Antibody-drug conjugates

Abstract

The present invention relates to an antibody-drug conjugate of Formula (I) as defined herein comprising the antibody trastuzumab for use in a method of treating endometrial cancer. The present invention also relates to an antibody-drug conjugate for use in a method of treating cancer, wherein the method comprises administering to a patient the antibody-drug conjugate or a pharmaceutically acceptable salt thereof at a dose ranging from 2.2 mg / kg to 12.0 mg / kg. The present invention also relates to an antibody-drug conjugate for use in a method of treating breast cancer in a patient previously treated with an anti-HER2 antibody and / or a taxane. The present invention also relates to a composition comprising the antibody-drug conjugate.

Description

Technical Field

[0001] This invention relates to antibody-drug conjugates comprising the antibody trastuzumab for use in methods of treating endometrial cancer. The invention also relates to antibody-drug conjugates for use in methods of treating cancer, wherein the method comprises administering the antibody-drug conjugate or a pharmaceutically acceptable salt thereof to a patient at a dose ranging from 2.2 mg / kg to 12.0 mg / kg. The invention further relates to antibody-drug conjugates for use in methods of treating breast cancer in patients previously treated with anti-HER2 antibodies and / or taxanes. The invention also relates to compositions comprising antibody-drug conjugates. Background Technology

[0002] Epidermal growth factor receptor 2 (EGFR2 or HER2) is shown to be amplified / overexpressed in more than 30% of all human cancers, including breast cancer, stomach, colon, salivary gland, bladder and uterine serous cancers, and its overexpression in tumors is associated with poor prognosis.

[0003] The clinical application of HER2-targeted therapy has improved outcomes for patients with HER2 amplification / overexpression.

[0004] Not all patients with HER2-positive tumors respond well to current therapies. Resistance to HER2-targeted therapies is common, manifesting as intrinsic or acquired resistance.

[0005] There is a need to develop cancer therapies with better therapeutic effects and / or safety. Summary of the Invention

[0006] This invention is based, in at least part, on antibody-drug conjugates developed by the inventors, which have particularly advantageous and surprising properties.

[0007] Specifically, the antibody-drug conjugates according to the present invention can be particularly effective in treating cancers, such as HER2-related cancers.

[0008] Therefore, in a first aspect, the present invention provides an antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R)5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; It is used in the treatment of endometrial cancer.

[0009] In a first aspect, the present invention provides an antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4-, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R)b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; It is used in the treatment of endometrial cancer.

[0010] In a first aspect, the present invention provides a composition comprising an antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Average number of connections N a It can be an integer or decimal from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2aEach R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; It is used in the treatment of endometrial cancer.

[0011] In a second aspect, the present invention provides an antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; - L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; Or its pharmaceutically acceptable salt. It is used in methods of treating cancer, wherein the method involves administering an antibody-drug conjugate or a pharmaceutically acceptable salt thereof to a patient at a dose ranging from 2.2 mg / kg to 12.0 mg / kg.

[0012] In some embodiments of the second aspect of the invention, the dosage may be in the range of 6.0 mg / kg to 10.0 mg / kg.

[0013] In a second aspect, the present invention provides an antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; Or its pharmaceutically acceptable salt. It is used in methods of treating cancer, wherein the method involves administering an antibody-drug conjugate or a pharmaceutically acceptable salt thereof to a patient at a dose ranging from 2.2 mg / kg to 12.0 mg / kg.

[0014] In some embodiments of the second aspect of the invention, the dosage may be in the range of 6.0 mg / kg to 10.0 mg / kg.

[0015] In a second aspect, the present invention provides a composition comprising an antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Average number of connections N a It can be an integer or decimal from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6)C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; Or a pharmaceutically acceptable salt thereof, for use in methods of treating cancer, wherein the method comprises administering an antibody-drug conjugate or a pharmaceutically acceptable salt thereof to a patient at a dose ranging from 2.2 mg / kg to 12.0 mg / kg.

[0016] In some embodiments of the second aspect of the invention, the dosage may be in the range of 6.0 mg / kg to 10.0 mg / kg.

[0017] In a third aspect of the invention, an antibody-drug conjugate having the structure shown in formula (I) is provided: , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 -R 2 -L 3 -, and R 2 For direct or indirect ligand linkage; L 3 -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4)-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R)b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; It is used in the treatment of breast cancer in patients who have previously been treated with anti-HER2 antibodies and / or taxanes.

[0018] In a third aspect, the present invention provides an antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a Integers from 1 to 10; L is -L a -L b -L c -; -La- is ; -Lb- is ; -Lc- is –CH2-; X 1 C is saturated, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L2 replace; L 2 -R 2 -L 3 -, and R 2 For direct or indirect ligand linkage; L 3 -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently converted by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently converted by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1aEach R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; It is used in the treatment of breast cancer in patients who have previously been treated with anti-HER2 antibodies and / or taxanes.

[0019] In a third aspect, the present invention provides a composition comprising an antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Average number of connections N a It can be an integer or decimal from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently converted by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently converted by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; It is used in the treatment of breast cancer in patients who have previously been treated with anti-HER2 antibodies and / or taxanes.

[0020] In some embodiments of the second aspect of the invention, the patient may have been diagnosed with cancer that is HER2-positive or HER2-overexpressing.

[0021] In some embodiments of the second aspect of the invention, the patient may have been diagnosed with cancer, which is HER2 low or HER2 negative cancer.

[0022] In some embodiments of the second aspect of the invention, the cancer may be selected from lung cancer, kidney cancer, urinary tract cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, esophageal cancer, and endometrial cancer.

[0023] In some embodiments of the second aspect of the invention, the cancer may be selected from breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, ovarian cancer, and vaginal cancer.

[0024] In some embodiments of the second aspect of the invention, the cancer may be breast cancer.

[0025] In some embodiments of the second aspect of the invention, the cancer may be HER2-positive breast cancer.

[0026] In some embodiments of the second aspect of the invention, the cancer may be HER2-low or HER2-negative breast cancer.

[0027] In some embodiments of the second aspect of the invention, the cancer may be endometrial cancer.

[0028] In some embodiments of the second aspect of the invention, the cancer may be HER2-positive endometrial cancer.

[0029] In some embodiments of the second aspect of the invention, the cancer may be HER2-low or HER2-negative endometrial cancer.

[0030] In one aspect, an antibody-drug conjugate of formula (I) as defined herein is provided for the treatment of HER2-positive unresectable / metastatic breast cancer in patients who have previously been treated with trastuzumab and taxane.

[0031] In some implementations, ring A can be a 4-membered saturated carbon cyclo group.

[0032] In some implementations, ring A can be 1 L 2 replace.

[0033] In some implementations, m can be 0, and L3 It can be a covalent bond.

[0034] In some implementations, n can be 1, and L 1 It can be -C(R) 5a (R) 5b )-, where L 1 One methylene unit can be replaced by -C(O)-.

[0035] In some implementations, the pharmaceutical portion may have the following structure IA: IA Where R 2 As defined in the first or second aspect of this invention.

[0036] In some embodiments, the antibody-drug conjugate may be compound 1 having the following structure:

[0037] Compound 1, Where N a N represents the average number of connections. a Integers or decimals selected from 7 to 8.

[0038] In some implementations, the antibody-drug conjugate or its pharmaceutically acceptable salt may be administered at a dose ranging from 2.2 mg / kg to 12.0 mg / kg.

[0039] In some implementations, the dosage can be in the range of 6.0 mg / kg to 10.0 mg / kg.

[0040] In some implementations, the antibody-drug conjugate or its pharmaceutically acceptable salt may be administered at a dose of 8.0 mg / kg.

[0041] In some implementations, the antibody-drug conjugate or its pharmaceutically acceptable salt may be administered every three weeks.

[0042] In some implementations, antibody-drug conjugates or their pharmaceutically acceptable salts can be formulated as compositions.

[0043] In some embodiments, antibody-drug conjugates or their pharmaceutically acceptable salts can be formulated into compositions comprising: Approximately 20 mg / ml of antibody-drug conjugate or its pharmaceutically acceptable salt; Approximately 25 mM histidine or a pharmaceutically acceptable salt thereof; Approximately 9% (w / v) sucrose; and Approximately 0.03% (w / v) polysorbate 80, Furthermore, the pH of the composition is approximately 5.5.

[0044] In one embodiment of the fourth aspect, the present invention provides a composition, typically an aqueous composition, comprising: An antibody-drug conjugate having the structure shown in formula (I) at a concentration of approximately 20 mg / ml: , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently converted by -N(R) 4 )C(O)-、-C(O)N(R4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently converted by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(Ra (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; Approximately 25 mM histidine or a pharmaceutically acceptable salt thereof; Approximately 9% (w / v) sucrose; and Approximately 0.03% (w / v) polysorbate 80, The pH of the composition is approximately 5.5.

[0045] In another embodiment of the fourth aspect, a composition, typically an aqueous composition, is provided, comprising: An antibody-drug conjugate having the structure shown in formula (I) at a concentration of approximately 20 mg / ml: , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently converted by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently converted by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; Approximately 0.82 mg / ml L-histidine; Approximately 4.14 mg / ml of L-histidine hydrochloride monohydrate; Approximately 90 mg / ml sucrose; and Approximately 0.3 mg / ml of polysorbate 80.

[0046] In one embodiment of the fifth aspect, the present invention also provides a lyophilized composition comprising: (a) Approximately 100 mg of an antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a Integers from 1 to 10; L is -L a -L b -L c -; -La- is ; -Lb- is ; -Lc- is –CH2-; X 1 For saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently converted by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently converted by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; (b) Approximately 4.1 mg of L-histidine; (c) Approximately 20.7 mg of L-histidine hydrochloride monohydrate; (d) Approximately 450 mg of sucrose; and (e) Approximately 1.5 mg of polysorbate 80.

[0047] In another embodiment of the fifth aspect, the present invention also provides a lyophilized composition comprising: (a) Antibody-drug conjugates having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a Integers from 1 to 10; L is -L a -L b -L c -; -La- is ; -Lb- is ; -Lc- is –CH2-; X 1 For saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently converted by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently converted by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6-, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; In approximately 100 parts by weight; (b) L-histidine, in an amount of about 4.1 parts by weight relative to 100 parts by weight of (a); (c) L-histidine hydrochloride monohydrate; in an amount of about 20.7 parts by weight relative to 100 parts by weight of (a); (d) Sucrose, in an amount of about 450 parts by weight relative to 100 parts by weight of (a); and (e) Polysorbate 80, in an amount of about 1.5 parts by weight relative to 100 parts by weight of (a).

[0048] In a sixth aspect, the present invention provides a method for preparing the composition of the fourth aspect, the method comprising reconstituted the lyophilized composition of the fifth aspect with a diluent. In one embodiment, the diluent is water, typically purified water as defined herein. In one embodiment, the water is water for injection (WFI).

