for overcoming existing treatment bottlenecks and improving the clinical prognosis of lung adenocarcinoma patients. Summary of the Invention

[0007] The purpose of this invention is to provide the application of a composition targeting the ERBB3 signaling pathway in the preparation of a drug for treating lung adenocarcinoma.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution: This invention provides a pharmaceutical composition for treating lung adenocarcinoma, comprising, by weight: 10-20 parts of seribantumab, 5-10 parts of neratinib (CAS No. 698387-09-6), 10-20 parts of TX1-85-1 (CAS No. 1603845-32-4), 5-10 parts of proanthocyanidin C1 (CAS No. 37064-30-5), and 3-5 parts of crotonin D (CAS No. 21499-66-1).

[0009] Preferably, the Seribantumab is an anti-HER3 monoclonal antibody (CAS No. 1334296-12-6).

[0010] Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

[0011] Preferably, the dosage form of the pharmaceutical composition is an injectable formulation.

[0012] This invention provides the use of the pharmaceutical composition described herein in the preparation of a drug for treating lung adenocarcinoma.

[0013] Preferably, the lung adenocarcinoma is EGFR wild-type lung adenocarcinoma or EGFR mutant lung adenocarcinoma.

[0014] The present invention provides a medicament for treating lung adenocarcinoma, the medicament being prepared from the aforementioned pharmaceutical composition.

[0015] Compared with the prior art, the present invention has the following beneficial effects: The composition of this invention constructs a multi-target, multi-level synergistic intervention network based on the mechanism of lung adenocarcinoma development. Specifically, seribantumab, as an anti-HER3 monoclonal antibody, can specifically block the binding of the ERBB3 receptor to its ligand and heterodimer, interfering with the signal activation of tumor cells at its source; neratinib, as a pan-HER family tyrosine kinase inhibitor, can simultaneously inhibit the phosphorylation cascade downstream of EGFR, HER2, and ERBB3. The combination of the two forms a dual blockade of the ERBB3 signaling axis through "membrane receptor blocking + intracellular kinase inhibition," effectively overcoming the compensatory activation that may be caused by a single targeting strategy. Furthermore, TX1-85-1, as a novel ERBB3-targeting regulatory molecule, further enhances the depth of intervention of the composition on the extracellular domain of ERBB3, and may also intervene in paracrine signaling communication between tumor cells and the microenvironment by affecting the release of soluble ERBB3 isoforms.

[0016] Meanwhile, the introduction of proanthocyanidin C1 and crocin D endows the composition with a unique functional dimension of regulating tumor-associated macrophage polarization. Proanthocyanidin C1 has clear anti-inflammatory and immunomodulatory activities, capable of inhibiting the expression of M2-like macrophage marker genes and promoting the transformation of macrophages into M1-like anti-tumor phenotypes; crocin D can weaken the intensity of immunosuppressive signals in the tumor microenvironment by interfering with the activity of key transcription factors such as NF-κB and STAT3. The combined action of these two natural products with antibodies and small molecule inhibitors targeting ERBB3 compensates for the shortcomings of existing technologies that only focus on the intrinsic signaling pathways of tumor cells, achieving a systematic intervention in the core links related to the progression of lung adenocarcinoma.

[0017] The pharmaceutical composition provided by this invention exhibits multidimensional anti-lung adenocarcinoma activity in in vitro pharmacodynamic evaluations. On one hand, the composition significantly inhibits the proliferative activity of lung adenocarcinoma cells, with a clear dose-response relationship between its potency and the administered concentration. This composition may have a durable effect on tumor stemness characteristics, thereby reducing the risk of recurrence. On the other hand, the composition also shows considerable migration inhibition ability in cell migration experiments, indicating its potential to intervene in the early stages of tumor invasion and metastasis, which is of great significance for improving the long-term survival prognosis of lung adenocarcinoma patients.

