Bivalent bet degraders and targeted molecule-drug conjugates

Abstract

This invention provides a divalent BET degrading agent and a targeted molecule-drug complex comprising the divalent BET degrading agent as a drug. As a divalent BET degrading agent, a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof is used (where R...). 1 and R 2 Whether they are the same or different, each represents a hydrogen atom or a lower alkyl group, R 3 R indicates a lower alkyl group. 4 R represents halogen. 5 R represents halogen. 6 Y represents a halogen or lower alkoxy group, 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

[0001] Citation of relevant applications 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. Technical Field

[0002] This invention relates to a divalent BET degrader that has a degrading effect on BET protein and a target molecule-drug complex containing the divalent BET degrader as a drug. Background Technology

[0003] In the human body, 46 bromodomain proteins that recognize acetylated lysine residues in histones are known. As one family, the BET (bromodomain and extra-terminal domain) family has been reported to recognize acetylated lysine residues in histones H3 and H4. Within the BET family, BRD (bromodomain containing protein) 2, BRD3, BRD4, and BRDT (bromodomain testis specific protein) are known. BET family proteins possess two bromodomains (BD1, BD2) at their N-terminus, and their sequences are highly conserved across families. Furthermore, BET proteins have been reported to participate in cancer proliferation [see Non-Patent Literature 1 and 2] and the progression of inflammation [see Non-Patent Literature 3].

[0004] BRD4 recruits P-TEBb to mitotic chromosomes, thereby increasing the expression of growth-promoting genes. Increased expression of c-MYC protein was confirmed in NUT-midline carcinoma (NMC) via the BRD4-NUT fusion protein [see Non-Patent Literature 4]. Furthermore, it has been reported that in MM1.S cells from human multiple myeloma, among genes whose expression was reduced by treatment with the BET inhibitor JQ-1, the reduction in MYC gene expression was the most significant [see Non-Patent Literature 5].

[0005] Representative BET inhibitors include RVX-208 / Apabetalone [see Non-Patent Literature 6], I-BET762 / GSK-525762A [see Non-Patent Literature 7], OTX-015 / MK8628 [see Non-Patent Literature 8], CPI-0610 [see Non-Patent Literature 9], TEN-010 [see Non-Patent Literature 10], and ABBV-075 [see Non-Patent Literature 11], but none have yet received pharmaceutical approval.

[0006] In addition, in recent years, compounds exhibiting stronger BET inhibitory activity by simultaneously inhibiting the BD1 and BD2 domains have been reported as divalent BET inhibitors [see Non-Patent Literature 12]. As such divalent BET inhibitors, compounds represented by the following formulas (P1) to (P6) are known, for example [see Non-Patent Literature 12 and 17, Patent Literature 1, 2 and 3].

[0007] [Chemical Formula 1] Furthermore, compounds that degrade BET protein via the ubiquitin-proteasome system have been reported as novel BET functional modulators. It is known that degrading BET protein can induce apoptosis in cancer cells more efficiently than BET inhibitors [see Non-Patent Literature 13]. Therefore, BET degraders are expected to become superior anticancer agents compared to BET inhibitors.

[0008] Regarding the aforementioned divalent form, it is also known that it can be used as a BET degrading agent by using spacer groups of specific structures to bond two small molecule ligands of BET proteins. More specifically, for example, as a compound Methyl-1-propionyl-1,2,3,4-tetrahydroquinoline-4-yl)amino)phenyl Methyl-1-propionyl-1,2,3,4-tetrahydroquinoline-4-yl)amino)phenyl)ureido)acetamide (hereinafter referred to as g in this specification) and the like are known [see Patent Document 4].

[0009] Antibody-drug complexes (ADCs) consist of monoclonal antibodies covalently bonded to a drug via a linker that is typically chemically synthesized. Combining the high specificity of antibodies with the potent killing effect of drugs enables the accurate and efficient removal of target cells. Currently, the cytotoxic payloads used in FDA-approved ADCs are primarily potent microtubule inhibitors, DNA damaging agents, and topoisomerase I inhibitors [see Non-Patent Literature 14].

[0010] An antibody-drug conjugate (ADC) has been reported, consisting of a drug that degrades BET protein (GNE-987) represented by formula (P7) [see Non-Patent Literature 15] and a drug that degrades BET protein (EBET-1593) represented by formula (P8) [see Non-Patent Literature 16], obtained by conjugating an antibody with a linker. However, no clinical trials have been conducted, and it is unclear whether BET degraders can function effectively as payloads for such antibody-drug complexes.

[0011] [Chemical Formula 2] Existing technical documents Patent documents Patent Document 1: International Publication No. 2013 / 033268 Patent Document 2: International Publication No. 2015 / 081284 Patent Document 3: International Publication No. 2017 / 091673 Patent Document 4: International Publication No. 2021 / 065980 Non-patent literature Non-patent literature 1: Nature, 2011, Vol. 478, pp. 524-528 Non-patent literature 2: Cell, 2011, Vol. 146, pp. 904-917 Non-patent literature 3: Nature, 2010, Vol. 468, pp. 1119-1123 Non-patent literature 4: Cancer Research (Cancer Res.), 2003, Vol. 63, pp. 304-307 Non-patent literature 5: Cell, 2013, Vol. 153, pp. 320-334 Non-patent literature 6: Proceedings of the National Academy of Sciences (Proc. Natl. Acad. Sci.), 2013, Vol. 110, pp. 19754-19759 Non-patent literature 7: Journal of Medicinal Chemistry (J. Med. Chem.), 2013, Vol. 56, pp. 7501-7515 Non-patent literature 8: Oncotarget, 2015, Vol. 6, pp. 17698-17712. Non-Patent Literature 9: Blood, 2015, Vol. 126, pp. 4255-4255 Non-patent literature 10: Molecular Cancer Therapeutics (Mol. Cancer Ther.), 2015, Vol. 14, A49 Non-patent literature 11: Cancer Research (Cancer Res.), 2016, Vol. 76, pp. 4718-4718. Non-patent literature 12: Nature Chemical Biology (Nat. Chem. Bio.), 2016, Vol. 112, pp. 1089-1096 Non-patent literature 13: Science, 2015, Vol. 348, pp. 1376-1381 Non-Patent Literature 14: Signal Transduction and Targeted Therapy (Sig TransductTarget Ther), 2022, Vol. 1, pp. 1-25 Non-patent literature 15: Journal of Medicinal Chemistry (J. Med. Chem.), 2021, Vol. 64, pp. 2576-2607 Non-patent literature 16: Nature Communications (Nat. Commun.), 2024, Vol. 15, pp. 2192-2208 Non-patent literature 17: Molecular Cancer Therapeutics (Mol. Cancer Ther.), 2016, Vol. 15, pp. 2563-2574 Summary of the Invention

[0012] The inventors of this application, while conducting drug development on divalent BET degraders, discovered that while known divalent BET degraders have been observed to have high antitumor activity, they also exhibit peripheral neurotoxicity, a safety concern that must be avoided. To address these issues, the inventors conducted various studies and discovered a divalent BET degrader that maintains high antitumor activity while avoiding the safety concerns of peripheral neurotoxicity. Furthermore, the inventors found that the discovered divalent BET degrader is also useful as a payload (drug) in targeted molecule-drug complexes such as antibody-drug complexes (ADCs).

[0013] The present invention includes the following [1] to

[162] .

[0014] This invention provides: [1] The following formula (I) represents a compound or a pharmaceutically acceptable salt thereof: [Chemical Formula 3] (In the formula, R 1 and R 2 Whether they are the same or different, they each represent a hydrogen atom or a lower alkyl group. R 3 Indicates a lower alkyl group. R 4 Indicates halogen, R 5 Indicates halogen, R 6 Indicates halogen or lower alkoxy group. Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-. Ring A represents: (i) An aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl. (ii) may be an aromatic heterocyclic group having 1 to 3 substituents selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkyl carbonyl, lower hydroxyalkyl carbonyl, lower alkoxycarbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl, or, (iii) It may have an aryl group having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl.

[0015] [2] The compound as described in [1] or a pharmaceutically acceptable salt thereof, wherein (i) the aliphatic heterocyclic group in ring A is a nitrogen-containing aliphatic heterocyclic group.

[0016] [3] The compound as described in [2] or a pharmaceutically acceptable salt thereof, wherein (i) the ring A represented by the nitrogen-containing aliphatic heterocyclic group is a ring A' as follows: [Chemical Formula 4] (In the formula, if ring A' has substituents, the meaning of substituents is the same as that of ring A).

[0017] [4] The compound or a pharmaceutically acceptable salt thereof as described in any one of [1] to [3], wherein the compound represented by formula (I) is the compound represented by formula (I') below: [Chemical Formula 5] (where R) 1 R 2 and R 3 The meaning is the same as that of equation (I). Cycle A' is a nitrogen-containing aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl.

[0018] [5] The compound or a pharmaceutically acceptable salt thereof as described in 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 group represented by the following formula (AG): [Chemical Formula 6] (In the formula, R A1 R B1 R D1 R E1 R F1 and R G1 Whether the groups are the same or different, they each represent lower alkyl, hydroxylower alkyl, lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl, or lower alkyl carbamoyl. R A2 R A3 R B2 R B3 R C1 and R C2 (Whether the same or different, each represents a hydrogen atom, oxo group, lower alkyl group, or hydroxyl lower alkyl group).

[0019] [6] The compound or a pharmaceutically acceptable salt thereof as described in any one of [1] to [5], wherein ring A is a nitrogen-containing aliphatic heterocyclic group represented by the following formula (AA): [Chemical Formula 7] (In the formula, R A1 Indicates a lower alkyl group, a lower alkyl carbonyl group, or a cycloalkyl carbonyl group. R A2 and R A3 (Whether the same or different, each represents a hydrogen atom, oxo group, lower alkyl group, or hydroxyl lower alkyl group).

[0020] [7] The compound as described in [6] or a pharmaceutically acceptable salt thereof, wherein R A1 It is a lower alkyl group or a lower alkyl carbonyl group.

[0021] [8] The compound as described in [6] or [7] or a pharmaceutically acceptable salt thereof, wherein R A2 and R A3 Whether they are the same or different, each is a hydrogen atom, an oxo group, or a lower alkyl group.

[0022] [9] The compound or a pharmaceutically acceptable salt thereof as described in any one of [6] to [8], wherein R A1 It is a lower alkyl group, R A2 and R A3 Whether they are the same or different, each is either an oxo group or a lower alkyl group.

[0023]

[10] The compound or a pharmaceutically acceptable salt thereof as described in any one of [1] to [5], wherein ring A is a nitrogen-containing aliphatic heterocyclic group represented by the following formula (AB): [Chemical Formula 8] (In the formula, R B1 Indicates a lower alkyl group or a lower alkyl carbonyl group. R B2 and R B3 Whether they are the same or different, they each represent a hydrogen atom or an oxo group.

[0024]

[11] The compound as described in

[10] or a pharmaceutically acceptable salt thereof, wherein R B1 It is a lower alkyl group.

[0025]

[12] The compound or a pharmaceutically acceptable salt thereof as described in any one of [1] to [5], wherein ring A is a nitrogen-containing aliphatic heterocyclic group represented by the following formula (AC): [Chemical Formula 9] (where R) C1 and R C2 Whether they are the same or different, they each represent a hydrogen atom or an oxo group.

[0026]

[13] The compound or a pharmaceutically acceptable salt thereof as described in any one of [1] to [5], wherein ring A is a nitrogen-containing aliphatic heterocyclic group represented by the following formula (AD): [Chemical Formula 10] (where R) D1(Indicates a lower alkyl carbonyl group).

[0027]

[14] The compound as described in [1] or a pharmaceutically acceptable salt thereof, wherein ring A is an aromatic heterocyclic group represented by the following formula (AE): [Chemical Formula 11] (where R) E1 (Indicates a lower alkyl group).

[0028]

[15] The compound as described in [1] or a pharmaceutically acceptable salt thereof, wherein ring A is an aromatic heterocyclic group represented by the following formula (AF): [Chemical Formula 12] (where R) F1 (Indicates a lower alkyl group).

[0029]

[16] The compound as described in [1] or a pharmaceutically acceptable salt thereof, wherein ring A is an aryl group represented by the following formula (AG): [Chemical Formula 13] (where R) G1 (Indicates a lower alkoxycarbonyl or a lower alkylcarbamoyl group).

[0030]

[17] The compound or a pharmaceutically acceptable salt thereof as described in any one of [1] to

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

[0031]

[18] The compound or a pharmaceutically acceptable salt thereof as described in any one of [1] to

[17] , wherein R 1 For hydrogen atoms, R 2 For methyl, R 3 It is an ethyl group.

[0032]

[19] Compounds or pharmaceutically acceptable salts thereof represented by the following formula: [Chemical Formula 14] .

[0033]

[20] Compounds or pharmaceutically acceptable salts thereof represented by the following formula: [Chemical Formula 15] .

[0034]

[21] Compounds or pharmaceutically acceptable salts thereof represented by the following formula: [Chemical Formula 16] .

[0035]

[22] Compounds or pharmaceutically acceptable salts thereof represented by the following formula: [Chemical Formula 17] .

[0036]

[23] Compounds or pharmaceutically acceptable salts thereof represented by the following formula: [Chemical Formula 18] .

[0037]

[24] A cancer treatment agent containing any one of the compounds described in [1] to

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

[0038]

[25] The therapeutic agent as described in

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

[0039]

[26] A treatment for cancer, comprising administering to a subject any one of [1] to

[23] a compound or a pharmaceutically acceptable salt thereof.

[0040]

[27] The method described in

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

[0041]

[28] The compound or a pharmaceutically acceptable salt thereof as described in any one of [1] to

[23] is used for the treatment of cancer.

[0042]

[29] The compound as described in

[28] or a pharmaceutically acceptable salt thereof, wherein the cancer is B-cell lymphoma.

[0043] Use of any compound or pharmaceutically acceptable salt thereof, as described in any one of

[30] [1] to

[23] , in the manufacture of a medicament for the treatment of cancer.

[0044]

[31] As described in

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

[0045]

[32] A target molecule-drug complex comprising a target molecule and a drug, wherein the drug is a compound or a pharmaceutically acceptable salt thereof, as described in any one of [1] to

[23] .

[0046]

[33] The target molecule-drug complex as described in

[32] , wherein the drug is connected to the target molecule via a connector.

[0047]

[34] The targeted molecule-drug complex as described in

[32] or

[33] , wherein the targeted molecule-drug complex is represented by the following formula (II): [Chemical Formula 19] (In the formula, R 1 and R 2 Whether they are the same or different, they each represent a hydrogen atom or a lower alkyl group. R 3 Indicates a lower alkyl group. R 4 Indicates halogen, R 5 Indicates halogen, R 6 Indicates halogen or lower alkoxy group. Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-. Ring A represents: (i) An aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl. (ii) It may be an aromatic heterocyclic group having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, lower alkoxy carbonyl, hydroxy-lower alkyl carbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl, or, (iii) may have an aryl group having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkyl carbonyl, hydroxy lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl; L indicates a connector. mm represents an integer from 1 to 8. Z represents the target molecule.

[0048]

[35] The compound as described in

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

[0049]

[36] The targeted molecule-drug complex as described in

[34] or

[35] , wherein (i) the ring A represented by the aliphatic heterocyclic group is a ring A' as follows: [Chemical Formula 20] (In the formula, when ring A' has substituents, the substituents in ring A' have the same meaning as the substituents in ring A).

[0050]

[37] The targeted molecule-drug complex as described in any one of

[33] to

[36] , wherein the targeted molecule-drug complex is represented by the following formula (II'): [Chemical Formula 21] (where R) 1 R 2 R 3 L, mm, and Z have the same meaning as in equation (II). Cycle A' is a nitrogen-containing aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl.

[0051]

[38] The targeted molecule-drug complex as described in any one of

[34] to

[36] , wherein L is represented by the following formula (III): [Chemical Formula 22] (In the formula, The wavy line 1 indicates the bonding site with Z. The wavy line 2 indicates the bonding site with the N atom. 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, sulfoalanine, arginine, asparagine, aspartic acid, glutamine, leucine, isoleucine, lysine, serine, proline, threonine, and tyrosine, or, (b) represents the peptide mimic shown in formula (IV) below: [Chemical Formula 23] ; q represents an integer from 1 to 5. r represents an integer from 2 to 24. s represents 0 or 1, t represents 1, 2, 3, or 4.

[0052]

[39] The targeted molecule-drug complex as described in

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

[0053]

[40] The targeted molecule-drug complex as described in

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

[0054]

[41] The targeted molecule-drug complex as described in any one of

[38] to

[40] , wherein t is 2.

[0055]

[42] The targeted molecule-drug complex as described in any one of

[38] to

[41] , wherein r is 6 or 12.

[0056]

[43] The targeted molecule-drug complex as described in any one of

[38] to

[41] , wherein r is 12.

[0057]

[44] The targeted molecule-drug complex as described in any one of

[38] to

[43] , wherein q is 2 or 5.

[0058]

[45] The targeted molecule-drug complex as described in any of

[38] to

[43] , wherein q is 2.

[0059]

[46] The targeted molecule-drug complex as described in any one of

[38] to

[45] , wherein s is 1.

[0060]

[47] The target molecule-drug complex as described in any one of

[32] to

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

[0061]

[48] ​​The target molecule-drug complex as described in any one of

[32] to

[46] , wherein the target molecule is an antibody or its antigen-binding fragment.

[0062]

[49] The targeted molecule-drug complex as described in

[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 antibody, or an anti-TROP2 antibody.

[0063]

[50] The targeted molecule-drug complex as described in

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

[0064]

[51] The targeted molecule-drug complex as described in

[50] , wherein the anti-CD79b antibody contains a heavy chain variable region (hereinafter sometimes referred to as "VH") comprising CDR1 consisting of the amino acid sequence described in sequence number 11, CDR2 consisting of the amino acid sequence described in sequence number 12 and CDR3 consisting of the amino acid sequence described in sequence number 13, and a light chain variable region (hereinafter sometimes referred to as "VL") comprising CDR1 consisting of the amino acid sequence described in sequence number 14, CDR2 consisting of the amino acid sequence described in sequence number 15 and CDR3 consisting of the amino acid sequence described in sequence number 16.

[0065]

[52] The targeted molecule-drug complex as described in

[50] or

[51] , wherein the amino acid sequence of the VH of the anti-CD79b antibody comprises the amino acid sequence described in Serial No. 5, and the amino acid sequence of the VL of the anti-CD79b antibody comprises the amino acid sequence described in Serial No. 6.

[0066]

[53] The targeted molecule-drug complex as described in any one of

[50] to

[52] , wherein the amino acid sequence of the VH of the anti-CD79b antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in Serial No. 5, and the amino acid sequence of the VL of the anti-CD79b antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in Serial No. 6.

[0067]

[54] The targeted molecule-drug complex as described in

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

[0068]

[55] The targeted molecule-drug complex as described in

[54] , wherein the anti-CD19 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 17, CDR2 consisting of the amino acid sequence described in sequence number 18 and CDR3 consisting of the amino acid sequence described in sequence number 19, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 20, CDR2 consisting of the amino acid sequence described in sequence number 21 and CDR3 consisting of the amino acid sequence described in sequence number 22.

[0069]

[56] The targeted molecule-drug complex as described in

[54] or

[55] , wherein the amino acid sequence of the VH of the anti-CD19 antibody comprises the amino acid sequence described in Serial No. 7, and the amino acid sequence of the VL of the anti-CD19 antibody comprises the amino acid sequence described in Serial No. 8.

[0070]

[57] The targeted molecule-drug complex as described in any one of

[54] to

[56] , wherein the amino acid sequence of the VH of the anti-CD19 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in Serial No. 7, and the amino acid sequence of the VL of the anti-CD19 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in Serial No. 8.

[0071]

[58] The targeted molecule-drug complex as described in

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

[0072]

[59] The targeted molecule-drug complex as described in

[58] , wherein the anti-CD22 antibody contains a VH comprising CDR1 composed of the amino acid sequence described in sequence number 23, CDR2 composed of the amino acid sequence described in sequence number 24 and CDR3 composed of the amino acid sequence described in sequence number 25, and a VL comprising CDR1 composed of the amino acid sequence described in sequence number 26, CDR2 composed of the amino acid sequence described in sequence number 27 and CDR3 composed of the amino acid sequence described in sequence number 28.

[0073]

[60] The targeted molecule-drug complex as described in

[58] or

[59] , wherein the amino acid sequence of the VH of the anti-CD22 antibody comprises the amino acid sequence described in Serial No. 9, and the amino acid sequence of the VL of the anti-CD22 antibody comprises the amino acid sequence described in Serial No. 10.

[0074]

[61] The targeted molecule-drug complex as described in any one of

[58] to

[60] , wherein the amino acid sequence of the VH of the anti-CD22 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in Serial No. 9, and the amino acid sequence of the VL of the anti-CD22 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in Serial No. 10.

[0075]

[62] The targeted molecule-drug complex as described in

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

[0076]

[63] The targeted molecule-drug complex as described in

[62] , wherein the anti-HER2 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 67, CDR2 consisting of the amino acid sequence described in sequence number 68 and CDR3 consisting of the amino acid sequence described in sequence number 69, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 70, CDR2 consisting of the amino acid sequence described in sequence number 71 and CDR3 consisting of the amino acid sequence described in sequence number 72.

[0077]

[64] The targeted molecule-drug complex as described in

[62] or

[63] , wherein the amino acid sequence of the VH of the anti-HER2 antibody comprises the amino acid sequence described in sequence number 29, and the amino acid sequence of the VL of the anti-HER2 antibody comprises the amino acid sequence described in sequence number 30.

[0078]

[65] The targeted molecule-drug complex as described in any one of

[62] to

[64] , wherein the amino acid sequence of the VH of the anti-HER2 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 29, and the amino acid sequence of the VL of the anti-HER2 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 30.

[0079]

[66] The targeted molecule-drug complex as described in

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

[0080]

[67] The targeted molecule-drug complex as described in

[66] , wherein the anti-DLL3 antibody comprises a VH consisting of CDR1 composed of the amino acid sequence described in Serial No. 73, CDR2 composed of the amino acid sequence described in Serial No. 74 and CDR3 composed of the amino acid sequence described in Serial No. 75, and a VL consisting of CDR1 composed of the amino acid sequence described in Serial No. 76, CDR2 composed of the amino acid sequence described in Serial No. 77 and CDR3 composed of the amino acid sequence described in Serial No. 78.

[0081]

[68] The targeted molecule-drug complex as described in

[66] or

[67] , wherein the amino acid sequence of the VH of the anti-DLL3 antibody comprises the amino acid sequence described in sequence number 31, and the amino acid sequence of the VL of the anti-DLL3 antibody comprises the amino acid sequence described in sequence number 32.

