Application of anti-interleukin-11 antibody in preparation of tumor treatment medicine

Abstract

The invention provides application of an anti-human interleukin-11 antibody or an antigen binding fragment thereof in preparation of a medicine for treating tumors related to IL-11 expression. Experiments prove that the anti-human interleukin-11 antibody or the antigen binding fragment thereof can block the formation of an IL-11 / IL-11R alpha / GP130 three-body complex and / or block the activation of an STAT3 signal channel by combining IL-11, so that the obvious inhibition effect on tumor growth is realized.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims the priority benefit of the Chinese invention patent application with application number CN202310941870.8 filed on July 28, 2023, the entire contents of which are hereby incorporated by reference. Technical Field

[0003] The present invention relates to the field of biomedicine, and in particular to application of an anti-interleukin-11 (IL-11) antibody in tumor treatment. Background Art

[0004] IL-11 is an important member of the IL-6 family, containing 178 amino acids and a molecular weight of approximately 19kDa. IL-11 can be expressed by various types of cells, including leukocytes, fibroblasts, and epithelial cells. IL-11 is an important inflammatory factor, and its expression is regulated by a variety of cytokines such as TGF-β, IL-1β, IL-22, IL-17F, IFN-γ, TNF-α, and COX-2. Studies have shown that IL-11 plays an important role in the progression of major diseases such as tumors, inflammatory diseases, acute liver injury, NASH, and fibrosis.

[0005] Studies have shown that IL-11 is upregulated in a variety of tumors, including melanoma, breast cancer, colorectal cancer, and non-small cell lung cancer. It was found that the high expression of IL-11 in non-small cell lung cancer is closely related to the patient's prognosis, so IL-11 is considered a potential biomarker; in breast cancer, the upregulated expression of IL-11 can further promote the bone metastasis of the tumor. In addition, IL-11 can bind to the IL-11 receptor alpha (IL-11Rα) and the gp130 receptor, and then activate the downstream signaling pathways with a 2:2:2 6-mer complex of IL-11 / IL-11Rα / gp130, including the three classic pathways of JAK / STAT3 pathway, Akt, and ERK. Among them, the activation of the JAK / STAT3 pathway caused by IL-11 is considered to be closely related to gastrointestinal tumors, and the inhibitors of the pathway can be used for the treatment of tumors; in the process of chronic gastritis turning into gastric cancer, the gradual increase of IL-11 and the activation of the signaling pathway are clearly observed. Inhibition of the IL-11 signaling pathway has a clear inhibitory effect on the growth and metastasis of various tumors, suggesting that the IL-11 signaling pathway plays an important role in maintaining the proliferation, survival and migration of tumor cells.

[0006] In addition, in recent years, a lot of research has been done on the role of IL-11 signaling pathways in non-tumor cells such as macrophages, DC cells, CD4+T cells, fibroblasts, etc., making people's understanding of the relationship between IL-11 and tumors more comprehensive and in-depth. For example, it was found that IL-11 can inhibit the activity of CD4+ positive T cells, thereby achieving immunosuppression; IL-11 induces mDSC differentiation by activating STAT3; tumors activate IL-11+ fibroblasts by expressing IL-11, and further chemotaxis or activation of more IL-11+ fibroblasts to secrete IL-11, forming a suppressive immune microenvironment driven by cancer-associated fibroblasts (CAF), promoting tumor growth and metastasis; and so on.

[0007] The above studies suggest that IL-11 affects the occurrence and progression of tumors in many ways. For example, in the tumor microenvironment, tumor cells and non-tumor cells jointly create an inhibitory immune microenvironment suitable for tumor growth through the IL-11 signaling pathway. Therefore, inhibitors targeting IL-11 can exert anti-tumor efficacy by directly affecting tumor cells and improving the inhibitory immune microenvironment. Summary of the invention

[0008] According to the data in the gepia2 database (http: / / gepia2.cancer-pku.cn / #general), IL-11 is expressed relatively high in breast cancer, thyroid cancer, urothelial carcinoma, lung adenocarcinoma, renal papillary cell carcinoma, prostate cancer, bile duct cancer, esophageal cancer, pancreatic cancer, and colon cancer ( Figure 1 ), and in renal papillary cell carcinoma, lung adenocarcinoma, pancreatic cancer, cervical cancer, and breast cancer, patients with relatively low expression of IL11 have a better prognosis ( Figure 2 ).