[0018] More importantly, the composition of this invention organically integrates an ERBB3 targeting strategy with macrophage polarization regulation, achieving for the first time at the technical level a synergistic intervention on the signal transduction of lung adenocarcinoma cells and the remodeling of the tumor immune microenvironment. This mode of action makes it applicable not only to EGFR wild-type lung adenocarcinoma but also to EGFR-mutant patients, potentially providing a new treatment option for drug-resistant populations. Furthermore, the diverse dosage form designs, including lyophilized powder for injection and liposome formulations, shown in the examples further demonstrate the composition's good formulation adaptability and process feasibility, laying a solid foundation for its clinical translation and industrial production. Detailed Implementation

[0019] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0020] Example 1

[0021] A pharmaceutical composition for treating lung adenocarcinoma, comprising, by weight: 10 parts of Seribantumab, 5 parts of neratinib, 10 parts of TX1-85-1, 5 parts of proanthocyanidin C1, and 3 parts of crotonin D.

[0022] Example 2

[0023] A pharmaceutical composition for treating lung adenocarcinoma, comprising, by weight: 20 parts of Seribantumab, 10 parts of neratinib, 20 parts of TX1-85-1, 10 parts of proanthocyanidin C1, and 5 parts of crotonin D.

[0024] Example 3

[0025] A pharmaceutical composition for treating lung adenocarcinoma, comprising, by weight: 15 parts of Seribantumab, 8 parts of neratinib, 15 parts of TX1-85-1, 8 parts of proanthocyanidin C1, and 4 parts of crotonin D.

[0026] Example 4

[0027] A pharmaceutical composition for treating lung adenocarcinoma, comprising, by weight: 12 parts of Seribantumab, 10 parts of neratinib, 18 parts of TX1-85-1, 6 parts of proanthocyanidin C1, and 3 parts of crotonin D.

[0028] Example 5

[0029] A pharmaceutical composition for treating lung adenocarcinoma, comprising, by weight: 18 parts of Seribantumab, 5 parts of neratinib, 12 parts of TX1-85-1, 10 parts of proanthocyanidin C1, and 5 parts of crotonin D.

[0030] Example 6 (Lyophilized Powder for Injection)

[0031] A lyophilized powder injection formulation for treating lung adenocarcinoma, comprising, by weight: 15 parts of Seribantumab, 8 parts of neratinib, 15 parts of TX1-85-1, 8 parts of proanthocyanidin C1, 4 parts of crotonin D, 30 parts of mannitol, an appropriate amount of histidine buffer (pH 6.2), and 0.03 parts of polysorbate 80.

[0032] Preparation method: (1) Solution preparation: Take the prescribed amount of histidine buffer (pH 6.2) and place it in a solution preparation tank. Cool it to 4°C and add 15 parts of Seribantumab, 8 parts of neratinib, 15 parts of TX1-85-1, 8 parts of proanthocyanidin C1 and 4 parts of crotonin D in sequence. Stir and dissolve at 4°C with a stirring speed of 180 rpm for 45 min to ensure complete dissolution. (2) Addition of excipients: Add 30 parts of mannitol and 0.03 parts of polysorbate 80 according to the prescription, continue stirring until dissolved evenly, add water for injection to the total volume, and adjust the pH to 6.2; (3) Sterilization filtration: The above-mentioned drug solution was filtered through 0.45μm and 0.22μm microporous membranes for two-stage sterilization, and then dispensed into 10 mL vials, with each vial containing 2 mL. (4) Freeze-drying: After partially sealing the dispensed vials, transfer them to a freeze dryer for freeze-drying. (5) Stopping and capping: After the freeze-drying is completed, the vial is stopped under vacuum, the vial is removed, and the vial is capped to obtain the freeze-dried powder for injection.

