Use of Anti-interleukin-11 antibody in preparation of drug for treating tumors

Abstract

Provided is the use of an anti-human interleukin-11 antibody or an antigen-binding fragment thereof in the preparation of a drug for treating tumors related to IL-11 expression. Experiments demonstrate that the anti-human interleukin-11 antibody or the antigen-binding fragment thereof can bind to IL-11 so as to block the formation of an IL-11 / IL-11Rα / GP130 ternary complex and / or block the activation of an STAT3 signalling pathway, thereby achieving an obvious inhibitory effect on tumor growth.

Description

Application of anti-interleukin-11 antibodies in the preparation of tumor therapeutic drugs

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This patent application claims the priority benefit of Chinese invention patent application No. 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 the use of an anti-interleukin-11 (IL-11) antibody in tumor treatment. Background Art

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

[0005] Studies have shown that IL-11 is upregulated in various tumors, including melanoma, breast cancer, colorectal cancer, and non-small cell lung cancer. High IL-11 expression in non-small cell lung cancer has been found to be closely associated with patient prognosis, making IL-11 a potential biomarker. In breast cancer, upregulated IL-11 expression can further promote bone metastasis. Furthermore, IL-11 binds to the IL-11 receptor alpha (IL-11Rα) and the gp130 receptor, thereby activating downstream signaling pathways through a 2:2:2 hexameric complex of IL-11 / IL-11Rα / gp130, including the three classic pathways of JAK / STAT3, Akt, and ERK. IL-11-induced activation of the JAK / STAT3 pathway is believed to be closely related to gastrointestinal cancers, and inhibitors of this pathway could be used for cancer treatment. In the progression of chronic gastritis to gastric cancer, a gradual increase in IL-11 levels and activation of signaling pathways 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 large number of studies have been conducted on the role of the IL-11 signaling pathway in non-tumor cells such as macrophages, DCs, CD4+ T cells, and fibroblasts, which has led to a more comprehensive and in-depth understanding of the relationship between IL-11 and tumors. For example, it has been found that IL-11 can inhibit the activity of CD4+ positive T cells, thereby achieving immunosuppression; IL-11 induces the differentiation of mDSCs 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 (CAFs), promoting tumor growth and metastasis; and so on.

[0007] These studies suggest that IL-11 influences tumor development and progression in multiple ways. For example, within the tumor microenvironment, tumor cells and non-tumor cells, through the IL-11 signaling pathway, jointly create a suppressive immune microenvironment that is conducive to tumor growth. Therefore, IL-11 inhibitors could exert their anti-tumor effects by directly affecting tumor cells and improving the suppressive immune microenvironment.

[0008] Summary of the Invention

[0009] According to data from the gepia2 database (http: / / gepia2.cancer-pku.cn / #general), IL-11 is expressed relatively highly 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). Furthermore, patients with relatively low IL-11 expression in renal papillary cell carcinoma, lung adenocarcinoma, pancreatic cancer, cervical cancer, and breast cancer have a better prognosis (Figure 2).

[0010] Based on the above research results, the inventors of the present invention attempted to use IL-11 as a target for tumor treatment 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.

[0011] The technical solutions of the present invention are as follows.

[0012] The present invention provides a use of an anti-IL-11 antibody or an antigen-binding fragment thereof in the preparation of a medicament for treating tumors associated with IL-11 expression (including overexpression).

[0013] In the present invention, the term "IL-11" refers to interleukin-11 derived from mammals, such as primates (eg, cynomolgus monkeys, humans) or rodents (eg, rats, mice).

[0014] 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.

[0015] In the present invention, the term "drug" encompasses any formulation of the anti-IL-11 antibody or antigen-binding fragment thereof that can be administered via any route, such as parenteral, intravenous, intraarterial, intraocular, intraconjunctival, intramuscular, subcutaneous, intradermal, intratumoral injection or infusion, and oral administration. Furthermore, the subject of the drug can be any mammal, preferably a human. The subject can be diagnosed with a tumor in need of treatment, or suspected of having such a tumor.

[0016] 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 set forth in the following amino acid sequences: the amino acid sequences set forth 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 set forth in the following amino acid sequences: the amino acid sequences set forth 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.

[0017] Each of the above amino acid sequences is the amino acid sequence of the heavy chain variable region or light chain variable region of the anti-IL-11 antibody provided herein. Using tools known in the art for defining complementarity-determining regions in antibody heavy or light chain variable regions (e.g., Chothia, Kabat, IMGT, Contact, etc.), those skilled in the art can readily determine the heavy chain CDRs and light chain CDRs contained therein. According to specific embodiments of the present invention, the Kabat tool can be used to delineate the CDRs within the variable region sequences.

