KR20250058158A - A pharmaceutical composition for the treatment of cancer - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating cancer, comprising a hepatocyte growth factor (hereinafter abbreviated as "HGF") neutralizing antibody as an active ingredient. In addition, the present invention relates to a pharmaceutical composition for treating cancer, comprising an HGF neutralizing antibody as an active ingredient, characterized in that it is administered to a patient with colon cancer. More specifically, the present invention relates to a pharmaceutical composition for treating colon cancer, comprising an HGF neutralizing antibody as an active ingredient, characterized in that it is administered to (i) a patient whose colon cancer is located on the right side, (ii) a patient with high expression of MCT4, or (iii) a patient with a high serum HGF level. Furthermore, the present invention relates to a pharmaceutical composition for treating metastatic or recurrent colorectal cancer, comprising an HGF neutralizing antibody as an active ingredient, wherein the pharmaceutical composition is administered to (i) a patient whose colorectal cancer is located on the right side, (ii) a patient with high MCT4 expression, or (iii) a patient with high serum HGF levels, thereby extending progression-free survival (PFS) or overall survival (OS).

Description

{A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF CANCER}

The present invention relates to a pharmaceutical composition for treating cancer, comprising a hepatocyte growth factor (hereinafter abbreviated as "HGF") neutralizing antibody as an active ingredient. In addition, the present invention relates to a pharmaceutical composition for treating cancer, comprising an HGF neutralizing antibody as an active ingredient, characterized in that it is administered to a patient with colon cancer. More specifically, the present invention relates to a pharmaceutical composition for treating colon cancer, comprising an HGF neutralizing antibody as an active ingredient, characterized in that it is administered to (i) a patient whose colon cancer is located on the right side, (ii) a patient with high expression of MCT4, or (iii) a patient with a high serum HGF level. Furthermore, the present invention relates to a pharmaceutical composition for treating metastatic or recurrent colorectal cancer, comprising an HGF neutralizing antibody as an active ingredient, wherein the pharmaceutical composition is administered to (i) a patient whose colorectal cancer is located on the right side, (ii) a patient with high MCT4 expression, or (iii) a patient with high serum HGF levels, thereby extending progression-free survival (PFS) or overall survival (OS).

HGF, also called Scatter Factor (SF), is a multifunctional heterodimeric polypeptide produced by mesenchymal stem cells that binds to its receptor c-MET and plays various roles related to cell growth, formation, motility, and survival. In particular, it is related to tumor development and prognosis, and it has been reported to be overexpressed in various cancer tissues including the brain, liver, prostate, colon, breast, and skin. This overexpression of HGF/c-MET induces increased tumor aggressiveness and metastasis, and is highly correlated with the prognosis of patients including shortened survival period, and is an important signaling system related to the occurrence and progression of cancer in various aspects such as conferring resistance to chemotherapy, radiotherapy, and anticancer treatments.

Structurally, human HGF is synthesized as a biologically inactive single-chain precursor. It is then cleaved by serum serine protease to form an alpha chain containing four Kringle domains (NK4, 4-K domain) and a beta chain with serine protease function, and then a heterodimer is formed in which these two chains are linked by a disulfide bond to form biologically active HGF. c-MET, the receptor for HGF, is a protein belonging to the receptor tyrosine kinase (RTK) subfamily and consists of two subunits, alpha and beta, and the sema domain of the beta unit is responsible for transmitting signals. c-MET forms a dimer upon binding to HGF, and autophosphorylates three tyrosine residues (Tyr1230, Tyr1234, Tyr1235), followed by phosphorylation of two tyrosine residues (Tyr1349, Tyr1356) at the carboxy terminus, forming a 'docking site'. Downstream signaling molecules that mediate the Ras/Raf, PI3K/AKT/mTOR, and STAT3 pathways are recruited in this vicinity, transmitting signals into the cell. This activation of c-MET induces increased cell proliferation, fluidity, invasion, angiogenesis, and anti-apoptotic action.