[0009] Based on the above research results, the inventors of the present invention tried to use IL-11 as a tumor treatment target and studied the application of anti-IL-11 antibodies in tumor treatment. The results showed that antibodies with high affinity for IL-11 have a significant growth inhibitory effect on tumors with high IL-11 expression.

[0010] The technical solution of the present invention is as follows.

[0011] The present invention provides use of an anti-IL-11 antibody or an antigen-binding fragment thereof in preparing a medicament for treating tumors associated with IL-11 expression (including overexpression).

[0012] In the present invention, the term "IL-11" refers to interleukin-11 derived from a mammal, such as a primate (eg, cynomolgus monkey, human) or a rodent (eg, rat, mouse).

[0013] The "treatment of IL-11 expression (including overexpression) related tumors" described in the present invention may refer to achieving the effect of inhibiting the proliferation and / or survival of tumor cells or inhibiting tumor growth. In the actual treatment process, the anti-IL-11 antibody or its antigen-binding fragment can be used alone or in combination with other therapeutic agents or treatment methods. Therefore, accordingly, the present invention includes a technical solution in which the anti-IL-11 antibody or its antigen-binding fragment is prepared alone as a drug for treating IL-11 expression (including overexpression) related tumors or is prepared together with other therapeutic agents or treatment methods as a drug for treating IL-11 expression (including overexpression) related tumors.

[0014] In the present invention, the term "drug" covers the anti-IL-11 antibody or its antigen-binding fragment that is prepared as a drug that can be administered by any route, for example, the route is parenteral, intravenous, intraarterial, intraocular, intraconjunctival, intramuscular, subcutaneous, intradermal, intratumor injection or infusion, and oral administration. In addition, the subject of the drug can be any mammal, preferably a human. The subject can be a person who has been diagnosed with a tumor that needs treatment, or is suspected of having the tumor.

[0015] In the present invention, the anti-IL-11 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and / or a light chain variable region (VL). The heavy chain variable region (VH) may comprise a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 (H-CDR1, H-CDR2, H-CDR3) derived from the heavy chain variable region shown in the following amino acid sequence: an amino acid sequence shown in SEQ ID NO.1, SEQ ID NO.3, SEQ ID NO.5, SEQ ID NO.7, SEQ ID NO.9 or SEQ ID NO.11. The light chain variable region (VL) may comprise a light chain CDR1, a light chain CDR2 and a light chain CDR3 (L-CDR1, L-CDR2, L-CDR3) derived from the heavy chain variable region shown in the following amino acid sequence: an amino acid sequence shown in SEQ ID NO.2, SEQ ID NO.4, SEQ ID NO.6, SEQ ID NO.8, SEQ ID NO.10 or SEQ ID NO.12.

[0016] The above-mentioned amino acid sequences are respectively the amino acid sequences of the heavy chain variable region or the light chain variable region of the anti-IL-11 antibody provided in the present invention. Using the definition tools of complementary determining regions in antibody heavy chain or light chain variable regions known in the art (such as Chothia, Kabat, IMGT, Contact, etc.), those skilled in the art can easily determine the heavy chain CDRs and light chain CDRs contained therein. According to a specific embodiment of the present invention, the Kabat tool can be used to divide the CDRs in the variable region sequence.

[0017] Preferably, the anti-IL-11 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), and the heavy chain variable region and the light chain variable region comprise a heavy chain CDR1, a heavy chain CDR2 and a heavy chain CDR3 (H-CDR1, H-CDR2, H-CDR3) and a light chain CDR1, a light chain CDR2 and a light chain CDR3 (L-CDR1, L-CDR2, L-CDR3) from the heavy chain variable region and the light chain variable region shown in the following amino acid sequence pairing:

[0018] (1) SEQ ID NO.1+SEQ ID NO.2;

[0019] (2) SEQ ID NO.3+SEQ ID NO.4;

[0020] (3) SEQ ID NO. 5 + SEQ ID NO. 6;

[0021] (4) SEQ ID NO.7+SEQ ID NO.8;

[0022] (5) SEQ ID NO.9+SEQ ID NO.10; or

[0023] (6) SEQ ID NO.11+SEQ ID NO.12.

[0024] As described above, the Kabat tool can be used to divide the CDRs in each variable region sequence in the above amino acid sequence pairing.