[0018] 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 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:

[0019] (1) SEQ ID NO. 1 + SEQ ID NO. 2;

[0020] (2) SEQ ID NO. 3 + SEQ ID NO. 4;

[0021] (3) SEQ ID NO. 5 + SEQ ID NO. 6;

[0022] (4) SEQ ID NO. 7 + SEQ ID NO. 8;

[0023] (5) SEQ ID NO. 9 + SEQ ID NO. 10; or

[0024] (6) SEQ ID NO.11+SEQ ID NO.12.

[0025] As described above, the Kabat tool can be used to delineate the CDRs in each variable region sequence in the above amino acid sequence pairing.

[0026] 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:

[0027] (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, and L-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 29, SEQ ID NO. 30, and SEQ ID NO. 31, respectively;

[0028] (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, and L-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 29, SEQ ID NO. 33, and SEQ ID NO. 31, respectively;

[0029] (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, and L-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 37, SEQ ID NO. 38, and SEQ ID NO. 39, respectively;

[0030] (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, and L-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 29, SEQ ID NO. 33, and SEQ ID NO. 31, respectively;

[0031] (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, and L-CDR3 comprising the amino acid sequences shown in SEQ ID NO. 43, SEQ ID NO. 38, and SEQ ID NO. 39, respectively; or

[0032] (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.

[0033] 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) each comprise an amino acid sequence combination selected from the following:

[0034] (1) the amino acid sequence shown in SEQ ID NO. 1, or an amino acid sequence having at least 75% identity thereto; and, the amino acid sequence shown in SEQ ID NO. 2, or an amino acid sequence having at least 75% identity thereto;

[0035] (2) the amino acid sequence shown in SEQ ID NO. 3, or an amino acid sequence having at least 75% identity thereto; and, the amino acid sequence shown in SEQ ID NO. 4, or an amino acid sequence having at least 75% identity thereto;

[0036] (3) the amino acid sequence shown in SEQ ID NO. 5, or an amino acid sequence having at least 75% identity thereto; and, the amino acid sequence shown in SEQ ID NO. 6, or an amino acid sequence having at least 75% identity thereto;

[0037] (4) the amino acid sequence shown in SEQ ID NO. 7, or an amino acid sequence having at least 75% identity thereto; and, the amino acid sequence shown in SEQ ID NO. 8, or an amino acid sequence having at least 75% identity thereto;

[0038] (5) the amino acid sequence shown in SEQ ID NO. 9, or an amino acid sequence having at least 75% identity thereto; and, the amino acid sequence shown in SEQ ID NO. 10, or an amino acid sequence having at least 75% identity thereto; or

[0039] (6) the amino acid sequence shown in SEQ ID NO. 11, or an amino acid sequence having at least 75% identity thereto; and, the amino acid sequence shown in SEQ ID NO. 12, or an amino acid sequence having at least 75% identity thereto.

[0040] In the present invention, the up to 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 other than 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" encompasses any percentage of identity between at least 75% identity and 100% identity, for example 75%, 80%, 85%, 90%, or even 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or even 100% identity.

[0041] The anti-IL-11 antibody or antigen-binding fragment thereof comprising the above-described amino acid sequence can be an antibody or antigen-binding fragment thereof of any structural configuration. For example, the antibody itself can be a monoclonal antibody, a bispecific antibody, or a multispecific antibody, or can be an antibody with a structure such as scFv, bsFv, dsFv, (dsFv)2, Fab, Fab', F(ab')2, or Fv; or any fragment thereof.

[0042] More preferably, the present invention provides the use of the anti-IL-11 antibody or its antigen-binding fragment in the preparation of a medicament 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.

[0043] 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 light chain respectively comprise an amino acid sequence combination selected from the following:

[0044] (1) the amino acid sequence shown in SEQ ID NO. 13, or an amino acid sequence having at least 75% identity thereto; and, the amino acid sequence shown in SEQ ID NO. 14, or an amino acid sequence having at least 75% identity thereto;

[0045] (2) the amino acid sequence shown in SEQ ID NO. 15, or an amino acid sequence having at least 75% identity thereto; and, the amino acid sequence shown in SEQ ID NO. 16, or an amino acid sequence having at least 75% identity thereto;

[0046] (3) the amino acid sequence shown in SEQ ID NO. 17, or an amino acid sequence having at least 75% identity thereto; and, the amino acid sequence shown in SEQ ID NO. 18, or an amino acid sequence having at least 75% identity thereto;

