Divalent bet decomposition agent and targeting molecule-drug complex

Abstract

Provided are a divalent BET decomposition agent and a targeting molecule-drug complex including the divalent BET decomposition agent as a drug. The present invention uses, as a divalent BET decomposition agent, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof (in the formula, R1 and R2 are identical or different from each other and each represent a hydrogen atom or lower alkyl, R3 represents lower alkyl, R4 represents a halogen, R5 represents a halogen, R6 represents a halogen or lower alkoxy, Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-, and ring A represents a group of (i), (ii), or (iii)).

Description

[Title of Invention] DIVALENT BET DEGRADER AND TARGETING MOLECULE-DRUG CONJUGATE [Cross-Reference to Related Application]

[0001] The present patent application claims priority to Japanese Patent Application No. 2023-212506 filed on December 15, 2023, and the entire disclosure of which is incorporated herein by reference. [Technical Field]

[0002] The present invention relates to a divalent BET degrader having degrading action on BET proteins and a targeting moleculedrug conjugate containing the divalent BET degrader as a drug. [Background Art]

[0003] In humans, 46 bromodomain proteins that recognize the acetylated lysine in histone proteins are known. The BET (bromodomain and extra-terminal domain) family has been reported as one of the families, and recognizes acetyllysine in histones H3 and H4. The BET family is known to include BRD (bromodomain containing protein) 2, BRD3, BRD4 and BRDT (bromodomain testis specific protein). BET family proteins have two bromo domains (BD1, BD2) at the N-terminus, and the sequences are strongly conserved between the families. Further, it has been reported that the BET protein is involved in cancer growth [see non-patent documents 1 and 2] and progression of inflammation [see non-patent document 3].

[0004] BRD4 enhances expression of genes that promote growth by recruiting P-TEBb on mitotic chromosomes. In NUT-midline carcinoma (NMC), increased expression of c-MYC protein has been confirmed by the BRD4-NUT fusion protein [see non-patent document 4]. It has also been reported that the degree of decrease in expression of the MYC gene is the most significant in the human multiple myeloma-derived MM1.S cells, among the genes whose expression is decreased by the BET inhibitor JQ-1 treatment [See non-patent document 5].

[0005] RVX-208 / Apabetalone [see non-patent document 6], I-BET762 / GSK-525762A [see non-patent document 7], OTX-015 / MK8628 [see non-patent document 8], CPI-0610 [see nonpatent document 9], TEN-010 [see non-patent document 10], ABBV-075 [see non-patent document 11], and the like have been reported as typical BET inhibitors, none of which have yet received drug's approval.

[0006] In addition, in recent years, a compound, as a bivalent BET inhibitor, having a stronger BET inhibitory activity by simultaneously inhibiting the BD1 and BD2 domains has also been reported [see non-patent document 12]. As the divalent BET inhibitor described above, for example, compounds represented by the following formulas (P1) to (P6) are known [see non-patent documents 12 and 17 and patent document s 1, 2, and 3].

[0007] [Chem. 1] Further, a compound that degrades BET proteins in the ubiquitin-proteasome system has been reported as a new BET function regulator. It is known that the compound more efficiently induces the apoptosis of cancer cells by the degradation of BET proteins than BET inhibitors [see non-patent document 13]. Therefore, the BET degrader can be expected to be capable of serving as an anticancer drug superior to BET inhibitors.

[0009] It is known that, as for the divalent forms mentioned above, two small-molecule ligands against BET proteins can be connected via a spacer having a specific structure and thereby used as a BET degrader. More specifically, for example, N-(4-(((2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)-2-(3-(4-(((2S*,4R*)-2-methyl-1-propionyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)phenyl)ureido)acetamide (hereinafter, referred to as "g" in the present specification) is known as compound 6j [see patent document 4].

[0010] An antibody-drug conjugate (ADC) is generally constituted by a monoclonal antibody covalently bound with a drug via a chemically synthesized linker. ADC is capable of accurately and efficiently removing target cells by combining both the advantages of highly specific targeting ability of the antibody and a strong killing effect of the drug. Cytotoxic payloads currently approved for their use in ADC by FDA are typically strong tubulin inhibitors, DNA damaging agents, and topoisomerase I inhibitors [see nonpatent document 14].

[0011] ADC has been reported in which a BET protein degrading drug represented by the formula (P7) given below (GNE-987) [see nonpatent document 15] or a BET protein degrading drug represented by (P8) (EBET-1593) [see non-patent document 16] is conjugated 5 with an antibody via a linker. However, no clinical trial has been conducted thereon, and it is therefore uncertain whether these BET degraders effectively function as payloads of antibody-drug conjugates.

[0012] 10 [Chem. 2] [PRIOR ART DOCUMENTS] [Patent Literature] Patent Literature 1: WO 2013 / 033268 Patent Literature 2: WO 2015 / 081284 Patent Literature 3: WO 2017 / 091673 Patent Literature 4: WO 2021 / 065980 [Non Patent Literature]

[0014] Non Patent Literature 1: Nature, 2011, vol. 478, p. 524-528 Non Patent Literature 2: Cell, 2011, vol. 146, p. 904-917 Non Patent Literature 3: Nature, 2010, vol. 468, p. 1119-1123 Non Patent Literature 4: Cancer Res., 2003, vol. 63, p. 304-307 Non Patent Literature 5: Cell, 2013, vol. 153, p. 320-334 Non Patent Literature 6: Proc. Natl. Acad. Sci., 2013, vol. 110, p. 19754-19759 Non Patent Literature 7: J. Med. Chem., 2013, vol. 56, p. 75017515 Non Patent Literature 8: Oncotarget, 2015, vol. 6, p. 17698-17712. Non Patent Literature 9: Blood, 2015, vol. 126, p. 4255-4255 Non Patent Literature 10: Mol. Cancer Ther., 2015, vol. 14, A49 Non Patent Literature 11: Cancer Res., 2016, vol. 76, p. 47184718. Non Patent Literature 12: Nat. Chem. Bio., 2016, vol. 112, p. 1089-1096 Non Patent Literature 13: Science, 2015, vol. 348, p. 1376-1381 Non Patent Literature 14: Sig Transduct Target Ther, 2022, vol. 1, p. 1-25 Non Patent Literature 15: J. Med. Chem., 2021, vol. 64, p. 25762607 Non Patent Literature 16: Nat. Commun., 2024, vol. 15, p. 21922208 Non Patent Literature 17: Mol. Cancer Ther., 2016, vol. 15, p. 2563-2574 [Summary of Invention]

[0015] The present inventors have pursued drug discovery research on divalent BET degraders and consequently found that the existing divalent BET degraders have peripheral neurotoxicity, a safety hazard that must be avoided, though exhibiting high antitumor activity. The present inventors have conducted various studies to solve the problem and found a divalent BET degrader that avoids the safety hazard, i.e., peripheral neurotoxicity, while maintaining high antitumor activity. The present inventors have also found that the divalent BET degrader found is also useful as a payload (drug) in a targeting molecule-drug conjugate such as an antibodydrug conjugate (ADC).

[0016] The present invention encompasses the following [1] to

[162] . [1] A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: (wherein, R1 and R2 are the same or different and each represents a hydrogen atom or lower alkyl, R3 represents lower alkyl, R4 represents halogen, R5 represents halogen, R6 represents halogen or lower alkoxy, Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-, and ring A represents (i) an aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, (ii) an aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, or (iii) aryl optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl). [2] The compound or the pharmaceutically acceptable salt thereof according to [1], wherein (i) the aliphatic heterocyclic group in ring A is a nitrogen-containing aliphatic heterocyclic group. [3] The compound or the pharmaceutically acceptable salt thereof according to [2], wherein ring A represented by (i) the nitrogen-containing aliphatic heterocyclic group is the following ring A': [Chem. 4] (wherein, when ring A' has a substituent, the substituent is as defined for the substituent of ring A). [4] The compound or the pharmaceutically acceptable salt thereof according to any of [1] to [3], wherein the compound represented by the formula (I) is a compound represented by the following formula (I'): (wherein, R1, R2, and R3 are as defined in the formula (I), and ring A' is a nitrogen-containing aliphatic heterocyclic group 5 optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl). [5] The compound or the pharmaceutically acceptable salt 10 thereof according to any of [1] to [4], wherein ring A is a nitrogencontaining aliphatic heterocyclic group represented by the following formula (AA), (AB), (AC), or (AD), an aromatic heterocyclic group represented by the following formula (AE) or (AF), or aryl represented by the following formula (AG): 15 [Chem. 6] (AE)            (AF)            (AG) (wherein, RA1, RB1, RD1, RE1, RF1, and RG1 are the same or different and each represents lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, or lower alkylcarbamoyl, and RA2, RA3, RB2, RB3, RC1, and RC2 are the same or different and each represents a hydrogen atom, oxo, lower alkyl, or hydroxylower alkyl). [6] The compound or the pharmaceutically acceptable salt thereof according to any of [1] to [5], wherein ring A is a nitrogencontaining aliphatic heterocyclic group represented by the following formula (AA): [Chem. 7] rA3 rA2 ( AA) (wherein, RA1 represents lower alkyl, lower alkylcarbonyl, or cycloalkylcarbonyl, and RA2 and RA3 are the same or different and each represents a hydrogen atom, oxo, lower alkyl, or hydroxy-lower alkyl). [7] The compound or the pharmaceutically acceptable salt thereof according to [6], wherein RA1 is lower alkyl or lower alkylcarbonyl. [8] The compound or the pharmaceutically acceptable salt thereof according to [6] or [7], wherein RA2 and RA3 are the same or different and are each a hydrogen atom, oxo, or lower alkyl. [9] The compound or the pharmaceutically acceptable salt thereof according to any of [6] to [8], wherein RA1 is lower alkyl, and RA2 and RA3 are the same or different and are each oxo or lower alkyl.

[10] The compound or the pharmaceutically acceptable salt thereof according to any of [1] to [5], wherein ring A is a nitrogencontaining aliphatic heterocyclic group represented by the following formula (AB): [Chem. 8] (AB) (wherein, RB1 represents lower alkyl or lower alkylcarbonyl, and RB2 and RB3 are the same or different and each represents a hydrogen atom or oxo).

[11] The compound or the pharmaceutically acceptable salt thereof according to

[10] , wherein RB1 is lower alkyl.

[12] The compound or the pharmaceutically acceptable salt thereof according to any of [1] to [5], wherein ring A is a nitrogen containing aliphatic heterocyclic group represented by the following formula (AC): [Chem. 9] 5 (wherein RC1 and RC2 are the same or different and each represents a hydrogen atom or oxo).

[13] The compound or the pharmaceutically acceptable salt thereof according to any of [1] to [5], wherein ring A is a nitrogencontaining aliphatic heterocyclic group represented by the following 10 formula (AD): [Chem. 10] (wherein RD1 represents lower alkylcarbonyl).

[14] The compound or the pharmaceutically acceptable salt 15 thereof according to [1], wherein ring A is an aromatic heterocyclic group represented by the following formula (AE): [Chem. 11] ( AE ) (wherein RE1 represents lower alkyl).

[15] The compound or the pharmaceutically acceptable salt thereof according to [1], wherein ring A is an aromatic heterocyclic group represented by the following formula (AF): 5 [Chem. 12] ( AF ) (wherein RF1 represents lower alkyl).

[16] The compound or the pharmaceutically acceptable salt thereof according to [1], wherein ring A is aryl represented by the 10 following formula (AG): [Chem. 13] (AG) (wherein RG1 represents lower alkoxycarbonyl or lower alkylcarbamoyl). 15

[17] The compound or the pharmaceutically acceptable salt thereof according to any of [1] to

[16] , wherein Y is -O-CH2-CH2-.

[18] The compound or the pharmaceutically acceptable salt thereof according to any of [1] to

[17] , wherein R1 is a hydrogen atom, R2 is methyl, and R3 is ethyl.

[19] A compound represented by the following formula or a pharmaceutically acceptable salt thereof: [Chem. 14] Compound 1

[20] A compound represented by the following formula or a pharmaceutically acceptable salt thereof: [Chem. 15] 'CH3 Compound 2 10

[21] A compound represented by the following formula or a pharmaceutically acceptable salt thereof: [Chem. 16]

[22] A compound represented by the following formula or a pharmaceutically acceptable salt thereof: [Chem. 17] Compound 19 5

[23] A compound represented by the following formula or a pharmaceutically acceptable salt thereof: [Chem. 18]

[24] A therapeutic agent for cancer, containing the compound or 10 the pharmaceutically acceptable salt thereof according to any of [1] to

[23] as an active ingredient.

[25] The agent according to

[24] , wherein the cancer is B cell lymphoma.

[26] A method for treating cancer, including administering the 15 compound or the pharmaceutically acceptable salt thereof according to any of [1] to

[23] to a subject.

[27] The method according to

[26] , wherein the cancer is B cell lymphoma.

[28] The compound or the pharmaceutically acceptable salt thereof according to any of [1] to

[23] for use in the treatment of cancer.

[29] The compound or the pharmaceutically acceptable salt thereof according to

[28] , wherein the cancer is B cell lymphoma.

[30] Use of the compound or the pharmaceutically acceptable salt thereof according to any of [1] to

[23] for the production of a drug for the treatment of cancer.

[31] The use according to

[30] , wherein the cancer is B cell lymphoma.

[32] A targeting molecule-drug conjugate containing a targeting molecule and a drug, wherein the drug is the compound or the pharmaceutically acceptable salt thereof according to any of [1] to

[23] .

[33] The targeting molecule-drug conjugate according to

[32] , wherein the drug is linked to the targeting molecule via a linker.

[34] The targeting molecule-drug conjugate according to

[32] or

[33] , wherein the targeting molecule-drug conjugate is represented by the following formula (II): [Chem. 19] (wherein, R1 and R2 are the same or different and each represents a hydrogen atom or lower alkyl, R3 represents lower alkyl, R4 represents halogen, R5 represents halogen, R6 represents halogen or lower alkoxy, Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-, ring A represents (i) an aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, (ii) an aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, hydroxy-lower alkylcarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, or (iii) aryl optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, L represents a linker, mm represents an integer of 1 to 8, and Z represents a targeting molecule).

[35] The compound or the pharmaceutically acceptable salt thereof according to

[34] , wherein (i) the aliphatic heterocyclic group in ring A is a nitrogen-containing aliphatic heterocyclic group.

[36] The targeting molecule-drug conjugate according to

[34] or

[35] , wherein ring A represented by (i) the aliphatic heterocyclic group is the following ring A': [Chem. 20] (wherein, when ring A' has a substituent, the substituent of ring A' is as defined for the substituent of ring A).

[37] The targeting molecule-drug conjugate according to any of

[33] to

[36] , wherein the targeting molecule-drug conjugate is represented by the following formula (II'): [Chem. 21] (wherein, R1, R2, R3, L, mm, and Z are as defined in the formula (II), and ring A' is a nitrogen-containing aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl).

[38] The targeting molecule-drug conjugate according to any of

[34] to

[36] , wherein L is represented by the following formula (III): [Chem. 22] (wherein, wavy line 1 represents a bonding site to Z, wavy line 2 represents a bonding site to the N atom, and each Xaa independently represents (a) a residue of at least one amino acid selected from the group consisting of valine, alanine, citrulline, glycine, phenylalanine, glutamic acid, cysteic acid, arginine, asparagine, aspartic acid, glutamine, leucine, isoleucine, lysine, serine, proline, threonine, and tyrosine, or represents (b) a peptide mimetic represented by the following formula (IV): [Chem. 23] wherein, q represents an integer of 1 to 5, r represents an integer of 2 to 24, s represents 0 or 1, and t represents 1, 2, 3, or 4).

[39] The targeting molecule-drug conjugate according to

[38] , wherein each Xaa is independently a residue of at least one amino acid selected from the group consisting of valine, alanine, citrulline, glycine, proline, phenylalanine, and glutamic acid, or is a peptide mimetic represented by the following formula (IV): [Chem. 24]

[40] The targeting molecule-drug conjugate according to

[38] , wherein each Xaa is independently a residue of an amino acid selected from valine and alanine.

[41] The targeting molecule-drug conjugate according to any of

[38] to

[40] , wherein t is 2.

[42] The targeting molecule-drug conjugate according to any of

[38] to

[41] , wherein r is 6 or 12.

[43] The targeting molecule-drug conjugate according to any of

[38] to

[41] , wherein r is 12.

[44] The targeting molecule-drug conjugate according to any of

[38] to

[43] , wherein q is 2 or 5.

[45] The targeting molecule-drug conjugate according to any of

[38] to

[43] , wherein q is 2.

[46] The targeting molecule-drug conjugate according to any of

[38] to

[45] , wherein s is 1.

[47] The targeting molecule-drug conjugate according to any of

[32] to

[46] , wherein the targeting molecule is an antibody or an antigen binding fragment thereof, a small-molecule compound, or a peptide.

[48] The targeting molecule-drug conjugate according to any of

[32] to

[46] , wherein the targeting molecule is an antibody or an antigen binding fragment thereof.

[49] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-Nectin4, or an anti-TROP2 antibody.

[50] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-CD79b antibody.

[51] The targeting molecule-drug conjugate according to

[50] , wherein the anti-CD79b antibody contains a heavy chain variable region (hereinafter, also referred to as "VH") containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 11, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 12, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 13, and a light chain variable region (hereinafter, also referred to as "VL") containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 14, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 15, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 16.

[52] The targeting molecule-drug conjugate according to

[50] or

[51] , wherein the amino acid sequence of VH of the anti-CD79b antibody contains the amino acid sequence set forth in SEQ ID NO: 5, and the amino acid sequence of VL of the anti-CD79b antibody contains the amino acid sequence set forth in SEQ ID NO: 6.

[53] The targeting molecule-drug conjugate according to any of

[50] to

[52] , wherein the amino acid sequence of VH of the anti-CD79b antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 5, and the amino acid sequence of VL of the anti-CD79b antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 6.

[54] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-CD19 antibody.

[55] The targeting molecule-drug conjugate according to

[54] , wherein the anti-CD19 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 17, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 18, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 19, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 20, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 21, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 22.

[56] The targeting molecule-drug conjugate according to

[54] or

[55] , wherein the amino acid sequence of VH of the anti-CD19 antibody contains the amino acid sequence set forth in SEQ ID NO: 7, and the amino acid sequence of VL of the anti-CD19 antibody contains the amino acid sequence set forth in SEQ ID NO: 8.

[57] The targeting molecule-drug conjugate according to any of

[54] to

[56] , wherein the amino acid sequence of VH of the anti-CD19 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 7, and the amino acid sequence of VL of the anti-CD19 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 8.

[58] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-CD22 antibody.

[59] The targeting molecule-drug conjugate according to

[58] , wherein the anti-CD22 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 23, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 24, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 25, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 26, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 27, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 28.

[60] The targeting molecule-drug conjugate according to

[58] or

[59] , wherein the amino acid sequence of VH of the anti-CD22 antibody contains the amino acid sequence set forth in SEQ ID NO: 9, and the amino acid sequence of VL of the anti-CD22 antibody contains the amino acid sequence set forth in SEQ ID NO: 10.

[61] The targeting molecule-drug conjugate according to any of

[58] to

[60] , wherein the amino acid sequence of VH of the anti-CD22 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 9, and the amino acid sequence of VL of the anti-CD22 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 10.

[62] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-HER2 antibody.

[63] The targeting molecule-drug conjugate according to

[62] , wherein the anti-HER2 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 67, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 68, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 69, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 70, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 71, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 72.

[64] The targeting molecule-drug conjugate according to

[62] or

[63] , wherein the amino acid sequence of VH of the anti-HER2 antibody contains the amino acid sequence set forth in SEQ ID NO: 29, the amino acid sequence of VL of the anti-HER2 antibody contains the amino acid sequence set forth in SEQ ID NO: 30.

[65] The targeting molecule-drug conjugate according to any of

[62] to

[64] , wherein the amino acid sequence of VH of the anti-HER2 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 29, and the amino acid sequence of VL of the anti-HER2 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 30.

[66] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-DLL3 antibody.

[67] The targeting molecule-drug conjugate according to

[66] , wherein the anti-DLL3 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 73, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 74, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 75, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 76, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 77, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 78.

[68] The targeting molecule-drug conjugate according to

[66] or

[67] , wherein the amino acid sequence of VH of the anti-DLL3 antibody contains the amino acid sequence set forth in SEQ ID NO: 31, and the amino acid sequence of VL of the anti-DLL3 antibody contains the amino acid sequence set forth in SEQ ID NO: 32.

[69] The targeting molecule-drug conjugate according to any of

[66] to

[68] , wherein the amino acid sequence of VH of the anti-DLL3 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 31, and the amino acid sequence of VL of the anti-DLL3 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 32.

[70] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-GM2 antibody.

[71] The targeting molecule-drug conjugate according to

[70] , wherein the anti-GM2 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 79, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 80, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 81, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 82, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 83, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 84.

[72] The targeting molecule-drug conjugate according to

[70] or

[71] , wherein the amino acid sequence of VH of the anti-GM2 antibody contains the amino acid sequence set forth in SEQ ID NO: 33, and the amino acid sequence of VL of the anti-GM2 antibody contains the amino acid sequence set forth in SEQ ID NO: 34.