[0082]

[69] The targeted molecule-drug complex as described in any one of

[66] to

[68] , wherein the amino acid sequence of the VH of the anti-DLL3 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 31, and the amino acid sequence of the VL of the anti-DLL3 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 32.

[0083]

[70] The targeted molecule-drug complex as described in

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

[0084]

[71] The targeted molecule-drug complex as described in

[70] , wherein the anti-GM2 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 79, CDR2 consisting of the amino acid sequence described in sequence number 80 and CDR3 consisting of the amino acid sequence described in sequence number 81, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 82, CDR2 consisting of the amino acid sequence described in sequence number 83 and CDR3 consisting of the amino acid sequence described in sequence number 84.

[0085]

[72] The targeted molecule-drug complex as described in

[70] or

[71] , wherein the amino acid sequence of the VH of the anti-GM2 antibody comprises the amino acid sequence described in sequence number 33, and the amino acid sequence of the VL of the anti-GM2 antibody comprises the amino acid sequence described in sequence number 34.

[0086]

[73] The targeted molecule-drug complex as described in any one of

[70] to

[72] , wherein the amino acid sequence of the VH of the anti-GM2 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 33, and the amino acid sequence of the VL of the anti-GM2 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 34.

[0087]

[74] The targeted molecule-drug complex as described in

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

[0088]

[75] The targeted molecule-drug complex as described in

[74] , wherein the anti-EphA2 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 85, CDR2 consisting of the amino acid sequence described in sequence number 86 and CDR3 consisting of the amino acid sequence described in sequence number 87, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 88, CDR2 consisting of the amino acid sequence described in sequence number 89 and CDR3 consisting of the amino acid sequence described in sequence number 90.

[0089]

[76] The targeted molecule-drug complex as described in

[74] or

[75] , wherein the amino acid sequence of the VH of the anti-EphA2 antibody comprises the amino acid sequence described in sequence number 35, and the amino acid sequence of the VL of the anti-EphA2 antibody comprises the amino acid sequence described in sequence number 36.

[0090]

[77] The targeted molecule-drug complex as described in any one of

[74] to

[76] , wherein the amino acid sequence of the VH of the anti-EphA2 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 35, and the amino acid sequence of the VL of the anti-EphA2 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 36.

[0091]

[78] The targeted molecule-drug complex as described in

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

[0092]

[79] The targeted molecule-drug complex as described in

[78] , wherein the anti-FAP antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in Serial No. 91, CDR2 consisting of the amino acid sequence described in Serial No. 92 and CDR3 consisting of the amino acid sequence described in Serial No. 93, and a VL comprising CDR1 consisting of the amino acid sequence described in Serial No. 94, CDR2 consisting of the amino acid sequence described in Serial No. 95 and CDR3 consisting of the amino acid sequence described in Serial No. 96.

[0093]

[80] The targeted molecule-drug complex as described in

[78] or

[79] , wherein the amino acid sequence of the VH of the anti-FAP antibody comprises the amino acid sequence described in Serial No. 37, and the amino acid sequence of the VL of the anti-FAP antibody comprises the amino acid sequence described in Serial No. 38.

[0094]

[81] The targeted molecule-drug complex as described in any one of

[78] to

[80] , wherein the amino acid sequence of the VH of the anti-FAP antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in Serial No. 37, and the amino acid sequence of the VL of the anti-FAP antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in Serial No. 38.

[0095]

[82] The targeted molecule-drug complex as described in

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

[0096]

[83] The targeted molecule-drug complex as described in

[82] , wherein the anti-SSTR2 antibody contains a VH comprising CDR1 composed of the amino acid sequence described in Serial No. 97, CDR2 composed of the amino acid sequence described in Serial No. 98 and CDR3 composed of the amino acid sequence described in Serial No. 99, and a VL comprising CDR1 composed of the amino acid sequence described in Serial No. 100, CDR2 composed of the amino acid sequence described in Serial No. 101 and CDR3 composed of the amino acid sequence described in Serial No. 102.

[0097]

[84] The targeted molecule-drug complex as described in

[82] or

[83] , wherein the amino acid sequence of the VH of the anti-SSTR2 antibody comprises the amino acid sequence described in sequence number 39, and the amino acid sequence of the VL of the anti-SSTR2 antibody comprises the amino acid sequence described in sequence number 40.

[0098]

[85] The targeted molecule-drug complex as described in any one of

[82] to

[84] , wherein the amino acid sequence of the VH of the anti-SSTR2 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 39, and the amino acid sequence of the VL of the anti-SSTR2 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 40.

[0099]

[86] The targeted molecule-drug complex as described in

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

[0100]

[87] The targeted molecule-drug complex as described in

[86] , wherein the anti-CD30 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 103, CDR2 consisting of the amino acid sequence described in sequence number 104 and CDR3 consisting of the amino acid sequence described in sequence number 105, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 106, CDR2 consisting of the amino acid sequence described in sequence number 107 and CDR3 consisting of the amino acid sequence described in sequence number 108.

[0101]

[88] The targeted molecule-drug complex as described in

[86] or

[87] , wherein the amino acid sequence of the VH of the anti-CD30 antibody comprises the amino acid sequence described in sequence number 41, and the amino acid sequence of the VL of the anti-CD30 antibody comprises the amino acid sequence described in sequence number 42.

[0102]

[89] The targeted molecule-drug complex as described in any one of

[86] to

[88] , wherein the amino acid sequence of the VH of the anti-CD30 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 41, and the amino acid sequence of the VL of the anti-CD30 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 42.

[0103]

[90] The targeted molecule-drug complex as described in

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

[0104]

[91] The targeted molecule-drug complex as described in

[90] , wherein the anti-BCMA antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 109, CDR2 consisting of the amino acid sequence described in sequence number 110 and CDR3 consisting of the amino acid sequence described in sequence number 111, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 112, CDR2 consisting of the amino acid sequence described in sequence number 113 and CDR3 consisting of the amino acid sequence described in sequence number 114.

[0105]

[92] The targeted molecule-drug complex as described in

[90] or

[91] , wherein the amino acid sequence of the VH of the anti-BCMA antibody comprises the amino acid sequence described in Serial No. 43, and the amino acid sequence of the VL of the anti-BCMA antibody comprises the amino acid sequence described in Serial No. 44.

[0106]

[93] The targeted molecule-drug complex as described in any one of

[90] to

[92] , wherein the amino acid sequence of the VH of the anti-BCMA antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 43, and the amino acid sequence of the VL of the anti-BCMA antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 44.

[0107]

[94] The targeted molecule-drug complex as described in

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

[0108]

[95] The targeted molecule-drug complex as described in

[94] , wherein the anti-CD33 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 115, CDR2 consisting of the amino acid sequence described in sequence number 116 and CDR3 consisting of the amino acid sequence described in sequence number 117, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 118, CDR2 consisting of the amino acid sequence described in sequence number 119 and CDR3 consisting of the amino acid sequence described in sequence number 120.

[0109]

[96] The targeted molecule-drug complex as described in

[94] or

[95] , wherein the amino acid sequence of the VH of the anti-CD33 antibody comprises the amino acid sequence described in sequence number 45, and the amino acid sequence of the VL of the anti-CD33 antibody comprises the amino acid sequence described in sequence number 46.

[0110]

[97] The targeted molecule-drug complex as described in any one of

[94] to

[96] , wherein the amino acid sequence of the VH of the anti-CD33 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 45, and the amino acid sequence of the VL of the anti-CD33 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 46.

[0111]

[98] The targeted molecule-drug complex as described in

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

[0112]

[99] The targeted molecule-drug complex as described in

[98] , wherein the anti-FoLRα antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 121, CDR2 consisting of the amino acid sequence described in sequence number 122 and CDR3 consisting of the amino acid sequence described in sequence number 123, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 124, CDR2 consisting of the amino acid sequence described in sequence number 125 and CDR3 consisting of the amino acid sequence described in sequence number 126.

[0113]

[100] The targeted molecule-drug complex as described in

[98] or

[99] , wherein the amino acid sequence of the VH of the anti-FoLRα antibody comprises the amino acid sequence described in Serial No. 47, and the amino acid sequence of the VL of the anti-FoLRα antibody comprises the amino acid sequence described in Serial No. 48.

[0114]

[101] The targeted molecule-drug complex as described in any one of

[98] to

[100] , wherein the amino acid sequence of the VH of the anti-FoLRα antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in Serial No. 47, and the amino acid sequence of the VL of the anti-FoLRα antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in Serial No. 48.

[0115]

[102] The targeted molecule-drug complex as described in

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

[0116]

[103] The targeted molecule-drug complex as described in

[102] , wherein the anti-CD25 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in Serial No. 127, CDR2 consisting of the amino acid sequence described in Serial No. 128 and CDR3 consisting of the amino acid sequence described in Serial No. 129, and a VL comprising CDR1 consisting of the amino acid sequence described in Serial No. 130, CDR2 consisting of the amino acid sequence described in Serial No. 131 and CDR3 consisting of the amino acid sequence described in Serial No. 132.

[0117]

[104] The targeted molecule-drug complex as described in

[102] or

[103] , wherein the amino acid sequence of the VH of the anti-CD25 antibody comprises the amino acid sequence described in sequence number 49, and the amino acid sequence of the VL of the anti-CD25 antibody comprises the amino acid sequence described in sequence number 50.

[0118]

[105] The targeted molecule-drug complex as described in any one of

[102] to

[104] , wherein the amino acid sequence of the VH of the anti-CD25 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 49, and the amino acid sequence of the VL of the anti-CD25 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 50.

[0119]

[106] The targeted molecule-drug complex as described in

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

[0120]

[107] The targeted molecule-drug complex as described in

[106] , wherein the anti-CADM1 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 133, CDR2 consisting of the amino acid sequence described in sequence number 134 and CDR3 consisting of the amino acid sequence described in sequence number 135, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 136, CDR2 consisting of the amino acid sequence described in sequence number 137 and CDR3 consisting of the amino acid sequence described in sequence number 138.

[0121]

[108] The targeted molecule-drug complex as described in

[106] or

[107] , wherein the amino acid sequence of the VH of the anti-CADM1 antibody comprises the amino acid sequence described in Serial No. 51, and the amino acid sequence of the VL of the anti-CADM1 antibody comprises the amino acid sequence described in Serial No. 52.

[0122]

[109] The targeted molecule-drug complex as described in any one of

[106] to

[108] , wherein the amino acid sequence of the VH of the anti-CADM1 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 51, and the amino acid sequence of the VL of the anti-CADM1 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 52.

[0123]

[110] The targeted molecule-drug complex as described in

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

[0124]

[111] The targeted molecule-drug complex as described in

[110] , wherein the anti-CLL1 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 139, CDR2 consisting of the amino acid sequence described in sequence number 140 and CDR3 consisting of the amino acid sequence described in sequence number 141, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 142, CDR2 consisting of the amino acid sequence described in sequence number 143 and CDR3 consisting of the amino acid sequence described in sequence number 144.

[0125]

[112] The targeted molecule-drug complex as described in

[110] or

[111] , wherein the amino acid sequence of the VH of the anti-CLL1 antibody comprises the amino acid sequence described in Serial No. 53, and the amino acid sequence of the VL of the anti-CLL1 antibody comprises the amino acid sequence described in Serial No. 54.

[0126]

[113] The targeted molecule-drug complex as described in any one of

[110] to

[112] , wherein the amino acid sequence of the VH of the anti-CLL1 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 53, and the amino acid sequence of the VL of the anti-CLL1 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 54.

[0127]

[114] The targeted molecule-drug complex as described in

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

[0128]

[115] The targeted molecule-drug complex as described in

[114] , wherein the anti-CD38 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 145, CDR2 consisting of the amino acid sequence described in sequence number 146 and CDR3 consisting of the amino acid sequence described in sequence number 147, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 148, CDR2 consisting of the amino acid sequence described in sequence number 149 and CDR3 consisting of the amino acid sequence described in sequence number 150.

[0129]

[116] The targeted molecule-drug complex as described in

[114] or

[115] , wherein the amino acid sequence of the VH of the anti-CD38 antibody comprises the amino acid sequence described in sequence number 55, and the amino acid sequence of the VL of the anti-CD38 antibody comprises the amino acid sequence described in sequence number 56.

[0130]

[117] The targeted molecule-drug complex as described in any one of

[114] to

[116] , wherein the amino acid sequence of the VH of the anti-CD38 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 55, and the amino acid sequence of the VL of the anti-CD38 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 56.

[0131]

[118] The targeted molecule-drug complex as described in

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

[0132]

[119] The targeted molecule-drug complex as described in

[118] , wherein the anti-CD74 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 151, CDR2 consisting of the amino acid sequence described in sequence number 152 and CDR3 consisting of the amino acid sequence described in sequence number 153, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 154, CDR2 consisting of the amino acid sequence described in sequence number 155 and CDR3 consisting of the amino acid sequence described in sequence number 156.

[0133]

[120] The targeted molecule-drug complex as described in

[118] or

[119] , wherein the amino acid sequence of the VH of the anti-CD74 antibody comprises the amino acid sequence described in Serial No. 57, and the amino acid sequence of the VL of the anti-CD74 antibody comprises the amino acid sequence described in Serial No. 58.

[0134]

[121] The targeted molecule-drug complex as described in any one of

[118] to

[120] , wherein the amino acid sequence of the VH of the anti-CD74 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in Serial No. 57, and the amino acid sequence of the VL of the anti-CD74 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in Serial No. 58.

[0135]

[122] The targeted molecule-drug complex as described in

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

[0136]

[123] The targeted molecule-drug complex as described in

[122] , wherein the anti-Nectin4 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in sequence number 187, CDR2 consisting of the amino acid sequence described in sequence number 188 and CDR3 consisting of the amino acid sequence described in sequence number 189, and a VL comprising CDR1 consisting of the amino acid sequence described in sequence number 190, CDR2 consisting of the amino acid sequence described in sequence number 191 and CDR3 consisting of the amino acid sequence described in sequence number 192.

[0137]

[124] The targeted molecule-drug complex as described in

[122] or

[123] , wherein the amino acid sequence of the VH of the anti-Nectin4 antibody comprises the amino acid sequence described in Serial No. 183, and the amino acid sequence of the VL of the anti-Nectin4 antibody comprises the amino acid sequence described in Serial No. 184.

[0138]

[125] The targeted molecule-drug complex as described in any one of

[122] to

[124] , wherein the amino acid sequence of the VH of the anti-Nectin4 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 183, and the amino acid sequence of the VL of the anti-Nectin4 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 184.

[0139]

[126] The targeted molecule-drug complex as described in

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

[0140]

[127] The targeted molecule-drug complex as described in

[126] , wherein the anti-TROP2 antibody contains a VH comprising CDR1 consisting of the amino acid sequence described in Serial No. 193, CDR2 consisting of the amino acid sequence described in Serial No. 194 and CDR3 consisting of the amino acid sequence described in Serial No. 195, and a VL comprising CDR1 consisting of the amino acid sequence described in Serial No. 196, CDR2 consisting of the amino acid sequence described in Serial No. 197 and CDR3 consisting of the amino acid sequence described in Serial No. 198.

[0141]

[128] The targeted molecule-drug complex as described in

[126] or

[128] , wherein the amino acid sequence of the VH of the anti-TROP2 antibody comprises the amino acid sequence described in sequence number 185, and the amino acid sequence of the VL of the anti-TROP2 antibody comprises the amino acid sequence described in sequence number 186.

[0142]

[129] The targeted molecule-drug complex as described in any one of

[126] to

[128] , wherein the amino acid sequence of the VH of the anti-TROP2 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 185, and the amino acid sequence of the VL of the anti-TROP2 antibody comprises an amino acid sequence having more than 90% sequence identity with respect to the amino acid sequence described in sequence number 186.

[0143]

[130] The target molecule-drug complex as described in any one of

[48] to

[129] , wherein the amino acid sequence of the heavy chain constant region of the antibody (hereinafter sometimes referred to as "CH") comprises: (a) The amino acid sequence recorded in sequence number 1, or, (b) An amino acid sequence that has more than 80% sequence identity with respect to the amino acid sequence recorded in sequence number 1.

[0144]

[131] The targeted molecule-drug complex as described in

[130] , wherein the amino acid sequence (b) is an amino acid sequence obtained by replacing at least one amino acid in the amino acid sequence described in Serial No. 1 with cysteine.

[0145]

[132] The targeted molecule-drug complex as described in any one of

[48] to

[129] , wherein the amino acid sequence of the CH of the antibody comprises the amino acid sequence described in sequence number 2.

[0146]

[133] The targeted molecule-drug complex as described in

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

[0147]

[134] The targeted molecule-drug complex as described in any one of

[48] to

[133] , wherein the amino acid sequence of the light chain constant region (hereinafter sometimes referred to as "CL") of the antibody comprises: (e) The amino acid sequence recorded in sequence number 3, or, (f) An amino acid sequence that has more than 80% sequence identity with respect to the amino acid sequence recorded in sequence number 3.

[0148]

[135] The targeted molecule-drug complex as described in

[134] , wherein the amino acid sequence (f) is an amino acid sequence obtained by replacing at least one amino acid in the amino acid sequence described in Serial No. 3 with cysteine.

[0149]

[136] The targeted molecule-drug complex as described in any one of

[48] to

[135] , wherein the amino acid sequence of the CL of the antibody comprises the amino acid sequence described in sequence number 4.

[0150]

[137] The targeted molecule-drug complex as described in

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

[0151]

[138] A cancer treatment agent containing, as an active ingredient, any one of

[32] to

[137] .

[0152]

[139] The reagent as described in

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

[0153]

[140] A treatment for cancer, comprising administering to a subject any of the targeted molecule-drug complexes described in any of

[32] to

[137] .

[0154]

[141] The method as described in

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

[0155]

[142] The targeted molecule-drug complex as described in any one of

[32] to

[137] , for the treatment of cancer.

[0156]

[143] The targeted molecule-drug complex as described in

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

[0157] Use of any of the targeted molecule-drug complexes described in any one of

[144] ,

[32] to

[137] in the manufacture of medicaments for the treatment of cancer.

[0158]

[145] The use as described in

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

[0159]

[146] A drug-connector complex comprising a drug and a connector attached to the drug. The drug is any one of the compounds described in [1] to

[23] or a pharmaceutically acceptable salt thereof.

[0160]

[147] The drug-connector complex as described in

[146] , wherein the drug-connector complex is represented by the following formula (V): [Chemical Formula 25] (In the formula, R 1 and R 2 Whether they are the same or different, they each represent a hydrogen atom or a lower alkyl group. R 3 Indicates a lower alkyl group. R 4 Indicates halogen, R 5 Indicates halogen, R 6 Indicates halogen or lower alkoxy group. Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-. Ring A represents: (i) A nitrogen-containing aliphatic heterocyclic group having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl. (ii) may be an aromatic heterocyclic group having 1 to 3 substituents selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkyl carbonyl, lower hydroxyalkyl carbonyl, lower alkoxycarbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl, or, (iii) may have an aryl group having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkyl carbonyl, hydroxy lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl; L indicates a connector.

[0161]

[148] The compound as described in

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

[0162]

[149] The drug-connector complex as described in

[147] or

[148] , wherein (i) the ring A represented by the aliphatic heterocyclic group is a ring A' as follows: [Chemical Formula 26] (In the formula, when ring A' has substituents, the substituents in ring A' have the same meaning as the substituents in ring A).

[0163]

[150] The drug-connector complex as described in any one of

[146] to

[149] , wherein the drug-connector complex is represented by the following formula (V'): [Chemical Formula 27] (where R) 1 R 2 R 3 And L has the same meaning as equation (V). Cycle A' is a nitrogen-containing aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl.

[0164]

[151] The drug-connector complex as described in

[147] , wherein the drug-connector complex is represented by the following formula (Va): [Chemical Formula 28] (In the formula, R 1 R 2 R 3 R 4 R 5 R 6 Y and ring A have the same meaning as above. 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, sulfoalanine, arginine, asparagine, aspartic acid, glutamine, leucine, isoleucine, lysine, serine, proline, threonine, and tyrosine, or, (b) represents the peptide mimic shown in formula (IV) below: [Chemical Formula 29] ; q represents an integer from 1 to 5. r represents an integer from 2 to 24. s represents 0 or 1, t represents 1, 2, 3, or 4.

[0165]

[152] The compound as described in

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

[0166]

[153] The drug-connector complex as described in

[151] or

[152] , wherein (i) the ring A represented by the aliphatic heterocyclic group is a ring A' as follows: [Chemical Formula 30] (In the formula, when ring A' has substituents, the substituents in ring A' have the same meaning as the substituents in ring A).

[0167]

[154] The drug-connector complex as described in any one of

[146] to

[153] , wherein the drug-connector complex is represented by the following formula (V'a): [Chemical Formula 31] (where R) 1 R 2 R 3 Xaa, q, r, s, and t have the same meaning as in equation (Va). Cycle A' is a nitrogen-containing aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl.

[0168]

[155] The drug-connector complex as described in any one of

[151] to

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

[0169]

[156] The drug-connector complex as described in any one of

[151] to

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

[0170]

[157] The drug-connector complex as described in any one of

[151] to

[156] , wherein t is 2.

[0171]

[158] The drug-connector complex as described in any one of

[151] to

[157] , wherein r is 6 or 12.

[0172]

[159] The drug-connector complex as described in any one of

[151] to

[158] , wherein r is 12.

[0173]

[160] The drug-connector complex as described in any one of

[151] to

[159] , wherein q is 2 or 5.

[0174]

[161] The drug-connector complex as described in any one of

[151] to

[160] , wherein q is 2.

[0175]

[162] The drug-connector complex as described in any one of

[151] to

[161] , wherein s is 1.

[0176] Compounds represented by formula (I) or pharmaceutically acceptable salts thereof are divalent BET degraders, which can avoid safety concerns such as peripheral neurotoxicity while maintaining high antitumor activity. Compounds represented by formula (I) or pharmaceutically acceptable salts thereof are also useful as payloads (drugs) in targeted molecule-drug complexes such as antibody-drug complexes (ADCs).

[0177] The inclusion of compounds represented by formula (I) or their pharmaceutically acceptable salts as drug-targeting molecules—drug complexes—can address safety concerns such as avoiding peripheral neurotoxicity while maintaining high antitumor activity. Attached Figure Description

[0178] [ Figure 1 ] Figure 1 The figure shows the results of Experiment 4 (in vivo efficacy evaluation of the compound and ADC).

