Combination of Anti-MUC1 antibody-drug conjugate with immune checkpoint inhibitor

Abstract

An object of the present invention is to provide a pharmaceutical product and a treatment method comprising administering an anti-MUC1 antibody-drug conjugate and an immune checkpoint inhibitor in combination. The present invention provides a pharmaceutical product comprising an anti-MUC1 antibody-drug conjugate and an immune checkpoint inhibitor to be administered in combination. The anti-MUC1 antibody can be an anti-TA-MUC1 antibody. The anti-MUC1 antibody-drug conjugate can be an anti-MUC1 antibody-drug conjugate in which a drug-linker represented by the following formula and the anti-MUC1 antibody are conjugated via a thioether bond. Formula (I).

Description

[0001] [Document Name] Description

[0002] [Title of Invention] COMBINATION OF ANTI-MUC1 ANTIBODYDRUG CONJUGATE WITH IMMUNE CHECKPOINT INHIBITOR

[0003] [Technical Field]

[0004]

[0001]

[0005] The present invention relates to a pharmaceutical product and a treatment method comprising administering an anti-MUCl antibody-drug conjugate and an immune checkpoint inhibitor in combination.

[0006] [Background Art]

[0007]

[0002]

[0008] Human mucin-1 (MUC1 ) is a protein that is highly glycosylated in normal tissues, is expressed on the apical surface of the epithelial layer and forms a mucosal barrier. In tumor tissues, however, the polarized expression is lost, and MUC1 is redistributed over the cell surface and is also observed in the cytoplasm (Non Patent Literature 1 ). In addition, increased expression of MUC1 is observed in various types of clinical cancers (Non Patent Literature 1 ) and in certain cancers such as bladder cancer, it has been reported that patients with high MUC1 expression have a poorer prognosis than patients with low MUC1 expression (Non Patent Literature 2 ). Furthermore, in tumor,

[0009] 15453442-1alterations in the expression of sialyltransferases involved in glycosylation are associated with the expression of hypoglycosylated MUC1 that exposes novel epitopes, referred to as tumor associated MUC1 (TA MUC1 ) (Non Patent Literature 1 ).

[0010]

[0003]

[0011] An antibody-drug conjugate (ADC) in which a cytotoxic drug is conjugated to an antibody that recognizes TA-MUC1 expressed on the surface of cancer cells and exhibits internalization activity can be expected to selectively deliver the drug to cancer cells, thereby enabling accumulation of the drug within cancer cells and inducing cancer cell death. The extracellular domain of MUC1 contains approximately 25 to 120 tandem repeat sequences each consisting of 20 amino acids (Non Patent Literature 3 and 4 ) which allows multiple antibodies to bind to a single MUC1 molecule.

[0012] Accordingly, by delivering a larger amount of a cytotoxic drug than conventional ADCs, such an ADC targeting MUC1 is expected to exhibit strong antitumor activity against tumors that have not responded to prior standard therapies.

[0013] As one example of an anti-MUCl antibody-drug conjugate, an antibody-drug conjugate comprising an anti- MUCl antibody and exatecan, a topoisomerase I inhibitor, is known (Patent Literature 4 ).

[0014]

[0004]

[0015] 15453442-1Immune checkpoint inhibitors are drugs that inhibit the immunosuppressive pathways and activate antitumor immune responses (Non Patent Literature 5 to 7 ).

[0016] Examples of immune checkpoint inhibitors include anti-PD-1 antibodies such as nivolumab (Patent Literature 5) and pembrolizumab (Patent Literature 6), anti-PD-Ll antibodies such as atezolizumab (Patent Literature 7 ), durvalumab (Patent Literature 8 ), and avelumab (Patent Literature 9), and anti-CTLA-4 antibodies such as ipilimumab (Patent Literature 10) and tremelimumab (Patent Literature 11 ).

[0017]

[0005]

[0018] Although cases in which an antibody-drug conjugate and an immune checkpoint inhibitor were administered in combination (Patent Literature 12 and Non Patent Literature 9 and 10) are known, there have been no known cases in which an anti-MUCl antibody-drug conjugate and an immune checkpoint inhibitor are administered in combination.

[0019] [Citation List]

[0020] [Patent Literature]

[0021]

[0006]

[0022] [Patent Literature 1 ] International Publication No. WO 2010 / 093395

[0023] [Patent Literature 2 ] U. S. Patent No. 7999083

[0024] 15453442-1[ Patent Literature 3 ] International Publication No. WO 2015 / 115091

[0025] [ Patent Literature 4 ] International Publication No. WO 2019 / 219891

[0026] [ Patent Literature 5 ] International Publication No. WO 2006 / 121168

[0027] [ Patent Literature 6 ] International Publication No. WO 2008 / 156712

[0028] [ Patent Literature 7 ] International Publication No. WO 2010 / 077634

[0029] [ Patent Literature 8 ] International Publication No. WO 2011 / 066389

[0030] [ Patent Literature 9 ] International Publication No. WO 2013 / 079174

[0031] [ Patent Literature 10 ] International Publication No. WO 2001 / 014424

[0032] [ Patent Literature 11 ] International Publication No. WO 2000 / 037504

[0033] [ Patent Literature 12 ] International Publication No. WO 2018 / 110515

[0034] [Non Patent Literature ]

[0035]

[0007]

[0036] [Non Patent Literature 1 ] Nath S, Mukherj ee P. Trends Mol Med. 2014; 20 ( 6 ): 332 -42

[0037] [Non Patent Literature 2 ] Qing L, Li Q, Yang Y, et al. BMC Urol. 2022; 22 ( 1 ): 114

[0038] 15453442-1[Non Patent Literature 3 ] Gendler SJ, Lancaster CA, Taylor-Papadimitriou J, et al. J Biol Chem. 1990; 265 ( 25 ): 15286- 93

[0039] [Non Patent Literature 4 ] Hanisch FG, Muller S.

[0040] Glycobiology. 2000; 10 ( 5 ): 439-49

[0041] [Non Patent Literature 5 ] Menon S. et al., Cancers ( 2016 ) 8, 106

[0042] [Non Patent Literature 6 ] Pardoll DM., Nat Rev Cancer ( 2012 ) 12, 252-264

[0043] [Non Patent Literature 7 ] Wolchok JD., Cell ( 2015 ) 162, 937

[0044] [Non Patent Literature 8 ] JD Twomey et al., AAPS J. 2021; 23-39

[0045] [Non Patent Literature 9 ] Muller P. et al., Science Translational Medicine ( 2015 ) 7 ( 315 ), 315ra188

[0046] [Non Patent Literature 10 ] Iwata TN. et al., Mol Cancer Ther. 2018; 17: 1494-503

[0047] [ Summary of Invention]

[0048] [ Technical Problem]

[0049]

[0008]

[0050] An obj ect of the present invention is to provide a pharmaceutical product and a treatment method comprising administering an anti-MUCl antibody-drug conj ugate and an immune checkpoint inhibitor in combination.

[0051] [ Solution to Problem]

[0052] 15453442-1

[0009]

[0053] The present inventors have found that an anti-MUCl antibody-drug conjugate and an immune checkpoint inhibitor, when administered in combination, exhibit an excellent antitumor effect. Specifically, the present invention provides the following

[0001] to

[0439] .

[0054]

[0010]

[0055]

[0001] A pharmaceutical product comprising an anti-MUCl antibody-drug conjugate and an immune checkpoint inhibitor to be administered in combination.

[0056]

[0002] The pharmaceutical product according to

[0001] , wherein the anti-MUCl antibody is an anti-TA-MUCl antibody.

[0057] [3] The pharmaceutical product according to

[0001] or

[0002] , wherein the anti-MUCl antibody-drug conjugate is an anti-MUCl antibody-drug conjugate in which a drug-linker represented by the formula:

[0058] [Formula 1 ]

[0059]

[0060] wherein A represents a connecting position to the anti- MUCl antibody

[0061] 15453442-1and the anti-MUCl antibody are conjugated via a thioether bond.

[0062]

[0004] The pharmaceutical product according to

[0001] or

[0002] , wherein the anti-MUCl antibody-drug conjugate comprises an anti-MUCl antibody and a drug-linker and is represented by the formula:

[0063] [Formula 8 ]

[0064]

[0065] wherein AB represents the anti-MUCl antibody, and the drug-linker and the anti-MUCl antibody are conjugated via a thioether bond; and wherein y represents the average number of units of the drug-linker conjugated per antibody.

[0066] [5] The pharmaceutical product according to any one of

[0001] to

[0004] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising CDRH1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 1, CDRH2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 7, and CDRH3 comprising or consisting of the amino acid

[0067] 15453442-1sequence represented by SEQ ID NO: 3, and a light chain comprising CDRL1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 4, CDRL2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 5, and CDRL3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0068]

[0006] The pharmaceutical product according to any one of

[0001] to [5], wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising CDRH1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 1, CDRH2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 2, and CDRH3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain comprising CDRL1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 4, CDRL2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 5, and CDRL3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0069]

[0007] The pharmaceutical product according to any one of

[0001] to [5], wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 8 or SEQ ID NO: 10, and a light chain comprising a light chain variable

[0070] 15453442-1region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 9.

[0071]

[0008] The pharmaceutical product according to any one of

[0001] to

[0007] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 8, and a light chain comprising a light chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 9.

[0072]

[0009] The pharmaceutical product according to any one of

[0001] to [5] and

[0007] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 11 or SEQ ID NO: 13, and a light chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0073]

[0010] The pharmaceutical product according to any one of

[0001] to

[0009] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 11, and a light chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0074]

[0011] The pharmaceutical product according to

[0009] or

[0010] , wherein a lysine residue at the carboxyl terminus of the heavy chain of the anti-MUCl antibody is deleted.

[0075] 15453442-1

[0012] The pharmaceutical product according to any one of

[0001] to

[0008] , wherein the heavy chain comprises or consists of the amino acid sequence of amino acid numbers 1 to 446 of SEQ ID NO: 11.

[0076]

[0013] The pharmaceutical product according to any one of

[0001] to

[0012] , wherein the average number of units of the drug-linker conj ugated per antibody in the anti-MUCl antibody-drug conj ugate is in the range of 7 to 8.

[0077]

[0014] The pharmaceutical product according to any one of

[0001] to

[0012] , wherein the average number of units of the drug-linker conjugated per antibody in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.

[0078]

[0015] The pharmaceutical product according to any one of

[0001] to

[0014] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0079]

[0016] The pharmaceutical product according to any one of

[0001] to

[0014] , wherein the immune checkpoint inhibitor is an anti-PD- 1 antibody.

[0080]

[0017] The pharmaceutical product according to

[0016] , wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, or clone RMP1-14.

[0081]

[0018] The pharmaceutical product according to

[0016] or

[0017] , wherein the anti-PD-1 antibody is nivolumab.

[0082]

[0019] The pharmaceutical product according to

[0016] or

[0017] , wherein the anti-PD-1 antibody is pembrolizumab.

[0083] 15453442-1

[0020] The pharmaceutical product according to any one of

[0001] to

[0014] , wherein the immune checkpoint inhibitor is an anti-PD-Ll antibody.

[0084]

[0021] The pharmaceutical product according to

[0020] , wherein the anti-PD-Ll antibody is atezolizumab, durvalumab, avelumab, or clone 10F.9G2.

[0085]

[0022] The pharmaceutical product according to

[0020] or

[0021] , wherein the anti-PD-Ll antibody is atezolizumab.

[0086]

[0023] The pharmaceutical product according to

[0020] or 21 ], wherein the anti-PD-L1 antibody is durvalumab.

[0087]

[0024] The pharmaceutical product according to

[0020] or

[0021] , wherein the anti-PD-L1 antibody is avelumab.

[0088]

[0025] The pharmaceutical product according to any one of

[0001] to

[0014] , wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.

[0089]

[0026] The pharmaceutical product according to

[0025] , wherein the anti-CTLA-4 antibody is ipilimumab, tremelimumab, or clone 9H10.

[0090]

[0027] The pharmaceutical product according to

[0025] or

[0026] , wherein the anti-CTLA-4 antibody is ipilimumab.

[0091]

[0028] The pharmaceutical product according to

[0025] or

[0026] , wherein the anti-CTLA-4 antibody is tremelimumab.

[0092]

[0029] The pharmaceutical product according to any one of

[0001] to

[0028] , wherein the anti-MUCl antibody-drug conj ugate and the immune checkpoint inhibitor are contained as active ingredients in separate preparations and are to be administered simultaneously or at di f ferent

[0093] 15453442-1times, or as a single preparation to be administered together.

[0094]

[0030] The pharmaceutical product according to any one of

[0001] to

[0029] , wherein the pharmaceutical product further comprises an anticancer agent.

[0095]

[0031] The pharmaceutical product according to

[0030] , wherein the anticancer agent is carboplatin or pemetrexed.

[0096]

[0032] The pharmaceutical product according to

[0030] or

[0031] , wherein the anticancer agent is to be administered simultaneously, separately, or continuously to the anti-MUC1 antibody-drug conjugate and the immune checkpoint inhibitor, or in a staggered manner.

[0097]

[0033] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 1 mg / kg to 6 mg / kg.

[0098]

[0034] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg to 6 mg / kg.

[0099]

[0035] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg.

[0100]

[0036] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug

[0101] 15453442-1conjugate is to be administered at a dose of about 3 mg / kg to 5 mg / kg.

[0102]

[0037] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg.

[0103]

[0038] The pharmaceutical product according to any one of

[0015] to

[0037] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody and wherein the anti-PD-1 antibody is to be administered at a dose of about 100 to 300 mg.

[0104]

[0039] The pharmaceutical product according to any one of

[0015] to

[0037] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody and wherein the anti-PD-1 antibody is to be administered at a dose of about 200 mg.

[0105]

[0040] The pharmaceutical product according to any one of

[0015] to

[0037] , wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is to be administered at a dose of about 100 to 300 mg.

[0106]

[0041] The pharmaceutical product according to any one of

[0015] to

[0037] , wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is to be administered at a dose of about 200 mg.

[0107]

[0042] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 1 mg / kg to 6 mg / kg,

[0108] 15453442-1wherein the immune checkpoint inhibitor is pembrolizumab, and

[0109] wherein pembrolizumab is to be administered at a dose of about 100 to 300 mg.

[0110]

[0043] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 1 mg / kg to 6 mg / kg,

[0111] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0112] wherein pembrolizumab is to be administered at a dose of about 200 mg.

[0113]

[0044] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg to 6 mg / kg,

[0114] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0115] wherein pembrolizumab is to be administered at a dose of about 200 mg.

[0116]

[0045] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg to 5 mg / kg,

[0117] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0118] 15453442-1wherein pembrolizumab is to be administered at a dose of about 200 mg.

[0119]

[0046] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg,

[0120] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0121] wherein pembrolizumab is to be administered at a dose of about 200 mg.

[0122]

[0047] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 4 mg / kg,

[0123] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0124] wherein pembrolizumab is to be administered at a dose of about 200 mg.

[0125]

[0048] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 5 mg / kg,

[0126] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0127] wherein pembrolizumab is to be administered at a dose of about 200 mg.

[0128] 15453442-1

[0049] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 6 mg / kg,

[0129] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0130] wherein pembrolizumab is to be administered at a dose of about 200 mg.

[0131]

[0050] The pharmaceutical product according to any one of

[0029] to

[0049] , wherein the anti-MUCl antibody-drug conjugate is to be administered via intravenous administration.

[0132]

[0051] The pharmaceutical product according to any one of

[0029] to

[0050] , wherein the anti-MUCl antibody-drug conjugate is to be administered once every two to four weeks

[0133]

[0052] The pharmaceutical product according to any one of

[0029] to

[0051] , wherein the anti-MUCl antibody-drug conjugate is to be administered via intravenous administration once every three weeks.

[0134]

[0053] The pharmaceutical product according to

[0038] or

[0039] , wherein the anti-PD-1 antibody is to be administered via intravenous administration.

[0135]

[0054] The pharmaceutical product according to any one of

[0038] ,

[0039] and

[0053] , wherein the anti-PD-1 antibody is to be administered once every two to four weeks.

[0136] 15453442-1

[0055] The pharmaceutical product according to any one of

[0038] ,

[0039] ,

[0053] and

[0054] , wherein the anti-PD-1 antibody is to be administered via intravenous administration once every three weeks.

[0137]

[0056] The pharmaceutical product according to any one of

[0040] to

[0049] , wherein pembrolizumab is to be administered via intravenous administration.

[0138]

[0057] The pharmaceutical product according to any one of

[0040] to

[0049] and

[0056] , wherein pembrolizumab is to be administered once every two to four weeks.

[0139]

[0058] The pharmaceutical product according to any one of

[0040] to

[0049] ,

[0056] and

[0057] , wherein pembrolizumab is to be administered via intravenous administration once every two to four weeks.

[0140]

[0059] The pharmaceutical product according to any one of

[0040] to

[0049] , and

[0056] to

[0058] , wherein the anti-MUCl antibody-drug conjugate is to be administered via intravenous administration once every two to four weeks, and

[0141] wherein pembrolizumab is to be administered via intravenous administration once every two to four weeks.

[0142]

[0060] The pharmaceutical product according to any one of

[0040] to

[0052] , and

[0056] to

[0059] , wherein the anti-MUCl antibody-drug conjugate is to be administered via intravenous administration once every three weeks, and wherein pembrolizumab is to be administered via intravenous administration once every three weeks.

[0143] 15453442-1

[0061] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0144] wherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0145]

[0062] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 4 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0146] wherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0147]

[0063] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 5 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0148] wherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0149] 15453442-1

[0064] The pharmaceutical product according to any one of

[0015] to

[0032] , wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 6 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0150] wherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0151]

[0065] The pharmaceutical product according to any one of

[0015] to

[0064] , wherein the pharmaceutical product further comprises carboplatin or pemetrexed,

[0152] wherein carboplatin is to be administered at a dose of AUC 4 to 6 mg*min / ml or pemetrexed is to be administered at a dose of 400 to 600 mg / m2.

[0153]

[0066] The pharmaceutical product according to any one of

[0015] to

[0064] , wherein the pharmaceutical product further comprises carboplatin or pemetrexed,

[0154] wherein carboplatin is to be administered at a dose of about AUC 5 mg*min / ml or pemetrexed is to be administered at a dose of about 500 mg / m2.

[0155]

[0067] The pharmaceutical product according to

[0065] or

[0066] , wherein carboplatin is to be administered via intravenous administration once every three weeks or pemetrexed is to be administered via intravenous administration once every three weeks.

[0156] 15453442-1

[0068] The pharmaceutical product according to any one of

[0015] to

[0067] , wherein the pharmaceutical product further comprises carboplatin or pemetrexed,

[0157] wherein carboplatin is to be administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is to be administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0158]

[0069] The pharmaceutical product according to any one of

[0065] to

[0068] ,

[0159] wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg via intravenous administration once every three weeks,

[0160] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0161] wherein carboplatin is to be administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is to be administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0162]

[0070] The pharmaceutical product according to any one of

[0065] to

[0068] ,

[0163] wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 4 mg / kg via intravenous administration once every three weeks,

[0164] 15453442-1wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0165] wherein carboplatin is to be administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is to be administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0166]

[0071] The pharmaceutical product according to any one of

[0065] to

[0068] ,

[0167] wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 5 mg / kg via intravenous administration once every three weeks,

[0168] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0169] wherein carboplatin is to be administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is to be administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0170]

[0072] The pharmaceutical product according to any one of

[0065] to

[0068] ,

[0171] 15453442-1wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 6 mg / kg via intravenous administration once every three weeks,

[0172] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0173] wherein carboplatin is to be administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is to be administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0174]

[0073] The pharmaceutical product according to any one of

[0001] to

[0072] for treating a cancer.

[0175]

[0074] The pharmaceutical product according to

[0073] , wherein the cancer expresses TA-MUC1.

[0176]

[0075] The pharmaceutical product according to

[0073] or

[0074] , wherein the cancer is selected from the group consisting of ovary cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, stomach cancer, liver cancer, kidney cancer, blood cancer, endometrial cancer, thyroid gland cancer, leukemia, seminoma, melanoma, carcinoma, teratoma, lymphoma, sarcoma, mesothelioma, neuroblastoma, glioma, rectal cancer, adrenal cancer, skin cancer, brain cancer, uterine cervical cancer, intestinal tract cancer, intestine cancer, head and neck cancer, gastrointestinal cancer, lymph node cancer,

[0177] 15453442-1esophageal cancer, colorectal cancer, ear, nose and throat (ENT ) cancer, prostate cancer, urinary bladder cancer, uterine cancer, bile duct cancer, and their metastatic cancers.

[0178]

[0076] The pharmaceutical product according to any one of

[0073] to

[0075] , the cancer is lung cancer.

[0179]

[0077] The pharmaceutical product according to

[0076] , the lung cancer is non-small cell lung cancer (NSCLC ).

[0180]

[0078] The pharmaceutical product according to

[0077] , the NSCLC is locally advanced or metastatic NSCLC.

[0181]

[0079] A pharmaceutical product comprising an anti-MUCl antibody-drug conj ugate, for use in combination with an immune checkpoint inhibitor.

[0182]

[0080] The pharmaceutical product according to

[0079] , wherein the anti-MUCl antibody-drug conj ugate is as defined in any one of

[0002] to

[0014] .

[0183]

[0081] The pharmaceutical product according to

[0079] or

[0080] , wherein the immune checkpoint inhibitor is as defined in any one of

[0015] to

[0028] .

[0184]

[0082] The pharmaceutical product according to

[0080] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 1 mg / kg to 6 mg / kg.

[0185]

[0083] The pharmaceutical product according to

[0081] or

[0082] , wherein the immune checkpoint inhibitor is pembroli zumab and wherein pembroli zumab is administered at a dose of about 200 mg.

[0186] 15453442-1

[0084] The pharmaceutical product according to any one of

[0079] to

[0083] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 1 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg.

[0187]

[0085] The pharmaceutical product according to any one of

[0079] to

[0084] for treating a cancer.

[0188]

[0086] The pharmaceutical product according to

[0085] , wherein the cancer is defined in any one of

[0074] to

[0078] .

[0189]

[0087] The pharmaceutical product according to any one of

[0079] to

[0086] , wherein the pharmaceutical product is for use in combination with an anticancer agent.

[0190]

[0088] The pharmaceutical product according to

[0087] , wherein the anticancer agent is carboplatin or pemetrexed.

[0191]

[0089] The pharmaceutical product according to

[0088] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 1 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembroli zumab and wherein pembrolizumab is administered at a dose of about 200 mg, wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml or pemetrexed is administered at a dose of about 500 mg / m2.

[0192]

[0011]

[0193]

[0090] A method for treating a disease, comprising administering an anti-MUCl antibody-drug conj ugate and an

[0194] 15453442-1immune checkpoint inhibitor in combination to a subject in need of treatment.

[0195]

[0091] The treatment method according to

[0090] , wherein the anti-MUCl antibody is an anti-TA-MUCl antibody.

[0196]

[0092] The treatment method according to

[0090] or

[0091] , wherein the anti-MUCl antibody-drug conjugate is an anti-MUCl antibody-drug conjugate in which a drug-linker represented by the formula:

[0197] [ Formula 2 ]

[0198]

[0199] wherein A represents a connecting position to the anti-MUCl antibody

[0200] and the anti-MUCl antibody are conjugated via a thioether bond.

[0201]

[0093] The treatment method according to

[0090] or

[0091] , wherein the anti-MUCl antibody-drug conjugate comprises an anti-MUCl antibody and a drug-linker and is represented by the formula:

[0202] [ Formula 8 ]

[0203] 15453442-1

[0204]

[0205] wherein AB represents the anti-MUCl antibody, and the drug-linker and the anti-MUCl antibody are conjugated via a thioether bond; and wherein y represents the average number of units of the drug-linker conjugated per antibody.

[0206]

[0094] The treatment method according to any one of

[0090] to

[0093] , wherein the anti-MUCl antibody is defined in any one of

[0005] to

[0012] .

[0207]

[0095] The treatment method according to any one of

[0090] to

[0094] , wherein the average number of units of the drug-linker conjugated per antibody in the anti-MUCl antibody-drug conjugate is in the range of 7 to 8.

[0208]

[0096] The treatment method according to any one of

[0090] to

[0094] , wherein the average number of units of the drug-linker conjugated per antibody in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.

[0209]

[0097] The treatment method according to any one of

[0090] to

[0096] , wherein the immune checkpoint inhibitor is an anti-

[0210] 15453442-1PD- 1 antibody, an anti-PD-Ll antibody, or an anti-CTLA-4 antibody.

[0211]

[0098] The treatment method according to any one of

[0090] to

[0096] , wherein the immune checkpoint inhibitor is an anti-PD- 1 antibody.

[0212]

[0099] The treatment method according to

[0098] , wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, or clone RMP1-14.

[0213]

[0100] The treatment method according to

[0098] or

[0099] , wherein the anti-PD-1 antibody is nivolumab.

[0214]

[0101] The treatment method according to

[0098] or

[0099] , wherein the anti-PD-1 antibody is pembrolizumab.

[0215]

[0102] The treatment method according to any one of

[0090] to

[0096] , wherein the immune checkpoint inhibitor is an anti-PD-Ll antibody.

[0216]

[0103] The treatment method according to

[0102] , wherein the anti-PD-Ll antibody is atezolizumab, durvalumab, avelumab, or clone 10F.9G2.

[0217]

[0104] The treatment method according to

[0102] or

[0103] , wherein the anti-PD-Ll antibody is atezolizumab.

[0218]

[0105] The treatment method according to

[0102] or

[0103] , wherein the anti-PD-L1 antibody is durvalumab.

[0219]

[0106] The treatment method according to

[0102] or

[0103] , wherein the anti-PD-L1 antibody is avelumab.

[0220]

[0107] The treatment method according to any one of

[0090] to

[0096] , wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.