[73] The targeting molecule-drug conjugate according to any of

[70] to

[72] , wherein the amino acid sequence of VH of the anti-GM2 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 33, and the amino acid sequence of VL of the anti-GM2 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 34.

[74] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-EphA2 antibody.

[75] The targeting molecule-drug conjugate according to

[74] , wherein the anti-EphA2 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 85, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 86, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 87, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 88, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 89, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 90.

[76] The targeting molecule-drug conjugate according to

[74] or

[75] , wherein the amino acid sequence of VH of the anti-EphA2 antibody contains the amino acid sequence set forth in SEQ ID NO: 35, and the amino acid sequence of VL of the anti-EphA2 antibody contains the amino acid sequence set forth in SEQ ID NO: 36.

[77] The targeting molecule-drug conjugate according to any of

[74] to

[76] , wherein the amino acid sequence of VH of the anti-EphA2 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 35, and the amino acid sequence of VL of the anti-EphA2 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 36.

[78] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-FAP antibody.

[79] The targeting molecule-drug conjugate according to

[78] , wherein the anti-FAP antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 91, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 92, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 93, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 94, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 95, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 96.

[80] The targeting molecule-drug conjugate according to

[78] or

[79] , wherein the amino acid sequence of VH of the anti-FAP antibody contains the amino acid sequence set forth in SEQ ID NO: 37, and the amino acid sequence of VL of the anti-FAP antibody contains the amino acid sequence set forth in SEQ ID NO: 38.

[81] The targeting molecule-drug conjugate according to any of

[78] to

[80] , wherein the amino acid sequence of VH of the antiFAP antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 37, and the amino acid sequence of VL of the anti-FAP antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 38.

[82] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-SSTR2 antibody.

[83] The targeting molecule-drug conjugate according to

[82] , wherein the anti-SSTR2 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 97, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 98, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 99, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 100, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 101, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 102.

[84] The targeting molecule-drug conjugate according to

[82] or

[83] , wherein the amino acid sequence of VH of the anti-SSTR2 antibody contains the amino acid sequence set forth in SEQ ID NO: 39, and the amino acid sequence of VL of the anti-SSTR2 antibody contains the amino acid sequence set forth in SEQ ID NO: 40.

[85] The targeting molecule-drug conjugate according to any of

[82] to

[84] , wherein the amino acid sequence of VH of the anti-SSTR2 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 39, and the amino acid sequence of VL of the anti-SSTR2 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 40.

[86] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-CD30 antibody.

[87] The targeting molecule-drug conjugate according to

[86] , wherein the anti-CD30 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 103, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 104, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 105, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 106, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 107, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 108.

[88] The targeting molecule-drug conjugate according to

[86] or

[87] , wherein the amino acid sequence of VH of the anti-CD30 antibody contains the amino acid sequence set forth in SEQ ID NO: 41, and the amino acid sequence of VL of the anti-CD30 antibody contains the amino acid sequence set forth in SEQ ID NO: 42.

[89] The targeting molecule-drug conjugate according to any of

[86] to

[88] , wherein the amino acid sequence of VH of the anti-CD30 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 41, and the amino acid sequence of VL of the anti-CD30 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 42.

[90] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-BCMA antibody.

[91] The targeting molecule-drug conjugate according to

[90] , wherein the anti-BCMA antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 109, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 110, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 111, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 112, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 113, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 114.

[92] The targeting molecule-drug conjugate according to

[90] or

[91] , wherein the amino acid sequence of VH of the anti-BCMA antibody contains the amino acid sequence set forth in SEQ ID NO: 43, and the amino acid sequence of VL of the anti-BCMA antibody contains the amino acid sequence set forth in SEQ ID NO: 44.

[93] The targeting molecule-drug conjugate according to any of

[90] to

[92] , wherein the amino acid sequence of VH of the anti-BCMA antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 43, and the amino acid sequence of VL of the anti-BCMA antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 44.

[94] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-CD33 antibody.

[95] The targeting molecule-drug conjugate according to

[94] , wherein the anti-CD33 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 115, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 116, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 117, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 118, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 119, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 120.

[96] The targeting molecule-drug conjugate according to

[94] or

[95] , wherein the amino acid sequence of VH of the anti-CD33 antibody contains the amino acid sequence set forth in SEQ ID NO: 45, and the amino acid sequence of VL of the anti-CD33 antibody contains the amino acid sequence set forth in SEQ ID NO: 46.

[97] The targeting molecule-drug conjugate according to any of

[94] to

[96] , wherein the amino acid sequence of VH of the anti- CD33 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 45, and the amino acid sequence of VL of the anti-CD33 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 46.

[98] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-FoLRa antibody.

[99] The targeting molecule-drug conjugate according to

[98] , wherein the anti-FoLRa antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 121, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 122, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 123, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 124, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 125, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 126.

[100] The targeting molecule-drug conjugate according to

[98] or

[99] , wherein the amino acid sequence of VH of the anti-FoLRa antibody contains the amino acid sequence set forth in SEQ ID NO: 47, and the amino acid sequence of VL of the anti-FoLRa antibody contains the amino acid sequence set forth in SEQ ID NO: 48.

[101] The targeting molecule-drug conjugate according to any of

[98] to

[100] , wherein the amino acid sequence of VH of the anti-FoLRa antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 47, and the amino acid sequence of VL of the anti-FoLRa antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 48.

[102] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-CD25 antibody.

[103] The targeting molecule-drug conjugate according to

[102] , wherein the anti-CD25 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 127, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 128, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 129, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 130, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 131, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 132.

[104] The targeting molecule-drug conjugate according to

[102] or

[103] , wherein the amino acid sequence of VH of the anti-CD25 antibody contains the amino acid sequence set forth in SEQ ID NO: 49, and the amino acid sequence of VL of the anti-CD25 antibody contains the amino acid sequence set forth in SEQ ID NO: 50.

[105] The targeting molecule-drug conjugate according to any of

[102] to

[104] , wherein the amino acid sequence of VH of the anti-CD25 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 49, and the amino acid sequence of VL of the anti-CD25 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 50.

[106] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-CADM1 antibody.

[107] The targeting molecule-drug conjugate according to

[106] , wherein the anti-CADM1 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 133, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 134, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 135, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 136, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 137, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 138.

[108] The targeting molecule-drug conjugate according to

[106] or

[107] , wherein the amino acid sequence of VH of the anti-CADM1 antibody contains the amino acid sequence set forth in SEQ ID NO: 51, and the amino acid sequence of VL of the anti-CADM1 antibody contains the amino acid sequence set forth in SEQ ID NO: 52.

[109] The targeting molecule-drug conjugate according to any of

[106] to

[108] , wherein the amino acid sequence of VH of the anti-CADM1 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 51, and the amino acid sequence of VL of the anti-CADM1 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 52.

[110] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-CLL1 antibody.

[111] The targeting molecule-drug conjugate according to

[110] , wherein the anti-CLL1 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 139, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 140, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 141, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 142, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 143, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 144.

[112] The targeting molecule-drug conjugate according to

[110] or

[111] , wherein the amino acid sequence of VH of the anti-CLL1 antibody contains the amino acid sequence set forth in SEQ ID NO: 53, and the amino acid sequence of VL of the anti-CLL1 antibody contains the amino acid sequence set forth in SEQ ID NO: 54.

[113] The targeting molecule-drug conjugate according to any of

[110] to

[112] , wherein the amino acid sequence of VH of the anti-CLL1 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 53, and the amino acid sequence of VL of the anti-CLL1 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 54.

[114] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-CD38 antibody.

[115] The targeting molecule-drug conjugate according to

[114] , wherein the anti-CD38 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 145, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 146, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 147, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 148, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 149, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 150.

[116] The targeting molecule-drug conjugate according to

[114] or

[115] , wherein the amino acid sequence of VH of the anti-CD38 antibody contains the amino acid sequence set forth in SEQ ID NO: 55, and the amino acid sequence of VL of the anti-CD38 antibody contains the amino acid sequence set forth in SEQ ID NO: 56.

[117] The targeting molecule-drug conjugate according to any of

[114] to

[116] , wherein the amino acid sequence of VH of the anti-CD38 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 55, and the amino acid sequence of VL of the anti-CD38 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 56.

[118] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-CD74 antibody.

[119] The targeting molecule-drug conjugate according to

[118] , wherein the anti-CD74 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 151, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 152, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 153, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 154, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 155, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 156.

[120] The targeting molecule-drug conjugate according to

[118] or

[119] , wherein the amino acid sequence of VH of the anti-CD74 antibody contains the amino acid sequence set forth in SEQ ID NO: 57, and the amino acid sequence of VL of the anti-CD74 antibody contains the amino acid sequence set forth in SEQ ID NO: 58.

[121] The targeting molecule-drug conjugate according to any of

[118] to

[120] , wherein the amino acid sequence of VH of the anti-CD74 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and the amino acid sequence of VL of the anti-CD74 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 58.

[122] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-Nectin4 antibody.

[123] The targeting molecule-drug conjugate according to

[122] , wherein the anti-Nectin4 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 187, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 188, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 189, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 190, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 191, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 192.

[124] The targeting molecule-drug conjugate according to

[122] or

[123] , wherein the amino acid sequence of VH of the anti-Nectin4 antibody contains the amino acid sequence set forth in SEQ ID NO: 183, and the amino acid sequence of VL of the anti-Nectin4 antibody contains the amino acid sequence set forth in SEQ ID NO: 184.

[125] The targeting molecule-drug conjugate according to any of

[122] to

[124] , wherein the amino acid sequence of VH of the anti-Nectin4 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 183, and the amino acid sequence of VL of the anti-Nectin4 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 184.

[126] The targeting molecule-drug conjugate according to

[48] , wherein the antibody is an anti-TROP2 antibody.

[127] The targeting molecule-drug conjugate according to

[126] , wherein the anti-TROP2 antibody contains VH containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 193, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 194, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 195, and VL containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 196, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 197, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 198.

[128] The targeting molecule-drug conjugate according to

[126] or

[128] , wherein the amino acid sequence of VH of the anti-TROP2 antibody contains the amino acid sequence set forth in SEQ ID NO: 185, and the amino acid sequence of VL of the anti-TROP2 antibody contains the amino acid sequence set forth in SEQ ID NO: 186.

[129] The targeting molecule-drug conjugate according to any of

[126] to

[128] , wherein the amino acid sequence of VH of the anti-TROP2 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 185, and the amino acid sequence of VL of the anti-TROP2 antibody contains an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 186.

[130] The targeting molecule-drug conjugate according to any of

[48] to

[129] , wherein an amino acid sequence of a heavy chain constant region (hereinafter, also referred to as "CH") of the antibody contains (a) the amino acid sequence set forth in SEQ ID NO: 1, or (b) an amino acid sequence having 80% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 1.

[131] The targeting molecule-drug conjugate according to

[130] , wherein the amino acid sequence (b) is an amino acid sequence derived from the amino acid sequence set forth in SEQ ID NO: 1 by the substitution of at least one amino acid by cysteine.

[132] The targeting molecule-drug conjugate according to any of

[48] to

[129] , wherein the amino acid sequence of CH of the antibody contains the amino acid sequence set forth in SEQ ID NO: 2.

[133] The targeting molecule-drug conjugate according to

[132] , wherein the antibody is connected to linker L via a sulfur atom of cysteine at position 239 of the heavy chain.

[134] The targeting molecule-drug conjugate according to any of

[48] to

[133] , wherein an amino acid sequence of a light chain constant region (hereinafter, also referred to as "CL") of the antibody contains (e) the amino acid sequence set forth in SEQ ID NO: 3, or (f) an amino acid sequence having 80% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 3.

[135] The targeting molecule-drug conjugate according to

[134] , wherein the amino acid sequence (f) is an amino acid sequence derived from the amino acid sequence set forth in SEQ ID NO: 3 by the substitution of at least one amino acid by cysteine.

[136] The targeting molecule-drug conjugate according to any of

[48] to

[135] , wherein the amino acid sequence of CL of the antibody contains the amino acid sequence set forth in SEQ ID NO: 4.

[137] The targeting molecule-drug conjugate according to

[136] , wherein the antibody is connected to linker L via a sulfur atom of cysteine at position 124 of the light chain.

[138] A therapeutic agent for cancer, containing the targeting molecule-drug conjugate according to any of

[32] to

[137] as an active ingredient.

[139] The agent according to

[138] , wherein the cancer is B cell lymphoma.

[140] A method for treating cancer, including administering the targeting molecule-drug conjugate according to any of

[32] to

[137] to a subject.

[141] The method according to

[140] , wherein the cancer is B cell lymphoma.

[142] The targeting molecule-drug conjugate according to any of

[32] to

[137] for use in the treatment of cancer.

[143] The targeting molecule-drug conjugate according to

[142] , wherein the cancer is B cell lymphoma.

[144] Use of the targeting molecule-drug conjugate according to any of

[32] to

[137] for the production of a drug for the treatment of cancer.

[145] The use according to

[144] , wherein the cancer is B cell lymphoma.

[146] A drug-linker conjugate comprising a drug and a linker linked to the drug, wherein the drug is the compound or the pharmaceutically acceptable salt thereof according to any of [1] to

[23] .

[147] The drug-linker conjugate according to

[146] , wherein the drug-linker conjugate is represented by the following formula (V): [Chem. 25] (wherein, R1 and R2 are the same or different and each represents a hydrogen atom or lower alkyl, R3 represents lower alkyl, R4 represents halogen, R5 represents halogen, R6 represents halogen or lower alkoxy, Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-, ring A represents (i) a nitrogen-containing aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, (ii) an aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, or (iii) aryl optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, and L represents a linker).

[148] The compound or the pharmaceutically acceptable salt thereof according to

[147] , wherein (i) the aliphatic heterocyclic group in ring A is a nitrogen-containing aliphatic heterocyclic group.

[149] The drug-linker conjugate according to

[147] or

[148] , wherein ring A represented by (i) the aliphatic heterocyclic group is the following ring A': [Chem. 26] (wherein, when ring A' has a substituent, the substituent of ring A' is as defined for the substituent of ring A).

[150] The drug-linker conjugate according to any of

[146] to

[149] , wherein the drug-linker conjugate is represented by the following formula (V'): [Chem. 27] 10 15 (wherein, R1, R2, R3, and L are as defined in the formula (V), and ring A' is a nitrogen-containing aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl).

[151] The drug-linker conjugate according to

[147] , wherein the drug-linker conjugate is represented by the following formula (Va): [Chem. 28] ( Va ) (wherein, R1, R2, R3, R4, R5, R6, Y, and ring A are as defined above, and each Xaa independently represents 5           (a) a residue of at least one amino acid selected from the group consisting of valine, alanine, citrulline, glycine, phenylalanine, glutamic acid, cysteic acid, arginine, asparagine, aspartic acid, glutamine, leucine, isoleucine, lysine, serine, proline, threonine, and tyrosine, or represents 10          (b) a peptide mimetic represented by the following formula (IV): [Chem. 29] wherein, 15        q represents an integer of 1 to 5, r represents an integer of 2 to 24, s represents 0 or 1, and t represents 1, 2, 3, or 4).

[152] The compound or the pharmaceutically acceptable salt thereof according to

[151] , wherein (i) the aliphatic heterocyclic group in ring A is a nitrogen-containing aliphatic heterocyclic group.

[153] The drug-linker conjugate according to

[151] or

[152] , wherein ring A represented by (i) the aliphatic heterocyclic group is the following ring A': [Chem. 30] (wherein, when ring A' has a substituent, the substituent of ring A' is as defined for the substituent of ring A).

[154] The drug-linker conjugate according to any of

[146] to

[153] , wherein the drug-linker conjugate is represented by the following formula (V'a): [Chem. 31] (wherein, R1, R2, R3, Xaa, q, r, s, and t are as defined in the formula (Va), and ring A' is a nitrogen-containing aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl).

[155] The drug-linker conjugate according to any of

[151] to

[154] , wherein each Xaa is independently a residue of an amino acid selected from valine, alanine, citrulline, glycine, phenylalanine, and glutamic acid, or is a peptide mimetic represented by the following formula (IV): [Chem. 32]

[156] The drug-linker conjugate according to any of

[151] to

[155] , wherein each Xaa is independently a residue of an amino acid selected from valine and alanine.

[157] The drug-linker conjugate according to any of

[151] to

[156] , wherein t is 2.

[158] The drug-linker conjugate according to any of

[151] to

[157] , wherein r is 6 or 12.

[159] The drug-linker conjugate according to any of

[151] to

[158] , wherein r is 12.

[160] The drug-linker conjugate according to any of

[151] to

[159] , wherein q is 2 or 5.

[161] The drug-linker conjugate according to any of

[151] to

[160] , wherein q is 2.

[162] The drug-linker conjugate according to any of

[151] to

[161] , wherein s is 1. is provided.

[0017] The compound represented by the formula (I) or the pharmaceutically acceptable salt thereof is a divalent BET degrader and can avoid the safety hazard, i.e., peripheral neurotoxicity, while maintaining high antitumor activity. The compound represented by the formula (I) or the pharmaceutically acceptable salt thereof is also useful as a payload (drug) in a targeting molecule-drug conjugate such as an antibody-drug conjugate (ADC).

[0018] The targeting molecule-drug conjugate containing the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof as a drug can avoid the safety hazard, i.e., peripheral neurotoxicity, while maintaining high antitumor activity. [Brief Description of Drawings]

[0019] [Figure 1] Figure 1 is a diagram showing results of Test Example 4 (in vivo drug efficacy evaluation of compound and ADC). [Figure 2] Figure 2 is a diagram showing results of Test Example 5 (BET protein degradation evaluation by Western blotting (WB) using SU-DHL-4 cell line). [Mode for Carrying Out the Invention]

[0020] Hereinafter, the present invention will be described. As used herein, the phrase "value A to value B" means the value A or more and the value B or less. Two or more embodiments described in the present specification can be combined, and such a combination of two or more embodiments is also encompassed by the present invention.

[0021] <<Description of term>> Hereinafter, terms used in the present specification will be described. The following description is applied to the entire present specification unless otherwise specified.

[0022] Oxo The oxo is a group represented by the formula: =O.

[0023] Lower alkyl The lower alkyl is, for example, linear or branched alkyl having 1 to 10 carbon atoms. Examples of the lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tertbutyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0024] Hydroxy-lower alkyl The hydroxy-lower alkyl is lower alkyl in which one or more hydrogen atoms are replaced by hydroxy. The definition of the lower alkyl is as described above. The position or the number of hydroxy in the hydroxy-lower alkyl is not particularly limited. The number of hydroxy is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, further preferably 1. Examples of the hydroxylower alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-dihydroxyethyl, and 1,2-dihydroxypropyl.

[0025] Lower alkylcarbonyl The lower alkylcarbonyl is a group represented by the formula: -CO-lower alkyl. The definition of the lower alkyl is as described above. Examples of the lower alkylcarbonyl include methylcarbonyl(acetyl), ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, secbutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, hexylcarbonyl, heptylcarbonyl, octylcarbonyl, nonylcarbonyl, and decylcarbonyl.

[0026] Hydroxy-lower alkylcarbonyl The hydroxy-lower alkylcarbonyl is a group represented by the formula: -CO-hydroxy-lower alkyl. The definition of the hydroxy-lower alkyl is as described above. Examples of the hydroxy-lower alkylcarbonyl include hydroxymethylcarbonyl, 1-hydroxyethylcarbonyl, 2-hydroxyethylcarbonyl, 1-hydroxypropylcarbonyl, 2-hydroxypropylcarbonyl, 1,2-dihydroxyethylcarbonyl, and 1,2-dihydroxypropylcarbonyl.

[0027] Cycloalkylcarbonyl The cycloalkylcarbonyl is a group represented by the formula: -CO-cycloalkyl. The number of carbon atoms in the cycloalkyl is, for example, 3 to 10. Examples of the cycloalkylcarbonyl include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, cyclononylcarbonyl, and cyclodecylcarbonyl.

[0028] Halogen The halogen is each of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

[0029] Lower alkoxy The lower alkoxy is, for example, linear or branched alkoxy having 1 to 10 carbon atoms, preferably alkoxy having 1 to 5 carbon atoms, more preferably alkoxy having 1 to 3 carbon atoms. Examples of the lower alkoxy include methoxy, ethoxy, propyloxy, i-propyloxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy, with methoxy being preferred.

[0030] Lower alkoxycarbonyl The lower alkoxycarbonyl is a group represented by the formula: -CO-lower alkoxy. The definition of the lower alkoxy is as described above. The lower alkoxycarbonyl is, for example, linear or branched alkoxycarbonyl having 1 to 11 carbon atoms, preferably alkoxycarbonyl having 1 to 5 carbon atoms, more preferably alkoxycarbonyl having 1 to 3 carbon atoms. Examples of the lower alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tertbutoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, and neopentoxycarbonyl, with methoxycarbonyl and ethoxycarbonyl being preferred.

