Divalent bet degrader and targeting molecule-drug conjugate

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

Bivalent BET Degraders and Targeting Molecule-Drug Conjugates REFERENCE TO RELATED APPLICATIONS

[0001] This patent application claims priority based on Japanese Patent Application No. 2023-212506, filed on December 15, 2023, the entire disclosure of which is incorporated herein by reference.

[0002] The present invention relates to a bivalent BET degrading agent that has a degrading effect on BET protein and a targeting molecule-drug conjugate that contains the bivalent BET degrading agent as a drug.

[0003] In humans, 46 bromodomain proteins that recognize acetylated lysines in histone proteins are known. Among these, the BET (bromodomain and extra-terminal domain) family has been reported, which recognizes acetyllysines in histones H3 and H4. The BET family includes BRD (bromodomain containing protein) 2, BRD3, BRD4, and BRDT (bromodomain testis specific protein). BET family proteins have two bromodomains (BD1 and BD2) at the N-terminus, and their sequences are highly conserved within the family. Furthermore, BET proteins have been reported to be involved in cancer proliferation [see Non-Patent Documents 1 and 2] and the progression of inflammation [see Non-Patent Document 3].

[0004] BRD4 recruits P-TEBb onto mitotic chromosomes, thereby enhancing the expression of proliferation-promoting genes. In NUT-midline carcinoma (NMC), the BRD4-NUT fusion protein has been shown to increase c-MYC protein expression [see Non-Patent Document 4]. It has also been reported that, among the genes whose expression is reduced by treatment with the BET inhibitor JQ-1 in human multiple myeloma-derived MM1.S cells, the degree of reduction in MYC gene expression is the most significant [see Non-Patent Document 5].

[0005] Representative BET inhibitors that have been reported include 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 Non-Patent Document 9], TEN-010 [see Non-Patent Document 10], and ABBV-075 [see Non-Patent Document 11], but no drugs have yet been approved by the Ministry of Health, Labour and Welfare.

[0006] In recent years, bivalent BET inhibitors have also been reported that exhibit stronger BET inhibitory activity by simultaneously inhibiting the BD1 and BD2 domains [see Non-Patent Document 12]. Known examples of such bivalent BET inhibitors include compounds represented by the following formulae (P1) to (P6) [see Non-Patent Documents 12 and 17, and Patent Documents 1, 2, and 3].

[0007]

[0008] Furthermore, compounds that degrade BET proteins via the ubiquitin-proteasome system have been reported as new BET function modulators. It is known that degrading BET proteins induces apoptosis in cancer cells more efficiently than BET inhibitors [see Non-Patent Document 13]. Therefore, BET degraders are expected to be more effective anticancer agents than BET inhibitors.

[0009] It is known that the above-mentioned bivalent compound can also be used as a BET degrading drug by linking two small molecule ligands for BET proteins via a spacer having a specific structure. More specifically, for example, compound 6j can be 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 this specification) is known [see Patent Document 4].

[0010] Antibody-drug conjugates (ADCs) generally consist of monoclonal antibodies covalently linked to drugs via chemically synthesized linkers. They combine the advantages of the highly specific targeting ability of antibodies and the potent killing effect of drugs, enabling precise and efficient elimination of target cells. Currently, the cytotoxic payloads used in FDA-approved ADCs are primarily potent tubulin inhibitors, DNA-damaging agents, and topoisomerase I inhibitors [see Non-Patent Document 14].

[0011] ADCs have been reported in which a drug that degrades BET protein, represented by the following formula (P7) (GNE-987) [see Non-Patent Document 15], and a drug that degrades BET protein, represented by the following formula (P8) (EBET-1593) [see Non-Patent Document 16], are conjugated to an antibody via a linker. However, no clinical trials have been conducted, and it was unclear whether BET degrading drugs effectively function as payloads for such antibody-drug conjugates.

[0012]

[0013] International Publication No. 2013 / 033268 Pamphlet International Publication No. 2015 / 081284 Pamphlet International Publication No. 2017 / 091673 Pamphlet International Publication No. 2021 / 065980 Pamphlet

[0014] Nature, 2011, Vol. 478, pp. 524-528; Cell, 2011, Vol. 146, pp. 904-917; Nature, 2010, Vol. 468, pp. 1119-1123; Cancer Res., 2003, Vol. 63, pp. 304-307; Cell, 2013, Vol. 153, pp. 320-334; Proceedings of the National Academy of Sciences (Proc. Natl. Acad. Sci.), 2013, Vol. 110, p. 19754-19759 Journal of Medicinal Chemistry (J. Med. Chem.), 2013, Vol. 56, pp. 7501-7515 Oncotarget, 2015, Vol. 6, pp. 17698-17712 Blood, 2015, Vol. 126, pp. 4255-4255 Molecular Cancer Ther., 2015, Vol. 14, A49 Cancer Res., 2016, Vol. 76, pp. 4718-4718 Nat. Chem. Bio., 2016, Vol. 112, pp. 17698-17712 1089-1096 Science, 2015, Vol. 348, pp. 1376-1381 Signal Transduct and Target Therapy, 2022, Vol. 1, pp. 1-25 Journal of Medicinal Chemistry (J. Med. Chem.), 2021, Vol. 64, pp. 2576-2607 Nature Communications (Nat. Commun.), 2024, Vol. 15, pp. 2192-2208 Molecular Cancer Therapeutics (Mol. Cancer Ther.), 2016, Vol. 15, pp. 2563-2574

[0015] In conducting drug discovery research into bivalent BET degraders, the present inventors discovered that while known bivalent BET degraders exhibit high antitumor activity, they suffer from peripheral neurotoxicity, a safety issue that must be avoided. The present inventors conducted various studies to solve the above-mentioned problem and discovered a bivalent BET degrader that avoids the safety issue of peripheral neurotoxicity while maintaining high antitumor activity. Furthermore, the present inventors found that the discovered bivalent BET degrader is also useful as a payload (drug) in a targeting molecule-drug conjugate such as an antibody-drug conjugate (ADC).

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

[162] . [1] A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: (In the formula, R １ and R ２ are the same or different and each represents a hydrogen atom or a lower alkyl; R ３ represents lower alkyl, R ４ represents a halogen; ５ represents a halogen; ６ represents halogen or lower alkoxy, Y is —O—CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ -, -CH=CH-CH ２ -, or -NH-C(=O)-CH ２-, 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 according to [1], wherein (i) the aliphatic heterocyclic group in ring A is a nitrogen-containing aliphatic heterocyclic group, or a pharmaceutically acceptable salt thereof. [3] The compound according to [2], wherein (i) ring A represented by a nitrogen-containing aliphatic heterocyclic group is the following ring A', or a pharmaceutically acceptable salt thereof: (In the formula, when ring A′ has a substituent, it has the same meaning as the substituent of ring A.) [4] The compound according to any one of [1] to [3], wherein the compound represented by formula (I) is a compound represented by the following formula (I′), or a pharmaceutically acceptable salt thereof: (In the formula, R １ , R ２ , and R ３has the same meaning as formula (I), 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. [5] The compound according to any one of [1] to [4], wherein 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 an aryl represented by the following formula (AG), or a pharmaceutically acceptable salt thereof: (In the formula, R Ａ１ , R Ｂ１ , R Ｄ１ , R Ｅ１ , R Ｆ１ and R Ｇ１ are the same or different and represent lower alkyl, hydroxy lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl or lower alkylcarbamoyl; R Ａ２ , R Ａ３ , R Ｂ２ , R Ｂ３ , R Ｃ１ and R Ｃ２ and each may be the same or different and represent a hydrogen atom, oxo, lower alkyl, or hydroxy lower alkyl. [6] The compound according to any one of [1] to [5], wherein ring A is a nitrogen-containing aliphatic heterocyclic group represented by the following formula (AA), or a pharmaceutically acceptable salt thereof: (In the formula, R Ａ１ represents lower alkyl, lower alkylcarbonyl or cycloalkylcarbonyl; R Ａ２ and R Ａ３ are the same or different and represent a hydrogen atom, oxo, lower alkyl, or hydroxy lower alkyl. [7] R Ａ１ [8] The compound according to [6], or a pharmaceutically acceptable salt thereof, wherein R is lower alkyl or lower alkylcarbonyl. Ａ２ and R Ａ３[9] The compound according to [6] or [7], or a pharmaceutically acceptable salt thereof, wherein R Ａ１ is lower alkyl, and R Ａ２ and R Ａ３

[10] The compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof, wherein ring A is a nitrogen-containing aliphatic heterocyclic group represented by the following formula (AB): (In the formula, R Ｂ１ represents lower alkyl or lower alkylcarbonyl; R Ｂ２ and R Ｂ３ are the same or different and represent a hydrogen atom or oxo.

[11] R Ｂ１

[12] The compound according to any one of [1] to [5], wherein ring A is a nitrogen-containing aliphatic heterocyclic group represented by the following formula (AC): (In the formula, R Ｃ１ and R Ｃ２ and each may be the same or different and represent a hydrogen atom or oxo.

[13] The compound according to any one of [1] to [5], wherein ring A is a nitrogen-containing aliphatic heterocyclic group represented by the following formula (AD), or a pharmaceutically acceptable salt thereof: (In the formula, R Ｄ１ represents a lower alkylcarbonyl).

[14] The compound according to [1], wherein ring A is an aromatic heterocyclic group represented by the following formula (AE), or a pharmaceutically acceptable salt thereof: (In the formula, R Ｅ１ represents lower alkyl).

[15] The compound according to [1], wherein ring A is an aromatic heterocyclic group represented by the following formula (AF), or a pharmaceutically acceptable salt thereof: (In the formula, R Ｆ１ represents lower alkyl).

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

[17] Y is —O—CH ２ -CH ２

[18] The compound according to any one of [1] to

[16] , wherein R １ is a hydrogen atom, and R ２ is methyl, and R ３

[19] The compound according to any one of [1] to

[17] , or a pharmaceutically acceptable salt thereof, wherein

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

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

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

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

[24] A cancer therapeutic agent comprising the compound according to any one of [1] to

[23] or a pharmaceutically acceptable salt thereof as an active ingredient.

[25] The agent according to

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

[26] A method for treating cancer, comprising administering to a subject the compound according to any one of [1] to

[23] or a pharmaceutically acceptable salt thereof.

[27] The method according to

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

[28] The compound according to any one of [1] to

[23] or a pharmaceutically acceptable salt thereof for use in treating cancer.

[29] The compound according to

[28] or a pharmaceutically acceptable salt thereof for use in treating B-cell lymphoma.

[30] Use of the compound according to any one of [1] to

[23] or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer.

[31] The use according to

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

[32] A targeting molecule-drug conjugate comprising a targeting molecule and a drug, wherein the drug is the compound according to any one of [1] to

[23] or a pharmaceutically acceptable salt thereof.

[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): (In the formula, R １ and R ２ are the same or different and each represents a hydrogen atom or a lower alkyl; R ３ represents lower alkyl, R ４ represents a halogen; ５ represents a halogen; ６ represents halogen or lower alkoxy, Y is —O—CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ -, -CH=CH-CH ２ -, or -NH-C(=O)-CH ２-, 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, (Z represents a targeting molecule.)

[35] The compound according to

[34] , or a pharmaceutically acceptable salt thereof, 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 (i) ring A represented by an aliphatic heterocyclic group is ring A' as follows: (In the formula, when ring A′ has a substituent, the substituent on ring A′ has the same meaning as the substituent on ring A.)

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

[33] to

[36] , wherein the targeting molecule-drug conjugate is represented by the following formula (II′): (In the formula, R １ , R ２ , R ３

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

[34] to

[36] , wherein L is represented by the following formula (III): (wherein, wavy line 1 represents a binding site to Z, wavy line 2 represents a binding site to an 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 (b) a residue of the following formula (IV): 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] 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 a peptide mimetic represented by the following formula (IV):

[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 one of

[38] to

[40] , wherein t is 2.

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

[38] to

[41] , wherein r is 6 or 12.

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

[38] to

[41] , wherein r is 12.

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

[38] to

[43] , wherein q is 2 or 5.

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

[38] to

[43] , wherein q is 2.

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

[38] to

[45] , wherein s is 1.

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

[32] to

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

[48] The targeting molecule-drug conjugate according to any one 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-FoLRα 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 anti-CD79b antibody has a heavy chain variable region (hereinafter sometimes referred to as "VH") comprising 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 sometimes referred to as "VL") comprising 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 of

[50] or

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

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

[50] to

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

[54] The targeting molecule-drug conjugate of

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

[55] The targeting molecule-drug conjugate according to

[54] , wherein the anti-CD19 antibody comprises a VH comprising CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 19, and a VL comprising CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 21, and a 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 the VH of the anti-CD19 antibody comprises the amino acid sequence set forth in SEQ ID NO: 7, and the amino acid sequence of the VL of the anti-CD19 antibody comprises 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 the VH of the anti-CD19 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 7, and the amino acid sequence of the VL of the anti-CD19 antibody comprises an amino acid sequence having 90% or more 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 of

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

[60] The targeting molecule-drug conjugate of

[58] or

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

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

[58] to

[60] , wherein the amino acid sequence of the VH of the anti-CD22 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 9, and the amino acid sequence of the VL of the anti-CD22 antibody comprises an amino acid sequence having 90% or more 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 comprises a VH comprising CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 67, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 68, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 69, and a VL comprising CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 70, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 71, and a 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 the VH of the anti-HER2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 29, and the amino acid sequence of the VL of the anti-HER2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 30.

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

[62] to

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

[66] The targeting molecule-drug conjugate of

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

[67] The targeting molecule-drug conjugate of

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

[68] The targeting molecule-drug conjugate of

[66] or

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

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

[66] to

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

[70] The targeting molecule-drug conjugate of

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

[71] The targeting molecule-drug conjugate according to

[70] , wherein the anti-GM2 antibody comprises a VH comprising 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 VL comprising 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 the VH of the anti-GM2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 33, and the amino acid sequence of the VL of the anti-GM2 antibody comprises 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 the VH of the anti-GM2 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 33, and the amino acid sequence of the VL of the anti-GM2 antibody comprises an amino acid sequence having 90% or more 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 of

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

[76] The targeting molecule-drug conjugate of

[74] or

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

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

[74] to

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

[78] The targeting molecule-drug conjugate of

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

[79] The targeting molecule-drug conjugate of

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

[80] The targeting molecule-drug conjugate of

[78] or

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

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

[78] to

[80] , wherein the amino acid sequence of the VH of the anti-FAP antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 37, and the amino acid sequence of the VL of the anti-FAP antibody comprises an amino acid sequence having 90% or more 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 comprises a VH comprising CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 97, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 99, and a VL comprising CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 100, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 101, and a 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 the VH of the anti-SSTR2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 39, and the amino acid sequence of the VL of the anti-SSTR2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 40.

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

[82] to

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

[86] The targeting molecule-drug conjugate of

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

[87] The targeting molecule-drug conjugate of

[86] , wherein the anti-CD30 antibody comprises a VH comprising CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 103, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 104, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 105, and a VL comprising CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 106, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 107, and a 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 the VH of the anti-CD30 antibody comprises the amino acid sequence of SEQ ID NO: 41, and the amino acid sequence of the VL of the anti-CD30 antibody comprises the amino acid sequence of SEQ ID NO: 42.