Dysregulation of HGF and c-MET and overexpression of c-MET in cancer cells are mainly activated through Met gene amplification, transcriptional up-regulation, point mutations, and autocrine or paracrine mechanisms of its ligand, HGF. Abnormal signaling between HGF and MET is involved in tumor growth, invasion, metastasis, and recurrence through survival, proliferation, migration, Epithelial-to-Mesenchymal Transition (EMT), angiogenesis, therapeutic resistance, and maintenance of stemness. In view of the fact that the HGF/c-MET signaling pathway plays a key role in tumor growth and development, the present inventors have studied and developed an HGF-neutralizing humanized monoclonal antibody that specifically binds to HGF and thereby inhibits its activity. (Refer to Korean Patent No. 10-0556660)

However, it is a widely known fact that even if it is a pathologically the same type of cancer, the amplified specific signaling system may be different, and for other unknown reasons, the therapeutic effect of the same cancer treatment may vary greatly depending on the individual patient. In other words, even if a remarkable therapeutic effect is shown in a specific patient, the desired therapeutic effect is often not shown in other patients, and accordingly, in clinical settings, cancer treatment is often selected based on the experience or intuition of the treating doctor, and if it is not effective, it is replaced with another treatment. In the meantime, the physical, mental, and economic inconveniences experienced by the patient are great, and furthermore, the survival period is often shortened due to missing the appropriate treatment period.

Accordingly, in order to increase the survival rate of cancer patients, it is necessary to identify which cancer treatment agent maximizes the therapeutic effect for each individual patient. However, to date, there is no information on which patients receive the treatment effect when treating colon cancer with HGF-neutralizing antibodies.

Republic of Korea Patent No. 10-0556660

The problem to be solved by the present invention is to provide a colon cancer treatment agent containing an HGF neutralizing antibody as an active ingredient, and to identify a specific patient group in which the therapeutic effect is maximized.

The problem of the present invention is solved by administering a cancer treatment composition containing an HGF neutralizing antibody as an active ingredient to a patient selected from the group consisting of the following.

(i) Patients with colorectal cancer on the right side;

(ii) Patients with high expression of MCT4 or

(iii) Patients with high serum HGF levels

A cancer treatment composition comprising an HGF neutralizing antibody as an active ingredient can be administered to (i) patients with right-sided colon cancer, (ii) patients with high MCT4 expression, or (iii) patients with high serum HGF levels, thereby treating colon cancer patients. The cancer treatment composition of the present invention extends progression-free survival (PFS) or overall survival (OS).

Figure 1 shows the results of measuring the anti-tumor activity of HGF neutralizing antibodies according to the location of occurrence of colon cancer.
Figure 2 shows the results of measuring the anti-tumor activity of HGF neutralizing antibodies according to the criteria of MCT4 expression in tumors and stroma.
Figure 3 shows the results of measuring the anti-tumor activity of HGF neutralizing antibodies according to the HGF concentration standard in serum.
Figure 4 shows the results of a risk function analysis with related factors in the drug reactivity of the HGF neutralizing antibody of the present invention.
Figure 5 shows the results of a risk function analysis according to a combination of related factors in the drug reactivity of the HGF neutralizing antibody of the present invention.
Figure 6 is about the sequence of YYB-101 of the present application.

The HGF neutralizing antibody of the present invention exhibits the activity of neutralizing HGF by binding to a neutralizable epitope, and includes an antibody or an antigen-binding fragment thereof that specifically binds to HGF.

Specifically, the HGF neutralizing antibody of the present invention has a VH region represented by the amino acid sequence of SEQ ID NO: 1 and a VL region represented by the amino acid sequence of SEQ ID NO: 2, and has four framework regions (FR) and three complementarity determining regions (CDRs) (SEQ ID NOs: 3 to 8). Furthermore, the heavy chain of the HGF neutralizing antibody of the present invention may be represented by the amino acid sequence of SEQ ID NO: 9, and the light chain may be represented by the amino acid sequence of SEQ ID NO: 10. The HGF neutralizing antibody of the present invention may be manufactured according to the contents disclosed in Republic of Korea Patent No. 556660, the entire contents of which are incorporated by reference.