[0033] Example 7 (Liposome Formulation for Injection)

[0034] An injectable liposomal formulation for treating lung adenocarcinoma, comprising, by weight: 15 parts of Seribantumab, 8 parts of neratinib, 15 parts of TX1-85-1, 8 parts of proanthocyanidin C1, 4 parts of crotonin D, 75 parts of soybean lecithin (SPC), 20 parts of cholesterol, 10 parts of distearate phosphatidylethanolamine-polyethylene glycol 2000 (DSPE-PEG2000), 150 parts of sucrose, and an appropriate amount of phosphate buffered saline (PBS, pH 6.5, 10 mM).

[0035] Preparation method: (1) Preparation of lipid phase: Weigh 75 parts of soybean lecithin, 20 parts of cholesterol and 10 parts of DSPE-PEG2000 according to the prescription amount, dissolve them in anhydrous ethanol (the mass-volume ratio of total lipids to anhydrous ethanol is 1:12, g / mL), and stir in a water bath at 45℃ until completely dissolved to obtain lipid phase solution. (2) Preparation of aqueous phase of drug: Take 8 parts of the prescribed amount of neratinib, TX1-85-115 parts, 8 parts of proanthocyanidin C1 and 4 parts of crotonin D, dissolve them in 10 mM PBS buffer (pH 6.5), stir and dissolve in a water bath at 45℃ to obtain the aqueous phase solution of drug; (3) Thin film dispersion: The lipid phase solution was transferred to a rotary evaporator and the organic solvent was removed by rotary evaporation (70 rpm) under a vacuum of -0.09 MPa in a water bath at 50℃ until a uniform phospholipid film was formed on the bottle wall. The solution was then dried under vacuum for 30 min to remove any remaining organic solvent. (4) Hydration: Preheat the aqueous solution of the drug to 58°C, add it to an evaporation flask containing a phospholipid membrane, and hydrate and stir in a 58°C water bath (180 rpm, 1.5 hours) to completely remove the membrane and hydrate to form a crude liposome suspension. (5) Particle size control (high pressure homogenization): The crude liposome suspension was transferred to a high pressure homogenizer and homogenized 3 times at 800 bar pressure at 58°C, and then homogenized 5 times at 1200 bar pressure. The homogenized liposome suspension was extruded 6 times through polycarbonate membrane extruders with pore sizes of 200 nm and 100 nm to obtain a liposome suspension with uniform particle size. The average particle size (D50) was controlled to be 120 nm and the polydispersity index (PDI) was 0.15. (6) Antibody conjugation / adsorption: Seribantumab antibody was dissolved in 10 mM PBS buffer (pH 6.5), and added to the above liposome suspension at a mass ratio of antibody to liposome phospholipid of 1:15. The mixture was stirred and incubated at 25°C (100 rpm for 1.5 hours) to allow the antibody to adsorb onto the surface of the liposomes. (7) Removal of free drug: Purification was performed using a tangential flow ultrafiltration system. An ultrafiltration membrane with a molecular weight cutoff of 300 kDa was selected. The membrane was washed with 6 volumes of 10 mM PBS buffer (pH 6.5) as the replacement solution to remove free unencapsulated drug and unbound antibody. The retentate was collected. (8) Addition of freeze-drying protectant and freeze-drying: Add 150 parts of the prescribed amount of sucrose to the purified liposome concentrate as freeze-drying protectant, stir to dissolve, filter through a 0.22 μm filter membrane for sterilization, dispense into vials, and dry; (9) Stopping and capping: After the freeze-drying is completed, nitrogen is filled and stopped, and then capped to obtain the freeze-dried liposome preparation for injection.

[0036] Comparative Example 1

[0037] The other methods are the same as in Example 5, except that the addition of proanthocyanidins C1 and crotonin D is omitted.

[0038] Comparative Example 2

[0039] The other methods are the same as in Example 5, except that the addition of Seribantumab is omitted.

[0040] Comparative Example 3

[0041] The other methods are the same as in Example 5, except that the addition of TX1-85-1 is omitted.