[0221] 15453442-1

[0108] The treatment method according to

[0107] , wherein the anti-CTLA-4 antibody is ipilimumab, tremelimumab, or clone 9H10.

[0222]

[0109] The treatment method according to

[0107] or

[0108] , wherein the anti-CTLA-4 antibody is ipilimumab.

[0223]

[0110] The treatment method according to

[0107] or

[0108] , wherein the anti-CTLA-4 antibody is tremelimumab.

[0224]

[0111] The treatment method according to any one of

[0090] to

[0110] , wherein the anti-MUCl antibody-drug conj ugate and the immune checkpoint inhibitor are contained as active ingredients in separate preparations and are administered simultaneously or at different times, or as a single preparation administered together.

[0225]

[0112] The treatment method according to any one of

[0090] to

[0111] , wherein the treatment method further comprises administering an anticancer agent.

[0226]

[0113] The treatment method according to

[0112] , wherein the anticancer agent is carboplatin or pemetrexed.

[0227]

[0114] The treatment method according to

[0112] or

[0113] , wherein the anticancer agent is administered simultaneously, separately, or continuously to the anti-MUCl antibody-drug conj ugate and the immune checkpoint inhibitor, or in a staggered manner.

[0228]

[0115] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 1 mg / kg to 6 mg / kg.

[0229] 15453442-1

[0116] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 3 mg / kg to 6 mg / kg.

[0230]

[0117] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg.

[0231]

[0118] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 3 mg / kg to 5 mg / kg.

[0232]

[0119] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg.

[0233]

[0120] The treatment method according to any one of

[0090] to

[0119] , wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 100 to 300 mg.

[0234]

[0121] The treatment method according to any one of

[0090] to

[0119] , wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg.

[0235]

[0122] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 1 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembroli zumab, and

[0236] 15453442-1wherein pembrolizumab is administered at a dose of about 100 to 300 mg.

[0237]

[0123] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 1 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0238] wherein pembrolizumab is administered at a dose of about 200 mg.

[0239]

[0124] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0240] wherein pembrolizumab is administered at a dose of about 200 mg.

[0241]

[0125] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 5 mg / kg, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0242] wherein pembrolizumab is administered at a dose of about 200 mg.

[0243]

[0126] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg,

[0244] 15453442-1wherein the immune checkpoint inhibitor is pembrolizumab, and

[0245] wherein pembrolizumab is administered at a dose of about 200 mg.

[0246]

[0127] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4 mg / kg,

[0247] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0248] wherein pembrolizumab is administered at a dose of about 200 mg.

[0249]

[0128] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5 mg / kg,

[0250] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0251] wherein pembrolizumab is administered at a dose of about 200 mg.

[0252]

[0129] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg,

[0253] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0254] wherein pembrolizumab is administered at a dose of about 200 mg.

[0255] 15453442-1

[0130] The treatment method according to any one of

[0111] to

[0129] , wherein the anti-MUCl antibody-drug conj ugate is administered via intravenous administration.

[0256]

[0131] The treatment method according to any one of

[0111] to

[0130] , wherein the anti-MUCl antibody-drug conj ugate is administered once every two to four weeks

[0257]

[0132] The treatment method according to any one of

[0111] to

[0131] , wherein the anti-MUCl antibody-drug conj ugate is administered via intravenous administration once every three weeks.

[0258]

[0133] The treatment method according to any one of

[0120] to

[0129] , wherein pembroli zumab is administered via intravenous administration.

[0259]

[0134] The treatment method according to any one of

[0120] to

[0129] and

[0133] , wherein pembroli zumab is administered once every two to four weeks.

[0260]

[0135] The treatment method according to any one of

[0120] to

[0129] ,

[0133] and

[0134] , wherein pembroli zumab is administered via intravenous administration once every two to four weeks.

[0261]

[0136] The treatment method according to any one of

[0120] to

[0129] , and

[0133] to

[0135] , wherein the anti-MUCl antibody-drug conj ugate is administered via intravenous administration once every two to four weeks, and wherein pembroli zumab is administered via intravenous administration once every two to four weeks.

[0262] 15453442-1

[0137] The treatment method according to any one of

[0120] to

[0136] , wherein the anti-MUCl antibody-drug conjugate is administered via intravenous administration once every three weeks, and

[0263] wherein pembrolizumab is administered via intravenous administration once every three weeks.

[0264]

[0138] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0265] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0266]

[0139] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0267] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0268]

[0140] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5 mg / kg via

[0269] 15453442-1intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0270] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0271]

[0141] The treatment method according to any one of

[0090] to

[0114] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0272] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0273]

[0142] The treatment method according to any one of

[0090] to

[0141] , wherein the treatment method further comprises administering carboplatin or pemetrexed,

[0274] wherein carboplatin is administered at a dose of AUC 4 to 6 mg*min / ml or pemetrexed is administered at a dose of 400 to 600 mg / m2.

[0275]

[0143] The treatment method according to any one of

[0090] to

[0141] , wherein the treatment method further comprises administering carboplatin or pemetrexed,

[0276] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml or pemetrexed is administered at a dose of about 500 mg / m2.

[0277] 15453442-1

[0144] The treatment method according to

[0142] or

[0143] , wherein carboplatin is administered via intravenous administration once every three weeks or pemetrexed is administered via intravenous administration once every three weeks.

[0278]

[0145] The treatment method according to any one of

[0090] to

[0144] , wherein the treatment method further comprises administering carboplatin or pemetrexed,

[0279] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0280]

[0146] The treatment method according to any one of

[0142] to

[0145] ,

[0281] wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg via intravenous administration once every three weeks,

[0282] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0283] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0284] 15453442-1

[0147] The treatment method according to any one of

[0142] to

[0145] ,

[0285] wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4 mg / kg via intravenous administration once every three weeks,

[0286] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0287] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0288]

[0148] The treatment method according to any one of

[0142] to

[0145] ,

[0289] wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5 mg / kg via intravenous administration once every three weeks,

[0290] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0291] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of

[0292] 15453442-1about 500 mg / m2via intravenous administration once every three weeks.

[0293]

[0149] The treatment method according to any one of

[0142] to

[0145] ,

[0294] wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 6 mg / kg via intravenous administration once every three weeks,

[0295] wherein the immune checkpoint inhibitor is pembroli zumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0296] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0297]

[0150] The treatment method according to any one of

[0090] to

[0149] , wherein the disease is a cancer.

[0298]

[0151] The treatment method according to

[0150] , wherein the cancer is as defined in any one of

[0074] to

[0078] .

[0299]

[0012]

[0300]

[0152] Use of an anti-MUCl antibody-drug conj ugate in the production of a drug for use in combination with an immune checkpoint inhibitor to treat a disease.

[0301]

[0153] The use according to

[0152] , wherein the anti-MUCl antibody is an anti-TA-MUCl antibody.

[0302] 15453442-1

[0154] The use according to

[0152] or

[0153] , wherein the anti-MUCl antibody-drug conjugate is an anti-MUCl antibody-drug conjugate in which a drug-linker represented by the formula:

[0303] [ Formula 3 ]

[0304]

[0305] wherein A represents a connecting position to the anti- MUCl antibody

[0306] and the anti-MUCl antibody are conj ugated via a thioether bond.

[0307]

[0155] The use according to

[0152] or

[0153] , wherein the anti-MUCl antibody-drug conj ugate comprises an anti-MUCl antibody and a drug-linker and is represented by the formula:

[0308] [ Formula 8 ]

[0309] 15453442-1

[0310]

[0311] wherein AB represents the anti-MUCl antibody, and the drug-linker and the anti-MUCl antibody are conjugated via a thioether bond; and wherein y represents the average number of units of the drug-linker conjugated per antibody.

[0312]

[0156] The use according to any one of

[0152] to

[0155] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising CDRH1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 1, CDRH2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 7, and CDRH3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain comprising CDRL1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 4, CDRL2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 5, and CDRL3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0313] 15453442-1

[0157] The use according to any one of

[0152] to

[0155] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising CDRH1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 1, CDRH2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 2, and CDRH3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain comprising CDRL1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 4, CDRL2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 5, and CDRL3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0314]

[0158] The use according to any one of

[0152] to

[0155] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 8 or SEQ ID NO: 10, and a light chain comprising a light chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 9.

[0315]

[0159] The use according to any one of

[0152] to

[0155] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 8, and a light chain comprising

[0316] 15453442-1a light chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 9.

[0317]

[0160] The use according to any one of

[0152] to

[0155] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 11 or SEQ ID NO: 13, and a light chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0318]

[0161] The use according to any one of

[0152] to

[0155] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 11, and a light chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0319]

[0162] The use according to

[0160] or

[0161] , wherein a lysine residue at the carboxyl terminus of the heavy chain of the anti-MUCl antibody is deleted.

[0320]

[0163] The use according to any one of

[0152] to

[0159] , wherein the heavy chain comprises or consists of the amino acid sequence of amino acid numbers 1 to 446 of SEQ ID NO: 11.

[0321]

[0164] The use according to any one of

[0152] to

[0163] , wherein the average number of units of the drug-linker conj ugated per antibody in the anti-MUCl antibody-drug conj ugate is in the range of 7 to 8.

[0322]

[0165] The use according to any one of

[0152] to

[0163] , wherein the average number of units of the drug-linker

[0323] 15453442-1conjugated per antibody in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.

[0324]

[0166] The use according to any one of

[0152] to

[0165] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0325]

[0167] The use according to any one of

[0152] to

[0165] , wherein the immune checkpoint inhibitor is an anti-PD- 1 antibody.

[0326]

[0168] The use according to

[0167] , wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, or clone RMP1-14.

[0327]

[0169] The use according to

[0167] or

[0168] , wherein the anti-PD-1 antibody is nivolumab.

[0328]

[0170] The use according to

[0167] or

[0168] , wherein the anti-PD-1 antibody is pembrolizumab.

[0329]

[0171] The use according to any one of

[0152] to

[0165] , wherein the immune checkpoint inhibitor is an anti-PD-L1 antibody.

[0330]

[0172] The use according to

[0171] , wherein the anti-PD-L1 antibody is atezolizumab, durvalumab, avelumab, or clone 10F.9G2.

[0331]

[0173] The use according to

[0171] or

[0172] , wherein the anti-PD-Ll antibody is atezolizumab.

[0332]

[0174] The use according to

[0171] or

[0172] , wherein the anti-PD-L1 antibody is durvalumab.

[0333]

[0175] The use according to

[0171] or

[0172] , wherein the anti-PD-L1 antibody is avelumab.

[0334] 15453442-1

[0176] The use according to any one of

[0152] to

[0165] , wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.

[0335]

[0177] The use according to

[0176] , wherein the anti-CTLA-4 antibody is ipilimumab, tremelimumab, or clone 9H10.

[0336]

[0178] The use according to

[0176] or

[0177] , wherein the anti-CTLA-4 antibody is ipilimumab.

[0337]

[0179] The use according to

[0176] or

[0177] , wherein the anti-CTLA-4 antibody is tremelimumab.

[0338]

[0180] The use according to any one of

[0152] to

[0179] , wherein the anti-MUCl antibody-drug conj ugate and the immune checkpoint inhibitor are contained as active ingredients in separate preparations and are administered simultaneously or at different times, or as a single preparation administered together.

[0339]

[0181] The use according to any one of

[0152] to

[0180] , wherein the anti-MUCl antibody-drug conj ugate and immune checkpoint inhibitor are used in combination with an anticancer agent.

[0340]

[0182] The use according to

[0181] , wherein the anticancer agent is carboplatin or pemetrexed.

[0341]

[0183] The use according to

[0181] or

[0182] , wherein the anticancer agent is administered simultaneously, separately, or continuously to the anti-MUCl antibodydrug conj ugate and the immune checkpoint inhibitor, or in a staggered manner.

[0342] 15453442-1

[0184] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 1 mg / kg to 6 mg / kg.

[0343]

[0185] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 3 mg / kg to 6 mg / kg.

[0344]

[0186] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg.

[0345]

[0187] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 3 mg / kg to 5 mg / kg.

[0346]

[0188] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg.

[0347]

[0189] The use according to any one of

[0152] to

[0188] , wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 100 to 300 mg.

[0348]

[0190] The use according to any one of

[0152] to

[0188] , wherein the immune checkpoint inhibitor is pembroli zumab and wherein pembroli zumab is administered at a dose of about 200 mg.

[0349] 15453442-1

[0191] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 1 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembroli zumab, and

[0350] wherein pembroli zumab is administered at a dose of about 100 to 300 mg.

[0351]

[0192] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 1 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembroli zumab, and

[0352] wherein pembroli zumab is administered at a dose of about 200 mg.

[0353]

[0193] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 3 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembroli zumab, and

[0354] wherein pembroli zumab is administered at a dose of about 200 mg.

[0355]

[0194] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 3 mg / kg to 5 mg / kg, wherein the immune checkpoint inhibitor is pembroli zumab, and

[0356] 15453442-1wherein pembroli zumab is administered at a dose of about 200 mg.

[0357]

[0195] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 3 mg / kg,

[0358] wherein the immune checkpoint inhibitor is pembroli zumab, and

[0359] wherein pembroli zumab is administered at a dose of about 200 mg.

[0360]

[0196] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 4 mg / kg,

[0361] wherein the immune checkpoint inhibitor is pembroli zumab, and

[0362] wherein pembroli zumab is administered at a dose of about 200 mg.

[0363]

[0197] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 5 mg / kg,

[0364] wherein the immune checkpoint inhibitor is pembroli zumab, and

[0365] wherein pembroli zumab is administered at a dose of about 200 mg.

[0366]

[0198] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conj ugate is administered at a dose of about 6 mg / kg,

[0367] 15453442-1wherein the immune checkpoint inhibitor is pembroli zumab, and

[0368] wherein pembroli zumab is administered at a dose of about 200 mg.

[0369]

[0199] The use according to any one of

[0180] to

[0198] , wherein the anti-MUCl antibody-drug conj ugate is administered via intravenous administration.

[0370]

[0200] The use according to any one of

[0180] to

[0199] , wherein the anti-MUCl antibody-drug conj ugate is administered once every two to four weeks

[0371]

[0201] The use according to any one of

[0180] to

[0200] , wherein the anti-MUCl antibody-drug conj ugate is administered via intravenous administration once every three weeks.

[0372]

[0202] The use according to any one of

[0189] to

[0198] , wherein pembroli zumab is administered via intravenous administration.

[0373]

[0203] The use according to any one of

[0189] to

[0198] and

[0202] , wherein pembroli zumab is administered once every two to four weeks.

[0374]

[0204] The use according to any one of

[0189] to

[0198] ,

[0202] and

[0203] , wherein pembroli zumab is administered via intravenous administration once every two to four weeks.

[0375]

[0205] The use according to any one of

[0189] to

[0198] , and

[0202] to

[0204] , wherein the anti-MUCl antibody-drug

[0376] 15453442-1conjugate is administered via intravenous administration once every two to four weeks, and

[0377] wherein pembrolizumab is administered via intravenous administration once every two to four weeks.

[0378]

[0206] The use according to any one of

[0189] to

[0205] , wherein the anti-MUCl antibody-drug conjugate is administered via intravenous administration once every three weeks, and

[0379] wherein pembrolizumab is administered via intravenous administration once every three weeks.

[0380]

[0207] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0381] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0382]

[0208] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0383] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0384] 15453442-1

[0209] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0385] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0386]

[0210] The use according to any one of

[0152] to

[0183] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0387] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0388]

[0211] The use according to any one of

[0152] to

[0210] , wherein the anti-MUCl antibody-drug conjugate and immune checkpoint inhibitor are used in combination with carboplatin or pemetrexed,

[0389] wherein carboplatin is administered at a dose of AUC 4 to 6 mg*min / ml or pemetrexed is administered at a dose of 400 to 600 mg / m2.

[0390]

[0212] The use according to any one of

[0152] to

[0210] , wherein the anti-MUCl antibody-drug conjugate and immune checkpoint inhibitor are used in combination with carboplatin or pemetrexed,

[0391] 15453442-1wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml or pemetrexed is administered at a dose of about 500 mg / m2.

[0392]

[0213] The use according to

[0211] or

[0212] , wherein carboplatin is administered via intravenous administration once every three weeks or pemetrexed is administered via intravenous administration once every three weeks.

[0393]

[0214] The use according to any one of

[0152] to

[0213] , wherein the anti-MUCl antibody-drug conjugate and immune checkpoint inhibitor are used in combination with carboplatin or pemetrexed,

[0394] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0395]

[0215] The use according to any one of

[0211] to

[0214] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg via intravenous administration once every three weeks,

[0396] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0397] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every

[0398] 15453442-1three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0399]

[0216] The use according to any one of

[0211] to

[0214] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4 mg / kg via intravenous administration once every three weeks,

[0400] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0401] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0402]

[0217] The use according to any one of

[0211] to

[0214] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5 mg / kg via intravenous administration once every three weeks,

[0403] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0404] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of

[0405] 15453442-1about 500 mg / m2via intravenous administration once every three weeks.

[0406]

[0218] The use according to any one of

[0211] to

[0214] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg via intravenous administration once every three weeks,

[0407] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0408] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0409]

[0219] The use according to any one of

[0152] to

[0218] , wherein the disease is a cancer.

[0410]

[0220] The use according to

[0219] , wherein the cancer expresses TA-MUC1.

[0411]

[0221] The use according to

[0219] or

[0220] , wherein the cancer is selected from the group consisting of ovary cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, stomach cancer, liver cancer, kidney cancer, blood cancer, endometrial cancer, thyroid gland cancer, leukemia, seminoma, melanoma, carcinoma, teratoma, lymphoma, sarcoma, mesothelioma, neuroblastoma, glioma, rectal cancer, adrenal cancer, skin cancer, brain

[0412] 15453442-1cancer, uterine cervical cancer, intestinal tract cancer, intestine cancer, head and neck cancer, gastrointestinal cancer, lymph node cancer, esophageal cancer, colorectal cancer, ear, nose and throat (ENT) cancer, prostate cancer, urinary bladder cancer, uterine cancer, bile duct cancer, and their metastatic cancers.

[0413]

[0222] The use according to any one of

[0219] to

[0221] , the cancer is lung cancer.

[0414]

[0223] The use according to

[0222] , the lung cancer is non-small cell lung cancer (NSCLC).

[0415]

[0224] The use according to

[0223] , the NSCLC is locally advanced or metastatic NSCLC.

[0416]

[0013]

[0417]

[0225] Use of an immune checkpoint inhibitor in the production of a drug for use in combination with an anti-MUC1 antibody-drug conjugate to treat a disease.

[0418]

[0226] The use according to

[0225] , wherein the anti-MUCl antibody is an anti-TA-MUCl antibody.

[0419]

[0227] The use according to

[0225] or

[0226] , wherein the anti-MUCl antibody-drug conjugate is an anti-MUCl antibody-drug conjugate in which a drug-linker represented by the formula:

[0420] [Formula 4 ]

[0421] 15453442-1

[0422]

[0423] OH 0 wherein A represents a connecting position to the anti- MUCl antibody

[0424] and the anti-MUCl antibody are conjugated via a thioether bond.

[0425]

[0228] The use according to

[0225] or

[0226] , wherein the anti-MUCl antibody-drug conjugate comprises an anti-MUCl antibody and a drug-linker and is represented by the formula:

[0426] [Formula 8 ]

[0427]

[0428] wherein AB represents the anti-MUCl antibody, and the drug-linker and the anti-MUCl antibody are conjugated via

[0429] 15453442-1a thioether bond; and wherein y represents the average number of units of the drug-linker conjugated per antibody.

[0430]

[0229] The use according to any one of

[0225] to

[0228] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising CDRH1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 1, CDRH2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 7, and CDRH3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain comprising CDRL1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 4, CDRL2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 5, and CDRL3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0431]

[0230] The use according to any one of

[0225] to

[0228] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising CDRH1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 1, CDRH2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 2, and CDRH3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain comprising CDRL1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 4, CDRL2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 5, and CDRL3

[0432] 15453442-1comprising or consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0433]

[0231] The use according to any one of

[0225] to

[0228] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 8 or SEQ ID NO: 10, and a light chain comprising a light chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 9.

[0434]

[0232] The use according to any one of

[0225] to

[0228] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 8, and a light chain comprising a light chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 9.

[0435]

[0233] The use according to any one of

[0225] to

[0228] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 11 or SEQ ID NO: 13, and a light chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0436]

[0234] The use according to any one of

[0225] to

[0228] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 11, and a light chain

[0437] 15453442-1comprising or consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0438]

[0235] The use according to

[0233] or

[0234] , wherein a lysine residue at the carboxyl terminus of the heavy chain of the anti-MUCl antibody is deleted.

[0439]

[0236] The use according to any one of

[0225] to

[0232] , wherein the heavy chain comprises or consists of the amino acid sequence of amino acid numbers 1 to 446 of SEQ ID NO: 11.

[0440]

[0237] The use according to any one of

[0225] to

[0236] , wherein the average number of units of the drug-linker conjugated per antibody in the anti-MUCl antibody-drug conjugate is in the range of 7 to 8.

[0441]

[0238] The use according to any one of

[0225] to

[0236] , wherein the average number of units of the drug-linker conjugated per antibody in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.

[0442]

[0239] The use according to any one of

[0225] to

[0238] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-Ll antibody, or an anti-CTLA-4 antibody.

[0443]

[0240] The use according to any one of

[0225] to

[0238] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0444]

[0241] The use according to

[0240] , wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, or clone RMP1-14.

[0445] 15453442-1

[0242] The use according to

[0240] or

[0241] , wherein the anti-PD-1 antibody is nivolumab.

[0446]

[0243] The use according to

[0240] or

[0241] , wherein the anti-PD-1 antibody is pembrolizumab.

[0447]

[0244] The use according to any one of

[0225] to

[0238] , wherein the immune checkpoint inhibitor is an anti-PD-Ll antibody.

[0448]

[0245] The use according to

[0244] , wherein the anti-PD-Ll antibody is atezolizumab, durvalumab, avelumab, or clone 10F.9G2.

[0449]

[0246] The use according to

[0244] or

[0245] , wherein the anti-PD-Ll antibody is atezolizumab.

[0450]

[0247] The use according to

[0244] or

[0245] , wherein the anti-PD-L1 antibody is durvalumab.

[0451]

[0248] The use according to

[0244] or

[0245] , wherein the anti-PD-L1 antibody is avelumab.

[0452]

[0249] The use according to any one of

[0225] to

[0238] , wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.

[0453]

[0250] The use according to

[0249] , wherein the anti-CTLA-4 antibody is ipilimumab, tremelimumab, or clone 9H10.

[0454]

[0251] The use according to

[0249] or

[0250] , wherein the anti-CTLA-4 antibody is ipilimumab.

[0455]

[0252] The use according to

[0249] or

[0250] , wherein the anti-CTLA-4 antibody is tremelimumab.

[0456]

[0253] The use according to any one of

[0225] to

[0252] , wherein the anti-MUCl antibody-drug conj ugate and the

[0457] 15453442-1immune checkpoint inhibitor are contained as active ingredients in separate preparations and are administered simultaneously or at different times, or as a single preparation administered together.

[0458]

[0254] The use according to any one of

[0225] to

[0253] , wherein the immune checkpoint inhibitor and anti-MUCl antibody-drug conjugate are used in combination with an anticancer agent.

[0459]

[0255] The use according to

[0254] , wherein the anticancer agent is carboplatin or pemetrexed.

[0460]

[0256] The use according to

[0254] or

[0255] , wherein the anticancer agent is administered simultaneously, separately, or continuously to the anti-MUCl antibodydrug conjugate and the immune checkpoint inhibitor, or in a staggered manner.

[0461]

[0257] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 1 mg / kg to 6 mg / kg.

[0462]

[0258] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 6 mg / kg.

[0463]

[0259] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg.

[0464] 15453442-1

[0260] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 5 mg / kg.

[0465]

[0261] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg.

[0466]

[0262] The use according to any one of

[0225] to

[0261] , wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 100 to 300 mg.

[0467]

[0263] The use according to any one of

[0225] to

[0261] , wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg.

[0468]

[0264] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 1 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0469] wherein pembrolizumab is administered at a dose of about 100 to 300 mg.

[0470]

[0265] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 1 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0471] 15453442-1wherein pembrolizumab is administered at a dose of about 200 mg.

[0472]

[0266] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0473] wherein pembrolizumab is administered at a dose of about 200 mg.

[0474]

[0267] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 5 mg / kg, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0475] wherein pembrolizumab is administered at a dose of about 200 mg.

[0476]

[0268] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg,

[0477] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0478] wherein pembrolizumab is administered at a dose of about 200 mg.

[0479]

[0269] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4 mg / kg,

[0480] 15453442-1wherein the immune checkpoint inhibitor is pembrolizumab, and

[0481] wherein pembrolizumab is administered at a dose of about 200 mg.

[0482]

[0270] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5 mg / kg,

[0483] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0484] wherein pembrolizumab is administered at a dose of about 200 mg.

[0485]

[0271] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg,

[0486] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0487] wherein pembrolizumab is administered at a dose of about 200 mg.

[0488]

[0272] The use according to any one of

[0253] to

[0271] , wherein the anti-MUCl antibody-drug conjugate is administered via intravenous administration.

[0489]

[0273] The use according to any one of

[0253] to

[0272] , wherein the anti-MUCl antibody-drug conjugate is administered once every two to four weeks

[0490]

[0274] The use according to any one of

[0253] to

[0273] , wherein the anti-MUCl antibody-drug conjugate is

[0491] 15453442-1administered via intravenous administration once every three weeks.

[0492]

[0275] The use according to any one of

[0262] to

[0271] , wherein pembrolizumab is administered via intravenous administration.

[0493]

[0276] The use according to any one of

[0262] to

[0271] and

[0275] , wherein pembrolizumab is administered once every two to four weeks.