[0049] In a seventh aspect, the present invention provides a method for preparing a freeze-dried composition of the fifth aspect, the method comprising freeze-drying the composition of the fourth aspect.

[0050] In an eighth aspect, the present invention provides a lyophilized composition that can be obtained by the method of the seventh aspect. Attached Figure Description

[0051] Figure 1 The best overall tumor changes from baseline are shown based on data available up to May 8, 2023; Figure 2 The response depth and duration are displayed based on data available as of May 8, 2023; Figure 3 The efficacy of the study, based on data available up to July 26, 2023, demonstrates the best overall tumor change from baseline in the subjects. Figure 4 The efficacy was demonstrated based on data available up to December 14, 2023, to assess the best overall tumor change from baseline in subjects; and Figure 5 The efficacy of the study, based on data available up to December 14, 2023, was demonstrated to assess the depth and duration of response in subjects. Detailed Implementation

[0052] Antibody-drug conjugates and compositions thereof

[0053] This invention generally relates to antibody-drug conjugates (ADCs) and compositions comprising them.

[0054] ADCs are a class of targeted therapies that improve drug selectivity and cytotoxic activity by targeting specific targets (such as cancer cells) with drugs (such as anticancer drugs).

[0055] Generally, an ADC comprises three main components: (i) an antibody (e.g., a monoclonal antibody) conjugated to (ii) a linker, which in turn conjugates to (iii) a cargo or payload (e.g., a cytotoxic or chemotherapeutic agent). Cytotoxic or chemotherapeutic agents are drugs that reduce or eliminate cell viability. Suitable cytotoxic or chemotherapeutic agents are known in the art.

[0056] Those skilled in the art will understand that all references to the term "antibody-drug conjugate" in this specification will also include compositions comprising mixtures of antibody-drug conjugates, each of which may have a different drug-antibody ratio (DAR). These will be described in more detail below with reference to the compositions. The drug-antibody ratio (DAR) of the antibody-drug conjugates described herein can vary. Therefore, compositions may comprise mixtures of antibody-drug conjugates having many different DARs, and thus may have a non-integer average DAR. In this specification, the terms "DAR" and "number of links" are synonymous, and the terms "average DAR" and "average number of links" are synonymous.

[0057] It will be understood that, when referring to a particular antibody-drug conjugate, the term “DAR” or “linkage number” refers to the number of drug molecules linked (e.g., conjugated) to an antibody (optionally via a linker) in any single antibody-drug conjugate. Therefore, the linkage number (referred to herein as “n”) can be considered as the specific number of linker-payload structures conjugated to the antibody in a given antibody-drug conjugate. It will also be understood that the linkage number n can affect the safety and therapeutic efficacy of the antibody-drug conjugate. The number of drug molecules per antibody molecule (also referred to herein as the drug-antibody ratio (DAR)) can be characterized by conventional methods such as UV / Vis spectroscopy, mass spectrometry, ELISA assays, and HPLC.

[0058] The inventors have surprisingly discovered that the antibody-drug conjugates according to the invention are particularly effective in treating cancers (e.g., HER2-related cancers).

[0059] According to a first aspect of the invention, an antibody-drug conjugate having the structure shown in formula (I) is provided: , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes: ; -L c - is –CH2-; X 1It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently converted by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently converted by -N(R) 6)C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; It is used in the treatment of endometrial cancer.

[0060] In a first aspect, the present invention provides an antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes: ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently converted by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently converted by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each Ra and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; It is used in the treatment of endometrial cancer.

[0061] In a first aspect, the present invention provides a composition comprising an antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Average number of connections N a Integers or decimals from 1 to 10; L is -L a -L b -L c -; -La- is ; -Lb- is: ; -Lc- is -CH2-; X 1 C is saturated, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently converted by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently converted by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5bEach R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; It is used in the treatment of endometrial cancer.

[0062] According to a second aspect of the invention, an antibody-drug conjugate having the structure shown in formula (I) as defined above, whether in its broadest or preferred aspect, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating cancer, wherein the method comprises administering the antibody-drug conjugate or a pharmaceutically acceptable salt thereof to a patient at a dose ranging from 6.0 mg / kg to 10.0 mg / kg.

[0063] Compounds of formula (I) and general and specific methods for their synthesis are described in WO2022 / 068878 and published national applications derived therefrom as formulas (II-D). x The compound was disclosed.

[0064] This invention also relates to compositions comprising antibody-drug conjugates (ADCs) and mixtures thereof as defined herein, for the uses defined herein. Those skilled in the art will understand that compositions may comprise multiple antibody-drug conjugates, and the drug-antibody ratio (as defined herein) of each antibody-drug conjugate may be the same or different.

[0065] Compared to the term "number of links" used alone, it will be understood that, in the context of a composition containing an antibody-drug conjugate, the term "average number of links N" is used more in the context of the composition. a "Number of drug molecules linked (e.g., conjugated) to the antibody in all ADCs present in the composition" refers to this average number. Therefore, "average number of linkages N" is... a "This can be considered as the average number of linked payloads (e.g., cytotoxic drugs) for each antibody in a given composition. As will be readily understood by those skilled in the art, the average number of links can therefore be an integer or a non-integer. It will also be understood that the average number of links N..." a This can affect the safety and therapeutic efficacy of antibody-drug conjugates. The number of drug molecules in each antibody molecule can be characterized using conventional methods such as UV / Vis spectroscopy, mass spectrometry, ELISA, and HPLC.

[0066] This article will explain the average number of connections N when an ADC is included in the composition. a It is related (and can be a non-integer), while a single ADC will have an integer number of connections from 1 to 10.

[0067] As used in this article, the average number of connections N a It can be an integer or decimal from 1 to 10.

[0068] As used in this article, the number of connections N a Integers from 1 to 10.

[0069] In some implementations, the average number of connections N a It can be an integer or decimal selected from the following range list: 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2.

[0070] In some implementations, the number of connections N a It can be an integer selected from the following range list: 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2.

[0071] In some implementations, the average number of connections N a It can be an integer or decimal selected from the following range list: 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, or 9 to 10.

[0072] In some implementations, the number of connections N a It can be an integer selected from the following range list: 1 to 10, 2 to 10, 3 to 10, 4 to 10, 5 to 10, 6 to 10, 7 to 10, 8 to 10, or 9 to 10.

[0073] In some implementations, the average number of connections N a It can be an integer or decimal selected from the following range list: 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, or 9 to 10.

[0074] In some implementations, the number of connections N a It can be an integer selected from the following range list: 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, or 9 to 10.

[0075] In some implementations, the average number of connections N a It can be an integer or decimal selected from the following range list: 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, or 7 to 8.

[0076] In some implementations, the number of connections N a It can be an integer selected from the following range list: 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, or 7 to 8.

[0077] In some implementations, the average number of connections N a You can select from the following integer groups: 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0078] In some implementations, the number of connections N a You can select from the following integer groups: 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.

[0079] In some implementations, the average number of connections N a It can be selected from approximately 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5 Integers or small arrays of 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0.

[0080] In some implementations, the average number of connections N a It can be an integer or a decimal selected from the range of about 7 to about 8. In some implementations, the average number of connections N a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some implementations, the average number of connections N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some implementations, the average number of connections N a It can be selected from integers or small numbers of approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0.

[0081] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be selected from integers or small numbers of approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0.

[0082] It will be understood that the term "pharmaceutically acceptable salt" has the generally known meaning of anionic and cationic ions, wherein one of the ions is the compound used in this invention and the other ion is a nontoxic anti-charge ion.

[0083] In some embodiments, the pharmaceutically acceptable salt may be a sodium salt or a potassium salt. In some embodiments, the pharmaceutically acceptable salt may be a sodium salt. In some embodiments, the pharmaceutically acceptable salt may be a potassium salt.

[0084] In one embodiment of the antibody-drug conjugate according to the invention, the antibody component, drug component, and / or, if present, the linker component may take the form of the structures shown herein. In another embodiment, the antibody component, drug component, and / or, if present, the linker component of the antibody-drug conjugate for use in the invention may take the form of tautomers, meta-isomers, racemates, enantiomers, or diastereomers of any structure shown herein, or mixtures thereof.

[0085] In some embodiments, the antibody-drug conjugate may be compound 1, which has the following structure:

[0086] Compound 1, Where N a N represents the average number of connections. a Integers or decimals selected from 7 to 8.

[0087] Compound 1 is disclosed as compound ADC-II-9, and its general and specific synthesis methods are disclosed in WO2022 / 068878 and published national applications derived therefrom. Compound 1 has been accepted by USAN for trastuzumab paminotecan.

[0088] In certain embodiments of any aspect of the invention, the antibody-drug conjugate is trastuzumab pamitec or a pharmaceutically acceptable salt thereof.

[0089] In the antibody-drug conjugate of the present invention, the antibody component and the drug component are connected to each other via a linker as defined in the claims (i.e., conjugated).

[0090] Such linkers typically have chemically reactive groups at each end. These linkers can form covalent links between two molecules, such as antibodies and drugs. Therefore, antibodies and drugs can be covalently linked to the linkers. Appropriately, one region of the linker can bind to an antibody and another region of the linker can bind to a drug.

[0091] In some embodiments, the connector may be a cuttable connector. In some embodiments, the connector may be a cuttable connector based on maleimide tetrapeptide.

[0092] Not wishing to be bound by theory, the antibody-drug conjugates according to the present invention may have (but are not limited to) one or more of the following characteristics: • High payload efficiency; High drug-to-antibody ratio; • Stable joint - effective load; • Tumor-selective cuttable connector; • Selective endocytosis into the lysosomes of HER2-positive cells; and / or • ADCC activity and bystander antitumor effect.

[0093] Not wishing to be bound by theory, as described in this paper and in the published national application WO2022 / 068878 and its derivatives, compound 1 also exhibits the following improved properties compared to the commercially available ADC trastuzumab derushetacan (Enhertu®, referred to as Reference ADC-1): • Compared with trastuzumab derutecan, it showed improved in vitro antiproliferative activity against tumor cell lines NCI-N87 (gastric cancer) and JIMT-1 (breast cancer); • Improved plasma stability compared to trastuzumab / druttec; • Compared with trastuzumab delutecan, tumor volume was reduced and in vivo tumor suppression was improved in xenograft mice carrying the NCI-N87 cell line (gastric cancer). Compared to trastuzumab / drutecan, in xenograft mice carrying the JIMT-1 cell line (breast cancer), tumor volume was reduced and in vivo tumor suppression was improved; and • Improved safety profile, including but not limited to improved safety and adverse events, such as gastrointestinal events and hair loss, compared to trastuzumab delutec, as detailed in Example 5 of this document.