[0025] According to a specific embodiment of the present invention, in the antibody or antigen-binding fragment thereof, the heavy chain variable region and the light chain variable region comprise a combination of heavy chain CDRs and light chain CDRs (H-CDR1, H-CDR2, H-CDR3; and, L-CDR1, L-CDR2, L-CDR3) selected from the following:

[0026] (1) H-CDR1, H-CDR2, H-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 28, and L-CDR1, L-CDR2, L-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 29, SEQ ID NO. 30, SEQ ID NO. 31, respectively;

[0027] (2) H-CDR1, H-CDR2, H-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 26, SEQ ID NO. 27, SEQ ID NO. 32, and L-CDR1, L-CDR2, L-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 29, SEQ ID NO. 33, SEQ ID NO. 31, respectively;

[0028] (3) H-CDR1, H-CDR2, H-CDR3 comprising the amino acid sequences shown in SEQ ID NO.34, SEQ ID NO.35, SEQ ID NO.36, and L-CDR1, L-CDR2, L-CDR3 comprising the amino acid sequences shown in SEQ ID NO.37, SEQ ID NO.38, SEQ ID NO.39, respectively;

[0029] (4) H-CDR1, H-CDR2, H-CDR3 comprising the amino acid sequences shown in SEQ ID NO.26, SEQ ID NO.27, SEQ ID NO.40, and L-CDR1, L-CDR2, L-CDR3 comprising the amino acid sequences shown in SEQ ID NO.29, SEQ ID NO.33, SEQ ID NO.31, respectively;

[0030] (5) H-CDR1, H-CDR2, H-CDR3 comprising the amino acid sequences shown in SEQ ID NO.41, SEQ ID NO.42, SEQ ID NO.36, and L-CDR1, L-CDR2, L-CDR3 comprising the amino acid sequences shown in SEQ ID NO.43, SEQ ID NO.38, SEQ ID NO.39, or

[0031] (6) H-CDR1, H-CDR2, and H-CDR3 comprising the amino acid sequences shown in SEQ ID NO.44, SEQ ID NO.42, and SEQ ID NO.36, respectively; and L-CDR1, L-CDR2, and L-CDR3 comprising the amino acid sequences shown in SEQ ID NO.37, SEQ ID NO.38, and SEQ ID NO.39, respectively.

[0032] Preferably, in the anti-IL-11 antibody or antigen-binding fragment thereof, the heavy chain variable region (VH) and the light chain variable region (VL) respectively comprise a combination of amino acid sequences selected from the following:

[0033] (1) the amino acid sequence shown in SEQ ID NO.1, or an amino acid sequence having at least 75% identity with said amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.2, or an amino acid sequence having at least 75% identity with said amino acid sequence;

[0034] (2) the amino acid sequence shown in SEQ ID NO.3, or an amino acid sequence having at least 75% identity with said amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.4, or an amino acid sequence having at least 75% identity with said amino acid sequence;

[0035] (3) the amino acid sequence shown in SEQ ID NO.5, or an amino acid sequence having at least 75% identity with said amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.6, or an amino acid sequence having at least 75% identity with said amino acid sequence;

[0036] (4) the amino acid sequence shown in SEQ ID NO.7, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.8, or an amino acid sequence having at least 75% identity with the amino acid sequence;

[0037] (5) the amino acid sequence shown in SEQ ID NO.9, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.10, or an amino acid sequence having at least 75% identity with the amino acid sequence; or

[0038] (6) the amino acid sequence shown in SEQ ID NO.11, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.12, or an amino acid sequence having at least 75% identity with the amino acid sequence.

[0039] In the present invention, the at most 25% difference in the amino acid sequence caused by the "at least 75% identity" may be present in any framework region in the heavy chain variable region or the light chain variable region, or in any domain or sequence outside the heavy chain variable region and the light chain variable region in the antibody or fragment thereof of the present invention. The difference may be caused by deletion, addition or substitution of amino acids at any position, wherein the substitution may be a conservative substitution or a non-conservative substitution. The "at least 75% identity" covers any percentage of identity between at least 75% identity and 100% identity, such as 75%, 80%, 85%, 90%, even 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or even 100% identity.

[0040] The anti-IL-11 antibody or antigen-binding fragment thereof comprising the above amino acid sequence may be an antibody or antigen-binding fragment thereof of any structural configuration. For example, the antibody itself may be a monoclonal antibody, a bispecific or multispecific antibody, or may be an antibody of a structure such as scFv, BsFv, dsFv, (dsFv)2, Fab, Fab', F(ab')2 or Fv; or a fragment of any form.

[0041] More preferably, the present invention provides the use of the anti-IL-11 antibody or its antigen-binding fragment in the preparation of a drug for treating IL-11 expression (including overexpression) related tumors, wherein the anti-IL-11 antibody is a humanized antibody. Preferably, the anti-IL-11 antibody comprises an IgG heavy chain constant region and / or a κ or λ type light chain constant region. According to a specific embodiment of the present invention, the anti-IL-11 antibody comprises an IgG1 type heavy chain constant region and a κ type light chain constant region. More specifically, the anti-IL-11 antibody is an IgG1 or κ type monoclonal antibody.