[0031] Lower alkylcarbamoyl The lower alkylcarbamoyl is a group represented by the formula: -CONH-lower alkyl. The definition of the lower alkyl is as described above. The lower alkylcarbamoyl is, for example, linear or branched alkylcarbamoyl having 1 to 11 carbon atoms, preferably alkylcarbamoyl having 1 to 5 carbon atoms, more preferably alkylcarbamoyl having 1 to 3 carbon atoms. Examples of the lower alkylcarbamoyl include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, and diethylcarbamoyl, with methylcarbamoyl and dimethylcarbamoyl being preferred.

[0032] Aliphatic heterocyclic group The aliphatic heterocyclic group contains, as ring-constituting elements, a carbon atom as well as one or more non-carbon heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. The number of heteroatoms in the aliphatic heterocyclic group is, for example, 1 to 3, preferably 1 or 2, more preferably 2. The number of carbon atoms in the aliphatic heterocyclic group is appropriately determined depending on the number of heteroatoms and the number of members in the aliphatic heterocyclic group.

[0033] Two carbon atoms constituting a ring in the aliphatic heterocyclic group may be bridged by an alkylene group. The number of carbon atoms in the alkylene group that bridges two carbon atoms constituting a ring is, for example, 1 to 3, preferably 1 or 2, further preferably 1.

[0034] The aliphatic heterocyclic group may be constituted only by saturated bonds or may contain a double bond and is preferably constituted only by saturated bonds.

[0035] The aliphatic heterocyclic group may be monocyclic or may be fused polycyclic. The fused polycyclic group is, for example, a fused bicyclic or fused tricyclic group, preferably a fused bicyclic group.

[0036] The number of members in the monocyclic aliphatic heterocyclic group is, for example, 3 to 8, preferably 4 to 8, more preferably 5 to 7, further preferably 6 or 7.

[0037] Examples of the monocyclic aliphatic heterocyclic group include aliphatic heterocyclic groups containing only a nitrogen atom as a heteroatom, such as aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, azepanyl, 1,4-diazepanyl, azocanyl, and diazocanyl. Examples of the aliphatic heterocyclic group containing a nitrogen atom and an oxygen atom as heteroatoms include oxazolidinyl, oxazolinyl, and morpholinyl. Examples of the aliphatic heterocyclic group containing a nitrogen atom and a sulfur atom as heteroatoms include thiazolidinyl, thiazolinyl, and thiomorpholinyl. Piperazinyl or 1,4-diazepanyl is preferred, with piperazinyl being more preferred.

[0038] Examples of the fused polycyclic aliphatic heterocyclic group include aliphatic heterocyclic groups containing only a nitrogen atom as a heteroatom, such as bicyclic or tricyclic nitrogencontaining aliphatic heterocyclic groups with 3- to 8-membered rings fused, specifically, hexahydropyrrolopyrazinyl, octahydropyridopyrazinyl, octahydropyrrolodiazepanyl, decahydropyridodiazepanyl, and decahydroazapinodiazepanyl.

[0039] Nitrogen-containing aliphatic heterocyclic group The nitrogen-containing aliphatic heterocyclic group is an aliphatic heterocyclic group containing a carbon atom as well as one or more nitrogen atoms as ring-constituting elements. The number of nitrogen atoms in the nitrogen-containing aliphatic heterocyclic group is, for example, 1 to 3, preferably 1 or 2, more preferably 2. The number of carbon atoms in the nitrogencontaining aliphatic heterocyclic group is appropriately determined depending on the number of heteroatoms and the number of members in the nitrogen-containing aliphatic heterocyclic group. The bonding hand of the nitrogen-containing aliphatic heterocyclic group is not particularly limited and, this bonding hand preferably has a nitrogen atom. The nitrogen-containing aliphatic heterocyclic group may contain one or more non-nitrogen heteroatoms selected from the group consisting of an oxygen atom and a sulfur atom. When the nitrogen-containing aliphatic heterocyclic group contains a non-nitrogen heteroatom, the number of non-nitrogen heteroatoms is, for example, 1 or 2, preferably 1.

[0040] Two carbon atoms constituting a ring in the nitrogencontaining aliphatic heterocyclic group may be bridged by an alkylene group. The number of carbon atoms in the alkylene group that bridges two carbon atoms constituting a ring is, for example, 1 to 3, preferably 1 or 2, further preferably 1.

[0041] The nitrogen-containing aliphatic heterocyclic group may be constituted only by saturated bonds or may contain a double bond and is preferably constituted only by saturated bonds.

[0042] The nitrogen-containing aliphatic heterocyclic group may be monocyclic or may be fused polycyclic. The fused polycyclic group is, for example, a fused bicyclic or fused tricyclic group, preferably a fused bicyclic group.

[0043] The number of members in the monocyclic nitrogencontaining aliphatic heterocyclic group is, for example, 3 to 8, preferably 4 to 8, more preferably 5 to 7, further preferably 6 or 7.

[0044] Examples of the monocyclic nitrogen-containing aliphatic heterocyclic group include aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, oxazolidinyl, oxazolinyl, pyrazolidinyl, pyrazolinyl, thiazolidinyl, thiazolinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, morpholinyl, thiomorpholinyl, azepanyl, 1,4-diazepanyl, azocanyl, and diazocanyl. Piperazinyl or 1,4-diazepanyl is preferred, with piperazinyl being more preferred.

[0045] Examples of the fused polycyclic nitrogen-containing aliphatic heterocyclic group include bicyclic or tricyclic nitrogen-containing aliphatic heterocyclic groups with 3- to 8-membered rings fused, specifically, hexahydropyrrolopyrazinyl, octahydropyridopyrazinyl, octahydropyrrolodiazepanyl, decahydropyridodiazepanyl, and decahydroazapinodiazepanyl.

[0046] Aromatic heterocyclic group The aromatic heterocyclic group contains, as ring-constituting elements, a carbon atom as well as one or more non-carbon heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. The number of heteroatoms in the aromatic heterocyclic group is, for example, 1 to 3, preferably 1 or 2. The number of carbon atoms in the aromatic heterocyclic group is appropriately determined depending on the number of heteroatoms and the number of members in the aromatic heterocyclic group.

[0047] The aromatic heterocyclic group may be monocyclic or may be fused polycyclic. The fused polycyclic group is, for example, a fused bicyclic or fused tricyclic group, preferably a fused bicyclic group.

[0048] The number of members in the aromatic heterocyclic group is, for example, 5 to 10, preferably 5 to 9, more preferably 5 or 6.

[0049] Examples of the aromatic heterocyclic group include 5membered aromatic heterocyclic groups such as pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl; 6membered aromatic heterocyclic groups such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl; 9membered aromatic heterocyclic groups such as indazolyl, indolizinyl, imidazopyridyl, and 1,3-benzodioxolyl; and 10membered aromatic heterocyclic groups such as quinolyl, isoquinolyl, quinazolinyl, naphthyridinyl, benzopyranyl, and dihydrobenzopyranyl. Oxazolyl or pyridyl is preferred.

[0050] Aryl The aryl (also referred to as an aryl group) means a monovalent aromatic hydrocarbon group obtained by removing one hydrogen atom from an aromatic carbocyclic ring. The number of carbon atoms in the aryl is not particularly limited and is, for example, 6 to 18, preferably, 6 to 10.

[0051] The aryl may be monocyclic or may be fused polycyclic. The fused polycyclic group is, for example, a fused bicyclic or fused tricyclic group, preferably a fused bicyclic group.

[0052] Examples of the aryl include phenyl, 1-naphthyl, and 2-naphthyl. Phenyl is preferred.

[0053] Antibody The antibody (immunoglobulin) is a glycoprotein made up of two heavy chains (hereinafter, also referred to as "H chains") and two light chains (hereinafter, also referred to as "L chains"). The antibody has five classes IgG, IgM, IgA, IgD, and IgE. The basic structure of the antibody is common among the classes, and two heavy chains and two light chains are joined through disulfide bonds and noncovalent bonds to form a Y-shaped four-chain structure.

[0054] Domains positioned at the N termini of both the heavy chain and the light chain are called variable regions, which are involved in the binding specificity of the antibody for an antigen. The amino acid sequences of C-terminal domains downstream of the variable regions are called constant regions (hereinafter, also referred to as "C regions"). The heavy chain has a heavy chain variable region (VH) and a heavy chain constant region (CH) from the N terminus toward the C terminus. CH is further divided into three domains, a CH1 domain, a CH2 domain, and a CH3 domain, in order from the N terminus. The light chain has a light chain variable region (VL) and a light chain constant region (CL) from the N terminus toward the C terminus.

[0055] VH and VL each have three complementarity determining regions (CDRs), i.e., CDR1, CDR2, and CDR3. Since CDRs determine specificity for an antigen, these regions largely differ in amino acid sequence among antibodies and are also called hypervariable domains. Moieties other than CDRs in the variable region are called framework regions (FRs) and relatively low vary in amino acid sequence. CDR1, CDR2, and CDR3 residing in VH are also called CDRH1, CDRH2, and CDRH3, respectively, and CDR1, CDR2, and CDR3 residing in VL are also called CDRL1, CDRL2, and CDRL3, respectively.

[0056] In the present specification, amino acid positions assigned to CDRs and FRs are defined according to the Kabat numbering (see Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md., (1987) and (1991)).

[0057] In the present specification, amino acid positions in the constant regions are defined according to the EU numbering of Kabat (see Sequences of proteins of immunological interest, NIH Publication No. 91-3242).

[0058] The antibody may be a polyclonal antibody or may be a monoclonal antibody and is preferably a monoclonal antibody.

[0059] Examples of the monoclonal antibody include antibodies produced by hybridomas, and gene recombinant antibodies produced by transformants obtained by transformation with expression vectors containing antibody genes.

[0060] The monoclonal antibody is an antibody secreted by a single clone of an antibody-producing cell and recognizes only one epitope (also called antigenic determinant). The amino acid sequence (primary structure) constituting the monoclonal antibody is homogeneous.

[0061] The hybridoma can be prepared, for example, by inducing an antibody-producing cell having antigen specificity using an animal immunized with an antigen, and fusing the antibody-producing cell with a myeloma cell. The monoclonal antibody can be obtained by culturing the hybridoma or administering the hybridoma cells to an animal to cause ascites cancer in the animal, and separating and purifying the monoclonal antibody from the culture solution or the ascitic fluid. Any animal can be used as the animal to be immunized with the antigen as long as the animal is capable of producing the hybridoma. Preferably, a mouse, a rat, a hamster, a chicken, a rabbit, or the like is used. The monoclonal antibody may be an antibody produced by a hybridoma produced by obtaining a cell having the ability to produce the antibody from the animal, and immunizing the cell in vitro, followed by fusion with a myeloma cell.

[0062] Examples of the gene recombinant antibody include antibodies produced by gene recombination, such as human-type chimeric antibodies, humanized antibodies, and human antibodies.

[0063] The human-type chimeric antibody is an antibody made up of VH and VL of a nonhuman animal antibody and CH and CL of a human antibody. The human-type chimeric antibody can be produced by obtaining DNAs encoding VH and VL of a nonhuman animal antibody, and respectively inserting the DNAs to expression vectors for animal cells having DNAs encoding CH and CL of a human antibody to construct a human-type chimeric antibody expression vector, which is then transferred to animal cells for expression.

[0064] CH of the human-type chimeric antibody may be any CH that belongs to a human immunoglobulin (hereinafter, also referred to as "hIg"). For example, CH of a hIgG class, specifically, CH of a hIgG subclass such as hIgG1, hIgG2, hIgG3, or hIgG4, or a variant thereof can be used. CL of the human-type chimeric antibody may be any CL that belongs to hIg. For example, CL of a human k chain or a human A chain can be used.

[0065] Examples of the humanized antibody include human-type CDR-grafted antibodies and humanized antibodies based on a resurfacing technique. The humanized antibody also includes an antibody produced by a combined method of methods for producing these humanized antibodies. The humanized antibody also includes an antibody that consists of an amino acid sequence derived by the deletion, substitution, insertion, or addition of one or more amino acids from the amino acid sequence of the humanized antibody designed by such a method, and binds (preferably, specifically binds) to the antigen of interest.

[0066] The human-type CDR-grafted antibody is an antibody wherein the amino acid sequences of nonhuman animal antibody VH and VL CDRs were grafted at proper positions of human antibody VH and VL. The human-type CDR-grafted antibody can be produced as follows: DNAs encoding V regions in which the amino acid sequences of VH and VL CDRs of a nonhuman animal monoclonal antibody that binds (preferably, specifically binds) to the antigen of interest are grafted in VH and VL framework regions (FRs) of a freely-selected human antibody, are constructed. Subsequently, the DNAs are respectively inserted to expression vectors for animal cells having DNAs encoding human antibody CH and CL to construct a human-type CDR-grafted antibody expression vector, which is then transferred to animal cells for expression.

[0067] The humanized antibody based on the resurfacing technique is an antibody in which, among the amino acids of nonhuman animal antibody variable regions, an amino acid residue of FR considered to have no influence on the binding activity of the antibody is substituted with an amino acid residue considered to reduce antigenicity by the resurfacing method (Proc. Natl. Acad. Sci. USA 1994,91 (3): 969-73 and Protein Engineering 1996, 10, 895-90). The humanized antibody based on the resurfacing technique can be produced as follows: DNAs encoding V regions in which a freely-selected amino acid residue in FRs of a nonhuman animal monoclonal antibody that binds (preferably, specifically binds) to the antigen of interest is substituted with another amino acid residue, are constructed. Subsequently, the DNAs are respectively inserted to expression vectors for animal cells having DNAs encoding human antibody CH and CL to construct a humanized antibody expression vector based on the resurfacing technique, which is then transferred to animal cells for expression.

[0068] CH of the humanized antibody may be any CH that belongs to a human immunoglobulin (hereinafter, also referred to as "hIg"). For example, CH of a hIgG class, specifically, CH of a hIgG subclass such as hIgG1, hIgG2, hIgG3, or hIgG4, or a variant thereof can be used. CL of the humanized antibody may be any CL that belongs to hIg. For example, CL of a human k chain or a human A chain can be used.

[0069] The human antibody originally means a naturally occurring antibody in the human body. The human antibody also includes, for example, antibodies obtained from a human antibody phage library and a human antibody-producing transgenic animal produced through recent advance in genetic engineering, cellular engineering, and developmental engineering techniques.

[0070] As for the naturally occurring antibody in the human body, for example, lymphocytes producing the antibody can be cultured by isolating human peripheral blood lymphocytes, immortalizing the lymphocytes by infection with EB virus or the like, and cloning the lymphocytes, and the antibody can be purified from the culture supernatant.

[0071] The human antibody phage library is a library allowed to express antibody fragments such as Fab or scFv on phage surface by inserting antibody genes prepared from human B cells or B cells of a human antibody-producing transgenic animal to phage genes. A phage expressing an antibody fragment having the desired antigen binding activity on the surface can be recovered from the library by using binding activity against an antigen-immobilized substrate as an index. The antibody fragment may be further converted to a human antibody molecule made up of two complete H chains and two complete L chains by a genetic engineering approach.

[0072] The human antibody-producing transgenic animal means an animal with a human antibody gene incorporated in cells. Specifically, for example, a human antibody-producing transgenic mouse can be produced by transferring a human antibody gene to mouse ES cells, and transplanting the ES cells to mouse early embryos, followed by development. The human antibody from the human antibody-producing transgenic animal can be produced by using a hybridoma production method that is usually used for nonhuman animals, obtaining human antibody-producing hybridomas, and culturing the hybridomas so that the human antibody is produced and accumulated in the culture supernatant. The human antibody gene can be isolated by isolating B cells of the human antibody-producing transgenic animal, and cloning the B cells.

[0073] Antigen binding fragment of antibody The antigen binding fragment of the antibody is a fragment of an antibody having binding activity against the antigen of interest. The antigen binding fragment of the antibody is also called functional fragment of the antibody. Examples of the antigen binding fragment of the antibody include Fab, F(ab')2, Fab', a single-chain variable fragment (scFv), a dimerized V region (diabody), a disulfide-stabilized variable fragment (dsFv), and peptides containing CDRs.

[0074] Fab is a fragment obtained by the papain treatment of the antibody and is a fragment that has about the half on the N-terminal side of the heavy chain and the whole L chain joined through a disulfide bond with a molecular weight of approximately 50000 and has antigen binding activity. Fab can be obtained by the papain treatment of the antibody. Also, Fab can be produced by inserting DNA encoding Fab of the antibody to an expression vector for a prokaryote or an expression vector for a eukaryote, and transferring the vector to a prokaryote or a eukaryote for expression.

[0075] F(ab')2 is obtained through pepsin which degrades the antibody at a site below the disulfide bonds in the hinge region, and is a fragment that is constituted by two Fab regions joined at the hinge moiety with a molecular weight of approximately 100000 and has antigen binding activity. F(ab')2 can be obtained by the pepsin treatment of the antibody. Also, F(ab')2 can be produced by joining Fab' units through thioether bonds or disulfide bonds.

[0076] Fab' is obtained by the cleavage of the disulfide bonds in the hinge region of F(ab')2, and is a fragment with a molecular weight of approximately 50000 having antigen binding activity. Fab' can be obtained by the treatment of F(ab')2 with a reducing agent such as dithiothreitol. Also, Fab' can be produced by inserting DNA encoding Fab' to an expression vector for a prokaryote or an expression vector for a eukaryote, and transferring the vector to a prokaryote or a eukaryote for expression.

[0077] scFv is a fragment that has one VH and one VL linked through an appropriate peptide linker (hereinafter, also referred to as "P") and has antigen binding activity, and is represented by VH-P-VL or VL-P-VH.

[0078] scFv can be produced by constructing DNA encoding scFv using DNAs encoding VH and VL, inserting the DNA to an expression vector for a prokaryote or an expression vector for a eukaryote, and transferring the expression vector to a prokaryote or a eukaryote for expression.

[0079] Diabody is a dimerized fragment of scFvs and has divalent antigen binding activity. The divalent antigen binding activity may be the same activity or different activities.

[0080] Diabody can be produced by constructing DNA encoding scFvs using DNAs encoding VH and VL so as to have an amino acid sequence length of 8 or less residues of a peptide linker, inserting the DNA to an expression vector for a prokaryote or an expression vector for a eukaryote, and transferring the expression vector to a prokaryote or a eukaryote for expression.

[0081] dsFv is a fragment in which polypeptides of VH and VL, one amino acid residue each of which is substituted with a cysteine residue, are joined via a disulfide bond between the cysteine residues. The amino acid residues to be substituted with a cysteine residue can be selected on the basis of the conformational prediction of the antibody according to a known method [Protein Engineering, 7, 697 (1994)].

[0082] dsFv can be produced by constructing DNA encoding dsFv using cDNAs encoding VH and VL, inserting the DNA to an expression vector for a prokaryote or an expression vector for a eukaryote, and transferring the expression vector to a prokaryote or a eukaryote for expression.

[0083] The peptide containing CDRs is constituted so as to contain at least one or more CDR regions of VH or VL. A plurality of peptides containing CDRs can be joined directly or via an appropriate peptide linker.

[0084] The peptide containing CDRs can be produced by constructing DNAs encoding VH and VL CDRs, inserting the DNAs to an expression vector for a prokaryote or an expression vector for a eukaryote, and transferring the expression vector to a prokaryote or a eukaryote for expression. Also, the peptide containing CDRs may be produced by a chemical synthesis technique such as an Fmoc technique or a Boc technique.

[0085] Bispecific antibody and multispecific antibody The antibody or the antigen binding fragment thereof may have binding specificity for one antigen or may have binding specificity for two or more different antigens. In the present specification, the antibody or the antigen binding fragment thereof having binding specificity for two or more different antigens is referred to as a multispecific antibody. The multispecific antibody is, for example, an antibody or an antigen binding fragment thereof having binding specificity for two different antigens (i.e., a bispecific antibody) and may be an antibody or an antigen binding fragment thereof having binding specificity for three or more different antigens.

[0086] Examples of the format of the multispecific antibody include formats described in WO 2009 / 131239, WO 2014 / 054804, WO 2001 / 077342, WO 2007 / 024715, Wu et al., Nature Biotechnology, 2007, 25 (11), p.1290-1297, Labrijn et al., PNAS 2013, vol.110, no.13, p.5145-5150, Jong et al., PLoS Biology 2016, vol. 14, no.1, e1002344, Kontermann et al., mAbs 2012, vol.4, issue 2, p.182197, Spiess et al., Molecular Immunology 67 (2015) 95-106, Ridgway et al., Protein engineering, 1996 vol. 9 no.7 p.617-621, WO 2009 / 080251, WO 2010 / 151792, and WO 2014 / 033074. The multispecific antibody can be prepared by use of methods described in these documents.

[0087] Deletion, substitution, insertion, or addition of amino acid The deletion, substitution, insertion, or addition of an amino acid as to a predetermined amino acid sequence can be performed by a well-known technique such as site-directed mutagenesis [Molecular Cloning 2nd Edition, Cold Spring Harbor Laboratory Press (1989), Current Protocols inmolecular Biology, John Wiley & Sons (1987-1997), Nucleic Acids Research, 10, 6487 (1982), Proc. Natl. Acad. Sci. USA, 79, 6409 (1982), Gene, 34, 315 (1985), Nucleic Acids Research, 13, 4431 (1985), Proc. Natl. Acad. Sci. USA, 82, 488 (1985)].