[0094] Antibody

[0095] The antibody-drug conjugate comprises an anti-HER2 antibody or a fragment thereof. The anti-HER2 antibody or a fragment thereof can specifically bind to HER2. The anti-HER2 antibody can be a monoclonal antibody. In some embodiments, the anti-HER2 antibody or a fragment thereof is a humanized antibody. In some embodiments, the anti-HER2 antibody or a fragment thereof is a monoclonal humanized antibody. Its fragment can be any antigen-binding fragment, such as Fab, Fab', F(ab')2, Fv, scFv, Fab'-SH, sdAb, or VHH. In some embodiments, the anti-HER2 antibody or a fragment thereof is a full-length anti-HER2 antibody.

[0096] Anti-HER2 antibodies or fragments thereof may include a variable region that specifically binds to HER2. In some embodiments, the anti-HER2 antibody or fragment thereof includes a heavy chain variable region and / or a light chain variable domain. In some embodiments, the anti-HER2 antibody or fragment thereof includes both a heavy chain variable region and a light chain variable domain. In some embodiments, the anti-HER2 antibody or fragment thereof includes a constant region, preferably derived from a human antibody, and preferably selected from the constant regions of human IgG1, IgG2, IgG3, or IgG4. In some embodiments, the anti-HER2 antibody or fragment thereof includes a heavy chain and / or a light chain. In some embodiments, the anti-HER2 antibody or fragment thereof includes both a heavy chain and a light chain. In some embodiments, the anti-HER2 antibody or fragment thereof comprises or consists of two heavy chains and two light chains.

[0097] It will be understood that the terms “integration to,” “integration,” “targeting,” and “targets” are interchangeable.

[0098] The antibodies described herein include polyclonal and monoclonal antibodies, and include IgA such as IgA1 or IgA2, IgG such as IgG1, IgG2, IgG3 or IgG4, IgE, IgM, and IgD antibodies. In various embodiments, the antibody is an IgG1 antibody, more particularly IgG1, κ, or IgG1,λ isotypes (i.e., IgG1, κ, λ), an IgG2a antibody (e.g., IgG2a, κ, λ), an IgG2b antibody (e.g., IgG2b, κ, λ), an IgG3 antibody (e.g., IgG3, κ, λ), or an IgG4 antibody (e.g., IgG4, κ, λ). In a preferred embodiment, the antibody is IgG1, preferably IgG1,λ.

[0099] Antibodies can be from any species (e.g., human, monkey, camel, llama, goat, sheep, rabbit, mouse, rat, hamster, or chicken), or they can be hybrids derived from more than one species. They can exist naturally, or they can be non-natural (i.e., isolated antibodies). Antibodies can be produced through genetic engineering (e.g., chimeric antibodies, humanized antibodies, camel-derived antibodies, intracellular antibodies, bispecific antibodies).

[0100] An antibody is a glycoprotein belonging to the immunoglobulin superfamily. The term "full-length antibody" can refer to an immunoglobulin molecule that binds to a target molecule and contains four peptide chains—two heavy chains and two light chains—linked together by disulfide bonds. Antibodies may contain several "regions" or "domains," and these terms are used interchangeably herein. Antibodies recognize antigens via a fragment antigen-binding (Fab) variable region. The fragment crystallization region (Fc region) is the tail region of the antibody, which enables the antibody to activate the immune system. The hinge region is the stretch of the heavy chain connecting the Fab and Fc regions. The heavy and light chains may each contain a variable domain and one or more constant domains. For example, in an IgG antibody, the heavy chain contains a variable domain (VH) and three constant domains (CH1, CH2, and CH3), and the light chain contains a variable domain (VL) and one constant domain (CL). Exemplary antibodies include human antibodies, humanized antibodies, chimeric antibodies, multispecific antibodies, monoclonal antibodies, and polyclonal antibodies.

[0101] The term "antibody fragment" can refer to a fragment of an antibody, or a genetically engineered product of one or more fragments of an antibody, that participates in binding to a target molecule. Examples of antibody fragments include antigen-binding fragments (Fab), Fab', Fab'-SH, fragment antibodies (F(ab')2), variable regions (Fv), single-chain variable fragments (scFv), single-domain antibodies (sdAb), nanobodies, VHH, and camel antibodies. The term "antigen-binding fragment" or "Fab" refers to a region of an antibody that binds to an antigen and consists of a constant region and a variable region of each of the heavy and light chains. The term "fragment antibody" or "F(ab')2" refers to the region of the antibody remaining after digestion of the Fc region while retaining a portion of the hinge region intact. The term "Fab'" refers to a fragment formed by reducing the F(ab')2 fragment. The term "Fab'-SH" refers to a Fab' fragment having free thiol groups. The term "single-chain variable fragment" or "scFv" refers to an engineered antibody composed of light chain variable regions and heavy chain variable regions linked together.

[0102] As used herein, a "variable region" refers to an antibody segment containing three CDRs (designated CDR1, CDR2, and CDR3). An antibody's "variable region" refers to either the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable region of the heavy chain may be referred to as "VH." The variable region of the light chain may be referred to as "VL." Typically, both the heavy and light chain variable regions contain three hypervariable regions, or CDRs, located within relatively conserved frame regions (FRs). CDRs are usually aligned with the frame regions to enable binding to specific epitopes. Generally, from the N-terminus to the C-terminus, the variable domains of both the light and heavy chains contain FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0103] The term "heavy chain" refers to a large protein subunit of an immunoglobulin. A heavy chain can be any immunoglobulin isotype (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), subtype (e.g., IgG1, IgG2, IgG2a, IgG2b, IgG2c, IgG3, IgG4, IgA1, or IgA2), or allotype.

[0104] The term "light chain" refers to a small protein subunit of an immunoglobulin. Light chains can be of any type (e.g., κ or λ), subtype, or allotype.

[0105] "CDR" or "CDRs" refers to the complementarity-determining regions (CDRs) in the variable regions of immunoglobulins. The variable regions of both the heavy and light chains each contain three CDRs, designated as CDR1, CDR2, and CDR3. The precise boundaries of these CDRs can be defined according to various numbering systems known in the art (see, for example, Dondelinger, M. et al., 2018. Frontiers in immunology, 9, p. 2278), such as the Kabat numbering system (Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition Public Health Service, National Institutes of Health, Bethesda, Md., 1991; Kabat et al., 1992, Sequences of Proteins of Immunological Interest, DIANE Publishing: 2719), the Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196: 901-917; Chothia et al. (1989) Nature 342: 878-883) or the IMGT numbering system (Lefranc et al., Dev. Comparat. Immunol. 27: 55-77, 2003; Ehrenmann F, Kaas Q, Lefranc MP. IMGT / 3Dstructure-DB and IMGT / DomainGapAlign: a database and a tool for immunoglobulins or antibodies, T cell receptors, MHC, IgSF and MhcSF[J]. Nucleic acids research, 2009;38(suppl_1):D301-D307). For a given antibody, those skilled in the art will readily identify the CDR defined by each numbering system. Furthermore, the correspondence between different numbering systems is well known to those skilled in the art (e.g., see Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003).

[0106] As used in this article, "Kabat" refers to the immunoglobulin alignment and numbering system pioneered by Elvin A. Kabat (1991)., 5th edition (Public Health Service, National Institutes of Health, Bethesda, Md.). One or more mutations (substitution, addition, or deletion) may be introduced into each CDR without negatively affecting binding activity. For example, each CDR may have one, two, or three amino acid mutations.

[0107] "Chimeric antibody" refers to an antibody in which a portion of the heavy chain and / or light chain is identical or homologous to the corresponding sequence in an antibody derived from a specific species (e.g., human) or belongs to a specific antibody class or subclass, while the remaining chain is identical or homologous to the corresponding sequence in an antibody derived from another species (e.g., mouse) or belongs to another antibody class or subclass, as well as fragments of such antibodies, provided they exhibit the desired biological activity.

[0108] "Human antibody" refers to an antibody that contains only the sequence of human immunoglobulin proteins. If produced in mice, in mouse cells, or in hybridomas derived from mouse cells, human antibodies may contain mouse carbohydrate chains. Similarly, "mouse antibody" or "rat antibody" refers to an antibody that contains only the sequence of mouse or rat immunoglobulins, respectively.

[0109] "Humanized antibodies" refer to a form of antibody that contains sequences derived from non-human (e.g., mouse) antibodies as well as human antibodies. Such antibodies contain minimal sequences derived from non-human immunoglobulins. Typically, humanized antibodies will contain at least one, and typically substantially all, of two variable domains, where all or substantially all of the hypervariable loops correspond to those of non-human immunoglobulins, and all or substantially all of the frames or FR regions are those of human immunoglobulin sequences.

[0110] The term "monoclonal antibody" refers to an antibody derived from a substantially homogeneous population of antibodies. The individual antibodies comprising this population can be identical, except for the possibility of naturally occurring mutations, which may be present in small amounts. Monoclonal antibodies are highly specific and target a single antigenic epitope. In contrast, polyclonal antibody formulations typically comprise a large number of antibodies specifically targeting different epitopes.

[0111] The term "multispecific antibody" refers to an antibody that recognizes two or more epitopes located on the same or different targets. Multispecific antibodies can be categorized into two main types: IgG-like antibody formats with an Fc domain and non-IgG-like antibody formats without an Fc domain (see, for example, Elshiaty, M. et al.). International Journal of Molecular Sciences , 2021, 22(11), 5632). Examples of multispecific antibodies include bispecific antibodies and trispecific antibodies.

[0112] A "single-domain antibody" (sdAb) is an antibody composed of an antibody fragment consisting of a single variable domain (e.g., a heavy chain variable region). Typically, single-domain antibodies, domain antibodies, or nanobodies consist of four frame regions (FR1-FR4) and three complementarity-determining regions (CDR1-CDR3). In some embodiments, the single-domain antibody of this application may have a structure of FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. These antibodies do not require a light chain variable region to bind antigens with high affinity and specificity. Examples of single-domain antibodies include, but are not limited to, VHH fragments and VNAR fragments. Compared to antibodies composed of heavy and light chains, single-domain antibodies exhibit high solubility, high stability to heat, pH, proteases, and other denaturing agents, and require only single-chain expression to facilitate large-scale production. As used herein, the terms "frame region" or "FR" residues refer to amino acid residues in the antibody variable region other than the aforementioned CDR residues.

[0113] The antibody-drug conjugate according to the present invention comprises an antibody, wherein the antibody is trastuzumab.

[0114] Techniques for preparing and using various antibody-based constructs and fragments are well known in the field.

[0115] In some embodiments, the antibody may include a heavy chain variable (VH) region and a light chain variable (VL) region. In some embodiments, the antibody may include a heavy chain variable (VH) region. In some embodiments, the antibody may include a light chain variable (VL) region.

[0116] It should be understood that the VH region can be called the VH structural domain. It should also be understood that the VL region can be called the VL structural domain.

[0117] A “heavy chain variable region” or “VH” refers to a segment of the heavy chain of an antigen-binding domain or antibody that contains three CDRs inserted between flanking chain segments called framework regions. The framework regions are more conserved than the CDRs and form a scaffold supporting them. A “light chain variable region” or “VL” refers to a segment of the light chain of an antigen-binding domain or antibody that contains three CDRs inserted between framework regions.