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

[86] to

[88] , wherein the amino acid sequence of the VH of the anti-CD30 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence of SEQ ID NO: 41, and the amino acid sequence of the VL of the anti-CD30 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence of 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 described in

[90] , wherein the anti-BCMA antibody comprises a VH comprising 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 VL comprising 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 of

[90] or

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

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

[90] to

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

[94] The targeting molecule-drug conjugate of

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

[95] The targeting molecule-drug conjugate of

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

[96] The targeting molecule-drug conjugate of

[94] or

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

[99] The targeting molecule-drug conjugate of

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

[100] The targeting molecule-drug conjugate of

[98] or

[99] , wherein the amino acid sequence of the VH of the anti-FoLRα antibody comprises the amino acid sequence set forth in SEQ ID NO: 47, and the amino acid sequence of the VL of the anti-FoLRα antibody comprises 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 the VH of the anti-FoLRα antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 47, and the amino acid sequence of the VL of the anti-FoLRα antibody comprises an amino acid sequence having 90% or more 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 comprises a VH comprising CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 127, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 128, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 129, and a VL comprising CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 130, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 131, and a 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 the VH of the anti-CD25 antibody comprises the amino acid sequence set forth in SEQ ID NO: 49, and the amino acid sequence of the VL of the anti-CD25 antibody comprises 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 the VH of the anti-CD25 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 49, and the amino acid sequence of the VL of the anti-CD25 antibody comprises an amino acid sequence having 90% or more 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 comprises a VH comprising 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 VL comprising 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 the VH of the anti-CADM1 antibody comprises the amino acid sequence of SEQ ID NO: 51, and the amino acid sequence of the VL of the anti-CADM1 antibody comprises the amino acid sequence of SEQ ID NO: 52.

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

[106] to

[108] , wherein the amino acid sequence of the VH of the anti-CADM1 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence of SEQ ID NO: 51, and the amino acid sequence of the VL of the anti-CADM1 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence of 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 comprises a VH comprising 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 VL comprising 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 the VH of the anti-CLL1 antibody comprises the amino acid sequence of SEQ ID NO: 53, and the amino acid sequence of the VL of the anti-CLL1 antibody comprises the amino acid sequence of SEQ ID NO: 54.

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

[110] to

[112] , wherein the amino acid sequence of the VH of the anti-CLL1 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence of SEQ ID NO: 53, and the amino acid sequence of the VL of the anti-CLL1 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence of 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 comprises a VH comprising CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 145, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 146, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 147, and a VL comprising CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 148, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 149, and a 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 the VH of the anti-CD38 antibody comprises the amino acid sequence set forth in SEQ ID NO: 55, and the amino acid sequence of the VL of the anti-CD38 antibody comprises 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 the VH of the anti-CD38 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 55, and the amino acid sequence of the VL of the anti-CD38 antibody comprises an amino acid sequence having 90% or more 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 of

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

[120] The targeting molecule-drug conjugate of

[118] or

[119] , wherein the amino acid sequence of the VH of the anti-CD74 antibody comprises the amino acid sequence set forth in SEQ ID NO: 57, and the amino acid sequence of the VL of the anti-CD74 antibody comprises 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 the VH of the anti-CD74 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and the amino acid sequence of the VL of the anti-CD74 antibody comprises an amino acid sequence having 90% or more 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-Nectin 4 antibody.

[123] The targeting molecule-drug conjugate according to

[122] , wherein the anti-Nectin 4 antibody comprises a VH comprising 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 VL comprising 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 the VH of the anti-Nectin4 antibody comprises the amino acid sequence set forth in SEQ ID NO: 183, and the amino acid sequence of the VL of the anti-Nectin4 antibody comprises 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 the VH of the anti-Nectin4 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 183, and the amino acid sequence of the VL of the anti-Nectin4 antibody comprises an amino acid sequence having 90% or more 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 comprises a VH comprising 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 VL comprising 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 the VH of the anti-TROP2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 185, and the amino acid sequence of the VL of the anti-TROP2 antibody comprises 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 the VH of the anti-TROP2 antibody comprises an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 185, and the amino acid sequence of the VL of the anti-TROP2 antibody comprises an amino acid sequence having 90% or more 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 the amino acid sequence of the antibody heavy chain constant region (hereinafter may be referred to as "CH") comprises: (a) the amino acid sequence of SEQ ID NO: 1, or (b) an amino acid sequence having 80% or more sequence identity to the amino acid sequence of SEQ ID NO: 1.

[131] The targeting molecule-drug conjugate according to

[130] , wherein the amino acid sequence (b) is an amino acid sequence in which at least one amino acid in the amino acid sequence of SEQ ID NO: 1 has been substituted with cysteine.

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

[48] to

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

[133] The targeting molecule-drug conjugate according to

[132] , wherein the antibody is bonded to a linker L via the 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 the amino acid sequence of the antibody light chain constant region (hereinafter sometimes referred to as "CL") comprises: (e) the amino acid sequence set forth in SEQ ID NO: 3, or (f) an amino acid sequence having 80% or more 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 the amino acid sequence set forth in SEQ ID NO: 3 in which at least one amino acid is substituted with cysteine.

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

[48] to

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

[137] The targeting molecule-drug conjugate according to

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

[138] A cancer therapeutic agent comprising the targeting molecule-drug conjugate according to any one of

[32] to

[137] as an active ingredient.

[139] The agent according to

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

[140] A cancer therapeutic method, comprising administering to a subject the targeting molecule-drug conjugate according to any one of

[32] to

[137] .

[141] The method according to

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

[142] The targeting molecule-drug conjugate according to any one 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 manufacture of a medicament for treating 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 according to any one of [1] to

[23] or a pharmaceutically acceptable salt thereof.

[147] The drug-linker conjugate according to

[146] , which is represented by the following formula (V): (In the formula, R １ and R ２ are the same or different and each represents a hydrogen atom or a lower alkyl; R ３ represents lower alkyl, R ４ represents a halogen; ５ represents a halogen; ６ represents halogen or lower alkoxy, Y is —O—CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ -, -CH=CH-CH ２ -, or -NH-C(=O)-CH ２(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) an 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 according to

[147] or a pharmaceutically acceptable salt thereof, 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 (i) ring A represented by an aliphatic heterocyclic group is ring A' shown below: (In the formula, when ring A′ has a substituent, the substituent on ring A′ has the same meaning as the substituent on ring A.)

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

[146] to

[149] , wherein the drug-linker conjugate is represented by the following formula (V′): (In the formula, R １ , R ２ , R ３ and L are as defined in 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): (In the formula, R １ , R ２, R ３ , R ４ , R ５ , R ６ , Y and ring A are as defined above, and each Xaa independently represents (a) at least one amino acid residue 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 (b) a group represented by the following formula (IV): 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.

[152] The compound according to

[151] or a pharmaceutically acceptable salt thereof, 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 (i) ring A represented by an aliphatic heterocyclic group is ring A' shown below: (In the formula, when ring A′ has a substituent, the substituent on ring A′ has the same meaning as the substituent on ring A.)

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

[146] to

[153] , wherein the drug-linker conjugate is represented by the following formula (V′a): (In the formula, R １ , R ２ , R ３ Xaa, q, r, s, and t are defined as in 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] Each Xaa is independently a residue of an amino acid selected from valine, alanine, citrulline, glycine, phenylalanine, and glutamic acid, or a group represented by the following formula (IV):

[156] The drug-linker conjugate of any of

[151] to

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

[157] The drug-linker conjugate of any of

[151] to

[156] , wherein t is 2.

[158] The drug-linker conjugate of any of

[151] to

[157] , wherein r is 6 or 12.

[159] The drug-linker conjugate of any of

[151] to

[158] , wherein r is 12.

[160] The drug-linker conjugate of any of

[151] to

[159] , wherein q is 2 or 5.

[161] The drug-linker conjugate of any of

[151] to

[160] , wherein q is 2.

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

[151] to

[161] , wherein s is 1.

[0017] The compound represented by formula (I) or a pharmaceutically acceptable salt thereof is a divalent BET degrader, and can avoid the safety issue of peripheral neurotoxicity while maintaining high antitumor activity. The compound represented by formula (I) or a 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] A targeting molecule-drug conjugate containing the compound represented by formula (I) or a pharmaceutically acceptable salt thereof as a drug can avoid the safety issue of peripheral neurotoxicity while maintaining high antitumor activity.

[0019] Figure 1 shows the results of Test Example 4 (in vivo efficacy evaluation of compounds and ADCs), and Figure 2 shows the results of Test Example 5 (evaluation of BET protein degradation by Western blotting (WB) using the SU-DHL-4 cell line).

[0020] The present invention will be described below. In this specification, the expression "value A to value B" means value A or more and value B or less. Two or more embodiments described in this specification can be combined, and such combinations of two or more embodiments are also encompassed by the present invention.

[0021] <Explanation of Terms> The terms used in this specification are explained below. The following explanations apply throughout this specification unless otherwise specified.

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

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

[0024] Hydroxy lower alkyl is a lower alkyl in which one or more hydrogen atoms are substituted with hydroxy. The explanation regarding lower alkyl is as above. The position and number of hydroxy in a hydroxy lower alkyl are not particularly limited. The number of hydroxy is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1. Examples of hydroxy lower alkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-dihydroxyethyl, and 1,2-dihydroxypropyl.

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

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

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

[0028] Halogens Halogens are fluorine, chlorine, bromine, and iodine atoms.

[0029] Lower alkoxy is, for example, a straight-chain or branched alkoxy having 1 to 10 carbon atoms, preferably an alkoxy having 1 to 5 carbon atoms, and more preferably an alkoxy having 1 to 3 carbon atoms. Examples of lower alkoxy include methoxy, ethoxy, propyloxy, i-propyloxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, etc., and preferably methoxy.

[0030] Lower alkoxycarbonyl Lower alkoxycarbonyl is a group represented by the formula: -CO-lower alkoxy. The explanation for lower alkoxy is as above. The lower alkoxycarbonyl is, for example, a straight-chain or branched alkoxycarbonyl having 1 to 11 carbon atoms, preferably an alkoxycarbonyl having 1 to 5 carbon atoms, and more preferably an alkoxycarbonyl having 1 to 3 carbon atoms. Examples of the lower alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, neopentoxycarbonyl, etc., and preferably methoxycarbonyl or ethoxycarbonyl.

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

[0032] Aliphatic heterocyclic group An aliphatic heterocyclic group contains, in addition to carbon atoms, one or more heteroatoms other than carbon atoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms as ring-constituting elements. The number of heteroatoms in the aliphatic heterocyclic group is, for example, 1 to 3, preferably 1 or 2, and 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 of the aliphatic heterocyclic group.

[0033] In the aliphatic heterocyclic group, two carbon atoms constituting the ring may be bridged by an alkylene group. The number of carbon atoms in the alkylene group bridging the two carbon atoms constituting the ring is, for example, 1 to 3, preferably 1 or 2, and even more preferably 1.

[0034] The aliphatic heterocyclic group may be composed of only saturated bonds or may contain double bonds, but is preferably composed of only saturated bonds.

[0035] The aliphatic heterocyclic group may be a monocyclic group or a fused polycyclic group, such as a fused bicyclic group or a fused tricyclic group, preferably a fused bicyclic group.

[0036] The monocyclic aliphatic heterocyclic group has, for example, 3 to 8 members, preferably 4 to 8 members, more preferably 5 to 7 members, and even more preferably 6 or 7 members.

[0037] Examples of monocyclic aliphatic heterocyclic groups include aliphatic heterocyclic groups containing only nitrogen atoms as heteroatoms, 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 aliphatic heterocyclic groups containing nitrogen and oxygen atoms as heteroatoms include oxazolidinyl, oxazolinyl, and morpholinyl. Examples of aliphatic heterocyclic groups containing nitrogen and sulfur atoms as heteroatoms include thiazolidinyl, thiazolinyl, and thiomorpholinyl. Preferred are piperazinyl and 1,4-diazepanyl, and more preferred is piperazinyl.

[0038] The fused polycyclic aliphatic heterocyclic group is, for example, an aliphatic heterocyclic group containing only nitrogen atoms as heteroatoms, such as a bicyclic or tricyclic nitrogen-containing aliphatic heterocyclic group in which 3- to 8-membered rings are fused, and specific examples thereof include hexahydropyrrolopyrazinyl, octahydropyridopyrazinyl, octahydropyrrolodiazepanyl, decahydropyridodiazepanyl, and decahydroazepinodiazepanyl.

[0039] Nitrogen-Containing Aliphatic Heterocyclic Group A nitrogen-containing aliphatic heterocyclic group is an aliphatic heterocyclic group containing, in addition to carbon atoms, one or more nitrogen atoms as ring constituent elements. The number of nitrogen atoms in the nitrogen-containing aliphatic heterocyclic group is, for example, 1 to 3, preferably 1 or 2, and more preferably 2. The number of carbon atoms in the nitrogen-containing aliphatic heterocyclic group is appropriately determined depending on the number of heteroatoms and the number of members of the nitrogen-containing aliphatic heterocyclic group. The bond of the nitrogen-containing aliphatic heterocyclic group is not particularly limited, but it is preferable that the bond be carried by a nitrogen atom. The nitrogen-containing aliphatic heterocyclic group may contain one or more heteroatoms other than nitrogen atoms selected from the group consisting of oxygen atoms and sulfur atoms. When the nitrogen-containing aliphatic heterocyclic group contains a heteroatom other than nitrogen atoms, the number of heteroatoms other than nitrogen atoms is, for example, 1 or 2, preferably 1.

[0040] In the nitrogen-containing aliphatic heterocyclic group, two carbon atoms constituting the ring may be bridged by an alkylene group. The number of carbon atoms in the alkylene group bridging the two carbon atoms constituting the ring is, for example, 1 to 3, preferably 1 or 2, and even more preferably 1.

[0041] The nitrogen-containing aliphatic heterocyclic group may be constituted solely by saturated bonds or may contain double bonds, but is preferably constituted solely by saturated bonds.

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

[0043] The monocyclic nitrogen-containing aliphatic heterocyclic group has, for example, 3 to 8 members, preferably 4 to 8 members, more preferably 5 to 7 members, and even more preferably 6 or 7 members.

[0044] Examples of monocyclic nitrogen-containing aliphatic heterocyclic groups 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, diazocanyl, etc. Preferred are piperazinyl or 1,4-diazepanyl, and more preferred is piperazinyl.

[0045] The fused polycyclic nitrogen-containing aliphatic heterocyclic group is, for example, a bicyclic or tricyclic nitrogen-containing aliphatic heterocyclic group in which 3- to 8-membered rings are fused, and specific examples thereof include hexahydropyrrolopyrazinyl, octahydropyridopyrazinyl, octahydropyrrolodiazepanyl, decahydropyridodiazepanyl, and decahydroazepinodiazepanyl.

[0046] Aromatic heterocyclic group An aromatic heterocyclic group contains, in addition to carbon atoms, one or more heteroatoms other than carbon atoms selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms as ring-constituting elements. 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 of the aromatic heterocyclic group.

[0047] The aromatic heterocyclic group may be a monocyclic group or a fused polycyclic group, such as a fused bicyclic group or a fused tricyclic group, preferably a fused bicyclic group.

[0048] The aromatic heterocyclic group has, for example, 5 to 10 members, preferably 5 to 9 members, and more preferably 5 or 6 members.

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

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

[0051] The aryl may be a monocyclic or a fused polycyclic ring, such as a fused bicyclic or fused tricyclic ring, preferably a fused bicyclic ring.

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

[0053] Antibodies Antibodies (immunoglobulins) are glycoproteins consisting of two heavy chains (hereinafter also referred to as "H chains") and two light chains (hereinafter also referred to as "L chains"). There are five classes of antibodies: IgG, IgM, IgA, IgD, and IgE. The basic structure of antibodies is common to all classes, with two heavy chains and two light chains bound by disulfide bonds and non-covalent bonds to form a Y-shaped four-chain structure.

[0054] The domain located at the N-terminus of both the heavy chain and the light chain is called the variable region and is involved in the binding specificity between the antibody and the antigen. The amino acid sequence of the domain on the C-terminal side downstream of the variable region is called the constant region (hereinafter also referred to as the "C region"). The heavy chain has a heavy chain variable region (VH) and a heavy chain constant region (CH) from the N-terminus to the C-terminus. The CH is further divided into three domains from the N-terminus: a CH1 domain, a CH2 domain, and a CH3 domain. The light chain has a light chain variable region (VL) and a light chain constant region (CL) from the N-terminus to the C-terminus.