[0042] According to a specific embodiment of the present invention, the anti-IL-11 antibody or antigen-binding fragment thereof comprises a heavy chain (HC) and a light chain (LC), and the heavy chain and the light chain respectively comprise an amino acid sequence combination selected from the following:

[0043] (1) the amino acid sequence shown in SEQ ID NO.13, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.14, or an amino acid sequence having at least 75% identity with the amino acid sequence;

[0044] (2) the amino acid sequence shown in SEQ ID NO.15, or an amino acid sequence having at least 75% identity with said amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.16, or an amino acid sequence having at least 75% identity with said amino acid sequence;

[0045] (3) the amino acid sequence shown in SEQ ID NO.17, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.18, or an amino acid sequence having at least 75% identity with the amino acid sequence;

[0046] (4) the amino acid sequence shown in SEQ ID NO.19, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.20, or an amino acid sequence having at least 75% identity with the amino acid sequence;

[0047] (5) the amino acid sequence shown in SEQ ID NO.21, or an amino acid sequence having at least 75% identity with said amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.22, or an amino acid sequence having at least 75% identity with said amino acid sequence; or

[0048] (6) the amino acid sequence shown in SEQ ID NO.23, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.24, or an amino acid sequence having at least 75% identity with the amino acid sequence.

[0049] According to a specific embodiment of the present invention, the heavy chain constant region in the anti-IL-11 antibody or antigen-binding fragment thereof can be replaced with the heavy chain constant region shown in SEQ ID NO.25.

[0050] Preferably, the tumor is a tumor associated with IL-11 expression (including overexpression), such as non-small cell lung cancer (lung adenocarcinoma, lung squamous cell carcinoma), pancreatic cancer or cervical cancer.

[0051] In the use provided by the present invention, the drug is used to treat a mammal, preferably a human. The mammal may be diagnosed with a tumor that needs to be treated, or suspected of having the tumor.

[0052] In another aspect, the present invention provides a method for treating a tumor, the method comprising administering an anti-IL-11 antibody or an antigen-binding fragment thereof to a subject in need thereof. The tumor is an IL-11 expression (including overexpression) related tumor, such as non-small cell lung cancer (lung adenocarcinoma, lung squamous cell carcinoma), pancreatic cancer or cervical cancer. The anti-IL-11 antibody or antigen-binding fragment thereof is as defined above.

[0053] In the method, the route of administration can be parenteral, intravenous, intraarterial, intraocular, intraconjunctival, intramuscular, subcutaneous, intradermal, intratumor injection or infusion, and oral. In addition, the subject can be any mammal, preferably a human. The subject can be diagnosed with a tumor in need of treatment, or suspected of having the tumor.

[0054] Preferably, in the method, a therapeutically effective amount of the anti-IL-11 antibody or antigen-binding fragment thereof is administered to the subject. In the present invention, the term "therapeutically effective amount" refers to an amount that can show a therapeutic benefit to the subject. The actual dose or administration regimen administered may depend on factors such as the nature and severity of the tumor.

[0055] The method for treating tumors provided by the present invention covers the administration of the anti-IL-11 antibody or its antigen-binding fragment alone or in combination with other therapeutic agents or treatment methods. In the present invention, the term "combined" administration refers to the administration of the anti-IL-11 antibody or its antigen-binding fragment and other therapeutic agents or treatment methods simultaneously or sequentially at a certain time interval; the time interval can be any time interval.

[0056] Compared with the prior art, the present invention proposes a new solution to treat tumors by using IL-11 as a tumor treatment target. Without being limited to any theory, the present invention uses a specific anti-interleukin-11 antibody as a therapeutic agent, which blocks the formation of the IL-11 / IL-11Rα / GP130 tribody complex and / or blocks the activation of the STAT3 signaling pathway by binding to IL-11 with high affinity, thereby achieving a significant inhibitory effect on tumor growth. BRIEF DESCRIPTION OF THE DRAWINGS

[0057] The embodiments of the present invention are described in detail below with reference to the accompanying drawings, wherein:

[0058] Figure 1 The expression of IL-11 at the transcript level in tumor tissues is shown.

[0059] Figure 2 The relationship between IL-11 and the prognosis of tumor patients is shown.