[0118] The term "chimeric antibody" generally refers to an antibody obtained by fusing the variable region of a mouse antibody with the constant region of a human antibody, which reduces the immune response induced by mouse antibodies. To create a chimeric antibody, a hybridoma secreting a mouse-specific monoclonal antibody can be constructed, and the variable region gene can be cloned from mouse hybridoma cells; then, the constant region gene of a human antibody can be cloned as needed, and the mouse variable region gene and the human constant region gene can be linked to form a chimeric gene; the chimeric gene is then inserted into an expression vector, where the chimeric antibody molecule can be expressed in either a eukaryotic or prokaryotic system.

[0119] The term "humanized antibody" (also known as a CDR-transplanted antibody) generally refers to an antibody generated by transplanting a mouse CDR sequence into a human antibody variable region framework, i.e., an antibody generated within a different type of human germline antibody framework sequence. This overcomes the heterogeneity caused by the presence of a large amount of mouse protein components in chimeric antibodies. Such framework sequences can be obtained from publicly available DNA databases or from publicly available literature containing germline antibody gene sequences. For example, germline DNA sequences of human heavy and light chain variable region genes are available from the "VBase" human germline sequence database.

[0120] The terms "fully humanized antibody," "fully human antibody," or "fully human antibody" (also known as "fully humanized monoclonal antibody") can possess humanized variable and constant regions to eliminate immunogenicity and toxic side effects. Monoclonal antibody development involves four stages: mouse monoclonal antibodies, chimeric monoclonal antibodies, humanized monoclonal antibodies, and fully humanized monoclonal antibodies. The antibodies or ligands described herein can be fully humanized monoclonal antibodies. Related technologies for preparing fully humanized antibodies include: human hybridoma technology, EBV-transformed B lymphocyte technology, phage display technology, transgenic mouse antibody preparation technology, and single B cell antibody preparation technology, etc.

[0121] In some implementations, the sequence of the antibody can be defined using a Kabat number (Kabat EA et al., (1991)).

[0122] Antibodies can be obtained using techniques including immunizing animals with target antigens and isolating antibodies from serum. Monoclonal antibodies can be prepared using the hybridoma method first described by Kohler et al., Nature 256:495 (1975), or using recombinant DNA methods (see, for example, U.S. Patent No. 4,816,567). Monoclonal antibodies can also be isolated from phage antibody libraries using techniques described in Clackson et al., Nature 352:624-628 (1991) and Marks et al., J. Mol. Biol. 222:581-597 (1991), for example. Antibodies can be chimeric or humanized antibodies.

[0123] The antibodies according to the present invention can have any binding affinity value. Binding affinity is generally described as the strength of the binding interaction between two molecules (e.g., the binding interaction between a receptor and its ligand or an antibody and its homoantigen). Binding affinity can be defined by determining the equilibrium dissociation constant (KD), which is used to measure the strength of the molecular interaction. A lower KD value indicates a higher binding affinity, and vice versa, a higher KD value indicates a lower binding affinity.

[0124] Binding affinity (e.g., KD value) can be quantitatively determined or measured using methods known in the art, such as by surface plasmon resonance (SPR), for example by using Biacore. ® Systems (e.g., Biacore T200). In addition to the equilibrium dissociation constant (KD), the association rate constant (Ka(1 / Ms)) and the dissociation rate constant (Kd(1 / s)) can also be determined.

[0125] Methods known in the art for determining the binding specificity of antibodies to specific antigens include, but are not limited to, ELISA, Western blotting, immunohistochemistry, flow cytometry, Förster resonance energy transfer (FRET), phage display libraries, yeast two-hybrid screening, co-immunoprecipitation, bimolecular fluorescence complementation, and tandem affinity purification. Binding affinity can also be determined using methods such as fluorescence quenching and isothermal titration calorimetry.

[0126] HER2 antibody - trastuzumab

[0127] Human epidermal growth factor receptor 2 (HER2) (also known as receptor tyrosine protein kinase erbB-2 (ERBB2) or CD340) is known to play a key role in the development and progression of certain types of cancer, such as breast cancer and endometrial cancer.

[0128] According to a first aspect of the invention, the antibody in the antibody-drug conjugate is trastuzumab. The antibody specifically binds to HER2.

[0129] According to a second aspect of the invention, the antibody in the antibody-drug conjugate is trastuzumab. The antibody specifically binds to HER2.

[0130] It should be understood that trastuzumab is marketed under the brand name Herceptin. ® For sale. However, in the context of this invention, it should be understood that any version or variant of the antibody known as trastuzumab may be used.

[0131] In some embodiments, the antibody may comprise the trastuzumab heavy chain amino acid sequence according to SEQ ID NO:1 or an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0132] In some embodiments, the antibody may comprise the trastuzumab light chain amino acid sequence according to SEQ ID NO:2 or an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0133] In some embodiments, the antibody may comprise (i) the heavy chain amino acid sequence of trastuzumab according to SEQ ID NO:1 or an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity therewith; and (ii) the light chain amino acid sequence of trastuzumab according to SEQ ID NO:2 or an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity therewith.

[0134] In some embodiments, the antibody may comprise the trastuzumab heavy chain amino acid sequence according to SEQ ID NO:1 and the trastuzumab light chain amino acid sequence according to SEQ ID NO:2.

[0135] SEQ ID NO:1 - Amino acid sequence of the heavy chain of trastuzumab

[0136] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRY

[0137] ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS

[0138] ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS

[0139] GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG

[0140] PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN

[0141] STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE

[0142] MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW

[0143] QQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0144] SEQ ID NO:2 - Amino acid sequence of the light chain of trastuzumab

[0145] DIQMTQSPSSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPS

[0146] RFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPP

[0147] SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT

[0148] LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0149] In some embodiments, the antibody may comprise the amino acid sequence of the heavy chain variable region of trastuzumab according to SEQ ID NO:3 or an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0150] In some embodiments, the antibody may comprise the amino acid sequence of the trastuzumab light chain variable region according to SEQ ID NO:4 or an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with it.

[0151] In some embodiments, the antibody may comprise (i) the amino acid sequence of the heavy chain variable region of trastuzumab according to SEQ ID NO:3 or an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity therewith; and (ii) the amino acid sequence of the light chain variable region of trastuzumab according to SEQ ID NO:4 or an amino acid sequence having 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity therewith.

[0152] In some embodiments, the antibody may comprise the amino acid sequence of the trastuzumab heavy chain variable region according to SEQ ID NO:3 and the amino acid sequence of the trastuzumab light chain variable region according to SEQ ID NO:4.

[0153] SEQ ID NO:3 - Amino acid sequence of the heavy chain variable region of trastuzumab

[0154] EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS

[0155] SEQ ID NO:4 - Amino acid sequence of the light chain variable region of trastuzumab

[0156] DIQMTQSPSSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK

[0157] In some embodiments, the antibody may comprise the same HCDR1-3 as trastuzumab, wherein HCDR1 may comprise the amino acid sequence described in SEQ ID NO:5, HCDR2 may comprise the amino acid sequence described in SEQ ID NO:6, and HCDR3 may comprise the amino acid sequence described in SEQ ID NO:7. CDRs may be defined according to Kabat.

[0158] In some embodiments, the antibody may comprise the same LCDR1-3 as trastuzumab, wherein LCDR1 may comprise the amino acid sequence described in SEQ ID NO:8, LCDR2 may comprise the amino acid sequence described in SEQ ID NO:9, and LCDR3 may comprise the amino acid sequence described in SEQ ID NO:10. CDR may be defined according to Kabat.

[0159] In some embodiments, the antibody may comprise the same LCDR1-3 and HCDR as trastuzumab, wherein LCDR1 may comprise the amino acid sequence described in SEQ ID NO:5, LCDR2 may comprise the amino acid sequence described in SEQ ID NO:6, LCDR3 may comprise the amino acid sequence described in SEQ ID NO:7, HCDR1 may comprise the amino acid sequence described in SEQ ID NO:8, HCDR2 may comprise the amino acid sequence described in SEQ ID NO:9, and HCDR3 may comprise the amino acid sequence described in SEQ ID NO:10. CDR may be defined according to Kabat.

[0160] SEQ ID NO:5 - Amino acid sequence of HCDR1 of trastuzumab

[0161] DTYIH

[0162] SEQ ID NO:6 - Amino acid sequence of HCDR2 of trastuzumab

[0163] RIYPTNGYTRYADSVK

[0164] SEQ ID NO:7 - Amino acid sequence of HCDR3 of trastuzumab

[0165] SRWGGDGFYAMDY

[0166] SEQ ID NO:8 - Amino acid sequence of LCDR1 of trastuzumab

[0167] RASQDVNTAVA

[0168] SEQ ID NO:9 - Amino acid sequence of LCDR2 of trastuzumab

[0169] SASFLYS

[0170] SEQ ID NO:10 - Amino acid sequence of LCDR3 of trastuzumab

[0171] QQHYTTPPT

[0172] connector

[0173] The antibody-drug conjugate of formula (I) above includes a linker L, which is a chemical structural fragment linked at one end to the antibody trastuzumab and at the other end to the cytotoxic drug, or linked to other linkers and then to the cytotoxic drug. Direct or indirect ligand linkage can mean that the group is directly linked to the ligand via a covalent bond, or it can be linked to the ligand via a linker structure.

[0174] The connector structure is shown as -L as defined in this document. a -L b -L c - structure.

[0175] Drug / Payload

[0176] The antibody-drug conjugate of formula (I) above contains a portion of the drug linked to the antibody trastuzumab Ab via the linker L. The remaining portion of the antibody-drug conjugate, i.e., including L... 2 All the structures on the right side of equation (I) are called the "drug portion" or "payload portion". In use, L and L 2 The bonds between them are cut, and L 2 It and all the structures to its right are released in the body.

[0177] In some implementation schemes, X 1 It is saturated C.

[0178] In some implementations, ring A is a 3-10 saturated carbon cycloalloy.

[0179] In some implementations, ring A is a 3-6 member saturated carbon cyclo group.

[0180] In some implementations, ring A is a 4-membered saturated carbon cyclo group.

[0181] In some implementations, ring A is cis-1,3-cyclobutyl.

[0182] In some implementations, ring A is replaced by 0 substituents R. 1a replace.

[0183] In some implementations, n is 1, and L 1 It is -C(R) 5a (R) 5b )-.

[0184] In some implementations, L 1 One methylene unit is -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted.

[0185] In some implementations, L 1 One methylene unit is replaced by -C(O)-.

[0186] In some implementations, n is 1, and L 1 One methylene unit is replaced by -C(O)-.

[0187] In some implementation schemes, R 2 Selected from: -O-, -(R 2a )N- and -S-.

[0188] In some implementation schemes, R 2 Yes -O-.