[0055] Each VH and VL has three complementarity-determining regions (CDRs): CDR1, CDR2, and CDR3. Because CDRs determine antigen specificity, their amino acid sequences vary significantly between antibodies and are also called hypervariable regions. The portions of the variable regions other than the CDRs are called framework regions (FRs), and show relatively little variation in amino acid sequence. CDR1, CDR2, and CDR3 present in VH are also called CDRH1, CDRH2, and CDRH3, respectively, and CDR1, CDR2, and CDR3 present in VL are also called CDRL1, CDRL2, and CDRL3, respectively.

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

[0057] As used herein, the amino acid positions of the constant region 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 a monoclonal antibody, but is preferably a monoclonal antibody.

[0059] Examples of monoclonal antibodies include antibodies produced by hybridomas and recombinant antibodies produced by transformants transformed with expression vectors containing antibody genes.

[0060] A monoclonal antibody is an antibody secreted by a single clone of antibody-producing cells, and recognizes only one epitope (also called an antigenic determinant). The amino acid sequence (primary structure) that constitutes a monoclonal antibody is uniform.

[0061] Hybridomas can be prepared, for example, by using an animal immunized with an antigen to induce antibody-producing cells with antigen specificity and fusing the antibody-producing cells with myeloma cells. Monoclonal antibodies can be obtained by culturing hybridomas or by administering the hybridoma cells to an animal to cause ascites cancer in the animal, and isolating and purifying monoclonal antibodies from the culture medium or ascites. Any animal can be immunized with the antigen as long as it is capable of producing hybridomas, but mice, rats, hamsters, chickens, rabbits, etc. are preferred. Monoclonal antibodies may also be antibodies produced by hybridomas produced by obtaining antibody-producing cells from an animal, immunizing the cells in vitro, and fusing the cells with myeloma cells.

[0062] Examples of recombinant antibodies include antibodies produced by genetic recombination, such as human chimeric antibodies, humanized antibodies, and human antibodies.

[0063] A human chimeric antibody is an antibody consisting of the VH and VL of an antibody of a non-human animal and the CH and CL of a human antibody. A human chimeric antibody can be produced by obtaining DNA encoding the VH and VL of an antibody of a non-human animal, inserting the DNA into an expression vector for animal cells containing DNA encoding the CH and CL of a human antibody to construct a human chimeric antibody expression vector, and introducing the vector into animal cells for expression.

[0064] The CH of the human chimeric antibody may be any one that belongs to the human immunoglobulin (hereinafter sometimes referred to as "hIg") class, for example, a CH of the hIgG class, specifically a CH of the hIgG subclass such as hIgG1, hIgG2, hIgG3, or hIgG4, or a modified version thereof. The CL of the human chimeric antibody may be any one that belongs to the hIg class, for example, a CL of a human κ chain or a human λ chain.

[0065] Humanized antibodies include human CDR-grafted antibodies and antibodies humanized by surface reconstruction. Antibodies produced by a combination of these humanized antibody production methods are also included in the humanized antibody category. Humanized antibodies also include antibodies that have an amino acid sequence in which one or more amino acids have been deleted, substituted, inserted, or added from the amino acid sequence of a humanized antibody designed by these methods, and that bind (preferably specifically bind) to a target antigen.

[0066] A human CDR-grafted antibody is an antibody in which the amino acid sequences of the CDRs of the VH and VL of a non-human animal antibody are grafted into appropriate positions in the VH and VL of a human antibody. Human CDR-grafted antibodies can be produced as follows: A DNA encoding a V region in which the amino acid sequences of the CDRs of the VH and VL of a non-human animal monoclonal antibody that binds (preferably specifically binds) to an antigen of interest are grafted into the framework regions (FR) of the VH and VL of any human antibody is constructed. The DNA is then inserted into an expression vector for animal cells containing DNA encoding the CH and CL of the human antibody to construct a human CDR-grafted antibody expression vector, which is then introduced into animal cells for expression.

[0067] Humanized antibodies using surface reconstruction methods are antibodies in which, using surface reconstruction methods (Proc. Natl. Acad. Sci. USA 1994, 91(3):969-73 and Protein Engineering 1996, 10, 895-90), amino acid residues in the FR of the variable regions of a non-human animal antibody that are thought not to affect the binding activity of the antibody are substituted with amino acid residues thought to reduce antigenicity. Humanized antibodies using surface reconstruction methods can be produced as follows. Specifically, DNA is constructed to encode a V region in which any amino acid residue in the FR of the VH and VL of a non-human animal monoclonal antibody that binds (preferably specifically binds) to the target antigen is substituted with another amino acid residue. The DNA is then inserted into an animal cell expression vector containing DNA encoding the CH and CL of the human antibody, respectively, to construct a humanized antibody expression vector using surface reconstruction methods, and the antibody is expressed by introducing it into animal cells.

[0068] The CH of the humanized antibody may be any one that belongs to the human immunoglobulin (hereinafter sometimes referred to as "hIg") class, for example, a CH of the hIgG class, specifically a CH of the hIgG subclass such as hIgG1, hIgG2, hIgG3, or hIgG4, or a modified version thereof. The CL of the humanized antibody may be any one that belongs to the hIg class, for example, a CL of a human κ chain or a human λ chain.

[0069] Human antibodies originally refer to antibodies that naturally occur in the human body, but also include human antibody phage libraries produced through recent advances in genetic engineering, cell engineering, and developmental engineering technologies, and antibodies obtained from human antibody-producing transgenic animals.

[0070] Antibodies naturally occurring in the human body can be obtained by, for example, isolating human peripheral blood lymphocytes, infecting them with EB virus or the like to immortalize them, cloning them, culturing lymphocytes that produce the antibodies, and purifying the antibodies from the culture supernatant.

[0071] A human antibody phage library is a library in which antibody fragments such as Fab and scFv are expressed on the surface of phages by inserting antibody genes prepared from human B cells or B cells of human antibody-producing transgenic animals into phage genes. Phages expressing antibody fragments with the desired antigen-binding activity on their surface can be recovered from the library using their binding activity toward an antigen-immobilized substrate as an indicator. These antibody fragments can also be converted into human antibody molecules consisting of two complete heavy chains and two complete light chains by genetic engineering techniques.

[0072] A human antibody-producing transgenic animal refers to an animal in which a human antibody gene has been incorporated into its cells. Specifically, for example, a human antibody-producing transgenic mouse can be produced by introducing a human antibody gene into mouse ES cells, transplanting the ES cells into an early mouse embryo, and then allowing the embryo to develop. Human antibodies from a human antibody-producing transgenic animal can be produced by obtaining a human antibody-producing hybridoma using a hybridoma production method typically used in non-human animals, culturing the hybridoma, and producing and accumulating human antibodies in the culture supernatant. Alternatively, human antibody genes can be isolated by isolating and cloning B cells from a human antibody-producing transgenic animal.

[0073] Antigen-binding fragment of antibody An antigen-binding fragment of an antibody is a fragment of an antibody that has binding activity to a target antigen. An antigen-binding fragment of an antibody is also called a functional fragment of an antibody. Examples of antigen-binding fragments of an antibody include Fab, F(ab') ２ , Fab', single chain antibodies (scFv), dimerized V regions (diabodies), disulfide stabilized V regions (dsFv), peptides containing CDRs, and the like.

[0074] Fab is a fragment obtained by treating an antibody with papain, in which approximately the N-terminal half of the heavy chain and the entire L chain are linked by a disulfide bond, and has a molecular weight of approximately 50,000 and has antigen-binding activity. Fab can be obtained by treating an antibody with papain. Fab can also be produced by inserting DNA encoding the Fab of an antibody into a prokaryotic or eukaryotic expression vector and introducing the vector into a prokaryotic or eukaryotic organism for expression.

[0075] F(ab') ２ F(ab') is a fragment with a molecular weight of approximately 100,000 that has antigen-binding activity and is composed of two Fab regions linked at the hinge region, obtained by pepsin digestion of the lower disulfide bond in the hinge region of an antibody. ２ can be obtained by treating an antibody with pepsin. ２ can be produced by bonding Fab' to a thioether bond or a disulfide bond.

[0076] Fab' is F(ab') ２ Fab' is a fragment having an antigen-binding activity and a molecular weight of approximately 50,000, which can be obtained by cleaving the disulfide bond in the hinge region of F(ab'). ２ Fab' can be obtained by treating Fab' with a reducing agent such as dithiothreitol. Fab' can also be produced by inserting a DNA encoding Fab' into an expression vector for prokaryotes or eukaryotes, and then introducing the vector into a prokaryote or eukaryote for expression.

[0077] An scFv is a fragment having antigen-binding activity in which one VH and one VL are linked by an appropriate peptide linker (hereinafter referred to as P), and is represented by VH-P-VL or VL-P-VH.

[0078] An scFv can be produced by constructing DNA encoding the scFv using DNA encoding VH and VL, inserting the DNA into an expression vector for prokaryotes or eukaryotes, and introducing the expression vector into a prokaryote or eukaryote for expression.

[0079] A diabody is a dimerized scFv fragment and has bivalent antigen-binding activity. The bivalent antigen-binding activities may be the same or different.

[0080] Diabodies can be produced by constructing DNA encoding scFv using DNA encoding VH and VL such that the amino acid sequence of the peptide linker is 8 residues or less in length, inserting the DNA into an expression vector for prokaryotes or eukaryotes, and introducing the expression vector into a prokaryote or eukaryote for expression.

[0081] dsFv is a polypeptide in which one amino acid residue in each of VH and VL is substituted with a cysteine ​​residue, and the cysteine ​​residues are linked via a disulfide bond between the two polypeptides. The amino acid residue to be substituted with a cysteine ​​residue can be selected based on the predicted three-dimensional structure of an antibody according to a known method [Protein Engineering, 7, 697 (1994)].

[0082] dsFv can be produced by constructing DNA encoding the dsFv using cDNA encoding VH and VL, inserting the DNA into an expression vector for prokaryotes or eukaryotes, and introducing the expression vector into a prokaryote or eukaryote for expression.

[0083] A CDR-containing peptide comprises at least one CDR region of VH or VL. Peptides containing multiple CDRs can be linked together directly or via a suitable peptide linker.

[0084] CDR-containing peptides can be produced by constructing DNA encoding the VH and VL CDRs, inserting the DNA into a prokaryotic or eukaryotic expression vector, and introducing the expression vector into a prokaryotic or eukaryotic organism for expression. CDR-containing peptides can also be produced by chemical synthesis methods such as the Fmoc method and the Boc method.

[0085] Bispecific and multispecific antibodies An antibody or its antigen-binding fragment may have binding specificity for one type of antigen, or may have binding specificity for two or more different antigens. Herein, an antibody or its antigen-binding fragment having binding specificity for two or more different antigens is referred to as a multispecific antibody. A multispecific antibody is, for example, an antibody or its antigen-binding fragment having binding specificity for two different antigens (i.e., a bispecific antibody), but it may also be an antibody or its antigen-binding fragment having binding specificity for three or more different antigens.

[0086] Examples of multispecific antibody formats include those described in WO 2009 / 131239, WO 2014 / 054804, WO 2001 / 077342, WO 2007 / 024715, Wu et al., Nature Biotechnology, 2007, 25(11), pp. 1290-1297, Labrijn et al., PNAS 2013, vol. 110, no. 13, pp. 5145-5150, Jong et al., PLoS Biology 2016, vol. 14, no. 1, e1002344, and Kontermann et al. , mAbs 2012, vol. 4, issue 2, pp. 182-197, Spiess et al., Molecular Immunology 67 (2015) 95-106, Ridgway et al., Protein engineering, 1996 vol. 9 no. 7 pp. 617-621, WO 2009 / 080251, WO 2010 / 151792, and WO 2014 / 033074, and the formats described therein can be prepared using the methods described in these documents.

[0087] Deletion, substitution, insertion or addition of amino acids Deletion, substitution, insertion or addition of amino acids to a predetermined amino acid sequence can be performed by site-directed mutagenesis [Molecular Cloning 2nd Edition, Cold Spring Harbor Laboratory Press (1989), Current Protocols in molecular 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 amino acids in a predetermined amino acid sequence includes cases where two or more types selected from deletion, substitution, insertion and addition occur.

[0089] The amino acid residues to be substituted, inserted, or added may be naturally occurring or non-naturally occurring. Examples of naturally occurring amino acids 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] Preferred examples of amino acids that can be substituted for each other are shown below. Amino acids in the same group can be substituted for each other. Group A: leucine, isoleucine, norleucine, valine, norvaline, alanine, 2-aminobutanoic acid, methionine, O-methylserine, t-butylglycine, t-butylalanine, cyclohexylalanine Group B: aspartic acid, glutamic acid, isoaspartic acid, isoglutamic acid, 2-aminoadipic acid, 2-aminosuberic acid Group C: asparagine, glutamine Group D: lysine, arginine, ornithine, 2,4-diaminobutanoic acid, 2,3-diaminopropionic acid Group E: proline, 3-hydroxyproline, 4-hydroxyproline Group F: serine, threonine, homoserine Group G: phenylalanine, tyrosine

[0091] Sequence Identity When used in relation to the sequence identity of two amino acid sequences, the term "%" refers to the percentage of the number of identical amino acids relative to the total number of amino acids (including gaps) when the two amino acid sequences are aligned to maximize amino acid identity.

[0092] <<First Aspect>> According to the first aspect of the present invention, there is provided a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof. In this specification, the compound represented by the following formula (I) may be referred to as "compound (I)." Compound (I) or a pharmaceutically acceptable salt thereof is a divalent BET degrader, and can avoid the safety issue of peripheral neurotoxicity while maintaining high antitumor activity. Compound (I) or a 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]

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

[0095] Compound (I) or a pharmaceutically acceptable salt thereof may exist as stereoisomers such as geometric isomers and optical isomers, tautomers, etc., and the present invention encompasses all possible isomers and mixtures thereof, including these.

[0096] Some or all of the atoms in compound (I) or a pharmaceutically acceptable salt thereof may be replaced with corresponding isotopic atoms, and the present invention also encompasses compounds replaced with these isotopic atoms. For example, some or all of the hydrogen atoms in compound (I) or a pharmaceutically acceptable salt thereof may be hydrogen atoms with an atomic weight of 2 (deuterium atoms).

[0097] A compound in which some or all of the atoms in compound (I) or a pharmaceutically acceptable salt thereof are replaced with the corresponding isotope atoms can be produced using commercially available building blocks in the same manner as the production method described below. Furthermore, a compound in which some or all of the hydrogen atoms in compound (I) or a pharmaceutically acceptable salt thereof are replaced with deuterium atoms can be produced by, for example, 1) a method of deuterizing carboxylic acids and the like under basic conditions using deuterium peroxide (see U.S. Pat. No. 3,849,458), 2) a method of deuterizing alcohols, carboxylic acids and the like using an iridium complex as a catalyst and heavy water as a deuterium source [see Journal of American Chemical Society (J. Am. Chem. Soc.), Vol. 124, No. 10, 2092 (2002)], or 3) a method of deuterizing fatty acids using palladium carbon as a catalyst and deuterium gas alone as a deuterium source [see Lipids, Vol. 9, No. 11, 913 (1974)], 4) a method of deuterizing acrylic acid, methyl acrylate, methacrylic acid, methyl methacrylate, or the like using a metal such as platinum, palladium, rhodium, ruthenium, iridium, or the like as a catalyst and heavy water or heavy water and deuterium gas as a heavy hydrogen source (see JP-B-5-19536, JP-A-61-277648, and JP-A-61-275241), 5) a method of deuterizing acrylic acid, methyl methacrylate, or the like using a catalyst such as palladium, nickel, copper, or copper chromite, and heavy water as a heavy hydrogen source (see JP-A-63-198638), or the like.