[0088] The deletion, substitution, insertion, or addition of an amino acid as to a predetermined amino acid sequence encompasses the case where two or more events selected from deletion, substitution, insertion, and addition occur.

[0089] The amino acid residue to be substituted, inserted, or added may be a natural form or may be a non-natural form. Examples of the natural amino acid include L-alanine, L-asparagine, L-aspartic acid, L-glutamine, L-glutamic acid, glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, L-valine, and L-cysteine.

[0090] Hereinafter, preferred examples of interchangeably substitutable amino acids will be shown. The amino acids included in the same group can be substituted with each other. Group A: leucine, isoleucine, norleucine, valine, norvaline, alanine, 2-aminobutanoic acid, methionine, O-methylserine, t-butylglycine, t-butylalanine, and cyclohexylalanine Group B: aspartic acid, glutamic acid, isoaspartic acid, isoglutamic acid, 2-aminoadipic acid, and 2-aminosuberic acid Group C: asparagine and glutamine Group D: lysine, arginine, ornithine, 2,4-diaminobutanoic acid, and 2,3-diaminopropionic acid Group E: proline, 3-hydroxyproline, and 4-hydroxyproline Group F: serine, threonine, and homoserine Group G: phenylalanine and tyrosine

[0091] Sequence identity The term "%" used for the sequence identity between two amino acid sequences means the percentage of the number of identical amino acids based on the total number of amino acids (including a gap) when two amino acid sequences are aligned so as to maximize the degree of match of amino acids.

[0092] <<First aspect>> A first aspect of the present invention provides a compound represented by the formula (I) given below or a pharmaceutically acceptable salt thereof. In the present specification, the compound represented by the formula (I) given below is also referred to as the "compound (I)". The compound (I) or the pharmaceutically acceptable salt thereof is a divalent BET degrader and can avoid the safety hazard, i.e., peripheral neurotoxicity, while maintaining high antitumor activity. The compound (I) or the pharmaceutically acceptable salt thereof is also useful as a payload (drug) in a targeting molecule-drug conjugate such as an antibody-drug conjugate (ADC).

[0093] [Chem. 33]

[0094] Examples of the pharmaceutically acceptable salt of the compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts. Examples of the pharmaceutically acceptable acid addition salt of the compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate; and organic acid salts such as acetate, oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate. Examples of the pharmaceutically acceptable metal salt of the compound (I) include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; aluminum salt; and zinc salt. Examples of the pharmaceutically acceptable ammonium salt of the compound (I) include salts of ammonium, tetramethylammonium, and the like. Examples of the pharmaceutically acceptable organic amine addition salt of the compound (I) include addition salts of morpholine, piperidine, and the like. Examples of the pharmaceutically acceptable amino acid addition salt of the compound (I) include addition salts of lysine, glycine, phenylalanine, aspartic acid, glutamic acid, and the like.

[0095] The compound (I) or the pharmaceutically acceptable salt thereof may have stereoisomers such as geometrical isomers or optical isomers, tautomers, or the like. The present invention encompasses all possible isomers including these and mixtures thereof.

[0096] A part or all of atoms in the compound (I) or the pharmaceutically acceptable salt thereof may be replaced by corresponding isotope atoms. The present invention also encompasses the compounds substituted with these isotope atoms. For example, a part or all of hydrogen atoms in the compound (I) or the pharmaceutically acceptable salt thereof may be hydrogen atoms having an atomic weight of 2 (deuterium atoms).

[0097] A compound obtained by replacing a part or all of atoms in the compound (I) or the pharmaceutically acceptable salt thereof with the corresponding isotope atoms can be produced by a method similar to each of production methods mentioned later using commercially available building blocks. A compound obtained by replacing a part or all of hydrogen atoms in the compound (I) or the pharmaceutically acceptable salt thereof with deuterium atoms can also be synthesized, for example, by 1) a method of deuterating a carboxylic acid and the like by using deuterium peroxide under a basic condition (see U.S. Patent No. 3849458), 2) a method of deuterating an alcohol, a carboxylic acid, and the like by using an iridium complex as a catalyst and heavy water as a deuterium source [see J. Am. Chem. Soc., Vol. 124, No. 10, 2092 (2002)], 3) a method of deuterating a fatty acid by using palladium-carbon as a catalyst and only deuterium gas as a deuterium source [see LIPIDS, Vol. 9, No. 11, 913 (1974)], 4) a method of deuterating acrylic acid, methyl acrylate, methacrylic acid, methyl methacrylate, and the like by using a metal such as platinum, palladium, rhodium, ruthenium, or iridium as a catalyst and heavy water or heavy water and deuterium gas as a deuterium source (see Japanese Examined Patent Application Publication No. H5-19536, Japanese Unexamined Patent Application Publication No. S61-277648, and Japanese Unexamined Patent Application Publication No. S61-275241), or 5) a method of deuterating acrylic acid, methyl methacrylate, and the like by using a catalyst such as palladium, nickel, copper, or copper chromite, and using heavy water as a deuterium source (see Japanese Unexamined Patent Application Publication No. S63-198638).

[0098] When the compound (I) or the pharmaceutically acceptable salt thereof is desired to be obtained, the compound (I) obtained in the form of a salt can be purified as it is, or the compound (I) obtained in a free form can be dissolved or suspended in an appropriate solvent and isolated and purified after forming a salt by the addition of an acid or a base.

[0099] The compound (I) or the pharmaceutically acceptable salt thereof may be present in the form of an adduct with water or various solvents. These adducts are also encompassed by the present invention. In the formula (I), R1 and R2 are the same or different and each represents a hydrogen atom or lower alkyl. The lower alkyls in R1 and R2 are the same or different and are each preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0101] In the formula (I), R3 represents lower alkyl. The lower alkyl in R3 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably ethyl.

[0102] In the formula (I), R4 represents halogen. The halogen in R4 is, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom or a chlorine atom. The number of R4 is 0 to 2, preferably 0 or 1. When two R4 are present, R4 may be the same as or different from each other.

[0103] In the formula (I), R5 represents halogen. The halogen in R5 is, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a chlorine atom. The number of R5 is 0 to 2, preferably 0 or 1. When two R5 are present, R5 may be the same as or different from each other.

[0104] In the formula (I), R6 represents halogen or lower alkoxy. The halogen in R6 is, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom. The lower alkoxy in R6 is preferably alkoxy having 1 to 5 carbon atoms, more preferably alkoxy having 1 to 3 carbon atoms, further preferably methoxy or ethoxy, further preferably methoxy. The number of R6 is 0 to 2, preferably 0 or 1. When two R6 are present, R6 may be the same as or different from each other.

[0105] In the formula (I), Y represents, for example, -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2- and is preferably -O-CH2-CH2-.

[0106] The compound of the present invention having one or more asymmetric carbon atoms may be present as two or more stereoisomers. Use of a solid line that represents a bond to the asymmetric carbon atom is meant to represent that all possible stereoisomers (e.g., diastereomer mixtures, racemic mixtures, and specific enantiomers) for the carbon atom are included.

[0107] In a preferred embodiment, R1 is a hydrogen atom, R2 is lower alkyl, R3 is lower alkyl, R4 is absent (i.e., 0) or halogen, R5 is absent (i.e., 0) or halogen, R6 is absent (i.e., 0), halogen, or lower alkoxy, and Y is -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-.

[0108] In a more preferred embodiment, R1 is a hydrogen atom, R2 is lower alkyl having 1 to 5 carbon atoms, R3 is lower alkyl having 1 to 5 carbon atoms, R4 is absent or a fluorine atom, R5 is absent or a chlorine atom, R6 is absent, a fluorine atom, or lower alkoxy having 1 to 5 carbon atoms, and Y is -O-CH2-CH2-. In a further preferred embodiment, R1 is a hydrogen atom, R2 is lower alkyl having 1 to 3 carbon atoms, R3 is lower alkyl having 1 to 3 carbon atoms, R4 is absent or a fluorine atom, R5 is absent or a chlorine atom, R6 is absent, a fluorine atom, or lower alkoxy having 1 to 3 carbon atoms, and Y is -O-CH2-CH2-.

[0110] In a further preferred embodiment, R1 is a hydrogen atom, R2 is methyl, R3 is ethyl, R4 is absent, R5 is absent, R6 is absent, and Y is -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-. In a further preferred alternative embodiment, R1 is a hydrogen atom, R2 is methyl, R3 is ethyl, R4 is a fluorine atom, R5 is absent, R6 is absent, and Y is -O-CH2-CH2-. In a further preferred alternative embodiment, R1 is a hydrogen atom, R2 is methyl, R3 is ethyl, R4 is absent, R5 is a chlorine atom, R6 is absent, and Y is -O-CH2-CH2-. In a further preferred alternative embodiment, R1 is a hydrogen atom, R2 is methyl, R3 is ethyl, R4 is absent, R5 is absent, R6 is a fluorine atom, and Y is -O-CH2-CH2- or -CH2-CH2-CH2-. In a further preferred alternative embodiment, R1 is a hydrogen atom, R2 is methyl, R3 is ethyl, R4 is absent, R5 is absent, R6 is methoxy, and Y is -O-CH2-CH2-.

[0111] In the formula (I), ring A represents (i) an aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, (ii) an aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, or (iii) aryl optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl.

[0112] The lower alkyl serving as a substituent for (i) the aliphatic heterocyclic group, (ii) the aromatic heterocyclic group, and (iii) the aryl is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0113] The lower alkyl in the hydroxy-lower alkyl, the lower alkylcarbonyl, the hydroxy-lower alkylcarbonyl, and the lower alkylcarbamoyl serving as a substituent for (i) the aliphatic heterocyclic group, (ii) the aromatic heterocyclic group, and (iii) the aryl is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0114] The position or the number of hydroxy in the hydroxy-lower alkyl and the hydroxy-lower alkylcarbonyl serving as a substituent for (i) the aliphatic heterocyclic group, (ii) the aromatic heterocyclic group, and (iii) the aryl is not particularly limited. The number of hydroxy is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, further preferably 1.

[0115] The cycloalkyl in the cycloalkylcarbonyl serving as a substituent for (i) the aliphatic heterocyclic group, (ii) the aromatic heterocyclic group, and (iii) the aryl is preferably cycloalkyl having 3 to 10 carbon atoms, more preferably cycloalkyl having 3 to 8 carbon atoms, further preferably cycloalkyl having 3 to 6 carbon atoms, further preferably cyclopropyl.

[0116] The lower alkoxy in the lower alkoxycarbonyl serving as a substituent for (i) the aliphatic heterocyclic group, (ii) the aromatic heterocyclic group, and (iii) the aryl is preferably alkoxy having 1 to 5 carbon atoms, more preferably alkoxy having 1 to 3 carbon atoms, further preferably methoxy or ethoxy, further preferably methoxy.

[0117] When ring A is (i) the aliphatic heterocyclic group, the 1 to 3 substituents in (i) the aliphatic heterocyclic group are each independently selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl. The 1 to 3 substituents in the aliphatic heterocyclic group are preferably selected from the group consisting of oxo, lower alkyl, and lower alkylcarbonyl.

[0118] In a preferred embodiment, (i) the aliphatic heterocyclic group in ring A is a nitrogen-containing aliphatic heterocyclic group.

[0119] In a more preferred embodiment, ring A represented by (i) the nitrogen-containing aliphatic heterocyclic group is the following ring A': [Chem. 34]

[0120] When ring A' has a substituent, the substituent of ring A' is as defined for the substituent of ring A which is (i) the aliphatic heterocyclic group. Specifically, ring A' may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, as in ring A which is (i) the aliphatic heterocyclic group. In this context, the dot (•) in the formula represents a bonding site to a linker.

[0121] In the nitrogen-containing aliphatic heterocyclic group (preferably ring A'), a nitrogen atom (except for a nitrogen atom having the bonding hand of the nitrogen-containing aliphatic heterocyclic group) may have a substituent, or a carbon atom may have a substituent. One carbon atom may have two substituents.

[0122] The nitrogen-containing aliphatic heterocyclic group (preferably ring A') is preferably an aliphatic heterocyclic group containing two nitrogen atoms, more preferably a monocyclic or bicyclic aliphatic heterocyclic group containing two nitrogen atoms, further preferably piperazinyl, 1,4-diazepanyl, or hexahydropyrrolopyrazinyl. The nitrogen-containing aliphatic heterocyclic group may be constituted only by saturated bonds or may contain a double bond and is preferably constituted only by saturated bonds. Two carbon atoms constituting a ring in the nitrogen-containing aliphatic heterocyclic group may be bridged by an alkylene group. The number of carbon atoms in the alkylene group that bridges two carbon atoms constituting a ring is, for example, 1 to 3, preferably 1 or 2, further preferably 1.

[0123] When the nitrogen-containing aliphatic heterocyclic group (preferably ring A') is a monocyclic aliphatic heterocyclic group containing two nitrogen atoms, one of the nitrogen atoms constitutes the bonding hand of the nitrogen-containing aliphatic heterocyclic group, and the other nitrogen atom preferably has a substituent selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, and cycloalkylcarbonyl. The substituent of the other nitrogen atom is more preferably selected from the group consisting of lower alkyl, lower alkylcarbonyl, and cycloalkylcarbonyl, and further preferably selected from the group consisting of lower alkyl and lower alkylcarbonyl. The monocyclic aliphatic heterocyclic group containing two nitrogen atoms may have 1 or 2 substituents other than the substituent of the other nitrogen atom. The 1 or 2 substituents other than the substituent of the other nitrogen atom are each independently preferably selected from the group consisting of oxo, lower alkyl, and hydroxy-lower alkyl, and more preferably selected from the group consisting of oxo and lower alkyl.

[0124] When the nitrogen-containing aliphatic heterocyclic group (preferably ring A') is a bicyclic aliphatic heterocyclic group containing two nitrogen atoms, one of the nitrogen atoms constitutes the bonding hand of the nitrogen-containing aliphatic heterocyclic group, and the other nitrogen atom is preferably shared by two rings (i.e., has no substituent). The bicyclic aliphatic heterocyclic group containing two nitrogen atoms preferably has oxo as a substituent. The bicyclic aliphatic heterocyclic group containing two nitrogen atoms may have 1 or 2 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, and cycloalkylcarbonyl, in addition to oxo.

[0125] In a preferred embodiment, when ring A is (i) the aliphatic heterocyclic group, the compound represented by the formula (I) is a compound represented by the following formula (I'): [Chem. 35] (wherein, R1, R2, and R3 are as defined in the formula (I), and ring A' is the nitrogen-containing aliphatic heterocyclic group described above).

[0126] In a preferred embodiment of the compound of the formula (I'), R1 is a hydrogen atom, R2 is lower alkyl, and R3 is lower alkyl.

[0127] In a more preferred embodiment of the compound of the formula (I'), R1 is a hydrogen atom, R2 is lower alkyl having 1 to 5 carbon atoms, and R3 is lower alkyl having 1 to 5 carbon atoms.

[0128] In a further preferred embodiment of the compound of the formula (I'), R1 is a hydrogen atom, R2 is lower alkyl having 1 to 3 carbon atoms, R3 is lower alkyl having 1 to 3 carbon atoms.

[0129] In a further preferred embodiment of the compound of the formula (I'), R1 is a hydrogen atom, R2 is methyl, and R3 is ethyl.

[0130] When ring A is (ii) the aromatic heterocyclic group, the 1 to 3 substituents in the aromatic heterocyclic group are each independently selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl. Each of the 1 to 3 substituents in the aromatic heterocyclic group is preferably lower alkyl.

[0131] In a preferred embodiment, (ii) the aromatic heterocyclic group in ring A is preferably a 5-membered aromatic heterocyclic group or a 6-membered aromatic heterocyclic group, more preferably a 5-membered aromatic heterocyclic group or a 6membered aromatic heterocyclic group containing a nitrogen atom and / or an oxygen atom, further preferably oxazolyl or pyridyl.

[0132] When ring A is (iii) the aryl, the 1 to 3 substituents in the aryl are each independently selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl. The 1 to 3 substituents in the aryl are preferably selected from the group consisting of lower alkoxycarbonyl and lower alkylcarbamoyl.

[0133] In a preferred embodiment, (iii) the aryl in ring A is preferably phenyl.

[0134] In a preferred embodiment, ring A (including the case where ring A is ring A') is a nitrogen-containing aliphatic heterocyclic group represented by the following formula (AA), (AB), (AC), or (AD), an aromatic heterocyclic group represented by the following formula (AE) or (AF), or aryl represented by the following formula (AG):

[0135] [Chem. 36] (AE)              (AF)              ( AG )

[0136] In the formulas (AA), (AB), (AC), (AD), (AE), (AF), and (AG), RA1, RB1, RD1, RE1, RF1, and RG1 are the same or different and each represents lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, or lower alkylcarbamoyl, and RA2, RA3, RB2, RB3, RC1, and RC2 are the same or different and each represents a hydrogen atom, oxo, lower alkyl, or hydroxy-lower alkyl.

[0137] The lower alkyl in RA1, RB1, RD1, RE1, RF1, and RG1 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0138] The lower alkyl in the hydroxy-lower alkyl, the lower alkylcarbonyl, the hydroxy-lower alkylcarbonyl, and the lower alkylcarbamoyl in RA1, RB1, RD1, RE1, RF1, and RG1 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl. In this context, when the hydroxy-lower alkyl, the lower alkylcarbonyl, the hydroxy-lower alkylcarbonyl, or the lower alkylcarbamoyl has two or more lower alkyl, the lower alkyl may be the same as or different from each other.

[0139] The position or the number of hydroxy in the hydroxy-lower alkyl and the hydroxy-lower alkylcarbonyl in RA1, RB1, RD1, RE1, RF1, and RG1 is not particularly limited. The number of hydroxy is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, further preferably 1.

[0140] The lower alkoxy in the lower alkoxycarbonyl in RA1, RB1, RD1, RE1, RF1, and RG1 is preferably alkoxy having 1 to 5 carbon atoms, more preferably alkoxy having 1 to 3 carbon atoms, further preferably methoxy or ethoxy, further preferably methoxy.

[0141] The cycloalkyl in the cycloalkylcarbonyl in RA1, RB1, RD1, RE1, RF1, and RG1 is preferably cycloalkyl having 3 to 10 carbon atoms, more preferably cycloalkyl having 3 to 8 carbon atoms, further preferably cycloalkyl having 3 to 6 carbon atoms, further preferably cyclopropyl.

[0142] The lower alkyl in RA2, RA3, RB2, RB3, RC1, and RC2 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0143] The lower alkyl in the hydroxy-lower alkyl in RA2, RA3, RB2, RB3, RC1, and RC2 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0144] The position or the number of hydroxy in the hydroxy-lower alkyl in RA2, RA3, RB2, RB3, RC1, and RC2 is not particularly limited. The number of hydroxy is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, further preferably 1.

[0145] In a preferred embodiment, ring A or ring A' is a nitrogencontaining aliphatic heterocyclic group represented by the formula (AA), and in the formula (AA), RA1 represents lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, or cycloalkylcarbonyl, and RA2 and RA3 are the same or different and each represents a hydrogen atom, oxo, lower alkyl, or hydroxy-lower alkyl.

[0146] The lower alkyl in RA1 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0147] The lower alkyl in the lower alkylcarbonyl and the hydroxylower alkylcarbonyl in RA1 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0148] The position or the number of hydroxy in the hydroxy-lower alkylcarbonyl in RA1 is not particularly limited. The number of hydroxy is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, further preferably 1.

[0149] The cycloalkyl in the cycloalkylcarbonyl in RA1 is preferably cycloalkyl having 3 to 10 carbon atoms, more preferably cycloalkyl having 3 to 8 carbon atoms, further preferably cycloalkyl having 3 to 6 carbon atoms, further preferably cyclopropyl.

[0150] The lower alkyl in RA2 and RA3 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0151] The lower alkyl in the hydroxy-lower alkyl in RA2 and RA3 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0152] The position or the number of hydroxy in the hydroxy-lower alkyl in RA2 and RA3 is not particularly limited. The number of hydroxy is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, further preferably 1.

[0153] When ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the formula (AA), RA1 is preferably lower alkyl or lower alkylcarbonyl.

[0154] When ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the formula (AA), RA2 and RA3 are the same or different and are each preferably a hydrogen atom, oxo, or lower alkyl.

[0155] When ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the formula (AA), more preferably, RA1 is lower alkyl or lower alkylcarbonyl, and RA2 and RA3 are the same or different and are each a hydrogen atom, oxo or lower alkyl.

[0156] When ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the formula (AA), further preferably, RA1 is lower alkyl, and RA2 and RA3 are the same or different and are each oxo or lower alkyl.

[0157] In a preferred embodiment, ring A or ring A' is a nitrogencontaining aliphatic heterocyclic group represented by the formula (AB), and in the formula (AB), RB1 represents lower alkyl or lower alkylcarbonyl, and RB2 and RB3 are the same or different and each represents a hydrogen atom or oxo.

