Anti-cancer combination comprising Anti-c-met antibody

Abstract

The present invention relates to a combination comprising: an antibody specifically binding to a liver cell growth factor receptor (c-Met) or an antigen-binding fragment thereof; and a second anticancer agent, and to use of the combination for preventing or treating cancer. The combination therapy of the anti-c-Met antibody and the second anticancer agent of the present invention has excellent anticancer activity, and exhibits a synergistic effect even in EGFR mutant cancer, which is difficult to overcome due to drug resistance, thereby killing cancer cells, and thus can be very effectively used for the prevention and treatment of cancer.

Description

Description of the invention

Title of invention

Technical Field

Background Technology

National Research and Development Project Supporting This Invention

Project Number

Task Number

Ministry Name

Project Management (Specialized) Institution Name

Research Project Name

Research Project Name

Name of the organization performing the project

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Contents of the invention

Technical Challenge

Technical Solution

[0011] [1] In the above, the platinum-based drug may be at least one selected from the group consisting of cisplatin, carboplatin, vinorelbine, etoposide, vinblastine, gemcitabine, docetaxel, pemetrexed, and paclitaxel.

[0012] In the above [1, the EGFR TKI is osimertinib, BI- It may be at least one selected from the group consisting of 4020, TAK-788, furmonertinib, erlotinib, gefitinib, afatinib, and dacomitinib.

[0013] In any one of the above [1] to

[0012] , the cancer may be EGFR mutation negative.

[0014] In any one of the above [1] to

[0012] , the cancer is EGFR-mutated It could be positive.

[0015] In the above

[0013] or

[0014] , the EGFR mutation may be at least one selected from the group consisting of an EGFR activating mutation, an exon 19 deletion, an exon 20 insertion, and an amino acid substitution mutation.

[0016] In the above

[0015] , the exon 19 deletion mutation may be at least one selected from the group consisting of deletion of E746 to A750, deletion of E746 to E749, deletion of L747 to E749, deletion of L747 to S752, deletion of L747 to K754, deletion of R748 to P753, deletion of S752 to 1759, and deletion of R748 to P753.

[0017] In the above

[0015] or

[0016] , the exon 20 insertion mutation may be at least one selected from the group consisting of an insertion of FQEA between A763 and Y764, an insertion of AI or A between M766 and A767, an insertion of SVA between S768 and V769, an insertion of NS between P772 and H773, and an insertion of AH or A between H773 and V774.

[0018] In any one of the above

[0015] to

[0017] , the amino acid substitution mutation is E709K, L718Q, L718V, G719A, G724S, I744T, E746K, L747S, E749Q, A750P, A755V, V765M, C775Y, T790M, L792H, L792V, G796S, G796R, G796C, C797S, T854I, It may be at least one selected from the group consisting of L858R and L858P.

[0019] In any one of the above

[0015] to

[0018] , the amino acid substitution mutation may be at least one selected from T790M, C797S, and L858R. [2] In any one of the above [1] to

[0019] , the cancer may be an EGFR double or triple mutation positive cancer including an EGFR C797S mutation.

[0021] In any one of the above [1] to [2], the cancer may be an EGFR double or triple mutation positive cancer comprising at least one EGFR mutation selected from the group consisting of EGFR C797S mutation; and exon 19 deletion, L858R and T790M.

[0022] In any one of the above [1] to

[0021] , the cancer may be an EGFR double or triple mutation positive cancer including an EGFR T790M mutation.

[0023] In any one of the above [1] to

[0022] , the cancer may be an EGFR double or triple mutation positive cancer comprising at least one EGFR mutation selected from the group consisting of EGFR T790M mutation; and exon 19 deletion, L858R and C797S mutation.

[0024] In any one of the above

[0013] to

[0023] , the EGFR mutation is T790M, C797S, and exon 19 deletion or L858R.

[0025] In any one of the above [1] to

[0024] , the (B) is the drug 1, and the cancer may include EGFR mutations such as T790M, C797S, and exon 19 deletion or L858R. In any one of [1] to

[0024] , (B) is the drug 2, and the cancer may contain an exon 20 insertion with an EGFR mutation.

[0027] In any one of the above [1] to

[0024] , the (B) is the drug 3, and the cancer may contain an EGFR mutation including exon 20 insertion; or T790M, C797S, and exon 19 deletion or L858R.

[0028] In any one of the above [1] to

[0024] , the (B) is the drug 4, and the cancer may contain an exon 20 insertion with an EGFR mutation.

[0029] In any one of the above [1] to

[0028] , the cancer may be a cancer that overexpresses c-Met, amplifies c-Met, or activates c-Met. [3] In any one of the above [1] to

[0029] , the c-Met may be represented by an amino acid sequence described in SEQ ID NO: 317.

[0031] In any one of the above [1] to [3], the antibody may bind to an epitope region described by the amino acid sequence of SEQ ID NO: 313, SEQ ID NO: 314, SEQ ID NO: 315 and SEQ ID NO: 316.

[0032] In any one of the above [1] to

[0031] , the antibody or antigen-binding fragment thereof has a binding affinity for human c-Met of 1 x 10' 7 Binds with a KD of less than or equal to M, wherein the KD can be determined by surface plasmon resonance (Biacore) analysis.

[0033] In any one of the above [1] to

[0032] , the antibody may be an antibody comprising a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO: 1; a light chain CDR2 as set forth in SEQ ID NO: 2; a light chain CDR3 as set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 as set forth in SEQ ID NO: 4; a heavy chain CDR2 as set forth in SEQ ID NO: 5; and a heavy chain CDR3 as set forth in SEQ ID NO: 6, or an affinity-optimized antibody thereof.

[0034] In any one of the above [1] to

[0033] , the antibody may include a light chain variable region described in SEQ ID NO: 7 and a heavy chain variable region described in SEQ ID NO: 8.

[0035] In any one of the above [1] to

[0034] , the antibody comprises (a) sequence number A light chain variable region described as SEQ ID NO: 11 and a heavy chain variable region described as SEQ ID NO: 13; or (b) a light chain variable region described as SEQ ID NO: 12 and a heavy chain variable region described as SEQ ID NO: 14.

[0036] In any one of the above [1] to

[0035] , the antibody may comprise a hinge region described in any one of SEQ ID NO: 19 to SEQ ID NO: 26.

[0037] In any one of the above [1] to

[0036] , the antibody is an antibody in which at least one amino acid sequence is substituted in an antibody comprising a light chain variable region comprising a light chain CDR1 set forth in SEQ ID NO: 1; a light chain CDR2 set forth in SEQ ID NO: 2; a light chain CDR3 set forth in SEQ ID NO: 3, and a heavy chain variable region comprising a heavy chain CDR1 set forth in SEQ ID NO: 4; a heavy chain CDR2 set forth in SEQ ID NO: 5; a heavy chain CDR3 set forth in SEQ ID NO: 6, wherein (i) G at the 1st position of the light chain CDR1 is A, E, K, L, N, R, S, V or W; A at the 2nd position is C, G, I, P, S, T or V; S at the 3rd position is G, M, N, P, Q, R, S or T; E at the 4th position is A, D, F, G, H, K, M, Q, R, S, T or V; N at the 5th position is A, D, E, G, K, L, P, Q, R, S, T or V; I at the 6th position is A, F, L, M, Q, R, S, T or V; Y at the 7th position is F, H, R or V; or G at the 8th position is D, F, H, M, N, R, S, T or substituted with V; (ii) G at the 1st position of the light chain CDR2 is D, F, H, K, P, Q, S, V or Y; T at the 3rd position is Q; or N at the 4th position is substituted with; (iii) Q at the 1st position of the light chain CDR3 is E, G, I, M or N; 凡 at the 2nd position is A, D, E, H, L, Q, S or T; V at the 3rd position is I, L, M, N, Q, S or T; L at the 4th position is F, H, I, M, R, S, V, W or Y; S at the 5th position is C, D, E, F, G, H, K, L, N, Q, R, T, V or Y; S at the 6th position is D, E, F, G, H, I, L, M, N, P, Q, R, T, V or Y; P at the 7th position is A, D, E, G, N, Q, S or V; Y at the 8th position is E, F, L, M or Q; or T at the 9th position is D, F, G, I, L, N, S, V, W or Y; (iv) 日 at the 1st position of the heavy chain CDR1 is G or Q; Y at the 2nd position is Q; or I at the 4th position is A or 이; (v) 도 at the 3rd position of the heavy chain CDR2 is D, E, W or Y; 으 at the 5th position is D, H or Y; 으 at the 6th position is F, P, W or Y; G at the 7th position is A, F, L, N or T; 凡 at the 8th position is F, P, S, T or Y; T at the 9th position is A, D, E, F, G, H, L, P, S or V; H at the 10th position is A, D, F, M, R, S, T, V, W or Y; F at the 11th position is G, H, I, L, M, N, P, Q, V or Y; S at the 12th position is A, D, G, H, I, L, P, T or V; A at the 13th position is D, E, F, G, H, I, K, L, M, P, R, S, T, V or Y; R at the 14th position is A, E, G, H, L, N, P, Q, S, W or Y; F at the 15th position is D, E, G, L, M, P, R, S, V or W; V at the 16th position is A, E, F, G, H, L, R, S, T, V or Y; or G at the 17th position is E, F, H, L, M, N, P, Q, R, S, T, V or W;Or (vi) in the heavy chain CDR3, G at the 1st position is replaced with E, F, H, N, Q, V or W; J at the 2nd position is replaced with E; O at the 3rd position is replaced with L, Q, T or V; U at the 4th position is replaced with W; F at the 5th position is replaced with L or Y; L at the 6th position is replaced with Q, S or Y; or Y at the 7th position is replaced with C, L, M, N or Y, wherein the light chain CDR1 may include 0 to 5 substitutions, the light chain CDR2 may include 0 to 1 substitution, the light chain CDR3 may include 0 to 7 substitutions, the heavy chain CDR1 may include 0 to 1 substitution, the heavy chain CDR2 may include 0 to 11 substitutions, and the heavy chain CDR3 may include 0 to 6 substitutions.

[0038] In any one of the above

[0033] to

[0037] , the affinity-optimized antibody comprises a light chain variable region comprising a light chain CDR1 as described in any one of SEQ ID NO: 1 and SEQ ID NOs: 211 to 250; a light chain CDR2 as described in any one of SEQ ID NO: 2, SEQ ID NOs: 164 to 172, SEQ ID NO: 209, and SEQ ID NO: 210; a light chain CDR3 as described in any one of SEQ ID NO: 3, SEQ ID NOs: 124 to 163, SEQ ID NOs: 173 to 208, and SEQ ID NOs: 251 to 283; and a heavy chain CDR1 as described in any one of SEQ ID NO: 4, and SEQ ID NOs: 90 to 94; a heavy chain CDR2 as described in any one of SEQ ID NO: 5, SEQ ID NOs: 36 to 45, SEQ ID NOs: 54 to 89, and SEQ ID NOs: 100 to 123; and a heavy chain CDR1 as described in any one of SEQ ID NO: 6, SEQ ID NOs: 46 to 53, and SEQ ID NO: 95. It may comprise a heavy chain variable region comprising a heavy chain CDR3 described as any one of SEQ ID NOS: 1 to 99.

[0039] In any one of the above

[0033] to

[0038] , the affinity optimized antibody may comprise a light chain variable region as set forth in any one of SEQ ID NOs: 11 and 288 to 293 and a heavy chain variable region as set forth in any one of SEQ ID NOs: 13 and 284 to 287. [4] In any one of the above

[0033] to

[0039] , the affinity-optimized antibody comprises (a) a light chain variable region as set forth in SEQ ID NO: 11 and a heavy chain variable region as set forth in SEQ ID NO: 284; (b) a light chain variable region as set forth in SEQ ID NO: 11 and a heavy chain variable region as set forth in SEQ ID NO: 287; (c) a light chain variable region as set forth in SEQ ID NO: 292 and a heavy chain variable region as set forth in SEQ ID NO: 13; (d) a light chain variable region as set forth in SEQ ID NO: 290 and a heavy chain variable region as set forth in SEQ ID NO: 287; (e) a light chain variable region as set forth in SEQ ID NO: 288 and a heavy chain variable region as set forth in SEQ ID NO: A heavy chain variable region described by SEQ ID NO: 285; (f) a light chain variable region described by SEQ ID NO: 289 and a heavy chain variable region described by SEQ ID NO: 286; (g) a light chain variable region described by SEQ ID NO: 290 and a heavy chain variable region described by SEQ ID NO: 286; (h) a light chain variable region described by SEQ ID NO: 291 and a heavy chain variable region described by SEQ ID NO: 286; (i) a light chain variable region described by SEQ ID NO: 293 and a heavy chain variable region described by SEQ ID NO: 286; or (j) a light chain variable region described by SEQ ID NO: 288 and a heavy chain variable region described by SEQ ID NO: 284.