[0098] When compound (I) or a pharmaceutically acceptable salt thereof is to be obtained, if compound (I) is obtained in the form of a salt, it may be purified as is, or if compound (I) is obtained in the free form, it may be dissolved or suspended in a suitable solvent, and an acid or a base may be added to form a salt, which may then be isolated and purified.

[0099] Furthermore, Compound (I) or a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also encompassed by the present invention.

[0100] In the above formula (I), R１ and R ２ are the same or different and each represents a hydrogen atom or a lower alkyl. １ and R ２ The lower alkyls in the formula (I) may be the same or different and are preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

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

[0102] In the above formula (I), R ４ represents a halogen. ４ Examples of the halogen in R include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and preferably a fluorine atom or a chlorine atom. ４ The number of R is 0 to 2, preferably 0 or 1. ４ If there are two R ４ may be the same or different.

[0103] In the above formula (I), R ５ represents a halogen. ５ Examples of the halogen in R include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a chlorine atom is preferred. ５ The number of R is 0 to 2, preferably 0 or 1. ５ If there are two R ５ may be the same or different.

[0104] In the above formula (I), R ６ represents halogen or lower alkoxy. ６ Examples of the halogen in R include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a fluorine atom is preferred. ６The lower alkoxy in R is preferably an alkoxy having 1 to 5 carbon atoms, more preferably an alkoxy having 1 to 3 carbon atoms, even more preferably methoxy or ethoxy, and even more preferably methoxy. ６ The number of R is 0 to 2, preferably 0 or 1. ６ If there are two R ６ may be the same or different.

[0105] In the above formula (I), Y is, for example, —O—CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ -, -CH=CH-CH ２ -, or -NH-C(=O)-CH ２ -, preferably -O-CH ２ -CH ２ - is.

[0106] Compounds of the invention having one or more asymmetric carbon atoms can exist as two or more stereoisomers. The use of a solid line to represent a bond to an asymmetric carbon atom is meant to indicate that all possible stereoisomers at that carbon atom are included (e.g., diastereomeric mixtures, racemic mixtures, specific enantiomers, etc.).

[0107] In a preferred embodiment, R １ is a hydrogen atom, and R ２ is lower alkyl, and R ３ is lower alkyl, and R ４ is absent (i.e., 0) or halogen, and R ５ is absent (i.e., 0) or halogen, and R ６ is absent (i.e., 0), halogen, or lower alkoxy, and Y is —O—CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ -, -CH=CH-CH ２ -, or -NH-C(=O)-CH ２ - is.

[0108] In a more preferred embodiment, R １ is a hydrogen atom, and R ２ is a lower alkyl having 1 to 5 carbon atoms, and R ３ is a lower alkyl having 1 to 5 carbon atoms, and R ４ is absent or a fluorine atom, and R ５ is absent or a chlorine atom, and R ６ is absent, a fluorine atom, or a lower alkoxy having 1 to 5 carbon atoms, and Y is —O—CH ２ -CH ２ - is.

[0109] In an even more preferred embodiment, R １ is a hydrogen atom, and R ２ is a lower alkyl having 1 to 3 carbon atoms, and R ３ is a lower alkyl having 1 to 3 carbon atoms, and R ４ is absent or a fluorine atom, and R ５ is absent or a chlorine atom, and R ６ is absent, a fluorine atom, or a lower alkoxy having 1 to 3 carbon atoms, and Y is —O—CH ２ -CH ２ - is.

[0110] In an even more preferred embodiment, R １ is a hydrogen atom, and R ２ is methyl, and R ３ is ethyl, and R ４ does not exist, and R ５ does not exist, and R ６ is not present and Y is —O—CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ -, -CH=CH-CH ２ -, or -NH-C(=O)-CH ２ In another even more preferred embodiment, R １ is a hydrogen atom, and R ２ is methyl, and R ３ is ethyl, and R ４ is a fluorine atom, and R ５ does not exist, and R ６is not present and Y is —O—CH ２ -CH ２ In another even more preferred embodiment, R １ is a hydrogen atom, and R ２ is methyl, and R ３ is ethyl, and R ４ does not exist, and R ５ is a chlorine atom, and R ６ is not present and Y is —O—CH ２ -CH ２ In another even more preferred embodiment, R １ is a hydrogen atom, and R ２ is methyl, and R ３ is ethyl, and R ４ does not exist, and R ５ does not exist, and R ６ is a fluorine atom, and Y is —O—CH ２ -CH ２ - or -CH ２ -CH ２ -CH ２ In another even more preferred embodiment, R １ is a hydrogen atom, and R ２ is methyl, and R ３ is ethyl, and R ４ does not exist, and R ５ does not exist, and R ６ is methoxy and Y is —O—CH ２ -CH ２ - is.

[0111] In the above 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 which is a substituent of (i) an aliphatic heterocyclic group, (ii) an aromatic heterocyclic group, and (iii) an aryl is preferably an alkyl having 1 to 5 carbon atoms, more preferably an alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0113] The lower alkyl in the hydroxy lower alkyl, lower alkylcarbonyl, hydroxy lower alkylcarbonyl and lower alkylcarbamoyl which are substituents of (i) an aliphatic heterocyclic group, (ii) an aromatic heterocyclic group and (iii) an aryl is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and still more preferably methyl.

[0114] The position and number of hydroxy in the hydroxy lower alkyl and hydroxy lower alkylcarbonyl which are substituents of (i) aliphatic heterocyclic groups, (ii) aromatic heterocyclic groups, and (iii) aryl are not particularly limited. The number of hydroxy is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

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

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

[0117] When ring A is (i) an aliphatic heterocyclic group, 1 to 3 substituents on the (i) 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 on 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, (i) ring A represented by the nitrogen-containing aliphatic heterocyclic group is ring A' shown below.

[0120] When ring A' has a substituent, the substituent on ring A' has the same meaning as the substituent on ring A which is (i) an aliphatic heterocyclic group. Specifically, ring A', like ring A which is (i) an aliphatic heterocyclic group, 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. Here, the dot (•) in the above formula represents the bonding site with the linker.

[0121] In the nitrogen-containing aliphatic heterocyclic group (preferably ring A'), a nitrogen atom (excluding a nitrogen atom having a bond in 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, and even more preferably piperazinyl, 1,4-diazepanyl, or hexahydropyrrolopyrazinyl. The nitrogen-containing aliphatic heterocyclic group may be constituted solely by saturated bonds or may contain double bonds, but is preferably constituted solely by saturated bonds. In the nitrogen-containing aliphatic heterocyclic group, two carbon atoms constituting the ring may be bridged by an alkylene group. The number of carbon atoms in the alkylene group bridging the two carbon atoms constituting the ring is, for example, 1 to 3, preferably 1 or 2, and even more preferably 1.

[0123] When the nitrogen-containing aliphatic heterocyclic group (preferably ring A') is a monocyclic aliphatic heterocyclic group containing two nitrogen atoms, it is preferred that one nitrogen atom constitutes a bond of the nitrogen-containing aliphatic heterocyclic group, and the other nitrogen atom has a substituent selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, and cycloalkylcarbonyl. The substituent on the other nitrogen atom is more preferably selected from the group consisting of lower alkyl, lower alkylcarbonyl, and cycloalkylcarbonyl, and even more preferably selected from the group consisting of lower alkyl and lower alkylcarbonyl. The monocyclic aliphatic heterocyclic group containing two nitrogen atoms may have one or two substituents other than the substituent on the other nitrogen atom. The one or two substituents other than the substituent on 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, it is preferred that one nitrogen atom constitutes a bond of the nitrogen-containing aliphatic heterocyclic group, and the other nitrogen atom is shared by the two rings (and therefore 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, in addition to oxo, one or two substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkylcarbonyl, hydroxy-lower alkylcarbonyl, and cycloalkylcarbonyl.

[0125] In a preferred embodiment, when ring A is (i) an aliphatic heterocyclic group, the compound represented by formula (I) is a compound represented by the following formula (I'). (In the formula, R １ , R ２ , and R ３ has the same meaning as in formula (I), and ring A' is the nitrogen-containing aliphatic heterocyclic group described above).

[0126] In a preferred embodiment of the compound of formula (I′), R １ is a hydrogen atom, and R ２ is lower alkyl, and R ３ is lower alkyl.

[0127] In a more preferred embodiment of the compound of formula (I'), R １ is a hydrogen atom, and R ２ is a lower alkyl having 1 to 5 carbon atoms, and R ３ is lower alkyl having 1 to 5 carbon atoms.

[0128] In an even more preferred embodiment of the compound of formula (I′), R １ is a hydrogen atom, and R ２ is a lower alkyl having 1 to 3 carbon atoms, and R ３ is lower alkyl having 1 to 3 carbon atoms.

[0129] In an even more preferred embodiment of the compound of formula (I′), R １ is a hydrogen atom, and R ２is methyl, and R ３ is ethyl.

[0130] When ring A is (ii) an aromatic heterocyclic group, 1 to 3 substituents on 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. The 1 to 3 substituents on the aromatic heterocyclic group are preferably lower alkyl.

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

[0132] When ring A is (iii) aryl, 1 to 3 substituents on 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. Preferably, 1 to 3 substituents on the aryl are selected from the group consisting of lower alkoxycarbonyl and lower alkylcarbamoyl.

[0133] In a preferred embodiment, (iii) 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 an aryl represented by the following formula (AG).

[0135]

[0136] In the above formulas (AA), (AB), (AC), (AD), (AE), (AF) and (AG), RＡ１ , R Ｂ１ , R Ｄ１ , R Ｅ１ , R Ｆ１ and R Ｇ１ are the same or different and represent lower alkyl, hydroxy lower alkyl, lower alkylcarbonyl, hydroxy lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl or lower alkylcarbamoyl; R Ａ２ , R Ａ３ , R Ｂ２ , R Ｂ３ , R Ｃ１ and R Ｃ２ are the same or different and each represents a hydrogen atom, oxo, lower alkyl or hydroxy lower alkyl.

[0137] R Ａ１ , R Ｂ１ , R Ｄ１ , R Ｅ１ , R Ｆ１ and R Ｇ１ The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0138] R Ａ１ , R Ｂ１ , R Ｄ１ , R Ｅ１ , R Ｆ１ and R Ｇ１ The lower alkyl in the hydroxy lower alkyl, lower alkylcarbonyl, hydroxy lower alkylcarbonyl and lower alkylcarbamoyl in the above is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl. When two or more lower alkyls are present in the hydroxy lower alkyl, lower alkylcarbonyl, hydroxy lower alkylcarbonyl and lower alkylcarbamoyl, they may be the same or different.

[0139] R Ａ１ , R Ｂ１ , R Ｄ１ , R Ｅ１ , R Ｆ１ and RＧ１ The position and number of hydroxy in the hydroxy lower alkyl and hydroxy lower alkylcarbonyl in the formula (I) are not particularly limited. The number of hydroxy is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0140] R Ａ１ , R Ｂ１ , R Ｄ１ , R Ｅ１ , R Ｆ１ and R Ｇ１ The lower alkoxy in the lower alkoxycarbonyl in the above is preferably alkoxy having 1 to 5 carbon atoms, more preferably alkoxy having 1 to 3 carbon atoms, even more preferably methoxy or ethoxy, and even more preferably methoxy.

[0141] R Ａ１ , R Ｂ１ , R Ｄ１ , R Ｅ１ , R Ｆ１ and R Ｇ１ The cycloalkyl in the cycloalkylcarbonyl in the above formula is preferably a cycloalkyl having 3 to 10 carbon atoms, more preferably a cycloalkyl having 3 to 8 carbon atoms, even more preferably a cycloalkyl having 3 to 6 carbon atoms, and even more preferably cyclopropyl.

[0142] R Ａ２ , R Ａ３ , R Ｂ２ , R Ｂ３ , R Ｃ１ and R Ｃ２ The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0143] R Ａ２ , R Ａ３ , R Ｂ２ , R Ｂ３ , R Ｃ１ and R Ｃ２The lower alkyl in the hydroxy lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0144] R Ａ２ , R Ａ３ , R Ｂ２ , R Ｂ３ , R Ｃ１ and R Ｃ２ The position and number of hydroxy in the hydroxy lower alkyl in the formula (I) are not particularly limited. The number of hydroxy is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0145] In a preferred embodiment, ring A or ring A′ is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AA), and in the above formula (AA), R Ａ１ represents lower alkyl, lower alkylcarbonyl, hydroxy lower alkylcarbonyl or cycloalkylcarbonyl, R Ａ２ and R Ａ３ are the same or different and each represents a hydrogen atom, oxo, lower alkyl or hydroxy lower alkyl.

[0146] R Ａ１ The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0147] R Ａ１ The lower alkyl in the lower alkylcarbonyl and hydroxy lower alkylcarbonyl in the above is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0148] R Ａ１ The position and number of hydroxy in the hydroxy-lower alkylcarbonyl in the formula (I) are not particularly limited. The number of hydroxy is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0149] R Ａ１ The cycloalkyl in the cycloalkylcarbonyl in the above formula is preferably a cycloalkyl having 3 to 10 carbon atoms, more preferably a cycloalkyl having 3 to 8 carbon atoms, even more preferably a cycloalkyl having 3 to 6 carbon atoms, and even more preferably cyclopropyl.

[0150] R Ａ２ and R Ａ３ The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0151] R Ａ２ and R Ａ３ The lower alkyl in the hydroxy lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0152] R Ａ２ and R Ａ３ The position and number of hydroxy in the hydroxy lower alkyl in the formula (I) are not particularly limited. The number of hydroxy is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0153] When ring A or ring A′ is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AA), R Ａ１ is preferably lower alkyl or lower alkylcarbonyl.

[0154] When ring A or ring A′ is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AA), R Ａ２ and R Ａ３ are preferably the same or different and each represent a hydrogen atom, oxo, or lower alkyl.

[0155] When ring A or ring A′ is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AA), R Ａ１ is lower alkyl or lower alkylcarbonyl, and R Ａ２ and R Ａ３More preferably, are the same or different and each is a hydrogen atom, oxo, or lower alkyl.

[0156] When ring A or ring A′ is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AA), R Ａ１ is lower alkyl, and R Ａ２ and R Ａ３ Even more preferably, each is the same or different and is oxo or lower alkyl.

[0157] In a preferred embodiment, ring A or ring A′ is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AB), and in the above formula (AB), R Ｂ１ represents lower alkyl or lower alkylcarbonyl, R Ｂ２ and R Ｂ３ are the same or different and each represents a hydrogen atom or oxo.

[0158] R Ｂ１ The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0159] R Ｂ１ The lower alkyl in the lower alkylcarbonyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0160] When ring A or ring A′ is a nitrogen-containing aliphatic heterocyclic group represented by formula (AB), R Ｂ１ is preferably lower alkyl.

[0161] In a preferred embodiment, ring A or ring A′ is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AC), and in the above formula (AC), R Ｃ１ and R Ｃ２ 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 nitrogen-containing aliphatic heterocyclic group represented by formula (AD), and in formula (AD), R Ｄ１ represents a lower alkylcarbonyl.

[0163] R Ｄ１ The lower alkyl in the lower alkylcarbonyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0164] In a preferred embodiment, ring A is an aromatic heterocyclic group represented by the above formula (AE), and in the above formula (AE), R Ｅ１ represents a lower alkyl.

[0165] R Ｅ１ The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0166] R Ｅ１ The number of is, for example, 0 to 2, preferably 1 or 2, and more preferably 2.

[0167] In a preferred embodiment, ring A is an aromatic heterocyclic group represented by the above formula (AF), and in the above formula (AF), R Ｆ１ represents a lower alkyl.