[0158] The lower alkyl in RB1 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0159] The lower alkyl in the lower alkylcarbonyl in RB1 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0160] When ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the formula (AB), RB1 is preferably lower alkyl.

[0161] In a preferred embodiment, ring A or ring A' is a nitrogencontaining aliphatic heterocyclic group represented by the formula (AC), and in the formula (AC), RC1 and RC2 are the same or different and each represents a hydrogen atom or oxo.

[0162] In a preferred embodiment, ring A or ring A' is a nitrogencontaining aliphatic heterocyclic group represented by the formula (AD), and in the formula (AD), RD1 represents lower alkylcarbonyl.

[0163] The lower alkyl in the lower alkylcarbonyl in RD1 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0164] In a preferred embodiment, ring A is an aromatic heterocyclic group represented by the formula (AE), and in the formula (AE), RE1 represents lower alkyl.

[0165] The lower alkyl in RE1 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0166] The number of RE1 is, for example, 0 to 2, preferably 1 or 2, more preferably 2.

[0167] In a preferred embodiment, ring A is an aromatic heterocyclic group represented by the formula (AF), and in the formula (AF), RF1 represents lower alkyl.

[0168] The lower alkyl in RF1 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl.

[0169] The number of RF1 is, for example, 0 to 2, preferably 1 or 2, more preferably 1.

[0170] In a preferred embodiment, ring A is aryl represented by the formula (AG), and in the formula (AG), RG1 represents lower alkoxycarbonyl or lower alkylcarbamoyl.

[0171] The lower alkoxy in the lower alkoxycarbonyl in RG1 is preferably alkoxy having 1 to 5 carbon atoms, more preferably alkoxy having 1 to 3 carbon atoms, further preferably methoxy or ethoxy, further preferably methoxy.

[0172] The lower alkyl in the lower alkylcarbamoyl in RG1 is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably methyl or ethyl, further preferably methyl. In this context, when the lower alkylcarbamoyl has two or more lower alkyl, the lower alkyl may be the same as or different from each other. Thus, the lower alkylcarbamoyl in RG1 is preferably N-methylcarbamoyl or N,N-dimethylcarbamoyl.

[0173] The number of RG1 is, for example, 0 to 2, preferably 1 or 2, more preferably 1.

[0174] In a preferred embodiment, ring A is (i) the nitrogencontaining aliphatic heterocyclic group, (ii) the aromatic heterocyclic group, or (iii) the aryl, more preferably the formula (AA), the formula (AB), the formula (AC), the formula (AD), the formula (AE), the formula (AF), or the formula (AG), wherein R1 is a hydrogen atom, R2 is methyl, R3 is ethyl, R4 is absent, R5 is absent, R6 is absent, and Y is -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-. In a preferred embodiment, ring A is (i) the nitrogen-containing aliphatic heterocyclic group, more preferably the formula (AA), wherein R1 is a hydrogen atom, R2 is methyl, R3 is ethyl, R4 is a fluorine atom, R5 is absent, R6 is absent, and Y is -O-CH2-CH2-. In a preferred alternative embodiment, ring A is (i)the nitrogen-containing aliphatic heterocyclic group, more preferably the formula (AA), wherein R1 is a hydrogen atom, R2 is methyl, R3 is ethyl, R4 is absent, R5 is a chlorine atom, R6 is absent, and Y is -O-CH2-CH2-. In a preferred alternative embodiment, ring A is (i) the nitrogen-containing aliphatic heterocyclic group, more preferably the formula (AA), (AB), or (AC), wherein R1 is a hydrogen atom, R2 is methyl, R3 is ethyl, R4 is absent, R5 is absent, R6 is a fluorine atom, and Y is -O-CH2-CH2- or -CH2-CH2-CH2-. In a preferred alternative embodiment, ring A is (i) the nitrogen-containing aliphatic heterocyclic group, more preferably the formula (AA), wherein R1 is a hydrogen atom, R2 is methyl, R3 is ethyl, R4 is absent, R5 is absent, R6 is methoxy, and Y is -O-CH2-CH2-.

[0175] In a preferred embodiment, the compound (I) or the pharmaceutically acceptable salt thereof is a compound represented by the following formula or a pharmaceutically acceptable salt thereof: 5 [Chem. 37]

[0176] In a preferred embodiment, the compound (I) or the pharmaceutically acceptable salt thereof is a compound 10 represented by the following formula or a pharmaceutically acceptable salt thereof: [Chem. 38] Compound 2

[0177] 15        In a preferred embodiment, the compound (I) or the pharmaceutically acceptable salt thereof is a compound represented by the following formula or a pharmaceutically acceptable salt thereof: [Chem. 39]

[0178] In a preferred embodiment, the compound (I) or the 5 pharmaceutically acceptable salt thereof is a compound represented by the following formula or a pharmaceutically acceptable salt thereof: [Chem. 40] Compound 19 10

[0179] In a preferred embodiment, the compound (I) or the pharmaceutically acceptable salt thereof is a compound represented by the following formula or a pharmaceutically acceptable salt thereof: 15 [Chem. 41]

[0180] <<Second aspect>> A second aspect of the present invention provides a targeting molecule-drug conjugate containing a targeting molecule and a drug, wherein the drug is the compound (I) or the pharmaceutically acceptable salt thereof. The targeting molecule-drug conjugate according to the second aspect can avoid the safety hazard, i.e., peripheral neurotoxicity, while maintaining high antitumor activity. The drug (divalent BET degrader) is conjugated with a targeting molecule so that the drug can be efficiently delivered to target cells. Thus, the drug (divalent BET degrader) conjugated with the targeting molecule can exhibit an antitumor effect in vivo in a smaller amount of the drug (in terms of the divalent BET degrader) as compared with the drug alone.

[0181] The targeting molecule is, for example, a molecule capable of binding to a molecule, such as a protein or a peptide, present on the surface of target cells. The targeting molecule can bind to a molecule, such as a protein or a peptide, present on the surface of target cells and thereby deliver the drug to the target cells. The targeting molecule is preferably capable of specific binding to a molecule, such as a protein or a peptide, present on the surface of target cells. The term "specific" means that the targeting molecule exhibits no significant binding activity against other substances.

[0182] The target cells are preferably cancer cells. Examples of the molecule, such as a protein or a peptide, present on the surface of cancer cells include receptors, cancer antigens, MHC antigens, and differentiation antigens. The protein or the peptide may be bound with an MHC class I molecule or an MHC class II molecule and presented on the surface of cancer cells.

[0183] The cancer is preferably blood cancer, more preferably lymphoma, further preferably B cell lymphoma. Thus, the molecule, such as a protein or a peptide, present on the surface of cancer cells is a molecule, such as a protein or a peptide, expressed on lymphocytes (preferably B cells) of an organism affected by preferably blood cancer, more preferably lymphoma, further preferably B cell lymphoma.

[0184] Examples of the molecule, such as a protein or a peptide, present on the surface of cancer cells include folate receptor a (FoLRa), somatostatin receptor (SSTR2), fibroblast activation protein (FAP), erythropoietin-producing hepatocellular receptor A2 (EphA2), CD79b, CD19, CD22, HER2, Nectin4, TROP2, DLL3, PSMA, B7H3, B7H4, CD30, CD33, CD25, CD38, CD74, GM2, CADM1, CLL1, BCMA, HER3, and CDH6. Among them, somatostatin receptor, fibroblast activation protein, erythropoietin-producing hepatocellular receptor A2, CD79b, CD19, CD22, HER2, Nectin4, TROP2, DLL3, CD30, CD33, CD25, CD38, CD74, GM2, CADM1, BCMA, and CLL1 are preferred, CD79b, CD19, CD22, CD30, CD33, CD25, CD38, BCMA, and CD74 are more preferred, and CD79b, CD19, CD22, CD30, and BCMA are further preferred.

[0185] The targeting molecule is, for example, an antibody or an antigen binding fragment thereof, a small-molecule compound, or a peptide.

[0186] Examples of the small-molecule compound include folate, oncoFAP, AAZ+, and 2-[3-(1,3-dicarboxypropyl)ureido]-pentanedioic acid (DUPA).

[0187] Folate can bind to folate receptor. Thus, the targeting molecule-drug conjugate containing folate as the targeting molecule can target cells having the folate receptor on the surface (C.P. Leamon et al., Cancer Res. 2008, 68, 9839-9844).

[0188] A synthetic small-molecule compound called oncoFAP can bind to fibroblast activation protein. Thus, the targeting moleculedrug conjugate containing octreotide as the targeting molecule can target cells having the fibroblast activation protein on the surface (J. Millu et al., Proc Natl Acad Sci USA. 2021, 118, e2101852118).

[0189] A synthetic small-molecule compound called AAZ+ can bind to carbonic anhydrase 9. Thus, the targeting molecule-drug conjugate containing AAZ+ as the targeting molecule can target cells having the carbonic anhydrase 9 on the surface (S. Cazzamalli et al., J Am Chem Soc, 2018, 140, 1617-1621.

[0190] DUPA can bind to prostate-specific membrane antigen. Thus, the targeting molecule-drug conjugate containing DUPA as the targeting molecule can target cells having the prostate-specific membrane antigen on the surface (J. Roy et al., J. Med. Chem. 2015, 58, 3094-3103).

[0191] Examples of the peptide include BCY6099, octreotide, RGD peptide, exendin-4, bombesin-like peptide, and BCY8234.

[0192] A bicyclic peptide called BCY6099 can bind to erythropoietinproducing hepatocellular receptor A2. Thus, the targeting molecule-drug conjugate containing BCY6099 as the targeting molecule can target cells having the erythropoietin-producing hepatocellular receptor A2 on the surface (G. Bennett et al., Mol Cancer Ther 2020, 19, 1385-1394).

[0193] Octreotide can bind to somatostatin receptor, particularly, somatostatin receptor subtype 2. Thus, the targeting moleculedrug conjugate containing octreotide as the targeting molecule can target cells having the somatostatin receptor subtype 2 on the surface (B.H. White et al., J. Med. Chem. 2019, 62, 2708-2719).

[0194] RGD peptide can bind to integrin receptor, particularly, av^3 integrin receptor. Thus, the targeting molecule-drug conjugate containing RGD peptide as the targeting molecule can target cells having the av^3 integrin receptor on the surface (M. Lelle et al., J. Med. Chem. 2005, 48, 1098-1106).

[0195] Exendin-4 can bind to glucagon-like peptide-1 receptor. Thus, the targeting molecule-drug conjugate containing exendin-4 as the targeting molecule can target cells having the glucagon-like peptide-1 receptor on the surface (S. Son et al., The International Journal of Biochemistry & Cell Biology. 105, 13-19).

[0196] Bombesin-like peptide can bind to bombesin-like peptide receptor. Thus, the targeting molecule-drug conjugate containing bombesin-like peptide as the targeting molecule can target cells having the bombesin-like peptide receptor on the surface (A. Safavy et al., Bioconjugate Chem. 2006, 17, 565-570).

[0197] BCY8234 can bind to nectin-4. Thus, the targeting moleculedrug conjugate containing BCY8234 as the targeting molecule can target cells having the nectin-4 on the surface (M. Rigby et al., Mol Cancer Ther MCT-21-0875).

[0198] In a preferred embodiment, the targeting molecule is an antibody or an antigen binding fragment thereof.

[0199] In a more preferred embodiment, the targeting molecule is an antibody.

[0200] In a further preferred embodiment, the antibody is an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody.

[0201] Hereinafter, an embodiment in which the antibody is an anti-CD79b antibody will be described.

[0202] The anti-CD79b antibody is an antibody that binds to CD79b. The anti-CD79b antibody is preferably an antibody that specifically binds to CD79b. The anti-CD79b antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CD79b antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0203] In one embodiment, the anti-CD79b antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of polatuzumab.

[0204] In one embodiment, the anti-CD79b antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 11, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 12, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 13, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 14, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 15, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 16. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0205] In an alternative embodiment, the amino acid sequence of VH of the anti-CD79b antibody contains the amino acid sequence set forth in SEQ ID NO: 5, and the amino acid sequence of VL of the anti-CD79b antibody contains the amino acid sequence set forth in SEQ ID NO: 6. The amino acid sequence of VH of the anti-CD79b antibody may consist of the amino acid sequence set forth in SEQ ID NO: 5, and the amino acid sequence of VL of the anti-CD79b antibody may consist of the amino acid sequence set forth in SEQ ID NO: 6.

[0206] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 5 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 11 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 12 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 13 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 6 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 14 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 15 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 16 (underlined in the table below).

[0207] [Table 1] SEQ ID NO: 5 EVQLVESGGGLVQPGGSLRLSCAASGYTFSSYWIEWVRQAPGKGLEWIGEILPGGGDTNYNEIFK GRATFSADTSKNTAYLQMNSLRAEDTAVYYCTRRVPIRLDYWGQGTLVTVSS SEQ ID NO: 6 D1QLTQSPSSLSASVGDRVTITCKASQSVDYEGDSFLNWYQQKPGKAPKLLIYAASNLESGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQSNEDPLTFGQGTKVEIK

[0208] In a further alternative embodiment, the amino acid sequence of VH of the anti-CD79b antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 5, and the amino acid sequence of VL of the anti-CD79b antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 6. The amino acid sequence of VH of the anti-CD79b antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 5, and the amino acid sequence of VL of the anti-CD79b antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 6. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 5 may be the amino acid sequence set forth in SEQ ID NO: 5, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 6 may be the amino acid sequence set forth in SEQ ID NO: 6.

[0209] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 5 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 11, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 12, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 13.

[0210] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 6 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 14, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 15, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 16.

[0211] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 5 has the activity of VH of the anti-CD79b antibody, i.e., binding activity against CD79b. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 5 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 5 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0212] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 6 has the activity of VL of the anti-CD79b antibody, i.e., binding activity against CD79b. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 6 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 6 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0213] Hereinafter, an embodiment in which the antibody is an anti-CD19 antibody will be described.

[0214] The anti-CD19 antibody is an antibody that binds to CD19. The anti-CD19 antibody is preferably an antibody that specifically binds to CD19. The anti-CD19 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CD19 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0215] In one embodiment, the anti-CD19 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of loncastuximab.

[0216] In one embodiment, the anti-CD19 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 17, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 18, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 19, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 20, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 21, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 22. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0217] In an alternative embodiment, the amino acid sequence of VH of the anti-CD19 antibody contains the amino acid sequence set forth in SEQ ID NO: 7, and the amino acid sequence of VL of the anti-CD19 antibody contains the amino acid sequence set forth in SEQ ID NO: 8. The amino acid sequence of VH of the anti-CD19 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 7, and the amino acid sequence of VL of the anti-CD19 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 8.

[0218] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 7 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 17 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 18 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 19 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 8 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 20 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 21 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 22 (underlined in the table below).

[0219] [Table 2] SEQ ID NO: 7 QVQLVQPGAEWKPGASVKLSCKTSGYTFTSNWMHWVKQAPGQGLEWIGEIDPSDSYTNYNQN FQGKAKLTVDKSTSTAYMEVSSLRSDDTAVYYCARGSNPYYYAMDYWGQGTSVTVSS SEQ ID NO: 8 EIVLTQSPAIMSASPGERVTMTGSASSGVNYMHWYQQKPGTSPRRWIYDTSKLASGVPARFSGS GSGTSYSLTISSMEPEDAATYYCHQRGSYTFGGGTKLEIK

[0220] In a further alternative embodiment, the amino acid sequence of VH of the anti-CD19 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 7, and the amino acid sequence of VL of the anti-CD19 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 8. The amino acid sequence of VH of the anti-CD19 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 7, and the amino acid sequence of VL of the anti-CD19 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 8. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 7 may be the amino acid sequence set forth in SEQ ID NO: 7, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 8 may be the amino acid sequence set forth in SEQ ID NO: 8.

[0221] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 7 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 17, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 18, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 19.

[0222] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 8 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 20, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 21, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 22.

[0223] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 7 has the activity of VH of the anti-CD19 antibody, i.e., binding activity against CD19. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 7 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 7 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0224] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 8 has the activity of VL of the anti-CD19 antibody, i.e., binding activity against CD19. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 8 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 8 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0225] Hereinafter, an embodiment in which the antibody is an anti-CD22 antibody will be described.

[0226] The anti-CD22 antibody is an antibody that binds to CD22. The anti-CD22 antibody is preferably an antibody that specifically binds to CD22. The anti-CD22 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CD22 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0227] In one embodiment, the anti-CD22 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of inotuzumab.

[0228] In one embodiment, the anti-CD22 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 23, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 24, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 25, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 26, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 27, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 28. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0229] In an alternative embodiment, the amino acid sequence of VH of the anti-CD22 antibody contains the amino acid sequence set forth in SEQ ID NO: 9, and the amino acid sequence of VL of the anti-CD22 antibody contains the amino acid sequence set forth in SEQ ID NO: 10. The amino acid sequence of VH of the anti-CD22 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 9, and the amino acid sequence of VL of the anti-CD22 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 10.

[0230] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 9 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 23 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 24 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 25 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 10 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 26 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 27 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 28 (underlined in the table below).

[0231] [Table 3] SEQ ID NO: 9 EVQLVQSGAEVKKPGASVKVSCKASGYRFTNYWIHWVRQAPGQGLEWIGGINPGNNYATYRRKF QGRVTMTADTSTSTVYMELSSLRSEDTAVYYCTREGYGNYGAWFAYWGQGTLVTVSS SEQ ID NO: 10 DVQVTQSPSSLSASVGDRVTITCRSSQSLANSYGNTFLSWYLHKPGKAPQLLIYG1SNRFSGVPD RFSGSGSGTDFTLTISSLQPEDFATYYCLQGTHQPYTFGQGTKVEIK

[0232] In a further alternative embodiment, the amino acid sequence of VH of the anti-CD22 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 9, and the amino acid sequence of VL of the anti-CD22 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 10. The amino acid sequence of VH of the anti-CD22 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 9, and the amino acid sequence of VL of the anti-CD22 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 10. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 9 may be the amino acid sequence set forth in SEQ ID NO: 9, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 10 may be the amino acid sequence set forth in SEQ ID NO: 10.

[0233] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 9 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 23, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 24, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 25.

[0234] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 10 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 26, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 27, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 28.

[0235] the activity of VH of the anti-CD22 antibody, i.e., binding activity against CD22. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 9 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 9 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0236] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 10 has the activity of VL of the anti-CD22 antibody, i.e., binding activity against CD22. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 10 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 10 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0237] Hereinafter, an embodiment in which the antibody is an anti-HER2 antibody will be described.

[0238] The anti-HER2 antibody is an antibody that binds to HER2. The anti-HER2 antibody is preferably an antibody that specifically binds to HER2. The anti-HER2 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-HER2 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0239] In one embodiment, the anti-HER2 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of trastuzumab.

[0240] In one embodiment, the anti-HER2 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 67, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 68, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 69, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 70, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 71, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 72. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0241] In an alternative embodiment, the amino acid sequence of VH of the anti-HER2 antibody contains the amino acid sequence set forth in SEQ ID NO: 29, and the amino acid sequence of VL of the anti-HER2 antibody contains the amino acid sequence set forth in SEQ ID NO: 30. The amino acid sequence of VH of the anti-HER2 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 29, and the amino acid sequence of VL of the anti-HER2 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 30.

[0242] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 29 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 67 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 68 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 69 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 30 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 70 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 71 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 72 (underlined in the table below).

[0243] [Table 4] SEQ ID NO: 29 EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSV KGRFT1SADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS SEQ ID NO: 30 DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSG SRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK

[0244] In a further alternative embodiment, the amino acid sequence of VH of the anti-HER2 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 29, and the amino acid sequence of VL of the anti-HER2 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 30. The amino acid sequence of VH of the anti-HER2 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 29, and the amino acid sequence of VL of the anti-HER2 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 30. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 29 may be the amino acid sequence set forth in SEQ ID NO: 29, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 30 may be the amino acid sequence set forth in SEQ ID NO: 30.

[0245] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 29 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 67, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 68, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 69.

[0246] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 30 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 70, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 71, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 72.

[0247] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 29 has the activity of VH of the anti-HER2 antibody, i.e., binding activity against HER2. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 29 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 29 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0248] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 30 has the activity of VL of the anti-HER2 antibody, i.e., binding activity against HER2. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 30 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 6 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0249] Hereinafter, an embodiment in which the antibody is an anti-DLL3 antibody will be described.

[0250] The anti-DLL3 antibody is an antibody that binds to DLL3. The anti-DLL3 antibody is preferably an antibody that specifically binds to DLL3. The anti-DLL3 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-DLL3 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0251] In one embodiment, the anti-DLL3 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of rovalpituzumab.

[0252] In one embodiment, the anti-DLL3 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 73, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 74, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 75, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 76, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 77, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 78. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0253] In an alternative embodiment, the amino acid sequence of VH of the anti-DLL3 antibody contains the amino acid sequence set forth in SEQ ID NO: 31, and the amino acid sequence of VL of the anti-DLL3 antibody contains the amino acid sequence set forth in SEQ ID NO: 32. The amino acid sequence of VH of the anti-DLL3 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 31, and the amino acid sequence of VL of the anti-DLL3 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 32.