[0060] Figure 3 The graph shows the growth curve (volume) of the tumor over time after subcutaneous transplantation of IL-11Rα knockout MC38 cells and wild-type MC38 cells into mice.

[0061] Figure 4 The graph shows the growth curve (volume) of tumors over time after subcutaneous transplantation of MC38 cells into wild-type mice and IL-11Rα knockout mice.

[0062] Figure 5The figure shows the tumor growth after administration of different antibodies in a mouse model of human lung adenocarcinoma; wherein, 5A: tumor growth curve (volume); 5B: tumor weight.

[0063] Figure 6 The figure shows the tumor growth after administration of different antibodies in the PDX mouse model of human lung adenocarcinoma; wherein, 6A: tumor growth curve (volume); 6B: tumor weight.

[0064] Figure 7 Shown are the tumor growth curves (volume) after administration of different antibodies in a PDX mouse model of human pancreatic cancer.

[0065] Figure 8 The figure shows the tumor growth after administration of different antibodies in the PDX mouse model of human cervical cancer; wherein, 8A: tumor growth curve (volume); 8B: tumor weight.

[0066] Fig. 9 The figure shows the tumor growth curve (volume) after administration of different antibodies in the PDX mouse model of human lung squamous cell carcinoma.

[0067] Best Mode for Carrying Out the Invention

[0068] The present invention is described below with reference to specific examples. It will be appreciated by those skilled in the art that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention in any way.

[0069] The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials, reagents, etc. used in the following examples are commercially available products unless otherwise specified.

[0070] The following examples use anti-IL-11 antibodies hz8C8m7, hz8C8m13, and hz18A10m19. These three antibodies are humanized monoclonal antibodies obtained by humanization based on mouse antibodies, and contain two heavy chains and two light chains. Experiments have shown that these three antibodies can bind to human IL-11 with high affinity and can block the formation of IL-11 / IL-11Ra / gp130 trimeric complex; see Chinese invention patent CN202310044074.4.

[0071] The amino acid sequences of the antibodies used in the present invention are as follows, wherein the sequences in italics are the heavy chain variable region or the light chain variable region, the underlined and bold sequences in the variable region are CDR1 to 3 (divided using the Kabat tool); the sequences in bold only are the heavy chain constant region or the light chain constant region:

[0072] 1.hz8C8m7:

[0073] >Heavy chain

[0074]

[0075] H-CDR1: SEQ ID NO.26

[0076] H-CDR2: SEQ ID NO.27

[0077] H-CDR3: SEQ ID NO.28

[0078] VH: SEQ ID NO.1

[0079] Heavy chain full length: SEQ ID NO.13

[0080] >Light Chain

[0081]

[0082] L-CDR1: SEQ ID NO.29 L-CDR2: SEQ ID NO.30 L-CDR3: SEQ ID NO.31 VL: SEQ ID NO.2 Full length of light chain: SEQ ID NO.142.hz8C8m13

[0083] >Heavy chain

[0084] H-CDR1: SEQ ID NO.26H-CDR2: SEQ ID NO.27H-CDR3: SEQ ID NO.32VH: SEQ ID NO.3Full length of heavy chain: SEQ ID NO.15>Light chain

[0085] L-CDR1: SEQ ID NO.29 L-CDR2: SEQ ID NO.33 L-CDR3: SEQ ID NO.31 VL: SEQ ID NO.4 Full length of light chain: SEQ ID NO.163.hz18A10m19

[0086] >Heavy chain

[0087] H-CDR1: SEQ ID NO.34 H-CDR2: SEQ ID NO.35 H-CDR3: SEQ ID NO.36 VH: SEQ ID NO.5 Full length of heavy chain: SEQ ID NO.17 > Light chain

[0088] L-CDR1: SEQ ID NO.37 L-CDR2: SEQ ID NO.38 L-CDR3: SEQ ID NO.39 VL: SEQ ID NO.6 Full length of light chain: SEQ ID NO.184.hz8C8m6

[0089] >Heavy chain

[0090]

[0091] H-CDR1: SEQ ID NO.26 H-CDR2: SEQ ID NO.27 H-CDR3: SEQ ID NO.40 VH: SEQ ID NO.7 Full length of heavy chain: SEQ ID NO.19 > Light chain

[0092] L-CDR1: SEQ ID NO.29 L-CDR2: SEQ ID NO.33 L-CDR3: SEQ ID NO.31 VL: SEQ ID NO.8 Full length of light chain: SEQ ID NO.205.hz18A10