[0042] Example 1: Evaluation of the in vitro anti-lung adenocarcinoma activity of the drug composition

[0043] 1. Tumor cell proliferation inhibition assay (AlamarBlue method)

[0044] Log-phase SPCA-1 human lung adenocarcinoma cells in good growth condition were collected, digested with trypsin, and then added to freshly prepared DMEM complete medium (containing 10% fetal bovine serum) to prepare a single-cell suspension. The cell concentration was adjusted to 2.5 × 10⁻⁶ cells / year. 4 Cells / mL. The cell suspension was seeded into 96-well plates at 200 μL per well (i.e., 5 × 10³ cells per well) and incubated at 37°C in a 5% CO2 incubator for 24 h to allow the cells to adhere completely.

[0045] The culture medium was aspirated, and 100 μL of serum-free DMEM medium containing the test drug (compositions of Examples 1-5 and Comparative Examples 1-3) at a final concentration of 20 μg / mL was added to each well. An equal volume of DMSO medium was used as a negative control, and cell-free medium wells were used as a blank control. Five replicates were set for each group. The wells were incubated at 37°C in a 5% CO2 incubator for 72 h. For the composition of Example 3, a concentration gradient group (0.625, 1.25, 2.5, 5, 10, 20, 40, 80 μg / mL) was also included to evaluate the dose-effect relationship.

[0046] After incubation, remove the culture medium and add 180 μL of fresh phenol red-free DMEM medium and 20 μL of LalamrBlue™ reagent (final concentration 0.075 mg / mL) to each well. Incubate at 37℃ in a 5% CO2 incubator in the dark for 2–6 h. After a significant color change in the negative control wells, measure the absorbance at 570 nm and 600 nm wavelengths using a microplate reader (A). 570 and A600 ).

[0047] The inhibition rate of each drug combination on SPCA-1 cell proliferation was calculated using the following formula: Inhibition rate (%) = [1 - (117216 × A)] 570 (Sample)-80586×A 600 (sample) / (117216×A) 570 (Control) -80586×A 600 (Comparison)]×100% 2. Plate colony formation experiment SPCA-1 cells in good logarithmic growth phase were collected, digested, and prepared into a single-cell suspension. The cell concentration was adjusted to 2 × 10⁻⁶ cells / cells. 5 Cells were seeded at a density of 1 mL / well in 12-well plates. The plates were then incubated at 37°C with 5% CO2 for 24 hours to allow cell adhesion.

[0048] Aspirate the culture medium and add 1 mL of culture medium containing the test drug at a final concentration of 20 μg / mL to each well. A separate well containing an equal volume of solvent serves as a negative control. After 48 h of treatment, aspirate the culture medium, wash the cells twice with PBS, digest with trypsin, collect the cells, and readjust the cell concentration to 0.2 × 10³ cells / mL. Seed the cell suspension into 6-well plates, 2 mL per well (400 cells per well). Continue culturing at 37°C in a 5% CO2 incubator, changing the culture medium every 3 days.

[0049] On day 14, remove the culture medium and wash the cells twice with pre-cooled PBS. Add 500 μL of 4% paraformaldehyde fixative to each well and fix at room temperature for 5 min. After fixation, remove the fixative, wash twice with PBS, stain with crystal violet for 3 min, then slowly wash away excess stain with running water and air dry at room temperature.

[0050] Count the number of clones containing more than 50 cells under a microscope. Calculate the colony formation inhibition rate using the following formula: Inhibition rate (%) = [1 - (number of clones in the drug-treated group / number of clones in the negative control group)] × 100% 3. Cell scratch migration assay SPCA-1 cells in good logarithmic growth phase were collected, digested, and prepared into a single-cell suspension. The cell concentration was adjusted to 5 × 10⁻⁶ cells / cells. 5 Cells were seeded at a density of 1 / mL into 6-well plates, 2 mL per well. The plates were incubated at 37°C with 5% CO2 for 24 h to allow cells to reach complete confluence.