[0254] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 31 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 73 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 74 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 75 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 32 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 76 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 77 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 78 (underlined in the table below).

[0255] [Table 5] SEQ ID NO: 31 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYAD DFKGRVTMTTDTSTSTAYMELRSLRSDDTAVYYCARIGDSSPSDYWGQGTLVTVSS SEQ ID NO: 32 EIVMTQSPATLSVSPGERATLSCKASQSVSNDVVWYQQKPGQAPRLUYYASNRYTGIPARFSGS GSGTEFTLTISSLQSEDFAVYYCQQDYTSPWTFGQGTKLEIK

[0256] In a further alternative embodiment, the amino acid sequence of VH of the anti-DLL3 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 31, and the amino acid sequence of VL of the anti-DLL3 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 32. The amino acid sequence of VH of the anti-DLL3 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 31, and the amino acid sequence of VL of the anti-DLL3 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 32. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 31 may be the amino acid sequence set forth in SEQ ID NO: 31, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 32 may be the amino acid sequence set forth in SEQ ID NO: 32.

[0257] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 31 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 73, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 74, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 75.

[0258] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 32 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 76, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 77, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 78.

[0259] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 31 has the activity of VH of the anti-DLL3 antibody, i.e., binding activity against DLL3. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 31 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 31 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0260] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 32 has the activity of VL of the anti-DLL3 antibody, i.e., binding activity against DLL3. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 32 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 32 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0261] Hereinafter, an embodiment in which the antibody is an anti-GM2 antibody will be described.

[0262] The anti-GM2 antibody is an antibody that binds to GM2. The anti-GM2 antibody is preferably an antibody that specifically binds to GM2. The anti-GM2 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-GM2 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0263] In one embodiment, the anti-GM2 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of KM8969 (WO 2001 / 023431).

[0264] In one embodiment, the anti-GM2 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 79, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 80, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 81, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 82, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 83, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 84. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0265] In an alternative embodiment, the amino acid sequence of VH of the anti-GM2 antibody contains the amino acid sequence set forth in SEQ ID NO: 33, and the amino acid sequence of VL of the anti-GM2 antibody contains the amino acid sequence set forth in SEQ ID NO: 34. The amino acid sequence of VH of the anti-GM2 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 33, and the amino acid sequence of VL of the anti-GM2 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 34.

[0266] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 33 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 79 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 80 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 81 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 34 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 82 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 83 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 84 (underlined in the table below).

[0267] [Table 6] SEQ ID NO: 33 EVQLVQSGAEVKKPGASVKVSCKASGYTFTDYNMDWVKQSPGQGLEWMGYIYPNNGGTGYNQ KFKSKVTITVDTSTSTAYMELHSLRSEDTAVYYCATYGHYYGYMFAYWGQGTLVTVSS SEQ ID NO: 34 DIQLTQSPSSLSASPGDRVTITCSASSSVSYMHWFQQKPGKAPKLWIYSTSNLASGVPARFSGS GSGTSYSLTISRLQPED1ATYYCQQRSSYPYTFGGGTKVEIK

[0268] In a further alternative embodiment, the amino acid sequence of VH of the anti-GM2 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 33, and the amino acid sequence of VL of the anti-GM2 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 34. The amino acid sequence of VH of the anti-GM2 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 33, and the amino acid sequence of VL of the anti-GM2 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 34. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 33 may be the amino acid sequence set forth in SEQ ID NO: 33, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 34 may be the amino acid sequence set forth in SEQ ID NO: 34.

[0269] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 33 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 79, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 80, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 81.

[0270] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 34 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 82, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 83, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 84.

[0271] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 33 has the activity of VH of the anti-GM2 antibody, i.e., binding activity against GM2. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 33 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 33 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0272] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 34 has the activity of VL of the anti-GM2 antibody, i.e., binding activity against GM2. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 34 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 34 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0273] Hereinafter, an embodiment in which the antibody is an anti-EphA2 antibody will be described.

[0274] The anti-EphA2 antibody is an antibody that binds to EphA2. The anti-EphA2 antibody is preferably an antibody that specifically binds to EphA2. The anti-EphA2 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-EphA2 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0275] In one embodiment, the anti-EphA2 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of 1C1 (U.S. Patent Application Publication No. 2009 / 0304721).

[0276] amino acid sequence set forth in SEQ ID NO: 85, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 86, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 87, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 88, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 89, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 90. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0277] In an alternative embodiment, the amino acid sequence of VH of the anti-EphA2 antibody contains the amino acid sequence set forth in SEQ ID NO: 35, and the amino acid sequence of VL of the anti-EphA2 antibody contains the amino acid sequence set forth in SEQ ID NO: 36. The amino acid sequence of VH of the anti-EphA2 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 35, and the amino acid sequence of VL of the anti-EphA2 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 36.

[0278] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 35 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 85 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 86 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 87 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 36 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 88 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 89 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 90 (underlined in the table below).

[0279] [Table 7] SEQ ID NO: 35 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVSRIGPSGGPTHYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGYDSGYDYVAVAGPAEYFQHWGQGTLVTV SS SEQ ID NO: 36 DIQMTQSPSSLSASVGDRVT1TCRASQS1STWLAWYQQKPGKAPKLLIYKASNLHTGVPSRFSGS GSGTEFSLT1SGLQPDDFATYYCQQYNSYSRTFGQGTKVEIK

[0280] In a further alternative embodiment, the amino acid sequence of VH of the anti-EphA2 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 35, and the amino acid sequence of VL of the anti-EphA2 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 36. The amino acid sequence of VH of the anti-EphA2 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 35, and the amino acid sequence of VL of the anti-EphA2 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 36. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 35 may be the amino acid sequence set forth in SEQ ID NO: 35, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 36 may be the amino acid sequence set forth in SEQ ID NO: 36.

[0281] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 35 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 85, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 86, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 87.

[0282] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 36 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 88, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 89, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 90.

[0283] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 35 has the activity of VH of the anti-EphA2 antibody, i.e., binding activity against EphA2. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 35 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 35 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0284] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 36 has the activity of VL of the anti-EphA2 antibody, i.e., binding activity against EphA2. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 36 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 36 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0285] Hereinafter, an embodiment in which the antibody is an antiFAP antibody will be described.

[0286] The anti-FAP antibody is an antibody that binds to FAP. The anti-FAP antibody is preferably an antibody that specifically binds to FAP. The anti-FAP antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-FAP antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0287] In one embodiment, the anti-FAP antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of hu36 (U.S. Patent No. 10864278).

[0288] In one embodiment, the anti-FAP antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 91, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 92, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 93, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 94, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 95, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 96. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0289] In an alternative embodiment, the amino acid sequence of VH of the anti-FAP antibody contains the amino acid sequence set forth in SEQ ID NO: 37, and the amino acid sequence of VL of the antiFAP antibody contains the amino acid sequence set forth in SEQ ID NO: 38. The amino acid sequence of VH of the anti-FAP antibody may consist of the amino acid sequence set forth in SEQ ID NO: 37, and the amino acid sequence of VL of the anti-FAP antibody may consist of the amino acid sequence set forth in SEQ ID NO: 38.

[0290] the amino acid sequence set forth in SEQ ID NO: 91 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 92 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 93 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 38 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 94 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 95 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 96 (underlined in the table below).

[0291] [Table 8] SEQ ID NO: 37 QVQLKQSGAELVKPGASVKLSCKTSGYTFTENIIHWVKQRSGQGLEW1GWFHPGSGSIKYNEKKD KATLTADKSSSTVYMELSRLTSEDSAVYFCARHGGTGRGAMDYWGQGTSVTVSS SEQ ID NO: 38 DILMTQS PASSVVSLSGQ RATIS CRASKSVSTSAYSYMHWYQQ KPG QPP KLLIY LASNLES GVPP RFSGSGSGTDFTLNIHPVEEEDAATYYCQHSRELPYTFGGGTKLE1K

[0292] In a further alternative embodiment, the amino acid sequence of VH of the anti-FAP antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 37, and the amino acid sequence of VL of the anti-FAP antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 38. The amino acid sequence of VH of the anti-FAP antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 37, and the amino acid sequence of VL of the anti-FAP antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 38. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 37 may be the amino acid sequence set forth in SEQ ID NO: 37, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 38 may be the amino acid sequence set forth in SEQ ID NO: 38.

[0293] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 37 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 91, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 92, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 93.

[0294] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 38 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 94, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 95, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 96.

[0295] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 37 has the activity of VH of the anti-FAP antibody, i.e., binding activity against FAP. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 37 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 37 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0296] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 38 has the activity of VL of the anti-FAP antibody, i.e., binding activity against FAP. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 38 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 38 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0297] Hereinafter, an embodiment in which the antibody is an anti-SSTR2 antibody will be described.

[0298] The anti-SSTR2 antibody is an antibody that binds to SSTR2. The anti-SSTR2 antibody is preferably an antibody that specifically binds to SSTR2. The anti-SSTR2 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-SSTR2 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0299] In one embodiment, the anti-SSTR2 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of anti-SSTR2 mAb (U.S. Patent Application Publication No. 2021 / 0340264).

[0300] In one embodiment, the anti-SSTR2 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 97, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 98, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 99, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 100, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 101, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 102. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0301] In an alternative embodiment, the amino acid sequence of VH of the anti-SSTR2 antibody contains the amino acid sequence set forth in SEQ ID NO: 39, and the amino acid sequence of VL of the anti-SSTR2 antibody contains the amino acid sequence set forth in SEQ ID NO: 40. The amino acid sequence of VH of the anti-SSTR2 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 39, and the amino acid sequence of VL of the anti-SSTR2 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 40.

[0302] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 39 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 97 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 98 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 99 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 40 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 100 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 101 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 102 (underlined in the table below).

[0303] [Table 9] SEQ ID NO: 39 tEVKLVESGGGLVQPGGSLRLSCATSGFTFTDYHLNWVRQPPGKALEWLALIRNKRYGYRTEYSA SVKGRFT1SRDNSQS1LYLQMNTLRAEDSATYYCARDFYDPFAYWGQGTLVTVSA SEQ ID NO: 40 DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQRPGQSPKLLIYKVSNRFSGVP DRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPFTFGSGTKLEIK

[0304] In a further alternative embodiment, the amino acid sequence of VH of the anti-SSTR2 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 39, and the amino acid sequence of VL of the anti-SSTR2 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 40. The amino acid sequence of VH of the anti-SSTR2 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 39, and the amino acid sequence of VL of the anti-SSTR2 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 40. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 39 may be the amino acid sequence set forth in SEQ ID NO: 39, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 40 may be the amino acid sequence set forth in SEQ ID NO: 40.

[0305] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 39 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 97, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 98, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 99.

[0306] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 40 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 100, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 101, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 102.

[0307] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 39 has the activity of VH of the anti-SSTR2 antibody, i.e., binding activity against SSTR2. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 39 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 39 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0308] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 40 has the activity of VL of the anti-SSTR2 antibody, i.e., binding activity against SSTR2. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 40 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 40 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0309] Hereinafter, an embodiment in which the antibody is an anti-CD30 antibody will be described.

[0310] The anti-CD30 antibody is an antibody that binds to CD30. The anti-CD30 antibody is preferably an antibody that specifically binds to CD30. The anti-CD30 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CD30 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0311] In one embodiment, the anti-CD30 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of brentuximab.

[0312] In one embodiment, the anti-CD30 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 103, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 104, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 105, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 106, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 107, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 108. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0313] In an alternative embodiment, the amino acid sequence of VH of the anti-CD30 antibody contains the amino acid sequence set forth in SEQ ID NO: 41, and the amino acid sequence of VL of the anti-CD30 antibody contains the amino acid sequence set forth in SEQ ID NO: 42. The amino acid sequence of VH of the anti-CD30 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 41, and the amino acid sequence of VL of the anti-CD30 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 42.

[0314] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 41 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 103 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 104 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 105 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 42 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 106 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 107 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 108 (underlined in the table below).

[0315] [Table 10] SEQ ID NO: 41 QIQLQQSGPEVVKPGASVKISGKASGYTFTDYYITWVKQKPGQGLEWIGWIYPGSGNTKYNEKFK GKATLTVDTSSSTAFMQLSSLTSEDTAVYFCANYGNYWFAYWGQGTQVTVSA SEQ ID NO: 42 DIVLTQSPASLAVSLGQRAT1SCKASQSVDFDGDSYMNWYQQKPGQPPKVLIYAASNLESGIPAR FSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPWTFGGGTKLEIK

[0316] In a further alternative embodiment, the amino acid sequence of VH of the anti-CD30 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 41, and the amino acid sequence of VL of the anti-CD30 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 42. The amino acid sequence of VH of the anti-CD30 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 41, and the amino acid sequence of VL of the anti-CD30 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 42. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 may be the amino acid sequence set forth in SEQ ID NO: 41, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 42 may be the amino acid sequence set forth in SEQ ID NO: 42.

[0317] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 103, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 104, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 105.

[0318] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 42 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 106, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 107, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 108.

[0319] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 has the activity of VH of the anti-CD30 antibody, i.e., binding activity against CD30. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 41 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0320] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 42 has the activity of VL of the anti-CD30 antibody, i.e., binding activity against CD30. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 42 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 42 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0321] Hereinafter, an embodiment in which the antibody is an anti-BCMA antibody will be described.

[0322] The anti-BCMA antibody is an antibody that binds to BCMA. The anti-BCMA antibody is preferably an antibody that specifically binds to BCMA. The anti-BCMA antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-BCMA antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0323] In one embodiment, the anti-BCMA antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of belantamab.

[0324] In one embodiment, the anti-BCMA antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 109, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 110, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 111, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 112, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 113, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 114. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0325] In an alternative embodiment, the amino acid sequence of VH of the anti-BCMA antibody contains the amino acid sequence set forth in SEQ ID NO: 43, and the amino acid sequence of VL of the anti-BCMA antibody contains the amino acid sequence set forth in SEQ ID NO: 44. The amino acid sequence of VH of the anti-BCMA antibody may consist of the amino acid sequence set forth in SEQ ID NO: 43, and the amino acid sequence of VL of the anti-BCMA antibody may consist of the amino acid sequence set forth in SEQ ID NO: 44.

[0326] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 43 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 109 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 110 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 111 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 44 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 112 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 113 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 114 (underlined in the table below).

[0327] [Table 11] SEQ ID NO: 43 IQVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYN QKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSS SEQ ID NO: 44 DIQMTQSPSSLSASVGDRVT1TCSASQDISNYLNWYQQKPGKAPKLL1YYTSNLHSGVPSRFSGS GSGTDFTLT1SSLQPEDFATYYCQQYRKLPWTFGQGTKLE1K

[0328] In a further alternative embodiment, the amino acid sequence of VH of the anti-BCMA antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 43, and the amino acid sequence of VL of the anti-BCMA antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 44. The amino acid sequence of VH of the anti-BCMA antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 43, and the amino acid sequence of VL of the anti-BCMA antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 44. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 43 may be the amino acid sequence set forth in SEQ ID NO: 43, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 44 may be the amino acid sequence set forth in SEQ ID NO: 44.

[0329] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 43 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 109, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 110, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 111.

[0330] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 44 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 112, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 113, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 114.

[0331] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 43 has the activity of VH of the anti-BCMA antibody, i.e., binding activity against BCMA. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 43 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 43 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0332] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 44 has the activity of VL of the anti-BCMA antibody, i.e., binding activity against BCMA. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 44 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 44 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0333] Hereinafter, an embodiment in which the antibody is an anti-CD33 antibody will be described.

[0334] The anti-CD33 antibody is an antibody that binds to CD33. The anti-CD33 antibody is preferably an antibody that specifically binds to CD33. The anti-CD33 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CD33 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0335] In one embodiment, the anti-CD33 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of gemtuzumab.

[0336] In one embodiment, the anti-CD33 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 115, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 116, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 117, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 118, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 119, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 120. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0337] In an alternative embodiment, the amino acid sequence of VH of the anti-CD33 antibody contains the amino acid sequence set forth in SEQ ID NO: 45, and the amino acid sequence of VL of the anti-CD33 antibody contains the amino acid sequence set forth in SEQ ID NO: 46. The amino acid sequence of VH of the anti-CD33 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 45, and the amino acid sequence of VL of the anti-CD33 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 46.

[0338] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 45 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 115 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 116 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 117 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 46 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 118 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 119 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 120 (underlined in the table below).

[0339] [Table 12] SEQ ID NO: 45 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYDINWVRQAPGQGLEWIGW1YPGDGSTKYNEKF KAKATLTADTSTSTAYMELRSLRSDDTAVYYCASGYEDAMDYWGQGTTVTVSS SEQ ID NO: 46 D1QMTQSPSSLSASVGDRVTINCKASQDINSYLSWFQQKPGKAPKTLIYRANRLVDGVPSRFSGS GSGQDYTLTISSLQPEDFATYYCLQYDEFPLTFGGGTKVEIK

[0340] In a further alternative embodiment, the amino acid sequence of VH of the anti-CD33 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 45, and the amino acid sequence of VL of the anti-CD33 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 46. The amino acid sequence of VH of the anti-CD33 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 45, and the amino acid sequence of VL of the anti-CD33 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 46. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 45 may be the amino acid sequence set forth in SEQ ID NO: 45, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 46 may be the amino acid sequence set forth in SEQ ID NO: 46.

[0341] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 45 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 115, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 116, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 117.

[0342] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 46 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 118, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 119, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 120.

[0343] the activity of VH of the anti-CD33 antibody, i.e., binding activity against CD33. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 45 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 45 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0344] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 46 has the activity of VL of the anti-CD33 antibody, i.e., binding activity against CD33. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 46 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 46 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0345] Hereinafter, an embodiment in which the antibody is an anti-FoLRa antibody will be described.

[0346] The anti-FoLRa antibody is an antibody that binds to FoLRa. The anti-FoLRa antibody is preferably an antibody that specifically binds to FoLRa. The anti-FoLRa antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-FoLRa antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0347] In one embodiment, the anti-FoLRa antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of mirvetuximab.

[0348] In one embodiment, the anti-FoLRa antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 121, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 122, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 123, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 124, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 125, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 126. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0349] In an alternative embodiment, the amino acid sequence of VH of the anti-FoLRa antibody contains the amino acid sequence set forth in SEQ ID NO: 47, and the amino acid sequence of VL of the anti-FoLRa antibody contains the amino acid sequence set forth in SEQ ID NO: 48. The amino acid sequence of VH of the anti-FoLRa antibody may consist of the amino acid sequence set forth in SEQ ID NO: 47, and the amino acid sequence of VL of the anti-FoLRa antibody may consist of the amino acid sequence set forth in SEQ ID NO: 48.

[0350] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 47 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 121 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 122 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 123 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 48 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 124 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 125 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 126 (underlined in the table below).

[0351] [Table 13] SEQ ID NO: 47 (EVQLVESGGGLVQPGGSLRLSCAASGFTFTDFYMNWVRQPPGKAPEWLGFIRNKANGYTTEFN PSVKGRFTISRDNSKNSLYLQMNSLKTEDTATYYCARTLYGYAYYYVMDAWGQGTLVTVSS SEQ ID NO: 48 DIQMTQSPSSLSASLGDRVT1TCRTSED1FRNLAWYQQKPGKAPKLLIYDTNRLADGVPSRFSGS GSGTDYTLTISSLQPEDFATYFCQQYDNYPLTFGQGTKLE1K

[0352] In a further alternative embodiment, the amino acid sequence of VH of the anti-FoLRa antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 47, and the amino acid sequence of VL of the anti-FoLRa antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 48. The amino acid sequence of VH of the anti-FoLRa antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 47, and the amino acid sequence of VL of the anti-FoLRa antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 48. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 47 may be the amino acid sequence set forth in SEQ ID NO: 47, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 48 may be the amino acid sequence set forth in SEQ ID NO: 48.

[0353] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 47 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 121, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 122, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 123.

[0354] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 48 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 124, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 125, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 126.

[0355] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 47 has the activity of VH of the anti-FoLRa antibody, i.e., binding activity against FoLRa. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 47 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 47 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0356] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 48 has the activity of VL of the anti-FoLRa antibody, i.e., binding activity against FoLRa. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 48 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 48 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0357] Hereinafter, an embodiment in which the antibody is an anti-CD25 antibody will be described. The anti-CD25 antibody is an antibody that binds to CD25. The anti-CD25 antibody is preferably an antibody that specifically binds to CD25. The anti-CD25 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CD25 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0359] In one embodiment, the anti-CD25 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of camidanlumab.

[0360] In one embodiment, the anti-CD25 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 127, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 128, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 129, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 130, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 131, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 132. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0361] In an alternative embodiment, the amino acid sequence of VH of the anti-CD25 antibody contains the amino acid sequence set forth in SEQ ID NO: 49, and the amino acid sequence of VL of the anti-CD25 antibody contains the amino acid sequence set forth in SEQ ID NO: 50. The amino acid sequence of VH of the anti-CD25 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 49, and the amino acid sequence of VL of the anti-CD25 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 50.