[0179] [ Figure 2 ] Figure 2 The figure shows the results of Experiment 5 (based on the evaluation of BET protein degradation using Western blot (WB) with SU-DHL-4 cell line). Detailed Implementation

[0180] The present invention will now be described. In this specification, the terms "value A to value B" refer to values ​​greater than A and less than B. Combinations of two or more embodiments described in this specification are also included in the present invention.

[0181] Glossary of Terms The following describes the terminology used in this specification. Unless otherwise specified, the following descriptions apply throughout this specification.

[0182] Oxide group The oxo group is a group represented by the formula: =O.

[0183] lower alkyl Lower alkyl groups are, for example, straight-chain or branched alkyl groups having 1 to 10 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.

[0184] hydroxyl lower alkyl A hydroxyl lower alkyl group is a lower alkyl group obtained by substituting one or more hydrogen atoms with hydroxyl groups. The description of lower alkyl groups is as described above. The position and number of hydroxyl groups in the hydroxyl lower alkyl group are not particularly limited. The number of hydroxyl groups is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1. Examples of hydroxyl lower alkyl groups include, for example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-dihydroxyethyl, 1,2-dihydroxypropyl, etc.

[0185] lower alkyl carbonyl Lower alkyl carbonyl groups are groups represented by the formula: -CO-lower alkyl. The description of lower alkyl groups is as described above. Examples of lower alkyl carbonyl groups include, for instance, methyl carbonyl (acetyl), ethyl carbonyl, n-propyl carbonyl, isopropyl carbonyl, n-butyl carbonyl, isobutyl carbonyl, sec-butyl carbonyl, tert-butyl carbonyl, n-pentyl carbonyl, isopentyl carbonyl, neopentyl carbonyl, hexyl carbonyl, heptyl carbonyl, octyl carbonyl, nonyl carbonyl, decyl carbonyl, etc.

[0186] hydroxyl lower alkyl carbonyl The hydroxy-lower alkyl carbonyl group is represented by the formula: -CO-hydroxy-lower alkyl. The description of hydroxy-lower alkyl groups is as described above. Examples of hydroxy-lower alkyl carbonyl groups include, for example, hydroxymethyl carbonyl, 1-hydroxyethyl carbonyl, 2-hydroxyethyl carbonyl, 1-hydroxypropyl carbonyl, 2-hydroxypropyl carbonyl, 1,2-dihydroxyethyl carbonyl, and 1,2-dihydroxypropyl carbonyl.

[0187] cycloalkyl carbonyl A cycloalkyl carbonyl group is a group represented by the formula: -CO-cycloalkyl. The number of carbon atoms in a cycloalkyl group is, for example, 3 to 10. Examples of cycloalkyl carbonyl groups include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclooctylcarbonyl, cyclononylcarbonyl, and cyclodecylcarbonyl.

[0188] halogen Halogens are atoms from fluorine, chlorine, bromine, and iodine.

[0189] lower alkoxy The lower alkoxy group is, for example, a straight-chain or branched alkoxy group having 1 to 10 carbon atoms, preferably an alkoxy group having 1 to 5 carbon atoms, and more preferably an alkoxy group having 1 to 3 carbon atoms. Examples of lower alkoxy groups include methoxy, ethoxy, propyloxy, isopropyloxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., with methoxy being preferred.

[0190] lower alkoxycarbonyl The lower alkoxy carbonyl group is a group represented by the formula: -CO-lower alkoxy. The description of the lower alkoxy group is as described above. The lower alkoxy carbonyl group is, for example, a straight-chain or branched alkoxy carbonyl group with 1 to 11 carbon atoms, preferably an alkoxy carbonyl group with 1 to 5 carbon atoms, and more preferably an alkoxy carbonyl group with 1 to 3 carbon atoms. Examples of lower alkoxy carbonyl groups include, for example, methoxy carbonyl, ethoxy carbonyl, propoxy carbonyl, isopropoxy carbonyl, butoxy carbonyl, isobutoxy carbonyl, sec-butoxy carbonyl, tert-butoxy carbonyl, pentoxy carbonyl, isopentoxy carbonyl, neopentoxy carbonyl, etc., with methoxy carbonyl and ethoxy carbonyl being preferred.

[0191] lower alkyl carbamoyl The lower alkyl carbamoyl group is a group represented by the formula: -CONH-lower alkyl. The description of the lower alkyl group is as described above. The lower alkyl carbamoyl group is, for example, a straight-chain or branched alkyl carbamoyl group with 1 to 11 carbon atoms, preferably an alkyl carbamoyl group with 1 to 5 carbon atoms, and more preferably an alkyl carbamoyl group with 1 to 3 carbon atoms. Examples of lower alkyl carbamoyl groups include, for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc., with methylcarbamoyl and dimethylcarbamoyl being preferred.

[0192] Aliphatic heterocyclic groups In an aliphatic heterocyclic group, in addition to carbon atoms, the ring-forming elements include one or more heteroatoms other than carbon atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms. 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 can be appropriately determined based on the number of heteroatoms and elements in the aliphatic heterocyclic group.

[0193] In aliphatic heterocyclic groups, the two carbon atoms constituting the ring can be bridged using 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 more preferably 1.

[0194] Aliphatic heterocyclic groups can consist of only saturated bonds or contain double bonds, but are preferably composed of only saturated bonds.

[0195] The aliphatic heterocyclic group can be monocyclic or fused polycyclic. Fused polycyclic groups are, for example, fused bicyclic or fused tricyclic, preferably fused bicyclic.

[0196] The number of elements in the monocyclic aliphatic heterocyclic group is, for example, 3 to 8, preferably 4 to 8, more preferably 5 to 7, and even more preferably 6 or 7.

[0197] Examples of monocyclic aliphatic heterocyclic groups include, for example, aliphatic heterocyclic groups containing only a nitrogen atom as a heteroatom, such as aziridinyl, aziridine, pyrrolyl, pyrrolinyl, imidazoalkyl, imidazolinyl, pyrazolyl, pyrazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiaranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, aziridine, 1,4-diazaheptanyl, aziridine octyl, and dizaheptanyl. Examples of aliphatic heterocyclic groups containing both nitrogen and oxygen atoms as heteroatoms include oxazolyl, oxazolinyl, and morpholinyl. Examples of aliphatic heterocyclic groups containing both nitrogen and sulfur atoms as heteroatoms include thiazoalkyl, thiazolinyl, and thiomorpholinyl. Piperazinyl or 1,4-diazaheptanyl is preferred, and piperazinyl is more preferred.

[0198] Fused polycyclic aliphatic heterocyclic groups are, for example, bicyclic or tricyclic nitrogen-containing aliphatic heterocyclic groups formed by the fusion of 3- to 8-membered rings of aliphatic heterocyclic groups containing only nitrogen atoms as heteroatoms. Specifically, examples include hexahydropyrrolopyrazinyl, octahydropyridinolpyrazinyl, octahydropyrrolodiazaheptanyl, decahydropyridinoldiazaheptanyl, and decahydrodiazazaheptanyl.

[0199] Nitrogen-containing aliphatic heterocyclic groups A nitrogen-containing aliphatic heterocyclic group is an aliphatic heterocyclic group that contains one or more nitrogen atoms as ring-forming elements in addition to carbon atoms. The number of nitrogen atoms in the nitrogen-containing aliphatic heterocyclic group is, for example, 1 to 3, preferably 1 or 2, more preferably 2. The number of carbon atoms in the nitrogen-containing aliphatic heterocyclic group can be appropriately determined according to the number of heteroatoms and elements in the nitrogen-containing aliphatic heterocyclic group. There is no particular limitation on the connecting bonds of the nitrogen-containing aliphatic heterocyclic group, but it is preferred that the connecting bonds are present in nitrogen atoms. The nitrogen-containing aliphatic heterocyclic group may also 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 heteroatoms other than nitrogen atoms, the number of heteroatoms other than nitrogen atoms is, for example, 1 or 2, preferably 1.

[0200] In nitrogen-containing aliphatic heterocyclic groups, the two carbon atoms constituting the ring can be bridged using 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 more preferably 1.

[0201] Nitrogen-containing aliphatic heterocyclic groups can consist of only saturated bonds or contain double bonds, but are preferably composed of only saturated bonds.

[0202] The nitrogen-containing aliphatic heterocyclic group can be monocyclic or fused polycyclic. Fused polycyclic groups are, for example, fused bicyclic or fused tricyclic, preferably fused bicyclic.

[0203] The number of numerators of the monocyclic nitrogen-containing aliphatic heterocyclic group is, for example, 3 to 8, preferably 4 to 8, more preferably 5 to 7, and even more preferably 6 or 7.

[0204] Examples of monocyclic nitrogen-containing aliphatic heterocyclic groups include aziridinyl, aziridine, pyrrolyl, pyrrolinyl, imidazoalkyl, imidazolinyl, oxazolyl, oxazolyl, pyrazolyl, pyrazolyl, thiazoalkyl, thiazolinyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiaranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, morpholinyl, thiomorpholinyl, aziridine-heptyl, 1,4-diazacycloheptyl, aziridine-octyl, and dizacyclooctyl. Piperazinyl or 1,4-diazacycloheptyl is preferred, and piperazinyl is more preferred.

[0205] Fused polycyclic nitrogen-containing aliphatic heterocyclic groups are, for example, bicyclic or tricyclic nitrogen-containing aliphatic heterocyclic groups formed by the fusion of 3 to 8-membered rings. Specifically, examples include hexahydropyrrolopyrazinyl, octahydropyridinolpyrazinyl, octahydropyrrolodiazaheptanyl, decahydropyridinoldiazaheptanyl, and decahydrodiazazaheptanyl.

[0206] Aromatic heterocyclic groups In aromatic heterocyclic groups, in addition to carbon atoms, the ring-forming elements include one or more heteroatoms other than carbon atoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms. The number of heteroatoms in an aromatic heterocyclic group is, for example, 1 to 3, preferably 1 or 2. The number of carbon atoms in an aromatic heterocyclic group can be appropriately determined based on the number of heteroatoms and elements in the aromatic heterocyclic group.

[0207] The aromatic heterocyclic group can be monocyclic or fused polycyclic. Fused polycyclic groups are, for example, fused bicyclic or fused tricyclic, preferably fused bicyclic.

[0208] The number of aromatic heterocyclic groups is, for example, 5 to 10, preferably 5 to 9, and more preferably 5 or 6.

[0209] Examples of aromatic heterocyclic groups include, for instance, 5-membered aromatic heterocyclic groups such as pyrroleyl, furanyl, thiopheneyl, pyrazolyl, imidazoleyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl; 6-membered aromatic heterocyclic groups such as pyridyl, pyridinyl, pyrazinyl, triazinyl, and tetrazinyl; 9-membered aromatic heterocyclic groups such as indazoleyl, indoleazinyl, imidazole-pyridyl, and 1,3-benzodioxonyl; and 10-membered aromatic heterocyclic groups such as quinolinyl, isoquinolinyl, quinazolinyl, naphthidyl, benzopyranyl, and dihydrobenzopyranyl. Oxazolyl or pyridyl is preferred.

[0210] Aryl Aryl (also known as Aryl group) refers to a monovalent aromatic hydrocarbon group formed by removing one hydrogen atom from an aromatic carbon ring. The number of carbon atoms in the aryl group is not particularly limited; for example, 6 to 18 are possible, but 6 to 10 are preferred.

[0211] The aryl group can be monocyclic or fused polycyclic. Fused polycyclic forms include, for example, fused bicyclic or fused tricyclic, with fused bicyclic being preferred.

[0212] Examples of aryl groups include phenyl, 1-naphthyl, and 2-naphthyl. Phenyl is preferred.

[0213] Antibody Antibodies (immunoglobulins) are glycoproteins consisting of two heavy chains (hereinafter referred to as "H chains") and two light chains (hereinafter referred to as "L chains"). There are five types of antibodies: IgG, IgM, IgA, IgD, and IgE. The basic structure of antibodies is common to all types: the two heavy chains and two light chains are bonded together by disulfide bonds and non-covalent bonds, forming a Y-shaped four-chain structure.

[0214] The N-terminal domains of both the heavy and light chains are called variable regions, which are related to the specificity of antibody-antigen binding. The amino acid sequence of the C-terminal domain 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 region is further divided into three domains from the N-terminus: CH1, CH2, and CH3. 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.

[0215] Both VH and VL antibodies contain three complementarity determining regions (CDRs): CDR1, CDR2, and CDR3. CDRs determine the specificity against the antigen, and therefore their amino acid sequences vary significantly between antibodies; they are also known as hypervariable domains. The regions outside the CDRs in the variable region are called frame regions (FRs), where the amino acid sequence changes less. CDR1, CDR2, and CDR3 in VH are also referred to as CDRH1, CDRH2, and CDRH3, respectively, while those in VL are referred to as CDRL1, CDRL2, and CDRL3, respectively.

[0216] In this specification, the amino acid positions assigned to CDR and FR are specified according to the Kabat number (see Sequences of Proteins of Immunological Interest (National Institute of Health, Bethesda, Md., (1987) and (1991)).

[0217] In this specification, the amino acid positions in the constant region are specified according to the Kabat EU number (see Sequences of proteins of immunological interest, NIH Publication No. 91-3242).

[0218] The antibody can be a polyclonal antibody or a monoclonal antibody, with monoclonal antibodies being preferred.

[0219] Examples of monoclonal antibodies include antibodies produced by hybridomas and recombinant antibodies produced by transformants obtained by transforming a vector containing an antibody gene.

[0220] Monoclonal antibodies are antibodies secreted by antibody-producing cells of a single clone, recognizing only one epitope (also known as an antigenic determinant). The amino acid sequence (primary structure) that makes up a monoclonal antibody is homogeneous.

[0221] Hybridomas can be prepared, for example, by inducing antigen-specific antibody-producing cells in animals immunized with an antigen, and then fusing these antibody-producing cells with myeloma cells. Monoclonal antibodies can be obtained by culturing the hybridoma, or by administering the hybridoma cells to an animal to induce ascites carcinogenesis, and then isolating and purifying the monoclonal antibodies from the culture medium or ascites. Any animal capable of producing a hybridoma can be used as the immunizing animal, but mice, rats, hamsters, chickens, and rabbits are preferred. Monoclonal antibodies can also be antibodies produced from hybridomas created by fusing antibody-producing cells obtained from animals with myeloma cells after in vitro immunization of these cells.

[0222] As examples of recombinant antibodies, human chimeric antibodies, humanized antibodies, and human antibodies are antibodies produced through gene recombination.

[0223] Human chimeric antibodies are antibodies containing the VH and VL of antibodies from animals other than humans, and the CH and CL of human antibodies. Human chimeric antibodies can be manufactured by obtaining the DNA encoding the VH and VL of antibodies from animals other than humans, inserting them into animal cell expression vectors containing the DNA encoding the CH and CL of human antibodies, respectively, to construct human chimeric antibody expression vectors, and then introducing them into animal cells for expression.

[0224] For human chimeric antibodies, the CH (chromatogram) can be any human immunoglobulin (hIg), for example, an hIgG subclass CH, specifically hIgG1, hIgG2, hIgG3, hIgG4, or their modifications. The CL (chromatogram) can be any hIg, for example, a CL of the human κ chain or human λ chain.

[0225] Examples of humanized antibodies include human CDR transplantation antibodies and humanized antibodies based on surface remodeling methods. Antibodies manufactured using methods combining these methods are also included in the category of humanized antibodies. Antibodies consisting of an amino acid sequence obtained by deleting, substituting, inserting, or adding one or more amino acids to the amino acid sequence of a humanized antibody designed using these methods, and capable of binding to a target antigen (preferably specifically binding), are also included in the category of humanized antibodies.

[0226] Human CDR transplanted antibodies are antibodies obtained by transplanting the amino acid sequences of the CDRs of the VH and VL regions of an animal antibody (excluding humans) to appropriate positions in the VH and VL regions of a human antibody. Human CDR transplanted antibodies can be manufactured as follows: DNA encoding the CDRs of the VH and VL regions of a monoclonal antibody (excluding humans) capable of binding (preferably specifically binding) to a target antigen is constructed by transplanting the amino acid sequences of the CDRs of the VH and VL regions of any human antibody into the frame region (FR) of the VH and VL regions. This results in the V region of the DNA. Subsequently, the DNA is inserted into an animal cell expression vector containing the CH and CL regions encoding the human antibody, respectively, to construct a human CDR transplanted antibody expression vector, which is then introduced into animal cells for expression.

[0227] Humanized antibodies based on surface remodeling are antibodies obtained by replacing amino acid residues in the variable region of antibodies from animals other than humans—specifically, the FR residues that are considered not to affect the binding activity of the antibody—with amino acid residues that are considered to reduce antigenicity using surface remodeling methods (Proc. Natl. Acad. Sci. USA 1994, 91(3): 969-73 and Protein Engineering 1996, 10, 895-90). Humanized antibodies based on surface remodeling can be manufactured as follows: DNA encoding a monoclonal antibody from an animal other than humans that can bind (preferably specifically binds) to a target antigen by replacing any amino acid residue in the FR region of the VH and VL regions with other amino acid residues. Then, these are inserted into animal cell expression vectors containing DNA encoding the CH and CL regions of a human antibody, respectively, to construct a humanized antibody expression vector based on surface remodeling, which is then introduced into animal cells for expression.

[0228] The CH of a humanized antibody can be any human immunoglobulin (hIg) as long as it belongs to the human immunoglobulin family. For example, it can be a CH of the hIgG class, specifically a CH of hIgG1, hIgG2, hIgG3, hIgG4, or their modifications. The CL of a humanized antibody can be any hIg as long as it belongs to the hIg family. For example, it can be a CL of the human κ chain or the human λ chain.

[0229] Human antibodies originally refer to antibodies that naturally exist in the human body, but antibodies obtained from human antibody phage libraries created using recent advancements in genetic engineering, cell engineering, and developmental engineering, as well as antibodies from transgenic animals that produce human antibodies, are also included in the category of human antibodies.

[0230] Regarding antibodies that naturally exist in the human body, for example, human peripheral blood lymphocytes can be isolated, infected with EB virus, etc. to make them immortal, cloned, and then cultured to produce lymphocytes that can produce the antibody. The antibody can then be purified from the culture supernatant.

[0231] Human antibody phage libraries are obtained by inserting antibody genes prepared from human B cells or B cells of transgenic animals producing human antibodies into phage genes, thereby expressing antibody fragments such as Fab and scFv on the surface of phages. Phages expressing antibody fragments with the desired antigen-binding activity can be recovered from this library using the binding activity against substrates with immobilized antigens as an indicator. These antibody fragments can also be further transformed into human antibody molecules containing two complete H chains and two complete L chains using genetic engineering methods.

[0232] Transgenic animals that produce human antibodies are animals whose cells have integrated human antibody genes. Specifically, for example, a human antibody gene can be introduced into mouse ES cells, and these ES cells can be transplanted into early mouse embryos to allow development, thereby creating transgenic mice that produce human antibodies. Human antibodies from transgenic animals that produce human antibodies can be produced as follows: using hybridoma manufacturing methods typically performed in animals other than humans, hybridomas producing human antibodies are obtained, cultured, and human antibodies are produced and accumulated in the culture supernatant. Alternatively, B cells from transgenic animals that produce human antibodies can be isolated, cloned, and the human antibody gene isolated.

[0233] Antigen-binding fragments of antibodies An antibody's antigen-binding fragment is a segment of the antibody that possesses binding activity against a target antigen. The antigen-binding fragment of an antibody is also called the functional fragment of the antibody. Examples of antigen-binding fragments of antibodies include Fab, F(ab')2, Fab', single-chain antibodies (scFv), dimerized V regions (diabody antibodies), disulfide-stabilized V regions (dsFv), and peptides containing CDRs.

[0234] Fab is a fragment with a molecular weight of approximately 50,000, possessing antigen-binding activity, formed by the bonding of approximately half of the N-terminal side of the heavy chain to the entire L chain via disulfide bonds, obtained by treating antibodies with papain. Fab can be obtained by treating antibodies with papain. Alternatively, Fab can be manufactured by inserting the DNA encoding the antibody into a prokaryotic or eukaryotic expression vector, introducing the vector into prokaryotes or eukaryotes, and expressing the expression.

[0235] F(ab')2 is a fragment with an antigen-binding activity, consisting of two Fab regions bonded together via the hinge region, obtained by degrading the lower part of the disulfide bond in the hinge region of an antibody using pepsin. F(ab')2 can be obtained by treating antibodies with pepsin. Alternatively, F(ab')2 can be manufactured by bonding the Fab' regions with thioether or disulfide bonds.

[0236] Fab' is a fragment with a molecular weight of approximately 50,000 that possesses antigen-binding activity, obtained by cleaving the disulfide bonds in the hinge region of F(ab')2. Fab' can be obtained by treating F(ab')2 with reducing agents such as dithiothreitol. Alternatively, Fab' can be manufactured by inserting DNA encoding Fab' into a prokaryotic or eukaryotic expression vector, introducing the vector into prokaryotes or eukaryotes, and expressing the expression.

[0237] scFv is an antigen-binding fragment obtained by linking one VH and one VL via a suitable peptide linker (hereinafter referred to as P), and is represented by VH-P-VL or VL-P-VH.

[0238] scFv can be manufactured by: constructing DNA encoding scFv using DNA encoding VH and VL, inserting the DNA into a prokaryotic or eukaryotic expression vector, and introducing the expression vector into a prokaryotic or eukaryotic organism for expression.

[0239] Dimeric antibodies are fragments obtained by dimerization of scFv and possess bivalent antigen-binding activity. The bivalent antigen-binding activities can be the same or different.

[0240] Bisomatic antibodies can be manufactured by using DNA encoding VH and VL, constructing DNA encoding scFv with the amino acid sequence of the peptide linker being less than 8 residues in length, inserting the DNA into a prokaryotic or eukaryotic expression vector, and introducing the expression vector into a prokaryote or eukaryote for expression.

[0241] dsFv is a polypeptide obtained by replacing one amino acid residue in each of VH and VL with a cysteine ​​residue, which is then bonded by disulfide bonds between the cysteine ​​residues. The amino acid residues to be replaced with cysteine ​​residues can be selected based on the stereostructure prediction of the antibody according to known methods [Protein Engineering, 7, 697 (1994)].

[0242] dsFv can be manufactured as follows: using cDNA encoding VH and VL, constructing DNA encoding dsFv, inserting the DNA into a prokaryotic or eukaryotic expression vector, introducing the expression vector into a prokaryotic or eukaryotic organism, and expressing it.

[0243] A peptide containing a CDR is composed of at least one region of a CDR containing either VH or VL. Multiple peptides containing CDRs can be directly bonded or bonded together via appropriate peptide linkers.