[0168] R Ｆ１ The lower alkyl in the formula (I) is preferably alkyl having 1 to 5 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0169] R Ｆ１ The number of is, for example, 0 to 2, preferably 1 or 2, and more preferably 1.

[0170] In a preferred embodiment, ring A is an aryl represented by the above formula (AG), and in the above formula (AG), R Ｇ１ represents a lower alkoxycarbonyl or a lower alkylcarbamoyl.

[0171] R Ｇ１ The lower alkoxy in the lower alkoxycarbonyl in the above is preferably alkoxy having 1 to 5 carbon atoms, more preferably alkoxy having 1 to 3 carbon atoms, even more preferably methoxy or ethoxy, and even more preferably methoxy.

[0172] R Ｇ１ The lower alkyl in the lower alkylcarbamoyl in the formula (I) is preferably an alkyl having 1 to 5 carbon atoms, more preferably an alkyl having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl. When two or more lower alkyls are present in the lower alkylcarbamoyl, they may be the same or different. Therefore, R Ｇ１ The lower alkylcarbamoyl in the formula (I) is preferably N-methylcarbamoyl or N,N-dimethylcarbamoyl.

[0173] R Ｇ１ The number of is, for example, 0 to 2, preferably 1 or 2, and more preferably 1.

[0174] In a preferred embodiment, ring A is (i) a nitrogen-containing aliphatic heterocyclic group, (ii) an aromatic heterocyclic group, or (iii) an aryl, more preferably, formula (AA), formula (AB), formula (AC), formula (AD), formula (AE), formula (AF), or formula (AG), and R １ is a hydrogen atom, and R ２ is methyl, and R ３ is ethyl, and R ４ does not exist, and R ５ does not exist, and R ６ is not present and Y is —O—CH ２ -CH ２ -, -CH ２ -CH ２ -CH ２ -, -CH=CH-CH ２ -, or -NH-C(=O)-CH ２ In a preferred embodiment, ring A is (i) a nitrogen-containing aliphatic heterocyclic group, more preferably represented by formula (AA), and R １ is a hydrogen atom, and R ２is methyl, and R ３ is ethyl, and R ４ is a fluorine atom, and R ５ does not exist, and R ６ is not present and Y is —O—CH ２ -CH ２ In another preferred embodiment, ring A is (i) a nitrogen-containing aliphatic heterocyclic group, more preferably represented by formula (AA), and R １ is a hydrogen atom, and R ２ is methyl, and R ３ is ethyl, and R ４ does not exist, and R ５ is a chlorine atom, and R ６ is not present and Y is —O—CH ２ -CH ２ In another preferred embodiment, ring A is (i) a nitrogen-containing aliphatic heterocyclic group, more preferably represented by formula (AA), (AB), or (AC), and R １ is a hydrogen atom, and R ２ is methyl, and R ３ is ethyl, and R ４ does not exist, and R ５ does not exist, and R ６ is a fluorine atom, and Y is —O—CH ２ -CH ２ - or -CH ２ -CH ２ -CH ２ In another preferred embodiment, ring A is (i) a nitrogen-containing aliphatic heterocyclic group, more preferably represented by formula (AA), and R １ is a hydrogen atom, and R ２ is methyl, and R ３ is ethyl, and R ４ does not exist, and R ５ does not exist, and R ６ is methoxy and Y is —O—CH ２ -CH ２ - is.

[0175] In a preferred embodiment, compound (I) or a pharmaceutically acceptable salt thereof has the following formula: or a pharmaceutically acceptable salt thereof.

[0176] In a preferred embodiment, compound (I) or a pharmaceutically acceptable salt thereof has the following formula: or a pharmaceutically acceptable salt thereof.

[0177] In a preferred embodiment, compound (I) or a pharmaceutically acceptable salt thereof has the following formula: or a pharmaceutically acceptable salt thereof.

[0178] In a preferred embodiment, compound (I) or a pharmaceutically acceptable salt thereof has the following formula: or a pharmaceutically acceptable salt thereof.

[0179] In a preferred embodiment, compound (I) or a pharmaceutically acceptable salt thereof has the following formula: or a pharmaceutically acceptable salt thereof.

[0180] <Second Aspect> According to the second aspect of the present invention, there is provided a targeting molecule-drug conjugate comprising a targeting molecule and a drug, wherein the drug is compound (I) or a pharmaceutically acceptable salt thereof. The targeting molecule-drug conjugate according to the second aspect can avoid the safety issue of peripheral neurotoxicity while maintaining high antitumor activity. By conjugating the drug (bivalent BET degrader) with the targeting molecule, the drug can be efficiently delivered to target cells. Therefore, by conjugating the drug (bivalent BET degrader) with the targeting molecule, an antitumor effect can be exhibited in vivo with a smaller amount of drug (in terms of bivalent BET degrader) compared to the drug alone.

[0181] A targeting molecule is, for example, a molecule that can bind to a molecule such as a protein or peptide present on the surface of a target cell. By binding a targeting molecule to a molecule such as a protein or peptide present on the surface of a target cell, a drug can be delivered to the target cell. Preferably, the targeting molecule can specifically bind to a molecule such as a protein or peptide present on the surface of the target cell. "Specific" means that the targeting molecule does not exhibit significant binding activity to other substances.

[0182] The target cells are preferably cancer cells. Examples of molecules such as proteins or peptides present on the surface of cancer cells include receptors, cancer antigens, MHC antigens, and differentiation antigens. The proteins or peptides may be presented on the surface of cancer cells by binding to MHC class I molecules or MHC class II molecules.

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

[0184] Examples of molecules such as proteins or peptides present on the surface of cancer cells include folate receptor alpha (FoLRα), somatostatin receptor (SSTR2), fibroblast activation protein (FAP), erythropoietin-producing hepatocyte 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. Of these, somatostatin receptor, fibroblast activation protein, erythropoietin-producing hepatocyte 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 even more 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 low molecular weight compounds include folic acid, oncoFAP, AAZ+, and 2-[3-(1,3-dicarboxypropyl)ureido]-pentanedioic acid (DUPA).

[0187] Folic acid can bind to folate receptors, and therefore, targeting molecule-drug conjugates containing folic acid as a targeting molecule can target cells that have folate receptors on their 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, a targeting molecule-drug conjugate containing octreotide as the targeting molecule can target cells that have fibroblast activation protein on their 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. Therefore, a targeting molecule-drug conjugate containing AAZ+ as a targeting molecule can target cells that have carbonic anhydrase 9 on their surface (S. Cazzamalli et al. J Am Chem Soc, 2018, 140, 1617-1621).

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

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

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

[0193] Octreotide can bind to somatostatin receptors, particularly somatostatin receptor subtype 2. Therefore, a targeting molecule-drug conjugate containing octreotide as a targeting molecule can target cells that have somatostatin receptor subtype 2 on their surface (B. H. White et al. J. Med. Chem. 2019, 62, 2708-2719).

[0194] RGD peptides can bind to integrin receptors, particularly αvβ3 integrin receptors, and therefore targeting molecule-drug conjugates containing RGD peptides as targeting molecules can target cells that have αvβ3 integrin receptors on their surface (M. Lelle et al. J. Med. Chem. 2005, 48, 1098-1106).

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

[0196] Bombesin-like peptides can bind to bombesin-like peptide receptors, and thus targeting molecule-drug conjugates containing bombesin-like peptides as targeting molecules can target cells that have bombesin-like peptide receptors on their surface (A. Safavy et al. Bioconjugate Chem. 2006, 17, 565-570).

[0197] BCY8234 can bind to nectin-4. Therefore, a targeting molecule-drug conjugate containing BCY8234 as a targeting molecule can target cells that have nectin-4 on their 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 an even more 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-FoLRα 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 either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-CD79b antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0204] In one embodiment, the anti-CD79b antibody comprises a heavy chain variable region (VH) comprising 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) comprising 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, according to the Kabat numbering system.

[0205] In another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody comprises the amino acid sequence set forth in SEQ ID NO: 5, and the amino acid sequence of the VL of the anti-CD79b antibody comprises the amino acid sequence set forth in SEQ ID NO: 6. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO:5 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:11, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:12, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:13, and the VL comprising the amino acid sequence set forth in SEQ ID NO:6 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:14, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:15, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:16.

[0207]

[0208] In yet another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 5, and the amino acid sequence of the VL of the anti-CD79b antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 6. The amino acid sequence of the VH of the anti-CD79b antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 5, and the amino acid sequence of the VL of the anti-CD79b antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 6. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 5 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 11, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 12, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 13.

[0210] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 6 preferably comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 14, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 15, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 16.

[0211] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 5 has the activity of an anti-CD79b antibody VH, i.e., binding activity to CD79b. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 5 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 5.

[0212] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 6 has the activity of an anti-CD79b antibody VL, i.e., binding activity to CD79b. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 6 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 6.

[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 either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-CD19 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0216] In one embodiment, the anti-CD19 antibody comprises a heavy chain variable region (VH) comprising 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) comprising 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, based on the Kabat numbering system.

[0217] In another embodiment, the amino acid sequence of the VH of the anti-CD19 antibody comprises the amino acid sequence set forth in SEQ ID NO: 7, and the amino acid sequence of the VL of the anti-CD19 antibody comprises the amino acid sequence set forth in SEQ ID NO: 8. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO: 7 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 19, and the VL comprising the amino acid sequence set forth in SEQ ID NO: 8 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 22.

[0219]

[0220] In yet another embodiment, the amino acid sequence of the VH of the anti-CD19 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 7, and the amino acid sequence of the VL of the anti-CD19 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 8. The amino acid sequence of the VH of the anti-CD19 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 7, and the amino acid sequence of the VL of the anti-CD19 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 8. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 7 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 17, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 18, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 19.

[0222] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 8 preferably comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 20, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 21, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 22.

[0223] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 7 has the activity of an anti-CD19 antibody VH, i.e., binding activity to CD 19. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 7 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 7.

[0224] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence of SEQ ID NO: 8 has the activity of an anti-CD19 antibody VL, i.e., binding activity to CD 19. Examples of amino acid sequences having the above sequence identity to the amino acid sequence of SEQ ID NO: 8 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence of SEQ ID NO: 8.

[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 either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-CD22 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0228] In one embodiment, the anti-CD22 antibody comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, based on the Kabat numbering system.

[0229] In another embodiment, the amino acid sequence of the VH of the anti-CD22 antibody comprises the amino acid sequence set forth in SEQ ID NO: 9, and the amino acid sequence of the VL of the anti-CD22 antibody comprises the amino acid sequence set forth in SEQ ID NO: 10. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO:9 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:23, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:24, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:25, and the VL comprising the amino acid sequence set forth in SEQ ID NO:10 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:26, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:27, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:28.

[0231]

[0232] In yet another embodiment, the amino acid sequence of the VH of the anti-CD22 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 9, and the amino acid sequence of the VL of the anti-CD22 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 10. The amino acid sequence of the VH of the anti-CD22 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 9, and the amino acid sequence of the VL of the anti-CD22 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 10. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 9 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 23, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 24, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 25.

[0234] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 10 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 26, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 27, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 28.

[0235] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 9 has the activity of an anti-CD22 antibody VH, i.e., binding activity to CD22. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 9 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 9.

[0236] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence of SEQ ID NO: 10 has the activity of an anti-CD22 antibody VL, i.e., binding activity to CD22. Examples of amino acid sequences having the above sequence identity to the amino acid sequence of SEQ ID NO: 10 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence of SEQ ID NO: 10.

[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 either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-HER2 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0240] In one embodiment, the anti-HER2 antibody comprises a heavy chain variable region (VH) comprising 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) comprising 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, according to the Kabat numbering system.

[0241] In another embodiment, the amino acid sequence of the VH of the anti-HER2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 29, and the amino acid sequence of the VL of the anti-HER2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 30. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO:29 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:67, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:68, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:69, and the VL comprising the amino acid sequence set forth in SEQ ID NO:30 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:70, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:71, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:72.

[0243]

[0244] In yet another embodiment, the amino acid sequence of the VH of the anti-HER2 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 29, and the amino acid sequence of the VL of the anti-HER2 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 30. The amino acid sequence of the VH of the anti-HER2 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 29, and the amino acid sequence of the VL of the anti-HER2 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 30. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO:29 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO:67, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO:68, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO:69.

[0246] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 30 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 70, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 71, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 72.

[0247] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 29 has the activity of an anti-HER2 antibody VH, i.e., binding activity to HER2. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 29 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 29.

[0248] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 30 has the activity of an anti-HER2 antibody VL, i.e., binding activity to HER2. An example of an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 30 is an amino acid sequence in which, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids have been deleted, substituted, inserted or added in the amino acid sequence set forth in SEQ ID NO: 6.

[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. Preferably, the anti-DLL3 antibody is an antibody that specifically binds to DLL3. The anti-DLL3 antibody may be either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-DLL3 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0252] In one embodiment, the anti-DLL3 antibody comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, according to the Kabat numbering system.

[0253] In another embodiment, the amino acid sequence of the VH of the anti-DLL3 antibody comprises the amino acid sequence set forth in SEQ ID NO: 31, and the amino acid sequence of the VL of the anti-DLL3 antibody comprises the amino acid sequence set forth in SEQ ID NO: 32. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO: 31 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 73, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 74, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 75, and the VL comprising the amino acid sequence set forth in SEQ ID NO: 32 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 76, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 77, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 78.

[0255]

[0256] In yet another embodiment, the amino acid sequence of the VH of the anti-DLL3 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 31, and the amino acid sequence of the VL of the anti-DLL3 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 32. The amino acid sequence of the VH of the anti-DLL3 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 31, and the amino acid sequence of the VL of the anti-DLL3 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 32. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 31 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 73, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 74, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 75.

[0258] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 32 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 76, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 77, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 78.

[0259] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence of SEQ ID NO: 31 has the activity of an anti-DLL3 antibody VH, i.e., binding activity to DLL3. Examples of amino acid sequences having the above sequence identity to the amino acid sequence of SEQ ID NO: 31 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence of SEQ ID NO: 31.

[0260] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence of SEQ ID NO: 32 has the activity of an anti-DLL3 antibody VL, i.e., binding activity to DLL3. Examples of amino acid sequences having the above sequence identity to the amino acid sequence of SEQ ID NO: 32 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence of SEQ ID NO: 32.

[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. Preferably, the anti-GM2 antibody is an antibody that specifically binds to GM2. The anti-GM2 antibody may be either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-GM2 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0264] In one embodiment, the anti-GM2 antibody comprises a heavy chain variable region (VH) comprising 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) comprising 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, according to the Kabat numbering system.

[0265] In another embodiment, the amino acid sequence of the VH of the anti-GM2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 33, and the amino acid sequence of the VL of the anti-GM2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 34. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO: 33 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 79, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 80, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 81, and the VL comprising the amino acid sequence set forth in SEQ ID NO: 34 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 82, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 83, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 84.

[0267]

[0268] In yet another embodiment, the amino acid sequence of the VH of the anti-GM2 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 33, and the amino acid sequence of the VL of the anti-GM2 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 34. The amino acid sequence of the VH of the anti-GM2 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 33, and the amino acid sequence of the VL of the anti-GM2 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 34. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 33 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 79, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 80, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 81.

[0270] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 34 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 82, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 83, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 84.

[0271] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 33 has the activity of an anti-GM2 antibody VH, i.e., binding activity to GM2. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 33 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 33.

[0272] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 34 has the activity of an anti-GM2 antibody VL, i.e., binding activity to GM2. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 34 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids are deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 34.

[0273] The following describes an embodiment in which the antibody is an anti-EphA2 antibody.

[0274] The anti-EphA2 antibody is an antibody that binds to EphA2. Preferably, the anti-EphA2 antibody is an antibody that specifically binds to EphA2. The anti-EphA2 antibody may be either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-EphA2 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0276] In one embodiment, the anti-EphA2 antibody comprises a heavy chain variable region (VH) comprising 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 a light chain variable region (VL) comprising 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, according to the Kabat numbering system.