[0494]

[0277] The use according to any one of

[0262] to

[0271] ,

[0275] and

[0276] , wherein pembrolizumab is administered via intravenous administration once every two to four weeks.

[0495]

[0278] The use according to any one of

[0262] to

[0271] , and

[0275] to

[0277] , wherein the anti-MUCl antibody-drug conjugate is administered via intravenous administration once every two to four weeks, and

[0496] wherein pembrolizumab is administered via intravenous administration once every two to four weeks.

[0497]

[0279] The use according to any one of

[0262] to

[0271] , and

[0275] to

[0278] , wherein the anti-MUCl antibody-drug conjugate is administered via intravenous administration once every three weeks, and

[0498] wherein pembrolizumab is administered via intravenous administration once every three weeks.

[0499]

[0280] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg via intravenous

[0500] 15453442-1administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0501] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0502]

[0281] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0503] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0504]

[0282] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0505] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0506]

[0283] The use according to any one of

[0225] to

[0256] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0507] 15453442-1wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0508]

[0284] The use according to any one of

[0225] to

[0283] , wherein the immune checkpoint inhibitor and anti-MUCl antibody-drug conjugate are used in combination with carboplatin or pemetrexed,

[0509] wherein carboplatin is administered at a dose of AUC 4 to 6 mg*min / ml or pemetrexed is administered at a dose of 400 to 600 mg / m2.

[0510]

[0285] The use according to any one of

[0225] to

[0283] , wherein the immune checkpoint inhibitor and anti-MUCl antibody-drug conjugate are used in combination with carboplatin or pemetrexed,

[0511] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml or pemetrexed is administered at a dose of about 500 mg / m2.

[0512]

[0286] The use according to

[0284] or

[0285] , wherein carboplatin is administered via intravenous administration once every three weeks or pemetrexed is administered via intravenous administration once every three weeks.

[0513]

[0287] The use according to any one of

[0225] to

[0286] , wherein the immune checkpoint inhibitor and anti-MUCl antibody-drug conjugate are used in combination with carboplatin or pemetrexed,

[0514] 15453442-1wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0515]

[0288] The use according to any one of

[0284] to

[0287] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg via intravenous administration once every three weeks,

[0516] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0517] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0518]

[0289] The use according to any one of

[0284] to

[0287] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4 mg / kg via intravenous administration once every three weeks,

[0519] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0520] 15453442-1wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0521]

[0290] The use according to any one of

[0284] to

[0287] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5 mg / kg via intravenous administration once every three weeks,

[0522] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0523] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0524]

[0291] The use according to any one of

[0284] to

[0287] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg via intravenous administration once every three weeks,

[0525] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0526] 15453442-1wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0527]

[0292] The use according to any one of

[0225] to

[0291] , wherein the disease is a cancer.

[0528]

[0293] The use according to

[0292] , wherein the cancer is as defined in any one of

[0074] to

[0078] .

[0529]

[0014]

[0530]

[0294] An anti-MUCl antibody-drug conjugate for use in combination with an immune checkpoint inhibitor in the treatment of a disease.

[0531]

[0295] An anti-MUCl antibody-drug conjugate for use in the treatment of a disease, wherein the immune checkpoint inhibitor is used in combination with an immune checkpoint inhibitor.

[0532]

[0296] The anti-MUCl antibody-drug conjugate according to

[0294] or

[0295] , wherein the anti-MUCl antibody is an anti-TA-MUCl antibody.

[0533]

[0297] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0296] , wherein the anti-MUCl antibody-drug conjugate is an anti-MUCl antibody-drug conjugate in which a drug-linker represented by the formula:

[0534] [Formula 5]

[0535] 15453442-1

[0536]

[0537] OH 0 wherein A represents a connecting position to the anti- MUCl antibody

[0538] and the anti-MUCl antibody are conjugated via a thioether bond.

[0539]

[0298] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0296] , wherein the anti-MUCl antibody-drug conjugate comprises an anti-MUCl antibody and a drug-linker and is represented by the formula:

[0540] [Formula 8 ]

[0541]

[0542] wherein AB represents the anti-MUCl antibody, and the drug-linker and the anti-MUCl antibody are conjugated via

[0543] 15453442-1a thioether bond; and wherein y represents the average number of units of the drug-linker conjugated per antibody.

[0544]

[0299] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0298] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising CDRH1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 1, CDRH2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 7, and CDRH3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain comprising CDRL1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 4, CDRL2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 5, and CDRL3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0545]

[0300] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0298] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising CDRH1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 1, CDRH2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 2, and CDRH3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain comprising CDRL1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 4, CDRL2

[0546] 15453442-1comprising or consisting of the amino acid sequence represented by SEQ ID NO: 5, and CDRL3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0547]

[0301] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0298] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 8 or SEQ ID NO: 10, and a light chain comprising a light chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 9.

[0548]

[0302] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0298] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising a heavy chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 8, and a light chain comprising a light chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 9.

[0549]

[0303] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0298] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 11 or SEQ ID NO: 13, and a light chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0550] 15453442-1

[0304] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0298] , wherein the anti-MUCl antibody is an antibody comprising a heavy chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 11, and a light chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0551]

[0305] The anti-MUCl antibody-drug conjugate according to

[0303] or

[0304] , wherein a lysine residue at the carboxyl terminus of the heavy chain of the anti-MUCl antibody is deleted.

[0552]

[0306] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0302] , wherein the heavy chain comprises or consists of the amino acid sequence of amino acid numbers 1 to 446 of SEQ ID NO: 11.

[0553]

[0307] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0306] , wherein the average number of units of the drug-linker conjugated per antibody in the anti-MUCl antibody-drug conjugate is in the range of 7 to 8.

[0554]

[0308] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0306] , wherein the average number of units of the drug-linker conjugated per antibody in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.

[0555]

[0309] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0308] , wherein the immune checkpoint

[0556] 15453442-1inhibitor is an anti-PD-1 antibody, an anti-PD-Ll antibody, or an anti-CTLA-4 antibody.

[0557]

[0310] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0308] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0558]

[0311] The anti-MUCl antibody-drug conjugate according to

[0310] , wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, or clone RMP1-14.

[0559]

[0312] The anti-MUCl antibody-drug conjugate according to

[0310] or

[0311] , wherein the anti-PD-1 antibody is nivolumab.

[0560]

[0313] The anti-MUCl antibody-drug conjugate according to

[0310] or

[0311] , wherein the anti-PD-1 antibody is pembrolizumab.

[0561]

[0314] The anti-MUCl antibody-drug conjugate or the pharmaceutical product according to any one of

[0294] to

[0308] , wherein the immune checkpoint inhibitor is an anti-PD-Ll antibody.

[0562]

[0315] The anti-MUCl antibody-drug conjugate according to

[0314] , wherein the anti-PD-Ll antibody is atezolizumab, durvalumab, avelumab, or clone 10F.9G2.

[0563]

[0316] The anti-MUCl antibody-drug conjugate according to

[0314] or

[0315] , wherein the anti-PD-Ll antibody is atezolizumab.

[0564]

[0317] The anti-MUCl antibody-drug conjugate according to

[0314] or

[0315] , wherein the anti-PD-L1 antibody is durvalumab.

[0565] 15453442-1

[0318] The anti-MUCl antibody-drug conjugate according to

[0314] or

[0315] , wherein the anti-PD-L1 antibody is avelumab.

[0566]

[0319] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0308] , wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.

[0567]

[0320] The anti-MUCl antibody-drug conjugate according to

[0319] , wherein the anti-CTLA-4 antibody is ipilimumab, tremelimumab, or clone 9H10.

[0568]

[0321] The anti-MUCl antibody-drug conjugate according to

[0319] or

[0320] , wherein the anti-CTLA-4 antibody is ipilimumab.

[0569]

[0322] The anti-MUCl antibody-drug conjugate according to

[0319] or

[0320] , wherein the anti-CTLA-4 antibody is tremelimumab.

[0570]

[0323] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0322] , wherein the anti-MUCl antibody-drug conjugate and the immune checkpoint inhibitor are contained as active ingredients in separate preparations and are administered simultaneously or at different times, or as a single preparation administered together.

[0571]

[0324] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0323] , wherein the anti-MUCl antibody-drug conjugate and immune checkpoint inhibitor are used in combination with an anticancer agent.

[0572] 15453442-1

[0325] The anti-MUCl antibody-drug conjugate according to

[0324] , wherein the anticancer agent is carboplatin or pemetrexed.

[0573]

[0326] The anti-MUCl antibody-drug conjugate according to

[0324] or

[0325] , wherein the anticancer agent is administered simultaneously, separately, or continuously to the anti-MUCl antibody-drug conjugate and the immune checkpoint inhibitor, or in a staggered manner.

[0574]

[0327] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 1 mg / kg to 6 mg / kg.

[0575]

[0328] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 6 mg / kg.

[0576]

[0329] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg.

[0577]

[0330] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 5 mg / kg.

[0578]

[0331] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl

[0579] 15453442-1antibody-drug conjugate is administered at a dose of about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg.

[0580]

[0332] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0331] , wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 100 to 300 mg.

[0581]

[0333] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0331] , wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg.

[0582]

[0334] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 1 mg / kg to 6 mg / kg,

[0583] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0584] wherein pembrolizumab is administered at a dose of about 100 to 300 mg.

[0585]

[0335] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 1 mg / kg to 6 mg / kg,

[0586] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0587] wherein pembrolizumab is administered at a dose of about 200 mg.

[0588] 15453442-1

[0336] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 6 mg / kg,

[0589] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0590] wherein pembrolizumab is administered at a dose of about 200 mg.

[0591]

[0337] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 5 mg / kg,

[0592] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0593] wherein pembrolizumab is administered at a dose of about 200 mg.

[0594]

[0338] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg,

[0595] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0596] wherein pembrolizumab is administered at a dose of about 200 mg.

[0597]

[0339] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl

[0598] 15453442-1antibody-drug conjugate is administered at a dose of about 4 mg / kg,

[0599] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0600] wherein pembrolizumab is administered at a dose of about 200 mg.

[0601]

[0340] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5 mg / kg,

[0602] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0603] wherein pembrolizumab is administered at a dose of about 200 mg.

[0604]

[0341] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg,

[0605] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0606] wherein pembrolizumab is administered at a dose of about 200 mg.

[0607]

[0342] The anti-MUCl antibody-drug conjugate according to any one of

[0323] to

[0341] , wherein the anti-MUCl antibody-drug conjugate is administered via intravenous administration.

[0608] 15453442-1

[0343] The anti-MUCl antibody-drug conjugate according to any one of

[0323] to

[0342] , wherein the anti-MUCl antibody-drug conjugate is administered once every two to four weeks

[0609]

[0344] The anti-MUCl antibody-drug conjugate according to any one of

[0323] to

[0343] , wherein the anti-MUCl antibody-drug conjugate is administered via intravenous administration once every three weeks.

[0610]

[0345] The anti-MUCl antibody-drug conjugate according to any one of

[0332] to

[0341] , wherein pembrolizumab is administered via intravenous administration.

[0611]

[0346] The anti-MUCl antibody-drug conjugate according to any one of

[0332] to

[0341] and

[0345] , wherein pembrolizumab is administered once every two to four weeks.

[0612]

[0347] The anti-MUCl antibody-drug conjugate according to any one of

[0332] to

[0341] ,

[0345] and

[0346] , wherein pembrolizumab is administered via intravenous administration once every two to four weeks.

[0613]

[0348] The anti-MUCl antibody-drug conjugate according to any one of

[0332] to

[0341] , and

[0345] to

[0347] , wherein the anti-MUCl antibody-drug conjugate is administered via intravenous administration once every two to four weeks, and

[0614] wherein pembrolizumab is administered via intravenous administration once every two to four weeks.

[0615] 15453442-1

[0349] The anti-MUCl antibody-drug conjugate according to any one of

[0332] to

[0341] , and

[0345] to

[0348] , wherein the anti-MUCl antibody-drug conjugate is administered via intravenous administration once every three weeks, and wherein pembrolizumab is administered via intravenous administration once every three weeks.

[0616]

[0350] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0617] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0618]

[0351] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0619] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0620]

[0352] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of

[0621] 15453442-1about 5 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0622] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0623]

[0353] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0326] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0624] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0625]

[0354] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0353] , wherein the anti-MUCl antibody-drug conjugate and immune checkpoint inhibitor are used in combination with carboplatin or pemetrexed, wherein carboplatin is administered at a dose of AUC 4 to 6 mg*min / ml or pemetrexed is administered at a dose of 400 to 600 mg / m2.

[0626]

[0355] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0353] , wherein the anti-MUCl antibody-drug conjugate and immune checkpoint inhibitor are used in combination with carboplatin or pemetrexed,

[0627] 15453442-1wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml or pemetrexed is administered at a dose of about 500 mg / m2.

[0628]

[0356] The anti-MUCl antibody-drug conjugate according to

[0354] or

[0355] , wherein carboplatin is administered via intravenous administration once every three weeks or pemetrexed is administered via intravenous administration once every three weeks.

[0629]

[0357] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0356] , wherein the anti-MUCl antibody-drug conjugate and immune checkpoint inhibitor are used in combination with carboplatin or pemetrexed, wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0630]

[0358] The anti-MUCl antibody-drug conjugate according to any one of

[0354] to

[0357] ,

[0631] wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg via intravenous administration once every three weeks,

[0632] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0633] 15453442-1wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0634]

[0359] The anti-MUCl antibody-drug conjugate according to any one of

[0354] to

[0357] ,

[0635] wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4 mg / kg via intravenous administration once every three weeks,

[0636] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0637] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0638]

[0360] The anti-MUCl antibody-drug conjugate according to any one of

[0354] to

[0357] ,

[0639] wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5 mg / kg via intravenous administration once every three weeks,

[0640] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of

[0641] 15453442-1about 200 mg via intravenous administration once every three weeks, and

[0642] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0643]

[0361] The anti-MUCl antibody-drug conjugate according to any one of

[0354] to

[0357] ,

[0644] wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg via intravenous administration once every three weeks,

[0645] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0646] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0647]

[0362] The anti-MUCl antibody-drug conjugate according to any one of

[0294] to

[0361] , wherein the disease is a cancer.

[0648]

[0363] The anti-MUCl antibody-drug conjugate according to

[0362] , wherein the cancer is defined in any one of

[0074] to

[0078] .

[0649] 15453442-1

[0015]

[0650]

[0364] An immune checkpoint inhibitor for use in combination with an anti-MUCl antibody-drug conjugate in the treatment of a disease.

[0651]

[0365] An immune checkpoint inhibitor for use in the treatment of a disease, wherein the immune checkpoint inhibitor is used in combination with an anti-MUCl antibody-drug conjugate.

[0652]

[0016]

[0653]

[0366] A kit comprising an anti-MUCl antibody-drug conjugate and an immune checkpoint inhibitor.

[0654]

[0367] The kit according to

[0366] , wherein the anti-MUCl antibody is an anti-TA-MUCl antibody.

[0655]

[0368] The kit according to

[0366] or

[0367] , wherein the anti-MUCl antibody-drug conjugate is an anti-MUCl antibody-drug conjugate in which a drug-linker represented by the formula:

[0656] [Formula 1 ]

[0657]

[0658] 15453442-1wherein A represents a connecting position to the anti-MUC1 antibody

[0659] and the anti-MUCl antibody are conjugated via a thioether bond.

[0660]

[0369] The kit according to

[0366] or

[0367] , wherein the anti-MUCl antibody-drug conjugate comprises an anti-MUCl antibody and a drug-linker and is represented by the formula:

[0661] [Formula 8 ]

[0662] OH W

[0663]

[0664] wherein AB represents the anti-MUCl antibody, and the drug-linker and the anti-MUCl antibody are conjugated via a thioether bond; and wherein y represents the average number of units of the drug-linker conjugated per antibody.

[0665]

[0370] The kit according to any one of

[0366] to

[0369] , wherein the anti-MUCl antibody is as defined in any one of [5] to

[0012] .

[0666]

[0371] The kit according to any one of

[0366] to

[0370] , wherein the average number of units of the drug-linker

[0667] 15453442-1conjugated per antibody in the anti-MUCl antibody-drug conjugate is in the range of 7 to 8.

[0668]

[0372] The kit according to any one of

[0366] to

[0370] , wherein the average number of units of the drug-linker conjugated per antibody in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.

[0669]

[0373] The kit according to any one of

[0366] to

[0372] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-Ll antibody, or an anti-CTLA-4 antibody.

[0670]

[0374] The kit according to any one of

[0366] to

[0373] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

[0671]

[0375] The kit according to

[0374] , wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, or clone RMP1-14.

[0672]

[0376] The kit according to

[0373] or

[0374] , wherein the anti-PD-1 antibody is nivolumab.

[0673]

[0377] The kit according to

[0373] or

[0374] , wherein the anti-PD-1 antibody is pembrolizumab.

[0674]

[0378] The kit according to any one of

[0366] to

[0373] , wherein the immune checkpoint inhibitor is an anti-PD-Ll antibody.

[0675]

[0379] The kit according to

[0378] , wherein the anti-PD-Ll antibody is atezolizumab, durvalumab, avelumab, or clone 10F. 9G2.

[0676]

[0380] The kit according to

[0378] or

[0379] , wherein the anti-PD-Ll antibody is atezolizumab.

[0677] 15453442-1

[0381] The kit according to

[0378] or

[0379] , wherein the anti-PD-L1 antibody is durvalumab.

[0678]

[0382] The kit according to

[0378] or

[0379] , wherein the anti-PD-L1 antibody is avelumab.

[0679]

[0383] The kit according to any one of

[0366] to

[0373] , wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.

[0680]

[0384] The kit according to

[0383] , wherein the anti-CTLA-4 antibody is ipilimumab, tremelimumab, or clone 9H10.

[0681]

[0385] The kit according to

[0383] or

[0384] , wherein the anti-CTLA-4 antibody is ipilimumab.

[0682]

[0386] The kit according to

[0383] or

[0384] , wherein the anti-CTLA-4 antibody is tremelimumab.

[0683]

[0387] The kit according to any one of

[0366] to

[0386] , wherein the anti-MUCl antibody-drug conj ugate and the immune checkpoint inhibitor are contained as active ingredients in separate preparations and are administered simultaneously or at different times, or as a single preparation administered together.

[0684]

[0388] The kit according to any one of

[0366] to

[0387] , wherein the kit further comprises an anticancer agent.

[0685]

[0389] The kit according to

[0388] , wherein the anticancer agent is carboplatin or pemetrexed.

[0686]

[0390] The kit according to

[0388] or

[0389] , wherein the anticancer agent is administered simultaneously, separately, or continuously to the anti-MUCl antibody-

[0687] 15453442-1drug conj ugate and the immune checkpoint inhibitor, or in a staggered manner.

[0688]

[0391] The kit according to any one of

[0366] to

[0390] , wherein the kit comprises a dosage form of the anti-MUCl antibody-drug conj ugate and a dosage form of the immune checkpoint inhibitor.

[0689]

[0392] The kit according to any one of

[0366] to

[0391] , wherein the kit further comprises a dosage form of carboplatin or pemetrexed.

[0690]

[0393] The kit according to any one of

[0366] to

[0392] , for treating a cancer.

[0691]

[0394] The kit according to

[0393] , wherein the cancer is as defined in any one of

[0074] to

[0078] .

[0692]

[0395] A pharmaceutical combination of an anti-MUCl antibody-drug conj ugate and an immune checkpoint inhibitor, for use in the treatment of cancer.

[0693]

[0396] The pharmaceutical combination according to

[0395] , wherein the anti-MUCl antibody-drug conj ugate is as defined in any one of

[0002] to

[0014] and / or the immune checkpoint inhibitor is as defined in any one of

[0015] to

[0028] , and / or wherein the cancer is as defined in any one of

[0074] to

[0078] .

[0694]

[0397] The pharmaceutical combination according to any one of

[0395] and

[0396] , wherein the pharmaceutical combination further comprises an anticancer agent.

[0695] 15453442-1

[0398] The pharmaceutical combination according to

[0397] , wherein the anticancer agent is carboplatin or pemetrexed.

[0696]

[0399] Use of an anti-MUCl antibody-drug conjugate and an immune checkpoint inhibitor for the manufacture of a medicament for treating a cancer.

[0697]

[0400] The use according to

[0399] , wherein the anti-MUCl antibody-drug conjugate is as defined in any one of

[0002] to

[0014] and / or the immune checkpoint inhibitor is as defined in any one of

[0015] to

[0028] , and / or wherein the cancer is as defined in any one of

[0074] to

[0078] .

[0698]

[0401] The use according to

[0399] or

[0400] , wherein the anti-MUCl antibody-drug conjugate and the immune checkpoint inhibitor are contained as active ingredients in separate preparations and are administered simultaneously or at different times, or as a single preparation administered together.

[0699]

[0402] The use according to any one of

[0399] to

[0401] , wherein the anti-MUCl antibody-drug conjugate and immune checkpoint inhibitor are used in combination with an anticancer agent.

[0700]

[0403] The use according to

[0402] , wherein the anticancer agent is carboplatin or pemetrexed.

[0701]

[0404] The use according to

[0402] or

[0403] , wherein the anticancer agent is administered simultaneously, separately, or continuously to the anti-MUCl antibody-

[0702] 15453442-1drug conjugate and the immune checkpoint inhibitor, or in a staggered manner.

[0703]

[0405] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 1 mg / kg to 6 mg / kg.

[0704]

[0406] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 6 mg / kg.

[0705]

[0407] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg.

[0706]

[0408] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 5 mg / kg.

[0707]

[0409] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg.

[0708]

[0410] The use according to any one of

[0399] to

[0409] , wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 100 to 300 mg.

[0709]

[0411] The use according to any one of

[0399] to

[0409] , wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg.

[0710] 15453442-1

[0412] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 1 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0711] wherein pembrolizumab is administered at a dose of about 100 to 300 mg.

[0712]

[0413] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 1 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0713] wherein pembrolizumab is administered at a dose of about 200 mg.

[0714]

[0414] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 6 mg / kg, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0715] wherein pembrolizumab is administered at a dose of about 200 mg.

[0716]

[0415] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg to 5 mg / kg, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0717] 15453442-1wherein pembrolizumab is administered at a dose of about 200 mg.

[0718]

[0416] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3mg / kg,

[0719] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0720] wherein pembrolizumab is administered at a dose of about 200 mg.

[0721]

[0417] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4mg / kg,

[0722] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0723] wherein pembrolizumab is administered at a dose of about 200 mg.

[0724]

[0418] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5mg / kg,

[0725] wherein the immune checkpoint inhibitor is pembrolizumab, and

[0726] wherein pembrolizumab is administered at a dose of about 200 mg.

[0727]

[0419] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg,

[0728] 15453442-1wherein the immune checkpoint inhibitor is pembrolizumab, and

[0729] wherein pembrolizumab is administered at a dose of about 200 mg.

[0730]

[0420] The use according to any one of

[0401] to

[0419] , wherein the anti-MUCl antibody-drug conjugate is administered via intravenous administration.

[0731]

[0421] The use according to any one of

[0401] to

[0420] , wherein the anti-MUCl antibody-drug conjugate is administered once every two to four weeks

[0732]

[0422] The use according to any one of

[0401] to

[0421] , wherein the anti-MUCl antibody-drug conjugate is administered via intravenous administration once every three weeks.

[0733]

[0423] The use according to any one of

[0410] to

[0419] , wherein pembrolizumab is administered via intravenous administration.

[0734]

[0424] The use according to any one of

[0410] to

[0419] and

[0423] , wherein pembrolizumab is administered once every two to four weeks.

[0735]

[0425] The use according to any one of

[0410] to

[0419] ,

[0423] and

[0424] , wherein pembrolizumab is administered via intravenous administration once every two to four weeks.

[0736]

[0426] The use according to any one of

[0410] to

[0419] , and

[0423] to

[0425] , wherein the anti-MUCl antibody-drug

[0737] 15453442-1conjugate is administered via intravenous administration once every two to four weeks, and

[0738] wherein pembrolizumab is administered via intravenous administration once every two to four weeks.

[0739]

[0427] The use according to any one of

[0410] to

[0419] , and

[0423] to

[0426] , wherein the anti-MUCl antibody-drug conjugate is administered via intravenous administration once every three weeks, and

[0740] wherein pembrolizumab is administered via intravenous administration once every three weeks.

[0741]

[0428] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0742] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0743]

[0429] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0744] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0745] 15453442-1

[0430] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0746] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0747]

[0431] The use according to any one of

[0399] to

[0404] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, and

[0748] wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks.

[0749]

[0432] The use according to any one of

[0399] to

[0431] , wherein the anti-MUCl antibody-drug conjugate and immune checkpoint inhibitor are used in combination with carboplatin or pemetrexed,

[0750] wherein carboplatin is administered at a dose of AUC 4 to 6 mg*min / ml or pemetrexed is administered at a dose of 400 to 600 mg / m2.

[0751]

[0433] The use according to any one of

[0399] to

[0431] , wherein the anti-MUCl antibody-drug conjugate and immune checkpoint inhibitor are used in combination with carboplatin or pemetrexed,

[0752] 15453442-1wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml or pemetrexed is administered at a dose of about 500 mg / m2.

[0753]

[0434] The use according to

[0432] or

[0433] , wherein carboplatin is administered via intravenous administration once every three weeks or pemetrexed is administered via intravenous administration once every three weeks.

[0754]

[0435] The use according to any one of

[0399] to

[0434] , wherein the anti-MUCl antibody-drug conjugate and immune checkpoint inhibitor are used in combination with carboplatin or pemetrexed,

[0755] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0756]

[0436] The use according to any one of

[0432] to

[0435] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg via intravenous administration once every three weeks,

[0757] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0758] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every

[0759] 15453442-1three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0760]

[0437] The use according to any one of

[0432] to

[0435] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 4 mg / kg via intravenous administration once every three weeks,

[0761] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0762] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0763]

[0438] The use according to any one of

[0432] to

[0435] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 5 mg / kg via intravenous administration once every three weeks,

[0764] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0765] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of

[0766] 15453442-1about 500 mg / m2via intravenous administration once every three weeks.