[0244] Peptides containing CDRs can be manufactured by constructing DNA encoding CDRs for VH and VL, inserting this DNA into a prokaryotic or eukaryotic expression vector, introducing the expression vector into a prokaryotic or eukaryotic organism, and expressing it. Alternatively, peptides containing CDRs can also be manufactured using chemical synthesis methods such as the Fmoc method and the Boc method.

[0245] Bispecific antibodies and multispecific antibodies An antibody or its antigen-binding fragment may have binding specificity for one antigen or for two or more different antigens. In this specification, an antibody or its antigen-binding fragment that has binding specificity for two or more different antigens is referred to as a multispecific antibody. For example, a multispecific antibody may be an antibody or its antigen-binding fragment that has binding specificity for two different antigens (i.e., a bispecific antibody), or it may be an antibody or its antigen-binding fragment that has binding specificity for three or more different antigens.

[0246] Examples of configurations for multispecific antibodies include, for instance, International Publication No. 2009 / 131239, International Publication No. 2014 / 054804, International Publication No. 2001 / 077342, International Publication No. 2007 / 024715, Wu et al., Nature Biotechnology, 2007, 25(11), p.1290-1297, Labrijn et al., PNAS2013, vol.110, no.13, p.5145-5150, Jong et al., PLoS Biology 2016, vol.14, no.1, e1002344, Kontermann et al., mAbs 2012, vol.4, issue2, p.182-197, and Spiesset et al., Molecular Immunology 67 (2015). The configurations described in documents such as 95-106, Ridgway et al., Proteinengineering, 1996 vol.9 no.7 p.617-621, International Publication No. 2009 / 080251, International Publication No. 2010 / 151792 and International Publication No. 2014 / 033074 can be prepared using the methods described in these documents.

[0247] Amino acid deletion, substitution, insertion or addition The deletion, substitution, insertion, or addition of amino acids in a specified amino acid sequence can be performed using known techniques such as 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)].

[0248] The deletion, substitution, insertion, or addition of amino acids for the specified amino acid sequence includes situations where two or more of the following are generated: deletion, substitution, insertion, and addition.

[0249] The substituted, inserted, or added amino acid residues can be either native or non-native. Examples of native 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.

[0250] The following shows preferred examples of amino acids that can be substituted for each other. Amino acids contained in the same group can be substituted for each other.

[0251] Group A: Leucine, Isoleucine, Norleucine, Valine, Norvaline, Alanine, 2-Aminobutyric acid, Methionine, O-Methylserine, Tert-Butylglycine, Tert-Butylalanine, Cyclohexylalanine Group B: Aspartic acid, glutamic acid, isoaspartic acid, isoglutamic acid, 2-aminohexanoic acid, 2-aminooctanoic acid Group C: Asparagine, glutamine Group D: Lysine, arginine, ornithine, 2,4-diaminobutyric acid, 2,3-diaminopropionic acid Group E: Proline, 3-hydroxyproline, 4-hydroxyproline Group F: Serine, Threonine, Homoserine Group G: Phenylalanine, Tyrosine Sequence identity The "%" used to refer to the sequence identity of two amino acid sequences refers to the percentage of identical amino acids relative to the total number of amino acids (including vacancies) when the two amino acid sequences are aligned (compared) in a manner that maximizes the amino acid similarity.

[0252] Method 1 According to a first aspect of the present invention, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be provided. In this specification, the compound represented by formula (I) is sometimes referred to as "compound (I)". Compound (I) or a pharmaceutically acceptable salt thereof is a divalent BET degrader, which can avoid safety issues such as peripheral neurotoxicity while maintaining high antitumor activity. Compound (I) or a pharmaceutically acceptable salt thereof is also useful as a payload (drug) in targeted molecule-drug complexes such as antibody-drug complexes (ADCs).

[0253] [Chemical Formula 33] Pharmaceutically acceptable salts of compound (I) include, for example, pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts. Pharmaceutically acceptable acid addition salts of compound (I) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, and phosphate; organic acid salts such as acetate, oxalate, maleate, fumarate, citrate, benzoate, and methanesulfonate. Pharmaceutically acceptable metal salts of compound (I) include, for example, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, aluminum salts, and zinc salts. Pharmaceutically acceptable ammonium salts of compound (I) include, for example, ammonium salts and tetramethylammonium salts. Pharmaceutically acceptable organic amine addition salts of compound (I) include, for example, addition salts of morpholine and piperidine. Pharmaceutically acceptable amino acid addition salts of compound (I) include, for example, addition salts of lysine, glycine, phenylalanine, aspartic acid, glutamic acid, etc.

[0254] The present invention includes all possible isomers and mixtures thereof, including geometric isomers, optical isomers, stereoisomers, tautomers, etc., in the compound (I) or its pharmaceutically acceptable salt.

[0255] Some or all of the atoms in compound (I) or its pharmaceutically acceptable salt may be replaced by their respective isotopic atoms, and the present invention also includes compounds in which these isotopic atoms have been replaced. For example, some or all of the hydrogen atoms in compound (I) or its pharmaceutically acceptable salt may be hydrogen atoms with an atomic weight of 2 (deuterium atoms).

[0256] Compounds obtained by replacing some or all of the atoms in compound (I) or its pharmaceutically acceptable salt with their respective corresponding isotopic atoms can be manufactured using commercially available building blocks, employing the same method as described later. Alternatively, compounds obtained by replacing some or all of the hydrogen atoms in compound (I) or its pharmaceutically acceptable salt with deuterium atoms can also be synthesized by methods such as: 1) deuterating carboxylic acids, etc., under alkaline conditions using deuterium peroxide (see U.S. Patent No. 3,849,458); 2) deuterating alcohols, carboxylic acids, etc., using an iridium complex as a catalyst and heavy water as a deuterium source (see Journal of the American Chemical Society (J.Am.Chem.Soc.), Vol.124, No.10, 2092 (2002)); 3) deuterating fatty acids using palladium on carbon as a catalyst and deuterium gas only as a deuterium source (see LIPIDS, Vol.9, No.11). 913 (1974)]; 4) A method for deuterating acrylic acid, methyl acrylate, methacrylic acid, methyl methacrylate, etc., using metals such as platinum, palladium, rhodium, ruthenium, and iridium as catalysts and heavy water or heavy water and deuterium gas as deuterium source (see Japanese Patent Application Publication No. 5-19536, Japanese Patent Application Publication No. 61-277648 and Japanese Patent Application Publication No. 61-275241); 5) A method for deuterating acrylic acid, methyl methacrylate, etc., using catalysts such as palladium, nickel, copper or copper chromite and heavy water as deuterium source (see Japanese Patent Application Publication No. 63-198638), etc.

[0257] When you want to obtain compound (I) or its pharmaceutically acceptable salt, if compound (I) is obtained in the form of a salt, it can be directly purified. Alternatively, if it is obtained in the free form, compound (I) can be dissolved or suspended in a suitable solvent, acid or base can be added to form a salt, and then separated and purified.

[0258] In addition, compound (I) or its pharmaceutically acceptable salts are sometimes present as adducts with water or various solvents, which are also included in this invention.

[0259] In the above formula (I), R 1 and R 2 The same or different, each representing a hydrogen atom or a lower alkyl group. R 1 and R 2 The lower alkyl groups may be the same or different, and each is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0260] In the above formula (I), R 3 Indicates a lower alkyl group. R 3 The lower alkyl group is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably ethyl.

[0261] In the above formula (I), R 4 Indicates halogen. R 4 Halogens in the formula can include, for example, fluorine, chlorine, bromine, and iodine atoms, with fluorine or chlorine atoms being preferred. 4 The number of elements is 0 to 2, preferably 0 or 1. R 4 In the case of two, each R 4 They can be the same or different.

[0262] In the above formula (I), R 5 Indicates halogen. R 5 Examples of halogens in R include fluorine, chlorine, bromine, and iodine atoms, with chlorine atoms being the most preferred. 5 The number of elements is 0 to 2, preferably 0 or 1. R 5 In the case of two, each R 5 They can be the same or different.

[0263] In the above formula (I), R 6 Indicates a halogen or a lower alkoxy group. R 6 Examples of halogens in R include fluorine, chlorine, bromine, and iodine atoms, with fluorine atoms being the most preferred. 6 The lower alkoxy group is preferably an alkoxy group with 1 to 5 carbon atoms, more preferably an alkoxy group with 1 to 3 carbon atoms, even more preferably a methoxy or ethoxy group, and even more preferably a methoxy group. 6 The number of elements is 0 to 2, preferably 0 or 1. R 6 In the case of two, each R 6 They can be the same or different.

[0264] In the above formula (I), Y represents, for example, -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-, preferably -O-CH2-CH2-.

[0265] The compounds of the present invention having one or more chiral carbon atoms can exist in two or more stereoisomers. The use of solid lines to indicate bonding with chiral carbon atoms means that all possible stereoisomers of carbon atoms are included (e.g., diastereomer mixtures, racemic mixtures, specific enantiomers, etc.).

[0266] In a preferred embodiment, R 1 For hydrogen atoms, R 2 It is a lower alkyl group, R 3 It is a lower alkyl group, R 4 The absence of (i.e., 0) or the presence of halogens, R 5 The absence of (i.e., 0) or the presence of halogens, R 6 It is absent (i.e., 0) or is a halogen or lower alkoxy group, and Y is -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-.

[0267] In a more preferred embodiment, R 1 For hydrogen atoms, R 2 R is a lower alkyl group having 1 to 5 carbon atoms. 3 R is a lower alkyl group having 1 to 5 carbon atoms. 4 The R is absent or contains fluorine atoms. 5 The R is absent or contains chlorine atoms. 6 It is absent or consists of a fluorine atom or a lower alkoxy group with 1 to 5 carbon atoms, and Y is -O-CH2-CH2-.

[0268] In a further preferred embodiment, R 1 For hydrogen atoms, R 2 R is a lower alkyl group having 1 to 3 carbon atoms. 3 R is a lower alkyl group having 1 to 3 carbon atoms. 4 The R is absent or contains fluorine atoms. 5 The R is absent or contains chlorine atoms. 6 It is either absent or consists of a fluorine atom or a lower alkoxy group with 1 to 3 carbon atoms, and Y is -O-CH2-CH2-.

[0269] In a further preferred embodiment, R 1 For hydrogen atoms, R 2 For methyl, R 3 For ethyl, R 4 It does not exist, R 5 It does not exist, R 6 It does not exist; Y is -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-. In a further preferred embodiment, R... 1 For hydrogen atoms, R 2 For methyl, R 3 For ethyl, R 4 R is a fluorine atom. 5 It does not exist, R 6 It does not exist; Y is -O-CH2-CH2-. In a further preferred embodiment, R1 For hydrogen atoms, R 2 For methyl, R 3 For ethyl, R 4 It does not exist, R 5 R is a chlorine atom. 6 It does not exist; Y is -O-CH2-CH2-.

[0270] In a further preferred embodiment, R 1 For hydrogen atoms, R 2 For methyl, R 3 For ethyl, R 4 It does not exist, R 5 It does not exist, R 6 Y is a fluorine atom, and Y is -O-CH2-CH2- or -CH2-CH2-CH2-. In a further preferred embodiment, R 1 For hydrogen atoms, R 2 For methyl, R 3 For ethyl, R 4 It does not exist, R 5 It does not exist, R 6 It is a methoxy group, and Y is -O-CH2-CH2-.

[0271] In formula (I) above, ring A represents: (i) an aliphatic heterocyclic group having 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl; (ii) an aromatic heterocyclic group having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl; or, (iii) an aryl group having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl.

[0272] The lower alkyl group that serves as a substituent for (i) an aliphatic heterocyclic group, (ii) an aromatic heterocyclic group, and (iii) an aryl group is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, and even more preferably methyl or ethyl, and even more preferably methyl.

[0273] The lower alkyl group among the substituents of (i) aliphatic heterocyclic group, (ii) aromatic heterocyclic group and (iii) aryl group, lower alkyl carbonyl group, lower alkyl carbonyl group and lower alkyl carbamoyl group is preferably an alkyl group with 1 to 5 carbon atoms, more preferably an alkyl group with 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0274] The position and number of hydroxyl groups in the hydroxyl lower alkyl group and the hydroxyl lower alkyl carbonyl group, which are substituents of (i) aliphatic heterocyclic group, (ii) aromatic heterocyclic group and (iii) aryl group, are not particularly limited. The number of hydroxyl groups is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0275] The cycloalkyl group in the cycloalkyl carbonyl group that is a substituent of (i) aliphatic heterocyclic group, (ii) aromatic heterocyclic group and (iii) aryl group is preferably a cycloalkyl group with 3 to 10 carbon atoms, more preferably a cycloalkyl group with 3 to 8 carbon atoms, even more preferably a cycloalkyl group with 3 to 6 carbon atoms, and even more preferably a cyclopropyl group.

[0276] The lower alkoxy group in the lower alkoxy carbonyl group that is a substituent of (i) aliphatic heterocyclic group, (ii) aromatic heterocyclic group and (iii) aryl group is preferably an alkoxy group with 1 to 5 carbon atoms, more preferably an alkoxy group with 1 to 3 carbon atoms, and even more preferably a methoxy or ethoxy group, and even more preferably a methoxy group.

[0277] When ring A is (i) an aliphatic heterocyclic group, the 1 to 3 substituents in (i) are each independently selected from the group consisting of an oxo group, a lower alkyl group, a hydroxy lower alkyl group, a lower alkyl carbonyl group, a hydroxy lower alkyl carbonyl group, a lower alkoxy carbonyl group, a cycloalkyl carbonyl group, and a lower alkyl carbamoyl group. Preferably, the 1 to 3 substituents in the aliphatic heterocyclic group are selected from the group consisting of an oxo group, a lower alkyl group, and a lower alkyl carbonyl group.

[0278] In a preferred embodiment, the (i) aliphatic heterocyclic group in ring A is a nitrogen-containing aliphatic heterocyclic group.

[0279] In a more preferred embodiment, (i) the ring A represented by the nitrogen-containing aliphatic heterocyclic group is the following ring A'.

[0280] [Chemical Formula 34] When ring A' has substituents, the substituents in ring A' have the same meaning as those in ring A as (i) aliphatic heterocyclic group. Specifically, ring A', like ring A as (i) aliphatic heterocyclic group, may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl. Here, the dot (·) in the above formula indicates the bonding site with the linker.

[0281] In the nitrogen-containing aliphatic heterocyclic group (preferably ring A'), the nitrogen atom (excluding the nitrogen atom with the connecting bond of the nitrogen-containing aliphatic heterocyclic group) may have substituents, and the carbon atom may also have substituents. One carbon atom may have two substituents.

[0282] 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-diazaheptanyl, or hexahydropyrrolopyrazinyl. The nitrogen-containing aliphatic heterocyclic group may consist only of saturated bonds or may contain double bonds, preferably only of saturated bonds. In the nitrogen-containing aliphatic heterocyclic group, the 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.

[0283] When the nitrogen-containing aliphatic heterocyclic group (preferably ring A') is a monocyclic aliphatic heterocyclic group containing two nitrogen atoms, it is preferable that one nitrogen atom forms the linking bond of the nitrogen-containing aliphatic heterocyclic group, and the other nitrogen atom has a substituent selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkyl carbonyl, lower hydroxyalkyl carbonyl, and cycloalkyl carbonyl. The substituent on the other nitrogen atom is more preferably selected from the group consisting of lower alkyl, lower alkyl carbonyl, and cycloalkyl carbonyl, and even more preferably from the group consisting of lower alkyl and lower alkyl carbonyl. The monocyclic aliphatic heterocyclic group containing two nitrogen atoms may also 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 preferably independently selected from the group consisting of oxo, lower alkyl, and lower hydroxyalkyl, and more preferably from the group consisting of oxo and lower alkyl.

[0284] When the nitrogen-containing aliphatic heterocyclic group (preferably ring A') is a bicyclic aliphatic heterocyclic group containing two nitrogen atoms, it is preferable that one nitrogen atom forms the linking bond of the nitrogen-containing aliphatic heterocyclic group, and the other nitrogen atom is shared by the two rings (therefore, it does not have a substituent). The bicyclic aliphatic heterocyclic group containing two nitrogen atoms preferably has an oxo group as a substituent. In addition to the oxo group, the bicyclic aliphatic heterocyclic group containing two nitrogen atoms may have one or two substituents selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkyl carbonyl, hydroxy lower alkyl carbonyl, and cycloalkyl carbonyl.

[0285] In a preferred embodiment, when ring A is an aliphatic heterocyclic group (i), the compound represented by formula (I) is the compound represented by formula (I') below.

[0286] [Chemical Formula 35] (where R) 1 R 2 and R 3 With the same meaning as in formula (I), ring A' is the nitrogen-containing aliphatic heterocyclic group described above.

[0287] In a preferred embodiment of the compound of formula (I'), R 1 For hydrogen atoms, R 2 It is a lower alkyl group, R 3 It is a lower alkyl group.

[0288] In a more preferred embodiment of the compound of formula (I'), R 1 For hydrogen atoms, R 2 R is a lower alkyl group having 1 to 5 carbon atoms. 3 It is a lower alkyl group having 1 to 5 carbon atoms.

[0289] In a further preferred embodiment of the compound of formula (I'), R 1 For hydrogen atoms, R 2 R is a lower alkyl group having 1 to 3 carbon atoms. 3 It is a lower alkyl group having 1 to 3 carbon atoms.

[0290] In a further preferred embodiment of the compound of formula (I'), R 1 For hydrogen atoms, R 2 For methyl, R 3 It is an ethyl group.

[0291] When ring A is (ii) an aromatic heterocyclic group, the 1 to 3 substituents in the aromatic heterocyclic group are each independently selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkyl carbonyl, lower hydroxyalkyl carbonyl, lower alkoxycarbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl. The 1 to 3 substituents in the aromatic heterocyclic group are preferably lower alkyl.

[0292] In a preferred embodiment, the aromatic heterocyclic group (ii) 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 an oxazolyl group or a pyridyl group.

[0293] When ring A is (iii) aryl, the 1 to 3 substituents in the aryl group are each independently selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkyl carbonyl, lower hydroxyalkyl carbonyl, lower alkoxycarbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl. Preferably, the 1 to 3 substituents in the aryl group are selected from the group consisting of lower alkoxycarbonyl and lower alkyl carbamoyl.

[0294] In a preferred embodiment, the (iii) aryl group in ring A is preferably phenyl.

[0295] 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 formulas (AA), (AB), (AC) or (AD), an aromatic heterocyclic group represented by the following formulas (AE) or (AF), or an aryl group represented by the following formula (AG).

[0296] [Chemical Formula 36] In the above equations (AA), (AB), (AC), (AD), (AE), (AF), and (AG), R A1 R B1 R D1 R E1 R F1 and R G1 Whether the groups are the same or different, each represents a lower alkyl group, a lower hydroxyalkyl group, a lower alkyl carbonyl group, a lower hydroxyalkyl carbonyl group, a lower alkoxycarbonyl group, a cycloalkyl carbonyl group, or a lower alkyl carbamoyl group, R A2 R A3 R B2 R B3 R C1 and R C2 Whether they are the same or different, they each represent a hydrogen atom, an oxo group, a lower alkyl group, or a hydroxyl lower alkyl group.

[0297] R A1 R B1 R D1 R E1 R F1 and R G1 The lower alkyl group is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0298] R A1 R B1 R D1 R E1 R F1 and R G1 The lower alkyl group in the hydroxy-lower alkyl group, lower alkyl carbonyl group, hydroxy-lower alkyl carbonyl group, and lower alkyl carbamoyl group is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl. Here, when there are two or more lower alkyl groups in the hydroxy-lower alkyl group, lower alkyl carbonyl group, hydroxy-lower alkyl carbonyl group, and lower alkyl carbamoyl group, they may be the same or different.

[0299] R A1 R B1 R D1 R E1 R F1 and R G1 The position and number of hydroxyl groups in the lower alkyl group and the carbonyl group of the lower alkyl group are not particularly limited. The number of hydroxyl groups is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0300] R A1 R B1 R D1 R E1 R F1 and R G1 The lower alkoxy group in the carbonyl group is preferably an alkoxy group with 1 to 5 carbon atoms, more preferably an alkoxy group with 1 to 3 carbon atoms, and even more preferably a methoxy or ethoxy group, and even more preferably a methoxy group.

[0301] R A1 R B1 R D1 R E1 R F1 and R G1 The cycloalkyl group in the cycloalkyl carbonyl group is preferably a cycloalkyl group with 3 to 10 carbon atoms, more preferably a cycloalkyl group with 3 to 8 carbon atoms, even more preferably a cycloalkyl group with 3 to 6 carbon atoms, and even more preferably a cyclopropyl group.

[0302] R A2 R A3 R B2 R B3 R C1 and R C2 The lower alkyl group is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0303] R A2 R A3 R B2 R B3 R C1 and R C2 The lower alkyl group in the hydroxyl group is preferably an alkyl group with 1 to 5 carbon atoms, more preferably an alkyl group with 1 to 3 carbon atoms, and even more preferably methyl or ethyl, and even more preferably methyl.

[0304] R A2 R A3 R B2 R B3R C1 and R C2 The position and number of hydroxyl groups in the lower alkyl group are not particularly limited. The number of hydroxyl groups is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0305] In a preferred embodiment, ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AA), wherein R A1 Indicates lower alkyl, lower alkyl carbonyl, hydroxy lower alkyl carbonyl, or cycloalkyl carbonyl, R A2 and R A3 Whether they are the same or different, they each represent a hydrogen atom, an oxo group, a lower alkyl group, or a hydroxyl lower alkyl group.

[0306] R A1 The lower alkyl group is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0307] R A1 The lower alkyl carbonyl group and hydroxyl lower alkyl carbonyl group are preferably alkyl groups with 1 to 5 carbon atoms, more preferably alkyl groups with 1 to 3 carbon atoms, and even more preferably methyl or ethyl, and even more preferably methyl.

[0308] R A1 The position and number of hydroxyl groups in the lower alkyl carbonyl group are not particularly limited. The number of hydroxyl groups is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0309] R A1 The cycloalkyl group in the cycloalkyl carbonyl group is preferably a cycloalkyl group with 3 to 10 carbon atoms, more preferably a cycloalkyl group with 3 to 8 carbon atoms, even more preferably a cycloalkyl group with 3 to 6 carbon atoms, and even more preferably a cyclopropyl group.

[0310] R A2 and R A3 The lower alkyl group is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0311] R A2 and R A3 The lower alkyl group in the hydroxyl group is preferably an alkyl group with 1 to 5 carbon atoms, more preferably an alkyl group with 1 to 3 carbon atoms, and even more preferably methyl or ethyl, and even more preferably methyl.