[0277] In another embodiment, the amino acid sequence of the VH of the anti-EphA2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 35, and the amino acid sequence of the VL of the anti-EphA2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 36. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO: 35 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 85, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 86, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 87, and the VL comprising the amino acid sequence set forth in SEQ ID NO: 36 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 88, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 89, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 90.

[0279]

[0280] In yet another embodiment, the amino acid sequence of the VH of the anti-EphA2 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 35, and the amino acid sequence of the VL of the anti-EphA2 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 36. The amino acid sequence of the VH of the anti-EphA2 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 35, and the amino acid sequence of the VL of the anti-EphA2 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 36. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 35 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 85, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 86, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 87.

[0282] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 36 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 88, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 89, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 90.

[0283] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence of SEQ ID NO: 35 has the activity of an anti-EphA2 antibody VH, i.e., EphA2-binding activity. Examples of amino acid sequences having the above sequence identity to the amino acid sequence of SEQ ID NO: 35 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence of SEQ ID NO: 35.

[0284] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence of SEQ ID NO: 36 has the activity of an anti-EphA2 antibody VL, i.e., EphA2-binding activity. Examples of amino acid sequences having the above sequence identity to the amino acid sequence of SEQ ID NO: 36 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added to the amino acid sequence of SEQ ID NO: 36.

[0285] Hereinafter, an embodiment in which the antibody is an anti-FAP 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 either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-FAP antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

[0287] In one embodiment, the anti-FAP antibody is an antibody having the heavy chain variable region (VH) and light chain variable region (VL) of hu36 (US Pat. No. 1,0864,278).

[0288] In one embodiment, the anti-FAP antibody comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, based on the Kabat numbering system.

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

[0290] As shown in the table below, the VH comprising the amino acid sequence set forth in SEQ ID NO: 37 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 91, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 92, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 93, and the VL comprising the amino acid sequence set forth in SEQ ID NO: 38 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 94, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 95, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 96.

[0291]

[0292] In yet another embodiment, the amino acid sequence of the VH of the anti-FAP antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 37, and the amino acid sequence of the VL of the anti-FAP antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 38. The amino acid sequence of the VH of the anti-FAP antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 37, and the amino acid sequence of the VL of the anti-FAP antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 38. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 37 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 91, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 92, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 93.

[0294] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 38 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 94, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 95, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 96.

[0295] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 37 has the activity of an anti-FAP antibody VH, i.e., binding activity to FAP. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 37 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 37.

[0296] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 38 has the activity of an anti-FAP antibody VL, i.e., binding activity to FAP. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 38 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 38.

[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. Preferably, the anti-SSTR2 antibody is an antibody that specifically binds to SSTR2. The anti-SSTR2 antibody may be either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-SSTR2 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0300] In one embodiment, the anti-SSTR2 antibody comprises a heavy chain variable region (VH) comprising 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) comprising 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, according to the Kabat numbering system.

[0301] In another embodiment, the amino acid sequence of the VH of the anti-SSTR2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 39, and the amino acid sequence of the VL of the anti-SSTR2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 40. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO: 39 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 97, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 99, and the VL comprising the amino acid sequence set forth in SEQ ID NO: 40 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 100, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 101, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 102.

[0303]

[0304] In yet another embodiment, the amino acid sequence of the VH of the anti-SSTR2 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 39, and the amino acid sequence of the VL of the anti-SSTR2 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 40. The amino acid sequence of the VH of the anti-SSTR2 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 39, and the amino acid sequence of the VL of the anti-SSTR2 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 40. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 39 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 97, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 98, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 99.

[0306] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 40 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 100, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 101, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 102.

[0307] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 39 has the activity of an anti-SSTR2 antibody VH, i.e., binding activity to SSTR2. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 39 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 39.

[0308] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 40 has the activity of an anti-SSTR2 antibody VL, i.e., binding activity to SSTR2. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 40 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 40.

[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 either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-CD30 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0312] In one embodiment, the anti-CD30 antibody comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, based on the Kabat numbering system.

[0313] In another embodiment, the amino acid sequence of the VH of the anti-CD30 antibody comprises the amino acid sequence set forth in SEQ ID NO: 41, and the amino acid sequence of the VL of the anti-CD30 antibody comprises the amino acid sequence set forth in SEQ ID NO: 42. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO:41 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:103, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:104, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:105, and the VL comprising the amino acid sequence set forth in SEQ ID NO:42 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:106, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:107, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:108.

[0315]

[0316] In yet another embodiment, the amino acid sequence of the VH of the anti-CD30 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 41, and the amino acid sequence of the VL of the anti-CD30 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 42. The amino acid sequence of the VH of the anti-CD30 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 41, and the amino acid sequence of the VL of the anti-CD30 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 42. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 103, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 104, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 105.

[0318] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 42 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 106, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 107, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 108.

[0319] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 has the activity of an anti-CD30 antibody VH, i.e., binding activity to CD30. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 41 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 41.

[0320] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 42 has the activity of an anti-CD30 antibody VL, i.e., binding activity to CD30. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 42 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 42.

[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 either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-BCMA antibody may be either a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0324] In one embodiment, the anti-BCMA antibody comprises a heavy chain variable region (VH) comprising 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) comprising 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, according to the Kabat numbering system.

[0325] In another embodiment, the amino acid sequence of the VH of the anti-BCMA antibody comprises the amino acid sequence set forth in SEQ ID NO: 43, and the amino acid sequence of the VL of the anti-BCMA antibody comprises the amino acid sequence set forth in SEQ ID NO: 44. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO:43 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:109, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:110, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:111, and the VL comprising the amino acid sequence set forth in SEQ ID NO:44 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:112, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:113, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:114.

[0327]

[0328] In yet another embodiment, the amino acid sequence of the VH of the anti-BCMA antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 43, and the amino acid sequence of the VL of the anti-BCMA antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 44. The amino acid sequence of the VH of the anti-BCMA antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 43, and the amino acid sequence of the VL of the anti-BCMA antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 44. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 43 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 109, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 110, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 111.

[0330] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 44 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 112, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 113, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 114.

[0331] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 43 has the activity of an anti-BCMA antibody VH, i.e., binding activity to BCMA. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 43 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 43.

[0332] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 44 has the activity of an anti-BCMA antibody VL, i.e., binding activity to BCMA. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 44 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 44.

[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 either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-CD33 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0336] In one embodiment, the anti-CD33 antibody comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, based on the Kabat numbering system.

[0337] In another embodiment, the amino acid sequence of the VH of the anti-CD33 antibody comprises the amino acid sequence set forth in SEQ ID NO: 45, and the amino acid sequence of the VL of the anti-CD33 antibody comprises the amino acid sequence set forth in SEQ ID NO: 46. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO:45 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:115, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:116, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:117, and the VL comprising the amino acid sequence set forth in SEQ ID NO:46 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:118, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:119, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:120.

[0339]

[0340] In yet another embodiment, the amino acid sequence of the VH of the anti-CD33 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 45, and the amino acid sequence of the VL of the anti-CD33 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 46. The amino acid sequence of the VH of the anti-CD33 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 45, and the amino acid sequence of the VL of the anti-CD33 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 46. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 45 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 115, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 116, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 117.

[0342] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 46 preferably comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 118, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 119, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 120.

[0343] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 45 has the activity of an anti-CD33 antibody VH, i.e., binding activity to CD33. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 45 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 45.

[0344] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 46 has the activity of an anti-CD33 antibody VL, i.e., binding activity to CD33. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 46 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 46.

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

[0346] The anti-FoLRα antibody is an antibody that binds to FoLRα. The anti-FoLRα antibody is preferably an antibody that specifically binds to FoLRα. The anti-FoLRα antibody may be either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-FoLRα antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0348] In one embodiment, the anti-FoLRα antibody comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, based on the Kabat numbering system.

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

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

[0351]

[0352] In yet another embodiment, the amino acid sequence of the VH of the anti-FoLRα antibody comprises an amino acid sequence that has 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 47, and the amino acid sequence of the VL of the anti-FoLRα antibody comprises an amino acid sequence that has 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 48. The amino acid sequence of the VH of the anti-FoLRα antibody may consist of an amino acid sequence that has 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 47, and the amino acid sequence of the VL of the anti-FoLRα antibody may consist of an amino acid sequence that has 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 48. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO:47 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO:121, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO:122, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO:123.

[0354] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO:48 preferably comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO:124, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO:125, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO:126.

[0355] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 47 has the activity of an anti-FoLRα antibody VH, i.e., binding activity to FoLRα. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 47 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 47.

[0356] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 48 has the activity of an anti-FoLRα antibody VL, i.e., binding activity to FoLRα. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 48 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 48.

[0357] Hereinafter, an embodiment in which the antibody is an anti-CD25 antibody will be described.

[0358] The anti-CD25 antibody is an antibody that binds to CD25. Preferably, the anti-CD25 antibody is an antibody that specifically binds to CD25. The anti-CD25 antibody may be either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-CD25 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0360] In one embodiment, the anti-CD25 antibody comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, according to the Kabat numbering system.

[0361] In another embodiment, the amino acid sequence of the VH of the anti-CD25 antibody comprises the amino acid sequence set forth in SEQ ID NO: 49, and the amino acid sequence of the VL of the anti-CD25 antibody comprises the amino acid sequence set forth in SEQ ID NO: 50. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO:49 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:127, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:128, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:129, and the VL comprising the amino acid sequence set forth in SEQ ID NO:50 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:130, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:131, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:132.

[0363]

[0364] In yet another embodiment, the amino acid sequence of the VH of the anti-CD25 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 49, and the amino acid sequence of the VL of the anti-CD25 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 50. The amino acid sequence of the VH of the anti-CD25 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 49, and the amino acid sequence of the VL of the anti-CD25 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 50. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] Preferably, a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO:49 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO:127, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO:128, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO:129.

[0366] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO:50 preferably comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO:130, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO:131, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO:132.

[0367] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 49 has the activity of an anti-CD25 antibody VH, i.e., binding activity to CD25. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 49 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 49.

[0368] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 50 has the activity of an anti-CD25 antibody VL, i.e., binding activity to CD25. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 50 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 50.

[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 either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-CADM1 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

[0371] In one embodiment, the anti-CADM1 antibody is an antibody having the heavy chain variable region (VH) and light chain variable region (VL) of PTA021_A3 (US Pat. No. 8,420,084).

[0372] In one embodiment, the anti-CADM1 antibody comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, based on the Kabat numbering system.

[0373] In another embodiment, the amino acid sequence of the VH of the anti-CADM1 antibody comprises the amino acid sequence set forth in SEQ ID NO: 51, and the amino acid sequence of the VL of the anti-CADM1 antibody comprises the amino acid sequence set forth in SEQ ID NO: 52. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO:51 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:133, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:134, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:135, and the VL comprising the amino acid sequence set forth in SEQ ID NO:52 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:136, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:137, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:138.

[0375]

[0376] In yet another embodiment, the amino acid sequence of the VH of the anti-CADM1 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 51, and the amino acid sequence of the VL of the anti-CADM1 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 52. The amino acid sequence of the VH of the anti-CADM1 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 51, and the amino acid sequence of the VL of the anti-CADM1 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 52. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO:51 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO:133, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO:134, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO:135.

[0378] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 52 preferably comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 136, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 137, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 138.

[0379] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 51 has the activity of an anti-CADM1 antibody VH, i.e., binding activity to CADM1. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 51 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 51.

[0380] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 52 has the activity of an anti-CADM1 antibody VL, i.e., binding activity to CADM1. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 52 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 52.

[0381] The following describes an embodiment in which the antibody is an anti-CLL1 antibody.

[0382] The anti-CLL1 antibody is an antibody that binds to CLL1. Preferably, the anti-CLL1 antibody is an antibody that specifically binds to CLL1. The anti-CLL1 antibody may be either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-CLL1 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0384] In one embodiment, the anti-CLL1 antibody comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, according to the Kabat numbering system.

[0385] In another embodiment, the amino acid sequence of the VH of the anti-CLL1 antibody comprises the amino acid sequence set forth in SEQ ID NO: 53, and the amino acid sequence of the VL of the anti-CLL1 antibody comprises the amino acid sequence set forth in SEQ ID NO: 54. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO:53 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:139, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:140, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:141, and the VL comprising the amino acid sequence set forth in SEQ ID NO:54 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:142, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:143, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:144.

[0387]

[0388] In yet another embodiment, the amino acid sequence of the VH of the anti-CLL1 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 53, and the amino acid sequence of the VL of the anti-CLL1 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 54. The amino acid sequence of the VH of the anti-CLL1 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 53, and the amino acid sequence of the VL of the anti-CLL1 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 54. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 53 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 139, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 140, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 141.

[0390] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 54 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 142, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 143, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 144.

[0391] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 53 has the activity of an anti-CLL1 antibody VH, i.e., binding activity to CLL1. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 53 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 53.

[0392] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 54 has the activity of an anti-CLL1 antibody VL, i.e., binding activity to CLL1. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 54 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 54.

[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 either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-CD38 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0396] In one embodiment, the anti-CD38 antibody comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, based on the Kabat numbering system.

[0397] In another embodiment, the amino acid sequence of the VH of the anti-CD38 antibody comprises the amino acid sequence set forth in SEQ ID NO: 55, and the amino acid sequence of the VL of the anti-CD38 antibody comprises the amino acid sequence set forth in SEQ ID NO: 56. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO:55 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:145, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:146, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:147, and the VL comprising the amino acid sequence set forth in SEQ ID NO:56 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:148, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:149, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:150.

[0399]

[0400] In yet another embodiment, the amino acid sequence of the VH of the anti-CD38 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 55, and the amino acid sequence of the VL of the anti-CD38 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 56. The amino acid sequence of the VH of the anti-CD38 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 55, and the amino acid sequence of the VL of the anti-CD38 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 56. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 55 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 145, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 146, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 147.

[0402] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 56 preferably comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 148, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 149, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 150.

[0403] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 55 has the activity of an anti-CD38 antibody VH, i.e., binding activity to CD38. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 55 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 55.

[0404] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 56 has the activity of an anti-CD38 antibody VL, i.e., binding activity to CD38. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 56 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 56.

[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. Preferably, the anti-CD74 antibody is an antibody that specifically binds to CD74. The anti-CD74 antibody may be either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-CD74 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0408] In one embodiment, the anti-CD74 antibody comprises a heavy chain variable region (VH) comprising 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) comprising 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, according to the Kabat numbering system.

[0409] In another embodiment, the amino acid sequence of the VH of the anti-CD74 antibody comprises the amino acid sequence set forth in SEQ ID NO: 57, and the amino acid sequence of the VL of the anti-CD74 antibody comprises the amino acid sequence set forth in SEQ ID NO: 58. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO:57 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:151, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:152, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:153, and the VL comprising the amino acid sequence set forth in SEQ ID NO:58 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:154, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:155, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:156.

[0411]

[0412] In yet another embodiment, the amino acid sequence of the VH of the anti-CD74 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and the amino acid sequence of the VL of the anti-CD74 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 58. The amino acid sequence of the VH of the anti-CD74 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 57, and the amino acid sequence of the VL of the anti-CD74 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 58. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO:57 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO:151, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO:152, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO:153.

[0414] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 58 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 154, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 155, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 156.

[0415] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 57 has the activity of an anti-CD74 antibody VH, i.e., binding activity to CD74. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 57 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 57.

[0416] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 58 has the activity of an anti-CD74 antibody VL, i.e., binding activity to CD74. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 58 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 58.