[0189] In some implementations, p is 1.

[0190] In some implementation schemes, R1a For H.

[0191] In some implementation schemes, R 1b For H.

[0192] In some implementation schemes, R 2a For H.

[0193] In some implementation schemes, R 3a and R 3b Each is H independently.

[0194] In some implementation schemes, R 4 For H.

[0195] In some implementation schemes, R 5a and R 5b Each is H independently.

[0196] In some implementation schemes, R 6 For H.

[0197] In some implementation schemes, R n For H.

[0198] In some implementations, R is H.

[0199] In some implementation schemes, R a For H.

[0200] In some implementation schemes, R b For H.

[0201] In some implementations, ring A is surrounded by 1 L 2 replace.

[0202] In some implementations, m is 0, and L 3 It is a covalent bond.

[0203] In some implementations, n is 1, and L 1 -C(R) 5a (R) 5b )-, where L 1 One methylene unit can be replaced by -C(O)-.

[0204] In some implementations, the pharmaceutical portion may have the following partial structure IA: IA Where R 2 As stated above, both in its broadest sense and in its preferred sense.

[0205] In some embodiments, the drug component is compound 2, having the following structure:

[0206] Compound 2 is disclosed as compound P-II-3, and general and specific methods for its synthesis are disclosed in WO2022 / 068878 and published national applications derived therefrom.

[0207] dose

[0208] In a first aspect of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at any dose.

[0209] In certain embodiments of the first aspect of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose ranging from 2.2 mg / kg to 12.0 mg / kg. In these embodiments or any embodiments herein, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N is... a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0210] In certain embodiments of the first aspect of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose ranging from 6.0 mg / kg to 10.0 mg / kg. In these embodiments or any embodiments herein, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N aIt can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0211] In a second aspect of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is administered to a patient at a dose ranging from 2.2 mg / kg to 12.0 mg / kg. In these embodiments, the antibody-drug conjugate is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N is [not specified]. a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0212] In certain embodiments of the second aspect of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 6.0 mg / kg to 10.0 mg / kg. In these embodiments or any embodiments herein, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0213] In some embodiments of the third aspect of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 6.0 mg / kg to 10.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 6.5 mg / kg to 9.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 7.0 mg / kg to 9.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 7.5 mg / kg to 8.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 7.8 mg / kg to 8.2 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose of about 8.0 mg / kg. In these embodiments or any of the embodiments herein, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0214] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 2.0 mg / kg to 12.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 2.5 mg / kg to 11.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 3.0 mg / kg to 11.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 3.5 mg / kg to 10.5 mg / kg. In each of these embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N is... a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0215] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 4.0 mg / kg to 10.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 4.5 mg / kg to 9.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 5.0 mg / kg to 9.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 5.5 mg / kg to 8.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 6.0 mg / kg to 8.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 6.5 mg / kg to 7.5 mg / kg. In each of these embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0216] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 2.0 mg / kg to 3.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 3.0 mg / kg to 4.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 4.0 mg / kg to 5.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 5.0 mg / kg to 6.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 6.0 mg / kg to 7.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 7.0 mg / kg to 8.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 8.0 mg / kg to 9.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 9.0 mg / kg to 10.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 10.0 mg / kg to 11.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 11.0 mg / kg to 12.0 mg / kg. In each of these embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N is... a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0217] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 2.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 2.1 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 2.2 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 2.3 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 2.4 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 2.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 2.6 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 2.7 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 2.8 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 2.9 mg / kg. In each of these embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0218] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 3.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 3.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 4.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 4.4 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 4.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 5.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 5.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 6.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 6.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 7.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 7.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 8.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 8.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 9.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 9.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 10.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 10.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 11.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 11.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 12.0 mg / kg. In each of these embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N aIt can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0219] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 6.5 mg / kg to 9.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 7.0 mg / kg to 9.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 7.5 mg / kg to 8.5 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 7.0 mg / kg to 8.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered to a patient at a dose ranging from 8.0 mg / kg to 9.0 mg / kg. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered at a dose of 8.0 mg / kg. In each of these embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0220] Preferably, the antibody-drug conjugate or its pharmaceutically acceptable salt is administered to the patient at a dose ranging from 6.0 mg / kg to 8.0 mg / kg, more preferably about 6, about 7 or about 8 mg / kg.

[0221] In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered during multiple treatment cycles (as defined herein). During each treatment cycle, the duration of administration of the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably 30 minutes to 3 hours, more preferably 40 minutes to 2 hours, even more preferably 60 to 90 minutes, and the rest period is preferably 7 to 35 days, more preferably 14 to 28 days, even more preferably 18 to 23 days, and most preferably 21 days.

[0222] In some embodiments of the present invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least one treatment cycle. In some embodiments of the present invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least two treatment cycles. In some embodiments of the present invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least three treatment cycles. In some embodiments of the present invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least four treatment cycles. In some embodiments of the present invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least five treatment cycles. In some embodiments of the present invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least six treatment cycles. In some embodiments of the present invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least seven treatment cycles. In some embodiments of the present invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least eight treatment cycles. In some embodiments of the present invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least nine treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least 10 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least 11 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least 12 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least 13 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered for at least 14 treatment cycles. In these embodiments, the antibody-drug conjugate is preferably administered every 3 weeks. In these embodiments, the antibody-drug conjugate is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N is... a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0223] In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered over 2 to 14 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered over 3 to 13 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered over 4 to 12 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered over 5 to 11 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered over 6 to 10 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered over 7 to 9 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered over 8 treatment cycles. In these embodiments, the antibody-drug conjugate is preferably administered every 3 weeks. In these embodiments, the antibody-drug conjugate is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N is... a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0224] It will be understood that the dosage should be selected based on considerations of age, weight, disease symptoms, disease progression and / or severity, sex and / or any other factors that may interfere with the therapeutic effect of the antibody-drug conjugate or its pharmaceutically acceptable salt according to the invention.

[0225] application

[0226] In some implementations, the antibody-drug conjugate or its pharmaceutically acceptable salt may be administered in a form suitable for oral, parenteral, intraperitoneal, systemic, intravenous (e.g., intravenous infusion or drip), intramuscular, subcutaneous, topical, inhalation, rectal, sublingual, transdermal, or vaginal administration.

[0227] In some implementations, the antibody-drug conjugate or its pharmaceutically acceptable salt can be administered intravenously (e.g., by injection into the subject).

[0228] In some implementations, the antibody-drug conjugate or its pharmaceutically acceptable salt may be administered to the subject once (i.e., as a one-off treatment). For example, the antibody-drug conjugate or its pharmaceutically acceptable salt may be administered to the subject once over a period of several hours or days.

[0229] In some implementations, the antibody-drug conjugate or its pharmaceutically acceptable salt may be administered to the subject on multiple separate occasions (e.g., as part of an ongoing treatment). For example, the antibody-drug conjugate or its pharmaceutically acceptable salt may be administered to the subject on multiple separate occasions over a period of time, such as total count hours, days, weeks, months, or years.

[0230] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered once daily. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered multiple times daily.

[0231] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered once weekly. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered multiple times weekly.

[0232] In some implementations, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered once every two weeks. In some implementations, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered multiple times every two weeks.

[0233] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered once every three weeks. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered multiple times every three weeks.

[0234] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered every four weeks. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered more than once every four weeks.

[0235] In some implementations, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered every five weeks. In some implementations, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered more than once every five weeks.

[0236] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered every six weeks. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered more than once every six weeks.

[0237] In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered once a month. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered more than once a month.

[0238] In some implementations, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered once a year. In some implementations, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof may be administered more than once a year.

[0239] Pharmaceutical Composition

[0240] This invention provides pharmaceutical compositions comprising an antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to the invention. In this specification, the terms "pharmaceutical composition" and "formulation" are synonymous.

[0241] In some embodiments, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, excipient or adjuvant, salt, and optionally one or more further pharmaceutically active peptides and / or compounds.

[0242] In some embodiments, in addition to the antibody-drug conjugate or its pharmaceutically acceptable salt according to the invention, the pharmaceutical composition according to the invention may contain one or more compounds, components and / or active agents.

[0243] Depending on the method of administration, in some embodiments the composition may contain 0.1 wt% to 99 wt% of the active compound (i.e., the antibody-drug conjugate according to the invention or a pharmaceutically acceptable salt thereof). In some embodiments, the composition may contain 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99 wt% of the antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to the invention.

[0244] Pharmaceutical compositions should generally be sterile and stable under manufacturing and storage conditions. Pharmaceutical compositions according to the invention can be prepared using current Good Manufacturing Practices (CGMP).

[0245] As used herein, the term "pharmaceutical composition" refers to a substance and / or combination of substances that can be used for the identification, prevention, or treatment of a tissue condition or disease. Pharmaceutical compositions are formulated to be suitable for administration to a patient for the prevention and / or treatment of disease. Furthermore, a pharmaceutical composition may refer to a combination of an active agent and a carrier (inert or active) that makes the composition suitable for therapeutic use. Pharmaceutical compositions can be formulated for oral, parenteral, topical, inhalation, rectal, sublingual, transdermal, subcutaneous, or vaginal administration based on their chemical and physical properties.

[0246] Pharmaceutical compositions may comprise solid, semi-solid, liquid, or transdermal therapeutic systems (TTS). Solid compositions are selected from tablets, coated tablets, powders, granules, pills, capsules, effervescent tablets, or transdermal therapeutic systems. Liquid compositions are also included, selected from solutions, syrups, infusion solutions, extracts, solutions for intravenous administration, solutions for infusion, or solutions of the carrier system of the present invention. Semi-solid compositions that may be used in the context of the present invention include emulsions, suspensions, creams, lotions, gels, microspheres, buccal tablets, and suppositories.

[0247] As used herein, the term "carrier" refers to a diluent, adjuvant, excipient, or medium that is administered with a therapeutic agent. Such drug carriers can be sterile liquids, such as saline solutions in water, and oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc.

[0248] When administering a pharmaceutical composition intravenously, sterile saline solution is the preferred carrier.

[0249] Saline solutions and aqueous solutions of dextran and glycerol can also be used as liquid carriers, especially for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, etc.

[0250] If desired, the composition may also contain small amounts of wetting agents, emulsifiers, or pH buffers. These compositions may be in the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release compositions, etc. The compositions may be formulated into suppositories using conventional binders and carriers such as triglycerides. The compounds of the present invention may be formulated into neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups, such as those derived from hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, tartaric acid, etc., and those formed with free carboxyl groups, such as those derived from sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, ferric hydroxide, isopropylamine, triethylamine, 2-ethylaminoethanol, histidine, procaine, etc. Examples of suitable pharmaceutical carriers are described in EW Martin's "Remington's Pharmaceutical Sciences". Such compositions will contain a therapeutically effective amount of the compound (preferably in purified form) and a suitable amount of carrier, thereby providing a form suitable for proper administration to the patient. The composition should be suitable for the mode of administration.