[0767]

[0439] The use according to any one of

[0432] to

[0435] , wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 6 mg / kg via intravenous administration once every three weeks,

[0768] wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is administered at a dose of about 200 mg via intravenous administration once every three weeks, and

[0769] wherein carboplatin is administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

[0770] [Advantageous Effects of Invention]

[0771]

[0017]

[0772] The present invention can provide a pharmaceutical product and a treatment method comprising administering an anti-MUCl antibody-drug conjugate and an immune checkpoint inhibitor in combination.

[0773]

[0018]

[0774] A kit and a pharmaceutical combination of the anti-MUCl antibody-drug conjugate and the immune checkpoint

[0775] 15453442-1inhibitor, and a use of the combination for treating a disease, for example cancer, are also provided.

[0776] [Brief Description of Drawings]

[0777]

[0019]

[0778] [Figure 1 ] This figure shows the antitumor effects of the TA-MUCl-DXd ADC, the anti-PD-1 antibody, and their combination in an hMUCl CT26.wt tumor bearing mouse model (Example 2 ). The horizontal axis represents days after initial administration and the vertical axis represents estimated tumor volume (mm3).

[0779] [Figure 2 ] This figure shows the survival curves of the TA-MUCl-DXd ADC, the anti-PD-1 antibody, and their combination (Example 4). The horizontal axis represents days after initial administration and the vertical axis represents survival rate (%).

[0780] [Figure 3] This figure shows the antitumor effects of the TA-MUCl-DXd ADC, the anti-PD-Ll antibody, and their combination in an hMUCl CT26.wt tumor bearing mouse model (Example 5). The horizontal axis represents days after initial administration and the vertical axis represents estimated tumor volume (mm3).

[0781] [Figure 4 ] This figure shows the survival curves of the TA-MUCl-DXd ADC, the anti-PD-Ll antibody, and their combination (Example 7). The horizontal axis represents days after initial administration and the vertical axis represents survival rate (%).

[0782] 15453442-1[Figure 5] This figure shows the amino acid sequence of the heavy chain of PM-N54Q (SEQ ID NO: 11 ).

[0783] [Figure 6] This figure shows the amino acid sequences of the light chains of PM-N54Q and PankoMab-GEX (R) (SEQ ID NO: 12 ).

[0784] [Figure 7 ] This figure shows the amino acid sequence of the heavy chain of PankoMab-GEX (R) (SEQ ID NO: 13).

[0785] [Description of Embodiments]

[0786]

[0020]

[0787] Hereinafter, preferable modes for carrying out the present invention will be described. The embodiments described below are given merely for illustrating one example of a typical embodiment of the present invention and are not intended to limit the scope of the present invention.

[0788]

[0021]

[0789] As used herein, the term "about" in association with a specified number means plus or minus 10% as well as the specified number. For example, "about 10" should be understood as both "10" and "10 plus or minus 10%", i. e. "9 to 11". Where the term "about" is used in association with a range, it should be understand as applying to both the upper and lower end of the range.

[0790]

[0022]

[0791] The terms "individual", "subject", and "patient" are used interchangeably herein, and refer to any individual

[0792] 15453442-1mammal, e. g., bovine, canine, feline, equine, simian, porcine, camelid, bat, or human, being treated according to the disclosed methods or uses. In preferred embodiments, the subject is a human.

[0793]

[0023]

[0794] The terms "treatment" or "treating" as used herein with reference to a cancer refer to reducing, suppressing, or eliminating the cancer; reducing, suppressing, or eliminating cancer cell growth; reducing, suppressing, or eliminating spread of the cancer; or causing a tumor or metastasis to regress or die.

[0795] Treatment and treating may also, optionally, mean improving quality of life or overall survival of a subject, even if cancer cell growth is not inhibited and / or the cancer does not die.

[0796]

[0024]

[0797] In the present description, the term "cancer" is used to have the same meaning as that of the term "tumor".

[0798]

[0025]

[0799] [Anti-MUCl antibody]

[0800] As used herein, the term " MUC1" refers to a protein MUC1 also known as mucin 1, polymorphic epithelial mucin (PEM), or cancer antigen 15-3, particularly, human MUC1 (accession No. P15941 ). MUC1 is a member of the mucin family and encodes a membrane-bound glycosylated phosphoprotein. MUC1 has a core protein molecular mass

[0801] 15453442-1of 120 to 225 kDa, which increases to 250 to 500 kDa upon glycosylation. MUC1 extends 200 to 500 nm beyond the cell surface. This protein is anchored via the transmembrane domain to the apical surface of many epithelial cells. The extracellular domain comprises a variable number tandem repeat (VNTR) domain consisting of 20-amino-acid repeats, with the number of repeats varying from 25 to 120 among individuals. These repeats are rich in serine, threonine, and proline residues which enables extensive O-glycosylation. In a certain embodiment, the term " MUC1" refers to tumor-associated MUC1 (" TA-MUC1" ). TA-MUC1 is MUC1 present on cancer cells. MUC1 on cancer cells differs from MUC1 present on non-cancerous cells in that it is expressed at much higher levels, has lost polarized expression, and is hypoglycosylated.

[0802] Particularly, TA-MUC1 is present in a non-polarized manner over the entire surface of cancer cells, whereas MUC1 in non-cancerous cells exhibits a strictly apical expression and therefore is inaccessible to systemically administered antibodies. Furthermore, TA-MUC1 possesses aberrant O-glycosylation that exposes new peptide epitopes within the MUC1 protein backbone and is characterized by tumor-associated carbohydrate antigens such as N-acetylgalactosamine (Tn), sialyl α2-6N-acetylgalactosamine (sTn), galactose β1-3N-acetylgalactosamine (TF), or galactose β1-3 (sialyl α2-6) N-acetylgalactosamine (sTF).

[0803] 15453442-1

[0026]

[0804] As used herein, the term "antibody" refers to a protein comprising at least two heavy chains and two light chains connected via disulfide bonds. The antibody may be, for example, a humanized antibody, a human antibody, or a chimeric antibody. The antibody includes multivalent and multispecific antibodies, i. e. antibody constructs having more than two binding sites that each bind to the same epitope and antibody constructs having one or more binding sites that bind to a first epitope and one or more binding sites that bind to a second epitope, and optionally even further binding sites that bind to further epitopes.

[0805]

[0027]

[0806] As used herein, the term "anti-MUCl antibody" refers to an antibody that specifically binds to MUC1 and preferably has the activity of being internalized in MUCl-expressing cells by binding to MUC1, and in other words, an antibody having the activity of migrating into MUCl-expressing cells after binding to MUC1.

[0807]

[0028]

[0808] As used herein, the term "specific binding" preferably means that an antibody binds more strongly to a specific target such as an epitope as compared with binding to another target. Examples of criteria for determining whether binding is specific or not can include a dissociation constant (referred to as " Kd" or

[0809] 15453442-1" Kd" in the present specification) or an affinity constant referred to as " Ka" or " Ka" in the present specification). An antibody binds more strongly to a first target compared to a second target when binding to the first target with a dissociation constant (K ) lower than that for the second target. Preferably, the dissociation constant for the target to which the antibody specifically binds is 100-fold, 200-fold, 500-fold, or 1000-fold lower than that for the target to which the antibody does not specifically bind. The "specific binding" particularly refers to binding affinity between binding partners with an affinity constant Kaof at least 106M-1, preferably at least 107M-1, more preferably at least 108M-1. An antibody specific for a certain antigen particularly refers to an antibody capable of binding to the antigen with affinity having Kaof at least 106M-1, preferably at least 107M-1, more preferably at least 108M-1. The "anti-MUCl antibody" used in the present invention refers to an antibody that specifically binds to MUC1 and is preferably capable of binding to MUC1 with affinity having Kaof at least 106M-1, preferably at least 107M-1, more preferably at least 108M-1.

[0810]

[0029]

[0811] The anti-MUCl antibody used in the present invention specifically binds to an epitope on MUC1. The epitope resides in extracellular tandem repeats of MUC1. The

[0812] 15453442-1anti-MUCl antibody used in the present invention binds to MUC1 in a glycosylation-dependent manner. Particularly, the anti-MUCl antibody binds more strongly when the tandem repeats are glycosylated at a threonine residue with N-acetyl galactosamine (Tn), sialyl α2-6 N-acetyl galactosamine (sTn), galactose β1-3 N-acetyl galactosamine (TF) or galactose β1-3 (sialyl α2-6) N-acetyl galactosamine (sTF), preferably Tn or TF.

[0813] Preferably, the carbohydrate moiety is bound to the threonine residue via an a-O-glycosidic bond. The epitope in the tandem repeat domain of MUC1 particularly comprises an amino acid sequence PDTR (SEQ ID NO: 14 ) or PESR (SEQ ID NO: 15). The binding to this epitope preferably is glycosylation-dependent, as described above. Particularly, the binding is increased when the carbohydrate moiety described above is attached to the threonine residue of each PDTR or PESR sequence.

[0814]

[0030]

[0815] The epitope for the anti-MUCl antibody used in the present invention is preferably an epitope of tumor-associated MUC1 (TA-MUC1 ). The TA-MUC1 epitope particularly refers to an epitope of MUC1 that is present on tumor cells but not on normal cells and / or that, when present on tumor cells, is accessible by antibodies in blood circulation and immune circulation, but is not accessible when present on normal cells. The epitope for the anti-MUCl antibody used in the present invention is

[0816] 15453442-1more preferably an epitope comprising at least one PDTR sequence in MUC1 tandem repeats, and the PDTR sequence is glycosylated at threonine with N-acetylgalactosamine (Tn) or galactose pi-3N-acetylgalactosamine (TF), preferably via an oc-O-glycosidic bond.

[0817]

[0031]

[0818] The anti-MUCl antibody used in the present invention can be obtained by an approach known in the art. For example, the antibody can be obtained by use of a method usually carried out in the art, which involves immunizing animals with an antigen MUC1 or an arbitrary polypeptide selected from the amino acid sequence of MUC1, or a human-derived cancer cell line and collecting and purifying antibodies produced in vivo. The origin of the antigen is not limited to humans, and the animals may be immunized with an antigen derived from a non-human animal such as a mouse or a rat.

[0819]

[0032]

[0820] Antibody-producing cells which produce antibodies against the antigen are fused with myeloma cells in accordance with a method known in the art (e. g., Kohler and Milstein, Nature ( 1975) 256, p. 495-497; and Kennet, R. ed., Monoclonal Antibodies, p. 365-367, Plenum Press, N. Y. ( 1980) ) to establish hybridomas, from which, in turn, monoclonal antibodies can be obtained.

[0821] The antigen can be obtained by allowing host cells to produce a gene encoding the antigenic protein

[0822] 15453442-1according to genetic manipulation. Specifically, a vector that permits expression of the antigen gene is prepared, and this vector is transferred to host cells so that the gene can be expressed therein, followed by the purification of the expressed antigen. The antibody can also be obtained by use of a method of immunizing an animal with these genetically manipulated antigenexpressing cells or a cell line expressing the antigen.

[0823]

[0033]

[0824] The anti-MUCl antibody used in the present invention is preferably a recombinant antibody obtained by artificial modification for the purpose of decreasing heterologous antigenicity to humans, for example, a chimeric antibody, a humanized antibody, or is preferably an antibody having only a human-derived antibody gene sequence, i. e., a human antibody. These antibodies can be produced by use of a known method.

[0825]

[0034]

[0826] Examples of the chimeric antibody can include an antibody in which antibody variable and constant regions are derived from different species, for example, a chimeric antibody in which a mouse- or rat-derived antibody variable region is connected to a human-derived antibody constant region (Proc. Natl. Acad. Sci. U. S. A., 81, 6851-6855, ( 1984 ) ).

[0827]

[0035]

[0828] 15453442-1Examples of the humani zed antibody can include an antibody obtained by integrating only complementarity determining regions ( CDRs ) of a heterologous antibody into a human-derived antibody (Nature ( 1986 ) 321, pp. 522-525 ), an antibody obtained by grafting the CDR sequences of a heterologous antibody as well as some framework amino acid residues of the heterologous antibody to a human antibody by a CDR grafting method ( International Publication No. WO 90 / 07861 ), and an antibody humani zed by use of a gene conversion mutagenesis strategy (U. S. Patent No. 5821337 ).

[0829]

[0036]

[0830] Examples of the human antibody can include an antibody prepared using a human antibody-producing mouse having a human chromosomal fragment comprising the heavy chain and light chain genes of a human antibody ( see, for example, Tomi zuka, K. et al., Nature Genetics ( 1997 ) 16, p. 133- 143; Kuroiwa, Y. et. al., Nucl. Acids Res. ( 1998 ) 26, p. 3447-3448; Yoshida, H. et. al., Animal Cell Technology: Basic and Applied Aspects vol. 10, p. 69-73 (Kitagawa, Y., Matsuda, T. and l ij ima, S. eds. ), Kluwer Academic Publishers, 1999; and Tomi zuka, K. et. al., Proc. Natl. Acad. Sci. USA ( 2000 ) 97, p. 722-727 ).

[0831] Alternative examples thereof can include an antibody selected from a human antibody library and obtained by phage display ( see, for example, Wormstone, I. M. et. al, Investigative Ophthalmology & Visual Science. ( 2002 ) 43

[0832] 15453442-1( 1 ), p. 2301-2308; Carmen, S. et. al., Briefings in Functional Genomics and Proteomics ( 2002 ), 1 ( 2 ), p. 189-203; and Siriwardena, D. et. al., Ophthalmology ( 2002 ) 109 ( 3 ), p. 427-431 ).

[0833]

[0037]

[0834] The anti-MUCl antibody used in the present invention also includes an antibody having the substitution of 1 to 3 amino acid residues in CDRs of the chimeric antibody, the humani zed antibody, or the human antibody by other amino acid residues as long as the antibody has the ability to speci fically bind to a MUC1 epitope. These antibodies can be produced by use of a known method.

[0835]

[0038]

[0836] The anti-MUCl antibody used in the present invention also includes a modified variant of the antibody. The modi fied variant refers to a variant obtained by subjecting the antibody according to the present invention to chemical or biological modi fication.

[0837] Examples of the chemically modi fied variant include chemically modi fied variants including a linkage of a chemical moiety to an amino acid skeleton or a linkage of a chemical moiety to an N-linked or O-linked carbohydrate chain, etc. Examples of the biologically modi fied variant include variants obtained by post-translational modi fication ( e. g., N-linked or O-linked glycosylation, N- or C-terminal processing, deamidation, isomeri zation of aspartic acid, or oxidation of methionine ), and

[0838] 15453442-1variants with a methionine residue added to the N terminus through expression in prokaryotic host cells. Further, such a modified variant is also meant to include an antibody labeled so as to permit detection or isolation of the anti-MUCl antibody used in the present invention or the antigen, for example, an enzyme-labeled antibody, a fluorescence-labeled antibody, and an affinity-labeled antibody. Such a modified variant of the anti-MUCl antibody used in the present invention is useful for improving the stability and blood retention of the antibody, reducing the antigenicity thereof, detecting or isolating the antibody or the antigen, and so on.

[0839]

[0039]

[0840] It is known for an antibody produced in a cultured mammalian cell that a lysine residue at the carboxyl terminus of its heavy chain is deleted (Journal of Chromatography A, 705: 129-134 ( 1995) ), and it is also known for an antibody produced in a cultured mammalian cell that two amino acid residues (glycine and lysine) at the carboxyl terminus of the heavy chain of are deleted and a proline residue newly located at the carboxyl terminus is amidated (Analytical Biochemistry, 360: 75-83 (2007 ) ). However, such deletion and modification of the heavy chain sequence do not affect the antigen-binding affinity and the effector function (the activation of complement, antibody-dependent cellular cytotoxicity,

[0841] 15453442-1etc. ) of the antibody. Therefore, in the anti-MUCl antibody used in the present invention, antibodies subjected to such modification and functional fragments of the antibody are also included, and deletion variants in which one or two amino acids have been deleted at the carboxyl terminus of the heavy chain, variants obtained by amidation of deletion variants ( for example, a heavy chain in which the carboxyl terminal proline residue has been amidated), and the like are also included. The two heavy chains constituting the anti-MUCl antibody used in the present invention may be of one type selected from the group consisting of a full-length heavy chain and the above-described deletion variant, or may be of two types in combination selected therefrom. The ratio of the amount of each deletion variant can be affected by the type of cultured mammalian cells which produce the anti-MUCl antibody used in the present invention and the culture conditions. Examples of the anti-MUCl antibody used in the present invention can preferably include an antibody having two heavy chains in which one amino acid residue is deleted from each of the carboxyl termini of both the heavy chains.

[0842]

[0040]

[0843] Examples of the isotype of the anti-MUCl antibody used in the present invention can include humanized or human IgG ( IgGl, IgG2, IgG3, and IgG4 ) and can preferably include IgGl and IgG4, more preferably IgGl. Their

[0844] 15453442-1variants can also be used as the anti-MUCl antibody according to the present invention.

[0845]

[0041]

[0846] Examples of the anti-MUCl antibody that can be used in the present invention can include PankoMab-GEX (R) ( International Publication No. WO 2011 / 012309), PM-N54Q ( International Publication No. WO 2019 / 219889), and their variants, active fragments, and modified variants and can preferably include PM-N54Q. These anti-MUCl antibodies can be produced by methods described in the documents. The amino acid sequences of a heavy chain and a light chain of PankoMab-GEX (R) are shown in SEQ ID NO: 13 (Figure 7 ) and SEQ ID NO: 12 (Figure 6), respectively. The amino acid sequences of a heavy chain and a light chain of PM-N54Q are shown in SEQ ID NO: 11 (Figure 5) and SEQ ID NO: 12 (Figure 6), respectively.

[0847]

[0042]

[0848] [Antibody-drug conjugate]

[0849] As used herein, the term "antibody-drug conjugate" refers to a conjugate with a cytotoxic drug conjugated with an antibody via a linker. Examples of the antibodydrug conjugate can include antibody-drug conjugates described in U. S. Patent No. 7097840, U. S. Patent No. 7999083, International Publication No. WO 2010 / 093395, International Publication No. WO 2014 / 057687, International Publication No. WO 2015 / 115091, International Publication No. WO 2017 / 083582, and

[0850] 15453442-1International Publication No. WO 2019 / 219891, preferably antibody-drug conjugates described in International Publication No. WO 2019 / 219891. These antibody-drug conjugates can be produced by methods described in the documents.

[0851]

[0043]

[0852] The cytotoxic drug is not particularly limited as long as the cytotoxic drug has an antitumor effect and has a substituent or a partial structure that can be connected to a linker. Examples thereof can include camptothecin, calicheamicin, doxorubicin, daunorubicin, mitomycin C, bleomycin, cyclocytidine, vincristine, vinblastine, methotrexate, cisplatin, auristatin E, maytansine, paclitaxel, pyrrolobenzodiazepine, and their derivatives, preferably camptothecin derivatives, and more preferably exatecan derivatives.

[0853]

[0044]

[0854] As used herein, the "drug-linker" refers to the drug and the linker moiety in the antibody-drug conjugate and in other words, a partial structure except for the antibody in the antibody-drug conjugate.

[0855]

[0045]

[0856] As used herein, the term "anti-MUCl antibody-drug conjugate" refers to an antibody-drug conjugate having an anti-MUCl antibody as the antibody. Examples of the anti-MUCl antibody-drug conjugate can include antibodydrug conjugates described in International Publication

[0857] 15453442-1No. WO 2019 / 219891, International Publication No. WO 2017 / 083582, and International Publication No. WO 2021 / 247798. These anti-MUCl antibody-drug conjugates can be produced by methods described in the documents.

[0858]

[0046]

[0859] The anti-MUCl antibody-drug conjugate more preferably used in the present invention is an anti-MUCl antibody-drug conjugate in which a drug-linker represented by the formula:

[0860] [Formula 7 ]

[0861]

[0862] OH 0 wherein A represents a connecting position to the anti-MUCl antibody

[0863] and the anti-MUCl antibody are conjugated via a thioether bond.

[0864] This drug-linker is connected to thiol groups (in other words, sulfur atoms of cysteine residues) formed in interchain disulfide bond sites (two locations between the heavy chain and the heavy chain and two locations

[0865] 15453442-1between the heavy chains and the light chains) of the antibody.

[0866]

[0047]

[0867] The above-described anti-MUCl antibody-drug conjugate more preferably used in the present invention can also be represented by the following formula:

[0868] [Formula 8 ]

[0869]

[0870] In the formula, AB represents the anti-MUCl antibody, and the drug-linker and the antibody are conjugated via a thioether bond, y has the same meaning as that of so-called DAR (Drug-to-Antibody Ratio), and represents the average number of units of the drug-linker conjugated per antibody. In this context, y indicates the average number of drug molecules (or units of the druglinker) conjugated per antibody molecule in a composition of antibody-drug conjugate molecules. Alternatively, in a different context, y may be an integer representing the number of drug molecules (or units of the drug-linker)

[0871] 15453442-1conjugated per antibody molecule in an anti-MUCl antibody-drug conjugate molecule.

[0872]

[0048]

[0873] The anti-MUCl antibody moiety of the anti-MUCl antibody-drug conjugate used in the present invention can be an antibody comprising a heavy chain comprising a complementarity determining region (CDR) CDRH1 having the amino acid sequence of SEQ ID NO: 1, CDRH2 having the amino acid sequence of SEQ ID NO: 2 or SEQ ID NO: 7, and CDRH3 having the amino acid sequence of SEQ ID NO: 3, and a light chain comprising a complementarity determining region (CDR) CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence SEQ ID NO: 5, and CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0874]

[0049]

[0875] The anti-MUCl antibody moiety is more preferably an antibody comprising a heavy chain comprising CDRH1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 1, CDRH2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 2, and CDRH3 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 3, and a light chain comprising CDRL1 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 4, CDRL2 comprising or consisting of the amino acid sequence represented by SEQ ID NO: 5, and CDRL3 comprising or

[0876] 15453442-1consisting of the amino acid sequence represented by SEQ ID NO: 6.

[0877]

[0050]

[0878] The anti-MUCl antibody moiety can be preferably an antibody comprising a heavy chain comprising a heavy chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 8 or SEQ ID NO: 10, and a light chain comprising a light chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 9.

[0879]

[0051]

[0880] The anti-MUCl antibody moiety is more preferably an antibody comprising a heavy chain comprising a heavy chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 8, and a light chain comprising a light chain variable region comprising or consisting of the amino acid sequence represented by SEQ ID NO: 9.

[0881]

[0052]

[0882] The anti-MUCl antibody moiety can be preferably an antibody comprising a heavy chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 11 or SEQ ID NO: 13, and a light chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 12, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted.

[0883] 15453442-1

[0053]

[0884] The anti-MUCl antibody moiety is more preferably an antibody comprising a heavy chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 11, and a light chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 12, or an antibody in which a lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted.

[0885]

[0054]

[0886] Embodiments of the antibody in which a lysine residue at the carboxyl terminus of the heavy chain of the antibody is deleted correspond to an antibody comprising a heavy chain comprising or consisting of the amino acid sequence of amino acid numbers 1 to 446 of SEQ ID NO: 11.

[0887]

[0055]

[0888] The anti-MUCl antibody moiety can be preferably an antibody comprising a heavy chain comprising or consisting of the amino acid sequence of amino acid numbers 1 to 446 of SEQ ID NO: 11 or the amino acid sequence of amino acid numbers 1 to 446 of SEQ ID NO: 13, and a light chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0889]

[0056]

[0890] The anti-MUCl antibody moiety is more preferably an antibody comprising a heavy chain comprising or consisting of the amino acid sequence of amino acid

[0891] 15453442-1numbers 1 to 446 of SEQ ID NO: 11, and a light chain comprising or consisting of the amino acid sequence represented by SEQ ID NO: 12.

[0892]

[0057]

[0893] A drug-linker intermediate for use in the production of the anti-MUCl antibody-drug conjugate described above is represented by the following formula:

[0894] [Formula 9]

[0895] ,0

[0896]

[0897]

[0058]

[0898] The drug-linker intermediate described above can be represented by the chemical name N- [ 6- ( 2, 5-dioxo-2, 5-dihydro-lH-pyrrol-l-yl ) hexanoyl ] gl y cyl glycyl -L-phenylalanyl-N- [ (2- { [ ( IS, 9S) -9-ethyl-5-f luoro-9-hydroxy-4-methyl-10, 13-dioxo-2, 3, 9, 10, 13, 15-hexahydro-lH, 12H-benzo [de ] pyrano [ 3 ', 4 ':, 7 ] indolizino [ 1, 2-b] quinolin- 1-yl ] amino } -2-oxoethoxy) methyl ] glycinamide, and can be produced with reference to the description of, for example, International Publication No. WO 2014 / 057687 and International Publication No. WO 2015 / 155998.

[0899] 15453442-1

[0059]

[0900] The anti-MUCl antibody-drug conjugate preferably used in the present invention can be produced by reacting the drug-linker intermediate mentioned above with an anti-MUCl antibody having a thiol group (or a sulfhydryl group).

[0901]

[0060]

[0902] The anti-MUCl antibody having a sulfhydryl group can be obtained by a method well known to those skilled in the art (Hermanson, G. T, Bioconjugate Techniques, pp. 56-136, pp. 456-493, Academic Press ( 1996) ). For example, an anti-MUCl antibody having a sulfhydryl group with interchain disulfide bonds partially or completely reduced can be obtained by using 0.3 to 3 molar equivalents of a reducing agent such as tris(2-carboxyethyl)phosphine hydrochloride (TCEP) per interchain disulfide bond in the antibody, and reacting the reducing agent with the anti-MUCl antibody in a buffer solution containing a chelating agent such as ethylenediaminetetraacetic acid (EDTA).