[0041] In any one of the above [1] to [4], the antibody may further comprise an antibody or an antigen-binding fragment thereof that specifically binds to epidermal growth factor receptor (EGFR).

[0042] In any one of the above [1] to

[0041] , the antibody may be one in which an antibody or an antigen-binding fragment thereof that binds to epidermal growth factor receptor (EGFR) is linked to one end of a light or heavy chain of an antibody that specifically binds c-Met.

[0043] In the above

[0041] or

[0042] , the antigen-binding fragment binding to the EGFR may be Fab, Fab', F(ab')2 or Fv.

[0044] In the above

[0043] , the Fv may be at least one scFv fragment selected from the group consisting of Erbitux, Vectibix, Portrazza, and TheraCIM.

[0045] In the above

[0044] , the Erbitux scFv may include an amino acid sequence described as SEQ ID NO: 295 or SEQ ID NO: 296.

[0046] In the above

[0044] , the Vect ibix scFv is described as sequence number 297. It may contain an amino acid sequence.

[0047] In any one of the above

[0041] to

[0046] , the connection of the antibody or antigen-binding fragment thereof that binds to the EGFR may be connected by a connector described in SEQ ID NO: 294.

[0048] In any one of the above [1] to

[0047] , the antibody or antigen-binding fragment thereof may include a light chain variable region as set forth in SEQ ID NO: 11 and any one of SEQ ID NOs: 288 to 293; and a heavy chain variable region as set forth in any one of SEQ ID NOs: 298 to 312.

[0049] In any one of the above [1] to

[0048] , the antibody or antigen-binding fragment thereof comprises (1) a light chain variable region as set forth in SEQ ID NO: 11 and a heavy chain variable region as set forth in SEQ ID NO: 298; (2) a light chain variable region as set forth in SEQ ID NO: 11 and a heavy chain variable region as set forth in SEQ ID NO: 299; (3) a light chain variable region as set forth in SEQ ID NO: 11 and a heavy chain variable region as set forth in SEQ ID NO: 302; (4) a light chain variable region as set forth in SEQ ID NO: 292 and a heavy chain variable region as set forth in SEQ ID NO: 298; (5) a light chain variable region as set forth in SEQ ID NO: 290 and a heavy chain variable region as set forth in SEQ ID NO: A heavy chain variable region described by SEQ ID NO: 302; (6) a light chain variable region described by SEQ ID NO: 288 and a heavy chain variable region described by SEQ ID NO: 300; (7) a light chain variable region described by SEQ ID NO: 289 and a heavy chain variable region described by SEQ ID NO: 301; (8) a light chain variable region described by SEQ ID NO: 290 and a heavy chain variable region described by SEQ ID NO: 301; (9) a light chain variable region described by SEQ ID NO: 291 and a heavy chain variable region described by SEQ ID NO: 301; (10) a light chain variable region described by SEQ ID NO: 293 and a heavy chain variable region described by SEQ ID NO: 301; (11) a sequence A light chain variable region described by SEQ ID NO: 288 and a heavy chain variable region described by SEQ ID NO: 299; (12) a light chain variable region described by SEQ ID NO: 11 and a heavy chain variable region described by SEQ ID NO: 303; (13) a light chain variable region described by SEQ ID NO: 11 and a heavy chain variable region described by SEQ ID NO: 304; (14) a light chain variable region described by SEQ ID NO: 11 and a heavy chain variable region described by SEQ ID NO: 307; (15) a light chain variable region described by SEQ ID NO: 292 and a heavy chain variable region described by SEQ ID NO: 303; (16) a light chain variable region described by SEQ ID NO: 290 and a heavy chain variable region described by SEQ ID NO: 307; (17) a light chain variable region described by SEQ ID NO: 288 and a heavy chain variable region described by SEQ ID NO: 305; (18) a light chain variable region described by SEQ ID NO: 289 and a heavy chain variable region described by SEQ ID NO: 306; (19) a light chain variable region described by SEQ ID NO: 290 and a heavy chain variable region described by SEQ ID NO: 306; (20) a light chain variable region described by SEQ ID NO: 291 and a heavy chain variable region described by SEQ ID NO: 306; (21) a light chain variable region described by SEQ ID NO: 293 and a heavy chain variable region described by SEQ ID NO: 306; (22) a light chain variable region described by SEQ ID NO: 288 and a heavy chain variable region described by SEQ ID NO: 304; (23) a light chain variable region described by SEQ ID NO: 11 and a heavy chain variable region described by SEQ ID NO: 308; (24) a light chain variable region described by SEQ ID NO: 11 and a heavy chain variable region described by SEQ ID NO: 309; (25) a light chain variable region described by SEQ ID NO: 11 and a heavy chain variable region described by SEQ ID NO: 312; (26) a light chain variable region described by SEQ ID NO: 292 and a heavy chain variable region described by SEQ ID NO: 308; (27) a light chain variable region described by SEQ ID NO: 290 and a heavy chain variable region described by SEQ ID NO: 312; (28) a light chain variable region described by SEQ ID NO: 288 and a heavy chain variable region described by SEQ ID NO: 310; (29) a light chain described by SEQ ID NO: 289 A variable region and a heavy chain variable region as set forth in SEQ ID NO: 311; (30) a light chain variable region as set forth in SEQ ID NO: 290 and a heavy chain variable region as set forth in SEQ ID NO: 311; (31) a light chain variable region as set forth in SEQ ID NO: 291 and a heavy chain variable region as set forth in SEQ ID NO: 311; (32) a light chain variable region as set forth in SEQ ID NO: 293 and a heavy chain variable region as set forth in SEQ ID NO: 311; or (33) a light chain variable region as set forth in SEQ ID NO: 288 and a heavy chain variable region as set forth in SEQ ID NO: 309. [5] In any one of the above [1] to

[0049] , the antibody or antigen-binding fragment thereof may comprise a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 11 and a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 308.

[0051] In any one of the above [1] to [5], the antibody or antigen-binding fragment thereof and at least one of drugs 1 to 4 may be administered simultaneously or separately.

[0052] In any one of the above [1] to

[0051] , the antibody or antigen-binding fragment thereof and at least one of drugs 1 to 4 may be administered sequentially.

[0053] In any one of the above [1] to

[0052] , the pharmaceutical composition may reduce the size of a tumor.

[0054] In any one of the above [1] to

[0053] , the pharmaceutical composition may increase at least one selected from the group consisting of progression-free survival (PFS), overall survival (OS), complete response rate, and partial response rate of the subject.

[0055] In any one of the above [1] to

[0054] , the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO: 1; a light chain CDR2 as set forth in SEQ ID NO: 2; a light chain CDR3 as set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 as set forth in SEQ ID NO: 4; a heavy chain CDR2 as set forth in SEQ ID NO: 5; and a heavy chain CDR3 as set forth in SEQ ID NO: 6, wherein (B) is the drug 1, and the cancer may be an EGFR mutation including T790M, C797S, and exon 19 deletion (e.g., deletion of E746 to A750) or L858R.

[0056] In any one of the above [1] to

[0054] , the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO: 1; a light chain CDR2 as set forth in SEQ ID NO: 2; a light chain CDR3 as set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 as set forth in SEQ ID NO: 4; a heavy chain CDR2 as set forth in SEQ ID NO: 5; and a heavy chain CDR3 as set forth in SEQ ID NO: 6, wherein (B) is the drug 2, and the cancer may be an EGFR mutation comprising an exon 20 insertion (for example, any one selected from the group consisting of an insertion of FQEA between A763 and Y764, an insertion of AI between M766 and A767, and an insertion of AH or A between H773 and V774).

[0057] In any one of the above [1] to

[0054] , the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO: 1; a light chain CDR2 as set forth in SEQ ID NO: 2; a light chain CDR3 as set forth in SEQ ID NO: 3; and a heavy chain CDR1 as set forth in SEQ ID NO: 4; a heavy chain CDR2 as set forth in SEQ ID NO: 5; and a heavy chain as set forth in SEQ ID NO: 6. A heavy chain variable region comprising CDR3, wherein (B) is the drug 3, and The cancer can comprise an EGFR mutation comprising an exon 20 insertion (e.g., any one selected from the group consisting of an insertion of FQEA between A763 and Y764, an insertion of AI between M766 and A767, and an insertion of AH or A between H773 and V774); or T790M, C797S, and an exon 19 deletion (e.g., a deletion of E746 to A750) or L858R.

[0058] In any one of the above [1] to

[0054] , the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO: 1; a light chain CDR2 as set forth in SEQ ID NO: 2; a light chain CDR3 as set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 as set forth in SEQ ID NO: 4; a heavy chain CDR2 as set forth in SEQ ID NO: 5; and a heavy chain CDR3 as set forth in SEQ ID NO: 6, wherein (B) is the drug 4, and the cancer may be an EGFR mutation comprising an exon 20 insertion (for example, any one selected from the group consisting of an insertion of FQEA between A763 and Y764, an insertion of AI between M766 and A767, and an insertion of AH or A between H773 and V774).

[0059] In any one of the above [1] to

[0058] , the antibody or antigen-binding fragment thereof may comprise a light chain variable region described in SEQ ID NO: 11 and a heavy chain variable region described in SEQ ID NO: 308. [6 The pharmaceutical composition for preventing or treating cancer according to the present invention comprises (A) an antibody or an antigen-binding fragment thereof that specifically binds to hepatocyte growth factor receptor (c-Met) that binds to at least one epitope region described by an amino acid sequence selected from the group consisting of SEQ ID NO: 313, SEQ ID NO: 314, SEQ ID NO: 315 and SEQ ID NO: 316 as an active ingredient, and the pharmaceutical composition comprises (B) (1) drug 1, (2) It may be administered to an individual in combination with at least one selected from the group consisting of drug 2, (3) drug 3, and (4) drug 4.

[0061] A method for preventing or treating cancer according to the present invention comprises the step of administering to a subject in need of prevention or treatment of cancer an antibody or an antigen-binding fragment thereof that specifically binds to hepatocyte growth factor receptor (c-Met) that binds to at least one epitope region described in an amino acid sequence selected from the group consisting of (A) SEQ ID NO: 313, SEQ ID NO: 314, SEQ ID NO: 315, and SEQ ID NO: 316, wherein the antibody or the antigen-binding fragment thereof may be administered in combination with (B) at least one selected from the group consisting of (1) Drug 1, (2) Drug 2, (3) Drug 3, and (4) Drug 4.

[0062] The use of an antibody or an antigen-binding fragment thereof that specifically binds to hepatocyte growth factor receptor (c-Met) that binds to at least one epitope region described in an amino acid sequence selected from the group consisting of (A) SEQ ID NO: 313, SEQ ID NO: 314, SEQ ID NO: 315, and SEQ ID NO: 316 according to the present invention for preventing or treating cancer may be that the antibody or the antigen-binding fragment thereof is administered in combination with (B) at least one selected from the group consisting of (1) Drug 1, (2) Drug 2, (3) Drug 3, and (4) Drug 4.

[0063] In the manufacture of a medicament for use in preventing or treating cancer according to the present invention, (A) a compound specifically binding to hepatocyte growth factor receptor (c-Met) that binds to at least one epitope region described by an amino acid sequence selected from the group consisting of SEQ ID NO: 313, SEQ ID NO: 314, SEQ ID NO: 315 and SEQ ID NO: 316 The use of the binding antibody or antigen-binding fragment thereof may be such that the antibody or antibody fragment is administered in combination with (B) at least one selected from the group consisting of (1) drug 1, (2) drug 2, (3) drug 3 and (4) drug 4.