[0251] In some implementations, the salt may contain a metal cation, such as a sodium or potassium salt.

[0252] In some embodiments, the pharmaceutical composition may contain an aqueous diluent or solvent. In some embodiments, the aqueous diluent or solvent may be an aqueous solution of phosphate buffered salts, such as a sterile aqueous solution of phosphate buffered salts.

[0253] In some embodiments, the pharmaceutical composition may be in a form suitable for intravenous infusion. In some embodiments, the pharmaceutical composition may be administered intravenously.

[0254] In some embodiments, the antibody-drug conjugate according to the invention can be formulated into compositions, such as the pharmaceutical compositions described herein.

[0255] In some embodiments, the composition may contain the antibody-drug conjugate according to the invention at a concentration of 1-100 mg / ml. In some embodiments, the composition may contain the antibody-drug conjugate according to the invention at a concentration of 10-50 mg / ml. In some embodiments, the composition may contain the antibody-drug conjugate according to the invention at a concentration of 10-30 mg / ml. In some embodiments, the composition may contain the antibody-drug conjugate according to the invention at a concentration of 30-50 mg / ml. In some embodiments, the composition may contain the antibody-drug conjugate according to the invention at a concentration of 15-25 mg / ml. In some embodiments, the composition may contain the antibody-drug conjugate according to the invention at a concentration of 17.5-22.5 mg / ml. In some embodiments, the composition may contain the antibody-drug conjugate according to the invention at a concentration of about 20 mg / ml.

[0256] In some embodiments, the composition further comprises histidine, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. In one embodiment, histidine is L-histidine, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof. In one embodiment, histidine is a free base. In one embodiment, histidine is an L-histidine free base. In one embodiment, histidine is histidine hydrochloride monohydrate. In one embodiment, histidine is L-histidine hydrochloride monohydrate.

[0257] In some embodiments, the composition further comprises a histidine buffer. In this specification, the term "histidine buffer" has its common meaning in solutions containing histidine and its pharmaceutically acceptable acid addition salts (containing their conjugate acids), the exact amount of each depending on the pH. In one embodiment, the histidine is L-histidine.

[0258] The counterion in a pharmaceutically acceptable salt of histidine can be formed from any pharmaceutically acceptable acid, examples of which include inorganic acids such as hydrohalic acids (hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid), nitric acid, sulfuric acid, or phosphoric acid, and organic acids such as acetic acid, citric acid, succinic acid, or tartaric acid. Preferably, the pharmaceutically acceptable salt is a hydrohalide salt, more preferably a hydrochloride salt. The pharmaceutically acceptable salt can be provided to the composition in the form of its solvate, such as a hydrate, preferably a monohydrate.

[0259] In some embodiments, the composition may contain about 1 to about 8 mg / mL of total histidine. In some embodiments, the composition may contain about 2 to about 5 mg / mL of histidine. In some embodiments, the composition may contain about 3.5 to about 4.5 mg / mL of total histidine. In some embodiments, the composition may contain about 3.88 mg / mL of total histidine. In these embodiments, the amount of histidine is expressed as the total amount of histidine in the composition, including the histidine component of the free base and any pharmaceutically acceptable salts present in the composition.

[0260] In some embodiments, the composition may contain a free histidine base. In some embodiments, the composition may contain about 0.1 to about 4 mg / ml of free histidine base. In some embodiments, the composition may contain about 0.2 to about 2 mg / ml of free histidine base. In some embodiments, the composition may contain about 0.4 to about 1.6 mg / ml of free histidine base. In some embodiments, the composition may contain about 0.6 to about 1 mg / ml of free histidine base. In some embodiments, the composition may contain about 0.82 mg / ml of free histidine base.

[0261] In some embodiments, the composition may comprise histidine hydrochloride monohydrate. In some embodiments, the composition may comprise about 0.5 to about 20 mg / mL histidine hydrochloride monohydrate. In some embodiments, the composition may comprise about 1 to about 10 mg / mL histidine hydrochloride monohydrate. In some embodiments, the composition may comprise about 2 to about 8 mg / mL histidine hydrochloride monohydrate. In some embodiments, the composition may comprise about 3 to about 5 mg / mL histidine hydrochloride monohydrate. In some embodiments, the composition may comprise about 4.14 mg / mL histidine hydrochloride monohydrate.

[0262] In some embodiments, the composition may contain 1 to 100 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may contain 10-50 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may contain 10-20 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may contain 20-30 mg / ml histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may contain 30-50 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may contain about 10 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may contain about 20 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may contain about 25 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may contain about 30 mM histidine or a pharmaceutically acceptable salt thereof. In these embodiments, the concentration of histidine is expressed as the total concentration of histidine in the composition, including the histidine component of the free base and any pharmaceutically acceptable salts present in the composition.

[0263] In some embodiments, the composition further comprises sucrose. In some embodiments, the composition may contain about 20 to about 160 mg / ml of sucrose. In some embodiments, the composition may contain about 40 to about 140 mg / ml of sucrose. In some embodiments, the composition may contain about 60 to about 120 mg / ml of sucrose. In some embodiments, the composition may contain about 80 to about 100 mg / ml of sucrose. In some embodiments, the composition may contain about 90 mg / ml of sucrose.

[0264] In some embodiments, the composition may contain 1 to 20% (w / v) sucrose. In some embodiments, the composition may contain 5-10% (w / v) sucrose. In some embodiments, the composition may contain 8-10% (w / v) sucrose. In some embodiments, the composition may contain about 5% (w / v) sucrose. In some embodiments, the composition may contain about 6% (w / v) sucrose. In some embodiments, the composition may contain about 7% (w / v) sucrose. In some embodiments, the composition may contain about 8% (w / v) sucrose. In some embodiments, the composition may contain about 9% (w / v) sucrose. In some embodiments, the composition may contain about 10% (w / v) sucrose.

[0265] In some embodiments, the composition further comprises polysorbate 80. In some embodiments, the composition may contain about 0.1 to about 0.5 mg / ml of polysorbate 80. In some embodiments, the composition may contain about 0.2 to about 0.4 mg / ml of polysorbate 80. In some embodiments, the composition may contain about 0.25 to about 0.35 mg / ml of polysorbate 80. In some embodiments, the composition may contain about 0.3 mg / L of polysorbate 80.

[0266] In some embodiments, the composition may contain 0.01 to 0.5% (w / v) polysorbate 80. In some embodiments, the composition may contain 0.05-0.1% (w / v) polysorbate 80. In some embodiments, the composition may contain 0.01-0.05% (w / v) polysorbate 80. In some embodiments, the composition may contain 0.015-0.045% (w / v) polysorbate 80. In some embodiments, the composition may contain about 0.02% (w / v) polysorbate 80. In some embodiments, the composition may contain about 0.03% (w / v) polysorbate 80.

[0267] In some embodiments, the pH of the composition can be 5 to 8. In some embodiments, the pH of the composition can be 5 to 7. In some embodiments, the pH of the composition can be 5 to 6. In some embodiments, the pH of the composition can be 5.3 to 5.7. In some embodiments, the pH of the composition can be about 5.5.

[0268] In some embodiments, the antibody-drug conjugate according to the present invention can be formulated as a composition comprising: Approximately 20 mg / ml of the antibody-drug conjugate according to the present invention; Approximately 25 mM histidine or a pharmaceutically acceptable salt thereof; Approximately 9% (w / v) sucrose; and Approximately 0.03% (w / v) polysorbate 80, The pH of the composition can be approximately 5.5.

[0269] The composition will be referred to as "Composition 1" below.

[0270] The present invention also provides a composition, typically an aqueous composition, comprising: Approximately 20 mg / ml of antibody-drug conjugate according to the first or second aspect of the present invention; Approximately 25 mM histidine or a pharmaceutically acceptable salt thereof; Approximately 9% (w / v) sucrose; and Approximately 0.03% (w / v) polysorbate 80, The pH of the composition is approximately 5.5.

[0271] The present invention also provides a composition, typically an aqueous composition, comprising: About 20 mg / ml of antibody-drug conjugate according to the first or second aspect of the present invention; Approximately 0.82 mg / ml L-histidine; Approximately 4.14 mg / ml of L-histidine hydrochloride monohydrate; Approximately 90 mg / ml sucrose; and Approximately 0.3 mg / ml of polysorbate 80.

[0272] In some embodiments, the antibody-drug conjugate according to the invention can be formulated as a lyophilized composition, such as a lyophilized powder composition.

[0273] In some embodiments, the lyophilized composition may contain about 5 to about 500 mg of the antibody-drug conjugate according to the invention. In some embodiments, the lyophilized composition may contain about 50 to about 250 mg of the antibody-drug conjugate according to the invention. In some embodiments, the lyophilized composition may contain about 50 to about 150 mg of the antibody-drug conjugate according to the invention. In some embodiments, the lyophilized composition may contain about 75 to about 125 mg of the antibody-drug conjugate according to the invention. In some embodiments, the lyophilized composition may contain about 90 to about 110 mg of the antibody-drug conjugate according to the invention. In some embodiments, the lyophilized composition may contain about 100 mg of the antibody-drug conjugate according to the invention.

[0274] In some embodiments, the lyophilized composition may contain histidine. In some embodiments, the lyophilized composition may contain about 5 to about 40 mg of total histidine. In some embodiments, the composition may contain about 10 to about 30 mg of histidine. In some embodiments, the lyophilized composition may contain about 15 to about 25 mg of total histidine. In some embodiments, the lyophilized composition may contain about 18 to about 22 mg of total histidine. In some embodiments, the lyophilized composition may contain about 19.42 mg of total histidine. In these embodiments, the amount of histidine is expressed as the total amount of histidine in the composition, including the histidine component of free bases and any pharmaceutically acceptable salts present in the composition.

[0275] In some embodiments, the lyophilized composition may contain a free histidine base. In some embodiments, the lyophilized composition may contain about 0.5 to about 20 mg of free histidine base. In some embodiments, the lyophilized composition may contain about 1 to about 10 mg of free histidine base. In some embodiments, the lyophilized composition may contain about 2 to about 8 mg of free histidine base. In some embodiments, the lyophilized composition may contain about 3 to about 5 mg of free histidine base. In some embodiments, the lyophilized composition may contain about 4.1 mg of free histidine base.

[0276] In some embodiments, the lyophilized composition may contain about 0.5 to about 20 parts by weight of free histidine base relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 1 to about 10 parts by weight of free histidine base relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 2 to about 8 parts by weight of free histidine base relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 3 to about 5 parts by weight of free histidine base relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 4.1 mg of free histidine base relative to 100 parts by weight of the antibody-drug conjugate.