Cancers that can be prevented or treated by the HGF neutralizing antibody of the present invention are not limited to cancers related to HGF, but may be colorectal cancer, for example, metastatic or recurrent colorectal cancer patients.

Colon cancer is the third most common cancer and has the highest mortality rate among all cancers worldwide. Its incidence is rapidly increasing in Asia, including Korea, and according to 2016 Korean statistics, it has the third highest mortality rate. If colon cancer is detected early, more than 90% of the subjects' life expectancy increases by more than 5 years, but only 40% of patients are diagnosed with colon cancer at an early stage. Early diagnosis of colon cancer is directly related to the patient's life and remains a challenging task to date.

The inventors of the present invention have discovered that the therapeutic effect is maximized when the HGF neutralizing antibody of the present invention is administered to a patient who exhibits a specific condition of the individual patient's disease or symptom or a specific biomarker in treating a patient with colorectal cancer, for example, metastatic or recurrent colorectal cancer, thereby leading to the present invention.

In the first aspect of the present invention, when the primary tumor location of colon cancer is the right side (right-side colon cancer), the therapeutic effect is maximized when the HGF neutralizing antibody of the present invention is administered. According to the study of the present inventors, when the primary tumor location of colon cancer is the right side (right-side colon cancer, RCC) and when it is the left side (left-side colon cancer, LCC), the progression of cancer and the responsiveness to the therapeutic agent may be different, and the HGF neutralizing antibody of the present invention further extends the progression-free survival (PFS) or overall survival (OS) in RCC. This suggests that even for the same cancer, different treatment methods or different drug therapies are needed depending on the occurrence method, and furthermore, it reaffirms the importance of accurately determining the tumor type of the target patient and applying personalized cancer treatment by targeting it accordingly in order to maximize the treatment outcome of colon cancer patients.

In a second aspect of the present invention, the HGF neutralizing antibody of the present invention has a maximized therapeutic effect when administered to a patient with high expression of MCT4 (Monocarboxylate transporter 4). In the present invention, the term "high expression of MCT4" means a patient whose H-score of MCT 4 shows ≥20 in the tumor. The H-score of MCT 4 in the stroma may be ≤40. When the HGF neutralizing antibody of the present invention is administered to such a patient, the progression-free survival period (PFS) is further extended.

As a third aspect of the present invention, the HGF neutralizing antibody of the present invention has a maximized therapeutic effect when administered to a patient with a high serum HGF level. In the present invention, the "patient with a high serum HGF level" means a patient with a serum HGF concentration of 2012 pg/mL or higher. When the HGF neutralizing antibody of the present invention is administered to such a patient, the progression-free survival period (PFS) is further extended.

The first, second and third aspects of the present invention can independently define patients, or can define patients in duplicate. For example, it is within the technical concept of the present invention to extend the progression-free survival period or the overall survival period by administering the HGF neutralizing antibody of the present invention to a patient whose colon cancer is located on the right side and has high MCT4 expression; or a patient whose MCT4 is highly expressed and has high serum HGF levels.

Furthermore, the present invention includes a method for predicting the therapeutic prognostic responsiveness to an HGF neutralizing antibody based on (i) the location of the colorectal cancer, (ii) the expression level of MCT4, and (iii) the serum HGF level. For example, before administering an HGF neutralizing antibody to a colorectal cancer patient, it is determined whether (i) the location of the colorectal cancer is right-sided, or (ii) MCT4 is ≥20 in the tumor, or (iii) the serum HGF level is ≥2012 pg/mL of HGF concentration, and if these conditions are satisfied, it can be determined that the therapeutic prognostic responsiveness to the HGF neutralizing antibody is excellent.

Hereinafter, clinical trials and results confirming the therapeutic effect of this invention are disclosed as examples. The examples below demonstrate the technical idea of the present invention through the symptom improvement effect of a specific individual patient or through statistical analysis, and it should be especially noted that the scope of the rights of the present invention is limited only by the matters described in the patent claims, and is not limited by the detailed clinical trial protocol below or its results.

Examples.