[0312] R A2 and R A3The position and number of hydroxyl groups in the lower alkyl group are not particularly limited. The number of hydroxyl groups is, for example, 1 to 4, preferably 1 to 3, more preferably 1 or 2, and even more preferably 1.

[0313] When ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AA), R is preferred. A1 It is a lower alkyl group or a lower alkyl carbonyl group.

[0314] When ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AA), R is preferred. A2 and R A3 Whether they are the same or different, each is a hydrogen atom, an oxo group, or a lower alkyl group.

[0315] When ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AA), R is more preferred. A1 It is a lower alkyl or lower alkyl carbonyl group, and R A2 and R A3 Whether they are the same or different, each is a hydrogen atom, an oxo group, or a lower alkyl group.

[0316] When ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AA), R is even more preferred. A1 It is a lower alkyl group, and R A2 and R A3 Whether they are the same or different, each is either an oxo group or a lower alkyl group.

[0317] In a preferred embodiment, ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AB), wherein R B1 Indicates a lower alkyl group or a lower alkyl carbonyl group, R B2 and R B3 Whether they are the same or different, they represent either hydrogen atoms or oxo groups.

[0318] R B1 The lower alkyl group is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0319] R B1 The lower alkyl group in the lower alkyl carbonyl group is preferably an alkyl group with 1 to 5 carbon atoms, more preferably an alkyl group with 1 to 3 carbon atoms, and even more preferably methyl or ethyl, and even more preferably methyl.

[0320] When ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AB), R B1 Preferably, it is a lower alkyl group.

[0321] In a preferred embodiment, ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AC), where R C1 and R C2 Whether they are the same or different, they represent either hydrogen atoms or oxo groups.

[0322] In a preferred embodiment, ring A or ring A' is a nitrogen-containing aliphatic heterocyclic group represented by the above formula (AD), where R D1 It indicates a lower alkyl carbonyl group.

[0323] R D1 The lower alkyl group in the lower alkyl carbonyl group is preferably an alkyl group with 1 to 5 carbon atoms, more preferably an alkyl group with 1 to 3 carbon atoms, and even more preferably methyl or ethyl, and even more preferably methyl.

[0324] In a preferred embodiment, ring A is an aromatic heterocyclic group represented by the above formula (AE), where R E1 It indicates a lower alkyl group.

[0325] R E1 The lower alkyl group is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0326] R E1 The number of them is, for example, 0 to 2, preferably 1 or 2, more preferably 2.

[0327] In a preferred embodiment, ring A is an aromatic heterocyclic group represented by the above formula (AF), where R F1 It indicates a lower alkyl group.

[0328] R F1 The lower alkyl group is preferably an alkyl group having 1 to 5 carbon atoms, more preferably an alkyl group having 1 to 3 carbon atoms, even more preferably methyl or ethyl, and even more preferably methyl.

[0329] R F1 The number of them is, for example, 0 to 2, preferably 1 or 2, and more preferably 1.

[0330] In a preferred embodiment, ring A is an aryl group represented by the above formula (AG), where R G1 It indicates a lower alkoxy carbonyl group or a lower alkyl carbamoyl group.

[0331] R G1 The lower alkoxy group in the carbonyl group is preferably an alkoxy group with 1 to 5 carbon atoms, more preferably an alkoxy group with 1 to 3 carbon atoms, and even more preferably a methoxy or ethoxy group, and even more preferably a methoxy group.

[0332] R G1 The lower alkyl group in the lower alkyl carbamoyl group is preferably an alkyl group with 1 to 5 carbon atoms, more preferably an alkyl group with 1 to 3 carbon atoms, and even more preferably methyl or ethyl, and even more preferably methyl. Here, when there are two or more lower alkyl groups in the lower alkyl carbamoyl group, they can be the same or different. Therefore, R G1 The lower alkyl carbamoyl group is preferably N-methylcarbamoyl or N,N-dimethylcarbamoyl.

[0333] R G1 The number of them is, for example, 0 to 2, preferably 1 or 2, and more preferably 1.

[0334] In a preferred embodiment, ring A is (i) a nitrogen-containing aliphatic heterocyclic group, (ii) an aromatic heterocyclic group, or (iii) an aryl group, more preferably of formula (AA), formula (AB), formula (AC), formula (AD), formula (AE), formula (AF), or formula (AG), R 1 For hydrogen atoms, R 2 For methyl, R 3 For ethyl, R 4 It does not exist, R 5 It does not exist, R 6 It does not exist; Y is -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-. In a preferred embodiment, ring A is (i) a nitrogen-containing aliphatic heterocyclic group, more preferably of formula (AA), R 1 For hydrogen atoms, R 2 For methyl, R 3 For ethyl, R 4 R is a fluorine atom. 5 It does not exist, R 6 It does not exist; Y is -O-CH2-CH2-. In another preferred embodiment, ring A is (i) a nitrogen-containing aliphatic heterocyclic group, more preferably of formula (AA), R 1 For hydrogen atoms, R 2 For methyl, R 3 For ethyl, R 4 It does not exist, R 5 R is a chlorine atom. 6 It does not exist; Y is -O-CH2-CH2-. In another preferred embodiment, ring A is (i) a nitrogen-containing aliphatic heterocyclic group, more preferably of formula (AA), (AB), or (AC), R 1 For hydrogen atoms, R 2 For methyl, R 3 For ethyl, R 4 It does not exist, R 5It does not exist, R 6 The atom is fluorine, and Y is -O-CH2-CH2- or -CH2-CH2-CH2-. In another preferred embodiment, ring A is (i) a nitrogen-containing aliphatic heterocyclic group, more preferably of formula (AA), R 1 For hydrogen atoms, R 2 For methyl, R 3 For ethyl, R 4 It does not exist, R 5 It does not exist, R 6 It is a methoxy group, and Y is -O-CH2-CH2-.

[0335] In a preferred embodiment, compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof represented by the following formula: [Chemical Formula 37] .

[0336] In a preferred embodiment, compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof represented by the following formula: [Chemical Formula 38] .

[0337] In a preferred embodiment, compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof represented by the following formula: [Chemical Formula 39] .

[0338] In a preferred embodiment, compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof represented by the following formula: [Chemical Formula 40] .

[0339] In a preferred embodiment, compound (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof represented by the following formula: [Chemical Formula 41] .

[0340] Method 2 According to a second aspect of the invention, a targeted molecule-drug complex can be provided, comprising a targeted molecule and a drug, wherein the drug is compound (I) or a pharmaceutically acceptable salt thereof. The targeted molecule-drug complex of the second aspect can avoid safety concerns such as peripheral neurotoxicity while maintaining high antitumor activity. By complexing the drug (bivalent BET degrader) with the targeted molecule, the drug can be efficiently delivered to target cells. Therefore, by complexing the drug (bivalent BET degrader) with the targeted molecule, an antitumor effect can be exhibited in vivo with a smaller amount of drug (converted to bivalent BET degrader) compared to the drug alone.

[0341] Target molecules are, for example, molecules that can bind to proteins or peptides present on the surface of target cells. By binding target molecules to proteins or peptides present on the surface of target cells, drugs can be delivered to the target cells. Preferably, the target molecule can specifically bind to proteins or peptides present on the surface of target cells. "Specificity" means that the target molecule does not show significant binding activity to other substances.

[0342] Target cells are preferably cancer cells. Examples of target cells include proteins or peptides present on the surface of cancer cells, such as receptors, cancer antigens, MHC antigens, and differentiation antigens. Proteins or peptides may also be presented on the surface of cancer cells by binding to MHC class I or MHC class II molecules.

[0343] The cancer is preferably a hematologic malignancy, more preferably a lymphoma, and even more preferably a B-cell lymphoma. Therefore, the proteins or peptides present on the surface of cancer cells are proteins or peptides expressed in the lymphocytes (preferably B cells) of an organism suffering from a hematologic malignancy, more preferably a lymphoma, and even more preferably a B-cell lymphoma.

[0344] Examples of molecules such as proteins or peptides present on the surface of cancer cells include folic acid receptor α (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. Among them, 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.

[0345] Target molecules include, for example, antibodies or their antigen-binding fragments, low molecular weight compounds, or peptides.

[0346] Examples of low molecular weight compounds include folic acid, oncoFAP, AAZ+, and 2-[3-(1,3-dicarboxypropyl)urea]-glutaric acid (DUPA).

[0347] Folic acid can bind to folate receptors. Therefore, a target molecule-drug complex containing folate as a target molecule can target cells with folate receptors on their surface (CPLeamon et al. Cancer Res. 2008, 68, 9839-9844).

[0348] The synthetic low-molecular-weight compound known as oncoFAP can bind to fibroblast activation proteins. Therefore, the targeting molecule-drug complex containing octreotide as the targeting molecule can target cells with fibroblast activation proteins on their surface (J. Millu et al. Proc Natl Acad Sci USA. 2021, 118,e2101852118).

[0349] Synthetic low-molecular-weight compounds known as AAZ+ can bind to carbonic anhydrase 9. Therefore, a target molecule-drug complex containing AAZ+ as a target molecule can target cells with carbonic anhydrase 9 on their surface (S. Cazzamalli et al. J Am Chem Soc, 2018, 140, 1617-1621).

[0350] DUPA can bind to prostate-specific membrane antigens. Therefore, a targeting molecule-drug complex containing DUPA as a targeting molecule can target cells with prostate-specific membrane antigens on their surface (J. Roy et al. J.Med. Chem. 2015, 58, 3094-3103).

[0351] Examples of peptides include BCY6099, octreotide, RGD peptide, Exendin-4, toad peptide-like peptide, and BCY8234.

[0352] The bicyclic peptide BCY6099 can bind to erythropoietin-producing hepatocellular receptor A2. Therefore, a targeting molecule-drug complex containing BCY6099 as the targeting molecule can target cells with erythropoietin-producing hepatocellular receptor A2 on their surface (G. Bennett et al. Mol Cancer Ther 2020, 19, 1385-1394).

[0353] Octreotide can bind to the somatostatin receptor, especially somatostatin receptor subtype 2. Therefore, a targeting molecule-drug complex containing octreotide as the targeting molecule can target cells with somatostatin receptor subtype 2 on their surface (BHWhite et al. J. Med. Chem. 2019, 62, 2708-2719).

[0354] RGD peptides can bind to integrin receptors, especially αvβ3 integrin receptors. Therefore, targeting molecule-drug complexes containing RGD peptides as targeting molecules can target cells with αvβ3 integrin receptors on their surface (M. Lelle et al. J. Med. Chem. 2005, 48, 1098-1106).

[0355] Exendin-4 can bind to the glucagon-like peptide-1 receptor. Therefore, a targeting molecule-drug complex containing Exendin-4 as the targeting molecule can target cells with glucagon-like peptide-1 receptors on their surface (S. Son et al. The International Journal of Biochemistry & Cell Biology. 105, 13-19.).

[0356] Bufotinoids can bind to bufotinoid receptors. Therefore, targeting molecule-drug complexes containing bufotinoids as targeting molecules can target cells with bufotinoid receptors on their surface (A. Safavy et al. Bioconjugate Chem. 2006, 17, 565-570).

[0357] BCY8234 can bind to Nectin-4. Therefore, a targeting molecule-drug complex containing BCY8234 as a targeting molecule can target cells with Nectin-4 on their surface (M. Rigby et al. Mol Cancer TherMCT-21-0875.).

[0358] In a preferred embodiment, the target molecule is an antibody or its antigen-binding fragment.

[0359] In a more preferred embodiment, the target molecule is an antibody.

[0360] In a further preferred embodiment, the antibody is an anti-CD79b antibody, an anti-CD19 antibody, an anti-CD22 antibody, an anti-HER2 antibody, an anti-DLL3 antibody, an anti-GM2 antibody, an anti-EphA2 antibody, an anti-FAP antibody, an anti-SSTR2 antibody, an anti-CD30 antibody, an anti-BCMA antibody, an anti-CD33 antibody, an anti-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.

[0361] The following describes the implementation method of using anti-CD79b antibody.

[0362] Anti-CD79b antibody is an antibody that binds to CD79b. Preferably, it is an antibody that specifically binds to CD79b. Anti-CD79b antibody can be any of polyclonal or monoclonal antibodies, preferably monoclonal. It can also be any of human chimeric antibody, humanized antibody, or human antibody, preferably humanized antibody.

[0363] In one embodiment, the anti-CD79b antibody is an antibody containing the heavy chain variable region (VH) and the light chain variable region (VL) of vepotuzumab.

[0364] In one embodiment, the anti-CD79b antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 11, CDR2 composed of the amino acid sequence described in sequence number 12, and CDR3 composed of the amino acid sequence described in sequence number 13, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 14, CDR2 composed of the amino acid sequence described in sequence number 15, and CDR3 composed of the amino acid sequence described in sequence number 16. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0365] In another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody comprises the amino acid sequence described in Serial No. 5, and the amino acid sequence of the VL of the anti-CD79b antibody comprises the amino acid sequence described in Serial No. 6. The amino acid sequence of the VH of the anti-CD79b antibody may also be composed of the amino acid sequence described in Serial No. 5, and the amino acid sequence of the VL of the anti-CD79b antibody may also be composed of the amino acid sequence described in Serial No. 6.

[0366] As shown in the table below, VH containing the amino acid sequence described in Serial No. 5 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 11, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 12, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 13. VL containing the amino acid sequence described in Serial No. 6 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 14, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 15, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 16.

[0367] [Table 1] In another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 5. Furthermore, the amino acid sequence of the VL of the anti-CD79b antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 6. The amino acid sequence of the VH of the anti-CD79b antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 5, and the amino acid sequence of the VL of the anti-CD79b antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 6. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence recorded in Serial No. 5 can also be an amino acid sequence recorded in Serial No. 5, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence recorded in Serial No. 6 can also be an amino acid sequence recorded in Serial No. 6.

[0368] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 5 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 11, CDR2 composed of the amino acid sequence described in Serial No. 12, and CDR3 composed of the amino acid sequence described in Serial No. 13.

[0369] The VL comprising an amino acid sequence having the above sequence identity relative to the amino acid sequence described in Serial No. 6 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 14, CDR2 composed of the amino acid sequence described in Serial No. 15, and CDR3 composed of the amino acid sequence described in Serial No. 16.

[0370] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 5 has the activity of an anti-CD79b antibody, that is, binding activity against CD79b. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 5 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, to the amino acid sequence described in Serial No. 5.

[0371] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 6 has the activity of an anti-CD79b antibody VL, that is, binding activity against CD79b. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 6 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 6.

[0372] The following describes the implementation method of using an anti-CD19 antibody.

[0373] Anti-CD19 antibody is an antibody that binds to CD19. Preferably, it is an antibody that specifically binds to CD19. Anti-CD19 antibody can be any of polyclonal or monoclonal antibodies, preferably monoclonal. Anti-CD19 antibody can be any of human chimeric antibody, humanized antibody, or human antibody, preferably humanized antibody.

[0374] 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.

[0375] In one embodiment, the anti-CD19 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 17, CDR2 composed of the amino acid sequence described in sequence number 18, and CDR3 composed of the amino acid sequence described in sequence number 19, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 20, CDR2 composed of the amino acid sequence described in sequence number 21, and CDR3 composed of the amino acid sequence described in sequence number 22. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0376] In another embodiment, the amino acid sequence of the VH of the anti-CD19 antibody comprises the amino acid sequence described in Serial Number 7, and the amino acid sequence of the VL of the anti-CD19 antibody comprises the amino acid sequence described in Serial Number 8. The amino acid sequence of the VH of the anti-CD19 antibody may also consist of the amino acid sequence described in Serial Number 7, and the amino acid sequence of the VL of the anti-CD19 antibody may also consist of the amino acid sequence described in Serial Number 8.

[0377] As shown in the table below, VH containing the amino acid sequence described in Serial No. 7 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 17, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 18, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 19. VL containing the amino acid sequence described in Serial No. 8 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 20, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 21, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 22.

[0378] [Table 2] In another embodiment, the amino acid sequence of the VH of the anti-CD19 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial Number 7. Furthermore, the amino acid sequence of the VL of the anti-CD19 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial Number 8. The amino acid sequence of the VH of the anti-CD19 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial Number 7, and the amino acid sequence of the VL of the anti-CD19 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial Number 8. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence recorded in Serial No. 7 can also be an amino acid sequence recorded in Serial No. 7, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence recorded in Serial No. 8 can also be an amino acid sequence recorded in Serial No. 8.

[0379] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 7 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 17, CDR2 composed of the amino acid sequence described in Serial No. 18, and CDR3 composed of the amino acid sequence described in Serial No. 19.

[0380] The VL comprising an amino acid sequence having the above sequence identity relative to the amino acid sequence described in Serial No. 8 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 20, CDR2 composed of the amino acid sequence described in Serial No. 21, and CDR3 composed of the amino acid sequence described in Serial No. 22.

[0381] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 7 has the activity of an anti-CD19 antibody VH, that is, binding activity against CD19. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 7 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 7.

[0382] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 8 has the activity of an anti-CD19 antibody VL, that is, binding activity against CD19. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 8 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, to the amino acid sequence described in Serial No. 8.

[0383] The following describes the implementation method of using anti-CD22 antibody.

[0384] Anti-CD22 antibody is an antibody that binds to CD22. Preferably, it is an antibody that specifically binds to CD22. Anti-CD22 antibody can be any of polyclonal or monoclonal antibodies, preferably monoclonal. Anti-CD22 antibody can be any of human chimeric antibody, humanized antibody, or human antibody, preferably humanized antibody.

[0385] In one embodiment, the anti-CD22 antibody is an antibody containing the heavy chain variable region (VH) and the light chain variable region (VL) of Inotuzumab.

[0386] In one embodiment, the anti-CD22 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 23, CDR2 composed of the amino acid sequence described in sequence number 24, and CDR3 composed of the amino acid sequence described in sequence number 25, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 26, CDR2 composed of the amino acid sequence described in sequence number 27, and CDR3 composed of the amino acid sequence described in sequence number 28. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0387] In another embodiment, the amino acid sequence of the VH of the anti-CD22 antibody comprises the amino acid sequence described in Serial No. 9, and the amino acid sequence of the VL of the anti-CD22 antibody comprises the amino acid sequence described in Serial No. 10. The amino acid sequence of the VH of the anti-CD22 antibody may also be composed of the amino acid sequence described in Serial No. 9, and the amino acid sequence of the VL of the anti-CD22 antibody may also be composed of the amino acid sequence described in Serial No. 10.

[0388] As shown in the table below, VH containing the amino acid sequence described in Serial No. 9 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 23, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 24, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 25. VL containing the amino acid sequence described in Serial No. 10 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 26, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 27, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 28.

[0389] [Table 3] In another embodiment, the amino acid sequence of the VH of the anti-CD22 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 9. Furthermore, the amino acid sequence of the VL of the anti-CD22 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 10. The amino acid sequence of the VH of the anti-CD22 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 9, and the amino acid sequence of the VL of the anti-CD22 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 10. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence recorded in Serial No. 9 can also be an amino acid sequence recorded in Serial No. 9, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence recorded in Serial No. 10 can also be an amino acid sequence recorded in Serial No. 10.

[0390] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 9 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 23, CDR2 composed of the amino acid sequence described in Serial No. 24, and CDR3 composed of the amino acid sequence described in Serial No. 25.

[0391] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 10 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 26, CDR2 composed of the amino acid sequence described in Serial No. 27, and CDR3 composed of the amino acid sequence described in Serial No. 28.

[0392] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 9 has the activity of an anti-CD22 antibody VH, that is, binding activity against CD22. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 9 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, to the amino acid sequence described in Serial No. 9.

[0393] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 10 has the activity of an anti-CD22 antibody VL, that is, binding activity against CD22. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 10 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 10.

[0394] The following describes the implementation method of using anti-HER2 antibodies.

[0395] Anti-HER2 antibodies are antibodies that bind to HER2. Preferably, anti-HER2 antibodies are antibodies that specifically bind to HER2. Anti-HER2 antibodies can be any of polyclonal or monoclonal antibodies, preferably monoclonal antibodies. Anti-HER2 antibodies can be any of human chimeric antibodies, humanized antibodies, or human antibodies, preferably humanized antibodies.

[0396] In one embodiment, the anti-HER2 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of trastuzumab.

[0397] In one embodiment, the anti-HER2 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 67, CDR2 composed of the amino acid sequence described in sequence number 68, and CDR3 composed of the amino acid sequence described in sequence number 69, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 70, CDR2 composed of the amino acid sequence described in sequence number 71, and CDR3 composed of the amino acid sequence described in sequence number 72. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0398] In another embodiment, the amino acid sequence of the VH of the anti-HER2 antibody comprises the amino acid sequence described in sequence number 29, and the amino acid sequence of the VL of the anti-HER2 antibody comprises the amino acid sequence described in sequence number 30. The amino acid sequence of the VH of the anti-HER2 antibody may also be composed of the amino acid sequence described in sequence number 29, and the amino acid sequence of the VL of the anti-HER2 antibody may also be composed of the amino acid sequence described in sequence number 30.

[0399] As shown in the table below, the VH containing the amino acid sequence described in sequence number 29 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 67, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 68, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 69. The VL containing the amino acid sequence described in sequence number 30 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 70, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 71, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 72.

[0400] [Table 4] In another embodiment, the amino acid sequence of the VH of the anti-HER2 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 29. Furthermore, the amino acid sequence of the VL of the anti-HER2 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 30. The amino acid sequence of the VH of the anti-HER2 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 29, and the amino acid sequence of the VL of the anti-HER2 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 30. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 29 may also be an amino acid sequence described in Serial No. 29, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 30 may also be an amino acid sequence described in Serial No. 30.

[0401] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 29 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 67, CDR2 composed of the amino acid sequence described in Serial No. 68, and CDR3 composed of the amino acid sequence described in Serial No. 69.

[0402] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 30 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 70, CDR2 composed of the amino acid sequence described in Serial No. 71, and CDR3 composed of the amino acid sequence described in Serial No. 72.

[0403] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 29 has the activity of an anti-HER2 antibody VH, that is, binding activity against HER2. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 29 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 29.

[0404] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 30 has the activity of an anti-HER2 antibody VL, that is, binding activity against HER2. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 30 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, to the amino acid sequence described in Serial No. 6.

[0405] The following describes the implementation method of using anti-DLL3 antibody.

[0406] Anti-DLL3 antibody is an antibody that binds to DLL3. Preferably, it is an antibody that specifically binds to DLL3. Anti-DLL3 antibody can be any of polyclonal or monoclonal antibodies, preferably monoclonal. Anti-DLL3 antibody can be any of human chimeric antibody, humanized antibody, or human antibody, preferably humanized antibody.

[0407] 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.