[0362] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 49 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 127 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 128 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 129 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 50 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 130 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 131 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 132 (underlined in the table below).

[0363] [Table 14] SEQ ID NO: 49 (QVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYI1NWVRQAPGQGLEWMGRIIPILGVENYAQKFQ GRVTITADKSTSTAYMELSSLRSEDTAVYYCARKDWFDYWGQGTLVTVSS SEQ ID NO: 50 EIVLTQSPGTLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGS GSGTDFTLTISRLEPEDFAVYYCQQYGSSPLTFGGGTKVEIK In a further alternative embodiment, the amino acid sequence of VH of the anti-CD25 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 49, and the amino acid sequence of VL of the anti-CD25 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 50. The amino acid sequence of VH of the anti-CD25 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 49, and the amino acid sequence of VL of the anti-CD25 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 50. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 49 may be the amino acid sequence set forth in SEQ ID NO: 49, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 50 may be the amino acid sequence set forth in SEQ ID NO: 50.

[0365] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 49 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 127, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 128, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 129.

[0366] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 50 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 130, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 131, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 132.

[0367] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 49 has the activity of VH of the anti-CD25 antibody, i.e., binding activity against CD25. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 49 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 49 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0368] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 50 has the activity of VL of the anti-CD25 antibody, i.e., binding activity against CD25. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 50 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 50 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0369] Hereinafter, an embodiment in which the antibody is an anti-CADM1 antibody will be described.

[0370] The anti-CADM1 antibody is an antibody that binds to CADM1. The anti-CADM1 antibody is preferably an antibody that specifically binds to CADM1. The anti-CADM1 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CADM1 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0371] In one embodiment, the anti-CADM1 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of PTA021_A3 (U.S. Patent No. 8420084).

[0372] In one embodiment, the anti-CADM1 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 133, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 134, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 135, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 136, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 137, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 138. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0373] In an alternative embodiment, the amino acid sequence of VH of the anti-CADM1 antibody contains the amino acid sequence set forth in SEQ ID NO: 51, and the amino acid sequence of VL of the anti-CADM1 antibody contains the amino acid sequence set forth in SEQ ID NO: 52. The amino acid sequence of VH of the anti-CADM1 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 51, and the amino acid sequence of VL of the anti-CADM1 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 52.

[0374] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 51 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 133 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 134 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 135 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 52 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 136 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 137 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 138 (underlined in the table below).

[0375] [Table 15] SEQ ID NO: 51 (Q1TLKESGPTLVKPTQTLTLTCTFSGFSLSTSGVGVGW1RQPPGKALEWLALIYWDDDKRYSPSL KSRLTITKDTSKNQVVLTMTNMDPVDTATYYCAHRRVEWVTLAGNWFDPWGQGTLVTVSS SEQ ID NO: 52 DIQMTQSPSSLSASVGDRVTITCRASQG1SSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGS GSGTDFTLT1SNLQPEDFATYYCQQYNSYPLTFGGGTKVE1K

[0376] In a further alternative embodiment, the amino acid sequence of VH of the anti-CADM1 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 51, and the amino acid sequence of VL of the anti-CADM1 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 52. The amino acid sequence of VH of the anti-CADM1 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 51, and the amino acid sequence of VL of the anti-CADM1 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 52. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 51 may be the amino acid sequence set forth in SEQ ID NO: 51, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 52 may be the amino acid sequence set forth in SEQ ID NO: 52.

[0377] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 51 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 133, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 134, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 135.

[0378] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 52 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 136, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 137, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 138.

[0379] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 51 has the activity of VH of the anti-CADM1 antibody, i.e., binding activity against CADM1. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 51 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 51 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0380] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 52 has the activity of VL of the anti-CADM1 antibody, i.e., binding activity against CADM1. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 52 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 52 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0381] Hereinafter, an embodiment in which the antibody is an anti-CLL1 antibody will be described.

[0382] The anti-CLL1 antibody is an antibody that binds to CLL1. The anti-CLL1 antibody is preferably an antibody that specifically binds to CLL1. The anti-CLL1 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CLL1 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0383] In one embodiment, the anti-CLL1 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of 6E7LAHle (WO 2016 / 205200).

[0384] In one embodiment, the anti-CLL1 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 139, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 140, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 141, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 142, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 143, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 144. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0385] In an alternative embodiment, the amino acid sequence of VH of the anti-CLL1 antibody contains the amino acid sequence set forth in SEQ ID NO: 53, and the amino acid sequence of VL of the anti-CLL1 antibody contains the amino acid sequence set forth in SEQ ID NO: 54. The amino acid sequence of VH of the anti-CLL1 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 53, and the amino acid sequence of VL of the anti-CLL1 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 54.

[0386] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 53 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 139 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 140 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 141 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 54 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 142 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 143 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 144 (underlined in the table below).

[0387] [Table 16] SEQ ID NO: 53 IEVQLVQSGAEVKKPGASVKVSCKASGYSFTDYYMHWVRQAPGQGLEW1GR1NPYAGAAFYSQN FKDRVTLTVDTSTSTAYLELSSLRSEDTAVYYCAIERGADLEGYAMDYWGQGTLVTVSS SEQ ID NO: 54 DIQMTQSPSSLSASVGDRVTITCRASQSVSTSSYNYMHWYQQKPGKPPKLLIKYASNLESGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCQHSWEIPLTFGQGTKVE1K

[0388] In a further alternative embodiment, the amino acid sequence of VH of the anti-CLL1 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 53, and the amino acid sequence of VL of the anti-CLL1 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 54. The amino acid sequence of VH of the anti-CLL1 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 53, and the amino acid sequence of VL of the anti-CLL1 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 54. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 53 may be the amino acid sequence set forth in SEQ ID NO: 53, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 54 may be the amino acid sequence set forth in SEQ ID NO: 54.

[0389] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 53 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 139, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 140, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 141.

[0390] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 54 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 142, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 143, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 144.

[0391] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 53 has the activity of VH of the anti-CLL1 antibody, i.e., binding activity against CLL1. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 53 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 53 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0392] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 54 has the activity of VL of the anti-CLL1 antibody, i.e., binding activity against CLL1. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 54 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 54 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0393] Hereinafter, an embodiment in which the antibody is an anti-CD38 antibody will be described.

[0394] The anti-CD38 antibody is an antibody that binds to CD38. The anti-CD38 antibody is preferably an antibody that specifically binds to CD38. The anti-CD38 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CD38 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0395] In one embodiment, the anti-CD38 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of daratumumab.

[0396] In one embodiment, the anti-CD38 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 145, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 146, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 147, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 148, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 149, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 150. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0397] In an alternative embodiment, the amino acid sequence of VH of the anti-CD38 antibody contains the amino acid sequence set forth in SEQ ID NO: 55, and the amino acid sequence of VL of the anti-CD38 antibody contains the amino acid sequence set forth in SEQ ID NO: 56. The amino acid sequence of VH of the anti-CD38 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 55, and the amino acid sequence of VL of the anti-CD38 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 56.

[0398] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 55 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 145 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 146 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 147 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 56 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 148 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 149 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 150 (underlined in the table below).

[0399] [Table 17] SEQ ID NO: 55 (EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDK1LWFGEPVFDYWGQGTLVTVSS SEQ ID NO: 56 EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLUYDASNRATGIPARFSGS GSGTDFTLT1SSLEPEDFAVYYCQQRSNWPPTFGQGTKVE1K

[0400] In a further alternative embodiment, the amino acid sequence of VH of the anti-CD38 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 55, and the amino acid sequence of VL of the anti-CD38 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 56. The amino acid sequence of VH of the anti-CD38 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 55, and the amino acid sequence of VL of the anti-CD38 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 56. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 55 may be the amino acid sequence set forth in SEQ ID NO: 55, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 56 may be the amino acid sequence set forth in SEQ ID NO: 56.

[0401] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 55 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 145, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 146, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 147.

[0402] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 56 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 148, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 149, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 150.

[0403] the activity of VH of the anti-CD38 antibody, i.e., binding activity against CD38. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 55 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 55 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0404] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 56 has the activity of VL of the anti-CD38 antibody, i.e., binding activity against CD38. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 56 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 56 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0405] Hereinafter, an embodiment in which the antibody is an anti-CD74 antibody will be described.

[0406] The anti-CD74 antibody is an antibody that binds to CD74. The anti-CD74 antibody is preferably an antibody that specifically binds to CD74. The anti-CD74 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CD74 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0407] In one embodiment, the anti-CD74 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of milatuzumab.

[0408] In one embodiment, the anti-CD74 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 151, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 152, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 153, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 154, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 155, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 156. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0409] In an alternative embodiment, the amino acid sequence of VH of the anti-CD74 antibody contains the amino acid sequence set forth in SEQ ID NO: 57, and the amino acid sequence of VL of the anti-CD74 antibody contains the amino acid sequence set forth in SEQ ID NO: 58. The amino acid sequence of VH of the anti-CD74 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 57, and the amino acid sequence of VL of the anti-CD74 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 58.

[0410] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 57 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 151 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 152 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 153 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 58 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 154 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 155 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 156 (underlined in the table below).

[0411] [Table 18] SEQ ID NO: 57 QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGVNWIKQAPGQGLQWMGW1NPNTGEPTFDDD FKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCSRSRGKNEAWFAYWGQGTLVTVSS SEQ ID NO: 58 DIQLTQSPLSLPVTLGQPASISCRSSQSLVHRNGNTYLHWFQQRPGQSPRLL1YTVSNRFSGVPD RFSGSGSGTDFTLKISRVEAEDVGVYFCSQSSHVPPTFGAGTRLEIK

[0412] In a further alternative embodiment, the amino acid sequence of VH of the anti-CD74 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and the amino acid sequence of VL of the anti-CD74 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 58. The amino acid sequence of VH of the anti-CD74 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and the amino acid sequence of VL of the anti-CD74 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 58. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 57 may be the amino acid sequence set forth in SEQ ID NO: 57, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 58 may be the amino acid sequence set forth in SEQ ID NO: 58.

[0413] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 57 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 151, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 152, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 153.

[0414] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 58 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 154, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 155, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 156.

[0415] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 57 has the activity of VH of the anti-CD74 antibody, i.e., binding activity against CD74. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 57 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 57 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0416] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 58 has the activity of VL of the anti-CD74 antibody, i.e., binding activity against CD74. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 58 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 58 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0417] Hereinafter, an embodiment in which the antibody is an anti-NECTIN4 antibody will be described.

[0418] that specifically binds to NECTIN4. The anti-NECTIN4 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-NECTIN4 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0419] In one embodiment, the anti-NECTIN4 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of enfortumab.

[0420] In one embodiment, the anti-NECTIN4 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 187, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 188, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 189, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 190, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 191, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 192. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0421] In an alternative embodiment, the amino acid sequence of VH of the anti-NECTIN4 antibody contains the amino acid sequence set forth in SEQ ID NO: 183, and the amino acid sequence of VL of the anti-NECTIN4 antibody contains the amino acid sequence set forth in SEQ ID NO: 184. The amino acid sequence of VH of the anti-NECTIN4 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 183, and the amino acid sequence of VL of the anti-NECTIN4 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 184.

[0422] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 183 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 187 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 188 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 189 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 184 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 190 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 191 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 192 (underlined in the table below).

[0423] [Table 19] SEQ ID NO: 183 E VQ LVES GGGLVQ PG G SLRLSCAASG FTFSSYNMNWV RQ APG KG LEWVSY1SSSSSTIYYADSV KGRFTISRDNAKNSLSLQMNSLRDEDTAVYYCARAYYYGMDVWGQGTTVTVSS SEQ ID NO: 184 DIQMTQSPSSVSASVGDRVT1TCRASQGISGWLAWYQQKPGKAPKFLIYAASTLQSGVPSRFSG SGSGTDFTLTISSLQPEDFATYYOQQANSFPPTFGGGTKVEIK

[0424] In a further alternative embodiment, the amino acid sequence of VH of the anti-NECTIN4 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 183, and the amino acid sequence of VL of the anti-NECTIN4 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 184. The amino acid sequence of VH of the anti-NECTIN4 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 183, and the amino acid sequence of VL of the anti-NECTIN4 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 184. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 183 may be the amino acid sequence set forth in SEQ ID NO: 183, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 184 may be the amino acid sequence set forth in SEQ ID NO: 184.

[0425] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 183 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 187, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 188, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 189.

[0426] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 184 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 190, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 191, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 192.

[0427] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 183 has the activity of VH of the anti-NECTIN4 antibody, i.e., binding activity against NECTIN4. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 183 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 183 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0428] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 184 has the activity of VL of the anti-NECTIN4 antibody, i.e., binding activity against NECTIN4. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 184 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 184 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0429] Hereinafter, an embodiment in which the antibody is an anti-TROP2 antibody will be described.

[0430] The anti-TROP2 antibody is an antibody that binds to TROP2. The anti-TROP2 antibody is preferably an antibody that specifically binds to TROP2. The anti-TROP2 antibody may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-TROP2 antibody may be a human-type chimeric antibody, a humanized antibody, or a human antibody and is preferably a humanized antibody.

[0431] In one embodiment, the anti-TROP2 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of sacituzumab.

[0432] In one embodiment, the anti-TROP2 antibody contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 193, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 194, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 195, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 196, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 197, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 198. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0433] In an alternative embodiment, the amino acid sequence of VH of the anti-TROP2 antibody contains the amino acid sequence set forth in SEQ ID NO: 185, and the amino acid sequence of VL of the anti-TROP2 antibody contains the amino acid sequence set forth in SEQ ID NO: 186. The amino acid sequence of VH of the anti-TROP2 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 185, and the amino acid sequence of VL of the anti-TROP2 antibody may consist of the amino acid sequence set forth in SEQ ID NO: 186.

[0434] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 185 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 193 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 194 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 195 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 186 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 196 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 197 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 198 (underlined in the table below).

[0435] [Table 20] SEQ ID NO: 185 QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTYTD DFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVSS SEQ ID NO: 186 DIQLTQSPSSLSASVGDRVSITCKASQDVS1AVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGS GSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIK

[0436] In a further alternative embodiment, the amino acid sequence of VH of the anti-TROP2 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 185, and the amino acid sequence of VL of the anti-TROP2 antibody contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 186. The amino acid sequence of VH of the anti-TROP2 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 185, and the amino acid sequence of VL of the anti-TROP2 antibody may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 186. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 185 may be the amino acid sequence set forth in SEQ ID NO: 185, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 186 may be the amino acid sequence set forth in SEQ ID NO: 186.

[0437] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 185 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 193, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 194, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 195.

[0438] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 186 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 196, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 197, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 198.

[0439] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 185 has the activity of VH of the anti-TROP2 antibody, i.e., binding activity against TROP2. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 185 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 185 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0440] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 186 has the activity of VL of the anti-TROP2 antibody, i.e., binding activity against TROP2. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 186 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 186 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0441] Hereinafer, an embodiment in which the antibody is an anti-CD79b antibody and is a human antibody G4055 (human antibody G4055) will be described (hereinafter, also referred to as the anti-CD79b antibody (human antibody G4055) or the anti-CD79b_G4055 antibody).

[0442] The anti-CD79b antibody (human antibody G4055) is an antibody that binds to CD79b. The anti-CD79b antibody (human antibody G4055) is preferably an antibody that specifically binds to CD79b. The anti-CD79b antibody (human antibody G4055) may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CD79b antibody (human antibody G4055) is a human antibody.

[0443] In one embodiment, the anti-CD79b antibody (human antibody G4055) contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 157, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 158, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 159, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 160, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 161, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 162. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0444] In an alternative embodiment, the amino acid sequence of VH of the anti-CD79b antibody (human antibody G4055) contains the amino acid sequence set forth in SEQ ID NO: 59, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4055) contains the amino acid sequence set forth in SEQ ID NO: 60. The amino acid sequence of VH of the anti-CD79b antibody (human antibody G4055) may consist of the amino acid sequence set forth in SEQ ID NO: 59, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4055) may consist of the amino acid sequence set forth in SEQ ID NO: 60.

[0445] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 59 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 157 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 158 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 159 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 60 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 160 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 161 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 162 (underlined in the table below).

[0446] [Table 21] SEQ ID NO: 59 IQVQLVESGGGVVQSGRSLRLSCATSGFTFSIYGMHWVRQAPGKGLEWVALIWYDGSNKYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGDYDDHYGMDVWGQGTTVTVSS SEQ ID NO: 60 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLL1YDASSLESGVPSRFSGS GSGTDFTLT1SSLQPEDFATYYCQQFNSFPLTFGGGTKVEIK

[0447] In a further alternative embodiment, the amino acid sequence of VH of the anti-CD79b antibody (human antibody G4055) contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 59, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4055) contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 60. The amino acid sequence of VH of the anti-CD79b antibody (human antibody G4055) may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 59, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4055) may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 60. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 59 may be the amino acid sequence set forth in SEQ ID NO: 59, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 60 may be the amino acid sequence set forth in SEQ ID NO: 60.

[0448] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 59 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 157, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 158, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 159.

[0449] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 60 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 160, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 161, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 162.

[0450] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 59 has the activity of VH of the anti-CD79b antibody (human antibody G4055), i.e., binding activity against CD79b. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 59 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 59 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0451] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 60 has the activity of VL of the anti-CD79b antibody (human antibody G4055), i.e., binding activity against CD79b. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 60 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 60 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0452] Hereinafter, an embodiment in which the antibody is an anti-CD79b antibody and is a human antibody G4022 (human antibody G4022) will be described (hereinafter, also referred to as the anti-CD79b antibody (human antibody G4022) or the anti-CD79b_G4022 antibody).

[0453] The anti-CD79b antibody (human antibody G4022) is an antibody that binds to CD79b. The anti-CD79b antibody (human antibody G4022) is preferably an antibody that specifically binds to CD79b. The anti-CD79b antibody (human antibody G4022) may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CD79b antibody (human antibody G4022) is a human antibody.

[0454] In one embodiment, the anti-CD79b antibody (human antibody G4022) contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 163, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 164, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 165, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 166, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 167, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 168. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0455] In an alternative embodiment, the amino acid sequence of VH of the anti-CD79b antibody (human antibody G4022) contains the amino acid sequence set forth in SEQ ID NO: 61, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4022) contains the amino acid sequence set forth in SEQ ID NO: 62. The amino acid sequence of VH of the anti-CD79b antibody (human antibody G4022) may consist of the amino acid sequence set forth in SEQ ID NO: 61, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4022) may consist of the amino acid sequence set forth in SEQ ID NO: 62.

[0456] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 61 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 163 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 164 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 165 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 62 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 166 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 167 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 168 (underlined in the table below).

[0457] [Table 22] SEQ ID NO: 61 (EVQLVESGGGLVQPGRSLRLSCAASGFTFDGYAMHWVRQAPGKGLEWVSGISWDGRHIGYADS VKGRFTiSRDMAKNSLYLQMNSLRAEDTALYYCSKDKGTVTSYYYYYGTDVWGQGTTVTVSS SEQ ID NO: 62 AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLL1YDASSLESGVPSRFSGS GSGTDFTLT1SSLQPEDFATYYCQQFNSYPFTFGPGTKVDIK

[0458] In a further alternative embodiment, the amino acid sequence of VH of the anti-CD79b antibody (human antibody G4022) contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 61, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4022) contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 62. The amino acid sequence of VH of the anti-CD79b antibody (human antibody G4022) may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 61, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4022) may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 62. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 61 may be the amino acid sequence set forth in SEQ ID NO: 61, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 62 may be the amino acid sequence set forth in SEQ ID NO: 62.

[0459] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 61 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 163, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 164, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 165.

[0460] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 62 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 166, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 167, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 168.

[0461] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 61 has the activity of VH of the anti-CD79b antibody (human antibody G4022), i.e., binding activity against CD79b. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 61 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 61 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0462] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 62 has the activity of VL of the anti-CD79b antibody (human antibody G4022), i.e., binding activity against CD79b. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 62 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 62 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0463] Hereinafter, an embodiment in which the antibody is an anti-CD79b antibody and is a human antibody G4046 (human antibody G4046) will be described (hereinafter, also referred to as the anti-CD79b antibody (human antibody G4046) or the anti-CD79b_G4046 antibody).

[0464] The anti-CD79b antibody (human antibody G4046) is an antibody that binds to CD79b. The anti-CD79b antibody (human antibody G4046) is preferably an antibody that specifically binds to CD79b. The anti-CD79b antibody (human antibody G4046) may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CD79b antibody (human antibody G4046) is a human antibody.

[0465] In one embodiment, the anti-CD79b antibody (human antibody G4046) contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 169, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 170, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 171, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 172, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 173, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 174. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0466] In an alternative embodiment, the amino acid sequence of VH of the anti-CD79b antibody (human antibody G4046) contains the amino acid sequence set forth in SEQ ID NO: 63, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4066) contains the amino acid sequence set forth in SEQ ID NO: 64. The amino acid sequence of VH of the anti-CD79b antibody (human antibody G4066) may consist of the amino acid sequence set forth in SEQ ID NO: 63, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4066) may consist of the amino acid sequence set forth in SEQ ID NO: 64.