[0903]

[0061]

[0904] Further, using 2 to 20 molar equivalents of the drug-linker intermediate per anti-MUCl antibody having a sulfhydryl group, the anti-MUCl antibody-drug conjugate in which 2 to 8 drug molecules are conjugated per antibody can be produced.

[0905]

[0062]

[0906] 15453442-1The average number of conjugated drug molecules per antibody of the produced anti-MUCl antibody-drug conjugate can be determined by, for example, a calculation method of measuring UV absorbance of the anti-MUCl antibody-drug conjugate and its conjugation precursor at two wavelengths of 280 nm and 370 nm (UV method), or a calculation method of treating the antibody-drug conjugate with a reducing agent and quantifying each fragment thus obtained by HPLC measurement (HPLC method).

[0907]

[0063]

[0908] The conjugation between the anti-MUCl antibody and the drug-linker intermediate, and the calculation of the average number of conjugated drug molecules per antibody of the anti-MUCl antibody-drug conjugate can be carried out with reference to the description of, for example, International Publication No. WO 2015 / 155998.

[0909]

[0064]

[0910] In some embodiments, the average number of units of the drug-linker conjugated per antibody of the anti-MUCl antibody-drug conjugate used in the present invention is preferably 2 to 8, more preferably 3 to 8, still more preferably 7 to 8, still more preferably 7.5 to 8, still more preferably approximately 8. In an alternative embodiment, the number of drug molecules or units of the drug-linker conjugated per antibody molecule in the anti-MUCl antibody-drug conjugate used in the present

[0911] 15453442-1invention is preferably in the range of 2 to 8, more preferably 2, 4, 6, or 8, still more preferably 8.

[0912]

[0065]

[0913] [ Immune checkpoint inhibitor]

[0914] As used herein, the term "immune checkpoint inhibitor" refers to an agent that inhibits the immunosuppressive system and activates tumor immunity.

[0915]

[0066]

[0916] Examples of the immune checkpoint inhibitor used in the present invention can preferably include, but are not particularly limited to, anti-PD-1 antibodies, anti-PD-Ll antibodies, and anti-CTLA-4 antibodies, more preferably anti-PD-1 antibodies and anti-PD-Ll antibodies.

[0917]

[0067]

[0918] As used herein, the "anti-PD-1 antibody" refers to an antibody having an effect of specifically binding to PD-1 (programmed cell death-1; CD279; PDCD1 ) and thereby reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between PD-1 and its binding partner PD-L1 or PD-L2. The anti-PD-1 antibody used in the present invention is not particularly limited as long as the antibody has been clinically confirmed to have effectiveness and safety. Preferable examples thereof can include nivolumab ( International Publication No. WO 2006 / 121168, etc. ) and pembrolizumab ( International Publication No. WO 2008 / 156712, etc. ). For example, a commercially

[0919] 15453442-1available anti-PD-1 antibody for research (e. g., clone RMP1-14 ) may be used for the purpose of confirming a combined effect with the antibody-drug conjugate used in the present invention in preclinical study.

[0920]

[0068]

[0921] As used herein, the "anti-PD-Ll antibody" refers to an antibody having an effect of specifically binding to PD-L1 (programmed cell death ligand 1; CD274; B7-H1 ) and thereby reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between PD-L1 and its binding partner PD-1 or B7. 1 (CD80). The anti-PD-Ll antibody used in the present invention is not particularly limited as long as the antibody has been clinically confirmed to have effectiveness and safety. Preferable examples thereof can include atezolizumab ( International Publication No. WO 2010 / 077634, etc. ), durvalumab ( International Publication No. WO 2011 / 066389, etc. ), and avelumab ( International Publication No. WO 2013 / 079174, etc. ). For example, a commercially available anti-PD-Ll antibody for research (e. g., clone 10F.9G2 ) may be used for the purpose of confirming a combined effect with the antibody-drug conjugate used in the present invention in preclinical study.

[0922]

[0069]

[0923] As used herein, the "anti-CTLA-4 antibody" refers to an antibody having an effect of specifically binding to

[0924] 15453442-1CTLA-4 (cytotoxic T-lymphocyte-associated protein 4;

[0925] CD152 ) and thereby reducing, inhibiting, and / or interfering with signal transduction resulting from the interaction between CTLA-4 and its binding partner B7. 1 (CD80) or B7.2 (CD86). The anti-CTLA-4 antibody used in the present invention is not particularly limited as long as the antibody has been clinically confirmed to have effectiveness and safety. Preferable examples thereof can include ipilimumab ( International Publication No. WO 2001 / 014424, etc. ) and tremelimumab ( International Publication No. WO 2000 / 037504, etc. ). For example, a commercially available anti-CTLA-4 antibody for research (e. g., clone 9H10) may be used for the purpose of confirming a combined effect with the antibody-drug conjugate used in the present invention in preclinical study.

[0926]

[0070]

[0927] [Pharmaceutical product and treatment method] Hereinafter, the pharmaceutical product and the treatment method according to the present invention, comprising administering an anti-MUCl antibody-drug conjugate and an immune checkpoint inhibitor in combination, will be described. Such disclosures are also relevant to the kit, the pharmaceutical combination and the uses of the present invention described above.

[0928]

[0071]

[0929] 15453442-1In some embodiments, the pharmaceutical product and the treatment method according to the present invention comprise administering an anti-MUCl antibody-drug conjugate and administering an immune checkpoint inhibitor in combination.

[0930]

[0072]

[0931] In the pharmaceutical product and the treatment method of the present invention, the anti-MUCl antibodydrug conjugate and the immune checkpoint inhibitor may be separately contained as active ingredients in different formulations and administered simultaneously or at different times, or the anti-MUCl antibody-drug conjugate and the immune checkpoint inhibitor may be contained as active ingredients in a single formulation and administered.

[0932]

[0073]

[0933] In the pharmaceutical product and the treatment method of the present invention, the anti-MUCl antibodydrug conjugate and the immune checkpoint inhibitor are administered in combination and are thereby capable of exhibiting significantly potentiated antitumor activity against a cancer, preferably a cancer expressing MUC1, more preferably a cancer expressing TA-MUC1, as compared with the anti-MUCl antibody-drug conjugate or the immune checkpoint inhibitor administered singly.

[0934]

[0074]

[0935] 15453442-1The pharmaceutical product and the treatment method of the present invention can be used for the treatment of a disease and can be preferably used for the treatment of a cancer. The cancer preferably expresses MUC1, more preferably expresses TA-MUC1, and still more preferably highly expresses TA-MUC1. The expression of MUC1 can be confirmed, for example, by detecting MUC1 at the gene product (protein) level using an immunohistochemical technique ( IHC), a flow cytometer, or Western blot, or by detecting the gene at the transcription level using in situ hybridization ( ISH) or quantitative PCR (q-PCR). Whether MUC1 is highly expressed or not can be determined by use of a method well known to those skilled in the art.

[0936]

[0075]

[0937] Examples of the cancer expressing MUC1 can include ovary cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, stomach cancer, liver cancer, kidney cancer, blood cancer, endometrial cancer, thyroid gland cancer, leukemia, seminoma, melanoma, carcinoma, teratoma, lymphoma, sarcoma, mesothelioma, neuroblastoma, glioma, rectal cancer, adrenal cancer, skin cancer, brain cancer, uterine cervical cancer, intestinal tract cancer, intestine cancer, head and neck cancer, gastrointestinal cancer, lymph node cancer, esophageal cancer, colorectal cancer, ear, nose and throat (ENT) cancer, prostate cancer, urinary bladder cancer, uterine cancer, bile duct

[0938] 15453442-1cancer and their metastatic cancers and can preferably include breast cancer, lung cancer, and urinary bladder cancer.

[0939]

[0076]

[0940] In some embodiments, the cancer is lung cancer.

[0941] Preferably, the lung cancer is non-small cell lung cancer (NSCLC). More preferably, the NSCLC is locally advanced or metastatic NSCLC.

[0942]

[0077]

[0943] In some embodiments, the pharmaceutical product and the treatment method of the present invention can be used for the treatment of a disease in a subject and can be preferably used for the treatment of a cancer in a subject.

[0944]

[0078]

[0945] In embodiments where the subject has NSCLC or locally advanced or metastatic NSCLC, preferably the patient to be treated has had no prior systemic therapy for NSCLC or for locally advanced or metastatic NSCLC.

[0946]

[0079]

[0947] The pharmaceutical product and the treatment method of the present invention can be selectively used as an agent for drug therapy, which is a main method for treating cancers, and as a result, can delay the growth of cancer cells, inhibit the proliferation thereof, and further kill the cancer cells. These effects can allow cancer patients to be free from symptoms caused by

[0948] 15453442-1cancers or achieve improvement in quality of life (QOL) of cancer patients and achieve a therapeutic effect by sustaining the lives of the cancer patients. The pharmaceutical product and the treatment method of the present invention, even if not accomplishing the killing of cancer cells, can achieve higher QOL of cancer patients while achieving longer-term survival, by suppressing or controlling the proliferation of cancer cells.

[0949]

[0080]

[0950] In such drug therapy, the pharmaceutical product and the treatment method of the present invention can be used as an agent singly and in addition, can be used as an agent to be combined with an additional therapy in adjuvant therapy, and can be combined with surgery, radiotherapy, hormone therapy, or the like. The pharmaceutical product and the treatment method of the present invention can also be used as an agent for drug therapy in neoadjuvant therapy.

[0951]

[0081]

[0952] In addition to the therapeutic use as described above, the pharmaceutical product and the treatment method of the present invention can also be expected to have a prophylactic suppressing effect on the proliferation of small metastatic cancer cells and further to have a killing effect on cells. For example, an inhibiting and killing effect on cancer cells in body

[0953] 15453442-1fluid in the course of metastasis or, for example, an inhibiting and killing effect on small cancer cells immediately after implantation in any tissue can be expected. Thus, the suppression of cancer metastasis or a prophylactic effect can be expected, particularly, after surgical removal of a cancer.

[0954]

[0082]

[0955] The pharmaceutical product and the treatment method of the present invention are applied as systemic therapy to a patient and in addition, can be expected to have a therapeutic effect by local application to cancer tissue.

[0956]

[0083]

[0957] The pharmaceutical product and the treatment method of the present invention can be preferably used for a mammal and can be more preferably used for a human.

[0958]

[0084]

[0959] The pharmaceutical product of the present invention can be administered as a pharmaceutical composition comprising one or more pharmaceutically compatible components. A substance for use in the pharmaceutical product of the present invention can be appropriately selected from pharmaceutical additives and so on usually used in the art according to a dose or an administration concentration, and applied thereto. For example, the pharmaceutical composition typically comprises one or more pharmaceutical carriers (e. g., sterilized liquids). In this context, the liquid includes, for example, water

[0960] 15453442-1and oil (including petroleum oil and oil of animal origin, plant origin, or synthetic origin). The oil can be, for example, peanut oil, soybean oil, mineral oil, or sesame oil. Water is a more typical carrier when the pharmaceutical composition is intravenously administered. An aqueous saline solution, an aqueous dextrose solution, and an aqueous glycerol solution can also be used as a liquid carrier, in particular, for an injection solution. A suitable pharmaceutical vehicle can be appropriately selected from those known in the art. If desired, the composition may also comprise a trace amount of a moisturizing agent, an emulsifying agent, or a pH buffering agent. Examples of suitable pharmaceutical carriers are disclosed in "Remington's Pharmaceutical Sciences" by E. W. Martin. The prescription corresponds to an administration mode.

[0961]

[0085]

[0962] Various delivery systems are known, and they can be used for administering the pharmaceutical product of the present invention. Examples of the administration route can include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, and subcutaneous routes. The administration can be made by injection or bolus injection, for example. In a particularly preferable embodiment, the administration of the antibody-drug conjugate and the immune checkpoint inhibitor used in the present invention is performed by

[0963] 15453442-1injection. Parenteral administration is a preferable administration route.

[0964]

[0086]

[0965] In a representative embodiment, the pharmaceutical product is prescribed, as a pharmaceutical composition suitable for intravenous administration to a human, in accordance with conventional procedures. The composition for intravenous administration is typically a solution in a sterile and isotonic aqueous buffer solution. If necessary, the pharmaceutical composition may also contain a solubilizing agent and a local anesthetic to alleviate pain at an injection area (e. g., lignocaine). In general, the components described above are provided, either separately or together in a mixture in a unit dosage form, as a freeze-dried powder or an anhydrous concentrate contained in a container which is obtained by sealing in (e. g., an ampoule or a sachet indicating the amount of the active agent). When the pharmaceutical composition is in a form to be administered by injection, it may be administered using, for example, an injection bottle containing water or saline of sterile pharmaceutical grade. When the pharmaceutical composition is to be administered by injection, an ampoule of sterile water or saline for injection may be provided such that the components described above are admixed with each other before administration.

[0966]

[0087]

[0967] 15453442-1The pharmaceutical product and the treatment method of the present invention may comprise a therapeutic agent for a cancer other than the anti-MUCl antibody-drug conjugate and the immune checkpoint inhibitor according to the present invention. The pharmaceutical product and the treatment method of the present invention may be administered in combination with an additional therapeutic agent for a cancer, and can thereby enhance an anticancer effect. The additional anticancer agent used for such a purpose and the pharmaceutical product of the present invention may be administered to an individual simultaneously, separately, or continuously, or may be administered in a staggered manner. Examples of such a therapeutic agent for a cancer can include paclitaxel, docetaxel, SBT-1214, cyclophosphamide, imatinib, pazopanib, capecitabine, cytarabine, vinorelbine, gemcitabine, daunorubicin, doxorubicin, epirubicin, idarubicin, valrubicin, mitoxantrone, aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 4-hydroxyandrostenedione, 1, 4, 6-androstatriene-3, 17-dione (ATD), 4-androstene-3, 6, 17-trione ( 6-oxo), irinotecan, topotecan, camptothecin, lamellarin D, etoposide, teniposide, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, HU-331, cisplatin, carboplatin, oxaliplatin, olaparib, rucaparib, niraparib, imiquimod, resiquimod, methotrexate, pemetrexed, raltitrexed,

[0968] 15453442-1pralatrexate, fluorouracil, gemcitabine, floxuridine, 5-f luorouracil, tegafur uracil, cetuximab, tomuzotuximab, panitumumab, zalutumumab, nimotuzumab, matuzumab, necitumumab, trastuzumab, timigutuzumab, pertuzumab, bevacizumab, alemtuzumab, brentuximab, gemtuzumab, rituximab, tositumomab, and ibritumomab and can preferably include paclitaxel, docetaxel, cisplatin, carboplatin, gemcitabine, and cetuximab, though the additional anticancer agent is not limited thereto as long as the agent has antitumor activity.

[0969]

[0088]

[0970] Preferably, the additional anticancer agent is carboplatin or pemetrexed.

[0971]

[0089]

[0972] In some embodiments, the pharmaceutical composition of the present invention comprises the anti-MUCl antibody-drug conjugate of the present invention, for use in combination with an immune checkpoint inhibitor. In some embodiments, the pharmaceutical composition of the present invention comprises the anti-MUCl antibody-drug conjugate of the present invention, for use in combination with pembrolizumab. In some embodiments, the pharmaceutical composition of the present invention comprises the anti-MUCl antibody-drug conjugate of the present invention, for use in combination with pembrolizumab and carboplatin. In some embodiments, the pharmaceutical composition of the present invention

[0973] 15453442-1comprises the anti-MUCl antibody-drug conjugate of the present invention, for use in combination with pembrolizumab and pemetrexed.

[0974]

[0090]

[0975] In some embodiments, the pharmaceutical combination of the present invention comprises the anti-MUCl antibody-drug conjugate of the present invention and an immune checkpoint inhibitor. In some embodiments, the pharmaceutical combination of the present invention comprises the anti-MUCl antibody-drug conjugate of the present invention and pembrolizumab. In some embodiments, the pharmaceutical combination of the present invention comprises the anti-MUCl antibody-drug conjugate of the present invention, pembrolizumab and carboplatin. In some embodiments, the pharmaceutical combination of the present invention comprises the anti-MUCl antibody-drug conjugate of the present invention, pembrolizumab and pemetrexed. In some embodiments of the pharmaceutical combination, the anti-MUCl antibody-drug conjugate and pembrolizumab are contained as active ingredients in separate preparations and are to be administered simultaneously or at different times, or as a single preparation to be administered together. In some embodiments of the pharmaceutical combination, the anti-MUCl antibody-drug conjugate, pembrolizumab and carboplatin or the anti-MUCl antibody-drug conjugate, pembrolizumab and pemetrexed are contained as active

[0976] 15453442-1ingredients in separate preparations and are to be administered simultaneously or at different times, or as a single preparation to be administered together.

[0977]

[0091]

[0978] In some embodiments, there is provided the use of an anti-MUCl antibody-drug conjugate and an immune checkpoint inhibitor for the manufacture of a medicament for treating a cancer. In some embodiments, there is provided the use of an anti-MUCl antibody-drug conjugate and pembrolizumab for the manufacture of a medicament for treating a cancer. In some embodiments, there is provided the use of the anti-MUCl antibody-drug conjugate for the manufacture of a medicament for the treatment of cancer, wherein the anti-MUCl antibody-drug conjugate is to be administered in combination with an immune checkpoint inhibitor. In some embodiments, there is provided the use of the anti-MUCl antibody-drug conjugate for the manufacture of a medicament for the treatment of cancer, wherein the anti-MUCl antibody-drug conjugate is to be administered in combination with pembrolizumab.

[0979]

[0092]

[0980] The pharmaceutical product of the present invention can be prepared as a formulation having a selected composition and a necessary purity in the form of a freeze-dried formulation or a liquid formulation. The freeze-dried formulation thus prepared may be a formulation containing an appropriate pharmaceutical

[0981] 15453442-1additive used in this field. Likewise, the liquid formulation can be prepared as a liquid formulation containing various pharmaceutical additives used in this field.

[0982]

[0093]

[0983] The composition and concentration of the pharmaceutical product also vary depending on the administration method. As for affinity for the antigen, i. e., a dissociation constant (Kd value) to the antigen, the anti-MUCl antibody-drug conjugate and the immune checkpoint inhibitor contained in the pharmaceutical product of the present invention having higher affinity (lower Kd value) can exert drug efficacy even at a smaller dose. Thus, the doses of the anti-MUCl antibodydrug conjugate and the immune checkpoint inhibitor may be set based on the status of the affinity for the antigen.

[0984]

[0094]

[0985] The dose per administration of the anti-MUCl antibody-drug conjugate used in the present invention is preferably in the range of 0.1 mg / kg to 50 mg / kg, more preferably in the range of 1 mg / kg to 25 mg / kg, still more preferably in the range of 3 mg / kg to 10 mg / kg.

[0986]

[0095]

[0987] In some embodiments, the dose per administration of the anti-MUCl antibody-drug conjugate used in the present invention is in the range of about 1 mg / kg to 6 mg / kg or about 1 mg / kg to 5 mg / kg, preferably about 2 mg / kg to 6

[0988] 15453442-1mg / kg or about 2 mg / kg to 5 mg / kg, more preferably about 3 mg / kg to 6 mg / kg or about 3 mg / kg to 5 mg / kg. In some embodiments, the dose per administration of the anti-MUCl antibody-drug conjugate used in the present invention is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg.

[0989]

[0096]

[0990] In some embodiments, where the human body weight is 60 kg, a dose of the anti-MUCl antibody-drug conjugate used in the present invention ranging from 60 mg to 360 mg is administered to a subject with cancer.

[0991]

[0097]

[0992] In some embodiments, where the human body weight is 60 kg, the dose of the anti-MUCl antibody-drug conjugate is 60 mg. In some embodiments, the dose of the anti-MUCl antibody-drug conjugate is 120 mg. In some embodiments, the dose of the anti-MUCl antibody-drug conjugate is 180 mg. In some embodiments, the dose of the anti-MUCl antibody-drug conjugate is 240 mg. In some embodiments, the dose of the anti-MUCl antibody-drug conjugate is 300 mg. In some embodiments, the dose of the anti-MUCl antibody-drug conjugate is 360 mg.

[0993]

[0098]

[0994] The anti-MUCl antibody-drug conjugate can be administered via intravenous administration.

[0995]

[0099]

[0996] 15453442-1In some embodiments, the anti-MUCl antibody-drug conjugate is administered via intravenous infusion, for example for about 30 minutes to about 240 minutes. In some embodiments, the anti-MUCl antibody-drug conjugate is administered via intravenous infusion for about 30 minutes, about 90 minutes, about 180 minutes, about 210 minutes, or about 240 minutes.

[0997]

[0100]

[0998] The dosing interval of the anti-MUCl antibody-drug conjugate used in the present invention is preferably once a week (qlw), once every two weeks (q2w), once every three weeks (q3w), or once every four weeks (q4w), more preferably once every three weeks (q3w).

[0999]

[0101]

[1000] The anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose of 0.1 mg / kg to 50 mg / kg at intervals of once per 1 to 4 weeks, more preferably at a dose of 1 mg / kg to 25 mg / kg at intervals of once every two to three weeks, still more preferably at a dose of 3 mg / kg to 10 mg / kg at intervals of once every three weeks.

[1001]

[0102]

[1002] The anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 1 mg / kg to 6 mg / kg via intravenous administration at intervals of once per 1 to 4 weeks, more preferably at a dose in the range of about

[1003] 15453442-11 mg / kg to 6 mg / kg via intravenous administration at intervals of once every two to three weeks, still more preferably at a dose in the range of about 1 mg / kg to 6 mg / kg via intravenous administration at intervals of once every three weeks.

[1004]

[0103]

[1005] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 2 mg / kg to 6 mg / kg via intravenous administration at intervals of once per 1 to 4 weeks, more preferably at a dose in the range of about 2 mg / kg to 6 mg / kg via intravenous administration at intervals of once every two to three weeks, still more preferably at a dose in the range of about 2 mg / kg to 6 mg / kg via intravenous administration at intervals of once every three weeks.

[1006]

[0104]

[1007] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 3 mg / kg to 6 mg / kg via intravenous administration at intervals of once per 1 to 4 weeks, more preferably at a dose in the range of about 3 mg / kg to 6 mg / kg via intravenous administration at intervals of once every two to three weeks, still more preferably at a dose in the range of about 3 mg / kg to 6 mg / kg via intravenous administration at intervals of once every three weeks.

[1008] 15453442-1

[0105]

[1009] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 3 mg / kg to 5 mg / kg via intravenous administration at intervals of once per 1 to 4 weeks, more preferably at a dose in the range of about 3 mg / kg to 5 mg / kg via intravenous administration at intervals of once every two to three weeks, still more preferably at a dose in the range of about 3 mg / kg to 5 mg / kg via intravenous administration at intervals of once every three weeks.

[1010]

[0106]

[1011] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg via intravenous administration at intervals of once per 1 to 4 weeks, more preferably at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg via intravenous administration at intervals of once every two to three weeks, still more preferably at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg via intravenous administration at intervals of once every three weeks.

[1012]

[0107]

[1013] 15453442-1In some embodiments, the immune checkpoint inhibitor is an anti-PD-1 antibody. The dose per administration of the anti-PD-1 antibody used in the present invention is preferably in the range of about 100 to 300 mg. More preferably, the dose per administration of the anti-PD-1 antibody used in the present invention is about 200 mg.

[1014]

[0108]

[1015] The anti-PD-1 antibody can be administered via intravenous administration.

[1016]

[0109]

[1017] In some embodiments, the anti-PD-1 antibody is administered via intravenous infusion, for example for about 20 minutes to about 120 minutes. In some embodiments, the anti-PD-1 antibody is administered via intravenous infusion for about 20 minutes, about 30 minutes, about 40 minutes, about 60 minutes, about 90 minutes, or about 120 minutes.

[1018]

[0110]

[1019] The dosing interval of the anti-PD-1 antibody used in the present invention is preferably once a week (qlw), once every two weeks (q2w), once every three weeks (q3w), or once every four weeks (q4w), more preferably once every three weeks (q3w).

[1020]

[0111]

[1021] In some embodiments, the anti-PD-1 antibody used in the present invention can be administered preferably at a dose in the range in the range of about 100 to 300 mg via

[1022] 15453442-1intravenous administration at intervals of once per 1 to 4 weeks, more preferably at a dose in the range of about 100 to 300 mg via intravenous administration at intervals of once every two to three weeks, still more preferably at a dose in the range of about 100 to 300 mg via intravenous administration at intervals of once every three weeks.

[1023]

[0112]

[1024] In some embodiments, the anti-PD-1 antibody used in the present invention can be administered preferably at a dose in the range of about 200 mg via intravenous administration at intervals of once per 1 to 4 weeks, more preferably at a dose of about 200 mg via intravenous administration at intervals of once every two to three weeks, still more preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1025]

[0113]

[1026] In some embodiments, the immune checkpoint inhibitor is pembrolizumab. The dose per administration of pembrolizumab used in the present invention is preferably in the range of about 100 to 300 mg. More preferably, the dose per administration of pembrolizumab used in the present invention is about 200 mg.

[1027]

[0114]

[1028] Pembrolizumab can be administered via intravenous administration.

[1029] 15453442-1

[0115]

[1030] In some embodiments, pembrolizumab is administered via intravenous infusion, for example for about 20 minutes to about 120 minutes. In some embodiments, pembrolizumab is administered via intravenous infusion for about 20 minutes, about 30 minutes, about 40 minutes, about 60 minutes, about 90 minutes, or about 120 minutes.

[1031]

[0116]

[1032] The dosing interval of pembrolizumab used in the present invention is preferably once a week (qlw), once every two weeks (q2w), once every three weeks (q3w), or once every four weeks (q4w), more preferably once every three weeks (q3w).