[0408] In one embodiment, the anti-DLL3 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 73, CDR2 composed of the amino acid sequence described in sequence number 74, and CDR3 composed of the amino acid sequence described in sequence number 75, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 76, CDR2 composed of the amino acid sequence described in sequence number 77, and CDR3 composed of the amino acid sequence described in sequence number 78. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0409] In another embodiment, the amino acid sequence of the VH of the anti-DLL3 antibody comprises the amino acid sequence described in Serial No. 31, and the amino acid sequence of the VL of the anti-DLL3 antibody comprises the amino acid sequence described in Serial No. 32. The amino acid sequence of the VH of the anti-DLL3 antibody may also be composed of the amino acid sequence described in Serial No. 31, and the amino acid sequence of the VL of the anti-DLL3 antibody may also be composed of the amino acid sequence described in Serial No. 32.

[0410] As shown in the table below, VH containing the amino acid sequence described in sequence number 31 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 73, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 74, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 75. VL containing the amino acid sequence described in sequence number 32 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 76, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 77, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 78.

[0411] [Table 5] In another embodiment, the amino acid sequence of the VH of the anti-DLL3 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 31. Furthermore, the amino acid sequence of the VL of the anti-DLL3 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 32. The amino acid sequence of the VH of the anti-DLL3 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 31, and the amino acid sequence of the VL of the anti-DLL3 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 32. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 31 can also be the amino acid sequence described in Serial No. 31, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 32 can also be the amino acid sequence described in Serial No. 32.

[0412] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 31 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 73, CDR2 composed of the amino acid sequence described in Serial No. 74, and CDR3 composed of the amino acid sequence described in Serial No. 75.

[0413] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 32 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 76, CDR2 composed of the amino acid sequence described in Serial No. 77, and CDR3 composed of the amino acid sequence described in Serial No. 78.

[0414] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 31 has the activity of an anti-DLL3 antibody, that is, binding activity against DLL3. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 31 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 31.

[0415] VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 32 has the activity of an anti-DLL3 antibody VL, that is, binding activity against DLL3. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 32 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 32.

[0416] The following describes the implementation method of using anti-GM2 antibody.

[0417] Anti-GM2 antibodies are antibodies that bind to GM2. Preferably, anti-GM2 antibodies are antibodies that specifically bind to GM2. Anti-GM2 antibodies can be any of polyclonal or monoclonal antibodies, preferably monoclonal antibodies. Anti-GM2 antibodies can be any of human chimeric antibodies, humanized antibodies, or human antibodies, preferably humanized antibodies.

[0418] In one embodiment, the anti-GM2 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of KM8969 (International Publication No. 2001 / 023431).

[0419] In one embodiment, the anti-GM2 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 79, CDR2 composed of the amino acid sequence described in sequence number 80, and CDR3 composed of the amino acid sequence described in sequence number 81, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 82, CDR2 composed of the amino acid sequence described in sequence number 83, and CDR3 composed of the amino acid sequence described in sequence number 84. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0420] In another embodiment, the amino acid sequence of the VH of the anti-GM2 antibody comprises the amino acid sequence described in sequence number 33, and the amino acid sequence of the VL of the anti-GM2 antibody comprises the amino acid sequence described in sequence number 34. The amino acid sequence of the VH of the anti-GM2 antibody may also be composed of the amino acid sequence described in sequence number 33, and the amino acid sequence of the VL of the anti-GM2 antibody may also be composed of the amino acid sequence described in sequence number 34.

[0421] As shown in the table below, VH containing the amino acid sequence described in sequence number 33 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 79, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 80, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 81. VL containing the amino acid sequence described in sequence number 34 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 82, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 83, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 84.

[0422] [Table 6] In another embodiment, the amino acid sequence of the VH of the anti-GM2 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 33. Furthermore, the amino acid sequence of the VL of the anti-GM2 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 34. The amino acid sequence of the VH of the anti-GM2 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 33, and the amino acid sequence of the VL of the anti-GM2 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 34. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 33 may also be an amino acid sequence described in Serial No. 33, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 34 may also be an amino acid sequence described in Serial No. 34.

[0423] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 33 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 79, CDR2 composed of the amino acid sequence described in Serial No. 80, and CDR3 composed of the amino acid sequence described in Serial No. 81.

[0424] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 34 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 82, CDR2 composed of the amino acid sequence described in Serial No. 83, and CDR3 composed of the amino acid sequence described in Serial No. 84.

[0425] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 33 has the activity of an anti-GM2 antibody VH, that is, binding activity against GM2. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 33 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 33.

[0426] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 34 has the activity of an anti-GM2 antibody VL, that is, binding activity against GM2. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 34 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 34.

[0427] The following describes the implementation method of using anti-EphA2 antibody.

[0428] Anti-EphA2 antibody is an antibody that binds to EphA2. Preferably, it is an antibody that specifically binds to EphA2. Anti-EphA2 antibody can be any of polyclonal or monoclonal antibodies, preferably monoclonal. Anti-EphA2 antibody can be any of human chimeric antibody, humanized antibody, or human antibody, preferably humanized antibody.

[0429] In one embodiment, the anti-EphA2 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) having 1C1 (US Patent Application Publication No. 2009 / 0304721).

[0430] In one embodiment, the anti-EphA2 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 85, CDR2 composed of the amino acid sequence described in sequence number 86, and CDR3 composed of the amino acid sequence described in sequence number 87, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 88, CDR2 composed of the amino acid sequence described in sequence number 89, and CDR3 composed of the amino acid sequence described in sequence number 90. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0431] In another embodiment, the amino acid sequence of the VH of the anti-EphA2 antibody comprises the amino acid sequence described in sequence number 35, and the amino acid sequence of the VL of the anti-EphA2 antibody comprises the amino acid sequence described in sequence number 36. The amino acid sequence of the VH of the anti-EphA2 antibody may also be composed of the amino acid sequence described in sequence number 35, and the amino acid sequence of the VL of the anti-EphA2 antibody may also be composed of the amino acid sequence described in sequence number 36.

[0432] As shown in the table below, VH containing the amino acid sequence described in sequence number 35 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 85, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 86, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 87. VL containing the amino acid sequence described in sequence number 36 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 88, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 89, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 90.

[0433] [Table 7] In another embodiment, the amino acid sequence of the VH of the anti-EphA2 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 35. Furthermore, the amino acid sequence of the VL of the anti-EphA2 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 36. The amino acid sequence of the VH of the anti-EphA2 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 35, and the amino acid sequence of the VL of the anti-EphA2 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 36. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 35 may also be an amino acid sequence described in Serial No. 35, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 36 may also be an amino acid sequence described in Serial No. 36.

[0434] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 35 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 85, CDR2 composed of the amino acid sequence described in Serial No. 86, and CDR3 composed of the amino acid sequence described in Serial No. 87.

[0435] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 36 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 88, CDR2 composed of the amino acid sequence described in Serial No. 89, and CDR3 composed of the amino acid sequence described in Serial No. 90.

[0436] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 35 has the activity of an anti-EphA2 antibody, that is, binding activity against EphA2. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 35 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 35.

[0437] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 36 has the activity of an anti-EphA2 antibody VL, that is, binding activity against EphA2. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 36 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 36.

[0438] The following describes the implementation method of using anti-FAP antibodies.

[0439] Anti-FAP antibodies are antibodies that bind to FAP. Preferably, anti-FAP antibodies are antibodies that specifically bind to FAP. Anti-FAP antibodies can be any of polyclonal or monoclonal antibodies, preferably monoclonal antibodies. Anti-FAP antibodies can be any of human chimeric antibodies, humanized antibodies, or human antibodies, preferably humanized antibodies.

[0440] In one embodiment, the anti-FAP antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of hu36 (US Patent No. 10,864,278).

[0441] In one embodiment, the anti-FAP antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 91, CDR2 composed of the amino acid sequence described in sequence number 92, and CDR3 composed of the amino acid sequence described in sequence number 93, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 94, CDR2 composed of the amino acid sequence described in sequence number 95, and CDR3 composed of the amino acid sequence described in sequence number 96. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0442] In another embodiment, the amino acid sequence of the VH of the anti-FAP antibody comprises the amino acid sequence described in Serial No. 37, and the amino acid sequence of the VL of the anti-FAP antibody comprises the amino acid sequence described in Serial No. 38. The amino acid sequence of the VH of the anti-FAP antibody may also be composed of the amino acid sequence described in Serial No. 37, and the amino acid sequence of the VL of the anti-FAP antibody may also be composed of the amino acid sequence described in Serial No. 38.

[0443] As shown in the table below, VH containing the amino acid sequence described in Serial No. 37 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 91, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 92, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 93. VL containing the amino acid sequence described in Serial No. 38 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 94, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 95, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 96.

[0444] [Table 8] In another embodiment, the amino acid sequence of the VH of the anti-FAP antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 37. Furthermore, the amino acid sequence of the VL of the anti-FAP antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 38. The amino acid sequence of the VH of the anti-FAP antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 37, and the amino acid sequence of the VL of the anti-FAP antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 38. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 37 may also be an amino acid sequence described in Serial No. 37, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 38 may also be an amino acid sequence described in Serial No. 38.

[0445] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 37 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 91, CDR2 composed of the amino acid sequence described in Serial No. 92, and CDR3 composed of the amino acid sequence described in Serial No. 93.

[0446] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 38 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 94, CDR2 composed of the amino acid sequence described in Serial No. 95, and CDR3 composed of the amino acid sequence described in Serial No. 96.

[0447] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 37 has the activity of an anti-FAP antibody VH, that is, binding activity against FAP. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 37 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 37.

[0448] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 38 has the activity of an anti-FAP antibody VL, i.e., binding activity against FAP. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 38 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 38.

[0449] The following describes the implementation method of using anti-SSTR2 antibody.

[0450] Anti-SSTR2 antibodies are antibodies that bind to SSTR2. Preferably, anti-SSTR2 antibodies are antibodies that specifically bind to SSTR2. Anti-SSTR2 antibodies can be any of polyclonal or monoclonal antibodies, preferably monoclonal antibodies. Anti-SSTR2 antibodies can be any of human chimeric antibodies, humanized antibodies, or human antibodies, preferably humanized antibodies.

[0451] In one embodiment, the anti-SSTR2 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of anti-SSTR2 mAb (US Patent Application Publication No. 2021 / 0340264).

[0452] In one embodiment, the anti-SSTR2 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 97, CDR2 composed of the amino acid sequence described in sequence number 98, and CDR3 composed of the amino acid sequence described in sequence number 99, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 100, CDR2 composed of the amino acid sequence described in sequence number 101, and CDR3 composed of the amino acid sequence described in sequence number 102. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0453] In another embodiment, the amino acid sequence of the VH of the anti-SSTR2 antibody comprises the amino acid sequence described in sequence number 39, and the amino acid sequence of the VL of the anti-SSTR2 antibody comprises the amino acid sequence described in sequence number 40. The amino acid sequence of the VH of the anti-SSTR2 antibody may also be composed of the amino acid sequence described in sequence number 39, and the amino acid sequence of the VL of the anti-SSTR2 antibody may also be composed of the amino acid sequence described in sequence number 40.

[0454] As shown in the table below, the VH containing the amino acid sequence described in sequence number 39 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 97, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 98, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 99. The VL containing the amino acid sequence described in sequence number 40 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 100, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 101, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 102.

[0455] [Table 9] In another embodiment, the amino acid sequence of the VH of the anti-SSTR2 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 39. Furthermore, the amino acid sequence of the VL of the anti-SSTR2 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 40. The amino acid sequence of the VH of the anti-SSTR2 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 39, and the amino acid sequence of the VL of the anti-SSTR2 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 40. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 39 may also be an amino acid sequence described in Serial No. 40, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 40 may also be an amino acid sequence described in Serial No. 40.

[0456] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 39 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 97, CDR2 composed of the amino acid sequence described in Serial No. 98, and CDR3 composed of the amino acid sequence described in Serial No. 99.

[0457] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 40 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 100, CDR2 composed of the amino acid sequence described in Serial No. 101, and CDR3 composed of the amino acid sequence described in Serial No. 102.

[0458] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 39 has the activity of an anti-SSTR2 antibody VH, that is, binding activity against SSTR2. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 39 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, to the amino acid sequence described in Serial No. 39.

[0459] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 40 has the activity of an anti-SSTR2 antibody VL, that is, binding activity against SSTR2. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 40 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, to the amino acid sequence described in Serial No. 40.

[0460] The following describes the implementation method of using anti-CD30 antibody.

[0461] Anti-CD30 antibodies are antibodies that bind to CD30. Preferably, anti-CD30 antibodies are antibodies that specifically bind to CD30. Anti-CD30 antibodies can be any of polyclonal or monoclonal antibodies, preferably monoclonal antibodies. Anti-CD30 antibodies can be any of human chimeric antibodies, humanized antibodies, or human antibodies, preferably humanized antibodies.

[0462] 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.

[0463] In one embodiment, the anti-CD30 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 103, CDR2 composed of the amino acid sequence described in sequence number 104, and CDR3 composed of the amino acid sequence described in sequence number 105, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 106, CDR2 composed of the amino acid sequence described in sequence number 107, and CDR3 composed of the amino acid sequence described in sequence number 108. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0464] In another embodiment, the amino acid sequence of the VH of the anti-CD30 antibody comprises the amino acid sequence described in sequence number 41, and the amino acid sequence of the VL of the anti-CD30 antibody comprises the amino acid sequence described in sequence number 42. The amino acid sequence of the VH of the anti-CD30 antibody may also be composed of the amino acid sequence described in sequence number 41, and the amino acid sequence of the VL of the anti-CD30 antibody may also be composed of the amino acid sequence described in sequence number 42.

[0465] As shown in the table below, VH containing the amino acid sequence described in sequence number 41 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 103, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 104, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 105. VL containing the amino acid sequence described in sequence number 42 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 106, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 107, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 108.

[0466] [Table 10] In another embodiment, the amino acid sequence of the VH of the anti-CD30 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in sequence number 41. Furthermore, the amino acid sequence of the VL of the anti-CD30 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in sequence number 42. The amino acid sequence of the VH of the anti-CD30 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in sequence number 41, and the amino acid sequence of the VL of the anti-CD30 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in sequence number 42. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence recorded in Serial No. 41 can also be the amino acid sequence recorded in Serial No. 41, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence recorded in Serial No. 42 can also be the amino acid sequence recorded in Serial No. 42.

[0467] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 41 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 103, CDR2 composed of the amino acid sequence described in Serial No. 104, and CDR3 composed of the amino acid sequence described in Serial No. 105.

[0468] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 42 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 106, CDR2 composed of the amino acid sequence described in Serial No. 107, and CDR3 composed of the amino acid sequence described in Serial No. 108.

[0469] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 41 has the activity of an anti-CD30 antibody VH, that is, binding activity against CD30. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 41 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 41.

[0470] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 42 has the activity of an anti-CD30 antibody VL, that is, binding activity against CD30. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 42 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 42.

[0471] The following describes the implementation method of using anti-BCMA antibodies.

[0472] Anti-BCMA antibodies are antibodies that bind to BCMA. Preferably, anti-BCMA antibodies are antibodies that specifically bind to BCMA. Anti-BCMA antibodies can be any of polyclonal or monoclonal antibodies, preferably monoclonal antibodies. Anti-BCMA antibodies can be any of human chimeric antibodies, humanized antibodies, or human antibodies, preferably humanized antibodies.

[0473] 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.

[0474] In one embodiment, the anti-BCMA antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 109, CDR2 composed of the amino acid sequence described in sequence number 110, and CDR3 composed of the amino acid sequence described in sequence number 111, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 112, CDR2 composed of the amino acid sequence described in sequence number 113, and CDR3 composed of the amino acid sequence described in sequence number 114. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0475] In another embodiment, the amino acid sequence of the VH of the anti-BCMA antibody comprises the amino acid sequence described in sequence number 43, and the amino acid sequence of the VL of the anti-BCMA antibody comprises the amino acid sequence described in sequence number 44. The amino acid sequence of the VH of the anti-BCMA antibody may also be composed of the amino acid sequence described in sequence number 43, and the amino acid sequence of the VL of the anti-BCMA antibody may also be composed of the amino acid sequence described in sequence number 44.

[0476] As shown in the table below, VH containing the amino acid sequence described in sequence number 43 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 109, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 110, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 111. VL containing the amino acid sequence described in sequence number 44 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 112, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 113, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 114.

[0477] [Table 11] In another embodiment, the amino acid sequence of the VH of the anti-BCMA antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 43. Furthermore, the amino acid sequence of the VL of the anti-BCMA antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 44. The amino acid sequence of the VH of the anti-BCMA antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 43, and the amino acid sequence of the VL of the anti-BCMA antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 44. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 43 may also be an amino acid sequence described in Serial No. 43, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 44 may also be an amino acid sequence described in Serial No. 44.

[0478] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 43 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 109, CDR2 composed of the amino acid sequence described in Serial No. 110, and CDR3 composed of the amino acid sequence described in Serial No. 111.

[0479] The VL containing an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 44 preferably contains CDR1 composed of the amino acid sequence described in Serial No. 112, CDR2 composed of the amino acid sequence described in Serial No. 113, and CDR3 composed of the amino acid sequence described in Serial No. 114.

[0480] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 43 has the activity of an anti-BCMA antibody VH, that is, binding activity against BCMA. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 43 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, to the amino acid sequence described in Serial No. 43.

[0481] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 44 has the activity of an anti-BCMA antibody VL, that is, binding activity against BCMA. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 44 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 44.

[0482] The following describes the implementation method of using anti-CD33 antibody.

[0483] Anti-CD33 antibodies are antibodies that bind to CD33. Preferably, anti-CD33 antibodies are antibodies that specifically bind to CD33. Anti-CD33 antibodies can be any of polyclonal or monoclonal antibodies, preferably monoclonal antibodies. Anti-CD33 antibodies can be any of human chimeric antibodies, humanized antibodies, or human antibodies, preferably humanized antibodies.

[0484] In one embodiment, the anti-CD33 antibody is an antibody containing the heavy chain variable region (VH) and the light chain variable region (VL) of gemtuzumab.

[0485] In one embodiment, the anti-CD33 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 115, CDR2 composed of the amino acid sequence described in sequence number 116, and CDR3 composed of the amino acid sequence described in sequence number 117, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 118, CDR2 composed of the amino acid sequence described in sequence number 119, and CDR3 composed of the amino acid sequence described in sequence number 120. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0486] In another embodiment, the amino acid sequence of the VH of the anti-CD33 antibody comprises the amino acid sequence described in sequence number 45, and the amino acid sequence of the VL of the anti-CD33 antibody comprises the amino acid sequence described in sequence number 46. The amino acid sequence of the VH of the anti-CD33 antibody may also be composed of the amino acid sequence described in sequence number 45, and the amino acid sequence of the VL of the anti-CD33 antibody may also be composed of the amino acid sequence described in sequence number 46.

[0487] As shown in the table below, VH containing the amino acid sequence described in sequence number 45 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 115, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 116, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 117. VL containing the amino acid sequence described in sequence number 46 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 118, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 119, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 120.

[0488] [Table 12] In another embodiment, the amino acid sequence of the VH of the anti-CD33 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in sequence number 45. Furthermore, the amino acid sequence of the VL of the anti-CD33 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in sequence number 46. The amino acid sequence of the VH of the anti-CD33 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in sequence number 45, and the amino acid sequence of the VL of the anti-CD33 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in sequence number 46. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 45 may also be an amino acid sequence described in Serial No. 45, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 46 may also be an amino acid sequence described in Serial No. 46.

[0489] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 45 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 115, CDR2 composed of the amino acid sequence described in Serial No. 116, and CDR3 composed of the amino acid sequence described in Serial No. 117.

[0490] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 46 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 118, CDR2 composed of the amino acid sequence described in Serial No. 119, and CDR3 composed of the amino acid sequence described in Serial No. 120.

[0491] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 45 has the activity of an anti-CD33 antibody VH, that is, binding activity against CD33. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 45 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 45.

[0492] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 46 has the activity of an anti-CD33 antibody VL, that is, binding activity against CD33. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 46 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 46.

[0493] The following describes the implementation method of using anti-FoLRα antibody.

[0494] Anti-FoLRα antibody is an antibody that binds to FoLRα. Preferably, anti-FoLRα antibody is an antibody that specifically binds to FoLRα. Anti-FoLRα antibody can be any antibody selected from polyclonal or monoclonal antibodies, preferably a monoclonal antibody. Anti-FoLRα antibody can be any antibody selected from human chimeric antibodies, humanized antibodies, or human antibodies, preferably a humanized antibody.

[0495] 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.

[0496] In one embodiment, the anti-FoLRα antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 121, CDR2 composed of the amino acid sequence described in sequence number 122, and CDR3 composed of the amino acid sequence described in sequence number 123, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 124, CDR2 composed of the amino acid sequence described in sequence number 125, and CDR3 composed of the amino acid sequence described in sequence number 126. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0497] In another embodiment, the amino acid sequence of the VH of the anti-FoLRα antibody comprises the amino acid sequence described in sequence number 47, and the amino acid sequence of the VL of the anti-FoLRα antibody comprises the amino acid sequence described in sequence number 48. The amino acid sequence of the VH of the anti-FoLRα antibody may also be composed of the amino acid sequence described in sequence number 47, and the amino acid sequence of the VL of the anti-FoLRα antibody may also be composed of the amino acid sequence described in sequence number 48.

[0498] As shown in the table below, VH containing the amino acid sequence described in Serial No. 47 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 121, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 122, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 123. VL containing the amino acid sequence described in Serial No. 48 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 124, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 125, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 126.

[0499] [Table 13] In another embodiment, the amino acid sequence of the VH of the anti-FoLRα antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 47. Furthermore, the amino acid sequence of the VL of the anti-FoLRα antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 48. The amino acid sequence of the VH of the anti-FoLRα antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 47, and the amino acid sequence of the VL of the anti-FoLRα antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 48. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 47 can also be the amino acid sequence described in Serial No. 47, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 48 can also be the amino acid sequence described in Serial No. 48.

[0500] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 47 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 121, CDR2 composed of the amino acid sequence described in Serial No. 122, and CDR3 composed of the amino acid sequence described in Serial No. 123.

[0501] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 48 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 124, CDR2 composed of the amino acid sequence described in Serial No. 125, and CDR3 composed of the amino acid sequence described in Serial No. 126.

[0502] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 47 has the activity of an anti-FoLRα antibody, that is, binding activity against FoLRα. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 47 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 47.

[0503] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 48 has the activity of an anti-FoLRα antibody VL, that is, binding activity against FoLRα. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 48 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 48.