[0064] In any one of the above [6] to

[0063] , (i) (A) an antibody or an antigen-binding fragment thereof that specifically binds to hepatocyte growth factor receptor (c-Met) that binds to at least one epitope region described in an amino acid sequence selected from the group consisting of SEQ ID NO: 313, SEQ ID NO: 314, SEQ ID NO: 315 and SEQ ID NO: 316, (ii) (B) drug 1, drug 2, drug 3, drug 4 or (iii) cancer may be substantially the same as described in [1] to

[0059] unless contradictory.

Effect of the invention

Brief description of the drawing

Best mode for carrying out the invention

Form for implementing the invention

【Table 11 Hybridoma light chain CDR

【Table 2 Hybridoma Heavy Chain CDR Specific consensus on the light and heavy chain variable regions of the 8C4 antibody of the present invention The sequence is shown in Table 3 below.

【Table 3] Consensus sequence for the light and heavy chain variable regions of the 8C4 antibody Example 2. Production of humanized antibody of 8C4 antibody For humanization design of the 8C4 antibody heavy chain, first, Ig Blast Heavy chain of mouse antibody 8C4 through (http: / / www.ncbi .nlm.nih.gov / igblast / ) We analyzed human germline genes with high homology to variable region genes. As a result, we confirmed that IGHV3-23 had 48% homology with 8C4 antibody at the amino acid level, and we confirmed that IGHV3-11 had 46% homology with 8C4 antibody at the amino acid level. CDR-H1, CDR-H2, and CDR— H3 of white mouse antibody 8C4 were defined by Rabat numbering, and hu8C4-1 was produced by designing the CDR portion of mouse antibody 8C4 to be introduced into the framework of IGHV3-23. At this time, 48 (V— I), 49 (S— G), 71 (R— A), Amino acids 73 (N—K), 78 (L—A), and 94 (K—G) were back-mutated to the amino acid sequence of the original mouse 8C4 antibody, ultimately constructing the heavy chain of hu8C4-1. In the case of hu8C4-2, the CDR portion of the mouse antibody 8C4 was designed to be introduced into the framework of IGHV3-11, and positions 48 (V—I), 49 (S—G), 71 (R—A), 73 (N—K), Amino acids 78 (L—A) and 94 (R—G) were back-mutated to the amino acid sequence of the original mouse 8C4 antibody, ultimately constructing the heavy chain of hu8C4-2. In the case of the 8C4 antibody light chain, for humanization design, human germline genes with high homology to the light chain variable region gene of mouse antibody 8C4 were analyzed through Ig Blast (http: / / www.ncbi .nlm.nih.gov / igblast / ). As a result, it was confirmed that IGKV1-27 had 65.3% homology with 8C4 antibody at the amino acid level, and IGKV1-33 had 64.2% homology with 8C4 antibody at the amino acid level. CDR-L1, CDR-L2, CDR— L3 of the white mouse antibody 8C4 were defined by Rabat numbering, and the CDR portion of the mouse antibody 8C4 was designed to be introduced into the framework of IGKV1-33 to produce hu8C4-1, and was designed to be introduced into the framework of IGKV1-27 to produce hu8C4-2. At this time, both hu8C4-1 and hu8C4-2 had amino acid position 69 (T—R) back-mutated to the amino acid sequence of the original mouse 8C4 antibody. The above 8C4 humanized antibody was expressed in 293T cells using the pCLS05 vector (Korean Patent No. 10-1420274). Specific consensus sequences for the light and heavy chain variable regions of the above hu8C4-l and hu8C4-2 humanized antibodies are shown in Table 4.

Table 4

Table 5

【Table 6]

【Table 7]

Table 8

【Table 2: List of sequences of variable region combinations of affinity-optimized antibodies Example 5. Production of bispecific antibody and in vitro tumor cell proliferation inhibitory activity In order to produce a bispecific antibody that specifically binds to c-Met and EGFR, scFv fragments of Erbitux (cetuximab) and Vect ibix (panitumumab), known to specifically bind to EGFR, were each linked to the heavy chain C-terminus of the c-Met antibody of the present invention using a GGGGSGGGGS (SEQ ID NO: 294) connector to produce a bispecific antibody. In order to increase the stability of the above-mentioned product, the 44th residue of the heavy chain and the 100th residue of the light chain were substituted with cysteine ​​(Reiter Y. et al., Biochemistry 33 (18): 5451- 5459 (1994)). The Erbitux and Vect ibix scFv sequences, bispecific antibody heavy chain amino acid sequences and bispecific antibody variable region combinations are shown in Tables 10 and 11 below.

【Table 10]

【Table 111 List of dual antibody variable region combination sequences Next, the tumor cell proliferation inhibition activity of the dual antibody linking Erbitux and Vectibix scFv fragments was evaluated using NCI-H1993 and NCI-H292 lung cancer cell lines. Specifically, the tumor cell proliferation inhibition activity was performed on NCI-H1993 (ATCC, #CRL-5909), a cell line in which c-Met gene is overexpressed, and NCI-H292 (ATCC, #CRL-1848), a cell line in which EGFR and c-Met are normally expressed, using the following method. Each cell line was diluted in RPMI-1640 medium (Gibco, #A10491) containing 10% (v / v) FBS. 2.0 x 10 in each well of a 96-well plate 3 After dispensing each well of the plate, they were cultured overnight at 37 °C, 5% C02. After that, each well of the plate was replaced with 100 M serum-free medium and cultured for 18 hours at 37 °C, 5% C02. Then, the medium was replaced with 100 C RPMI-1640 medium containing 2% (v / v) FBS or HGF 50 ng / ml, and the test antibodies were serially diluted 1 / 10 from 100 nM to 0.001 nM (i.e., 100 nM, 10 nM, 1 nM, 100 pM, 10 pM, and 1 pM) and added to each well at 100 M. Then, the above plate was cultured for 5 days at 37 °C, 5% C02, the medium was removed, and 200 M TCA solution was added to each well to fix the cells. The cells in the plate were stained according to the conventional SRB colorimetric assay method, and the absorbance of each well was measured at a wavelength of 540 nm using a microplate reader. The results of proliferation inhibition activity in each cell line are shown in Table 12, Table 13, Figures 2 and 3.

Table 12

Table 13

Table 14

【Table 15] No growth inhibitory effect of CM01 alone was observed in the evaluated cell lines. BI- In the case of 4020 alone, it showed cell growth effects in PC-9-EGFR del l9 / T790M / C797S, NCI-H1975-EGFR L858R / T790M / C797S, BaF3-EGFR del l9 / T790M / C797S, and Ba / F3-EGFR L858R / T790M / C797S, and IC5o of 20.44, 288.51, 1.90, and 1.79 nM, respectively. CM01 and BI- When combined with 4020, IC5o in each cell line was 4.94, 160.46, 0.38, and 0.37 nM, respectively. It was confirmed that there was a significant decrease compared to treatment with CM-01 or BI-4020 alone. (2) Confirmation of changes in signal transmission pathway Experiments were conducted to determine whether cMET, EGFR and downstream cell signaling were reduced by single or combined treatment with CM01 and BI-4020 in EGFR triple mutant (del l9 or L858R / T790M / C797S) cell lines. 3 x 10 5 The cells were divided and cultured at 37 °C, 5% C02, and then replaced with a medium containing 2% (v / v) FBS the next day and cultured for 24 hours. HGF (hepatocyte growth factor) was diluted to 50 ng / ml in a culture medium containing 2% FBS. CM01 and BI-4020 were diluted in this solution and drug treatment was performed and cultured for 24 hours. The medium was removed and the remaining medium was washed with PBS. After removal, RIPA buffer was used to lyse all cells in RIPA buffer. The cell lysate was reacted at 4 °C for 30 minutes, centrifuged at 15,000 g for 15 minutes, and the supernatant was collected and mixed with 5X SDS sample buffer containing a reducing agent. After that, samples were prepared and the expression level of each protein was compared using the Western blot method. As a result, in the case of CM01 treatment alone, no decrease in p-cMET, p-EGFR, p-ERKl / 2, and p-AKT was observed in the PC9-EGFR del l9 / T790M / C797S cell line (Creat ive Biogene, #CSC- R00456), but in the case of BI-4020 treatment alone, it was confirmed that p-EGFR, p-cMET decreased from 1 nM and p-ERK1 / 2 from 10 nM. When the two drugs were used together, a greater decrease in signaling substances was observed compared to the single treatment, and in the case of p-ERK1 / 2 and p-EGFR, the signals were confirmed to be completely inhibited at the highest concentration (Fig. 11). In addition, in the H1975-EGFR L858R / T790M / C797S cell line (Creat ive Biogene, #CSC- R00455), it was confirmed that p-EGFR, Total-EGFR, p-cMET, and Total cMET were decreased by CM()1, but no decrease in the lower levels of p-ERK1 / 2 and p-AKT was observed. In the case of BI-4020 treatment alone, p-EGFR was decreased, but no decrease in other signaling substances was observed (Fig. 12). From the above results, it was confirmed that when CM01 and BI-4020 were used together, p-EGFR, p-cMET, p-ERKl / 2, and p-AKT were effectively reduced compared to when each drug was used alone. (3) In vivo combination test In a CDX animal model transplanted with EGFR triple mutant (L858R / T790M / C797S) cell lines The anti-tumor effects of CM01 and BI-4020 or osimertinib alone or in combination were confirmed. Ba / F3 EGFR L858R / T790M / C797S mutant cell line (Creat ive Biogene, #CSC-R00139) was cultured in RPMI1640 medium (supplemented with 10% FBS and 1% penicillin-streptomycin) at 37 °C in a 5% C02 incubator. The cultured cells were collected and seeded in serum-free RPMI medium at a density of 2.5 X 10 7 The cells were prepared under the condition of 10 cells / ml. The prepared cells were placed in a syringe at 0.2 ml each and injected into Balb / c-nu mice at a density of 5 X 10 per mouse. 6 The cells were inoculated subcutaneously. The tumor volume was approximately 150 mm on average. 3 When the target was reached, the subjects were randomized and drug administration was initiated simultaneously. CM01 was administered intraperitoneally at 30 mg / kg twice a week for 3 weeks, and osimertinib and BI-4020 were administered orally at 10 mg / kg once a day. During the trial, tumor size was measured twice a week using a caliper. Tumor volume (mm 3 ) and tumor growth inhibition (%) formulas were calculated as follows: Tumor volume (mm 3 ) = long axis length X (short axis length) 2 X 0.5 Tumor growth inhibition (%) = {(mean tumor volume of control group - mean tumor volume of treatment group) / mean tumor volume of control group} X 100. The weight and survival of mice were measured and observed three times a week. Tumor volume compared to the control group was analyzed by Dunnett's T3 multi comparison test, and survival analysis was performed by 1 og-1 ank test and Statistical analysis was performed using the Bonferroni method. The test results are shown in Table 16, Figures 13 and 14.