[0047] (4) the amino acid sequence shown in SEQ ID NO. 19, or an amino acid sequence having at least 75% identity thereto; and, the amino acid sequence shown in SEQ ID NO. 20, or an amino acid sequence having at least 75% identity thereto;

[0048] (5) the amino acid sequence shown in SEQ ID NO. 21, or an amino acid sequence having at least 75% identity thereto; and, the amino acid sequence shown in SEQ ID NO. 22, or an amino acid sequence having at least 75% identity thereto; or

[0049] (6) the amino acid sequence shown in SEQ ID NO. 23, or an amino acid sequence having at least 75% identity thereto; and, the amino acid sequence shown in SEQ ID NO. 24, or an amino acid sequence having at least 75% identity thereto.

[0050] 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.

[0051] Preferably, 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.

[0052] In the use provided by the present invention, the drug is used to treat a mammal, preferably a human, and the mammal may have been diagnosed with a tumor requiring treatment, or is suspected of having the tumor.

[0053] In another aspect, the present invention provides a method for treating a tumor, comprising administering an anti-IL-11 antibody or an antigen-binding fragment thereof to a subject in need thereof. 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. The anti-IL-11 antibody or antigen-binding fragment thereof is as defined above.

[0054] In the method, the route of administration can be parenteral, intravenous, intraarterial, intraocular, intraconjunctival, intramuscular, subcutaneous, intradermal, intratumoral injection or infusion, and oral administration. 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.

[0055] 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.

[0056] The methods for treating tumors provided herein encompass administration of the anti-IL-11 antibody or antigen-binding fragment thereof alone or in combination with other therapeutic agents or treatment modalities. In the present invention, the term "combination" refers to administering the anti-IL-11 antibody or antigen-binding fragment thereof and the other therapeutic agent or treatment modality simultaneously or sequentially at a predetermined time interval; the time interval can be any time interval.

[0057] Compared to existing technologies, this invention proposes a novel approach to treating tumors by targeting IL-11. Without being bound by theory, the invention utilizes a specific anti-IL-11 antibody as a therapeutic agent. By binding to IL-11 with high affinity, it blocks the formation of the IL-11 / IL-11Rα / GP130 triad complex and / or activation of the STAT3 signaling pathway, resulting in significant inhibition of tumor growth. BRIEF DESCRIPTION OF THE DRAWINGS

[0058] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings, in which:

[0059] FIG1 shows the expression of IL-11 transcript levels in tumor tissues.

[0060] FIG2 shows the relationship between IL-11 and the prognosis of tumor patients.

[0061] FIG3 shows the growth curve (volume) of tumors over time after subcutaneous transplantation of IL-11Rα knockout MC38 cells and wild-type MC38 cells into mice.

[0062] FIG4 shows the growth curves (volume) of tumors over time after subcutaneous transplantation of MC38 cells into wild-type mice and IL-11Rα knockout mice.

[0063] FIG5 shows the tumor growth in a mouse model of human lung adenocarcinoma after administration of different antibodies; 5A: tumor growth curve (volume); 5B: tumor weight.

[0064] FIG6 shows the tumor growth in a PDX mouse model of human lung adenocarcinoma after administration of different antibodies; 6A: tumor growth curve (volume); 6B: tumor weight.

[0065] FIG7 shows the tumor growth curves (volume) after administration of different antibodies in a PDX mouse model of human pancreatic cancer.

[0066] FIG8 shows the tumor growth in the PDX mouse model of human cervical cancer after administration of different antibodies; 8A: tumor growth curve (volume); 8B: tumor weight.

[0067] FIG9 shows the tumor growth curves (volume) after administration of different antibodies in a PDX mouse model of human lung squamous cell carcinoma.

[0068] Best Mode for Carrying Out the Invention

[0069] The present invention is described below with reference to specific examples. Those skilled in the art will appreciate 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.

[0070] 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.

[0071] The following examples utilize the anti-IL-11 antibodies hz8C8m7, hz8C8m13, and hz18A10m19. These three antibodies are humanized monoclonal antibodies derived from mouse antibodies and comprise two heavy chains and two light chains. Experiments have demonstrated that all three antibodies bind to human IL-11 with high affinity and can block the formation of the IL-11 / IL-11Ra / gp130 trimeric complex; see Chinese invention patent CN202310044074.4.