Measuring protein expression levels

The present invention relates to a process for confirming the presence or absence, location, and expression level of a protein from a gene, which measures the presence or absence and expression level of a specific protein using an antigen-antibody reaction. As an analysis method for this, immunohistochemistry (IHC), a staining method using an antigen-antibody reaction that utilizes the property of antibodies binding to specific antigen substances, digitally read H-score {0 to 300 as staining intensity (1,2,3) x staining area (%)}, and enzyme linked immunosorbent assay (ELISA) can be utilized.

Target patient selection and analysis of results according to patient characteristics

In the clinical trial, patients who had previously received standard chemotherapy including fluoropyrimidines, oxaliplatin, and irinotecan, and had received chemotherapy including irinotecan for at least 6 weeks, and had progression confirmed by imaging during or within 6 months (24 weeks) after the end of chemotherapy were analyzed for the results of a total of 35 patients who were administered YYB-101 (lab code of the HGF neutralizing antibody of the present invention) and irinotecan in combination at 2-week intervals.

In this example, to evaluate the progression-free survival (PFS) and overall survival (OS) according to patient characteristics for YYB-101 and Irinotecan, analysis was performed according to various characteristics such as age, sex, ECOG (Eastern cooperative oncology group) performance status, tumor location, metastatic site, and previous treatment line, and the results are described in [Table 1].

YYB-101 Colon Cancer Clinical Patient Information Factor N (%) median PFS (week)
[95% CI] p-value ^† median OS
(week)
[95% CI] p-value ^† Age, years <60 18 (51.43) 15.43
(11.43, 34.71) 0.018 62.57
(32.43, -) 0.2 ≥60 17 (48.57) 43.71
(21.14, -) -
(40.43, -) Sex Male 20 (57.14) 21.43
(17.57, 60.00) 0.7 64.71
(36.57, -) 0.8 Female 15 (42.86) 19.14
(13.00, -) 89.57
(40.43, -) ECOG PS 0 6 (17.14) 19.79
(12.14, -) 0.7 92.57
(62.57, -) 0.7 1 29 (82.86) 20.86
(17.14, 50.43) 64.71
(40.43, -) Site of primary tumor Colon 20 (57.14) 21.43
(18.14, 67.14) 0.3 92.57
(50.86, -) 0.043 Rectum 15 (42.86) 17.57
(12.14, -) 40.43
(34.43, -) No. of metastatic sites 1 10 (28.57) 14.64
(8.14, -) 0.2 89.57
(89.57, -) 0.4 2 17 (48.57) 18.14
(13.71, -) 62.57
(34.43, -) ≥3 8 (22.86) 66.00
(38.43, -) -
(29.71, -) Lines of previous Tx 2 10 (28.57) 17.64
(11.43, -) 0.9 92.57
(-, -) 0.055 3 10 (28.57) 21.14
(12.14, -) -
(40.43, -) ≥4 15 (42.86) 21.14
(17.57, -) 34.43
(29.71, -)

^† Log-rank test

Preparation of tumor tissue and serum

In patients with colon cancer, colon cancer tissue and serum were collected through biopsy for diagnosis before drug administration, and the tissue and serum collection was performed after prior consent.

MCT4 immunohistochemical staining analysis

Monocarboxylate transporters (MCTs) are a family of transporters that transport molecules containing monocarboxylates, including lactate, pyruvate, and ketones. The main role of monocarboxylate transporters is to exchange lactate, which cancer cells produce through glycolysis. There are 14 types of monocarboxylate transporters, and the monocarboxylates that are closely related to cancer are MCT1 (Monocarboxylate transporter 1) and MCT4 (Monocarboxylate transporter 4).