[0051] Using a 10 μL pipette tip, make three parallel scribbles perpendicular to the bottom of each well (approximately 0.5–1 cm apart). Keep the pipette tip perpendicular to ensure consistent scribble width. After scribbling, gently wash the cells twice with pre-cooled PBS to remove any detached cell debris.

[0052] Two mL of serum-free DMEM medium containing the test drug at a final concentration of 20 μg / mL was added to each well. An equal volume of medium was added as a negative control. The wells were incubated at 37°C with 5% CO2 for 48 h. Images were taken at the same location in each well using an inverted microscope at 0 h and 48 h.

[0053] The area or width of the scratch region at each time point was measured using ImageJ software, and the cell migration inhibition rate was calculated using the following formula: Migration inhibition rate (%) = [1 - (scratch healing rate in drug-treated group / scratch healing rate in negative control group)] × 100% Wherein: Scratch healing rate (%) = (0 h scratch area - 48 h scratch area) / 0 h scratch area × 100% Table 1. Inhibition rate (%) of the drug composition on SPCA-1 cell proliferation

[0054] Table 2. Inhibition rate of SPCA-1 cell proliferation at different concentration gradients of the composition in Example 3.

[0055] Table 3. Inhibition rate (%) of the drug composition on SPCA-1 cell colony formation.

[0056] Table 4. Inhibition rate (%) of the drug composition on SPCA-1 cell migration

[0057] Based on the experimental data in Tables 1 to 4, analysis of the in vitro anti-lung adenocarcinoma activity of the pharmaceutical composition reveals that the composition of this invention exhibits significant anti-tumor effects in multiple dimensions. Regarding cell proliferation inhibition, all example groups demonstrated good inhibitory capabilities, with Example 3 showing particularly outstanding effects. Furthermore, its inhibitory effect exhibited a clear dose-dependent relationship, indicating that the composition possesses controllable and predictable efficacy and modality. In clonogenic and cell migration experiments, each example also showed a superior trend compared to the comparative example, further verifying that the composition not only inhibits the proliferative activity of tumor cells but also effectively weakens their clonal growth and migration abilities, the latter being closely related to tumor metastatic potential.

[0058] From a comparative analysis perspective, the performance of each control group in terms of proliferation inhibition, colony formation inhibition, and migration inhibition was generally lower than that of the example group, suggesting a synergistic relationship between the components in the composition. In particular, when key components such as proanthocyanidin C1, crotonin D, or seribantumab were omitted, the overall activity decreased significantly, further confirming the synergistic mechanism of the components in this composition in targeting the ERBB3 signaling pathway and regulating the biological behavior of tumor cells.

[0059] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A pharmaceutical composition for treating lung adenocarcinoma, characterized in that, The pharmaceutical composition comprises, by weight, 10-20 parts of Seribantumab, 5-10 parts of neratinib, 10-20 parts of TX1-85-1, 5-10 parts of proanthocyanidin C1, and 3-5 parts of crotonin D.

2. The pharmaceutical composition according to claim 1, characterized in that, Seribantumab is an anti-HER3 monoclonal antibody.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The pharmaceutical composition also includes a pharmaceutically acceptable carrier or excipient.

4. The pharmaceutical composition according to claim 3, characterized in that, The dosage form of the pharmaceutical composition is an injectable formulation.

5. Use of the pharmaceutical composition according to any one of claims 1 to 4 in the preparation of a medicament for treating lung adenocarcinoma.

6. The application according to claim 5, characterized in that, The lung adenocarcinoma is either EGFR wild-type lung adenocarcinoma or EGFR mutant lung adenocarcinoma.

7. A drug for treating lung adenocarcinoma, characterized in that, The drug is prepared from the pharmaceutical composition according to any one of claims 1 to 4.

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