[1033]

[0117]

[1034] In some embodiments, pembrolizumab used in the present invention can be administered preferably at a dose in the range in the range of about 100 to 300 mg via intravenous administration at intervals of once per 1 to 4 weeks, more preferably at a dose in the range of about 100 to 300 mg via intravenous administration at intervals of once every two to three weeks, still more preferably at a dose in the range of about 100 to 300 mg via intravenous administration at intervals of once every three weeks.

[1035]

[0118]

[1036] In some embodiments, pembrolizumab used in the present invention can be administered preferably at a

[1037] 15453442-1dose in the range of about 200 mg via intravenous administration at intervals of once per 1 to 4 weeks, more preferably at a dose of about 200 mg via intravenous administration at intervals of once every two to three weeks, still more preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1038]

[0119]

[1039] In some embodiments, the dose per administration of anti-MUCl antibody-drug conjugate used in the present invention is preferably in the range of about 1 mg / kg to 6 mg / kg, and the dose per administration of pembrolizumab used in the present invention is preferably in the range of about 100 to 300 mg.

[1040]

[0120]

[1041] In some embodiments, the dose per administration of anti-MUCl antibody-drug conjugate used in the present invention is preferably in the range of about 3 mg / kg to 6 mg / kg, and the dose per administration of pembrolizumab used in the present invention is preferably in the range of about 100 to 300 mg.

[1042]

[0121]

[1043] In some embodiments, the dose per administration of anti-MUCl antibody-drug conjugate used in the present invention is preferably in the range of about 3 mg / kg to 5 mg / kg, and the dose per administration of pembrolizumab

[1044] 15453442-1used in the present invention is preferably in the range of about 100 to 300 mg.

[1045]

[0122]

[1046] In some embodiments, the dose per administration of anti-MUCl antibody-drug conjugate used in the present invention is preferably about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg, and the dose per administration of pembrolizumab used in the present invention is preferably in the range of about 100 to 300 mg.

[1047]

[0123]

[1048] In some embodiments, the dose per administration of anti-MUCl antibody-drug conjugate used in the present invention is preferably in the range of about 1 mg / kg to 6 mg / kg, and the dose per administration of pembrolizumab used in the present invention is preferably about 200 mg.

[1049]

[0124]

[1050] In some embodiments, the dose per administration of anti-MUCl antibody-drug conjugate used in the present invention is preferably in the range of about 3 mg / kg to 6 mg / kg, and the dose per administration of pembrolizumab used in the present invention is preferably about 200 mg.

[1051]

[0125]

[1052] In some embodiments, the dose per administration of anti-MUCl antibody-drug conjugate used in the present invention is preferably in the range of about 3 mg / kg to

[1053] 15453442-15 mg / kg, and the dose per administration of pembrolizumab used in the present invention is preferably about 200 mg.

[1054]

[0126]

[1055] In some embodiments, the dose per administration of anti-MUCl antibody-drug conjugate used in the present invention is preferably about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg, and the dose per administration of pembrolizumab used in the present invention is preferably about 200 mg.

[1056]

[0127]

[1057] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 1 mg / kg to 6 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose in the range of about 100 to 300 mg via intravenous administration at intervals of once every three weeks.

[1058]

[0128]

[1059] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 1 mg / kg to 5 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose in the range of about 100 to 300 mg

[1060] 15453442-1via intravenous administration at intervals of once every three weeks.

[1061]

[0129]

[1062] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 2 mg / kg to 6 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose in the range of about 100 to 300 mg via intravenous administration at intervals of once every three weeks.

[1063]

[0130]

[1064] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 2 mg / kg to 5 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose in the range of about 100 to 300 mg via intravenous administration at intervals of once every three weeks.

[1065]

[0131]

[1066] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 3 mg / kg to 6 mg / kg via intravenous administration at

[1067] 15453442-1intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose in the range of about 100 to 300 mg via intravenous administration at intervals of once every three weeks.

[1068]

[0132]

[1069] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 3 mg / kg to 5 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose in the range of about 100 to 300 mg via intravenous administration at intervals of once every three weeks.

[1070]

[0133]

[1071] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose in the range of about 100 to 300 mg via intravenous administration at intervals of once every three weeks.

[1072]

[0134]

[1073] 15453442-1In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 1 mg / kg to 6 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1074]

[0135]

[1075] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 1 mg / kg to 5 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1076]

[0136]

[1077] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 2 mg / kg to 6 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1078]

[0137]

[1079] 15453442-1In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 2 mg / kg to 5 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1080]

[0138]

[1081] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 3 mg / kg to 6 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1082]

[0139]

[1083] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose in the range of about 3 mg / kg to 5 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1084]

[0140]

[1085] 15453442-1In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1086]

[0141]

[1087] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose of about 1 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1088]

[0142]

[1089] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose of about 2 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1090] 15453442-1

[0143]

[1091] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose of about 3 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1092]

[0144]

[1093] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose of about 4 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1094]

[0145]

[1095] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose of about 5 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1096] 15453442-1

[0146]

[1097] In some embodiments, the anti-MUCl antibody-drug conjugate used in the present invention can be administered preferably at a dose of about 6 mg / kg via intravenous administration at intervals of once every three weeks, and pembrolizumab used in the present invention can be administered preferably at a dose of about 200 mg via intravenous administration at intervals of once every three weeks.

[1098]

[0147]

[1099] In some embodiments, the additional anticancer agent used in the present invention is carboplatin.

[1100]

[0148]

[1101] The dose per administration of carboplatin used in the present invention is preferably in the range of about AUC 4 to 6 mg*min / ml, more preferably at a dose of about AUC 5 mg*min / ml.

[1102]

[0149]

[1103] Carboplatin can be administered via intravenous administration. In some embodiments, carboplatin is administered via intravenous infusion.

[1104]

[0150]

[1105] The dosing interval of carboplatin used in the present invention is preferably once a week (qlw), once every two weeks (q2w), once every three weeks (q3w), or once every four weeks (q4w), more preferably once every three weeks (q3w).

[1106] 15453442-1

[0151]

[1107] In some embodiments, carboplatin can be administered preferably at a dose in the range of about AUC 4 to 6 mg*min / ml via intravenous administration at intervals of once every three weeks, more preferably at a dose of about AUC 5 mg*min / ml via intravenous administration at intervals of once every three weeks.

[1108]

[0152]

[1109] In some embodiments, the anti-MUCl antibody-drug conjugate can be administered preferably at a dose in the range of about 1 mg / kg to 6 mg / kg or about 1 mg / kg to 5 mg / kg via intravenous administration at intervals of once every three weeks, pembrolizumab can be administered preferably at a dose in the range of about 100 to 300 mg, preferably about 200 mg, via intravenous administration at intervals of once every three weeks, and carboplatin can be administered preferably at a dose in the range of about AUC 4 to 6 mg*min / ml via intravenous administration at intervals of once every three weeks, more preferably at a dose of about AUC 5 mg*min / ml via intravenous administration at intervals of once every three weeks.

[1110]

[0153]

[1111] In some embodiments, the anti-MUCl antibody-drug conjugate can be administered preferably at a dose in the range of about 2 mg / kg to 6 mg / kg or about 2 mg / kg to 5 mg / kg via intravenous administration at intervals of once every three weeks, pembrolizumab can be administered

[1112] 15453442-1preferably at a dose in the range of about 100 to 300 mg, preferably about 200 mg, via intravenous administration at intervals of once every three weeks, and carboplatin can be administered preferably at a dose in the range of about AUC 4 to 6 mg*min / ml via intravenous administration at intervals of once every three weeks, more preferably at a dose of about AUC 5 mg*min / ml via intravenous administration at intervals of once every three weeks.

[1113]

[0154]

[1114] In some embodiments, the anti-MUCl antibody-drug conjugate can be administered preferably at a dose in the range of about 3 mg / kg to 6 mg / kg or about 3 mg / kg to 5 mg / kg via intravenous administration at intervals of once every three weeks, pembrolizumab can be administered preferably at a dose in the range of about 100 to 300 mg, preferably about 200 mg, via intravenous administration at intervals of once every three weeks, and carboplatin can be administered preferably at a dose in the range of about AUC 4 to 6 mg*min / ml via intravenous administration at intervals of once every three weeks, more preferably at a dose of about AUC 5 mg*min / ml via intravenous administration at intervals of once every three weeks.

[1115]

[0155]

[1116] In some embodiments, the anti-MUCl antibody-drug conjugate can be administered preferably at a dose in the range of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg or about 6 mg / kg via

[1117] 15453442-1intravenous administration at intervals of once every three weeks, pembrolizumab can be administered preferably at a dose in the range of about 100 to 300 mg, preferably about 200 mg, via intravenous administration at intervals of once every three weeks, and carboplatin can be administered preferably at a dose in the range of about AUC 4 to 6 mg*min / ml via intravenous administration at intervals of once every three weeks, more preferably at a dose of about AUC 5 mg*min / ml via intravenous administration at intervals of once every three weeks.

[1118]

[0156]

[1119] In some embodiments, the additional anticancer agent used in the present invention is pemetrexed.

[1120]

[0157]

[1121] The dose per administration of pemetrexed used in the present invention is preferably in the range of about 400 to 600 mg / m2, more preferably at a dose of about 500 mg / m2.

[1122]

[0158]

[1123] Pemetrexed can be administered via intravenous administration. In some embodiments, pemetrexed is administered via intravenous infusion.

[1124]

[0159]

[1125] The dosing interval of pemetrexed used in the present invention is preferably once a week (qlw), once every two weeks (q2w), once every three weeks (q3w), or

[1126] 15453442-1once every four weeks (q4w), more preferably once every three weeks (q3w).

[1127]

[0160]

[1128] In some embodiments, pemetrexed can be administered preferably at a dose in the range of about 400 to 600 mg / m2via intravenous administration at intervals of once every three weeks, more preferably at a dose of about 500 mg / m2via intravenous administration at intervals of once every three weeks.

[1129]

[0161]

[1130] In some embodiments, the anti-MUCl antibody-drug conjugate can be administered preferably at a dose in the range of about 1 mg / kg to 6 mg / kg or about 1 mg / kg to 5 mg / kg via intravenous administration at intervals of once every three weeks, pembrolizumab can be administered preferably at a dose in the range of about 100 to 300 mg, preferably about 200 mg, via intravenous administration at intervals of once every three weeks, and pemetrexed can be administered preferably at a dose in the range of about 400 to 600 mg / m2via intravenous administration at intervals of once every three weeks, more preferably at a dose of about 500 mg / m2via intravenous administration at intervals of once every three weeks.

[1131]

[0162]

[1132] In some embodiments, the anti-MUCl antibody-drug conjugate can be administered preferably at a dose in the range of about 2 mg / kg to 6 mg / kg or about 2 mg / kg to 5

[1133] 15453442-1mg / kg via intravenous administration at intervals of once every three weeks, pembrolizumab can be administered preferably at a dose in the range of about 100 to 300 mg, preferably about 200 mg, via intravenous administration at intervals of once every three weeks, and pemetrexed can be administered preferably at a dose in the range of about 400 to 600 mg / m2via intravenous administration at intervals of once every three weeks, more preferably at a dose of about 500 mg / m2via intravenous administration at intervals of once every three weeks.

[1134]

[0163]

[1135] In some embodiments, the anti-MUCl antibody-drug conjugate can be administered preferably at a dose in the range of about 3 mg / kg to 6 mg / kg or about 3 mg / kg to 5 mg / kg via intravenous administration at intervals of once every three weeks, pembrolizumab can be administered preferably at a dose in the range of about 100 to 300 mg, preferably about 200 mg, via intravenous administration at intervals of once every three weeks, and pemetrexed can be administered preferably at a dose in the range of about 400 to 600 mg / m2via intravenous administration at intervals of once every three weeks, more preferably at a dose of about 500 mg / m2via intravenous administration at intervals of once every three weeks.

[1136]

[0164]

[1137] In some embodiments, the anti-MUCl antibody-drug conjugate can be administered preferably at a dose in the

[1138] 15453442-1range of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg or about 6 mg / kg via intravenous administration at intervals of once every three weeks, pembrolizumab can be administered preferably at a dose in the range of about 100 to 300 mg, preferably about 200 mg, via intravenous administration at intervals of once every three weeks, and pemetrexed can be administered preferably at a dose in the range of about 400 to 600 mg / m2via intravenous administration at intervals of once every three weeks, more preferably at a dose of about 500 mg / m2via intravenous administration at intervals of once every three weeks.

[1139]

[0165]

[1140] The dosage values and dosage regime (administration type and / or dosing interval) described above are particularly preferred for treating NSCLC, more preferably locally advanced or metastatic NSCLC.

[1141]

[0166]

[1142] In some embodiments, the patient with cancer to be treated has had no prior systemic therapy for NSCLC or for locally advanced or metastatic NSCLC.

[1143]

[0167]

[1144] In some embodiments, the pharmaceutical product can be administered to treat a patient that has one or more or all of the following criteria:

[1145] • The patient is an adult >18 years of age.

[1146] 15453442-1• The patient has histologically documented* Stage Illb, IIIC, or Stage IV NSQ NSCLC without known AGA meeting the following criteria at the time of treatment (based on the American Joint Committee on Cancer, Eighth Edition):

[1147] Genetic test

[1148] • A patient has tested negative for both EGFR and ALK genomic alterations.

[1149] • A patient has no known other AGAs that have locally available therapies targeting their AGAs in the first-line advanced / metastatic setting. AGA includes but not limited to ROS1, NTRK, B-RAF, MET exon 14 skipping, c-Met, RET, KRAS, or HER2 mutation.

[1150] • A patient with mixed histology may be treated where adenocarcinoma is the predominant histology. Mixed tumors are classified based on the predominant cell type.

[1151] • The patient has a LVEF ≥50% by either an ECHO or MUGA within 28 days of the first treatment.

[1152] • The patient has provided consent to provide mandatory baseline tumor tissue samples and submitted it prior to treatment. If an adequate archival tumor tissue sample (i.e., obtained from a lesion not previously irradiated within 6 months prior to informed consent and after completion of the most recent anticancer treatment regimen) is not available, a newly obtained tumor tissue

[1153] 15453442-1biopsy is mandatory if deemed medically feasible by the investigator.

[1154] • The patient has ECOG PS of 0 or 1 assessed no more than 14 days prior to initiation of treatment.

[1155] • The patient has adequate organ function within 7 days before the first administration of treatment.

[1156] Adequate organ function is defined as shown in Table a:

[1157] [Table a]

[1158] Absolute neutrophil

[1159] ≥1.5 × 109 / L

[1160] count

[1161] Platelets ≥100 × 109 / L

[1162] Hemoglobin ≥9.0 g / dL

[1163] ≤2.5 × ULN (no liver

[1164] ALT and AST metastases); ≤5.0 ULN (with liver metastases at baseline) ≤1.5 × ULN (≤3.0 × ULN if liver metastases at baseline or documented Gilbert's syndrome (unconjugated hyperbilirubinemia) Creatinine clearance* ≥60 mL / min

[1165] PT / INR and either aPTT ≤1.5 × ULN unless the patient is or PTT receiving anticoagulant therapy, as long as PT / INR or aPTT / PTT is within the therapeutic range of intended use of anticoagulant Serum albumin ≥2.5 g / dL

[1166]

[1167] *Estimated creatinine clearance as calculated by Cockcroft-Gault Equation

[1168] • The patient has an adequate treatment washout period prior to start of treatment, defined as:

[1169] a) Major surgery: ≥3 weeks (or 2 weeks for low-invasive cases [e.g., colostomy]).

[1170] 15453442-1b) Radiation therapy (curative) and palliative radiation therapy to the chest: ≥4 weeks, no more than 30 Gy can be received in the lung fields within the past 6 months; ≥2 weeks for palliative radiation therapy to other areas [i.e., limited field and 10 or fewer days or fractions] including whole brain radiotherapy).

[1171] c) Anticancer therapy (including immunotherapy [nonantibody-based therapy], retinoid therapy): ≥2 weeks or 5 times the t½ of the therapeutic agent (whichever is longer); ≥6 weeks for nitrosoureas or mitomycin C, ≥1 week for tyrosine kinase inhibitors. d) Antibody-based anticancer therapy: ≥4 weeks.

[1172] • The patient has not received prior systemic therapy for locally advanced or metastatic NSCLC. A patient who has received neoadjuvant or adjuvant therapy other than those listed in the exclusion criteria may be treated if they have experienced relapsed or disease progression during or after that treatment, and the clinician determines that re-treatment with the same therapy class in the advanced disease setting is clinically appropriate.

[1173] • The patient has measurable disease by clinical assessment according to RECIST v1.1.

[1174] a) A patient with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated

[1175] 15453442-1unequivocal progression since completion of radiation therapy.

[1176] • The patient has PD-L1 IHC status.

[1177] • The patient has a life expectancy ≥3 months.

[1178] • A male or female patient of reproductive / childbearing potential has agreed to use a highly effective form of contraception or avoid intercourse during and upon completion of this treatment and for at least 8 months for female and 5 months for males after the last dose of treatment.

[1179] • Starting at the first dose of treatment, a male patient has not frozen or donated sperm at any time during this treatment for at least 5 months after the last dose of treatment.

[1180] • Starting at the first dose of treatment, a female patient has not donated, or retrieved for their own use, ova at any time during treatment for at least 8 months after the last dose of treatment.

[1181] • The patient is willing and able to comply with scheduled visits, a drug administration plan, laboratory tests, other treatment procedures, and treatment restrictions.

[1182]

[0168]

[1183] In some embodiments, the patient to whom the pharmaceutical product is administered does not have one or more or all of the following criteria:

[1184] 15453442-1• The patient has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE V5.0, Grade ≤1 or baseline. A patient may be treated with chronic, stable Grade 2 toxicities (defined as no worsening to Grade >2 for at least 3 months prior to C1D1 and managed with standard of care treatment) that the clinician deems related to previous anticancer therapy, including:

[1185] a) Chemotherapy-induced neuropathy

[1186] b) Fatigue

[1187] c) Residual toxicities from prior immune-oncology treatment: Grade 1 or Grade 2 endocrinopathies which may include:

[1188] i. Hypothyroidism / hyperthyroidism ii. Type I diabetes

[1189] iii. Hyperglycemia

[1190] iv. Adrenal insufficiency

[1191] v. Adrenalitis

[1192] vi. Skin hypopigmentation (vitiligo) • The patient has had treatment with any of the following:

[1193] a) History of an allogeneic bone marrow or allogeneic T-cell therapy, or solid organ transplant within 3 months before the start of treatment.

[1194] b) Has prior treatment history targeting MUC1 or TA- MUC1.

[1195] 15453442-1• The patient has any history or current presence of CNS metastases, except that a patient who fulfills all the following criteria within 4 weeks before the start of treatment is allowed:

[1196] a) No evidence of disease progression in the CNS and leptomeningeal metastasis

[1197] b) No requirement for chronic corticosteroid therapy c) Asymptomatic CNS metastases

[1198] • The patient has any history of hypersensitivity to any excipients in the treatment or any known contraindications to treatment, including hypersensitivity to the drug substance, its inactive ingredients, or other monoclonal antibodies.

[1199] • The patient has multiple primary malignancies, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated with no evidence of disease for ≥3 years prior to C1D1.

[1200] • The patient has any history of ILD / pneumonitis irrespective of steroid use, or current ILD, or suspected ILD, or ILD that cannot be ruled out by imaging at screening. The patient may be treated if they had a history of radiation pneumonitis that did not require steroids. Examples of suspected ILD / pneumonitis by imaging include the presence of lung parenchymal fibrosis, such as combined pulmonary fibrosis and emphysema, and any radiographic features consistent with

[1201] 15453442-1interstitial lung abnormalities, including but not limited to, extensive ground glass opacities, reticular opacities, traction bronchiectasis, and honeycombing. • The patient has any lung-specific intercurrent clinically significant illnesses such as the following:

[1202] a) Any underlying pulmonary disorder (e. g., acute or unresolved chronic pulmonary embolism within 3 months of the first treatment, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, clinically significant pleural effusion).

[1203] b) Any autoimmune, connective tissue, or inflammatory disorders (e. g., rheumatoid arthritis, Sjogren' s, sarcoidosis) where there is documented, or a suspicion of, pulmonary involvement at the time of Screening.

[1204] c) Prior pneumonectomy (such as unilateral pneumectomy.

[1205] Wedge resection or lobectomy is allowed if the remaining lung volume and function is clinically sufficient).

[1206] • The patient has clinically significant pulmonary compromise or requirement for supplemental oxygen.

[1207] • The patient has any active or chronic corneal disorders, other active ocular conditions requiring ongoing therapy, or any clinically significant corneal disease, that prevents adequate monitoring of drug-induced corneopathy or keratopathy.

[1208] 15453442-1• The patient has any evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection.

[1209] • The patient has active or uncontrolled HIV infection. The patient may be treated if:

[1210] a) CD4+ T-cell count >350 cells / mm3 at the time of Screening.

[1211] b) Virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) at the time of Screening and for at least 12 weeks before Screening.

[1212] c) No AIDS-def ining opportunistic infections or conditions within the past 12 months.

[1213] d) On stable ART regimen, without changes in drugs or dose modification, for at least 4 weeks before treatment and agree to continue ART throughout treatment.

[1214] • The patient has active or uncontrolled HBV infection. The patient may be treated if:

[1215] a) A HBsAg positive patient may be treated if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to allocation.

[1216] b) The patient remains on antiviral therapy throughout treatment and is subject to HBV antiviral therapy post completion of treatment.

[1217] c) The patient has normal transaminase values, or, if liver metastases are present, abnormal transaminases

[1218] 15453442-1with a result of AST / ALT <3 x ULN, which are not attributable to HBV infection.

[1219] • The patient has an active or uncontrolled HCV infection. A patient may treated if:

[1220] a) The patient' s HCV viral load is below the level of detection in the absence of antiviral therapy during the previous 4 weeks before the start of treatment. b) The patient has normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST / ALT <3 x ULN, which are not attributable to HCV infection

[1221] • A female patient who is breastfeeding (women who are willing to temporarily interrupt breastfeeding will also be excluded) or pregnant as confirmed by pregnancy tests performed within 7 days before the start of treatment. If a pregnancy is expected per the clinician discretion, the patient will be excluded regardless of the pregnancy test result.

[1222] • A female patient who is pregnant or planning to become pregnant while in the treatment and for at least 8 months after the last administration of treatment.

[1223] • A male patient who intends to father a child while in the treatment and for at least 5 months after the last administration of treatment.

[1224] • The patient has any of the following within the past 6 months: cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event.

[1225] 15453442-1• The patient has any uncontrolled or clinically significant cardiovascular disease, including the following:

[1226] a) The patient has a QTcF interval >470 ms (average of triplicate determinations at Screening).

[1227] b) The patient has diagnosed or suspected long QT syndrome, or known family history of long QT syndrome.

[1228] c) The patient has a history of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes.

[1229] d) The patient has known or persistent (i. e., demonstrated in 2 separated measurements) bradycardia of <50 bpm, unless the participant has a pacemaker.

[1230] e) The patient has a history of second- or third-degree heart block. Candidates with a history of heart block may be eligible if they currently have pacemakers or otherwise are medically manageable and have no history of fainting or clinically relevant arrhythmia with pacemakers.

[1231] f ) The patient has had a myocardial infarction within 6 months prior to the first treatment.

[1232] g) The patient has had uncontrolled, unstable, or untreated angina pectoris within 6 months prior to Screening.

[1233] 15453442-1h) The patient has NYHA Class 2 to 4 congestive heart failure.

[1234] i) The patient has had a coronary / peripheral artery bypass graft within 6 months prior to Screening. j ) The patient has had a coronary intervention including angioplasty or stent implantation within 6 months prior to Screening.

[1235] k) The patient has arterial hypertension with persistent systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg or status posthypertensive crisis within 6 months prior to treatment.

[1236] l) The patient has complete left bundle branch block. • The patient has a clinically active (i. e., symptomatic and / or on-treatment), known, or suspected autoimmune disease. The following examples may be enrolled as an exception: type I diabetes mellitus / hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.

[1237] • The patient is a current participant in other therapeutic investigational procedures, except for participation in LTSFU without any investigational treatment.

[1238] 15453442-1• The patient has received an attenuated live vaccine within 30 days prior to the first dose of treatment.

[1239] Examples of live vaccines include the following: measles, mumps, rubella, varicella / zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. Messenger ribonucleic acid and replicationdeficient adenoviral vaccines are not considered attenuated live vaccines and are allowed.

[1240] • The patient has psychological, social, familial, or geographical factors that would prevent regular followup.

[1241] • The patient has severe or uncontrolled systemic diseases, including uncontrolled hypertension, uncontrolled diabetes mellitus, active bleeding or severe bleeding diatheses, substance abuse, or other medical condition that would increase the risk of toxicity or interfere with treatment. Screening for chronic conditions is not required.

[1242] • The patient has previously received topoisomerase 1 inhibitor or topoisomerase 1 inhibitor-based ADCs such as datopotamab deruxtexan and sacituzumab govitecan.

[1243] • The patient has received prior treatment with a PD-1 / PD-L1 inhibitor for any malignancy (such as

[1244] 15453442-1atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab).

[1245] • The patient has previously received any prior treatment with an agent directed to another stimulatory or co-inhibitory T-cell receptor (such as CD137 agonists, CTLA-4 inhibitors, or OX 40 agonists).

[1246] • The patient has uncontrolled diabetes. Uncontrolled diabetes is defined as HbAlc >8% or HbAlc 7% to <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.

[1247] • The patient has any condition requiring high doses of steroids (>10 mg / day of prednisone or equivalent) or other immunosuppressive medications.

[1248] • The patient has an active autoimmune disease that has required systemic treatment in past 2 years.

[1249] [Examples ]

[1250]

[0169]

[1251] The present invention will be specifically described with reference to Examples given below. The present invention is not limited by these examples. Furthermore, these examples should not be construed in a limited manner by any means.