[0277] In some embodiments, the lyophilized composition may contain histidine hydrochloride monohydrate. In some embodiments, the lyophilized composition may contain about 2.5 to about 100 mg of histidine hydrochloride monohydrate. In some embodiments, the lyophilized composition may contain about 5 to about 50 mg of histidine hydrochloride monohydrate. In some embodiments, the lyophilized composition may contain about 10 to about 40 mg of histidine hydrochloride monohydrate. In some embodiments, the lyophilized composition may contain about 15 to about 25 mg of histidine hydrochloride monohydrate. In some embodiments, the lyophilized composition may contain about 20.7 mg of histidine hydrochloride monohydrate.

[0278] In some embodiments, the lyophilized composition may contain about 2.5 to about 100 parts by weight of histidine hydrochloride monohydrate relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 5 to about 50 parts by weight of histidine hydrochloride monohydrate relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 10 to about 40 parts by weight of histidine hydrochloride monohydrate relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 15 to about 25 parts by weight of histidine hydrochloride monohydrate relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 20.7 parts by weight of histidine hydrochloride monohydrate relative to 100 parts by weight of the antibody-drug conjugate.

[0279] In some embodiments, the lyophilized composition may contain sucrose. In some embodiments, the lyophilized composition may contain about 100 to about 800 mg of sucrose. In some embodiments, the lyophilized composition may contain about 200 to about 700 mg of sucrose. In some embodiments, the lyophilized composition may contain about 300 to about 600 mg of sucrose. In some embodiments, the lyophilized composition may contain about 400 to about 500 mg of sucrose. In some embodiments, the composition may contain about 450 mg of sucrose.

[0280] In some embodiments, the lyophilized composition may contain about 100 to about 800 parts by weight of sucrose relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 200 to about 700 parts by weight of sucrose relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 300 to about 600 parts by weight of sucrose relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 400 to about 500 parts by weight of sucrose relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the composition may contain about 450 parts by weight of sucrose relative to 100 parts by weight of the antibody-drug conjugate.

[0281] In some embodiments, the lyophilized composition may contain polysorbate 80. In some embodiments, the lyophilized composition may contain about 0.5 to about 2.5 mg of polysorbate 80. In some embodiments, the lyophilized composition may contain about 1 to about 2 mg of polysorbate 80. In some embodiments, the lyophilized composition may contain about 1.3 to about 1.7 mg of polysorbate 80. In some embodiments, the lyophilized composition may contain about 1.5 mg of polysorbate 80.

[0282] In some embodiments, the lyophilized composition may contain about 0.5 to about 2.5 parts by weight of polysorbate 80 relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 1 to about 2 parts by weight of polysorbate 80 relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 1.3 to about 1.7 parts by weight of polysorbate 80 relative to 100 parts by weight of the antibody-drug conjugate. In some embodiments, the lyophilized composition may contain about 1.5 parts by weight of polysorbate 80 relative to 100 parts by weight of the antibody-drug conjugate.

[0283] In one embodiment, a lyophilized composition, typically a lyophilized powder composition, is provided, comprising: (a) Approximately 100 mg of an antibody-drug conjugate as defined herein; (b) Approximately 4.1 mg of L-histidine; (c) Approximately 20.7 mg of L-histidine hydrochloride monohydrate; (d) Approximately 450 mg of sucrose; and (e) Approximately 1.5 mg of polysorbate 80.

[0284] In one embodiment, a lyophilized composition, typically a lyophilized powder composition, is provided, comprising: (a) Antibody-drug conjugates as defined herein, in an amount of approximately 100 parts by weight; (b) L-histidine, in an amount of about 4.1 parts by weight relative to 100 parts by weight (a); (c) L-histidine hydrochloride monohydrate, in an amount of about 20.7 parts by weight relative to 100 parts by weight (a); (d) Sucrose, in an amount of about 450 parts by weight relative to 100 parts by weight of (a); and (e) Polysorbate 80, in an amount of about 1.5 parts by weight relative to 100 parts by weight (a).

[0285] A method for preparing compositions as defined herein is also provided, the method comprising reconstituted a lyophilized composition as defined herein with a diluent. In one embodiment, the diluent is water. In one embodiment, the water is substantially free of impurities.

[0286] In one embodiment, the water comprises purified water. As known to those skilled in the art, purified water is water that has been mechanically filtered or processed to remove impurities. Typical processes for purifying water include distillation, deionization, vapor compression, reverse osmosis, carbon filtration, microfiltration, ultrafiltration, ultraviolet oxidation, or electro-deionization. A combination of several of these processes can be used to produce ultrapure water as generally defined herein.

[0287] Typical impurities that may need to be removed to purify water include inorganic ions (usually monitored as conductivity or resistivity or by specific tests), organic compounds (usually monitored as TOC or by specific tests), bacteria (usually monitored by total viable count or epifluorescence), endotoxins and nucleases (usually monitored by LAL or specific enzyme tests), particles (usually controlled by filtration) and gases (usually managed by degassing if necessary).

[0288] In one embodiment, the water comprises water for injection (WFI). In one embodiment, the water consists essentially of water for injection (WFI). In one embodiment, the water consists of water for injection (WFI). As known to those skilled in the art, water for injection (WFI) is sterile, hypotonic, nonpyrogenic, and free of bacteriostatic or antimicrobial agents. Water for injection is described in the European Pharmacopoeia (Ph. Eur.) 11.4, Special Issue No. 0169 and the United States Pharmacopeia (USP) Special Issue No. 1231 "Water for Pharmaceutical Manufacturing," which are incorporated herein by reference.

[0289] In one embodiment, the water comprises water having a purity level equivalent to or higher than that of water for injection (WFI) or meeting the standards for water for injection (WFI) as defined in European Pharmacopoeia (Ph. Eur.) 11.4, Special Issue No. 0169 and / or United States Pharmacopeia (USP) Special Issue No. 1231. In another embodiment, the water is substantially composed of water having a purity level equivalent to or higher than that of water for injection (WFI) or meeting the standards for water for injection (WFI) as defined in European Pharmacopoeia (Ph. Eur.) 11.4, Special Issue No. 0169 and / or United States Pharmacopeia (USP) Special Issue No. 1231. In yet another embodiment, the water comprises water having a purity level equivalent to or higher than that of water for injection (WFI) or meeting the standards for water for injection (WFI) as defined in European Pharmacopoeia (Ph. Eur.) 11.4, Special Issue No. 0169 and / or United States Pharmacopeia (USP) Special Issue No. 1231.

[0290] In these embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N aIt can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or decimal selected from approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.

[0291] Medical use

[0292] In a first aspect of the invention, an antibody-drug conjugate or a pharmaceutically acceptable salt thereof is used as a medicine in the treatment of endometrial cancer. In other words, in a first aspect of the invention, an antibody-drug conjugate or a pharmaceutically acceptable salt thereof is used in a method of treating endometrial cancer.

[0293] In a second aspect of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is used as a medicine in the treatment of cancer. In other words, in a second aspect of the invention, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is used in a method of treating cancer.

[0294] The present invention also provides a method for treating and / or preventing endometrial cancer, comprising administering to a subject in need an antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to the first aspect of the present invention.

[0295] The present invention also provides a method for treating and / or preventing cancer, comprising administering to a subject in need an antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to a second aspect of the present invention.

[0296] The present invention also provides the use of an antibody-drug conjugate or a pharmaceutically acceptable salt thereof according to the first aspect of the invention in the preparation of a medicament for the treatment and / or prevention of endometrial cancer in a subject.

[0297] The present invention also provides the use of an antibody-drug conjugate or a pharmaceutically acceptable salt thereof, according to a second aspect of the invention, in the preparation of a medicament for the treatment and / or prevention of cancer in a subject.

[0298] In some embodiments of the second aspect of the invention, the patient may have been diagnosed with HER2-positive cancer. In some embodiments of the second aspect of the invention, the patient may have been diagnosed with HER2-overexpressing cancer. It should be understood that “HER2-positive cancer” or “HER2-overexpressing cancer” is cancer associated with increased expression of HER2, wherein the level of HER2 expression is considered increased compared to, for example, HER2 expression in non-cancerous cells or tissues that may not express HER2 or may express HER2 at baseline levels.

[0299] In some embodiments of the second aspect of the invention, the patient may have been diagnosed with HER2-low cancer. In some embodiments of the second aspect of the invention, the patient may have been diagnosed with HER2-negative cancer. It should be understood that "HER2-low cancer" or "HER2-negative cancer" is cancer that is unrelated to or associated with low levels of HER2 expression, wherein low levels of HER2 expression are considered to be reduced compared to HER2 expression in, for example, non-cancer cells or tissues.

[0300] In some embodiments of the second aspect of the invention, the cancer is a HER2-overexpressing cancer (also as described herein, a HER2-positive cancer).

[0301] In some implementations, HER2-overexpressing cancer is defined as cancer with a HER2 expression score of 3+ in immunohistochemistry.

[0302] In some embodiments, HER2-overexpressing cancers are identified as HER2-positive cancers by immunohistochemistry to assign a HER2 expression score of 2+ and by in situ hybridization. The in situ hybridization methods of this invention include fluorescence in situ hybridization (FISH) and two-color in situ hybridization (DISH).

[0303] In some implementations, the cancer is a cancer with low HER2 expression (also described in this article as HER2-low cancer).

[0304] In some implementations, cancers with low HER2 expression are identified as HER2-negative cancers by immunohistochemistry to give a HER2 expression score of 2+ and by in situ hybridization.

[0305] In some implementations, cancers with low HER2 expression are classified as HER2-expressing cancers by immunohistochemistry with a HER2 expression score of 1+.

[0306] In some implementations, cancers with low HER2 expression are treated with immunohistochemistry for cancers with a HER2 expression score >0 and <1+.

[0307] Methods for scoring HER2 expression levels using immunohistochemistry or for determining HER2 expression positivity or negativity using in situ hybridization are not particularly limited, provided they are acceptable to those skilled in the art. Examples of such methods may include those described in ASCO 2018 for breast and endometrial cancer. Specifically, algorithms for assessing HER2 protein expression by immunohistochemical (IHC) assay of the invasive component of breast cancer specimens, algorithms for in situ hybridization (ISH) assay of the invasive component of breast cancer specimens using a single-signal (HER2 gene) assay (single-probe ISH), and algorithms for in situ hybridization (ISH) assay of the invasive component of breast cancer specimens using a dual-signal (HER2 gene) assay (dual-probe ISH) were published by ASCO in 2018. These algorithms are derived from recommendations in Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology / College of American Pathologists Clinical Practice Guideline Focused Update.

[0308] In some embodiments of the second aspect of the invention, the cancer may be selected from lung cancer, kidney cancer, urinary tract cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, esophageal cancer, uterine cancer, and endometrial cancer.

[0309] In some implementations, cancer can be carcinoma. In some implementations, cancer can be adenocarcinoma.

[0310] In some implementations, endometrial cancer and / or uterine cancer can be serous endometrial cancer.

[0311] In some embodiments of the second aspect of the invention, the cancer may be breast cancer.