【Table 16] * NS:not signi fi cant As a result, on the 14th day after drug administration, the osimertinib administration group showed no efficacy (tumor growth inhibition rate: -5.09%), whereas the BI-4020 monotherapy group and the BI-4020 plus CM01 combination administration group showed tumor growth inhibition rates of 77.41% and 96.78%, respectively, and the average tumor volume showed a statistically significant difference compared to the control group. In the survival rate analysis, the BI-4020 monotherapy group and the combination administration group showed a median survival day of 31 days and 46 days, respectively, and the survival rate showed a statistically significant difference compared to the control group (19.5 days). The combination administration group showed a statistically significant difference compared to the BI-4020 monotherapy group, with an increase in the tumor growth inhibition rate of 19.37% and a median survival day of 15 days. There was no difference in the mouse weight between the groups. These results suggest that Ba / F3 EGFR The combination therapy of BI-4020 and CM01 was confirmed to be effective in the L858R / T790M / C797S mutant mouse tumor model. Example 10. Combination therapy of anti-c-Met antibodies in EGFR exon 20 insertion mutant cancer (1) In vitro combination test The combined effect of CM01 and furmonatinib, osimertinib, or TAK-788 was investigated using cell lines harboring insertion mutations in EGFR exon 20. 1-1. SNU-3173 (EGFR-H773insAH) SNU-3173 cells (Korea Cell Line Bank, #03173) were diluted in RPMI-1640 culture medium containing 10% (v / v) FBS and seeded at 8.0 x 10 per well of a 96-well plate. 3After adding 100 M each at a concentration of dog cells, the plates were cultured for 18 to 24 hours at 37 °C, 5% (v / v) C02. Then, the cell culture medium in each well was removed, and CM01 and furmonatinib, osimertinib, or TAK-788 drugs were mixed at a 1:1 ratio in RPMI-1640 medium containing 2% (v / v) FBS and 50 ng / ml HGF, diluted to a final concentration (1,000 nM), and then serially diluted by 1 / 3.16 and added to each well at 100 M. The plates were then cultured for 120 hours at 37 °C, 5% (v / v) C02. Then, the medium of the above plate was removed, 10% TCA solution was added to each well (100 M each) to fix the cells, and the cells in the plate were counted according to the conventional SRB colorimetric assay method. The staining was performed and the absorbance was measured at a wavelength of 540 nm using a microplate reader. The degree of cell proliferation was quantified by calculating the difference in absorbance values ​​120 hours after drug treatment compared to the day of drug treatment. The combination index (CI) was calculated using Compusyn software (Table 17; Leukemia&Lymphoma, 2008, 49(11):2059).

【Table 17] The test results are shown in Table 18 and Figures 15 to 17.

【Table 18] The combination treatment of CM01 with pimonetinib or TAK-788 demonstrated a very strong synergistic effect on cell proliferation inhibition, with CI values ​​of 0.014 to 0.048 in all 50%, 75%, and 90% growth inhibition rate sections. The combination treatment of CM01 with osimertinib demonstrated a very strong synergistic effect on cell proliferation inhibition in the 50% and 75% cell growth inhibition sections, and a synergistic effect in the 90% cell growth inhibition section. 1-2. Ba / F3-EGFR M766_A767 ins_AI Ba / F3-EGFR M766_A767 ins_AI cells (Signosi s, #EL-018-FP) were diluted in RPMI-1640 culture medium containing 10% (v / v) FBS and seeded at 5.0 X 10 per well of a 96-well plate. 2 After adding 100 M each at a concentration of 10 cells, the plates were cultured at 37 °C in 5% (v / v) C02 for 18–24 h. Then, the cell culture medium in each well was removed, and CM01 and pimotinib, osimertinib, or TAK-788 drugs were mixed at a 1:1 ratio in RPMI-1640 medium containing 10% (v / v) FBS to prepare a 3-fold concentration. Then, after diluting to the final concentration (100 nM), 1 / 3. 16 were serially diluted, and 50 M was added to each well. The plates were then cultured at 37 °C, 5% (v / v) C02 for 72 hours. Then, 50 M of Cel lTi ter-Glo® reagent was added to each well of the plates, and the cells were lysed and stabilized at room temperature for 30 minutes, and then luminescence was measured using a luminometer. The degree of cell proliferation was quantified by calculating the difference between the drug-treated value and the untreated value, and the combination index (CI) was calculated using Compusyn software. The test results are shown in Table 19 and Figures 18 to 20.

【Table 19] CI values ​​at 50%, 75%, and 90% growth inhibition intervals by combination treatment with CM01 and furmonatinib or osimertinib in Ba / F3-EGFR M766_A767 ins_AI cells The synergy effect was confirmed at 0.357 - 0.564. When CM01 and TAK-788 were used together, Strong synergy or synergy effect was confirmed with CI values ​​of 0.294 - 0.473 in the 50%, 75%, and 90% growth inhibition intervals. 1-3. Ba / F3-EGFR A763_Y764 ins_FQEA Ba / F3-EGFR A763_Y764 ins_FQEA cells (Signosi s, #EL-009-FP) were diluted in RPMI-1640 culture medium containing 10% (v / v) FBS and 10 ng / ml Murine IL-3 and seeded at a density of 5.0 x 10 per well of a 96-well plate. 2After adding 100 M each at a concentration of 10 cells, the plates were cultured for 18 to 24 hours at 37 °C under 5% (v / v) C02 conditions. Then, the cell culture medium in each well was removed, and CM01 and furmonatinib, osimertinib, or TAK-788 drugs were mixed at a 1:1 ratio in RPMI-1640 medium containing 10% (v / v) FBS to prepare a 3-fold concentration. Then, after diluting to a final concentration (100 nM), 1 / 3. 16 were serially diluted and added to each well at 50 M. The plates were then cultured for 72 hours at 37 °C under 5% (v / v) C02 conditions. Then, 50 mL of Cel lTi ter-Glo® reagent was added to each well of the plate, and the cells were lysed and stabilized at room temperature for 30 minutes. Then, luminescence was measured using a luminometer. The degree of cell proliferation was quantified by calculating the difference between the drug-treated value and the value without drug treatment, and the combination index (CI) was calculated using Compusyn software. The test results are shown in Table 20 and Figures 21 to 23.

【Table 20] The CI value in the 75% and 90% growth inhibition intervals was 0.040 - 0.083, demonstrating a very strong synergistic effect in inhibiting Ba / F3-EGFR A763_Y764 ins_FQEA cell proliferation when combined with CM01 and pimonetinib, osimertinib or TAK-788. In the 50% growth inhibition interval, very strong synergy was confirmed with the combined treatment of CM01 and pimonetinib, and synergy or strong synergy was confirmed with the combined treatment of osimertinib or TAK-788. The combined results (IC50) of anti-cMet antibodies in EGFR exon 20 insertion mutation cancers are summarized in Table 21.

【Table 21] (2) 5 x 10 the day before the experiment to confirm the change in signal transmission pathway 5 BaF3 (EGFR A763_Y764 ins FQEA) cells (Signosi s, #EL-009-FP) were seeded on 60 mm plates and cultured at 37 °C, 5% C02 for 18–24 h. CM01 and TAK-788 were diluted to twice the treatment concentration and treated with the plates. After 6 h, the cells and culture medium were collected and centrifuged at 1500 g for 3 minutes to separate the culture medium and cells, and the upper culture medium was discarded. RIPA buffer 500 M was mixed with the remaining cells using a pipette until all cells were lysed in the RIPA buffer. After reacting the cell lysate at 4 °C for 30 minutes, it was fractionated using a centrifuge at 15000 g for 15 minutes, and the supernatant was collected. Afterwards, the sample was prepared by mixing with 5X SDS sample buffer containing reducing agent and heating. The amount of each protein was compared using the Western blot method from the sample obtained in this way. When CM01 and TAK-788 were treated alone in BaF3 (EGFR A763_Y764 ins FQEA) cell line, p-EGFR, p-cMET, and p-AKT were confirmed to decrease in a concentration-dependent manner. (Fig. 24). Complete disappearance of signaling substances could not be confirmed at 10 nM when treated alone, but when treated together with CM01 and TAK-788, it was confirmed that the expression of signaling substances of p-EGFR, p-ERKl / 2, and p-AKT disappeared. In BaF3 (EGFR H773_V774 insH), it was confirmed that when treated together with CM01 and TAK-788 at 10 nM, p-EGFR, p-AKT, and p-ERK1 / 2 were effectively reduced compared to when treated alone (Fig. 25). (3) In vivo combination test The anti-tumor effect of combined treatment with CM01 and furmonatinib or TAK-788 was confirmed in a CDX animal model transplanted with cell lines having insertion mutations in EGFR exon 20. 3-1. Ba / F3-EGFR H773_V774InsH model The cell line (Signosis, #EL-019-FP) in which the H773_V774InsH mutation of the EGFR gene was introduced into Ba / F3 cells was cultured in RPMI1640 medium containing 10% FBS and 5 ug murine IL-3 (PEPROTECH, 213-13) at 37 °C and 5% C02. Then, 5 x 10 Ba / F3 (EGFR H773_V774InsH) cells were inoculated into the flank of 6-week-old male nude mice (BALB / c nude) per mouse. 6 The cells / 200 M were inoculated subcutaneously. After confirming that the formed tumor volume reached approximately 100-120 mF, group separation was performed. Permonatinib was administered orally daily at 30 mg / kg, and CM01 was administered intraperitoneally twice a week at 30 mg / kg. Body weight was measured daily for administration, and tumor volume was measured twice a week. The weight and survival of mice were measured and observed three times a week. Tumor volume compared to the control group was statistically analyzed by Dunnett's T3 multiple comparison test, and survival analysis was performed by 1 og-1 ank test and Bonferroni method. The test results are shown in Table 22, Figures 26 and 27.

【Table 22] - MTV: Mean tumor volume - TGI (%): Tumor growth inhibition rate - CR: Complete regression The analysis was conducted on day 17 when all the solvent control groups were alive. As a result, the CM01 administration group and the furmonatinib administration group showed a statistically significant reduction in tumor volume with a TGI (Tumor Growth Inhibition) value of 64.06% and 36%, respectively, compared to the control group. The combined administration group of CM01 and furmonatinib showed a TGI value of 95.64% compared to the control group, significantly reducing tumor growth and demonstrating excellent anti-tumor efficacy. When analyzing the survival rate, the median survival days were confirmed to be 50 days, 36 days, and 71 days in the CM01 administration group, the furmonatinib administration group, and the combination administration group, respectively, confirming that the survival rate significantly increased when combined administration was performed (Fig. 27). 3-2. BaF / 3 (EGFR M766_A767 insAI) model Ba / F3 EGFR M766_A767insAI mutant cell line (Signosis, #EL-018-FP) was cultured in RPMI1640 medium (supplemented with 10% FBS, 1% penicillin-streptomycin, and 10 ng / ml murine IL-3) at 37 °C, 5% C02 in an incubator. The cultured cells were collected and seeded at 5 x 10 in serum-free RPMI medium. 7 The cells were prepared under the condition of 10 cells / ml. The prepared cells were placed in a syringe at 0.2 ml each and injected into Balb / c-nu mice at a dose of 1 x 10 7 The cells were inoculated subcutaneously. The tumor volume was about 100–200 mm on average. 3 When the target was reached, the mice were randomly grouped and drug administration was initiated simultaneously. CM01 was administered intraperitoneally at 30 mg / kg twice a week for 3 weeks, and TAK-788 was administered orally at 10 mg / kg once a day. During the test period, tumor size was measured twice a week using a caliper, and mouse weight was measured using an electronic scale. Tumor volume (mm 3) and tumor growth inhibition (%) formulas were calculated as follows. Analysis of tumor volume compared to the control group was statistically analyzed using Dunnett's multiple comparison test. Tumor volume (mm 3 ) = major axis length X (minor axis length) 2 X 0.5 Tumor growth inhibition (%) = {(mean tumor volume of control group - mean tumor volume of treatment group) {Average tumor volume of the control group} X 100. The test results are shown in Table 23 and Fig. 28.

【Table 23] On the 14th day after drug administration, the TAK-788 and CM01 monotherapy group and the TAK-788 and CM01 combination therapy group showed tumor growth inhibition rates of 40.64%, 36.76%, and 69.95%, respectively, and all groups showed statistically significant differences in the average tumor volume compared with the control group. The combination therapy group showed a statistically significant difference compared with TAK-788, and the tumor growth inhibition rate increased by 29.31% (Fig. 28). There was no difference in the mouse weights between the groups. These results demonstrate that the TAK-788 and CM01 combination therapy exhibits excellent anticancer activity in the Ba / F3 EGFR M766_A767insAI mutant mouse tumor model. 3-3. BaF / 3 (EGFR H773_V774insH) model Cell line in which the H773_V774InsH mutation of the EGFR gene was introduced into Ba / F3 cells (Signosis, #EL-019-FP) were cultured in RPMI1640 medium containing 10% FBS, 5 ug murine IL-3, etc. at 37 °C, 5% C02 conditions. Then, Ba / F3 (EGFR H773_V774InsH) cells were subcutaneously inoculated into the flank of 7-week-old male nude mice (BALB / c nude) at 5 X 10 cells / 200 M per mouse. The tumor volume formed 15 days after inoculation was approximately 100-200 mm. 3 After confirming that the target was reached, group separation was performed, and TAK-788 was administered orally daily at 10 mg / kg, and CM01 was administered intraperitoneally twice a week at 10 mg / kg. The administration period was conducted for a total of 3 weeks, body weight was measured daily for administration, and tumor volume was measured twice a week. Analysis of tumor volume compared to the control group was statistically analyzed using Dunnett's multiple comparison test. The test results are shown in Table 24 and Fig. 29.