[1252]

[0170]

[1253] [Example 1: Preparation of anti-MUCl antibody-drug conj ugate ]

[1254] 15453442-1An anti-TA-MUCl antibody-drug conjugate in which a drug-linker represented by

[1255] [Formula 10]

[1256]

[1257] OH 0 wherein A represents a connecting position to the antibody

[1258] and an anti-TA-MUCl antibody were conjugated via a thioether bond (in the present invention, referred to as TA-MUCl-DXd ADC) was prepared using a humanized anti-TA-MUCl antibody (PM-N54Q) in accordance with the method described in International Publication No. WO 2019 / 219891. The average number of conjugated drug molecules per antibody (drug to antibody ratio; DAR) in TA-MUCl-DXd ADC is 7.9.

[1259]

[0171]

[1260] TA-MUCl-DXd ADC is also known as " DS-3939" or " DS-3939a" (as used herein). The terms may be used interchangeably.

[1261]

[0172]

[1262] 15453442-1[Example 2: Evaluation of antitumor efficacy of TA-MUC1-DXd ADC, anti-PD-1 antibody, and their combination in hMUCl-CT26. wt xenograft mouse model]

[1263] 2-1 Cell line

[1264] hMUCl-CT26. wt cells (Clone: Muc1-40r-CT26.wt-50-100-P10123-D3) allowed to stably express human MUC1 by introducing the human MUC1 gene to mouse colorectal cancer line CT26.wt cells purchased from American Type Culture Collection (Cat. No. CRL-2638 ) were used. The cell line was established at Glycotope GmbH and confirmed to express TA-MUC1 (Gellert J, Jakel A, Danielczyk A, et al., Int J Mol Sci. 2024; 25 (3): 1406).

[1265]

[0173]

[1266] 2-2 Antitumor activity evaluation

[1267] Five-week-old female BALB / cAJcl mice were purchased from CLEA Japan, Inc. The hMUCl-CT26. wt cells were suspended in physiological saline (Otsuka Pharmaceutical Factory, Inc. ) and then subcutaneously transplanted at 2 × 106cells to the right flank of each mouse. The length and width (mm) of each tumor was measured using an electronic digital caliper (CD-15AX or CD-15CX, Mitsutoyo Corp. ), and body weight (g) was measured using an electronic balance (UW2200H, Shimadzu Corp. ).

[1268]

[0174]

[1269] 7 days after transplantation, the mice were grouped (Day 0, n = 18 ). TA-MUCl-DXd ADC prepared in Example 1 was prepared into 1 mg / mL using ABS buffer ( 10 mM acetate

[1270] 15453442-1buffer solution, pH 5.5, 5% sorbitol) and administered intravenously via the tail vein at 10 mg / kg (Day 0 and Day 7 ). An anti-PD-1 antibody ( InVivoMAb anti-mouse PD-1 [CD279], clone RMP1-14, purchased from Bio X Cell) was prepared into 1 mg / mL using D-PBS (-) (FUJIFILM Wako Pure Chemical Corp. ) and administered intraperitoneally at 10 mg / kg (Days 0, 3, 7, and 10). A group given both TA-MUCl-DXd ADC and the anti-PD-1 antibody was regarded as a combination group. For a vehicle group, ABS buffer was administered on Day 0. After administration, the length and width (mm) of the tumor and the body weight (g) were measured two or more times a week. An estimated tumor volume was calculated on the basis of the measured tumor length and width. The estimated tumor volume was calculated as follows.

[1271] Estimated tumor volume (mm3) = length (mm) × width (mm)2 / 2

[1272]

[0175]

[1273] In the experiment, the final measurement day was set as Day 35. However, an individual having an estimated tumor volume which exceeded 2500 mm3was euthanized at the time from the viewpoint of animal experimentation ethics.

[1274]

[0176]

[1275] Comparisons of antitumor activity based on estimated tumor volume were conducted using Steel's test.

[1276] Multiplicity-adjusted p-values were reported to four

[1277] 15453442-1decimal places; if the p-value was less than 0.0001, it was reported as P < 0.0001. A p-value < 0.05 was considered statistically significant.

[1278] The effects of TA-MUCl-DXd ADC and the anti-PD-1 antibody relative to the vehicle group, as well as the effects of the combination group relative to each monotherapy group, were evaluated at the final time point at which all animals were alive (Day 14 ).

[1279]

[0177]

[1280] Figure 1 shows changes in estimated tumor volume in the antitumor activity evaluation test described above. The horizontal axis represents days after initial administration and the vertical axis represents estimated tumor volumes (mm3).

[1281] On Day 14, the TA-MUCl-DXd ADC group (mean ETV: 922 mm3) exhibited a significant antitumor effect compared to the vehicle group (mean ETV: 1826 mm3) (P = 0.0112 ). The anti-PD-1 antibody group (mean ETV: 965 mm3) also showed a significant antitumor effect compared to the vehicle group (P = 0.0027 ). Furthermore, the combination group (mean ETV: 137 mm3) exhibited a significant antitumor effect compared to the TA-MUCl-DXd ADC group (P = 0.0186) and anti-PD-1 antibody group (P = 0.0020). No significant body weight loss attributed to drug administration was observed.

[1282]

[0178]

[1283] 15453442-1[Example 3: Comparison of the number of complete responders among TA-MUC1-DXd ADC, anti-PD-1 antibody, and their combination groups]

[1284] The comparison was conducted within the same study as in Example 2. Animals in which the tumors completely regressed and the estimated tumor volume reached 0 mm3were defined as complete responders. The number of complete responder animals in the TA-MUCl-DXd ADC group, the anti-PD-1 antibody group, and the combination group were compared on Day 35.

[1285]

[0179]

[1286] Comparisons of antitumor activity based on the number of complete responders were performed using the Fisher' s exact test (2 x 2 ). The effects of the combination group compared to each monotherapy group were evaluated based on the number of complete responders. Bonferroni correction was applied to the p-values. The p-values were reported to four decimal places; if the p-value was less than 0.0001, it was reported as P < 0.0001. A p-value < 0.05 was considered statistically significant.

[1287]

[0180]

[1288] The number of mice achieving complete response is shown in Table 1. Complete response was confirmed in 5 out of 18 cases in the TA-MUCl-DXd ADC group and 4 out of 18 cases in the anti-PD-1 antibody group. Furthermore, complete response was confirmed in 14 out of 18 cases in

[1289] 15453442-1the combination group, indicating a significant increase in the number of mice achieving complete response as compared with the TA-MUCl-DXd ADC group (P = 0.0134 ) or the anti-PD-1 antibody group (P = 0.0044 ).

[1290]

[0181]

[1291] [Table 1 ]

[1292]

[1293] Group Treatment N Complete Response 1 Vehicle 18 0 2 TA-MUC1-DXd ADC 10 mg / kg 18 5 3 Anti-PD-1 antibody 10 mg / kg 18 4 4 TA-MUC1-DXd ADC 10 mg / kg + Anti-PD-1 antibody 10 mg / kg 18 14

[1294]

[0182]

[1295] [Example 4: Survival evaluation of TA-MUCl-DXd ADC, anti-PD-1 antibody, and their combination]

[1296] The evaluation was conducted within the same study as in Example 2. Survival curve and a median survival time (MST) were estimated using the Kaplan-Meier method, and MST was expressed as an integer. The mice with an estimated tumor volume exceeding 2500 mm3were euthanized at that time point. Survival duration for each mouse was defined as the period from the day of initial dosing to the day of euthanasia. The mice surviving until Day 35 were censored, with survival duration defined as the period from Day 0 to Day 35.

[1297]

[0183]

[1298] 15453442-1Comparisons based on survival time were performed using the log-rank test ( for multiple group comparisons). The effects of each monotherapy compared to the vehicle group, as well as the effects of the combination group compared to each monotherapy group were evaluated. The p-values were reported to four decimal places; if the p-value was less than 0.0001, it was reported as P < 0.0001. A p-value < 0.05 was considered statistically significant.

[1299]

[0184]

[1300] Kaplan-Meier survival curves are shown in Figure 2. The horizontal axis represents days after initial administration and the vertical axis represents survival rate (%). Compared with the vehicle group (MST: 16 days), the TA-MUCl-DXd ADC group (MST: 28 days) and anti-PD-1 antibody group (MST: 27 days) showed a significant prolongation of survival (P = 0.0013 and P = 0.0036, respectively). Furthermore, their combination group (MST: >35 days) demonstrated significantly longer survival compared with the TA-MUCl-DXd ADC group (P = 0.0115) as well as the anti-PD-1 antibody group (P = 0.0029).

[1301]

[0185]

[1302] The above results suggested that TA-MUCl-DXd ADC and the anti-PD-1 antibody exhibit significant antitumor activity against TA-MUCl-expressing tumor. In addition, the combination of these drugs exhibited enhanced

[1303] 15453442-1antitumor efficacy compared with administration of either monotherapy.

[1304]

[0186]

[1305] [Example 5: Evaluation of antitumor efficacy of TA-MUC1-DXd ADC, anti-PD-Ll antibody, and their combination in hMUCl-CT26. wt xenograft mouse model]

[1306] Five-week-old female BALB / cAJcl mice were purchased from CLEA Japan, Inc. The hMUCl-CT26. wt cells described in Example 2 were suspended in physiological saline (Otsuka Pharmaceutical Factory, Inc. ) and then subcutaneously transplanted at 2 × 106cells to the right flank of each mouse. The length and width (mm) of each tumor was measured using an electronic digital caliper (CD-15AX or CD-15CX, Mitsutoyo Corp. ), and body weight (g) was measured using an electronic balance (UW2200H, Shimadzu Corp. ).

[1307]

[0187]

[1308] 7 days after transplantation, the mice were grouped (Day 0, n = 18 ). TA-MUCl-DXd ADC prepared in Example 1 was prepared into 1 mg / mL using ABS buffer ( 10 mM acetate buffer solution, pH 5.5, 5% sorbitol) and administered intravenously via the tail vein at 10 mg / kg (Day 0 and Day 7 ). An anti-PD-Ll antibody ( InVivoMAb anti-mouse PD-L1 [B7-H1 ], clone 10F.9G2, purchased from Bio X Cell) was prepared into 0.5 mg / mL using D-PBS (-) (FUJIFILM Wako Pure Chemical Corp. ) and administered intraperitoneally at 5 mg / kg (Day 0 and Day 4 ). A group given both TA-

[1309] 15453442-1MUCl-DXd ADC and the anti-PD-Ll antibody was regarded as a combination group. For a vehicle group, ABS buffer was administered on Day 0. After administration, the length and width (mm) of the tumor and the body weight (g) were measured two or more times a week. An estimated tumor volume was calculated on the basis of the measured tumor length and width. The estimated tumor volume was calculated as follows.

[1310] Estimated tumor volume (mm3) = length (mm) × width (mm)2 / 2

[1311]

[0188]

[1312] In the experiment, the final measurement day was set as Day 35. However, an individual having an estimated tumor volume which exceeded 2500 mm3, was euthanized at the time from the viewpoint of animal experimentation ethics.

[1313]

[0189]

[1314] Comparisons of antitumor activity based on estimated tumor volume were conducted using Steel's test.

[1315] Multiplicity-adjusted p-values were reported to four decimal places; if the p-value was less than 0.0001, it was reported as P < 0.0001. A p-value < 0.05 was considered statistically significant. The effects of TA-MUCl-DXd ADC and the anti-PD-Ll antibody relative to the vehicle group, as well as the effects of the combination group relative to each monotherapy group, were evaluated

[1316] 15453442-1at the final time point at which all animals were alive (Day 14 ).

[1317]

[0190]

[1318] Figure 3 shows changes in estimated tumor volume in the antitumor activity evaluation test described above. The horizontal axis represents days after initial administration and the vertical axis represents estimated tumor volumes (mm3). On Day 14, the TA-MUCl-DXd ADC group (mean ETV: 643 mm3) exhibited a significant antitumor effect compared to the vehicle group (mean ETV: 1805 mm3) (P = 0.0010). While no significant antitumor effect was observed in the anti-PD-Ll antibody group (mean ETV: 1359 mm3) (P = 0.1980) compared to the vehicle group, their combination group (mean ETV: 270 mm3) exhibited a significant antitumor effect compared to the anti-PD-Ll antibody group (P = 0.0001 ). No significant body weight loss attributed to drug administration was observed.

[1319]

[0191]

[1320] [Example 6: Comparison of the number of complete responders among TA-MUCl-DXd ADC, anti-PD-Ll antibody, and their combination groups]

[1321] The comparison was conducted within the same study as in Example 5. Animals in which the tumors completely regressed and the estimated tumor volume reached 0 mm3were defined as complete responders. The numbers of complete responder animals in the TA-MUCl-DXd ADC group,

[1322] 15453442-1the anti-PD-Ll antibody group, and the combination group were compared on Day 35.

[1323]

[0192]

[1324] Evaluation of antitumor efficacy of TA-MUCl-DXd ADC, anti-PD-Ll antibody, and their combination in hMUCl-CT26.wt xenograft mouse model. Comparisons of antitumor activity based on the number of complete responders were performed using the Fisher' s exact test (2 x 2 ). The effects of the combination group compared to each monotherapy group were evaluated based on the number of complete responders. Bonferroni correction was applied to the p-values. The p-values were reported to four decimal places; if the p-value was less than 0.0001, it was reported as P < 0.0001. A p-value < 0.05 was considered statistically significant.

[1325]

[0193]

[1326] The number of mice achieving complete response are shown in Table 2. Complete response was confirmed in 6 out of 18 cases in the TA-MUCl-DXd ADC group and 1 out of 18 cases in the anti-PD-Ll antibody group. Furthermore, complete response was confirmed in 11 out of 18 cases in the combination group, indicating significant increase in the number of mice achieving complete response (P = 0.0018 ) as compared with the anti-PD-Ll antibody group.

[1327]

[0194]

[1328] [Table 2 ]

[1329] 15453442-1Group! o:a:rie;i. N Complete Response Vehicle I A-MUCl-DXd ADC 10 mgrkg 18

[1330]

[1331] Anti-PD-Ll antibody 5 ttig / kg 4 TA-MUCl-DXd ADC 10 mg / kg + Anii-f’D-tl antibody 5 m / g 18 U

[1332]

[0195]

[1333] [Example 7: Survival evaluation of TA-MUCl-DXd ADC, anti-PD-L1 antibody, and their combination]

[1334] The evaluation was conducted within the same study as in Example 5. Survival curve and a median survival time (MST) were estimated using the Kaplan-Meier method, and MST was expressed as an integer. The mice with an estimated tumor volume exceeding 2500 mm3were euthanized at that time point. Survival duration for each mouse was defined as the period from the day of initial dosing to the day of euthanasia. The mice surviving until Day 35 were censored, with survival duration defined as the period from Day 0 to Day 35.

[1335]

[0196]

[1336] Comparisons based on survival time were performed using the log-rank test ( for multiple group comparisons). The effects of each monotherapy compared to the vehicle group, as well as the effects of the combination group compared to each monotherapy group were evaluated. The p-values were reported to four decimal places; if the p-value was less than 0.0001, it was reported as P <

[1337] 15453442-10.0001. A p-value < 0.05 was considered statistically significant.

[1338]

[0197]

[1339] Kaplan-Meier survival curves are shown in Figure 4. The horizontal axis represents days after initial administration and the vertical axis represents survival rate (%). Compared with the vehicle group (MST: 16 days), the TA-MUCl-DXd ADC group (MST: 31 days) showed a significant prolongation of survival (P = 0.0002 ). While there was no significant prolongation of survival in the anti-PD-Ll antibody group (MST: 20 days) compared to the vehicle group (P = 0.2260), the combination group (MST: >35 days) demonstrated a significantly longer survival compared with the anti-PD-Ll antibody group (P = 0.0003).

[1340]

[0198]

[1341] The above result suggested that TA-MUCl-DXd ADC and the anti-PD-Ll antibody exhibit a positive combination effect against TA-MUCl-expressing tumor.

[1342]

[0199]

[1343] [Example 8: A Phase lb / 2, Multicenter, 2-Part, Open-Label Trial to Evaluate DS-3939a in Participants with Solid Tumors. Substudy 1: DS-3939a in Combination with Immunotherapy Agents With or Without Chemotherapy in Participants with No Prior Therapy for Locally Advanced / Metastatic NSCLC. ]

[1344]

[0200]

[1345] 15453442-1The study is designed to assess the safety, tolerability, and efficacy of DS-3939a in combination with immunotherapy plus chemotherapy (either carboplatin or pemetrexed) in participants with locally advanced or metastatic NSCLC.

[1346]

[0201]

[1347] The primary obj ective of the study is to evaluate the safety and tolerability of trial interventions with DS-3939a in combination with pembrolizumab plus chemotherapy (either carboplatin or pemetrexed), to determine the recommended dose for expansions, and to evaluate the efficacy of the trial intervention as measured by obj ective response.

[1348]

[0202]

[1349] The secondary obj ectives include:

[1350] 1. To evaluate the efficacy of trial intervention as measured by DoR.

[1351] 2. To evaluate the efficacy of trial intervention as measured by DCR.

[1352] 3. To evaluate the efficacy of trial intervention as measured by TTR.

[1353] 4. To evaluate the efficacy of trial intervention as measured by best percentage change in the SoD of measurable tumors.

[1354] 5. To evaluate the efficacy of trial intervention as measured by PFS.

[1355] 15453442-16. To evaluate the efficacy of trial intervention as measured by OS.

[1356] 7. To assess the PK of DS-3939a when dosed in combination with other agents.

[1357] 8. To assess the immunogenicity of DS-3939a when dosed in combination with other agents.

[1358]

[0203]

[1359] The study is designed as an open-label, multi-center, randomized Phase lb / 2 study of DS-3939a in combination with pembrolizumab (Cohort A), pembrolizumab plus carboplatin (Cohort B), and pembrolizumab plus pemetrexed (Cohort C) in participants with no prior therapy for locally advanced / metastatic NSCLC. The study includes a control arm that receives pembrolizumab plus carboplatin and pemetrexed (Cohort D). The treatment groups are provided below.

[1360]

[0204]

[1361] Participants receive either:

[1362] A. DS-3939a + pembrolizumab (200 mg Q3W TV) (Cohort A) or,

[1363] B. DS-3939a + pembrolizumab (200 mg Q3W TV) + carboplatin (AUC5* Q3W TV) (Cohort B) or,

[1364] C. DS-3939a + pembrolizumab (200 mg Q3W TV) + pemetrexed (500 mg / m2Q3W TV) (Cohort C) or,

[1365] D. pembrolizumab (200 mg Q3W TV) + carboplatin (AUC5* Q3W TV) + pemetrexed (500 mg / m2Q3W TV) (Cohort D)

[1366] 15453442-1*carboplatin was administered at a dose of AUC 5 mg*min / ml

[1367]

[0205]

[1368] Participants continue receiving the assigned dose of the study drug (s) until one of the following occurs first: death, an adverse event (AE), radiographic disease progression as determined by the investigator according to RECIST VI. 1, clinical progression, withdrawal of consent ( for the study drug), a physician' s decision, loss to follow-up, pregnancy, protocol deviation, study termination by Daiichi Sankyo, or any other reason.

[1369] Participants may receive up to 35 cycles of pembrolizumab and up to 4 cycles of carboplatin.

[1370]

[0206]

[1371] No dose adjustments for pembrolizumab are recommended. Pembrolizumab will be withheld for treatment-related toxicities as appropriate. Participants should receive appropriate supportive care measures deemed necessary. The dose of pembrolizumab will remain constant at [200 mg Q3W] for each dose level in each arm.

[1372]

[0207]

[1373] The recommended dose adjustment for carboplatin and pemetrexed follows the local practice.

[1374]

[0208]

[1375] The recommended dose reductions for DS-3939a are shown in Table 3. Dose reductions beyond the second dose reduction are not allowed for DS-3939a.

[1376] 15453442-1

[0209]

[1377] [Table 3]

[1378] Q3W IV DS-3939a

[1379] Starting 3 mg / kg 4 mg / kg 5 mg / kg 6 mg / kg Dose

[1380] -1 2 mg / kg 3 mg / kg 4 mg / kg 5 mg / kg -2 1 mg / kg 2 mg / kg 3 mg / kg 4 mg / kg

[1381]

[1382]

[0210]

[1383] The inclusion criteria include:

[1384] • Sign and date the Main Trial IGF, prior to the start of any trial-specific procedures.

[1385] • Adults >18 years of age at the time the Main Trial IGF is signed ( follow local regulatory requirements if the legal age of consent for trial participation is >18 years old).

[1386] • Histologically documented* Stage IIIb, IIIC, or Stage IV NSQ NSCLC without known AGA meeting the following criteria at the time of enrollment (based on the American Joint Committee on Cancer, Eighth Edition):

[1387] Genetic test

[1388] • Participants must have documented negative test results for both EGFR and ALK genomic alterations. If prior test results are unavailable, participants are required to undergo locally approved / validated testing for these specific genomic alterations.

[1389] • Participants have no known other AGAs (based on existing test result of local test) that have locally available therapies targeting their AGAs in

[1390] 15453442-1the first-line advanced / metastatic setting. AGA includes but not limited to ROS1, NTRK, B-RAF, MET exon 14 skipping, c-Met, RET, KRAS, or HER2 mutation.

[1391] * Participants with mixed histology are eligible if adenocarcinoma is the predominant histology. Mixed tumors will be classified based on the predominant cell type.

[1392] • Has a LVEF ≥50% by either an ECHO or MUGA within 28 days of the first trial intervention.

[1393] • Consent to provide mandatory baseline tumor tissue samples and submit it prior to enrollment / randomization. If an adequate archival tumor tissue sample (ie, obtained from a lesion not previously irradiated within 6 months prior to informed consent and after completion of the most recent anticancer treatment regimen) is not available, a newly obtained tumor tissue biopsy is mandatory if deemed medically feasible by the investigator.

[1394] • ECOG PS of 0 or 1 assessed no more than 14 days prior to initiation of trial interventions.

[1395] • Has adequate organ function within 7 days before the first administration of trial intervention. Adequate organ function is defined as shown in Table 4:

[1396] [Table 4 ]

[1397] Absolute neutrophil

[1398] ≥1.5 × 109 / L

[1399] count

[1400] Platelets ≥100 × 109 / L

[1401]

[1402] 15453442-1Hemoglobin ≥9.0 g / dL

[1403] ≤2.5 × ULN (no liver

[1404] ALT and AST metastases); ≤5.0 ULN (with liver metastases at baseline) ≤1.5 × ULN (≤3.0 × ULN if liver metastases at baseline or documented Gilbert's syndrome (unconjugated hyperbilirubinemia) Creatinine clearance* ≥60 mL / min

[1405] PT / INR and either aPTT ≤1.5 × ULN unless the participant or PTT is receiving anticoagulant therapy, as long as PT / INR or aPTT / PTT is within the therapeutic range of intended use of anticoagulant

[1406] Serum albumin ≥2.5 g / dL

[1407]

[1408] *Estimated creatinine clearance as calculated by Cockcroft-Gault Equation

[1409] • Has an adequate treatment washout period prior to start of trial intervention, defined as:

[1410] e) Major surgery: >3 weeks (or 2 weeks for low-invasive cases [eg, colostomy] ).

[1411] f ) Radiation therapy (curative) and palliative radiation therapy to the chest: >4 weeks, no more than 30 Gy can be received in the lung fields within the past 6 months; >2 weeks for palliative radiation therapy to other areas [ie, limited field and 10 or fewer days or fractions] including whole brain radiotherapy).

[1412] g) Anticancer therapy (including immunotherapy [nonantibody-based therapy], retinoid therapy): >2 weeks or 5 times the t½ of the therapeutic agent

[1413] 15453442-1(whichever is longer); >6 weeks for nitrosoureas or mitomycin C, ≥1 week for tyrosine kinase inhibitors. h) Antibody-based anticancer therapy: ≥4 weeks.

[1414] • Participants must not have received prior systemic therapy for locally advanced or metastatic NSCLC.

[1415] Subj ects who received neoadjuvant or adjuvant therapy other than those listed in the exclusion criteria are eligible if they have experienced relapsed or disease progression during or after that treatment, and the investigator determines that re-treatment with the same therapy class in the advanced disease setting is clinically appropriate.

[1416] • Participants must have measurable disease by investigator assessment according to RECIST v1.1.

[1417] b) Participants with prior definitive radiation therapy must have measurable disease per RECIST v1.1 that is outside the radiation field or has demonstrated unequivocal progression since completion of radiation therapy.

[1418] • Participants must have documented PD-L1 IHC status.

[1419] • Has a life expectancy >3 months based on Investigator ' s assessment.

[1420] • Male and female participants of reproductive / childbearing potential must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of this study and

[1421] 15453442-1for at least 8 months for female and 5 months for males after the last dose of trial intervention.

[1422] • Starting at the first dose of trial intervention, male participants must not freeze or donate sperm at any time during this study for at least 5 months after the last dose of trial intervention. Preservation of sperm should be considered prior to the first dose of trial intervention.

[1423] • Starting at the first dose of trial intervention, female participants must not donate, or retrieve for their own use, ova at any time during this study for at least 8 months after the last dose of trial intervention. Preservation of ova should be considered prior to the first dose of trial intervention.

[1424] • Is willing and able to comply with scheduled visits, a drug administration plan, laboratory tests, other trial procedures, and trial restrictions.

[1425]

[0211]

[1426] The exclusion criteria includes:

[1427] • Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE V5.0, Grade ≤1 or baseline. Participants may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade >2 for at least 3 months prior to C1D1 and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, including:

[1428] 15453442-1d) Chemotherapy-induced neuropathy

[1429] e) Fatigue

[1430] f ) Residual toxicities from prior immune-oncology treatment: Grade 1 or Grade 2 endocrinopathies which may include:

[1431] vii. Hypothyroidism / hyperthyroidism

[1432] viii. Type I diabetes

[1433] ix. Hyperglycemia

[1434] x. Adrenal insufficiency

[1435] xi. Adrenalitis

[1436] xii. Skin hypopigmentation (vitiligo) • Treatment with any of the following:

[1437] c) History of an allogeneic bone marrow or allogeneic T-cell therapy, or solid organ transplant within 3 months before the start of trial intervention. d) Has prior treatment history targeting MUC1 or TA- MUC1.