[0093] >Heavy chain

[0094] H-CDR1: SEQ ID NO.41H-CDR2: SEQ ID NO.42H-CDR3: SEQ ID NO.36VH: SEQ ID NO.9Full length of heavy chain: SEQ ID NO.21>Light chain

[0095] L-CDR1: SEQ ID NO.43 L-CDR2: SEQ ID NO.38 L-CDR3: SEQ ID NO.39 VL: SEQ ID NO.10 Full length of light chain: SEQ ID NO.226.hz18A10m6

[0096] >Heavy chain

[0097] H-CDR1: SEQ ID NO.44 H-CDR2: SEQ ID NO.42 H-CDR3: SEQ ID NO.36 VH: SEQ ID NO.11 Full length of heavy chain: SEQ ID NO.23

[0098] >Light Chain

[0099]

[0100] L-CDR1: SEQ ID NO.37

[0101] L-CDR2: SEQ ID NO.38

[0102] L-CDR3: SEQ ID NO.39

[0103] VL: SEQ ID NO.12

[0104] Full length of light chain: SEQ ID NO.24

[0105] The heavy chain constant regions of the above antibodies can be replaced with the following heavy chain constant regions (SEQ ID NO.25): ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0106] Example 1 Effects of blocking IL-11 signaling pathway on tumor growth

[0107] IL-11Rα was knocked out in mouse colorectal cancer cells MC38 (purchased from Kangyuan Bochuang Biotechnology Co., Ltd., KC-2286). The cells were named "MC38-IL-11RαKO cells"; IL-11Rα was knocked out to block the IL-11 signaling pathway on the cells. MC38-IL-11RαKO cells and wild-type MC38 cells (named "MC38-WT cells") were transplanted subcutaneously into C57BL / 6 mice at the same dose, and the growth of tumors over time was observed. The results showed that ( Figure 3 ), compared with MC38-WT cells, the tumor growth rate in mice transplanted with MC38-IL-11RαKO cells was significantly slower.

[0108] IL-11Rα knockout C57BL / mice were obtained (purchased from Shanghai Model Organisms Technology Co., Ltd., catalog number NM-KO-190453) and named IL-11RαKO mice. MC38-WT cells were inoculated into IL-11RαKO mice and wild-type C57BL / mice (named "WT mice") at the same dose, and the growth of tumors over time was observed. The results showed that ( Figure 4 ), compared with WT mice, the tumor growth rate in IL-11RαKO mice was significantly slower.

[0109] The above results show that the IL-11 signaling pathway acts on both tumor cells and non-tumor cells in the host immune microenvironment, thereby promoting tumor growth and development from multiple angles. Therefore, there is room for benefit in the treatment of tumors by neutralizing antibodies that block IL-11.

[0110] Example 2 Anti-tumor efficacy of anti-IL-11 antibodies

[0111] (1) Evaluation of the anti-tumor efficacy of anti-IL-11 antibodies in a mouse model bearing human lung adenocarcinoma cells

[0112] Six-week-old female Balb / C nude mice were subcutaneously inoculated with 3×10 6 Personal lung adenocarcinoma A549 cells, when the tumor grows to 60mm 3 The mice were randomly divided into groups of 8 at about 1:10 pm, and the groups, dosage and frequency of administration are shown in Table 1. The tumor volume and weight of mice were measured at the same time of administration. When the weight of mice decreased by more than 15%, or the tumor volume of a single animal exceeded 3000 mm 3 Or the average tumor volume of a group of animals exceeds 2000mm 3 The experiments on the relevant mice were stopped and the mice were euthanized.

[0113] Table 1. Animal groups and dosing for antibody administration in a mouse model bearing human lung adenocarcinoma cells

[0114] Group (n=8) drug Dosage (mg / kg) Dosage Dosing frequency 1 hz8C8m7 0.4 ip Biw×9 2 hz8C8m7 2 ip Biw×9 3 hz8C8m13 10 ip Biw×9 4 hz18A10m19 10 ip Biw×9 5 NC-hIgG1 10 ip Biw×9

[0115] At the end of the experiment, the tumors of the euthanized mice were removed and weighed, and the tumor growth volume inhibition rate (TGI TV (%)) and tumor weight inhibition rate (TGI TW (%):

[0116] The formula for calculating tumor volume (TV) is: volume (TV) = 0.5 × long diameter × short diameter 2The T / C value was calculated based on the tumor volume (TV) and relative tumor volume (RTV), where RTV is the ratio of the tumor volume after administration to that before administration, and T / C = mean RTV of the treatment group / mean RTV of the control group. TV (%)) = (1-T / C) × 100%.