[0072] 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 (delineated using the Kabat tool), and the sequences in bold alone are the heavy chain constant region or the light chain constant region:

[0073] 1.hz8C8m7:

[0074] >Heavy chain

[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] L-CDR1: SEQ ID NO. 29

[0082] L-CDR2: SEQ ID NO. 30

[0083] L-CDR3: SEQ ID NO. 31

[0084] VL: SEQ ID NO.2

[0085] Full length light chain: SEQ ID NO.14

[0086] 2.hz8C8m13

[0087] >Heavy chain

[0088] H-CDR1: SEQ ID NO. 26

[0089] H-CDR2: SEQ ID NO. 27

[0090] H-CDR3: SEQ ID NO. 32

[0091] VH: SEQ ID NO.3

[0092] Heavy chain full length: SEQ ID NO.15

[0093] >Light chain

[0094] L-CDR1: SEQ ID NO. 29

[0095] L-CDR2: SEQ ID NO. 33

[0096] L-CDR3: SEQ ID NO. 31

[0097] VL: SEQ ID NO.4

[0098] Full length light chain: SEQ ID NO.16

[0099] 3.hz18A10m19

[0100] >Heavy chain

[0101] H-CDR1: SEQ ID NO. 34

[0102] H-CDR2: SEQ ID NO. 35

[0103] H-CDR3: SEQ ID NO. 36

[0104] VH: SEQ ID NO.5

[0105] Heavy chain full length: SEQ ID NO.17

[0106] >Light chain

[0107] L-CDR1: SEQ ID NO. 37

[0108] L-CDR2: SEQ ID NO. 38

[0109] L-CDR3: SEQ ID NO. 39

[0110] VL: SEQ ID NO.6

[0111] Full length light chain: SEQ ID NO.18

[0112] 4.hz8C8m6

[0113] >Heavy chain

[0114] H-CDR1: SEQ ID NO. 26

[0115] H-CDR2: SEQ ID NO. 27

[0116] H-CDR3: SEQ ID NO. 40

[0117] VH: SEQ ID NO.7

[0118] Heavy chain full length: SEQ ID NO.19

[0119] >Light chain

[0120] L-CDR1: SEQ ID NO. 29

[0121] L-CDR2: SEQ ID NO. 33

[0122] L-CDR3: SEQ ID NO. 31

[0123] VL: SEQ ID NO.8

[0124] Full length light chain: SEQ ID NO.20

[0125] 5.hz18A10

[0126] >Heavy chain

[0127] H-CDR1: SEQ ID NO. 41

[0128] H-CDR2: SEQ ID NO. 42

[0129] H-CDR3: SEQ ID NO. 36

[0130] VH: SEQ ID NO.9

[0131] Heavy chain full length: SEQ ID NO.21

[0132] >Light chain

[0133] L-CDR1: SEQ ID NO. 43

[0134] L-CDR2: SEQ ID NO. 38

[0135] L-CDR3: SEQ ID NO. 39

[0136] VL: SEQ ID NO.10

[0137] Full length light chain: SEQ ID NO.22

[0138] 6.hz18A10m6

[0139] >Heavy chain

[0140] H-CDR1: SEQ ID NO. 44

[0141] H-CDR2: SEQ ID NO. 42

[0142] H-CDR3: SEQ ID NO. 36

[0143] VH: SEQ ID NO.11

[0144] Heavy chain full length: SEQ ID NO.23

[0145] >Light chain

[0146] L-CDR1: SEQ ID NO. 37

[0147] L-CDR2: SEQ ID NO. 38

[0148] L-CDR3: SEQ ID NO. 39

[0149] VL: SEQ ID NO.12

[0150] Full length light chain: SEQ ID NO.24

[0151] The heavy chain constant regions of the above antibodies can be replaced with the following heavy chain constant regions (SEQ ID NO.25):

[0152] Example 1 Effect of Blocking IL-11 Signaling Pathway on Tumor Growth

[0153] MC38 cells, mouse colorectal cancer cells in which IL-11Rα was knocked out, were obtained (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 (Figure 3) that compared with MC38-WT cells, the tumor growth rate in mice transplanted with MC38-IL-11RαKO cells was significantly slower.

[0154] IL-11Rα knockout C57BL / / mice were obtained (purchased from Shanghai Model Organisms Science Co., Ltd., catalog number NM-KO-190453) and designated IL-11RαKO mice. MC38-WT cells were inoculated at the same dose into IL-11RαKO mice and wild-type C57BL / / mice (designated "WT mice"), and tumor growth was observed over time. The results (Figure 4) showed that tumor growth in IL-11RαKO mice was significantly slower than that in WT mice.

[0155] These results demonstrate that the IL-11 signaling pathway acts simultaneously on tumor cells and non-tumor cells within the host immune microenvironment, thereby promoting tumor growth and development from multiple angles. Therefore, neutralizing antibodies that block IL-11 have potential benefits in tumor treatment.