Table 24

Claims

【Scope of Claims】 【 Claim 11 (A) an antibody or an antigen-binding fragment thereof that specifically binds to hepatocyte growth factor receptor (c-Met) that binds to at least one epitope region described by an amino acid sequence selected from the group consisting of SEQ ID NO: 313, SEQ ID NO: 314, SEQ ID NO: 315, and SEQ ID NO: 316, and (B) A pharmaceutical composition for preventing or treating cancer, comprising as an active ingredient at least one selected from the group consisting of (1) drug 1, (2) drug 2, (3) drug 3, and (4) drug 4: (1) Drug 1: BI-4020 represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 1] (2) Drug 2: TAK-788 represented by the following chemical formula 2, an optical isomer thereof, or Pharmaceutically acceptable salts thereof [Chemical formula 2] (3) Drug 3: Furmonertinib represented by the following chemical formula 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 3] (4) Drug 4: Osimertinib represented by the following chemical formula 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 4]

1. A pharmaceutical composition wherein (B) is drug 1. 【

3. A pharmaceutical composition according to claim 2, wherein the cancer is lung cancer. 【

4. A pharmaceutical composition according to claim 2, wherein the cancer is non-small cell lung cancer. 【

5. In claim 2, the antibody comprises a light chain CDR1 described by sequence number 1; sequence number A light chain variable region comprising a light chain CDR2 described by SEQ ID NO: 2; a light chain CDR3 described by SEQ ID NO: 3; and a heavy chain CDR1 described by SEQ ID NO: 4; a heavy chain CDR2 described by SEQ ID NO: 5; A pharmaceutical composition comprising an antibody comprising a heavy chain variable region comprising a heavy chain CDR3 as set forth in SEQ ID NO: 6, or an affinity-optimized antibody thereof. 【

6. In claim 5, the affinity-optimized antibody is an antibody having at least one amino acid sequence substituted in an antibody comprising a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO: 1; a light chain CDR2 as set forth in SEQ ID NO: 2; a light chain CDR3 as set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 as set forth in SEQ ID NO: 4; a heavy chain CDR2 as set forth in SEQ ID NO: 5; and a heavy chain CDR3 as set forth in SEQ ID NO: 6, wherein (i) G at the 1st position of the light chain CDR1 is A, E, K, L, N, R, S, V or W; A at the 2nd position is C, G, I, P, S, T or V; E at the 3rd position is G, M, N, P, Q, R, S or T; E at the 4th position is A, D, F, G, H, K, M, Q, R, S, T or V; N in the 5th position is A, D, E, G, K, L, P, Q, R, S, T or V; I in the 6th position is A, F, L, M, Q, R, S, T or V; Y in the 7th position is F, H, R or V; or G at position 8 is replaced with D, F, H, M, N, R, S, T or V; (ii) G at position 1 of light chain CDR2 is replaced with D, F, H, K, P, Q, S, V or Y; T at position 3 is replaced with Q; or N at position 4 is replaced with G; (iii) Q at the 1st position of light chain CDR3 is E, G, I, M or N; N at the 2nd position is A, D, E, H, L, Q, S or T; V at the 3rd position is I, L, M, N, Q, S or T; L at the 4th position is F, H, I, M, R, S, V, W or Y; S at the 5th position is C, D, E, F, G, H, K, L, N, Q, R, T, V or Y; S at the 6th position is D, E, F, G, H, I, L, M, N, P, Q, R, T, V or Y; P at the 7th position is A, D, E, G, N, Q, S or V; Y at the 8th position is E, F, L, M or Q; or T at the 9th position is replaced by D, F, G, I, L, N, S, V, W or Y; (iv) 日 at the 1st position of the heavy chain CDR1 is G or Q; Y at the 2nd position is Q; or I at the 4th position is replaced by A or 이; (v) F at the 3rd position of the heavy chain CDR2 is D, E, W or Y; G at the 5th position is D, H or Y; 으 at the 6th position is F, P, W or Y; G at the 7th position is A, F, L, N or T; N at the 8th position is F, P, S, T or Y; T at the 9th position is A, D, E, F, G, H, L, P, S or V; H at the 10th position is A, D, F, M, R, S, T, V, W or Y; F at the 11th position is G, H, I, L, M, N, P, Q, V or Y; 으 at the 12th position is A, D, G, H, I, L, P, T or V; A at the 13th position is D, E, F, G, H, I, K, L, M, P, R, S, T, V or Y; R at the 14th position is A, E, G, H, L, N, P, Q, S, W or Y; F at the 15th position is D, E, G, L, M, P, R, S, V or W; 오 at the 16th position is A, E, F, G, H, L, R, S, T, V or Y; or G at the 17th position is replaced by E, F, H, L, M, N, P, Q, R, S, T, V or W; or (vi) G at the 1st position of the heavy chain CDR3 is E, F, H, N, Q, V or W; 日 at the 2nd position is E; Y at the 3rd position is L, Q, T or V; G at the 4th position is W; F at the 5th position is L or Y; L at the 6th position is Q, S or Y; or Y at the 7th position is replaced by C, L, M, N or 이, where the light chain CDR1 is 0 to 5, the light chain CDR2 is 0 to 1, the light chain CDR3 is 0 to 7, the heavy chain A pharmaceutical composition wherein CDR1 comprises 0 to 1 substitution, heavy chain CDR2 comprises 0 to 11 substitutions, and heavy chain CDR3 comprises 0 to 6 substitutions. 【

7. A pharmaceutical composition in claim 2, wherein the antibody further comprises an antibody or an antigen-binding fragment thereof that specifically binds to epidermal growth factor receptor (EGFR). 【

8. A pharmaceutical composition according to claim 2, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region set forth in SEQ ID NO: 11 and any one of SEQ ID NOs: 288 to 293; and a heavy chain variable region set forth in any one of SEQ ID NOs: 298 to 312.

2. A pharmaceutical composition, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 11 and a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO:

308.

10. A pharmaceutical composition according to claim 2, wherein the cancer is EGFR mutation positive.

11. A pharmaceutical composition according to claim 1, wherein (B) is drug 2. 【Claim 1: A pharmaceutical composition according to claim 11, wherein the cancer is lung cancer. 【

13. A pharmaceutical composition according to claim 11, wherein the cancer is non-small cell lung cancer. 【

14. The pharmaceutical composition of claim 11, wherein the antibody is an antibody comprising a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO: 1; a light chain CDR2 as set forth in SEQ ID NO: 2; a light chain CDR3 as set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 as set forth in SEQ ID NO: 4; a heavy chain CDR2 as set forth in SEQ ID NO: 5; and a heavy chain CDR3 as set forth in SEQ ID NO: 6, or an affinity-optimized antibody thereof. 【

15. In claim 14, the affinity-optimized antibody is an antibody having at least one amino acid sequence substituted in an antibody comprising a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO: 1; a light chain CDR2 as set forth in SEQ ID NO: 2; a light chain CDR3 as set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 as set forth in SEQ ID NO: 4; a heavy chain CDR2 as set forth in SEQ ID NO: 5; and a heavy chain CDR3 as set forth in SEQ ID NO: 6, wherein (i) the light chain In CDR1, G at position 1 is replaced with A, E, K, L, N, R, S, V or W; A at position 2 is replaced with C, G, I, P, S, T or V; S at position 3 is replaced with G, M, N, P, Q, R, S or T; E at position 4 is replaced with A, D, F, G, H, K, M, Q, R, S, T or V; N at position 5 is replaced with A, D, E, G, K, L, P, Q, R, S, T or V; I at position 6 is replaced with A, F, L, M, Q, R, S, T or V; Y at position 7 is replaced with F, H, R or V; or G at position 8 is replaced with D, F, H, M, N, R, S, T or V; ( ii ) G at the 1st position of light chain CDR2 is replaced with D, F, H, K, P, Q, S, V or Y; T at the 3rd position is replaced with Q; or N at the 4th position is replaced with ; ( iii ) Q at the 1st position of light chain CDR3 is replaced with E, G, I, M or N; V at the 2nd position is replaced with A, D, E, H, L, Q, S or T; V at the 3rd position is replaced with I, L, M, N, Q, S or T; L at the 4th position is replaced with F, H, I, M, R, S, V, W or Y; S at the 5th position is replaced with C, D, E, F, G, H, K, L, N, Q, R, T, V or Y; S at the 6th position is replaced with D, E, F, G, H, I, L, M, N, P, Q, R, T, V or Y; P at the 7th position is replaced with A, D, E, G, N, Q, S or V; Y at the 8th position is E, F, L, M or Q; or T at the 9th position is replaced by D, F, G, I, L, N, S, V, W or Y; (iv) 日 at the 1st position of the heavy chain CDR1 is G or Q; Y at the 2nd position is Q; or I at the 4th position is replaced by A or 이; (v) 도 at the 3rd position of the heavy chain CDR2 is D, E, W or Y; 으 at the 5th position is D, H or Y; 으 at the 6th position is F, P, W or Y; G at the 7th position is A, F, L, N or T; 凡 at the 8th position is F, P, S, T or Y; T at the 9th position is A, D, E, F, G, H, L, P, S or V; H at the 10th position is A, D, F, M, R, S, T, V, W or Y; F at the 11th position is G, H, I, L, M, N, P, Q, V or Y; S at the 12th position is A, D, G, H, I, L, P, T or V; A at the 13th position is D, E, F, G, H, I, K, L, M, P, R, S, T, V or Y; the 14th It should be noted that there are some characters in the original text that seem to be incorrect or unrecognized characters (such as "日", "도", "으", "凡", "이"), and this translation is based on simply replacing them with the nearest possible symbols or leaving them as they are for the purpose of following the translation rules. If these are actual specific biological or chemical notations, a more accurate translation might be possible with further clarification. R in the position is replaced by A, E, G, H, L, N, P, Q, S, W or Y; F in the 15th position is replaced by D, E, G, L, M, P, R, S, V or W; V in the 16th position is replaced by {A, E, F, G, H, L, R, S, T, V or Y; or G in the 17th position is replaced by E, F, H, L, M, N, P, Q, R, S, T, V or W; Or (vi) a pharmaceutical composition wherein G at position 1 of heavy chain CDR3 is replaced with E, F, H, N, Q, V or W; J at position 2 is replaced with E; O at position 3 is replaced with L, Q, T or V; U at position 4 is replaced with W; F at position 5 is replaced with L or Y; L at position 6 is replaced with Q, S or Y; or Y at position 7 is replaced with C, L, M, N or Y, wherein light chain CDR1 comprises 0 to 5 substitutions, light chain CDR2 comprises 0 to 1 substitution, light chain CDR3 comprises 0 to 7 substitutions, heavy chain CDR1 comprises 0 to 1 substitution, heavy chain CDR2 comprises 0 to 11 substitutions, and heavy chain CDR3 comprises 0 to 6 substitutions. 【

16. A pharmaceutical composition according to claim 11, wherein the antibody further comprises an antibody or an antigen-binding fragment thereof that specifically binds to epidermal growth factor receptor (EGFR).