Experimental method

We used immunohistochemistry (IHC) to analyze the expression of MCT4 in the tissues of the participating patients. Specifically, patient tissues were sectioned at 3 μm thickness and mounted on MATSUNAMI PLATINUM PRO MICRO SLIDE GLASS. Bond Dewax solution was added to melt the paraffin block and reacted at 72°C. Bond ER solution was used for the antigen retrieval step after the reaction. After the reaction was completed, peroxidase was reacted for 5 minutes at room temperature to prevent nonspecific reactions. After the reaction was completed, the tissue sections were reacted with rabbit polyclonal antibody MCT4 (1:200, 22787-1-AP, Proteintech) at room temperature for 15 minutes using Bond-RX autoimmune stainer (Leica Biosystem, Melbourne, Australia). For immunohistochemical staining of MCT4, a polymer-based method with higher sensitivity than Avidin-Biotin Complex (ABC) and Labeled Streptavidin-Biotin (LSAB) was used. After binding with MCT4 antibody, the primer (HRP) was used for reaction at room temperature for 8 minutes. After the reaction was completed, a polymer was used for reaction at room temperature for 8 minutes to enhance the HRP reaction. After that, the substrate reaction was performed at room temperature for 10 minutes using Mixed DAB, and the nucleus was stained using Hematoxylin and then analysis was performed.

Interpretation of MCT4 immunohistochemical staining was recorded as intensity (0~+3) and percentage (e.g., Intensity 3+, percentage 100%) when both cytoplasmic/membranous staining was positive. Tissues that did not undergo immunohistochemical staining at all were interpreted as negative. Interpretation of MCT4 can be interpreted by dividing into tumor and stroma, and the standard for stroma means the immediate surroundings of the tumor (about 1~200 um).

Experimental Results

The results are described in [Table 2]. The results of MCT4 immunohistochemical staining were analyzed by dividing 33 tissue samples into tumors and stroma. In tumors, about 60% of 20 samples out of 33 were found to be positive, and the expression level ranged from 10 to 240 in terms of intensity and percentage. In stroma, about 55% of 18 samples out of 33 were found to be positive, and the expression level ranged from 2 to 120, indicating that although the expression level was lower than that of tumors, MCT4 was confirmed in the stroma in a variety of ranges.

[Table 2] MCT4 immunohistochemical staining analysis in tumors and stroma

Measurement of HGF expression level in serum using ELISA analysis

To determine the level of HGF expression before drug administration to colon cancer patients, a Human HGF immunoassay kit (R&D systems) was used, and the test method was performed according to the manufacturer's instructions. A brief experimental method is as follows.

Add 100 uL assay diluent RD1-38 to each well of a 96-well human HGF microplate, then add 50 uL standard and patient blood. Allow the samples to react at room temperature for 2 hours.

1st wash and Human HGF conjugate reaction

After 2 hours, wash each well with 400 uL wash buffer, and repeat the same process 4 times. After removing all buffer remaining in the washed wells, add 200 uL human HGF Conjugate to each well and incubate for 1 hour at room temperature.

Second wash and Streptavidin-HRP reaction

After 2 hours, wash each well with 400 uL wash buffer and repeat the same process 4 times. After removing all remaining buffer from the washed well, add 200 uL Streptavidin-HRP. Incubate the sample at room temperature for 30 minutes.

3rd Wash and Substrate Reaction

After 30 minutes, wash each well with 400 uL wash buffer, and repeat the same process 4 times. After removing all remaining buffer from the washed well, add 200 uL substrate solution. Incubate the sample in the dark at room temperature for 30 minutes.

Check HGF concentration

After 30 minutes, add 50 uL stop solution and check the HGF concentration at 450 nm using a microplate reader.

The results are shown in [Table 3]. The serum HGF concentrations of 35 patients are described. The concentrations of HGF ranged from 1004.37 pg/mL to 5177.07 pg/mL.

[Table 3] HGF concentration in serum through ELISA analysis

Experimental Example 1. Measurement of anti-tumor activity of anti-HGF (YYB-101) according to the location of colon cancer occurrence

The present inventors analyzed the tumor location of 35 colon cancer patients to analyze the correlation between the median progression-free survival (mPFS) and median overall survival (mOS) in anti-HGF (YYB-101) drug response. As a result of analyzing the tumor location, 26 out of 35 patients were confirmed to have the left side, 5 were the right side, and 4 were Colon-unknown, as shown in [Table 4].

As a result of analyzing whether anti-HGF (YYB-101) drug response and tumor location were related to anti-tumor activity, the median progression-free survival (mPFS) was 19.1 weeks for 26 patients whose tumors were located on the left side, and 43.7 weeks for 5 patients whose tumors were located on the right side. In addition, the median overall survival (mOS) was 64.7 weeks for 26 patients whose tumors were located on the left side, and 5 patients whose tumors were located on the right side were not analyzed because no patient died.