[0156] Example 2 Anti-tumor efficacy of anti-IL-11 antibodies

[0157] (1) Evaluation of the anti-tumor efficacy of anti-IL-11 antibodies in a mouse model bearing human lung adenocarcinoma cells

[0158] Six-week-old female Balb / C nude mice were subcutaneously inoculated with 3×10 6 Human lung adenocarcinoma A549 cells, wait until the tumor grows to 60 mm 3 The mice were randomly divided into groups of 8 at about 12 hr. The groups, dosage and frequency of administration are shown in Table 1. The tumor volume and weight of the mice were measured at the same time of administration. When the weight of the 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.

[0159] Table 1. Animal groups and dosing for antibody administration in a mouse model bearing human lung adenocarcinoma cells

[0160] 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 (%)):

[0161] The formula for calculating tumor volume (TV) is: volume (TV) = 0.5 × long diameter × short diameter 2 The 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 before and after administration, and T / C = mean RTV of the treatment group / mean RTV of the control group. TV (%)) = (1-T / C) × 100%.

[0162] 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%.

[0163] T Test was used for statistical analysis of differences.

[0164] The results showed (Figure 5, Table 2) that all anti-IL-11 antibodies clearly inhibited tumor growth compared with the control group of mice given isotype antibodies, and the inhibition was statistically significant.

[0165] Table 2. Tumor growth inhibition rate after antibody administration in a mouse model bearing human lung adenocarcinoma cells

[0166] (2) Evaluate the anti-tumor efficacy of anti-IL-11 antibodies in PDX mouse models bearing different types of tumors

[0167] Six-week-old female Balb / C nude mice were subcutaneously inoculated with human lung adenocarcinoma (P7 generation) tumors, human lung squamous cell carcinoma (P10 generation) tumors, human cervical cancer (P6 generation) tumors, and human pancreatic cancer (P9 generation) tumors (all of the above tumors were provided by Yikang (Beijing) Pharmaceutical Technology Co., Ltd.). The inoculation volume was 2 mm × 2 mm × 2 mm per mouse. The mice were inoculated until the tumors grew to 70 mm. 3 -100mm 3 The mice were randomly divided into two groups. The groups, dosage and frequency of administration are shown in Table 3. Tumor volume and mouse weight 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.

[0168] Table 3. Animal groups and dosing for antibody administration in PDX mouse models bearing different types of tumors

[0169] 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.

[0170] In a PDX mouse model bearing human lung adenocarcinoma, the results showed (Figure 6) that the anti-IL-11 antibody hz8C8m7 clearly inhibited tumor growth compared to the control mice administered with the isotype antibody. TV =28% (p<0.05), TGI TW =23%.

[0171] In a PDX mouse model bearing human pancreatic cancer, the results showed (Figure 7) that the anti-IL-11 antibody hz8C8m7 clearly inhibited tumor growth compared with the control mice administered with the isotype antibody, and TGI TV =18% (p<0.05).

[0172] In a PDX mouse model bearing human cervical cancer, the results showed (Figure 8) that the anti-IL-11 antibody hz8C8m7 could clearly inhibit tumor growth compared with the control mice administered with the isotype antibody. TV =31%, TGI TW =31%.

[0173] In a PDX mouse model bearing human lung squamous cell carcinoma, the results showed (Figure 9) that the anti-IL-11 antibody hz8C8m7 could clearly inhibit tumor growth compared with the control mice administered with the same type of antibody. TV =23%.

[0174] The above description of the specific embodiments of the present invention does not limit the present invention. Those skilled in the art can 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 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; Preferably, the anti-IL-11 antibody further comprises an IgG heavy chain constant region and / or a κ or λ type light chain constant region; more preferably, the anti-IL-11 antibody is an IgG1 or κ type monoclonal antibody.

6. The use according to any one of claims 1 to 5, 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. amino acid sequences having at least 75% identity; (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.

7. The use according to any one of claims 1 to 6, characterized in that The tumor is an IL-11 expression-related tumor, such as non-small cell lung cancer, pancreatic cancer or cervical cancer.

8. The use according to any one of claims 1 to 7, characterized in that The medicament is for use in treating mammals, preferably humans.

9. A method for treating a tumor, comprising administering an anti-IL-11 antibody or an antigen-binding fragment thereof to a subject in need thereof.

10. The method according to claim 9, characterized in that The tumor is an IL-11 expression-related tumor, such as non-small cell lung cancer, pancreatic cancer or cervical cancer; the anti-IL-11 antibody or antigen-binding fragment thereof is as defined in any one of claims 3 to 6.

Images