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

[0418] The anti-NECTIN4 antibody is an antibody that binds to NECTIN4. Preferably, the anti-NECTIN4 antibody is an antibody that specifically binds to NECTIN4. The anti-NECTIN4 antibody may be either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-NECTIN4 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0420] In one embodiment, the anti-NECTIN4 antibody comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, according to the Kabat numbering system.

[0421] In another embodiment, the amino acid sequence of the VH of the anti-NECTIN4 antibody comprises the amino acid sequence set forth in SEQ ID NO: 183, and the amino acid sequence of the VL of the anti-NECTIN4 antibody comprises the amino acid sequence set forth in SEQ ID NO: 184. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO: 183 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 187, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 188, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 189, and the VL comprising the amino acid sequence set forth in SEQ ID NO: 184 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 190, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 191, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 192.

[0423]

[0424] In yet another embodiment, the amino acid sequence of the VH of the anti-NECTIN4 antibody comprises an amino acid sequence that has 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 183, and the amino acid sequence of the VL of the anti-NECTIN4 antibody comprises an amino acid sequence that has 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 184. The amino acid sequence of the VH of the anti-NECTIN4 antibody may consist of an amino acid sequence that has 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 183, and the amino acid sequence of the VL of the anti-NECTIN4 antibody may consist of an amino acid sequence that has 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 184. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 183 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 187, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 188, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 189.

[0426] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 184 preferably comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 190, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 191, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 192.

[0427] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 183 has the activity of an anti-NECTIN4 antibody VH, i.e., binding activity to NECTIN4. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 183 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added to the amino acid sequence set forth in SEQ ID NO: 183.

[0428] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 184 has the activity of an anti-NECTIN4 antibody VL, i.e., binding activity to NECTIN4. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 184 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added to the amino acid sequence set forth in SEQ ID NO: 184.

[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. Preferably, the anti-TROP2 antibody is an antibody that specifically binds to TROP2. The anti-TROP2 antibody may be either a polyclonal antibody or a monoclonal antibody, but is preferably a monoclonal antibody. The anti-TROP2 antibody may be any of a human chimeric antibody, a humanized antibody, or a human antibody, but is preferably a humanized antibody.

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

[0432] In one embodiment, the anti-TROP2 antibody comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, according to the Kabat numbering system.

[0433] In another embodiment, the amino acid sequence of the VH of the anti-TROP2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 185, and the amino acid sequence of the VL of the anti-TROP2 antibody comprises the amino acid sequence set forth in SEQ ID NO: 186. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO: 185 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 193, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 194, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 195, and the VL comprising the amino acid sequence set forth in SEQ ID NO: 186 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 196, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 197, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 198.

[0435]

[0436] In yet another embodiment, the amino acid sequence of the VH of the anti-TROP2 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 185, and the amino acid sequence of the VL of the anti-TROP2 antibody comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 186. The amino acid sequence of the VH of the anti-TROP2 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 185, and the amino acid sequence of the VL of the anti-TROP2 antibody may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 186. An amino acid sequence having 90% or more 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 an amino acid sequence having 90% or more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 185 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 193, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 194, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 195.

[0438] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 186 preferably comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 196, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 197, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 198.

[0439] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 185 has the activity of an anti-TROP2 antibody VH, i.e., binding activity to TROP2. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 185 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 185.

[0440] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 186 has the activity of an anti-TROP2 antibody VL, i.e., binding activity to TROP2. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 186 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added to the amino acid sequence set forth in SEQ ID NO: 186.

[0441] Hereinafter, an embodiment will be described in which the antibody is an anti-CD79b antibody and is human antibody G4055 (human antibody G4055) (hereinafter also referred to as anti-CD79b antibody (human antibody G4055) or 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 either a polyclonal antibody or a monoclonal antibody, but 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) comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, based on the Kabat numbering system.

[0444] In another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4055) comprises the amino acid sequence set forth in SEQ ID NO: 59, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4055) comprises the amino acid sequence set forth in SEQ ID NO: 60. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO:59 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:157, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:158, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:159, and the VL comprising the amino acid sequence set forth in SEQ ID NO:60 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:160, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:161, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO:162.

[0446]

[0447] In yet another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4055) comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO:59, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4055) comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO:60. The amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4055) may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 59, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4055) may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 60. The amino acid sequence having 90% or more 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 more 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] It is preferable that a VH comprising an amino acid sequence having the above-mentioned sequence identity to the amino acid sequence set forth in SEQ ID NO:59 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO:157, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO:158, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO:159.

[0449] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 60 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 160, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 161, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 162.

[0450] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 59 has the activity of the VH of an anti-CD79b antibody (human antibody G4055), i.e., binding activity to CD79b. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 59 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 59.

[0451] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 60 has the activity of the VL of an anti-CD79b antibody (human antibody G4055), i.e., binding activity to CD79b. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 60 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 60.

[0452] Hereinafter, an embodiment will be described in which the antibody is an anti-CD79b antibody and is human antibody G4022 (human antibody G4022) (hereinafter also referred to as anti-CD79b antibody (human antibody G4022) or 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 either a polyclonal antibody or a monoclonal antibody, but 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) comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, based on the Kabat numbering system.

[0455] In another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4022) comprises the amino acid sequence set forth in SEQ ID NO: 61, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4022) comprises the amino acid sequence set forth in SEQ ID NO: 62. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO: 61 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 163, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 164, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 165, and the VL comprising the amino acid sequence set forth in SEQ ID NO: 62 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 166, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 167, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 168.

[0457]

[0458] In yet another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4022) comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 61, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4022) comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 62. The amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4022) may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 61, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4022) may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 62. The amino acid sequence having 90% or more 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 more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 61 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 163, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 164, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 165.

[0460] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 62 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 166, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 167, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 168.

[0461] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 61 has the activity of the VH of an anti-CD79b antibody (human antibody G4022), i.e., binding activity to CD79b. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 61 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 61.

[0462] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 62 has the activity of the VL of an anti-CD79b antibody (human antibody G4022), i.e., binding activity to CD79b. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 62 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 62.

[0463] Hereinafter, an embodiment will be described in which the antibody is an anti-CD79b antibody and is human antibody G4046 (human antibody G4046) (hereinafter also referred to as anti-CD79b antibody (human antibody G4046) or 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 either a polyclonal antibody or a monoclonal antibody, but 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) comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, based on the Kabat numbering system.

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

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

[0468]

[0469] In yet another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4046) comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 63, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4046) comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 64. The amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4046) may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 63, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4046) may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 64. The amino acid sequence having 90% or more 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 more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 63 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 169, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 170, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 171.

[0471] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 64 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 172, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 173, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 174.

[0472] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 63 has the activity of the VH of an anti-CD79b antibody (human antibody G4046), i.e., binding activity to CD79b. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 63 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 63.

[0473] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 64 has the activity of the VL of an anti-CD79b antibody (human antibody G4046), i.e., binding activity to CD79b. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 64 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 64.

[0474] Hereinafter, an embodiment will be described in which the antibody is an anti-CD79b antibody and is human antibody G4047 (human antibody G4047) (hereinafter also referred to as anti-CD79b antibody (human antibody G4047) or 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 either a polyclonal antibody or a monoclonal antibody, but 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) comprises a heavy chain variable region (VH) including 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) including 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. Note that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3, respectively, based on the Kabat numbering system.

[0477] In another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4047) comprises the amino acid sequence set forth in SEQ ID NO: 65, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4047) comprises the amino acid sequence set forth in SEQ ID NO: 66. The amino acid sequence of the 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 the 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, the VH comprising the amino acid sequence set forth in SEQ ID NO: 65 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 175, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 176, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 177, and the VL comprising the amino acid sequence set forth in SEQ ID NO: 66 comprises a CDR1 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 178, a CDR2 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 179, and a CDR3 (underlined in the table below) consisting of the amino acid sequence set forth in SEQ ID NO: 180.

[0479]

[0480] In yet another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4047) comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 65, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4047) comprises an amino acid sequence having 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 66. The amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4047) may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 65, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4047) may consist of an amino acid sequence having 90% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 66. The amino acid sequence having 90% or more 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 more 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] It is preferable that a VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 65 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 175, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 176, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 177.

[0482] It is preferable that a VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 66 comprises a CDR1 consisting of the amino acid sequence set forth in SEQ ID NO: 178, a CDR2 consisting of the amino acid sequence set forth in SEQ ID NO: 179, and a CDR3 consisting of the amino acid sequence set forth in SEQ ID NO: 180.

[0483] A VH comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 65 has the activity of the VH of an anti-CD79b antibody (human antibody G4047), i.e., binding activity to CD79b. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 65 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 65.

[0484] A VL comprising an amino acid sequence having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 66 has the activity of the VL of an anti-CD79b antibody (human antibody G4047), i.e., binding activity to CD79b. Examples of amino acid sequences having the above sequence identity to the amino acid sequence set forth in SEQ ID NO: 66 include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 66.

[0485] The heavy chain constant region (CH) of an 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-FoLRα 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 below.

[0486] The CH of the antibody (e.g., anti-CD79b antibody, anti-CD19 antibody, anti-CD22 antibody, anti-HER2 antibody, anti-DLL3 antibody, anti-GM2 antibody, anti-EphA2 antibody, anti-FAP antibody, anti-SSTR2 antibody, anti-CD30 antibody, anti-BCMA antibody, anti-CD33 antibody, anti-FoLRα antibody, anti-CD25 antibody, anti-CADM1 antibody, anti-CLL1 antibody, anti-CD38 antibody, anti-CD74 antibody, anti-NECTIN4 antibody, or anti-TROP2 antibody) may be any CH as long as it belongs to human immunoglobulin (hereinafter may be abbreviated as "hIg"). For example, a CH of the hIgG class, specifically a CH of a hIgG subclass such as hIgG1, hIgG2, hIgG3, or hIgG4, or a modified version thereof, can be used.

[0487] The CH of the antibody (e.g., anti-CD79b antibody, anti-CD19 antibody, anti-CD22 antibody, anti-HER2 antibody, anti-DLL3 antibody, anti-GM2 antibody, anti-EphA2 antibody, anti-FAP antibody, anti-SSTR2 antibody, anti-CD30 antibody, anti-BCMA antibody, anti-CD33 antibody, anti-FoLRα antibody, anti-CD25 antibody, anti-CADM1 antibody, anti-CLL1 antibody, anti-CD38 antibody, anti-CD74 antibody, anti-NECTIN4 antibody, or anti-TROP2 antibody) is, for example, a CH of hIgG1 or a modified version thereof, or a CH of hIgG4 or a modified version thereof.

[0488] In one embodiment, the amino acid sequence of the 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-FoLRα 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) comprises (a) the amino acid sequence set forth in SEQ ID NO: 1, or (b) an amino acid sequence having 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, even more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more 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 an antibody (e.g., anti-CD79b antibody, anti-CD19 antibody, anti-CD22 antibody, anti-HER2 antibody, anti-DLL3 antibody, anti-GM2 antibody, anti-EphA2 antibody, anti-FAP antibody, anti-SSTR2 antibody, anti-CD30 antibody, anti-BCMA antibody, anti-CD33 antibody, anti-FoLRα antibody, anti-CD25 antibody, anti-CADM1 antibody, anti-CLL1 antibody, anti-CD38 antibody, anti-CD74 antibody, anti-NECTIN4 antibody, or anti-TROP2 antibody) may consist of amino acid sequence (a) or (b). Examples of amino acid sequence (b) include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 1. An example of the amino acid sequence (b) is an amino acid sequence in which at least one amino acid in the amino acid sequence set forth in SEQ ID NO: 1 has been substituted with cysteine. The amino acid substituted with cysteine ​​is an amino acid other than cysteine.

[0489] In another embodiment, the amino acid sequence of the 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-FoLRα 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) comprises (c) the amino acid sequence set forth in SEQ ID NO: 2, or (d) an amino acid sequence having 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, even more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 2. The amino acid sequence of the CH of an 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-FoLRα 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 amino acid sequence (c) or (d). Examples of the amino acid sequence (d) include, for example, an amino acid sequence in which, in the amino acid sequence set forth in SEQ ID NO: 2, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added. Examples of the amino acid sequence (d) include, for example, an amino acid sequence in which, in the amino acid sequence set forth in SEQ ID NO: 2, at least one amino acid has been substituted with cysteine. The amino acid substituted for cysteine ​​is an amino acid other than cysteine.

[0490] In another embodiment, the amino acid sequence of the 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-FoLRα 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) comprises (i) the amino acid sequence set forth in SEQ ID NO: 181, or (j) an amino acid sequence having 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, even more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 181. The amino acid sequence of CH of an 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-FoLRα 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 amino acid sequence (i) or (j). Examples of amino acid sequence (j) include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 181. An example of the amino acid sequence (j) is an amino acid sequence in which at least two amino acids in the amino acid sequence set forth in SEQ ID NO: 181 are substituted with cysteine ​​and lysine. The amino acid substituted with cysteine ​​is an amino acid other than cysteine, and the amino acid substituted with lysine is an amino acid other than lysine.

[0491] In another embodiment, the amino acid sequence of the 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-FoLRα 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) comprises: (k) the amino acid sequence set forth in SEQ ID NO: 182; or (l) an amino acid sequence having 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, even more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 182. The amino acid sequence of CH of an 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-FoLRα 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 amino acid sequence (k) or (l). Examples of amino acid sequence (l) include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 182. An example of the amino acid sequence (1) is an amino acid sequence in which at least two amino acids in the amino acid sequence set forth in SEQ ID NO: 182 are substituted with cysteine ​​and phenylalanine. The amino acid substituted with cysteine ​​is an amino acid other than cysteine, and the amino acid substituted with phenylalanine is an amino acid other than phenylalanine.

[0492] As shown in the table below, the amino acid sequence of SEQ ID NO: 2 is the amino acid sequence of SEQ ID NO: 1 in which serine at position 239 of the heavy chain according to Kabat EU numbering (underlined in the table below) has been substituted with cysteine ​​(underlined in the table below). Hereinafter, the substitution of serine at position 239 of the heavy chain with cysteine ​​may be referred to as "S239C mutation." The linker in the drug-linker conjugate can be bonded to the CH of an 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-FoLRα 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 the sulfur atom of the cysteine ​​introduced by the S239C mutation.

[0493]

[0494] In the amino acid sequence (d), it is preferable that the S239C mutation is maintained.

[0495] As shown in the table below, the amino acid sequence set forth in SEQ ID NO: 181 is an amino acid sequence in the human IgG4 heavy chain constant region (CH) in which the serine at position 239 of the heavy chain as shown by Kabat EU numbering is substituted with cysteine ​​(underlined in the table below) and the arginine at position 409 of the heavy chain is substituted with lysine (underlined in the table below). An IgG4 variant comprising or consisting of the above sequence as the heavy chain constant region can be used as a nullbody type with weakened binding to Fcγ receptors (FcgR). The substitution of serine at position 239 of the heavy chain with cysteine ​​is hereinafter sometimes referred to as the "S239C mutation," and the substitution of arginine at position 409 of the heavy chain with lysine is hereinafter sometimes referred to as the "R409K mutation." The linker in the drug-linker conjugate can be bonded to the CH of an 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-FoLRα 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 the sulfur atom of the cysteine ​​introduced by the S239C mutation.

[0496]

[0497] In the amino acid sequence (j), it is preferable that the S239C mutation and the R409K mutation are retained.

[0498] As shown in the table below, the amino acid sequence set forth in SEQ ID NO: 182 is an amino acid sequence in the human IgG4 heavy chain constant region (CH) in which the serine at position 239 of the heavy chain as shown by Kabat EU numbering is substituted with cysteine ​​(underlined in the table below) and the histidine at position 435 of the heavy chain is substituted with phenylalanine (underlined in the table below). An IgG4 variant comprising or consisting of the above sequence as the heavy chain constant region can be used as a short-half-life form with weakened binding to fetal Fc receptor (FcRn). The substitution of serine at position 239 of the heavy chain with cysteine ​​is hereinafter sometimes referred to as the "S239C mutation," and the substitution of histidine at position 435 of the heavy chain with phenylalanine is hereinafter sometimes referred to as the "H435F mutation." The linker in the drug-linker conjugate can be bonded to the CH of an 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-FoLRα 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 the sulfur atom of the cysteine ​​introduced by the S239C mutation.