[1438] • Has history or current presence of CNS metastases, except for participants who fulfill all the following criteria within 4 weeks before the start of trial intervention is allowed:

[1439] d) No evidence of disease progression in the CNS and leptomeningeal metastasis

[1440] e) No requirement for chronic corticosteroid therapy f ) Asymptomatic CNS metastases

[1441] • History of hypersensitivity to any excipients in the trial interventions or any known contraindications to

[1442] 15453442-1treatment, including hypersensitivity to the drug substance, its inactive ingredients, or other monoclonal antibodies.

[1443] • Has multiple primary malignancies, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, or other solid tumors curatively treated with no evidence of disease for ≥3 years prior to C1D1.

[1444] • Has any history of ILD / pneumonitis irrespective of steroid use, or current ILD, or suspected ILD, or ILD that cannot be ruled out by imaging at screening.

[1445] Participants may be eligible if they had history of radiation pneumonitis that did not require steroids.

[1446] Examples of suspected ILD / pneumonitis by imaging include the presence of lung parenchymal fibrosis, such as combined pulmonary fibrosis and emphysema, and any radiographic features consistent with interstitial lung abnormalities, including but not limited to, extensive ground glass opacities, reticular opacities, traction bronchiectasis, and honeycombing.

[1447] • Lung-specific intercurrent clinically significant illnesses including, but not limited to, the following:

[1448] d) Any underlying pulmonary disorder (eg, acute or unresolved chronic pulmonary embolism within 3 months of the first trial intervention, severe asthma, severe chronic obstructive pulmonary disease, restrictive lung disease, clinically significant pleural effusion, etc. ).

[1449] 15453442-1e) Any autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis, Sjogren' s, sarcoidosis, etc. ) where there is documented, or a suspicion, of pulmonary involvement at the time of Screening.

[1450] f ) Prior pneumonectomy (such as unilateral pneumectomy.

[1451] Wedge resection or lobectomy is allowed if the remaining lung volume and function is clinically sufficient).

[1452] • Has clinically significant pulmonary compromise or requirement for supplemental oxygen.

[1453] • Has any active or chronic corneal disorders, other active ocular conditions requiring ongoing therapy, or any clinically significant corneal disease, that prevents adequate monitoring of drug-induced corneopathy or keratopathy.

[1454] • Evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection.

[1455] • Has active or uncontrolled HIV infection.

[1456] Participants must be tested for HIV viral load during the Screening Period if acceptable by local regulations or IRBs / IECs. Participants are eligible if:

[1457] e) CD4+ T-cell count >350 cells / mm3 at the time of Screening.

[1458] f ) Virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of

[1459] 15453442-1detection) at the time of Screening and for at least 12 weeks before Screening.

[1460] g) No AIDS-def ining opportunistic infections or conditions within the past 12 months.

[1461] h) On stable ART regimen, without changes in drugs or dose modification, for at least 4 weeks before trial entry (Day 1 ) and agree to continue ART throughout the study.

[1462] • Has active or uncontrolled HBV infection (Hepatitis B screening testing per local guidance is required).

[1463] Participants are eligible if:

[1464] d) HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to allocation. e) Participants should remain on antiviral therapy throughout trial intervention and follow local guidelines for HBV antiviral therapy post completion of trial intervention.

[1465] f ) Have normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST / ALT <3 x ULN, which are not attributable to HBV infection.

[1466] • Has an active or uncontrolled HCV infection.

[1467] (Hepatitis C screening testing per local guidance is required). Participants are eligible if:

[1468] c) History of hepatitis C infection eligible if the HCV viral load is below the level of detection in the

[1469] 15453442-1absence of antiviral therapy during the previous 4 weeks before the start of trial intervention.

[1470] d) Have normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST / ALT <3 x ULN, which are not attributable to HCV infection

[1471] • Female who is breastfeeding (women who are willing to temporarily interrupt breastfeeding will also be excluded) or pregnant as confirmed by pregnancy tests performed within 7 days before the start of trial intervention. If a pregnancy is expected per the investigator discretion, the participant will be excluded regardless of the pregnancy test result.

[1472] • Female who is pregnant or planning to become pregnant while in the trial and for at least 8 months after the last administration of trial intervention.

[1473] • Male who intends to father a child while in the trial and for at least 5 months after the last administration of trial intervention.

[1474] • Any of the following within the past 6 months: cerebrovascular accident, transient ischemic attack, or other arterial thromboembolic event.

[1475] • Uncontrolled or clinically significant cardiovascular disease, including the following:

[1476] m) QTcF interval >470 ms (average of triplicate determinations at Screening).

[1477] 15453442-1n) Diagnosed or suspected long QT syndrome, or known family history of long QT syndrome.

[1478] o) History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes. p) Participant has known or persistent (i. e., demonstrated in 2 separated measurements) bradycardia of <50 bpm, unless the participant has a pacemaker.

[1479] q) History of second- or third-degree heart block.

[1480] Candidates with a history of heart block may be eligible if they currently have pacemakers or otherwise are medically manageable and have no history of fainting or clinically relevant arrhythmia with pacemakers.

[1481] r) Myocardial infarction within 6 months prior to the first trial intervention.

[1482] s ) Uncontrolled, unstable, or untreated angina pectoris within 6 months prior to Screening.

[1483] t) NYHA Class 2 to 4 congestive heart failure.

[1484] u) Coronary / peripheral artery bypass graft within 6 months prior to Screening.

[1485] v) Coronary intervention including angioplasty or stent implantation within 6 months prior to Screening. w) Arterial hypertension with persistent systolic blood pressure >160 mmHg or diastolic blood pressure >100

[1486] 15453442-1mmHg or status post-hypertensive crisis within 6 months prior to Screening.

[1487] x) Complete left bundle branch block.

[1488] • Has a clinically active (ie, symptomatic and / or on-treatment), known, or suspected autoimmune disease. The following examples may be enrolled as an exception: type I diabetes mellitus / hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.

[1489] • Current participation in other therapeutic investigational procedures, except for participation in LTSFU without any investigational treatment.

[1490] • Has received an attenuated live vaccine within 30 days prior to the first dose of trial intervention.

[1491] Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella / zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine.

[1492] Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. Messenger ribonucleic acid and replication-deficient adenoviral vaccines are not considered attenuated live vaccines and are allowed.

[1493] 15453442-1• Psychological, social, familial, or geographical factors that would prevent regular follow-up.

[1494] • As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, uncontrolled diabetes mellitus, active bleeding or severe bleeding diatheses, substance abuse, or other medical condition that would increase the risk of toxicity or interfere with participation of the participant or evaluation of the clinical trial. Screening for chronic conditions is not required.

[1495] • Participants who have previously received topoisomerase 1 inhibitor or topoisomerase 1 inhibitorbased ADCs including but not limited to datopotamab deruxtexan and sacituzumab govitecan.

[1496] • Participants who have received prior treatment with a PD-1 / PD-L1 inhibitor for any malignancy (including, but not limited to, atezolizumab, pembrolizumab, nivolumab, durvalumab, or avelumab).

[1497] • Participants who have previously received any prior treatment with an agent directed to another stimulatory or co inhibitory T-cell receptor (including but not limited to CD137 agonists, CTLA-4 inhibitors, or OX 40 agonists).

[1498] • Participants with uncontrolled diabetes.

[1499] Uncontrolled diabetes is defined as HbAlc >8% or HbAlc 7%

[1500] 15453442-1to <8% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.

[1501] • Participants with conditions requiring high doses of steroids (>10 mg / day of prednisone or equivalent) or other immunosuppressive medications.

[1502] • Has an active autoimmune disease that has required systemic treatment in past 2 years.

[1503] [Free Text of Sequence Listing]

[1504]

[0212]

[1505] SEQ ID NO: 1: Amino acid sequence of CDRH1 of humanized anti-TA-MUCl antibody PM-N54Q and humanized anti-TA-MUCl antibody PankoMab-GEX (R)

[1506] SEQ ID NO: 2: Amino acid sequence of PM-N54Q CDRH2

[1507] SEQ ID NO: 3: Amino acid sequence of PM-N54Q and PankoMab-GEX (R) CDRH3

[1508] SEQ ID NO: 4: Amino acid sequence of PM-N54Q and PankoMab-GEX (R) CDRL1

[1509] SEQ ID NO: 5: Amino acid sequence of PM-N54Q and PankoMab-GEX (R) CDRL2

[1510] SEQ ID NO: 6: Amino acid sequence of PM-N54Q and PankoMab-GEX (R) CDRL3

[1511] SEQ ID NO: 7: Amino acid sequence of PankoMab-GEX (R) CDRH2

[1512] SEQ ID NO: 8: Amino acid sequence of PM-N54Q heavy chain variable region

[1513] 15453442-1SEQ ID NO: 9: Amino acid sequence of PM-N54Q and PankoMab-GEX (R) light chain variable region

[1514] SEQ ID NO: 10: Amino acid sequence of PankoMab-GEX (R) heavy chain variable region

[1515] SEQ ID NO: 11: Amino acid sequence of PM-N54Q heavy chain SEQ ID NO: 12: Amino acid sequence of PM-N54Q and PankoMab-GEX (R) light chain

[1516] SEQ ID NO: 13: Amino acid sequence of PankoMab-GEX (R) heavy chain

[1517] SEQ ID NO: 14: Amino acid sequence of PDTR of epitope in MUC1 tandem repeat domain

[1518] SEQ ID NO: 15: Amino acid sequence of PESR of epitope in MUC1 tandem repeat domain

[1519] 15453442-1

Claims

[Document Name] Claims

1. A pharmaceutical product comprising an anti-MUCl antibody-drug conjugate and an immune checkpoint inhibitor to be administered in combination.

2. The pharmaceutical product according to claim 1, wherein the anti-MUCl antibody is an anti-TA-MUCl antibody.

3. The pharmaceutical product according to claim 1 or 2, wherein the anti-MUCl antibody-drug conjugate is an anti-MUCl antibody-drug conjugate in which a drug-linker represented by the formula:[Formula 1 ]wherein A represents a connecting position to the anti- MUC1 antibody15453442-1and the anti-MUCl antibody are conjugated via a thioether bond.

4. The pharmaceutical product according to any one of claims 1 to 3, wherein the anti-MUCl antibody is an antibody comprisinga heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 1, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 2 or SEQ ID NO: 7, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 3, anda light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 4, CDRL2 consisting of the amino acid sequence represented by SEQ ID NO: 5, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 6.

5. The pharmaceutical product according to any one of claims 1 to 3, wherein the anti-MUCl antibody is an antibody comprisinga heavy chain comprising CDRH1 consisting of the amino acid sequence represented by SEQ ID NO: 1, CDRH2 consisting of the amino acid sequence represented by SEQ ID NO: 2, and CDRH3 consisting of the amino acid sequence represented by SEQ ID NO: 3, anda light chain comprising CDRL1 consisting of the amino acid sequence represented by SEQ ID NO: 4, CDRL215453442-1consisting of the amino acid sequence represented by SEQ ID NO: 5, and CDRL3 consisting of the amino acid sequence represented by SEQ ID NO: 6.

6. The pharmaceutical product according to any one of claims 1 to 3, wherein the anti-MUCl antibody is an antibody comprisinga heavy chain comprising a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 8 or SEQ ID NO: 10, anda light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9.

7. The pharmaceutical product according to any one of claims 1 to 3, wherein the anti-MUCl antibody is an antibody comprisinga heavy chain comprising a heavy chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 8, anda light chain comprising a light chain variable region consisting of the amino acid sequence represented by SEQ ID NO: 9.

8. The pharmaceutical product according to any one of claims 1 to 3, wherein the anti-MUCl antibody is an antibody comprising15453442-1a heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11 or SEQ ID NO: 13, anda light chain consisting of the amino acid sequence represented by SEQ ID NO: 12.

9. The pharmaceutical product according to any one of claims 1 to 3, wherein the anti-MUCl antibody is an antibody comprisinga heavy chain consisting of the amino acid sequence represented by SEQ ID NO: 11, anda light chain consisting of the amino acid sequence represented by SEQ ID NO: 12.

10. The pharmaceutical product according to claim 8 or 9, wherein a lysine residue at the carboxyl terminus of the heavy chain of the anti-MUCl antibody is deleted.

11. The pharmaceutical product according to any one of claims 1 to 10, wherein the average number of units of the drug-linker conjugated per antibody in the anti-MUCl antibody-drug conjugate is in the range of 7 to 8.

12. The pharmaceutical product according to any one of claims 1 to 10, wherein the average number of units of the drug-linker conjugated per antibody in the anti-MUC1 antibody-drug conjugate is in the range of 7.5 to 8.15453442-1

13. The pharmaceutical product according to any one of claims 1 to 12, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-Ll antibody, or an anti-CTLA-4 antibody.

14. The pharmaceutical product according to any one of claims 1 to 12, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody.

15. The pharmaceutical product according to claim 14, wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, or clone RMP1-14.

16. The pharmaceutical product according to claim 14, wherein the anti-PD-1 antibody is nivolumab.

17. The pharmaceutical product according to claim 14, wherein the anti-PD-1 antibody is pembrolizumab.

18. The pharmaceutical product according to any one of claims 1 to 12, wherein the immune checkpoint inhibitor is an anti-PD-Ll antibody.

19. The pharmaceutical product according to claim 18, wherein the anti-PD-Ll antibody is atezolizumab, durvalumab, avelumab, or clone 10F.9G2.15453442-1

20. The pharmaceutical product according to claim 19, wherein the anti-PD-Ll antibody is atezolizumab.

21. The pharmaceutical product according to claim 19, wherein the anti-PD-L1 antibody is durvalumab.

22. The pharmaceutical product according to claim 19, wherein the anti-PD-L1 antibody is avelumab.

23. The pharmaceutical product according to any one of claims 1 to 12, wherein the immune checkpoint inhibitor is an anti-CTLA-4 antibody.

24. The pharmaceutical product according to claim 23, wherein the anti-CTLA-4 antibody is ipilimumab, tremelimumab, or clone 9H10.

25. The pharmaceutical product according to claim 23, wherein the anti-CTLA-4 antibody is ipilimumab.

26. The pharmaceutical product according to claim 23, wherein the anti-CTLA-4 antibody is tremelimumab.

27. The pharmaceutical product according to any one of claims 1 to 26, wherein the anti-MUCl antibody-drug conjugate and the immune checkpoint inhibitor are15453442-1contained as active ingredients in separate preparations and are to be administered simultaneously or at different times, or as a single preparation to be administered together.

28. The pharmaceutical product according to any one of claims 1 to 27, wherein the pharmaceutical product further comprises an anticancer agent.

29. The pharmaceutical product according to claim 28, wherein the anticancer agent is carboplatin or pemetrexed.

30. The pharmaceutical product according to claim 28 or 29, wherein the anticancer agent is to be administered simultaneously, separately, or continuously to the anti-MUC1 antibody-drug conjugate and the immune checkpoint inhibitor, or in a staggered manner.

31. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 1 mg / kg to 6 mg / kg.

32. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug15453442-1conjugate is to be administered at a dose of about 3 mg / kg to 6 mg / kg.

33. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, or about 6 mg / kg.

34. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg to 5 mg / kg.

35. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg, about 4 mg / kg, or about 5 mg / kg.

36. The pharmaceutical product according to any one of claims 13 to 35, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody and wherein the anti-PD-1 antibody is to be administered at a dose of about 100 to 300 mg.

37. The pharmaceutical product according to any one of claims 13 to 35, wherein the immune checkpoint inhibitor15453442-1is an anti-PD-1 antibody and wherein the anti-PD-1 antibody is to be administered at a dose of about 200 mg.

38. The pharmaceutical product according to any one of claims 13 to 35, wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is to be administered at a dose of about 100 to 300 mg.

39. The pharmaceutical product according to any one of claims 13 to 35, wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is to be administered at a dose of about 200 mg.

40. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 1 mg / kg to 6 mg / kg,wherein the immune checkpoint inhibitor is pembrolizumab, andwherein pembrolizumab is to be administered at a dose of about 100 to 300 mg.

41. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 1 mg / kg to 6 mg / kg,15453442-1wherein the immune checkpoint inhibitor is pembrolizumab, andwherein pembrolizumab is to be administered at a dose of about 200 mg.

42. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg to 6 mg / kg,wherein the immune checkpoint inhibitor is pembrolizumab, andwherein pembrolizumab is to be administered at a dose of about 200 mg.

43. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg to 5 mg / kg,wherein the immune checkpoint inhibitor is pembrolizumab, andwherein pembrolizumab is to be administered at a dose of about 200 mg.

44. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg,15453442-1wherein the immune checkpoint inhibitor is pembrolizumab, andwherein pembrolizumab is to be administered at a dose of about 200 mg.

45. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 4 mg / kg,wherein the immune checkpoint inhibitor is pembrolizumab, andwherein pembrolizumab is to be administered at a dose of about 200 mg.

46. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 5 mg / kg,wherein the immune checkpoint inhibitor is pembrolizumab, andwherein pembrolizumab is to be administered at a dose of about 200 mg.

47. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 6 mg / kg,15453442-1wherein the immune checkpoint inhibitor is pembrolizumab, andwherein pembrolizumab is to be administered at a dose of about 200 mg.

48. The pharmaceutical product according to any one of claims 31 to 47, wherein the anti-MUCl antibody-drug conjugate is to be administered via intravenous administration.

49. The pharmaceutical product according to any one of claims 31 to 48, wherein the anti-MUCl antibody-drug conjugate is to be administered once every two to four weeks

50. The pharmaceutical product according to any one of claims 31 to 49, wherein the anti-MUCl antibody-drug conjugate is to be administered via intravenous administration once every three weeks.

51. The pharmaceutical product according to claim 36 or 37, wherein the anti-PD-1 antibody is to be administered via intravenous administration.

52. The pharmaceutical product according to any one of claims 36, 37 and 51, wherein the anti-PD-1 antibody is to be administered once every two to four weeks.15453442-1

53. The pharmaceutical product according to any one of claims 36, 37, 51 and 52, wherein the anti-PD-1 antibody is to be administered via intravenous administration once every three weeks.

54. The pharmaceutical product according to any one of claims 38 to 47, wherein pembrolizumab is to be administered via intravenous administration.

55. The pharmaceutical product according to any one of claims 38 to 47 and 54, wherein pembrolizumab is to be administered once every two to four weeks.

56. The pharmaceutical product according to any one of claims 38 to 47, 54 and 55, wherein pembrolizumab is to be administered via intravenous administration once every two to four weeks.

57. The pharmaceutical product according to any one of claims 38 to 47, and 54 to 56, wherein the anti-MUCl antibody-drug conjugate is to be administered via intravenous administration once every two to four weeks, andwherein pembrolizumab is to be administered via intravenous administration once every two to four weeks.

58. 15453442-1The pharmaceutical product according to any one of claims 38 to 47, and 54 to 57, wherein the anti-MUCl antibody-drug conjugate is to be administered via intravenous administration once every three weeks, and wherein pembrolizumab is to be administered via intravenous administration once every three weeks.

59. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 3 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, andwherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks.

60. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 4 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, andwherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks.

61. 15453442-1The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 5 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, andwherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks.

62. The pharmaceutical product according to any one of claims 13 to 30, wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 6 mg / kg via intravenous administration once every three weeks, wherein the immune checkpoint inhibitor is pembrolizumab, andwherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks.

63. The pharmaceutical product according to any one of claims 13 to 62, wherein the pharmaceutical product further comprises carboplatin or pemetrexed,wherein carboplatin is to be administered at a dose of AUC 4 to 6 mg*min / ml or pemetrexed is to be administered at a dose of 400 to 600 mg / m2.

64. 15453442-1The pharmaceutical product according to any one of claims 13 to 62, wherein the pharmaceutical product further comprises carboplatin or pemetrexed,wherein carboplatin is to be administered at a dose of about AUC 5 mg*min / ml or pemetrexed is to be administered at a dose of about 500 mg / m2.

65. The pharmaceutical product according to claim 63 or 64, wherein carboplatin is to be administered via intravenous administration once every three weeks or pemetrexed is to be administered via intravenous administration once every three weeks.

66. The pharmaceutical product according to any one of claims 13 to 65, wherein the pharmaceutical product further comprises carboplatin or pemetrexed,wherein carboplatin is to be administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is to be administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

67. The pharmaceutical product according to any one of claims 63 to 66,wherein the anti-MUCl antibody-drug conjugate is administered at a dose of about 3 mg / kg via intravenous administration once every three weeks,15453442-1wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks, andwherein carboplatin is to be administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is to be administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

68. The pharmaceutical product according to any one of claims 63 to 66,wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 4 mg / kg via intravenous administration once every three weeks,wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks, andwherein carboplatin is to be administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is to be administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

69. The pharmaceutical product according to any one of claims 63 to 66,15453442-1wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 5 mg / kg via intravenous administration once every three weeks,wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks, andwherein carboplatin is to be administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is to be administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.

70. The pharmaceutical product according to any one of claims 63 to 66,wherein the anti-MUCl antibody-drug conjugate is to be administered at a dose of about 6 mg / kg via intravenous administration once every three weeks,wherein the immune checkpoint inhibitor is pembrolizumab and wherein pembrolizumab is to be administered at a dose of about 200 mg via intravenous administration once every three weeks, andwherein carboplatin is to be administered at a dose of about AUC 5 mg*min / ml via intravenous administration once every three weeks or pemetrexed is to be administered at a dose of about 500 mg / m2via intravenous administration once every three weeks.15453442-1

71. A pharmaceutical product comprising an anti-MUCl antibody-drug conjugate, for use in combination with an immune checkpoint inhibitor.

72. The pharmaceutical product according to claim 71, wherein the anti-MUCl antibody-drug conjugate is as defined in any one of claims 2 to 12.

73. The pharmaceutical product according to claim 71 or 72, wherein the immune checkpoint inhibitor is as defined in any one of claims 13 to 26.

74. The pharmaceutical product according to any one of claims 71 to 73, wherein the pharmaceutical product is for use in combination with an anticancer agent.

75. The pharmaceutical product according to claim 74, wherein the anticancer agent is carboplatin or pemetrexed.

76. The pharmaceutical product according to any one of claims 1 to 75 for use in treating a cancer.

77. The pharmaceutical product according to claim 76, wherein the cancer expresses TA-MUC1.

78. 15453442-1The pharmaceutical product according to claim 76 or 77, wherein the cancer is selected from the group consisting of ovary cancer, breast cancer, pancreatic cancer, lung cancer, colon cancer, stomach cancer, liver cancer, kidney cancer, blood cancer, endometrial cancer, thyroid gland cancer, leukemia, seminoma, melanoma, carcinoma, teratoma, lymphoma, sarcoma, mesothelioma, neuroblastoma, glioma, rectal cancer, adrenal cancer, skin cancer, brain cancer, uterine cervical cancer, intestinal tract cancer, intestine cancer, head and neck cancer, gastrointestinal cancer, lymph node cancer, esophageal cancer, colorectal cancer, ear, nose and throat (ENT) cancer, prostate cancer, urinary bladder cancer, uterine cancer, bile duct cancer, and their metastatic cancers.

79. The pharmaceutical product according to any one of claims 76 to 78, the cancer is lung cancer.

80. The pharmaceutical product according to claim 79, the lung cancer is non-small cell lung cancer (NSCLC).

81. The pharmaceutical product according to claim 80, the NSCLC is locally advanced or metastatic NSCLC.

82. A kit comprising an anti-MUCl antibody-drug conjugate and an immune checkpoint inhibitor.15453442-1

83. A method for treating a disease, comprising administering an anti-MUCl antibody-drug conjugate and an immune checkpoint inhibitor in combination to a subject in need of treatment.

84. Use of an anti-MUCl antibody-drug conjugate in the production of a drug for use in combination with an immune checkpoint inhibitor to treat a disease.

85. Use of an immune checkpoint inhibitor in the production of a drug for use in combination with an anti-MUCl antibody-drug conjugate to treat a disease.

86. An anti-MUCl antibody-drug conjugate for use in the treatment of a disease, wherein the anti-MUCl antibody-drug conjugate is used in combination with an immune checkpoint inhibitor.

87. An immune checkpoint inhibitor for use in the treatment of a disease, wherein the immune checkpoint inhibitor is used in combination with an anti-MUCl antibody-drug conjugate.

88. The method, use, anti-MUCl antibody-drug conjugate for use or immune checkpoint inhibitor for use according15453442-1any one of claims 83 to 87, wherein the disease is a cancer.

89. The kit, method, use, anti-MUCl antibody-drug conjugate for use or immune checkpoint inhibitor for use according any one of claims 82 to 88, wherein the anti-MUCl antibody-drug conjugate is as defined in any one of claims 2 to 12.

90. The kit, method, use, anti-MUCl antibody-drug conjugate for use or immune checkpoint inhibitor for use according any one of claims 82 to 89, wherein the immune checkpoint inhibitor is as defined in any one of claims 13 to 26.

91. The kit according to any one of claims 82, and 88 to 90, wherein the kit further comprises an anticancer agent.

92. The method according to any one of claims 83, and 88 to 90, wherein the method further comprises administering an anticancer agent.

93. The use, anti-MUCl antibody-drug conjugate for use or immune checkpoint inhibitor for use according to any one of claims 84 to 90, wherein the anti-MUCl antibody-15453442-1drug conjugate and immune checkpoint inhibitor are used in combination with an anticancer agent.

94. The kit, method, use, anti-MUCl antibody-drug conjugate for use or immune checkpoint inhibitor for use according to any one of claims 91 to 93, wherein the anticancer agent is carboplatin or pemetrexed.15453442-1

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