The difference according to the location of the colorectal cancer was confirmed to have a statistically significant correlation with the anti-HGF (YYB-101) drug response. In patients with the colorectal cancer on the right side, the median progression-free survival (mPFS) was 24.6 weeks longer than in patients with the colorectal cancer on the left side (Fig. 1).

That is, it was confirmed that when the location of colon cancer development is on the right side, drug sensitivity is high, whereas when the location of development is on the left side, resistance to anti-HGF (YYB-101) drugs is high. As a result, the results of analyzing the correlation between anti-HGF (YYB-101) drug responsiveness and tumor development location showed that patients whose tumors developed on the right side had better drug responsiveness than patients whose tumors developed on the left side.

[Table 4] Location of colon cancer in patients

Experimental Example 2. Measurement of anti-tumor activity of anti-HGF (YYB-101) based on MCT4 expression in tumors and stroma

We analyzed the correlation between MCT4 expression and median progression-free survival (mPFS) in anti-HGF (YYB-101) drug response, with expression in tumors and stroma as ≥20 in tumors and ≤40 in stroma.

As a result of analyzing whether there is a relationship between anti-HGF (YYB-101) drug response and MCT4 expression, as shown in Fig. 2, the median progression-free survival (mPFS) was 33.4 weeks for patients whose MCT4 expression satisfied the criteria of 20 or more in the tumor and 40 or less in the stroma, and 17.6 weeks for patients whose MCT4 expression did not satisfy the criteria of 20 or more in the tumor and 40 or less in the stroma.

The difference in the expression level of MCT4 was confirmed to have a statistically significant correlation with the anti-HGF (YYB-101) drug response. In patients who met the criteria of MCT4 expression ≥ 20 in the tumor and ≤ 40 in the stroma, the median progression-free survival (mPFS) was 15.8 weeks longer than in patients who did not meet the criteria of MCT4 expression ≥ 20 in the tumor and ≤ 40 in the stroma.

As a result, when analyzing the correlation between anti-HGF (YYB-101) drug response and tumor MCT4 expression, patients with MCT4 expression ≥ 20 in tumor and ≤ 40 in stroma had better drug response than patients without such expression.

Experimental Example 3. Measurement of anti-tumor activity of anti-HGF (YYB-101) according to HGF concentration standard in serum

The present inventors analyzed the correlation between serum HGF concentration and anti-HGF (YYB-101) drug response. As a result of analyzing the correlation between anti-HGF (YYB-101) drug response and serum HGF concentration, it was confirmed that the difference in serum HGF concentration showed a correlation with anti-HGF (YYB-101) drug response, as shown in Fig. 3. It was confirmed that patients with serum HGF concentrations of 2012 pg/mL or higher had an increased progression-free survival period compared to patients without such concentrations.

That is, when the serum HGF concentration was 2012 pg/mL or higher, the drug sensitivity was confirmed to be high. As a result, when the correlation between anti-HGF (YYB-101) drug reactivity and serum HGF concentration was analyzed, the drug reactivity was better in patients with serum HGF concentrations of 2012 pg/mL or higher than in patients without.

Experimental Example 4. Risk function analysis with related factors in anti-HGF (YYB-101) drug response

We analyzed the hazard function according to the location of colorectal cancer (left and right), MCT4 expression level, tumor ≥ 20, stroma ≤ 40, and HGF concentration for progression-free survival (PFS) in response to anti-HGF (YYB-101) drug.

The results are shown in [Figure 4]. Specifically, in terms of progression-free survival (PFS) for anti-HGF (YYB-101) drugs, the location of colorectal cancer occurrence (left and right), conditions of MCT4 expression, tumor ≥ 20, stroma ≤ 40, and HGF concentration criteria, the hazard function was analyzed to be the lowest (Hazard ratio, 0.430) when the condition of MCT4 expression was tumor ≥ 20, stroma ≤ 40, and the hazard function was analyzed to be the next lowest when the HGF serum concentration was higher (Hazard ratio, 0.434). On the other hand, in terms of PFS for anti-HGF (YYB-101) drugs, low HGF serum concentration was analyzed to have the highest hazard function (Hazard ratio, 2.305) compared to other factors.