[0117] The T / C value was calculated based on the tumor weight (TW) of the treatment group and the tumor weight (TW) of the control group. T / C = mean tumor weight (TW) of the treatment group / mean tumor weight (TW) of the control group. TW (%) = (1-T / C) × 100%.

[0118] T Test was used for statistical analysis of differences.

[0119] The results show that ( Figure 5 , Table 2), all anti-IL-11 antibodies clearly inhibited tumor growth compared with the control group mice administered with isotype antibodies, and the results were statistically significant.

[0120] Table 2. Tumor growth inhibition rate after antibody administration in a mouse model bearing human lung adenocarcinoma cells

[0121]

[0122] (2) Evaluation of the anti-tumor efficacy of anti-IL-11 antibodies in PDX mouse models bearing different types of tumors

[0123] Six-week-old female Balb / C nude mice were subcutaneously inoculated with human lung adenocarcinoma (P7 generation), human lung squamous cell carcinoma (P10 generation), human cervical cancer (P6 generation) and human pancreatic cancer (P9 generation) tumors (all of the above tumors were provided by Yikang (Beijing) Pharmaceutical Technology Co., Ltd.) with an inoculation volume of 2 mm×2 mm×2 mm / mouse. The mice were inoculated until the tumors grew to 70 mm. 3 -100mm 3 The mice were randomly divided into two groups at the same time. The groups, dosage and frequency of administration are shown in Table 3. The tumor volume and weight of mice were measured at the same time of administration. When the weight of mice decreased by more than 15%, or the tumor volume of a single animal exceeded 3000mm 3 Or the average tumor volume of a group of animals exceeds 2000mm 3 The experiments on the relevant mice were stopped and the mice were euthanized.

[0124] Table 3. Animal groups and dosing for antibody administration in PDX mouse models bearing different types of tumors

[0125]

[0126] At the end of the experiment, the tumors of the euthanized mice were removed and weighed, and the tumor growth volume inhibition rate (TGI TV (%)) and tumor weight inhibition rate (TGI TW (%)), calculated in the same way as above.

[0127] In a PDX mouse model bearing human lung adenocarcinoma, the results showed that ( Figure 6 ), anti-IL-11 antibody hz8C8m7 clearly inhibited tumor growth compared with control mice given isotype antibody, TGI TV =28% (p<0.05), TGI TW =23%.

[0128] In a PDX mouse model bearing human pancreatic cancer, the results showed that ( Figure 7 ), anti-IL-11 antibody hz8C8m7 clearly inhibited tumor growth compared with control mice given isotype antibody, TGI TV =18% (p<0.05).

[0129] In a PDX mouse model bearing human cervical cancer, the results showed that ( Figure 8 ), anti-IL-11 antibody hz8C8m7 clearly inhibited tumor growth compared with control mice given isotype antibody, TGI TV =31%, TGI TW =31%.

[0130] In a PDX mouse model bearing human lung squamous cell carcinoma, the results showed that ( Fig. 9 ), anti-IL-11 antibody hz8C8m7 clearly inhibited tumor growth compared with control mice given isotype antibody, TGI TV =23%.

[0131] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art may make various changes or modifications based on the present invention. As long as they do not depart from the spirit of the present invention, they should all fall within the scope of the claims attached to the present invention.

Claims

1. Use of an anti-IL-11 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating IL-11 expression-related tumors.

2. The use according to claim 1, characterized in that The drug for treating IL-11 expression-related tumors can inhibit the proliferation and / or survival of tumor cells, or inhibit tumor growth.