[0504] The following describes the implementation method of using anti-CD25 antibody.

[0505] Anti-CD25 antibodies are antibodies that bind to CD25. Preferably, anti-CD25 antibodies are antibodies that specifically bind to CD25. Anti-CD25 antibodies can be any of polyclonal or monoclonal antibodies, preferably monoclonal antibodies. Anti-CD25 antibodies can be any of human chimeric antibodies, humanized antibodies, or human antibodies, preferably humanized antibodies.

[0506] In one embodiment, the anti-CD25 antibody is an antibody containing the heavy chain variable region (VH) and the light chain variable region (VL) of camidanlumab.

[0507] In one embodiment, the anti-CD25 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 127, CDR2 composed of the amino acid sequence described in sequence number 128, and CDR3 composed of the amino acid sequence described in sequence number 129, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 130, CDR2 composed of the amino acid sequence described in sequence number 131, and CDR3 composed of the amino acid sequence described in sequence number 132. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0508] In another embodiment, the amino acid sequence of the VH of the anti-CD25 antibody comprises the amino acid sequence described in sequence number 49, and the amino acid sequence of the VL of the anti-CD25 antibody comprises the amino acid sequence described in sequence number 50. The amino acid sequence of the VH of the anti-CD25 antibody may also be composed of the amino acid sequence described in sequence number 49, and the amino acid sequence of the VL of the anti-CD25 antibody may also be composed of the amino acid sequence described in sequence number 50.

[0509] As shown in the table below, the VH containing the amino acid sequence described in sequence number 49 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 127, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 128, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 129. The VL containing the amino acid sequence described in sequence number 50 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 130, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 131, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 132.

[0510] [Table 14] In another embodiment, the amino acid sequence of the VH of the anti-CD25 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in sequence number 49. Furthermore, the amino acid sequence of the VL of the anti-CD25 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in sequence number 50. The amino acid sequence of the VH of the anti-CD25 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in sequence number 49, and the amino acid sequence of the VL of the anti-CD25 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in sequence number 50. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 49 may also be an amino acid sequence described in Serial No. 49, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 50 may also be an amino acid sequence described in Serial No. 50.

[0511] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 49 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 127, CDR2 composed of the amino acid sequence described in Serial No. 128, and CDR3 composed of the amino acid sequence described in Serial No. 129.

[0512] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 50 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 130, CDR2 composed of the amino acid sequence described in Serial No. 131, and CDR3 composed of the amino acid sequence described in Serial No. 132.

[0513] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 49 has the activity of an anti-CD25 antibody VH, that is, binding activity against CD25. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 49 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, to the amino acid sequence described in Serial No. 49.

[0514] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 50 has the activity of an anti-CD25 antibody VL, that is, binding activity against CD25. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 50 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, to the amino acid sequence described in Serial No. 50.

[0515] The following describes the implementation method of using an anti-CADM1 antibody.

[0516] Anti-CADM1 antibody is an antibody that binds to CADM1. Preferably, it is an antibody that specifically binds to CADM1. Anti-CADM1 antibody can be any of polyclonal or monoclonal antibodies, preferably monoclonal. Anti-CADM1 antibody can be any of human chimeric antibody, humanized antibody, or human antibody, preferably humanized antibody.

[0517] In one embodiment, the anti-CADM1 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) of PTA021_A3 (US Patent No. 8420084).

[0518] In one embodiment, the anti-CADM1 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 133, CDR2 composed of the amino acid sequence described in sequence number 134, and CDR3 composed of the amino acid sequence described in sequence number 135, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 136, CDR2 composed of the amino acid sequence described in sequence number 137, and CDR3 composed of the amino acid sequence described in sequence number 138. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0519] In another embodiment, the amino acid sequence of the VH of the anti-CADM1 antibody comprises the amino acid sequence described in sequence number 51, and the amino acid sequence of the VL of the anti-CADM1 antibody comprises the amino acid sequence described in sequence number 52. The amino acid sequence of the VH of the anti-CADM1 antibody may also be composed of the amino acid sequence described in sequence number 51, and the amino acid sequence of the VL of the anti-CADM1 antibody may also be composed of the amino acid sequence described in sequence number 52.

[0520] As shown in the table below, VH containing the amino acid sequence described in sequence number 51 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 133, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 134, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 135. VL containing the amino acid sequence described in sequence number 52 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 136, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 137, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 138.

[0521] [Table 15] In another embodiment, the amino acid sequence of the VH of the anti-CADM1 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 51. Furthermore, the amino acid sequence of the VL of the anti-CADM1 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 52. The amino acid sequence of the VH of the anti-CADM1 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 51, and the amino acid sequence of the VL of the anti-CADM1 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 52. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence recorded in Serial No. 51 can also be the amino acid sequence recorded in Serial No. 51, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence recorded in Serial No. 52 can also be the amino acid sequence recorded in Serial No. 52.

[0522] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 51 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 133, CDR2 composed of the amino acid sequence described in Serial No. 134, and CDR3 composed of the amino acid sequence described in Serial No. 135.

[0523] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 52 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 136, CDR2 composed of the amino acid sequence described in Serial No. 137, and CDR3 composed of the amino acid sequence described in Serial No. 138.

[0524] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 51 has the activity of an anti-CADM1 antibody VH, that is, binding activity against CADM1. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 51 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, to the amino acid sequence described in Serial No. 51.

[0525] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 52 has the activity of an anti-CADM1 antibody VL, that is, binding activity against CADM1. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 52 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 52.

[0526] The following describes the implementation method of using anti-CLL1 antibody.

[0527] Anti-CLL1 antibody is an antibody that binds to CLL1. Preferably, it is an antibody that specifically binds to CLL1. Anti-CLL1 antibody can be any of polyclonal or monoclonal antibodies, preferably monoclonal. Anti-CLL1 antibody can be any of human chimeric antibody, humanized antibody, or human antibody, preferably humanized antibody.

[0528] In one embodiment, the anti-CLL1 antibody is an antibody having a heavy chain variable region (VH) and a light chain variable region (VL) having 6E7LAHle (International Publication No. 2016 / 205200).

[0529] In one embodiment, the anti-CLL1 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 139, CDR2 composed of the amino acid sequence described in sequence number 140, and CDR3 composed of the amino acid sequence described in sequence number 141, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 142, CDR2 composed of the amino acid sequence described in sequence number 143, and CDR3 composed of the amino acid sequence described in sequence number 144. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0530] In another embodiment, the amino acid sequence of the VH of the anti-CLL1 antibody comprises the amino acid sequence described in sequence number 53, and the amino acid sequence of the VL of the anti-CLL1 antibody comprises the amino acid sequence described in sequence number 54. The amino acid sequence of the VH of the anti-CLL1 antibody may also be composed of the amino acid sequence described in sequence number 53, and the amino acid sequence of the VL of the anti-CLL1 antibody may also be composed of the amino acid sequence described in sequence number 54.

[0531] As shown in the table below, VH containing the amino acid sequence described in sequence number 53 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 139, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 140, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 141. VL containing the amino acid sequence described in sequence number 54 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 142, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 143, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 144.

[0532] [Table 16] In another embodiment, the amino acid sequence of the VH of the anti-CLL1 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 53. Furthermore, the amino acid sequence of the VL of the anti-CLL1 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 54. The amino acid sequence of the VH of the anti-CLL1 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 53, and the amino acid sequence of the VL of the anti-CLL1 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 54. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 53 may also be an amino acid sequence described in Serial No. 53, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 54 may also be an amino acid sequence described in Serial No. 54.

[0533] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 53 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 139, CDR2 composed of the amino acid sequence described in Serial No. 140, and CDR3 composed of the amino acid sequence described in Serial No. 141.

[0534] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 54 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 142, CDR2 composed of the amino acid sequence described in Serial No. 143, and CDR3 composed of the amino acid sequence described in Serial No. 144.

[0535] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 53 has the activity of an anti-CLL1 antibody VH, that is, binding activity against CLL1. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 53 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, to the amino acid sequence described in Serial No. 53.

[0536] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 54 has the activity of an anti-CLL1 antibody VL, that is, binding activity against CLL1. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 54 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 54.

[0537] The following describes the implementation method of using anti-CD38 antibody.

[0538] Anti-CD38 antibody is an antibody that binds to CD38. Preferably, it is an antibody that specifically binds to CD38. Anti-CD38 antibody can be any of polyclonal or monoclonal antibodies, preferably monoclonal. Anti-CD38 antibody can be any of human chimeric antibody, humanized antibody, or human antibody, preferably humanized antibody.

[0539] 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.

[0540] In one embodiment, the anti-CD38 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 145, CDR2 composed of the amino acid sequence described in sequence number 146, and CDR3 composed of the amino acid sequence described in sequence number 147, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 148, CDR2 composed of the amino acid sequence described in sequence number 149, and CDR3 composed of the amino acid sequence described in sequence number 150. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0541] In another embodiment, the amino acid sequence of the VH of the anti-CD38 antibody comprises the amino acid sequence described in sequence number 55, and the amino acid sequence of the VL of the anti-CD38 antibody comprises the amino acid sequence described in sequence number 56. The amino acid sequence of the VH of the anti-CD38 antibody may also be composed of the amino acid sequence described in sequence number 55, and the amino acid sequence of the VL of the anti-CD38 antibody may also be composed of the amino acid sequence described in sequence number 56.

[0542] As shown in the table below, VH containing the amino acid sequence described in Serial No. 55 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 145, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 146, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 147. VL containing the amino acid sequence described in Serial No. 56 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 148, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 149, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in Serial No. 150.

[0543] [Table 17] In another embodiment, the amino acid sequence of the VH of the anti-CD38 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 55. Furthermore, the amino acid sequence of the VL of the anti-CD38 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 56. The amino acid sequence of the VH of the anti-CD38 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 55, and the amino acid sequence of the VL of the anti-CD38 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 56. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 55 may also be an amino acid sequence described in Serial No. 55, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 56 may also be an amino acid sequence described in Serial No. 56.

[0544] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 55 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 145, CDR2 composed of the amino acid sequence described in Serial No. 146, and CDR3 composed of the amino acid sequence described in Serial No. 147.

[0545] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 56 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 148, CDR2 composed of the amino acid sequence described in Serial No. 149, and CDR3 composed of the amino acid sequence described in Serial No. 150.

[0546] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 55 has the activity of an anti-CD38 antibody VH, that is, binding activity against CD38. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 55 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, to the amino acid sequence described in Serial No. 55.

[0547] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 56 has the activity of an anti-CD38 antibody VL, that is, binding activity against CD38. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 56 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 56.

[0548] The following describes the implementation method of using anti-CD74 antibody.

[0549] Anti-CD74 antibody is an antibody that binds to CD74. Preferably, it is an antibody that specifically binds to CD74. Anti-CD74 antibody can be any of polyclonal or monoclonal antibodies, preferably monoclonal. Anti-CD74 antibody can be any of human chimeric antibody, humanized antibody, or human antibody, preferably humanized antibody.

[0550] In one embodiment, the anti-CD74 antibody is an antibody containing the heavy chain variable region (VH) and the light chain variable region (VL) of milatuzumab.

[0551] In one embodiment, the anti-CD74 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 151, CDR2 composed of the amino acid sequence described in sequence number 152, and CDR3 composed of the amino acid sequence described in sequence number 153, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 154, CDR2 composed of the amino acid sequence described in sequence number 155, and CDR3 composed of the amino acid sequence described in sequence number 156. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0552] In another embodiment, the amino acid sequence of the VH of the anti-CD74 antibody comprises the amino acid sequence described in sequence number 57, and the amino acid sequence of the VL of the anti-CD74 antibody comprises the amino acid sequence described in sequence number 58. The amino acid sequence of the VH of the anti-CD74 antibody may also be composed of the amino acid sequence described in sequence number 57, and the amino acid sequence of the VL of the anti-CD74 antibody may also be composed of the amino acid sequence described in sequence number 58.

[0553] As shown in the table below, VH containing the amino acid sequence described in sequence number 57 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 151, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 152, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 153. VL containing the amino acid sequence described in sequence number 58 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 154, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 155, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 156.

[0554] [Table 18] In another embodiment, the amino acid sequence of the VH of the anti-CD74 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 57. Furthermore, the amino acid sequence of the VL of the anti-CD74 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in Serial No. 58. The amino acid sequence of the VH of the anti-CD74 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 57, and the amino acid sequence of the VL of the anti-CD74 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in Serial No. 58. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 57 can also be the amino acid sequence described in Serial No. 57, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 58 can also be the amino acid sequence described in Serial No. 58.

[0555] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 57 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 151, CDR2 composed of the amino acid sequence described in Serial No. 152, and CDR3 composed of the amino acid sequence described in Serial No. 153.

[0556] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 58 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 154, CDR2 composed of the amino acid sequence described in Serial No. 155, and CDR3 composed of the amino acid sequence described in Serial No. 156.

[0557] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 57 has the activity of an anti-CD74 antibody VH, that is, binding activity against CD74. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 57 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 57.

[0558] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 58 has the activity of an anti-CD74 antibody VL, that is, binding activity against CD74. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 58 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 58.

[0559] The following describes the implementation method of using anti-NECTIN4 antibody.

[0560] Anti-NECTIN4 antibody is an antibody that binds to NECTIN4. Preferably, it is an antibody that specifically binds to NECTIN4. Anti-NECTIN4 antibody can be any of polyclonal or monoclonal antibodies, preferably monoclonal. It can also be any of human chimeric antibodies, humanized antibodies, or human antibodies, preferably humanized antibodies.

[0561] In one embodiment, the anti-NECTIN4 antibody is an antibody containing the heavy chain variable region (VH) and the light chain variable region (VL) of enfortumab.

[0562] In one embodiment, the anti-NECTIN4 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 187, CDR2 composed of the amino acid sequence described in sequence number 188, and CDR3 composed of the amino acid sequence described in sequence number 189, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 190, CDR2 composed of the amino acid sequence described in sequence number 191, and CDR3 composed of the amino acid sequence described in sequence number 192. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0563] In another embodiment, the amino acid sequence of VH of the anti-NECTIN4 antibody comprises the amino acid sequence described in sequence number 183, and the amino acid sequence of VL of the anti-NECTIN4 antibody comprises the amino acid sequence described in sequence number 184. The amino acid sequence of VH of the anti-NECTIN4 antibody may also be composed of the amino acid sequence described in sequence number 183, and the amino acid sequence of VL of the anti-NECTIN4 antibody may also be composed of the amino acid sequence described in sequence number 184.

[0564] As shown in the table below, VH containing the amino acid sequence described in sequence number 183 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 187, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 188, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 189. VL containing the amino acid sequence described in sequence number 184 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 190, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 191, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 192.

[0565] [Table 19] In another embodiment, the amino acid sequence of the VH of the anti-NECTIN4 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in sequence number 183. Furthermore, the amino acid sequence of the VL of the anti-NECTIN4 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in sequence number 184. The amino acid sequence of the VH of the anti-NECTIN4 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in sequence number 183, and the amino acid sequence of the VL of the anti-NECTIN4 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in sequence number 184. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 183 may also be an amino acid sequence described in Serial No. 183, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 184 may also be an amino acid sequence described in Serial No. 184.

[0566] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 183 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 187, CDR2 composed of the amino acid sequence described in Serial No. 188, and CDR3 composed of the amino acid sequence described in Serial No. 189.

[0567] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 184 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 190, CDR2 composed of the amino acid sequence described in Serial No. 191, and CDR3 composed of the amino acid sequence described in Serial No. 192.

[0568] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 183 has the activity of an anti-NECTIN4 antibody, that is, binding activity against NECTIN4. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 183 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 183.

[0569] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 184 has the activity of an anti-NECTIN4 antibody VL, that is, binding activity against NECTIN4. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 184 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 184.

[0570] The following describes the implementation method of using an anti-TROP2 antibody.

[0571] Anti-TROP2 antibody is an antibody that binds to TROP2. Preferably, it is an antibody that specifically binds to TROP2. Anti-TROP2 antibody can be any of polyclonal or monoclonal antibodies, preferably monoclonal. Anti-TROP2 antibody can be any of human chimeric antibody, humanized antibody, or human antibody, preferably humanized antibody.

[0572] In one embodiment, the anti-TROP2 antibody is an antibody containing the heavy chain variable region (VH) and the light chain variable region (VL) of sacituzumab.

[0573] In one embodiment, the anti-TROP2 antibody comprises a heavy chain variable region (VH) consisting of CDR1 composed of the amino acid sequence described in sequence number 193, CDR2 composed of the amino acid sequence described in sequence number 194, and CDR3 composed of the amino acid sequence described in sequence number 195, and a light chain variable region (VL) consisting of CDR1 composed of the amino acid sequence described in sequence number 196, CDR2 composed of the amino acid sequence described in sequence number 197, and CDR3 composed of the amino acid sequence described in sequence number 198. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0574] In another embodiment, the amino acid sequence of the VH of the anti-TROP2 antibody comprises the amino acid sequence described in sequence number 185, and the amino acid sequence of the VL of the anti-TROP2 antibody comprises the amino acid sequence described in sequence number 186. The amino acid sequence of the VH of the anti-TROP2 antibody may also be composed of the amino acid sequence described in sequence number 185, and the amino acid sequence of the VL of the anti-TROP2 antibody may also be composed of the amino acid sequence described in sequence number 186.

[0575] As shown in the table below, VH containing the amino acid sequence described in sequence number 185 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 193, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 194, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 195. VL containing the amino acid sequence described in sequence number 186 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 196, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 197, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 198.

[0576] [Table 20] In another embodiment, the amino acid sequence of the VH of the anti-TROP2 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in sequence number 185. Furthermore, the amino acid sequence of the VL of the anti-TROP2 antibody comprises an amino acid sequence having at least 90%, preferably at least 95%, more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, and even more preferably at least 99% sequence identity relative to the amino acid sequence described in sequence number 186. The amino acid sequence of the VH of the anti-TROP2 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in sequence number 185, and the amino acid sequence of the VL of the anti-TROP2 antibody may also consist of an amino acid sequence having at least 90% sequence identity relative to the amino acid sequence described in sequence number 186. An amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 185 may also be an amino acid sequence described in Serial No. 185, and an amino acid sequence that has more than 90% sequence identity with the amino acid sequence described in Serial No. 186 may also be an amino acid sequence described in Serial No. 186.

[0577] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 185 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 193, CDR2 composed of the amino acid sequence described in Serial No. 194, and CDR3 composed of the amino acid sequence described in Serial No. 195.

[0578] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 186 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 196, CDR2 composed of the amino acid sequence described in Serial No. 197, and CDR3 composed of the amino acid sequence described in Serial No. 198.

[0579] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 185 has the activity of an anti-TROP2 antibody, that is, binding activity against TROP2. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 185 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 185.

[0580] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 186 has the activity of an anti-TROP2 antibody VL, that is, binding activity against TROP2. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 186 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 186.

[0581] The following describes an embodiment in which the antibody is an anti-CD79b antibody and is a human antibody G4055 (hereinafter also referred to as anti-CD79b antibody (human antibody G4055) or anti-CD79b_G4055 antibody).

[0582] Anti-CD79b antibody (human antibody G4055) is an antibody that binds to CD79b. Anti-CD79b antibody (human antibody G4055) is preferably an antibody that specifically binds to CD79b. Anti-CD79b antibody (human antibody G4055) can be any antibody, either polyclonal or monoclonal, preferably a monoclonal antibody. Anti-CD79b antibody (human antibody G4055) is a human antibody.

[0583] In one embodiment, the anti-CD79b antibody (human antibody G4055) contains a heavy chain variable region (VH) comprising CDR1 composed of the amino acid sequence described in sequence number 157, CDR2 composed of the amino acid sequence described in sequence number 158, and CDR3 composed of the amino acid sequence described in sequence number 159, and a light chain variable region (VL) comprising CDR1 composed of the amino acid sequence described in sequence number 160, CDR2 composed of the amino acid sequence described in sequence number 161, and CDR3 composed of the amino acid sequence described in sequence number 162. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0584] In another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4055) comprises the amino acid sequence described in sequence number 59, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4055) comprises the amino acid sequence described in sequence number 60. The amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4055) may also be composed of the amino acid sequence described in sequence number 59, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4055) may also be composed of the amino acid sequence described in sequence number 60.

[0585] As shown in the table below, VH containing the amino acid sequence described in sequence number 59 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 157, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 158, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 159. VL containing the amino acid sequence described in sequence number 60 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 160, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 161, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 162.

[0586] [Table 21] In another embodiment, the amino acid sequence of VH of the anti-CD79b antibody (human antibody G4055) comprises an amino acid sequence having a sequence identity of 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, even more preferably 99% or more, relative to the amino acid sequence described in sequence number 59; and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4055) comprises an amino acid sequence having a sequence identity of 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, even more preferably 99% or more, relative to the amino acid sequence described in sequence number 60. The amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4055) can also be composed of an amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 59, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4055) can also be composed of an amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 60. The amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 59 can also be the amino acid sequence described in sequence number 59, and the amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 60 can also be the amino acid sequence described in sequence number 60.

[0587] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 59 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 157, CDR2 composed of the amino acid sequence described in Serial No. 158, and CDR3 composed of the amino acid sequence described in Serial No. 159.

[0588] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 60 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 160, CDR2 composed of the amino acid sequence described in Serial No. 161, and CDR3 composed of the amino acid sequence described in Serial No. 162.

[0589] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 59 has the activity of an anti-CD79b antibody (human antibody G4055), that is, binding activity against CD79b. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 59 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 59.

[0590] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 60 has the activity of an anti-CD79b antibody (human antibody G4055), that is, binding activity against CD79b. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 60 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 60.

[0591] The following describes an embodiment in which the antibody is an anti-CD79b antibody and is a human antibody G4022 (hereinafter also referred to as anti-CD79b antibody (human antibody G4022) or anti-CD79b_G4022 antibody).

[0592] Anti-CD79b antibody (human antibody G4022) is an antibody that binds to CD79b. Preferably, anti-CD79b antibody (human antibody G4022) is an antibody that specifically binds to CD79b. Anti-CD79b antibody (human antibody G4022) can be any antibody, either polyclonal or monoclonal, preferably a monoclonal antibody. Anti-CD79b antibody (human antibody G4022) is a human antibody.

[0593] In one embodiment, the anti-CD79b antibody (human antibody G4022) contains a heavy chain variable region (VH) comprising CDR1 composed of the amino acid sequence described in sequence number 163, CDR2 composed of the amino acid sequence described in sequence number 164, and CDR3 composed of the amino acid sequence described in sequence number 165, and a light chain variable region (VL) comprising CDR1 composed of the amino acid sequence described in sequence number 166, CDR2 composed of the amino acid sequence described in sequence number 167, and CDR3 composed of the amino acid sequence described in sequence number 168. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0594] In another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4022) comprises the amino acid sequence described in sequence number 61, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4022) comprises the amino acid sequence described in sequence number 62. The amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4022) may also be composed of the amino acid sequence described in sequence number 61, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4022) may also be composed of the amino acid sequence described in sequence number 62.