We analyzed the hazard function according to a combination of factors related to the location of colorectal cancer (left and right), MCT4 expression level, tumor ≥ 20, stroma ≤ 40, and HGF concentration in progression-free survival (PFS) responsive to anti-HGF (YYB-101) drugs.

The results are shown in [Figure 5]. Specifically, the progression-free survival (PFS) for anti-HGF (YYB-101) drugs was analyzed to have the lowest hazard function (Hazard ratio, 0.165) when the colon cancer was located on the right side and the HGF concentration was high, and the hazard function was analyzed to be the next lowest (Hazard ratio, 0.230) when the colon cancer was located on the right side and the conditions of MCT4 expression of 20 or more in the tumor and 40 or less in the stroma were satisfied. On the other hand, the progression-free survival (PFS) for anti-HGF (YYB-101) drugs was analyzed to have the highest hazard function (Hazard ratio, 2.567) when the colon cancer was located on the left side and the HGF concentration was low.

As a result, for the anti-HGF (YYB-101) drug, it was confirmed that the drug response was good when the location of colon cancer was on the right side, the HGF concentration was high, and the expression of MCT4 was 20 or more in the tumor and 40 or less in the stroma.

Attach electronic file of sequence list

Claims (13)

A pharmaceutical composition for treating colon cancer, comprising an HGF neutralizing antibody as an active ingredient, characterized in that the pharmaceutical composition is administered to at least one patient selected from the group consisting of (i) patients whose colon cancer is located on the right side, (ii) patients with high expression of MCT4, or (iii) patients with high serum HGF levels. A pharmaceutical composition according to claim 1, wherein the HGF neutralizing antibody has a CDR represented by an amino acid sequence of SEQ ID NO: 3 to 8. A pharmaceutical composition according to claim 1 or 2, characterized in that the HGF neutralizing antibody has a VH region represented by the amino acid sequence of SEQ ID NO: 1 and a VL region represented by the amino acid sequence of SEQ ID NO: 2. A pharmaceutical composition according to claim 2 or 3, characterized in that the HGF neutralizing antibody has a heavy chain represented by the amino acid sequence of SEQ ID NO: 9 and a light chain represented by the amino acid sequence of SEQ ID NO: 10. A pharmaceutical composition according to claim 1 or 2, characterized in that the patient in which MCT 4 is highly expressed exhibits an H-score of MCT 4 of ≥20 in the tumor. In claim 5, a pharmaceutical composition characterized in that the patient in which the MCT 4 is highly expressed exhibits an H-score of MCT 4 of ≤40 in the stroma. A pharmaceutical composition according to claim 1 or 2, characterized in that the patient having a high serum HGF level is a patient having an HGF concentration of 2012 pg/mL or higher. A pharmaceutical composition according to claim 1 or 2, characterized in that the colon cancer is metastatic or recurrent colorectal cancer. A pharmaceutical composition characterized in that it extends the progression-free survival period or overall survival period of patients with metastatic or recurrent colorectal cancer in claim 8. A pharmaceutical composition according to claim 1, characterized in that the patient is a patient in whom (i) the location of the colorectal cancer is on the right side and (ii) MCT4 is highly expressed. A pharmaceutical composition characterized in that in claim 1, (i) the location of the colorectal cancer is on the right side, and (iii) the patient has a high serum HGF level. A method for predicting therapeutic prognosis responsiveness to HGF neutralizing antibodies based on (i) the location of colorectal cancer, (ii) the expression level of MCT4, and (iii) the serum HGF level. A method according to claim 12, wherein the prognostic response to HGF neutralizing antibody is determined to be excellent when (i) the location of the colorectal cancer is on the right side, (ii) MCT4 is ≥20 in the tumor, or (iii) the serum HGF level is an HGF concentration of 2012 pg/mL or higher.