3. The use according to claim 1 or 2, characterized in that The anti-IL-11 antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the heavy chain variable region and the light chain variable region comprise a combination of heavy chain CDRs and light chain CDRs selected from the following: (H-CDR1, H-CDR2, H-CDR3; and, L-CDR1, L-CDR2, L-CDR3): (1) H-CDR1, H-CDR2, and H-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 26, SEQ ID NO. 27, and SEQ ID NO. 28, respectively; and, L-CDR1, L-CDR2, L-CDR3 comprising the amino acid sequences shown in SEQ ID NO.29, SEQ ID NO.30, SEQ ID NO.31, respectively; (2) H-CDR1, H-CDR2, and H-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 26, SEQ ID NO. 27, and SEQ ID NO. 32, respectively; and, L-CDR1, L-CDR2, L-CDR3 comprising the amino acid sequences shown in SEQ ID NO.29, SEQ ID NO.33, and SEQ ID NO.31, respectively; (3) H-CDR1, H-CDR2, and H-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 34, SEQ ID NO. 35, and SEQ ID NO. 36, respectively; and, L-CDR1, L-CDR2, L-CDR3 comprising the amino acid sequences shown in SEQ ID NO.37, SEQ ID NO.38, and SEQ ID NO.39, respectively; (4) H-CDR1, H-CDR2, and H-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 26, SEQ ID NO. 27, and SEQ ID NO. 40, respectively; and, L-CDR1, L-CDR2, L-CDR3 comprising the amino acid sequences shown in SEQ ID NO.29, SEQ ID NO.33, and SEQ ID NO.31, respectively; (5) H-CDR1, H-CDR2, and H-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 41, SEQ ID NO. 42, and SEQ ID NO. 36, respectively; and, L-CDR1, L-CDR2, L-CDR3 comprising the amino acid sequences shown in SEQ ID NO.43, SEQ ID NO.38, and SEQ ID NO.39, respectively; or (6) H-CDR1, H-CDR2, and H-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 44, SEQ ID NO. 42, and SEQ ID NO. 36, respectively; and, L-CDR1, L-CDR2, and L-CDR3 comprising the amino acid sequences shown in SEQ ID NO.37, SEQ ID NO.38, and SEQ ID NO.39, respectively.

4. The use according to any one of claims 1 to 3, characterized in that The heavy chain variable region (VH) and the light chain variable region (VL) respectively comprise an amino acid sequence combination selected from the following: (1) the amino acid sequence shown in SEQ ID NO.1, or an amino acid sequence having at least 75% identity with said amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.2, or an amino acid sequence having at least 75% identity with said amino acid sequence; (2) the amino acid sequence shown in SEQ ID NO.3, or an amino acid sequence having at least 75% identity with said amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.4, or an amino acid sequence having at least 75% identity with said amino acid sequence; (3) the amino acid sequence shown in SEQ ID NO.5, or an amino acid sequence having at least 75% identity with said amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.6, or an amino acid sequence having at least 75% identity with said amino acid sequence; (4) the amino acid sequence shown in SEQ ID NO.7, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.8, or an amino acid sequence having at least 75% identity with the amino acid sequence; (5) the amino acid sequence shown in SEQ ID NO.9, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.10, or an amino acid sequence having at least 75% identity with the amino acid sequence; or (6) the amino acid sequence shown in SEQ ID NO.11, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.12, or an amino acid sequence having at least 75% identity with the amino acid sequence.

5. The use according to any one of claims 1 to 4, characterized in that The anti-IL-11 antibody is a humanized antibody.

6. The use according to any one of claims 1 to 5, characterized in that The anti-IL-11 antibody further comprises an IgG heavy chain constant region and / or a κ or λ type light chain constant region; Preferably, the anti-IL-11 antibody is an IgG1 or κ type monoclonal antibody.

7. The use according to any one of claims 1 to 6, characterized in that The anti-IL-11 antibody or antigen-binding fragment thereof comprises a heavy chain (HC) and a light chain (LC), and the heavy chain and the light chain respectively comprise an amino acid sequence combination selected from the following: (1) the amino acid sequence shown in SEQ ID NO.13, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.14, or an amino acid sequence having at least 75% identity with the amino acid sequence; (2) the amino acid sequence shown in SEQ ID NO.15, or an amino acid sequence having at least 75% identity with said amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.16, or an amino acid sequence having at least 75% identity with said amino acid sequence; (3) the amino acid sequence shown in SEQ ID NO.17, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.18, or an amino acid sequence having at least 75% identity with the amino acid sequence; (4) the amino acid sequence shown in SEQ ID NO.19, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.20, or an amino acid sequence having at least 75% identity with the amino acid sequence; (5) the amino acid sequence shown in SEQ ID NO.21, or an amino acid sequence having at least 75% identity with said amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.22, or an amino acid sequence having at least 75% identity with said amino acid sequence; or (6) the amino acid sequence shown in SEQ ID NO.23, or an amino acid sequence having at least 75% identity with the amino acid sequence; and, the amino acid sequence shown in SEQ ID NO.24, or an amino acid sequence having at least 75% identity with the amino acid sequence.

8. The use according to any one of claims 1 to 7, characterized in that The tumor is an IL-11 expression-related tumor.

9. The use according to any one of claims 1 to 8, characterized in that The tumor is non-small cell lung cancer, pancreatic cancer or cervical cancer.

10. The use according to any one of claims 1 to 9, characterized in that The medicament is for use in treating mammals, preferably humans.

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