[0595] As shown in the table below, VH containing the amino acid sequence described in sequence number 61 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 163, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 164, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 165. VL containing the amino acid sequence described in sequence number 62 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 166, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 167, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 168.

[0596] [Table 22] In another embodiment, the amino acid sequence of VH of the anti-CD79b antibody (human antibody G4022) comprises an amino acid sequence having a sequence identity of 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, even more preferably 99% or more, relative to the amino acid sequence described in sequence number 61, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4022) comprises an amino acid sequence having a sequence identity of 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, even more preferably 99% or more, relative to the amino acid sequence described in sequence number 62. The amino acid sequence of VH of the anti-CD79b antibody (human antibody G4022) can also be composed of an amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 61, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4022) can also be composed of an amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 62. The amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 61 can also be the amino acid sequence described in sequence number 61, and the amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 62 can also be the amino acid sequence described in sequence number 62.

[0597] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 61 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 163, CDR2 composed of the amino acid sequence described in Serial No. 164, and CDR3 composed of the amino acid sequence described in Serial No. 165.

[0598] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 62 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 166, CDR2 composed of the amino acid sequence described in Serial No. 167, and CDR3 composed of the amino acid sequence described in Serial No. 168.

[0599] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 61 has the activity of an anti-CD79b antibody (human antibody G4022), that is, binding activity against CD79b. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 61 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 61.

[0600] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 62 has the activity of an anti-CD79b antibody (human antibody G4022), that is, binding activity against CD79b. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 62 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 62.

[0601] The following describes an embodiment in which the antibody is an anti-CD79b antibody and a human antibody G4046 (human antibody G4046) (hereinafter also referred to as anti-CD79b antibody (human antibody G4046) or anti-CD79b_G4046 antibody).

[0602] Anti-CD79b antibody (human antibody G4046) is an antibody that binds to CD79b. Preferably, anti-CD79b antibody (human antibody G4046) is an antibody that specifically binds to CD79b. Anti-CD79b antibody (human antibody G4046) can be any antibody, either polyclonal or monoclonal, preferably a monoclonal antibody. Anti-CD79b antibody (human antibody G4046) is a human antibody.

[0603] In one embodiment, the anti-CD79b antibody (human antibody G4046) contains a heavy chain variable region (VH) comprising CDR1 composed of the amino acid sequence described in sequence number 169, CDR2 composed of the amino acid sequence described in sequence number 170, and CDR3 composed of the amino acid sequence described in sequence number 171, and a light chain variable region (VL) comprising CDR1 composed of the amino acid sequence described in sequence number 172, CDR2 composed of the amino acid sequence described in sequence number 173, and CDR3 composed of the amino acid sequence described in sequence number 174. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0604] In another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4046) comprises the amino acid sequence described in sequence number 63, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4046) comprises the amino acid sequence described in sequence number 64. The amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4046) may also be composed of the amino acid sequence described in sequence number 63, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4046) may also be composed of the amino acid sequence described in sequence number 64.

[0605] As shown in the table below, VH containing the amino acid sequence described in sequence number 63 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 169, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 170, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 171. VL containing the amino acid sequence described in sequence number 64 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 172, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 173, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 174.

[0606] [Table 23] In another embodiment, the amino acid sequence of VH of the anti-CD79b antibody (human antibody G4046) comprises an amino acid sequence having a sequence identity of 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, even more preferably 99% or more, relative to the amino acid sequence described in sequence number 63, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4046) comprises an amino acid sequence having a sequence identity of 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, even more preferably 99% or more, relative to the amino acid sequence described in sequence number 64. The amino acid sequence of VH of the anti-CD79b antibody (human antibody G4046) can also be composed of an amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 63, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4046) can also be composed of an amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 64. The amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 63 can also be the amino acid sequence described in sequence number 63, and the amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 64 can also be the amino acid sequence described in sequence number 64.

[0607] The VH comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 63 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 169, CDR2 composed of the amino acid sequence described in Serial No. 170, and CDR3 composed of the amino acid sequence described in Serial No. 171.

[0608] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 64 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 172, CDR2 composed of the amino acid sequence described in Serial No. 173, and CDR3 composed of the amino acid sequence described in Serial No. 174.

[0609] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 63 has the activity of an anti-CD79b antibody (human antibody G4046), that is, binding activity against CD79b. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 63 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 63.

[0610] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 64 has the activity of an anti-CD79b antibody (human antibody G4046), that is, binding activity against CD79b. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 64 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 64.

[0611] The following describes an implementation of an antibody that is an anti-CD79b antibody and a human antibody G4047 (hereinafter also referred to as anti-CD79b antibody (human antibody G4047) or anti-CD79b_G4047 antibody).

[0612] Anti-CD79b antibody (human antibody G4047) is an antibody that binds to CD79b. Preferably, anti-CD79b antibody (human antibody G4047) is an antibody that specifically binds to CD79b. Anti-CD79b antibody (human antibody G4047) can be any antibody, either polyclonal or monoclonal, preferably a monoclonal antibody. Anti-CD79b antibody (human antibody G4047) is a human antibody.

[0613] In one embodiment, the anti-CD79b antibody (human antibody G4047) contains a heavy chain variable region (VH) comprising CDR1 composed of the amino acid sequence described in sequence number 175, CDR2 composed of the amino acid sequence described in sequence number 176, and CDR3 composed of the amino acid sequence described in sequence number 177, and a light chain variable region (VL) comprising CDR1 composed of the amino acid sequence described in sequence number 178, CDR2 composed of the amino acid sequence described in sequence number 179, and CDR3 composed of the amino acid sequence described in sequence number 180. It should be noted that CDR1, CDR2, and CDR3 are CDR1, CDR2, and CDR3 based on Kabat numbering, respectively.

[0614] In another embodiment, the amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4047) comprises the amino acid sequence described in sequence number 65, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4047) comprises the amino acid sequence described in sequence number 66. The amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4047) may also be composed of the amino acid sequence described in sequence number 65, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4047) may also be composed of the amino acid sequence described in sequence number 66.

[0615] As shown in the table below, VH containing the amino acid sequence described in sequence number 65 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 175, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 176, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 177. VL containing the amino acid sequence described in sequence number 66 includes CDR1 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 178, CDR2 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 179, and CDR3 (underlined portion in the table below) composed of the amino acid sequence described in sequence number 180.

[0616] [Table 24] In another embodiment, the amino acid sequence of VH of the anti-CD79b antibody (human antibody G4047) comprises an amino acid sequence having a sequence identity of 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, even more preferably 99% or more, relative to the amino acid sequence described in sequence number 65, and the amino acid sequence of VL of the anti-CD79b antibody (human antibody G4047) comprises an amino acid sequence having a sequence identity of 90% or more, preferably 95% or more, more preferably 96% or more, even more preferably 97% or more, even more preferably 98% or more, even more preferably 99% or more, relative to the amino acid sequence described in sequence number 66. The amino acid sequence of the VH of the anti-CD79b antibody (human antibody G4047) can also consist of an amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 65, and the amino acid sequence of the VL of the anti-CD79b antibody (human antibody G4047) can also consist of an amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 66. The amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 65 can also be the amino acid sequence described in sequence number 65, and the amino acid sequence having more than 90% sequence identity with the amino acid sequence described in sequence number 66 can also be the amino acid sequence described in sequence number 66.

[0617] The VH comprising an amino acid sequence having the above sequence identity relative to the amino acid sequence described in Serial No. 65 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 175, CDR2 composed of the amino acid sequence described in Serial No. 176, and CDR3 composed of the amino acid sequence described in Serial No. 177.

[0618] The VL comprising an amino acid sequence having the above sequence identity with respect to the amino acid sequence described in Serial No. 66 preferably comprises CDR1 composed of the amino acid sequence described in Serial No. 178, CDR2 composed of the amino acid sequence described in Serial No. 179, and CDR3 composed of the amino acid sequence described in Serial No. 180.

[0619] A VH containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 65 has the activity of an anti-CD79b antibody (human antibody G4047), that is, binding activity against CD79b. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 65 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 65.

[0620] A VL containing an amino acid sequence having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 66 has the activity of an anti-CD79b antibody (human antibody G4047), that is, binding activity against CD79b. Examples of amino acid sequences having the above-described sequence identity with respect to the amino acid sequence described in Serial No. 66 include, for example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 66.

[0621] The following describes the heavy chain constant region (CH) 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-97 antibody, anti-SSTR2 antibody, anti-CD30 antibody, anti-BCMA antibody, anti-CD33 antibody, anti-FoLRα antibody, anti-antibody, anti-CADM1 antibody, anti-CLL1 antibody, anti-CD38 antibody, anti-CD74 antibody, anti-NECTIN4 antibody, or anti-TROP2 antibody).

[0622] The 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) can be any CH as long as it belongs to human immunoglobulins (sometimes referred to as "hIg" below). For example, the CH of the hIgG class, specifically the CH of the hIgG subclass such as hIgG1, hIgG2, hIgG3, hIgG4, or their modifications can be used.

[0623] 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, the CH of hIgG1 or a modified version thereof, or the CH of hIgG4 or a modified version thereof.

[0624] In one embodiment, the amino acid sequence of 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) comprises: (a) the amino acid sequence described in Serial No. 1; or (b) an amino acid sequence having at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, even more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, even more preferably at least 99% sequence identity with respect to the amino acid sequence described in Serial No. 1. The amino acid sequence described in Serial No. 1 is the amino acid sequence of the CH of hIgG1. The amino acid sequence of the 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 also consist of amino acid sequences (a) or (b). For example, amino acid sequences obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 1. For example, amino acid sequences obtained by replacing at least one amino acid in the amino acid sequence described in Serial No. 1 with a cysteine ​​residue. It should be noted that the amino acid that is replaced by cysteine ​​is any amino acid other than cysteine.

[0625] In another embodiment, the amino acid sequence of 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) comprises: (c) the amino acid sequence described in Serial No. 2; or (d) an amino acid sequence having at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, even more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, even more preferably at least 99% sequence identity with respect to the amino acid sequence described in Serial No. 2. The amino acid sequence of the 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 also consist of amino acid sequences (c) or (d). For example, an amino acid sequence (d) obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5, amino acids in the amino acid sequence described in Serial No. 2 can be cited as an example. Another example of an amino acid sequence (d) is an amino acid sequence obtained by replacing at least one amino acid in the amino acid sequence described in Serial No. 2 with a cysteine ​​residue. It should be noted that the amino acid that is replaced by cysteine ​​is any amino acid other than cysteine.

[0626] In another embodiment, the amino acid sequence of 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) comprises: (i) the amino acid sequence described in Serial 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, even more preferably 99% or more sequence identity with respect to the amino acid sequence described in Serial No. 181. The amino acid sequence of the 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 also consist of amino acid sequences (i) or (j). For example, amino acid sequence (j) can be obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5 amino acids, in the amino acid sequence described in Serial No. 181. For example, amino acid sequence (j) can be obtained by substituting at least two amino acids in the amino acid sequence described in Serial No. 181 with cysteine ​​and lysine. It should be noted that the amino acids that are replaced by cysteine ​​are all amino acids other than cysteine, and the amino acids that are replaced by lysine are all amino acids other than lysine.

[0627] In another embodiment, the amino acid sequence of 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) comprises: (k) the amino acid sequence described in sequence number 182; or (l) an amino acid sequence having at least 80%, preferably at least 85%, more preferably at least 90%, even more preferably at least 95%, even more preferably at least 96%, even more preferably at least 97%, even more preferably at least 98%, even more preferably at least 99% sequence identity with respect to the amino acid sequence described in sequence number 182. The amino acid sequence of the 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 also consist of amino acid sequences (k) or (l). For example, an amino acid sequence (l) obtained by deleting, substituting, inserting, or adding, for example, 1 to 20, preferably 1 to 10, more preferably 1 to 5, amino acids in the amino acid sequence described in Serial No. 182. For example, an amino acid sequence obtained by substituting at least two amino acids in the amino acid sequence described in Serial No. 182 with cysteine ​​and phenylalanine. It should be noted that the amino acids that are replaced by cysteine ​​are all amino acids other than cysteine, and the amino acids that are replaced by phenylalanine are all amino acids other than phenylalanine.

[0628] As shown in the table below, the amino acid sequence described in Serial No. 2 is obtained by replacing the serine at position 239 (underlined in the table below) of the heavy chain, represented by the EU number of Kabat, in the amino acid sequence described in Serial No. 1 with a cysteine ​​(underlined in the table below). The substitution of serine at position 239 of the heavy chain with a cysteine ​​is sometimes referred to as the "S239C mutation". The linker in the drug-linker complex, and 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) can be bonded by the sulfur atom of the cysteine ​​residue introduced through the S239C mutation.

[0629] [Table 25] In the amino acid sequence (d), the S239C mutation is preferably retained.

[0630] As shown in the table below, the amino acid sequence described in sequence number 181 is obtained by replacing serine at position 239 of the heavy chain (represented by the EU number Kabat) in the human IgG4 heavy chain constant region (CH) with cysteine ​​(underlined in the table below) and arginine at position 409 with lysine (underlined in the table below). IgG4 variants containing or composed of the above sequences in the heavy chain constant region can be used as nullbody types with weakened binding to the Fcγ receptor (FcgR). Hereinafter, the substitution of serine at position 239 of the heavy chain with cysteine ​​is sometimes referred to as the "S239C mutation," and the sub...

Claims

1. A compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In formula (I), R 1 and R 2 Whether they are the same or different, they each represent a hydrogen atom or a lower alkyl group. R 3 Indicates a lower alkyl group. R 4 Indicates halogen, R 5 Indicates halogen, R 6 Indicates halogen or lower alkoxy group. Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-. Ring A represents: (i) An aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl. (ii) may be an aromatic heterocyclic group having 1 to 3 substituents selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkyl carbonyl, lower hydroxyalkyl carbonyl, lower alkoxycarbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl, or, (iii) may have an aryl group having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl.

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

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein, (i) The ring A represented by the nitrogen-containing aliphatic heterocyclic group is the following ring A': [Chemical Formula 2] In the formula, when ring A' has substituents, the substituents in ring A' have the same meaning as the substituents in ring A.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, The compound represented by formula (I) is the same as the compound represented by formula (I') below: [Chemical Formula 3] In equation (I'), R 1 R 2 and R 3 The meaning is the same as that of equation (I). Cycle A' is a nitrogen-containing aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy lower alkyl, lower alkyl carbonyl, hydroxy lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, 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): [Chemical Formula 4] In the formula, R A1 R B1 R D1 R E1 R F1 and R G1 Whether the terms are the same or different, they each represent lower alkyl, hydroxylower alkyl, lower alkyl carbonyl, hydroxylower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl, or lower alkyl carbamoyl. R A2 R A3 R B2 R B3 R C1 and R C2 Whether they are the same or different, they each represent a hydrogen atom, an oxo group, a lower alkyl group, or a hydroxyl lower alkyl group.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring A is an aliphatic heterocyclic group represented by the following formula (AA): [Chemical Formula 5] In formula (AA), R A1 Indicates a lower alkyl group, a lower alkyl carbonyl group, or a cycloalkyl carbonyl group. R A2 and R A3 Whether they are the same or different, they each represent a hydrogen atom, an oxo group, a lower alkyl group, or a hydroxyl lower alkyl group.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring A is an aliphatic heterocyclic group represented by the following formula (AB): [Chemical Formula 6] In formula (AB), R B1 Indicates a lower alkyl group or a lower alkyl carbonyl group. R B2 and R B3 Whether they are the same or different, they represent either hydrogen atoms or oxo groups.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring A is an aliphatic heterocyclic group represented by the following formula (AC): [Chemical Formula 7] In equation (AC), R C1 and R C2 Whether they are the same or different, they represent either hydrogen atoms or oxo groups.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring A is an aliphatic heterocyclic group represented by the following formula (AD): [Chemical Formula 8] In formula (AD), R D1 It indicates a lower alkyl carbonyl group.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring A is an aromatic heterocyclic group represented by the following formula (AE): [Chemical Formula 9] In formula (AE), R E1 It indicates a lower alkyl group.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring A is an aromatic heterocyclic group represented by the following formula (AF): [Chemical Formula 10] In formula (AF), R F1 It indicates a lower alkyl group.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Ring A is an aryl group represented by the following formula (AG): [Chemical Formula 11] In formula (AG), R G1 It indicates a lower alkoxy carbonyl group or a lower alkyl carbamoyl group.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein, Y is -O-CH2-CH2-.

14. Targeted molecule-drug complex, which is a targeted molecule-drug complex containing both a targeted molecule and a drug. The drug is any one of the compounds according to claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. The targeted molecule-drug complex of claim 14, wherein, The drug connects to the target molecule via a connector.

16. The targeted molecule-drug complex of claim 15, wherein, The targeted molecule-drug complex is represented by the following formula (II): [Chemical Formula 12] In formula (II), R 1 and R 2 Whether they are the same or different, they each represent a hydrogen atom or a lower alkyl group. R 3 Indicates a lower alkyl group. R 4 Indicates halogen, R 5 Indicates halogen, R 6 Indicates halogen or lower alkoxy group. Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-. Ring A represents: (i) An aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl. (ii) may be an aromatic heterocyclic group having 1 to 3 substituents selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkyl carbonyl, lower hydroxyalkyl carbonyl, lower alkoxycarbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl, or, (iii) may have an aryl group having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkyl carbonyl, hydroxy lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl; L indicates a connector. mm represents an integer from 1 to 8. Z represents the target molecule.

17. The targeted molecule-drug complex of claim 16, wherein, (i) The ring A represented by the aliphatic heterocyclic group is the following ring A': [Chemical Formula 13] In the formula, when ring A' has substituents, the substituents in ring A' have the same meaning as the substituents in ring A.

18. The targeted molecule-drug complex of claim 16, wherein, The targeted molecule-drug complex is represented by the following formula (II'): [Chemical Formula 14] In equation (II'), R 1 R 2 R 3 L, mm, and Z have the same meaning as in equation (II). Cycle A' is a nitrogen-containing aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy lower alkyl, lower alkyl carbonyl, hydroxy lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl.

19. The targeted molecule-drug complex of claim 16, wherein, L is represented by the following equation (III): [Chemical Formula 15] In formula (III), The wavy line 1 indicates the bonding site with Z. The wavy line 2 indicates the bonding site with the N atom. 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, sulfoalanine, arginine, asparagine, aspartic acid, glutamine, leucine, isoleucine, lysine, serine, proline, threonine, and tyrosine, or, (b) represents the peptide mimic shown in formula (IV) below: [Chemical Formula 16] ； q represents an integer from 1 to 5. r represents an integer from 2 to 24. s represents 0 or 1, t represents 1, 2, 3 or 4.

20. The targeted molecule-drug complex of claim 14, wherein, The target molecule is an antibody or its antigen-binding fragment, a low molecular weight compound, or a peptide.

21. The targeted molecule-drug complex of claim 14, wherein, The target molecule is an antibody.

22. The targeted molecule-drug complex of claim 21, wherein, The antibodies are 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 or anti-TROP2 antibody.

23. A drug-connector complex, comprising a drug and a connector attached to the drug. The drug is any one of the compounds according to claims 1 to 13 or a pharmaceutically acceptable salt thereof.

24. The drug-connector complex of claim 23, wherein, The drug-connector complex is represented by the following formula (V): [Chemical Formula 17] In equation (V), R 1 and R 2 Whether they are the same or different, they each represent a hydrogen atom or a lower alkyl group. R 3 Indicates a lower alkyl group. R 4 Indicates halogen, R 5 Indicates halogen, R 6 Indicates halogen or lower alkoxy group. Y represents -O-CH2-CH2-, -CH2-CH2-CH2-, -CH=CH-CH2-, or -NH-C(=O)-CH2-. Ring A represents: (i) An aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy-lower alkyl, lower alkyl carbonyl, hydroxy-lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl. (ii) may be an aromatic heterocyclic group having 1 to 3 substituents selected from the group consisting of lower alkyl, lower hydroxyalkyl, lower alkyl carbonyl, lower hydroxyalkyl carbonyl, lower alkoxycarbonyl, cycloalkyl carbonyl, and lower alkyl carbamoyl, or, (iii) may have an aryl group having 1 to 3 substituents selected from the group consisting of lower alkyl, hydroxy lower alkyl, lower alkyl carbonyl, hydroxy lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl; L indicates a connector.

25. The drug-connector complex of claim 24, wherein, (i) The ring A represented by the aliphatic heterocyclic group is the following ring A': [Chemical Formula 18] In the formula, when ring A' has substituents, the substituents in ring A' have the same meaning as the substituents in ring A.

26. The drug-connector complex of claim 24, wherein, The drug-connector complex is represented by the following formula (V'): [Chemical Formula 19] In equation (V'), R 1 R 2 R 3 And L has the same meaning as equation (V). Cycle A' is a nitrogen-containing aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy lower alkyl, lower alkyl carbonyl, hydroxy lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl.

27. The drug-connector complex of claim 24, wherein, The drug-connector complex is represented by the following formula (Va): [Chemical Formula 20] In equation (Va), R 1 R 2 R 3 R 4 R 5 R 6 Y and ring A have the same meaning as above. 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, sulfoalanine, arginine, asparagine, aspartic acid, glutamine, leucine, isoleucine, lysine, serine, proline, threonine, and tyrosine, or, (b) represents the peptide mimic shown in formula (IV) below: [Chemical Formula 21] ； q represents an integer from 1 to 5. r represents an integer from 2 to 24. s represents 0 or 1, t represents 1, 2, 3 or 4.

28. The drug-connector complex of claim 27, wherein, (i) The ring A represented by the aliphatic heterocyclic group is the following ring A': [Chemical Formula 22] In the formula, when ring A' has substituents, the substituents in ring A' have the same meaning as the substituents in ring A.

29. The drug-connector complex of claim 27, wherein, The drug-connector complex is represented by the following formula (V'a): [Chemical Formula 23] In equation (V'a), R 1 R 2 R 3 Xaa, q, r, s, and t have the same meaning as in equation (Va). Cycle A' is a nitrogen-containing aliphatic heterocyclic group that may have 1 to 3 substituents selected from the group consisting of oxo, lower alkyl, hydroxy lower alkyl, lower alkyl carbonyl, hydroxy lower alkyl carbonyl, lower alkoxy carbonyl, cycloalkyl carbonyl and lower alkyl carbamoyl.

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