17. A pharmaceutical composition according to claim 11, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region set forth in SEQ ID NO: 11 and any one of SEQ ID NOs: 288 to 293; and a heavy chain variable region set forth in any one of SEQ ID NOs: 298 to 312. 130

18. A pharmaceutical composition according to claim 11, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 11 and a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO:

308. 【Claim 1: A pharmaceutical composition according to claim 11, wherein the cancer is EGFR mutation positive. 【

20. A pharmaceutical composition according to claim 1, wherein (B) is drug 3. 【

21. A pharmaceutical composition according to claim 20, wherein the cancer is lung cancer. 【 Claim 2: A pharmaceutical composition according to claim 20, wherein the cancer is non-small cell lung cancer. 【

23. In claim 20, the antibody comprises a light chain CDR1 described by sequence number 1; sequence number 131 A pharmaceutical composition, which is an antibody comprising a light chain variable region comprising a light chain CDR2 as described in SEQ ID NO: 2; a light chain CDR3 as described in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 as described in SEQ ID NO: 4; a heavy chain CDR2 as described in SEQ ID NO: 5; and a heavy chain CDR3 as described in SEQ ID NO: 6, or an affinity-optimized antibody thereof.

24. The affinity-optimized antibody of claim 23, wherein the affinity-optimized antibody comprises a light chain variable region comprising a light chain CDR1 set forth in SEQ ID NO: 1; a light chain CDR2 set forth in SEQ ID NO: 2; a light chain CDR3 set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 set forth in SEQ ID NO: 4; a heavy chain CDR2 set forth in SEQ ID NO: 5; and a heavy chain CDR3 set forth in SEQ ID NO: 6, wherein at least one amino acid sequence is substituted in an antibody, wherein (i) G at the 1st position of the light chain CDR1 is A, E, K, L, N, R, S, V or W; A at the 2nd position is C, G, I, P, S, T or V; S at the 3rd position is G, M, N, P, Q, R, S or T; E at the 4th position is A, D, F, G, H, K, M, Q, R, S, T or V; N at the 5th position is A, D, E, G, K, L, P, Q, R, S, T or V; I in the 6th position is A, F, L, M, Q, R, S, T or V; Y in the 7th position is F, H, R or V; or G in the 8th position is D, F, H, M, N, R, S, T or V is substituted; (ii) G at position 1 of light chain CDR2 is D, F, H, K, P, Q, S, V or Y; The T at the 3rd position is substituted with Q; or the N at the 4th position is substituted with ; (iii) The Q at the 1st position of the light chain CDR3 is E, G, I, M or N; the at the 2nd position is A, D, E, H, L, Q, S or T; the V at the 3rd position is I, L, M, N, Q, S or T; the L at the 4th position is F, H, I, M, R, S, V, W The S at the 5th position of 132 or Y is C, D, E, F, G, H, K, L, N, Q, R, T, V or Y; the S at the 6th position is D, E, F, G, H, I, L, M, N, P, Q, R, T, V or Y; the P at the 7th position is A, D, E, G, N, Q, S or V; the Y at the 8th position is E, F, L, M or Q; or the T at the 9th position is replaced by D, F, G, I, L, N, S, V, W or Y; (iv) the 日 at the 1st position of the heavy chain CDR1 is replaced by G or Q; the Y at the 2nd position is Q; or the I at the 4th position is replaced by A or 이; (v) the 도 at the 3rd position of the heavy chain CDR2 is D, E, W or Y; the 으 at the 5th position is D, H or Y; the 으 at the 6th position is F, P, W or Y; the G at the 7th position is A, F, L, N or T; the 凡 at the 8th position is F, P, S, T or Y; the T at the 9th position is A, D, E, F, G, H, L, P, S or V; the H at the 10th position is A, D, F, M, R, S, T, V, W or Y; the F at the 11th position is G, H, I, L, M, N, P, Q, V or Y; the S at the 12th position is A, D, G, H, I, L, P, T or V; the A at the 13th position is D, E, F, G, H, I, K, L, M, P, R, S, T, V or Y; the R at the 14th position is A, E, G, H, L, N, P, Q, S, W or Y; the F at the 15th position is D, E, G, L, M, P, R, S, V or W; the V at the 16th position} A, E, F, G, H, L, R, S, T, V or Y; or the G at the 17th position is replaced by E, F, H, L, M, N, P, Q, R, S, T, V or W;or (vi) a pharmaceutical composition wherein G at position 1 of heavy chain CDR3 is replaced with E, F, H, N, Q, V or W; J at position 2 is replaced with E; O at position 3 is replaced with L, Q, T or V; U at position 4 is replaced with W; F at position 5 is replaced with L or Y; L at position 6 is replaced with Q, S or Y; or Y at position 7 is replaced with C, L, M, N or Y, wherein light chain CDR1 comprises 0 to 5 substitutions, light chain CDR2 comprises 0 to 1 substitution, light chain CDR3 comprises 0 to 7 substitutions, heavy chain CDR1 comprises 0 to 1 substitution, heavy chain CDR2 comprises 0 to 11 substitutions, and heavy chain CDR3 comprises 0 to 6 substitutions. 【 The pharmaceutical composition according to claim 20, wherein the antibody further comprises an antibody specifically binding to an epidermal growth factor receptor (EGFR) or an antigen-binding fragment thereof. 【 The pharmaceutical composition according to claim 20, wherein the antibody or the antigen-binding fragment thereof comprises a light chain variable region described by any one of SEQ ID NO: 11 and SEQ ID NOs: 288 to 293; and a heavy chain variable region described by any one of SEQ ID NOs: 298 to 312. 【 The pharmaceutical composition according to claim 20, wherein the antibody or the antigen-binding fragment thereof comprises a light chain variable region comprising the amino acid sequence described by SEQ ID NO: 11 and a heavy chain variable region comprising the amino acid sequence described by SEQ ID NO:

308. 【 The pharmaceutical composition according to claim 20, wherein the cancer is EGFR-positive. The pharmaceutical composition according to claim 1, wherein the (B) is the drug 4. 【 The pharmaceutical composition according to claim 29, wherein the cancer is lung cancer. 【 The pharmaceutical composition according to claim 29, wherein the cancer is non-small cell lung cancer. 【 The pharmaceutical composition according to claim 29, wherein the antibody comprises a light chain variable region comprising the light chain CDR1 described by SEQ ID NO: 1; the light chain CDR2 described by SEQ ID NO: 2; the light chain CDR3 described by SEQ ID NO: 3, and a heavy chain variable region comprising the heavy chain CDR1 described by SEQ ID NO: 4; the heavy chain CDR2 described by SEQ ID NO: 5; the heavy chain CDR3 described by SEQ ID NO: 6, or an affinity-optimized antibody thereof. 【

33. In claim 32, the affinity-optimized antibody comprises a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO: 1; a light chain CDR2 as set forth in SEQ ID NO: 2; a light chain CDR3 as set forth in SEQ ID NO: 3; and a heavy chain CDR1 as set forth in SEQ ID NO: 4; a light chain CDR3 as set forth in SEQ ID NO:

5. 135 heavy chain CDR2; An antibody having at least one amino acid sequence substituted in an antibody comprising a heavy chain variable region including a heavy chain CDR3 set forth in SEQ ID NO: 6, wherein (i) G at the 1st position of the light chain CDR1 is A, E, K, L, N, R, S, V or W; A at the 2nd position is C, G, I, P, S, T or V; S at the 3rd position is G, M, N, P, Q, R, S or T; E at the 4th position is A, D, F, G, H, K, M, Q, R, S, T or V; N at the 5th position is A, D, E, G, K, L, P, Q, R, S, T or V; I at the 6th position is A, F, L, M, Q, R, S, T or V; Y at the 7th position is F, H, R or V; or G at the 8th position is D, F, H, M, N, R, S, T or V; (ii) G at position 1 of light chain CDR2 is replaced with D, F, H, K, P, Q, S, V or Y; T at position 3 is replaced with Q; or N at position 4 is replaced with ; ( iii ) Q at the 1st position of light chain CDR3 is E, G, I, M or N; V at the 2nd position is A, D, E, H, L, Q, S or T; V at the 3rd position is I, L, M, N, Q, S or T; L at the 4th position is F, H, I, M, R, S, V, W or Y; S at the 5th position is C, D, E, F, G, H, K, L, N, Q, R, T, V or Y; S at the 6th position is D, E, F, G, H, I, L, M, N, P, Q, R, T, V or Y; P at the 7th position is A, D, E, G, N, Q, S or V; Y at the 8th position is replaced by E, F, L, M or Q; or T at the 9th position is replaced by D, F, G, I, L, N, S, V, W or Y; (iv) 日 at the 1st position of the heavy-chain CDR1 is replaced by G or Q; Y at the 2nd position is replaced by Q; or I at the 4th position is replaced by A or 이; (v) 도 at the 3rd position of the heavy-chain CDR2 is replaced by D, E, W or Y; 으 at the 5th position is replaced by D, H or Y; 으 at the 6th position is replaced by F, P, W or Y; G at the 7th position is replaced by A, F, L, N or T; 凡 at the 8th position is replaced by F, P, S, T or Y; T at the 9th position is replaced by A, D, E, F, G, H, L, P, S or V; H at the 10th position is replaced by A, D, F, M, R, S, T, V, W or Y; F at the 11th position is 136 G, H, I, L, M, N, P, Q, V or Y; S in the 12th position is replaced by A, D, G, H, I, L, P, T or V; A in the 13th position is replaced by D, E, F, G, H, I, K, L, M, P, R, S, T, V or Y; R in the 14th position is replaced by A, E, G, H, L, N, P, Q, S, W or Y; F in the 15th position is replaced by D, E, G, L, M, P, R, S, V or W; V in the 16th position is replaced by {A, E, F, G, H, L, R, S, T, V or Y; or G in the 17th position is replaced by E, F, H, L, M, N, P, Q, R, S, T, V or W; Or (vi) a pharmaceutical composition wherein G at position 1 of heavy chain CDR3 is replaced with E, F, H, N, Q, V or W; J at position 2 is replaced with E; O at position 3 is replaced with L, Q, T or V; U at position 4 is replaced with W; F at position 5 is replaced with L or Y; L at position 6 is replaced with Q, S or Y; or Y at position 7 is replaced with C, L, M, N or Y, wherein light chain CDR1 comprises 0 to 5 substitutions, light chain CDR2 comprises 0 to 1 substitution, light chain CDR3 comprises 0 to 7 substitutions, heavy chain CDR1 comprises 0 to 1 substitution, heavy chain CDR2 comprises 0 to 11 substitutions, and heavy chain CDR3 comprises 0 to 6 substitutions.

34. A pharmaceutical composition according to claim 29, wherein the antibody further comprises an antibody or an antigen-binding fragment thereof that specifically binds to epidermal growth factor receptor (EGFR). 【

35. In claim 29, the antibody or antigen-binding fragment thereof comprises a light chain variable region as set forth in SEQ ID NO: 11 and any one of SEQ ID NOs: 288 to 293; and A pharmaceutical composition comprising a heavy chain variable region as set forth in any one of SEQ ID NOs: 298 to 312. 【

36. A pharmaceutical composition according to claim 29, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 11 and a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO:

308. 【

37. A pharmaceutical composition according to claim 29, wherein the cancer is EGFR mutation positive.

38. (A) A pharmaceutical composition for the prevention or treatment of cancer, comprising as an active ingredient an antibody or an antigen-binding fragment thereof that specifically binds to hepatocyte growth factor receptor (c-Met) that binds to at least one epitope region described in an amino acid sequence selected from the group consisting of SEQ ID NO: 313, SEQ ID NO: 314, SEQ ID NO: 315, and SEQ ID NO: 316, wherein the pharmaceutical composition is administered to a subject in combination with (B) at least one selected from the group consisting of (1) Drug 1, (2) Drug 2, (3) Drug 3, and (4) Drug 4: (1) Drug 1: BI-4020 represented by the following chemical formula 1, an optical isomer thereof, or 138 Pharmaceutically acceptable salts thereof [Chemical Formula 1] (2) Drug 2: TAK-788 represented by the following chemical formula 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical formula 2] (3) Drug 3: Furmonert inib represented by the following chemical formula 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof 139 [Chemical Formula 3] (4) Drug 4: Osimertinib represented by the following chemical formula 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 4] 【Claim 3: A pharmaceutical composition according to claim 38, wherein (B) is drug 1.