[0499]

[0500] In the amino acid sequence (1), it is preferable that the S239C mutation and the H435F mutation are retained.

[0501] The antibody (e.g., anti-CD79b antibody, anti-CD19 antibody, anti-CD22 antibody, anti-HER2 antibody, anti-DLL3 antibody, anti-GM2 antibody, anti-EphA2 antibody, anti-FAP antibody, anti-SSTR2 antibody, anti-CD30 antibody, anti-BCMA antibody, anti-CD33 antibody, anti-FoLRα antibody, anti-CD25 antibody, anti-CADM1 antibody, anti-CLL1 antibody, anti-CD38 antibody, anti-CD74 antibody, anti-NECTIN4 antibody, or anti-TROP2 antibody) may have one or more sugar chains bound to CH. The sugar chain possessed by an 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-FoLRα 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-type sugar chain and an O-type sugar chain, but is preferably an N-type sugar chain. An N-type sugar chain is, for example, an N-type sugar chain bound to an asparagine residue in CH, and an O-type sugar chain is, for example, an O-type sugar chain bound to a serine or threonine residue in CH. Examples of N-type sugar chains include complex sugar chains, high mannose sugar chains, and hybrid sugar chains. Examples of O-type sugar chains include core 1 to core 8.

[0502] The light chain constant region (CL) of an 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-FoLRα 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 below.

[0503] The CL of the antibody (e.g., anti-CD79b antibody, anti-CD19 antibody, anti-CD22 antibody, anti-HER2 antibody, anti-DLL3 antibody, anti-GM2 antibody, anti-EphA2 antibody, anti-FAP antibody, anti-SSTR2 antibody, anti-CD30 antibody, anti-BCMA antibody, anti-CD33 antibody, anti-FoLRα antibody, anti-CD25 antibody, anti-CADM1 antibody, anti-CLL1 antibody, anti-CD38 antibody, anti-CD74 antibody, anti-NECTIN4 antibody, or anti-TROP2 antibody) may be any CL belonging to the hIg group, and for example, a CL of a human κ chain or a human λ chain, or a modified version thereof, can be used.

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

[0505] In one embodiment, the amino acid sequence of the 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-FoLRα 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) comprises: (e) the amino acid sequence set forth in SEQ ID NO: 3; or (f) an amino acid sequence having 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, even more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more 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 human κ chain. The amino acid sequence of CL of an antibody (e.g., anti-CD79b antibody, anti-CD19 antibody, anti-CD22 antibody, anti-HER2 antibody, anti-DLL3 antibody, anti-GM2 antibody, anti-EphA2 antibody, anti-FAP antibody, anti-SSTR2 antibody, anti-CD30 antibody, anti-BCMA antibody, anti-CD33 antibody, anti-FoLRα antibody, anti-CD25 antibody, anti-CADM1 antibody, anti-CLL1 antibody, anti-CD38 antibody, anti-CD74 antibody, anti-NECTIN4 antibody, or anti-TROP2 antibody) may consist of amino acid sequence (e) or (f). Examples of amino acid sequence (f) include amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 3. An example of the amino acid sequence (f) is an amino acid sequence in which at least one amino acid in the amino acid sequence set forth in SEQ ID NO: 3 has been substituted with cysteine. The amino acid substituted with cysteine ​​is an amino acid other than cysteine.

[0506] In another 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-FoLRα 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) comprises (g) the amino acid sequence set forth in SEQ ID NO: 4, or (h) an amino acid sequence having 80% or more, preferably 85% or more, more preferably 90% or more, even more preferably 95% or more, even more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, and even more preferably 99% or more sequence identity to the amino acid sequence set forth in SEQ ID NO: 4. The amino acid sequence of CL of an antibody (e.g., anti-CD79b antibody, anti-CD19 antibody, anti-CD22 antibody, anti-HER2 antibody, anti-DLL3 antibody, anti-GM2 antibody, anti-EphA2 antibody, anti-FAP antibody, anti-SSTR2 antibody, anti-CD30 antibody, anti-BCMA antibody, anti-CD33 antibody, anti-FoLRα antibody, anti-CD25 antibody, anti-CADM1 antibody, anti-CLL1 antibody, anti-CD38 antibody, anti-CD74 antibody, anti-NECTIN4 antibody, or anti-TROP2 antibody) may consist of amino acid sequence (g) or (h). Examples of amino acid sequence (h) include, for example, amino acid sequences in which, for example, 1 to 20, preferably 1 to 10, and more preferably 1 to 5 amino acids have been deleted, substituted, inserted, or added in the amino acid sequence set forth in SEQ ID NO: 4. Examples of amino acid sequence (h) include, for example, amino acid sequences in which at least one amino acid in the amino acid sequence set forth in SEQ ID NO: 4 has been substituted with cysteine. The amino acid substituted for cysteine ​​is an amino acid other than cysteine.

[0507] As shown in the table below, the amino acid sequence of SEQ ID NO: 4 is the amino acid sequence of SEQ ID NO: 3 in which glutamine at position 124 of the light chain as shown by Kabat EU numbering (underlined in the table below) is substituted with cysteine ​​(underlined in the table below). The substitution of glutamine at position 124 of the light chain with cysteine ​​may be referred to as a "Q124C mutation" hereinafter. The linker in the drug-linker conjugate and the CL of the antibody (e.g., anti-CD79b antibody, anti-CD19 antibody, or anti-CD22 antibody) can be bonded via the sulfur atom of the cysteine ​​introduced by the Q124C mutation.

[0508]

[0509] In the amino acid sequence (h), it is preferred that the Q124C mutation be maintained.

[0510] Combinations of CH and CL of antibodies (e.g., anti-CD79b antibody, anti-CD19 antibody, anti-CD22 antibody, anti-HER2 antibody, anti-DLL3 antibody, anti-GM2 antibody, anti-EphA2 antibody, anti-FAP antibody, anti-SSTR2 antibody, anti-CD30 antibody, anti-BCMA antibody, anti-CD33 antibody, anti-FoLRα antibody, anti-CD25 antibody, anti-CADM1 antibody, anti-CLL1 antibody, anti-CD38 antibody, anti-CD74 antibody, anti-NECTIN4 antibody, or anti-TROP2 antibody) will be described below.

[0511] In one embodiment, the amino acid sequence of the CH of an 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-FoLRα 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 amino acid sequence (c) or (d), preferably amino acid sequence (c ), and the amino acid sequence of CL of the antibody (e.g., anti-CD79b antibody, anti-CD19 antibody, anti-CD22 antibody, anti-HER2 antibody, anti-DLL3 antibody, anti-GM2 antibody, anti-EphA2 antibody, anti-FAP antibody, anti-SSTR2 antibody, anti-CD30 antibody, anti-BCMA antibody, anti-CD33 antibody, anti-FoLRα antibody, anti-CD25 antibody, anti-CADM1 antibody, anti-CLL1 antibody, anti-CD38 antibody, anti-CD74 antibody, anti-NECTIN4 antibody, or anti-TROP2 antibody) comprises amino acid sequence (e) or (f), preferably amino acid sequence (e).

[0512] In another embodiment, the amino acid sequence of the 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-FoLRα 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 selected from the group consisting of amino acid sequence (a) and (b), preferably amino acid sequence (c). a), and the amino acid sequence of CL of the antibody (e.g., anti-CD79b antibody, anti-CD19 antibody, anti-CD22 antibody, anti-HER2 antibody, anti-DLL3 antibody, anti-GM2 antibody, anti-EphA2 antibody, anti-FAP antibody, anti-SSTR2 antibody, anti-CD30 antibody, anti-BCMA antibody, anti-CD33 antibody, anti-FoLRα antibody, anti-CD25 antibody, anti-CADM1 antibody, anti-CLL1 antibody, anti-CD38 antibody, anti-CD74 antibody, anti-NECTIN4 antibody, or anti-TROP2 antibody) comprises amino acid sequence (g) or (h), preferably amino acid sequence (g).

[0513] In yet another embodiment, the amino acid sequence of the 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-FoLRα antibo...

Claims

1. A compound represented by the following formula (I) or a pharma- ceutically acceptable salt thereof: (In the formula, R １ and R ２ are the same or different and each represents a hydrogen atom or a lower alkyl; R ３ represents lower alkyl; R ４ represents a halogen; ５ represents a halogen; ６ represents halogen or lower alkoxy; Y represents -O-CH ２ -CH ２ --, --CH ２ -CH ２ -CH ２ -, -CH=CH-CH ２ -, or -NH-C(=O)-CH ２ -, Ring A represents (i) an aliphatic heterocyclic group which 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, (ii) an aromatic heterocyclic group which may have 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) an aryl which may have 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 according to claim 1 or a pharma- ceutically acceptable salt thereof, wherein (i) the aliphatic heterocyclic group in ring A is a nitrogen-containing aliphatic heterocyclic group.

3. The compound according to claim 2, wherein (i) ring A represented by a nitrogen-containing aliphatic heterocyclic group is ring A' as follows: (In the formula, when ring A' has a substituent, the substituent on ring A' has the same meaning as the substituent on ring A).

4. The compound according to claim 1, wherein the compound represented by formula (I) is a compound represented by the following formula (I') or a pharma- ceutically acceptable salt thereof: (In the formula, R １ , R ２ , and R ３ has the same meaning as in formula (I), 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).

5. The compound 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 an aryl group represented by the following formula (AG), or a pharma- ceutically acceptable salt thereof: (In the formula, R Ａ１ , R Ｂ１ , R Ｄ１ , R Ｅ１ , R Ｆ１ and R Ｇ１ are the same or different and each represents lower alkyl, hydroxy lower alkyl, lower alkylcarbonyl, hydroxy lower alkylcarbonyl, lower alkoxycarbonyl, cycloalkylcarbonyl or lower alkylcarbamoyl; R Ａ２ , R Ａ３ , R Ｂ２ , R Ｂ３ , R Ｃ１ and R Ｃ２ and each may be the same or different and represent a hydrogen atom, oxo, lower alkyl, or hydroxy-lower alkyl.

6. The compound according to claim 1, wherein ring A is an aliphatic heterocyclic group represented by the following formula (AA), or a pharma- ceutically acceptable salt thereof: (In the formula, R Ａ１ represents lower alkyl, lower alkylcarbonyl or cycloalkylcarbonyl; R Ａ２ and R Ａ３ and each may be the same or different and represent a hydrogen atom, oxo, lower alkyl, or hydroxy-lower alkyl.

7. The compound according to claim 1, wherein ring A is an aliphatic heterocyclic group represented by the following formula (AB), or a pharma- ceutically acceptable salt thereof: (In the formula, R Ｂ１ represents lower alkyl or lower alkylcarbonyl; R Ｂ２ and R Ｂ３ and each may be the same or different and represent a hydrogen atom or oxo.

8. The compound according to claim 1, wherein ring A is an aliphatic heterocyclic group represented by the following formula (AC), or a pharma- ceutically acceptable salt thereof: (In the formula, R Ｃ１ and R Ｃ２ and each may be the same or different and represent a hydrogen atom or oxo.

9. The compound according to claim 1, wherein ring A is an aliphatic heterocyclic group represented by the following formula (AD), or a pharma- ceutically acceptable salt thereof: (In the formula, R Ｄ１ represents lower alkylcarbonyl).

10. The compound according to claim 1, wherein ring A is an aromatic heterocyclic group represented by the following formula (AE), or a pharma- ceutically acceptable salt thereof: (In the formula, R Ｅ１ represents lower alkyl).

11. The compound according to claim 1, wherein ring A is an aromatic heterocyclic group represented by the following formula (AF), or a pharma- ceutically acceptable salt thereof: (In the formula, R Ｆ１ represents lower alkyl).

12. The compound according to claim 1, wherein ring A is an aryl represented by the following formula (AG), or a pharma- ceutically acceptable salt thereof: (In the formula, R Ｇ１ represents lower alkoxycarbonyl or lower alkylcarbamoyl).

13. Y is -O-CH ２ -CH ２ The compound according to claim 1, wherein R is - or a pharma- ceutically acceptable salt thereof.

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

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

16. The targeting molecule-drug conjugate of claim 15, wherein the targeting molecule-drug conjugate is represented by formula (II): (In the formula, R １ and R ２ are the same or different and each represents a hydrogen atom or a lower alkyl; R ３ represents lower alkyl; R ４ represents a halogen; ５ represents a halogen; ６ represents halogen or lower alkoxy; Y represents -O-CH ２ -CH ２ --, --CH ２ -CH ２ -CH ２ -, -CH=CH-CH ２ -, or -NH-C(=O)-CH ２ 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) an 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, Z represents a targeting molecule).

17. The targeting molecule-drug conjugate according to claim 16, wherein (i) ring A represented by an aliphatic heterocyclic group is ring A' as follows: (In the formula, when ring A' has a substituent, the substituent on ring A' has the same meaning as the substituent on ring A).

18. The targeting molecule-drug conjugate of claim 16, wherein the targeting molecule-drug conjugate is represented by the following formula (II'): (In the formula, R １ , R ２ , R ３ , L, mm, and Z are defined as in 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).

19. The targeting molecule-drug conjugate of claim 16, wherein L is represented by formula (III): (wherein wavy line 1 represents a bonding site to Z, wavy line 2 represents a bonding site to an 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 (b) a residue of the following formula (IV): wherein q is an integer from 1 to 5, r is an integer from 2 to 24, s is 0 or 1, and t is 1, 2, 3, or 4.

20. The targeting molecule-drug conjugate of 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 of claim 14, wherein the targeting molecule is an antibody.

22. The targeting molecule-drug conjugate of 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-FoLRα 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, wherein the drug is a compound according to any one of claims 1 to 13 or a pharma- ceutically acceptable salt thereof.

24. The drug-linker conjugate of claim 23, wherein the drug-linker conjugate is represented by formula (V): (In the formula, R １ and R ２ are the same or different and each represents a hydrogen atom or a lower alkyl; R ３ represents lower alkyl; R ４ represents a halogen; ５ represents a halogen; ６ represents halogen or lower alkoxy; Y represents -O-CH ２ -CH ２ --, --CH ２ -CH ２ -CH ２ -, -CH=CH-CH ２ -, or -NH-C(=O)-CH ２ (i) an aliphatic heterocyclic group which 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, (ii) an aromatic heterocyclic group which may have 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) an aryl which may have 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).

25. The drug-linker conjugate according to claim 24, wherein (i) ring A represented by an aliphatic heterocyclic group is ring A' as follows: (In the formula, when ring A' has a substituent, the substituent on ring A' has the same meaning as the substituent on ring A).

26. The drug-linker conjugate of claim 24, wherein the drug-linker conjugate is represented by formula (V'): (In the formula, R １ , R ２ , R ３ and L are as defined in 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).

27. The drug-linker conjugate of claim 24, wherein the drug-linker conjugate is represented by formula (Va): (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ each Xaa independently represents (a) at least one amino acid residue 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 (b) a group represented by the following formula (IV): wherein q is an integer from 1 to 5, r is an integer from 2 to 24, s is 0 or 1, and t is 1, 2, 3, or 4.

28. The drug-linker conjugate according to claim 27, wherein (i) ring A represented by an aliphatic heterocyclic group is ring A' as follows: (In the formula, when ring A' has a substituent, the substituent on ring A' has the same meaning as the substituent on ring A).

29. The drug-linker conjugate of claim 27, wherein the drug-linker conjugate is represented by the following formula (V'a): (In the formula, R １ , R ２ , R ３ Xaa, q, r, s, and t are defined as in 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).

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