[0467] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 63 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 169 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 170 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 171 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 64 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 172 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 173 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 174 (underlined in the table below).

[0468] [Table 23] SEQ ID NO: 63 QVQLVESGGGVVQPGRSLRLSCAASGFTFSIYGMHWVRQAPGKGLEWVALIWYDGSNKYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGDYDYHYGMDVWGQGTTVTVSS SEQ ID NO: 64 AIQLTQSPSSLSASVGDRVT1TCRASQG1SSALAWYQQKPGKPPKLLIYDASSLESGVPSRFSGS GSGTDFTLTISSLQPEDFATYYCQQFNSFPLTFGGGTKVEIK

[0469] In a further alternative embodiment, the amino acid sequence of VH of the anti-CD79b antibody (human antibody G4046) contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 63, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4046) contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 64. The amino acid sequence of VH of the anti-CD79b antibody (human antibody G4046) may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 63, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4046) may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 64. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 63 may be the amino acid sequence set forth in SEQ ID NO: 63, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 64 may be the amino acid sequence set forth in SEQ ID NO: 64.

[0470] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 63 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 169, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 170, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 171.

[0471] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 64 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 172, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 173, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 174.

[0472] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 63 has the activity of VH of the anti-CD79b antibody (human antibody G4046), i.e., binding activity against CD79b. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 63 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 63 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0473] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 64 has the activity of VL of the anti-CD79b antibody (human antibody G4046), i.e., binding activity against CD79b. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 64 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 64 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0474] Hereinafter, an embodiment in which the antibody is an anti-CD79b antibody and is a human antibody G4047 (human antibody G4047) will be described (hereinafter, also referred to as the anti-CD79b antibody (human antibody G4047) or the anti-CD79b_G4047 antibody).

[0475] The anti-CD79b antibody (human antibody G4047) is an antibody that binds to CD79b. The anti-CD79b antibody (human antibody G4047) is preferably an antibody that specifically binds to CD79b. The anti-CD79b antibody (human antibody G4047) may be a polyclonal antibody or a monoclonal antibody and is preferably a monoclonal antibody. The anti-CD79b antibody (human antibody G4047) is a human antibody.

[0476] In one embodiment, the anti-CD79b antibody (human antibody G4047) contains a heavy chain variable region (VH) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 175, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 176, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 177, and a light chain variable region (VL) containing CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 178, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 179, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 180. CDR1, CDR2, and CDR3 are CDR1, CDR2 and, CDR3, respectively, based on the Kabat numbering.

[0477] In an alternative embodiment, the amino acid sequence of VH of the anti-CD79b antibody (human antibody G4047) contains the amino acid sequence set forth in SEQ ID NO: 65, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4047) contains the amino acid sequence set forth in SEQ ID NO: 66. The amino acid sequence of VH of the anti-CD79b antibody (human antibody G4047) may consist of the amino acid sequence set forth in SEQ ID NO: 65, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4047) may consist of the amino acid sequence set forth in SEQ ID NO: 66.

[0478] As shown in the table below, VH containing the amino acid sequence set forth in SEQ ID NO: 65 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 175 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 176 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 177 (underlined in the table below), and VL containing the amino acid sequence set forth in SEQ ID NO: 66 contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 178 (underlined in the table below), CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 179 (underlined in the table below), and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 180 (underlined in the table below).

[0479] [Table 24] SEQ ID NO: 65 IQVQ LVESGGGVVQPGRSLRLSCAASGFTFSIYGMHWVRQAPGKG LEWVALIWYDGSNKYYADS VKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGGDYYDSGSSYYHYGMDVWGQGTTVTVSS SEQ ID NO: 66 AIQLTQSPSSLSASVGDRVT1TCRASQGVSSALAWYQQKPGKPPKLLIYDASSLESGVPSRFSGS GSGTDFTLT1SSLQPEDFATYYCQQFNSFPLTFGGGTKVEIK

[0480] In a further alternative embodiment, the amino acid sequence of VH of the anti-CD79b antibody (human antibody G4047) contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 65, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4047) contains an amino acid sequence having 90% or higher, preferably 95% or higher, more preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 66. The amino acid sequence of VH of the anti-CD79b antibody (human antibody G4047) may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 65, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4047) may consist of an amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 66. The amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 65 may be the amino acid sequence set forth in SEQ ID NO: 65, and the amino acid sequence having 90% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 66 may be the amino acid sequence set forth in SEQ ID NO: 66.

[0481] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 65 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 175, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 176, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 177.

[0482] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 66 preferably contains CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 178, CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 179, and CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 180.

[0483] VH containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 65 has the activity of VH of the anti-CD79b antibody (human antibody G4047), i.e., binding activity against CD79b. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 65 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 65 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0484] VL containing the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 66 has the activity of VL of the anti-CD79b antibody (human antibody G4047), i.e., binding activity against CD79b. Examples of the amino acid sequence having the sequence identity to the amino acid sequence set forth in SEQ ID NO: 66 include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 66 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids.

[0485] Hereinafter, the heavy chain constant region (CH) of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-97 antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti- antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) will be described.

[0486] CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADMl antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) may be any CH that belongs to a human immunoglobulin (hereinafter, also referred to as "hIg"). For example, CH of a hIgG class, specifically, CH of a hIgG subclass such as hIgG1, hIgG2, hIgG3, or hIgG4, or a variant thereof can be used.

[0487] CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADMl antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) is, for example, hIgG1 CH or a variant thereof, or hIgG4 CH or a variant thereof.

[0488] In one embodiment, the amino acid sequence of CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) contains (a) the amino acid sequence set forth in SEQ ID NO: 1, or (b) an amino acid sequence having 80% or higher, preferably 85% or higher, more preferably 90% or higher, further preferably 95% or higher, further preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 1. The amino acid sequence set forth in SEQ ID NO: 1 is the amino acid sequence of CH of hIgG1. The amino acid sequence of CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) may consist of the amino acid sequence (a) or (b). Examples of the amino acid sequence (b) include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 1 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids. Examples of the amino acid sequence (b) include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 1 by the substitution of at least one amino acid by cysteine. The amine acid to be substituted by cysteine is an amino acid other than cysteine.

[0489] In an alternative embodiment, the amino acid sequence of CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) contains (c) the amino acid sequence set forth in SEQ ID NO: 2, or (d) an amino acid sequence having 80% or higher, preferably 85% or higher, more preferably 90% or higher, further preferably 95% or higher, further preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 2. The amino acid sequence of CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) may consist of the amino acid sequence (c) or (d). Examples of the amino acid sequence (d) include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 2 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids. Examples of the amino acid sequence (d) include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 2 by the substitution of at least one amino acid by cysteine. The amine acid to be substituted by cysteine is an amino acid other than cysteine.

[0490] In an alternative embodiment, the amino acid sequence of CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) contains (i) the amino acid sequence set forth in SEQ ID NO: 181, or (j) an amino acid sequence having 80% or higher, preferably 85% or higher, more preferably 90% or higher, further preferably 95% or higher, further preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 181. The amino acid sequence of CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) may consist of the amino acid sequence (i) or (j). Examples of the amino acid sequence (j) include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 181 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids. Examples of the amino acid sequence (j) include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 181 by the substitution of at least two amino acids by cysteine and lysine. The amine acid to be substituted by cysteine is an amino acid other than cysteine, and the amino acid to be substituted by lysine is an amino acid other than lysine.

[0491] In an alternative embodiment, the amino acid sequence of CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) contains (k) the amino acid sequence set forth in SEQ ID NO: 182, or (l) an amino acid sequence having 80% or higher, preferably 85% or higher, more preferably 90% or higher, further preferably 95% or higher, further preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 182. The amino acid sequence of CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) may consist of the amino acid sequence (k) or (l). Examples of the amino acid sequence (l) include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 182 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids. Examples of the amino acid sequence (l) include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 182 by the substitution of at least two amino acids by cysteine and phenylalanine. The amine acid to be substituted by cysteine is an amino acid other than cysteine, and the amino acid to be substituted by phenylalanine is an amino acid other than phenylalanine.

[0492] As shown in the table below, the amino acid sequence set forth in SEQ ID NO: 2 is an amino acid sequence derived from the amino acid sequence set forth in SEQ ID NO: 1 by the substitution of serine (underlined in the table below) at position 239 of the heavy chain designated by the EU numbering of Kabat by cysteine (underlined in the table below). Hereinafter, the substitution of serine at position 239 of the heavy chain by cysteine is also referred to as a "S239C mutation". The linker in the drug-linker conjugate can be connected to CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) via a sulfur atom of cysteine introduced by the S239C mutation.

[0493] [Table 25] SEQ ID NO: 1 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPP IKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK SEQ ID NO: 2 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPCVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK

[0494] The amino acid sequence (d) preferably retains the S239C mutation. 5

[0495] As shown in the table below, the amino acid sequence set forth in SEQ ID NO: 181 is an amino acid sequence derived from the human IgG4 heavy chain constant region (CH) by the substitution of serine (underlined in the table below) at position 10  239 of the heavy chain designated by the EU numbering of Kabat by cysteine (underlined in the table below) and the substitution of arginine at position 409 of the heavy chain by lysine (underlined in the table below). An IgG4 variant containing or consisting of the sequence as the heavy chain constant region can be used as a null 15 body form with attenuated binding to Fcy receptor (FcgR). Hereinafter, the substitution of serine at position 239 of the heavy chain by cysteine is also referred to as a "S239C mutation", and the substitution of arginine at position 409 of the heavy chain by lysine is also referred to as a "R409K mutation". The linker in the drug-linker conjugate can be connected to CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) via a sulfur atom of cysteine introduced by the S239C mutation.

[0496] [Table 26] SEQ ID NO: 181 IASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPCVFLFPPKPK DTLM1SRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDI AVEWESNGQPENNYKTTPPVLDSDGSFFLYSKTVDKSRWQEGNVFSCSVMHEALHNHYTQKSL SLSLGK

[0497] The amino acid sequence (j) preferably retains the S239C mutation and the R409K mutation.

[0498] As shown in the table below, the amino acid sequence set forth in SEQ ID NO: 182 is an amino acid sequence derived from the human IgG4 heavy chain constant region (CH) by the substitution of serine at position 239 of the heavy chain designated by the EU numbering of Kabat by cysteine (underlined in the table below) and the substitution of histidine at position 435 of the heavy chain by phenylalanine (underlined in the table below). An IgG4 variant containing or consisting of the sequence as the heavy chain constant region can be used as a short-half-life form with attenuated binding to neonatal Fc receptor (FcRn). Hereinafter, the substitution of serine at position 239 of the heavy chain by cysteine is also referred to as a "S239C mutation", and the substitution of histidine at position 435 of the heavy chain by phenylalanine is also referred to as a "H435F mutation". The linker in the drug-linker conjugate can be connected to CH of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) via a sulfur atom of cysteine introduced by the S239C mutation.

[0499] [Table 27] SEQ ID NO: 182 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYS LSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPCVFLFPP KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVL HQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNFYTQ KSLSLSPGK The amino acid sequence (l) preferably retains the S239C mutation and the H435F mutation.

[0501] The antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) may have one or two or more glycans linked to CH. The glycan of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) can be selected from, for example, an N-linked glycan and an O-linked glycan and is preferably an N-linked glycan. The N-linked glycan is, for example, an N-linked glycan that is linked to an asparagine residue of CH, and the O-linked glycan is, for example, an O-linked glycan that is linked to a serine residue or a threonine residue of CH. Examples of the N-linked glycan include complex glycans, high-mannose glycans, and hybrid glycans. Examples of the O-linked glycan include core 1 to core 8.

[0502] Hereinafter, the light chain constant region (CL) of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) will be described.

[0503] CL of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADMl antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) may be any CL that belongs to hIg. For example, CL of a human k chain or a human A chain or a variant thereof can be used.

[0504] CL of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) is, for example, CL of a human k chain or a variant thereof.

[0505] In one embodiment, the amino acid sequence of CL of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) contains (e) the amino acid sequence set forth in SEQ ID NO: 3, or (f) an amino acid sequence having 80% or higher, preferably 85% or higher, more preferably 90% or higher, further preferably 95% or higher, further preferably 96% or higher, further preferably 97% or higher, further preferably 98% or higher, further preferably 99% or higher sequence identity to the amino acid sequence set forth in SEQ ID NO: 3. The amino acid sequence set forth in SEQ ID NO: 3 is the amino acid sequence of CH of a human k chain. The amino acid sequence of CL of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-NECTIN4 antibody, or an anti-TROP2 antibody) may consist of the amino acid sequence (e) or (f). Examples of the amino acid sequence (f) include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 3 by the deletion, substitution, insertion, or addition of, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids. Examples of the amino acid sequence (f) include amino acid sequences derived from the amino acid sequence set forth in SEQ ID NO: 3 by the substitution of at least one amino acid by cysteine. The amine acid to be substituted by cysteine is an amino acid other than cysteine.

[0506] In an alternative embodiment, the amino acid sequence of CL of the antibody (e.g., an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-...

Claims

1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:[Chem. 1](wherein,R1 and R2 are the same or different and each represents a hydrogen atom or lower alkyl,R3 represents lower alkyl,R4 represents halogen,R5 represents halogen,R6 represents halogen or lower alkoxy,Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-, andring A represents(i) an aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl,(ii) an aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, or(iii) aryl optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl).

2. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein (i) the aliphatic heterocyclic group in ring A is a nitrogen-containing aliphatic heterocyclic group.

3. The compound or the pharmaceutically acceptable salt thereof according to claim 2, wherein ring A represented by (i) the nitrogen-containing aliphatic heterocyclic group is the following ring A':[Chem. 2](wherein, when ring A' has a substituent, the substituent of ring A' is as defined for the substituent of ring A).

4. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by the formula (I) is a compound represented by the following formula (I'): [Chem. 3](wherein,R1, R2, and R3 are as defined in the formula (I), andring A' is a nitrogen-containing aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl).

5. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is an aliphatic heterocyclic group represented by the following formula (AA), (AB), (AC), or (AD), an aromatic heterocyclic group represented by the following formula (AE) or (AF), or aryl represented by the following formula (AG): [Chem. 4](wherein,RA1, RB1, RD1, RE1, RF1, and RG1 are the same or different and 5 each represents lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, or lower alkylcarbamoyl, andRA2, RA3, RB2, RB3, RC1, and RC2 are the same or different and each represents a hydrogen atom, oxo, lower alkyl, or hydroxy-10 lower alkyl).

6. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is an aliphatic heterocyclic group represented by the following formula (AA): 15 [Chem. 5]( AA )(wherein,RA1 represents lower alkyl, lower alkylcarbonyl, or cycloalkylcarbonyl, andRA2 and RA3 are the same or different and each represents a hydrogen atom, oxo, lower alkyl, or hydroxy-lower alkyl).

7. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is an aliphatic heterocyclic group represented by the following formula (AB): [Chem. 6]1015(AB)(wherein,RB1 represents lower alkyl or lower alkylcarbonyl, andRB2 and RB3 are the same or different and each represents a hydrogen atom or oxo).

8. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is an aliphatic heterocyclic group represented by the following formula (AC): [Chem. 7]RC2(AC)(wherein, RC1 and RC2 are the same or different and each represents a hydrogen atom or oxo).

9. 5        The compound or the pharmaceutically acceptable saltthereof according to claim 1, wherein ring A is an aliphatic heterocyclic group represented by the following formula (AD): [Chem. 8]( AD)10 (wherein, RD1 represents lower alkylcarbonyl).

10. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is an aromatic heterocyclic group represented by the following formula (AE):15 [Chem. 9](wherein, RE1 represents lower alkyl).

11. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is an aromatic heterocyclic group represented by the following formula (AF): [Chem. 10]10(wherein, RF1 represents lower alkyl).

12. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is aryl represented by the following formula (AG): [Chem. 11](wherein, RG1 represents lower alkoxycarbonyl or lower alkylcarbamoyl).

13. The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein Y is -O-CH2-CH2-.

14. A targeting molecule-drug conjugate comprising a targeting molecule and a drug,wherein the drug is the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 13.

15. The targeting molecule-drug conjugate according to claim 14, wherein the drug is linked to the targeting molecule via a linker.

16. The targeting molecule-drug conjugate according to claim 15, wherein the targeting molecule-drug conjugate is represented by the following formula (II): [Chem. 12](wherein,R1 and R2 are the same or different and each represents a hydrogen atom or lower alkyl,R3 represents lower alkyl,R4 represents halogen,R5 represents halogen,R6 represents halogen or lower alkoxy,Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-,ring A represents(i) an aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl,(ii) an aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, or(iii) aryl optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl,L represents a linker,mm represents an integer of 1 to 8, andZ represents a targeting molecule).The targeting molecule-drug conjugate according to claim 16,wherein ring A represented by (i) the aliphatic heterocyclic group isthe following ring A': [Chem. 13]5(wherein, when ring A' has a substituent, the substituent of ring A' is as defined for the substituent of ring A).

18. The targeting molecule-drug conjugate according to claim 16, 10 wherein the targeting molecule-drug conjugate is represented by the following formula (II'): [Chem. 14](wherein,15         R1, R2, R3, L, mm, and Z are as defined in the formula (II),andring A' is a nitrogen-containing aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, loweralkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl).

19. The targeting molecule-drug conjugate according to claim 16, wherein L is represented by the following formula (III): [Chem. 15](wherein,wavy line 1 represents a bonding site to Z,wavy line 2 represents a bonding site to the N atom, and each Xaa independently represents(a) a residue of at least one amino acid selected from the group consisting of valine, alanine, citrulline, glycine, phenylalanine, glutamic acid, cysteic acid, arginine, asparagine, aspartic acid, glutamine, leucine, isoleucine, lysine, serine, proline, threonine, and tyrosine, or represents(b) a peptide mimetic represented by the following formula (IV):[Chem. 16]wherein,q represents an integer of 1 to 5,r represents an integer of 2 to 24,s represents 0 or 1, and t represents 1, 2, 3, or 4).

20. The targeting molecule-drug conjugate according to claim 14, wherein the targeting molecule is an antibody or an antigen binding fragment thereof, a small-molecule compound, or a peptide.

21. The targeting molecule-drug conjugate according to claim 14, wherein the targeting molecule is an antibody.

22. The targeting molecule-drug conjugate according to claim 21, wherein the antibody is an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-FoLRa antibody, an anti-CD25 antibody, an anti-CADM1 antibody, an anti-CLL1 antibody, an anti-CD38 antibody, an anti-CD74 antibody, an anti-Nectin4, or an anti-TROP2 antibody.

23. A drug-linker conjugate comprising a drug and a linker linked to the drug, whereinthe drug is the compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 13.The drug-linker conjugate according to claim 23, wherein the drug-linker conjugate is represented by the following formula (V): [Chem. 17](wherein,R1 and R2 are the same or different and each represents a hydrogen atom or lower alkyl,R3 represents lower alkyl,R4 represents halogen,R5 represents halogen,R6 represents halogen or lower alkoxy,Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-,ring A represents(i) an aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl,(ii) an aromatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-loweralkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, or(iii) aryl optionally having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl, andL represents a linker).

25. The drug-linker conjugate according to claim 24, wherein ring A represented by (i) the aliphatic heterocyclic group is the following ring A':[Chem. 18](wherein, when ring A' has a substituent, the substituent of ring A' is as defined for the substituent of ring A).

26. The drug-linker conjugate according to claim 24, wherein the drug-linker conjugate is represented by the following formula (V'): [Chem. 19](wherein,R1, R2, R3, and L are as defined in the formula (V), andring A' is a nitrogen-containing aliphatic heterocyclic group optionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl).

27. The drug-linker conjugate according to claim 24, wherein the drug-linker conjugate is represented by the following formula (Va): [Chem. 20](wherein,R1, R2, R3, R4, R5, R6, Y, and ring A are as defined above, and each Xaa independently represents(a) a residue of at least one amino acid selected from the group consisting of valine, alanine, citrulline, glycine, phenylalanine, glutamic acid, cysteic acid, arginine, asparagine, aspartic acid, glutamine, leucine, isoleucine, lysine, serine, proline, threonine, and tyrosine, or represents(b) a peptide mimetic represented by the following formula (IV):wherein,q represents an integer of 1 to 5,r represents an integer of 2 to 24,5        s represents 0 or 1, andt represents 1, 2, 3, or 4).

28. The drug-linker conjugate according to claim 27, wherein ringA represented by (i) the aliphatic heterocyclic group is the following10 ring A':[Chem. 22](wherein, when ring A' has a substituent, the substituent of ring A' is as defined for the substituent of ring A).15

29. The drug-linker conjugate according to claim 27, wherein the drug-linker conjugate is represented by the following formula (V'a): [Chem. 23](wherein,R1, R2, R3, Xaa, q, r, s, and t are as defined in the formula (Va), and5         ring A' is a nitrogen-containing aliphatic heterocyclic groupoptionally having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl, and lower alkylcarbamoyl).10

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