40. A pharmaceutical composition according to claim 39, wherein the cancer is lung cancer.

41. A pharmaceutical composition according to claim 39, wherein the cancer is non-small cell lung cancer. 【 A pharmaceutical composition according to claim 4, wherein the antibody is an antibody comprising a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO: 1; a light chain CDR2 as set forth in SEQ ID NO: 2; a light chain CDR3 as set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 as set forth in SEQ ID NO: 4; a heavy chain CDR2 as set forth in SEQ ID NO: 5; and a heavy chain CDR3 as set forth in SEQ ID NO: 6, or an affinity-optimized antibody thereof.

43. The affinity-optimized antibody of claim 42, wherein the affinity-optimized antibody comprises a light chain variable region comprising a light chain CDR1 set forth in SEQ ID NO: 1; a light chain CDR2 set forth in SEQ ID NO: 2; a light chain CDR3 set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 set forth in SEQ ID NO: 4; a heavy chain CDR2 set forth in SEQ ID NO: 5; and a heavy chain CDR3 set forth in SEQ ID NO: 6, wherein at least one amino acid sequence is substituted in an antibody, wherein (i) G at the 1st position of the light chain CDR1 is A, E, K, L, N, R, S, V or W; A at the 2nd position is C, G, I, P, S, T or V; S at the 3rd position is G, M, N, P, Q, R, S or T; and S at the 4th position is 141 E is A, D, F, G, H, K, M, Q, R, S, T or V; N in the 5th position is A, D, E, G, K, L, P, Q, R, S, T or V; I at position 6 is replaced with A, F, L, M, Q, R, S, T or V; Y at position 7 is replaced with F, H, R or V; or G at position 8 is replaced with D, F, H, M, N, R, S, T or V; (ii) G at position 1 of light chain CDR2 is replaced with D, F, H, K, P, Q, S, V or Y; T at position 3 is replaced with Q; or N at position 4 is replaced with ; ( iii ) Q at the 1st position of light chain CDR3 is E, G, I, M or N; V at the 2nd position is A, D, E, H, L, Q, S or T; V at the 3rd position is I, L, M, N, Q, S or T; L at the 4th position is F, H, I, M, R, S, V, W or Y; S at the 5th position is C, D, E, F, G, H, K, L, N, Q, R, T, V or Y; S at the 6th position is D, E, F, G, H, I, L, M, N, P, Q, R, T, V or Y; P at the 7th position is A, D, E, G, N, Q, S or V; Y at the 8th position is E, F, L, M or Q; or T at the 9th position is replaced by D, F, G, I, L, N, S, V, W or Y; (iv) 日 at the 1st position of the heavy chain CDR1 is G or Q; Y at the 2nd position is Q; or I at the 4th position is replaced by A or i; (v) 도 at the 3rd position of the heavy chain CDR2 is D, E, W or Y; 으 at the 5th position is D, H or Y; 으 at the 6th position is F, P, W or Y; G at the 7th position is A, F, L, N or T; 凡 at the 8th position is F, P, S, T or Y; T at the 9th position is A, D, E, F, G, H, L, P, S or V; H at the 10th position is A, D, F, M, R, S, T, V, W or Y; F at the 11th position is G, H, I, L, M, N, P, Q, V or Y; S at the 12th position is A, D, G, H, I, L, P, T or V; A at the 13th position is D, E, F, G, H, I, K, L, M, P, R, S, T, V or Y; R at the 14th position is A, E, G, H, L, N, P, Q, S, W or Y; F at the 15th position is D, E, G, L, M, P, R, S, V or W; V at the 16th position is A, E, F, G, H, L, R, S, T, V or Y; A pharmaceutical composition, wherein G at position 142 or 17 is replaced with E, F, H, L, M, N, P, Q, R, S, T, V or W; or (vi) in heavy chain CDR3, G at position 1 is replaced with E, F, H, N, Q, V or W; J at position 2 is replaced with E; O at position 3 is replaced with L, Q, T or V; U at position 4 is replaced with W; F at position 5 is replaced with L or Y; L at position 6 is replaced with Q, S or Y; or Y at position 7 is replaced with C, L, M, N or Y, wherein light chain CDR1 comprises 0 to 5 substitutions, light chain CDR2 comprises 0 to 1 substitution, light chain CDR3 comprises 0 to 7 substitutions, heavy chain CDR1 comprises 0 to 1 substitution, heavy chain CDR2 comprises 0 to 11 substitutions, and heavy chain CDR3 comprises 0 to 6 substitutions.

44. A pharmaceutical composition according to claim 39, wherein the antibody further comprises an antibody or an antigen-binding fragment thereof that specifically binds to epidermal growth factor receptor (EGFR).

45. A pharmaceutical composition according to claim 39, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region set forth in SEQ ID NO: 11 and any one of SEQ ID NOs: 288 to 293; and a heavy chain variable region set forth in any one of SEQ ID NOs: 298 to 312.

46. A pharmaceutical composition according to claim 39, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 11 and a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO:

308.

47. A pharmaceutical composition according to claim 39, wherein the cancer is EGFR mutation positive. 【

48. A pharmaceutical composition according to claim 38, wherein (B) is drug 2. 【 A pharmaceutical composition according to claim 48, wherein the cancer is lung cancer. 【

50. A pharmaceutical composition according to claim 48, wherein the cancer is non-small cell lung cancer. 【

51. In claim 48, the antibody comprises a light chain CDR1 described by sequence number 1; sequence number A light chain variable region comprising a light chain CDR2 described by SEQ ID NO: 2; a light chain CDR3 described by SEQ ID NO: 3; and a heavy chain CDR1 described by SEQ ID NO: 4; a heavy chain CDR2 described by SEQ ID NO: 5; A pharmaceutical composition comprising an antibody comprising a heavy chain variable region comprising a heavy chain CDR3 as set forth in SEQ ID NO: 144, or an affinity-optimized antibody thereof. 【 Claim 5 is an antibody according to claim 51, wherein the affinity-optimized antibody comprises a light chain variable region comprising a light chain CDR1 set forth in SEQ ID NO: 1; a light chain CDR2 set forth in SEQ ID NO: 2; a light chain CDR3 set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 set forth in SEQ ID NO: 4; a heavy chain CDR2 set forth in SEQ ID NO: 5; and a heavy chain CDR3 set forth in SEQ ID NO: 6, wherein at least one amino acid sequence is substituted in an antibody, wherein (i) G at the 1st position of the light chain CDR1 is A, E, K, L, N, R, S, V or W; A at the 2nd position is C, G, I, P, S, T or V; S at the 3rd position is G, M, N, P, Q, R, S or T; E at the 4th position is A, D, F, G, H, K, M, Q, R, S, T or V; N at the 5th position is A, D, E, G, K, L, P, Q, R, S, T or V; I in the 6th position is A, F, L, M, Q, R, S, T or V; Y in the 7th position is F, H, R or V; or G in the 8th position is D, F, H, M, N, R, S, T or V is substituted; (ii) G at position 1 of light chain CDR2 is D, F, H, K, P, Q, S, V or Y; T at the 3rd position is replaced with Q; or N at the 4th position is replaced with ; (iii) Q at the 1st position of light chain CDR3 is E, G, I, M or N; V at the 2nd position is A, D, E, H, L, Q, S or T; V at the 3rd position is I, L, M, N, Q, S or T; L at the 4th position is F, H, I, M, R, S, V, W or Y; S at the 5th position is C, D, E, F, G, H, K, L, N, Q, R, T, V or Y; S at the 6th position is D, E, F, G, H, I, L, M, N, P, Q, R, T, V or Y; P at the 7th position is 145 A, D, E, G, N, Q, S or V; Y at the 8th position is replaced by E, F, L, M or Q; or T at the 9th position is replaced by D, F, G, I, L, N, S, V, W or Y; (iv) 日 at the 1st position of the heavy-chain CDR1 is replaced by G or Q; Y at the 2nd position is replaced by Q; or I at the 4th position is replaced by A or 이; (v) 도 at the 3rd position of the heavy-chain CDR2 is replaced by D, E, W or Y; 으 at the 5th position is replaced by D, H or Y; 으 at the 6th position is replaced by F, P, W or Y; G at the 7th position is replaced by A, F, L, N or T; 凡 at the 8th position is replaced by F, P, S, T or Y; T at the 9th position is replaced by A, D, E, F, G, H, L, P, S or V; H at the 10th position is replaced by A, D, F, M, R, S, T, V, W or Y; F at the 11th position is replaced by G, H, I, L, M, N, P, Q, V or Y; S at the 12th position is replaced by A, D, G, H, I, L, P, T or V; A at the 13th position is replaced by D, E, F, G, H, I, K, L, M, P, R, S, T, V or Y; R at the 14th position is replaced by A, E, G, H, L, N, P, Q, S, W or Y; F at the 15th position is replaced by D, E, G, L, M, P, R, S, V or W; V at the 16th position} A, E, F, G, H, L, R, S, T, V or Y; or G at the 17th position is replaced by E, F, H, L, M, N, P, Q, R, S, T, V or W;or (vi) a pharmaceutical composition wherein G at position 1 of heavy chain CDR3 is replaced with E, F, H, N, Q, V or W; J at position 2 is replaced with E; O at position 3 is replaced with L, Q, T or V; U at position 4 is replaced with W; F at position 5 is replaced with L or Y; L at position 6 is replaced with Q, S or Y; or Y at position 7 is replaced with C, L, M, N or Y, wherein light chain CDR1 comprises 0 to 5 substitutions, light chain CDR2 comprises 0 to 1 substitution, light chain CDR3 comprises 0 to 7 substitutions, heavy chain CDR1 comprises 0 to 1 substitution, heavy chain CDR2 comprises 0 to 11 substitutions, and heavy chain CDR3 comprises 0 to 6 substitutions.

53. A pharmaceutical composition according to claim 48, wherein the antibody further comprises an antibody or an antigen-binding fragment thereof that specifically binds to epidermal growth factor receptor (EGFR).

54. A pharmaceutical composition according to claim 48, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region set forth in SEQ ID NO: 11 and any one of SEQ ID NOs: 288 to 293; and a heavy chain variable region set forth in any one of SEQ ID NOs: 298 to 312. 【

55. A pharmaceutical composition according to claim 48, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 11 and a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO:

308. 【

56. A pharmaceutical composition according to claim 48, wherein the cancer is EGFR mutation positive. 【

57. A pharmaceutical composition according to claim 38, wherein (B) is drug 3. 147

58. A pharmaceutical composition according to claim 57, wherein the cancer is lung cancer. 【 A pharmaceutical composition according to claim 5, wherein the cancer is non-small cell lung cancer. 【

60. A pharmaceutical composition according to claim 57, wherein the antibody is an antibody comprising a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO: 1; a light chain CDR2 as set forth in SEQ ID NO: 2; a light chain CDR3 as set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 as set forth in SEQ ID NO: 4; a heavy chain CDR2 as set forth in SEQ ID NO: 5; and a heavy chain CDR3 as set forth in SEQ ID NO: 6, or an affinity-optimized antibody thereof. 【

61. In claim 60, the affinity-optimized antibody is an antibody having at least one amino acid sequence substituted in an antibody comprising a light chain variable region comprising a light chain CDR1 as set forth in SEQ ID NO: 1; a light chain CDR2 as set forth in SEQ ID NO: 2; a light chain CDR3 as set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 as set forth in SEQ ID NO: 4; a heavy chain CDR2 as set forth in SEQ ID NO: 5; and a heavy chain CDR3 as set forth in SEQ ID NO: 6, wherein (i) the light chain 148 In CDR1, G at position 1 is replaced with A, E, K, L, N, R, S, V or W; A at position 2 is replaced with C, G, I, P, S, T or V; S at position 3 is replaced with G, M, N, P, Q, R, S or T; E at position 4 is replaced with A, D, F, G, H, K, M, Q, R, S, T or V; N at position 5 is replaced with A, D, E, G, K, L, P, Q, R, S, T or V; I at position 6 is replaced with A, F, L, M, Q, R, S, T or V; Y at position 7 is replaced with F, H, R or V; or G at position 8 is replaced with D, F, H, M, N, R, S, T or V; ( ii ) G at the 1st position of light chain CDR2 is replaced with D, F, H, K, P, Q, S, V or Y; T at the 3rd position is replaced with Q; or N at the 4th position is replaced with ; ( iii ) Q at the 1st position of light chain CDR3 is replaced with E, G, I, M or N; V at the 2nd position is replaced with A, D, E, H, L, Q, S or T; V at the 3rd position is replaced with I, L, M, N, Q, S or T; L at the 4th position is replaced with F, H, I, M, R, S, V, W or Y; S at the 5th position is replaced with C, D, E, F, G, H, K, L, N, Q, R, T, V or Y; S at the 6th position is replaced with D, E, F, G, H, I, L, M, N, P, Q, R, T, V or Y; P at the 7th position is replaced with A, D, E, G, N, Q, S or V; Y at the 8th position is E, F, L, M or Q; or T at the 9th position is replaced by D, F, G, I, L, N, S, V, W or Y; (iv) 日 at the 1st position of the heavy chain CDR1 is G or Q; Y at the 2nd position is Q; or I at the 4th position is replaced by A or 이; (v) 도 at the 3rd position of the heavy chain CDR2 is D, E, W or Y; 으 at the 5th position is D, H or Y; 으 at the 6th position is F, P, W or Y; G at the 7th position is A, F, L, N or T; 凡 at the 8th position is F, P, S, T or Y; T at the 9th position is A, D, E, F, G, H, L, P, S or V; H at the 10th position is A, D, F, M, R, S, T, V, W or Y; F at the 11th position is G, H, I, L, M, N, P, Q, V or Y; S at the 12th position is A, D, G, H, I, L, P, T or V; A at the 13th position is D, E, F, G, H, I, K, L, M, P, R, S, T, V or Y; 14th It should be noted that there seem to be some non-standard or unrecognized characters in the original text (such as "日", "도", "으", "凡", "이"), which may affect the accuracy and comprehensibility of the translation. If possible, it is recommended to clarify or correct these characters for a more accurate translation. R at position 149 is replaced by A, E, G, H, L, N, P, Q, S, W or Y; F at position 15 is replaced by D, E, G, L, M, P, R, S, V or W; V at position 16 is replaced by {A, E, F, G, H, L, R, S, T, V or Y; or G at position 17 is replaced by E, F, H, L, M, N, P, Q, R, S, T, V or W; Or (vi) a pharmaceutical composition wherein G at position 1 of heavy chain CDR3 is replaced with E, F, H, N, Q, V or W; J at position 2 is replaced with E; O at position 3 is replaced with L, Q, T or V; U at position 4 is replaced with W; F at position 5 is replaced with L or Y; L at position 6 is replaced with Q, S or Y; or Y at position 7 is replaced with C, L, M, N or Y, wherein light chain CDR1 comprises 0 to 5 substitutions, light chain CDR2 comprises 0 to 1 substitution, light chain CDR3 comprises 0 to 7 substitutions, heavy chain CDR1 comprises 0 to 1 substitution, heavy chain CDR2 comprises 0 to 11 substitutions, and heavy chain CDR3 comprises 0 to 6 substitutions. 【 A pharmaceutical composition according to claim 6 of claim 57, wherein the antibody further comprises an antibody or an antigen-binding fragment thereof that specifically binds to epidermal growth factor receptor (EGFR). 【

63. A pharmaceutical composition according to claim 57, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region set forth in SEQ ID NO: 11 and any one of SEQ ID NOs: 288 to 293; and a heavy chain variable region set forth in any one of SEQ ID NOs: 298 to 312. 150

64. A pharmaceutical composition according to claim 57, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence set forth in SEQ ID NO: 11 and a heavy chain variable region comprising an amino acid sequence set forth in SEQ ID NO:

308. 【

65. A pharmaceutical composition according to claim 57, wherein the cancer is EGFR mutation positive. 【

66. A pharmaceutical composition according to claim 38, wherein the EGFR inhibitor is drug 4. 【

67. A pharmaceutical composition according to claim 66, wherein the cancer is lung cancer. 【

68. A pharmaceutical composition according to claim 66, wherein the cancer is non-small cell lung cancer. 【 Claim 6 is in claim 66, wherein the antibody comprises a light chain CDR1 described by sequence number 1; sequence number 151 A pharmaceutical composition, which is an antibody comprising a light chain variable region comprising a light chain CDR2 as described in SEQ ID NO: 2; a light chain CDR3 as described in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 as described in SEQ ID NO: 4; a heavy chain CDR2 as described in SEQ ID NO: 5; and a heavy chain CDR3 as described in SEQ ID NO: 6, or an affinity-optimized antibody thereof. 【

70. The antibody of claim 69, wherein the affinity-optimized antibody comprises a light chain variable region comprising a light chain CDR1 set forth in SEQ ID NO: 1; a light chain CDR2 set forth in SEQ ID NO: 2; a light chain CDR3 set forth in SEQ ID NO: 3; and a heavy chain variable region comprising a heavy chain CDR1 set forth in SEQ ID NO: 4; a heavy chain CDR2 set forth in SEQ ID NO: 5; and a heavy chain CDR3 set forth in SEQ ID NO: 6, wherein at least one amino acid sequence is substituted in an antibody, wherein (i) G at the 1st position of the light chain CDR1 is A, E, K, L, N, R, S, V or W; A at the 2nd position is C, G, I, P, S, T or V; S at the 3rd position is G, M, N, P, Q, R, S or T; E at the 4th position is A, D, F, G, H, K, M, Q, R, S, T or V; N at the 5th position is A, D, E, G, K, L, P, Q, R, S, T or V; I in the 6th position is A, F, L, M, Q, R, S, T or V; Y in the 7th position is F, H, R or V; or G in the 8th position is D, F, H, M, N, R, S, T or V is substituted; (ii) G at position 1 of light chain CDR2 is D, F, H, K, P, Q, S, V or Y; The T at the 3rd position is Q; or the N at the 4th position is substituted with ; (iii) The Q at the 1st position of the light-chain CDR3 is E, G, I, M or N; the at the 2nd position is A, D, E, H, L, Q, S or T; the V at the 3rd position is I, L, M, N, Q, S or T; the L at the 4th position is F, H, I, M, R, S, V, W The S at the 5th position of 152 or Y is C, D, E, F, G, H, K, L, N, Q, R, T, V or Y; the S at the 6th position is D, E, F, G, H, I, L, M, N, P, Q, R, T, V or Y; the P at the 7th position is A, D, E, G, N, Q, S or V; the Y at the 8th position is E, F, L, M or Q; or the T at the 9th position is replaced by D, F, G, I, L, N, S, V, W or Y; (iv) the 日 at the 1st position of the heavy chain CDR1 is replaced by G or Q; the Y at the 2nd position is replaced by Q; or the I at the 4th position is replaced by A or 이; (v) the 도 at the 3rd position of the heavy chain CDR2 is D, E, W or Y; the 으 at the 5th position is D, H or Y; the 으 at the 6th position is F, P, W or Y; the G at the 7th position is A, F, L, N or T; the 凡 at the 8th position is F, P, S, T or Y; the T at the 9th position is A, D, E, F, G, H, L, P, S or V; the H at the 10th position is A, D, F, M, R, S, T, V, W or Y; the F at the 11th position is G, H, I, L, M, N, P, Q, V or Y; the S at the 12th position is A, D, G, H, I, L, P, T or V; the A at the 13th position is D, E, F, G, H, I, K, L, M, P, R, S, T, V or Y; the R at the 14th position is A, E, G, H, L, N, P, Q, S, W or Y; the F at the 15th position is D, E, G, L, M, P, R, S, V or W; the V at the 16th position} A, E, F, G, H, L, R, S, T, V or Y; or the G at the 17th position is replaced by E, F, H, L, M, N, P, Q, R, S, T, V or W;or (vi) a pharmaceutical composition wherein G at position 1 of heavy chain CDR3 is replaced with E, F, H, N, Q, V or W; J at position 2 is replaced with E; O at position 3 is replaced with L, Q, T or V; U at position 4 is replaced with W; F at position 5 is replaced with L or Y; L at position 6 is replaced with Q, S or Y; or Y at position 7 is replaced with C, L, M, N or Y, wherein light chain CDR1 comprises 0 to 5 substitutions, light chain CDR2 comprises 0 to 1 substitution, light chain CDR3 comprises 0 to 7 substitutions, heavy chain CDR1 comprises 0 to 1 substitution, heavy chain CDR2 comprises 0 to 11 substitutions, and heavy chain CDR3 comprises 0 to 6 substitutions. 153

71. The pharmaceutical composition according to claim 66, wherein the antibody further comprises an antibody specifically binding to an epidermal growth factor receptor (EGFR) or an antigen-binding fragment thereof. 【

72. The pharmaceutical composition according to claim 66, wherein the antibody or an antigen-binding fragment thereof comprises a light-chain variable region described by any one of SEQ ID NO: 11 and SEQ ID NOs: 288 to 293; and a heavy-chain variable region described by any one of SEQ ID NOs: 298 to 312. 【

73. The pharmaceutical composition according to claim 66, wherein the antibody or an antigen-binding fragment thereof comprises a light-chain variable region comprising the amino acid sequence described by SEQ ID NO: 11 and a heavy-chain variable region comprising the amino acid sequence described by SEQ ID NO:

308.

74. The pharmaceutical composition according to claim 66, wherein the cancer is EGFR-positive. 154

75. A method for preventing or treating cancer, comprising administering to a subject in need of preventing or treating cancer (A) an antibody specifically binding to a hepatocyte growth factor receptor (c-Met) that binds to any one or more epitope regions described by an amino acid sequence selected from the group consisting of SEQ ID NO: 313, SEQ ID NO: 314, SEQ ID NO: 315 and SEQ ID NO: 316, or an antigen-binding fragment thereof, wherein the antibody or an antigen-binding fragment thereof is administered in combination with at least one selected from the group consisting of (B) the following (1) Drug 1, (2) Drug 2, (3) Drug 3 and (4) Drug 4: (1) Drug 1: BI-4020 represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 1] (2) Drug 2: TAK-788 represented by the following chemical formula 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof 155 [Chemical formula 2] (3) Drug 3: Furmonertinib represented by the following chemical formula 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 3] (4) Drug 4: Osimertinib represented by the following chemical formula 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 4] 156

76. (A) An antibody or antigen-binding fragment thereof that specifically binds to hepatocyte growth factor receptor (c-Met) that binds to at least one epitope region described in an amino acid sequence selected from the group consisting of SEQ ID NO: 313, SEQ ID NO: 314, SEQ ID NO: 315, and SEQ ID NO: 316, for use in preventing or treating cancer, wherein the antibody or antigen-binding fragment thereof is administered in combination with (B) at least one selected from the group consisting of (1) Drug 1, (2) Drug 2, (3) Drug 3, and (4) Drug 4: (1) Drug 1: BI-4020 represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 1] 157 (2) Drug 2: TAK-788 represented by the following chemical formula 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical formula 2] (3) Drug 3: Furmonert inib represented by the following chemical formula 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 3] 158 (4) Drug 4: Osimertinib represented by the following chemical formula 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 4] 【

77. In the manufacture of a medicament for use in preventing or treating cancer, (A) an antibody specifically binding to hepatocyte growth factor receptor (c-Met) that binds to at least one epitope region described by an amino acid sequence selected from the group consisting of SEQ ID NO: 313, SEQ ID NO: 314, SEQ ID NO: 315 and SEQ ID NO: 316, or a derivative thereof 159 For the purpose of antigen-binding fragments, said antibody or antibody fragment is administered in combination with at least one selected from the group consisting of (B) (1) Drug 1, (2) Drug 2, (3) Drug 3 and (4) Drug 4, for use: (1) Drug 1: BI-4020 represented by the following chemical formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 1] (2) Drug 2: TAK-788 represented by the following chemical formula 2, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical formula 2] 160 (3) Drug 3: Furmonertinib represented by the following chemical formula 3, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 3] (4) Drug 4: Osimertinib represented by the following chemical formula 4, an optical isomer thereof, or a pharmaceutically acceptable salt thereof [Chemical Formula 4] 161

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