[0312] In some embodiments of the second aspect of the invention, the cancer may be HER2-positive breast cancer.

[0313] In some embodiments of the second aspect of the invention, the cancer may be HER2-overexpressing breast cancer.

[0314] In some embodiments of the second aspect of the invention, the cancer may be HER2-low or HER2-negative breast cancer.

[0315] In some embodiments of the second aspect of the invention, the cancer may be endometrial cancer.

[0316] In some embodiments of the second aspect of the invention, the cancer may be HER2-positive endometrial cancer.

[0317] In some embodiments of the second aspect of the invention, the cancer may be HER2-overexpressing endometrial cancer.

[0318] In some embodiments of the second aspect of the invention, the cancer may be HER2-low or HER2-negative endometrial cancer.

[0319] In some implementations, the cancer may be advanced endometrial cancer. In some implementations, the cancer may be metastatic endometrial cancer.

[0320] In some implementation schemes, cancer can be a solid tumor.

[0321] In some implementations, the cancer can be HER2-expressing recurrent or metastatic endometrial cancer.

[0322] In some implementations, the cancer can be HER2-low, hormone receptor-positive (HR+) metastatic breast cancer.

[0323] In some implementations, the cancer can be metastatic breast cancer in patients with low HER2 and positive hormone receptors (HR+). In some implementations, the patient can be someone whose disease has progressed on endocrine therapy (ET).

[0324] In some implementations, the cancer can be breast cancer in patients with low HER2 (IHC 2+ / ISH- and IHC 1+) and HR+. In some implementations, the patient can be someone whose disease has progressed on at least two previous lines of ET. In some implementations, the patient can be someone whose disease has progressed in a metastatic setting within 6 months after first-line ET+CDK4 / 6i.

[0325] In some embodiments of the third aspect of the invention, the cancer is HER2-positive breast cancer.

[0326] In some embodiments of the third aspect of the invention, the cancer is breast cancer with HER2 overexpression.

[0327] Preferred examples of HER2-overexpressing or HER2-positive breast cancer include breast cancer with a HER2 expression score of 3+ by immunohistochemistry, and breast cancer with a HER2 expression score of 2+ by immunohistochemistry and confirmed as HER2-positive by in situ hybridization.

[0328] In some embodiments of the third aspect of the invention, the cancer is unresectable breast cancer.

[0329] In some embodiments of the third aspect of the invention, the cancer is metastatic breast cancer.

[0330] In some embodiments of the third aspect of the invention, the cancer is HER2-positive unresectable or metastatic breast cancer.

[0331] In each of these embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is preferably compound 1 or a pharmaceutically acceptable salt thereof. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a It can be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is compound 1 or a pharmaceutically acceptable salt thereof, and the average number of linkages N a You can choose any integer or subarray consisting of approximately 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, and 8.0.

[0332] Cancer is a well-known term that refers to a disease or group of diseases involving abnormal cell growth. The term "cancer" is used interchangeably with "tumor" or "cancer-related disease."

[0333] The terms “disease” and “symptom” used interchangeably in this article refer to an abnormal condition, particularly an abnormal medical condition, such as a disease or injury, in which cells, tissues, organs, or individuals are no longer able to perform their functions effectively. Usually, but not necessarily, a disease is associated with specific symptoms or signs that indicate its presence. Thus, the presence of such symptoms or signs indicates that a cell, tissue, organ, or individual is diseased. Changes in such symptoms or signs indicate disease progression. Disease progression is typically characterized by an increase or decrease in such symptoms or signs, which indicates “worsening” or “improving” the disease. “Worsening” of a disease is characterized by a decrease in the ability of a cell, tissue, organ, or individual / patient to perform its functions effectively, while “improving” of a disease is typically characterized by an increase in the ability of a cell, tissue, organ, or individual / patient to perform its functions effectively.

[0334] The terms “treat,” “treatment,” and “treating” refer to the reduction, decrease, or improvement of one or more symptoms associated with an existing disease or condition and / or slowing, reducing, or stopping the progression of the disease or condition and / or delaying or preventing the onset of symptoms of the disease or condition (such as further symptoms).

[0335] The terms “prevent,” “prevention,” and “preventing” refer to preventing the onset of symptoms of a disease or condition, and therefore include preventive treatment.

[0336] In some embodiments, the antibody-drug conjugates or pharmaceutically acceptable salts thereof according to the invention may result in a reduced incidence of disease or symptoms, a delayed onset of disease or symptoms, and / or a reduced severity of disease or symptoms compared to other therapies known in the art.

[0337] The medical uses and treatments described herein may be used in combination with other treatments and / or medications. For example, the medical uses and treatments described herein may be used in combination with known chemotherapy, immunomodulatory and / or radiation therapy as a combination therapy or treatment.

[0338] In some embodiments, the antibody-drug conjugates or pharmaceutically acceptable salts thereof according to the invention can be used for diagnostic purposes, namely for diagnosing HER2-related cancers and / or testing HER2 expression in tissue samples (e.g., tissue biopsies). The antibody-drug conjugates or pharmaceutically acceptable salts thereof according to the invention can be used in any diagnostic assay, including (but not limited to) diagnostic assays involving ELISA, flow cytometry, immunohistochemistry, and histology.

[0339] In some embodiments, antibody-drug conjugates or pharmaceutically acceptable salts thereof can be used to provide prognostic information regarding disease progression. In some embodiments, antibody-drug conjugates or pharmaceutically acceptable salts thereof can be used to determine the suitability of further anticancer treatment.

[0340] In some embodiments, antibody-drug conjugates or pharmaceutically acceptable salts thereof may be used in diagnostic methods of biopsy. In some embodiments, the biopsy may be a breast biopsy. In some embodiments, the biopsy may be a uterine and / or endometrial biopsy.

[0341] The antibody-drug conjugate or its pharmaceutically acceptable salt according to the present invention may have inhibitory activity against the in vitro proliferation of tumor cells. The inhibitory activity may be: compared to a tumor cell culture medium in which a negative control or control drug is added, the proliferation capacity of tumor cells is reduced by not less than 1%, not less than 2%, not less than 4%, not less than 5%, not less than 8%, not less than 10%, not less than 15%, not less than 18%, not less than 20%, not less than 25%, not less than 40%, not less than 50%, not less than 60%, not less than 70%, not less than 80%, not less than 90%, or not less than 95%. For example, the inhibitory activity may be an IC50 value for tumor cells. 50Value (nM), which is not greater than 10000, not greater than 5000, not greater than 4000, not greater than 3000, not greater than 2000, not greater than 1000, not greater than 500, not greater than 400, not greater than 300, not greater than 200, not greater than 150, not greater than 120, not greater than 110, not greater than 100, not greater than 99, not greater than 98, not greater than 97, not greater than 95, not greater than 90, not greater than 80, not greater than 75, not greater than 70, not greater than 65, not greater than 62, not greater than 60, not greater than 50, not greater than 40, not greater than 30, not greater than 25, not greater than 23, not greater than 22, not greater than 20, not greater than 19, not greater than 18, not greater than 18.5, not greater than 17, not greater than 15, not greater than 12, not greater than 10, not greater than 9 Not greater than 8.5, not greater than 7, not greater than 6.7, not greater than 6, not greater than 5.9, not greater than 5.5, not greater than 5.0, not greater than 4.8, not greater than 4.5, not greater than 4.4, not greater than 4, not greater than 3.5, not greater than 3, not greater than 2.5, not greater than 2, not greater than 1.5, not greater than 1.0, not greater than 0.5, not greater than 0.3, not greater than 0.29, not greater than 0.25, not greater than 0.21, not greater than 0.20, not greater than 0.18, not greater than 0.17, not greater than 0.15, not greater than 0.12, not greater than 0.10, not greater than 0.09, not greater than 0.08, not greater than 0.07, not greater than 0.06, not greater than 0.05, not greater than 0.04, not greater than 0.03, not greater than 0.02 or not greater than 0.01.

[0342] The antibody-drug conjugate or its pharmaceutically acceptable salt according to the present invention may have targeted inhibitory activity. Targeted inhibitory activity may be: compared to a culture medium in which a compound disclosed herein is added, the proliferation capacity of tumor cells highly expressing a specific target is reduced by not less than 1%, not less than 2%, not less than 4%, not less than 5%, not less than 8%, not less than 10%, not less than 15%, not less than 18%, not less than 20%, not less than 25%, not less than 40%, not less than 50%, not less than 60%, not less than 70%, not less than 80%, not less than 90%, or not less than 95%. For example, targeted inhibitory activity may be an IC50 effect on tumor cells highly expressing a specific target. 50 Value (nM), this IC 50Values ​​not greater than 10000, 5000, 4000, 3000, 2000, 1000, 500, 400, 300, 200, 185, 150, 120, 110, 100, 99, 98, 97, 95, 91, 80, 74, 70, 65, 62, 60, 50, 40, 30, 25, 23, 22, 20, 19, 18, 18.5, 17, 15, 12, 10, and above. 9. Not greater than 8.5, not greater than 7, not greater than 6.7, not greater than 6, not greater than 5.9, not greater than 5.5, not greater than 5.0, not greater than 4.8, not greater than 4.5, not greater than 4.4, not greater than 4, not greater than 3.5, not greater than 3, not greater than 2.5, not greater than 2, not greater than 1.5, not greater than 1.0, not greater than 0.5, not greater than 0.3, not greater than 0.29, not greater than 0.25, not greater than 0.21, not greater than 0.20, not greater than 0.18, not greater than 0.17, not greater than 0.15, not greater than 0.12, not greater than 0.10, not greater than 0.09, not greater than 0.08, not greater than 0.07, not greater than 0.06, not greater than 0.05, not greater than 0.04, not greater than 0.03, not greater than 0.02 or not greater than 0.01.

[0343] The antibody-drug conjugate or its pharmaceutically acceptable salt according to the present invention can have plasma stability. Plasma stability can be defined as the release of no more than 50%, 40%, 30%, 20%, 10%, 7%, 5%, 4%, 3%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% of the cytotoxic drug from the antibody-drug conjugate or its pharmaceutically acceptable salt after 1, 3, 5, 7, 14, 20, or 30 days following the addition of the compound to plasma.

[0344] The antibody-drug conjugate or its pharmaceutically acceptable salt according to the present invention can have an in vivo tumor-suppressive effect. The tumor-suppressive effect can be: compared to administration of a negative control or control drug to a subject, at 1 day, 3 days, 5 days, 7 days, 14 days, 20 days, 21 days, or 30 days after administration of the antibody-drug conjugate or its pharmaceutically acceptable salt, the tumor volume of the subject is reduced by not less than 1%, not less than 2%, not less than 4%, not less than 5%, not less than 8%, not less than 10%, not less than 15%, not less than 18%, not less than 20%, not less than 25%, not less than 40%, not less than 50%, not less than 55%, not less than 60%, not less than 70%, not less than 73%, and not less than 73%. Less than 75%, not less than 80%, not less than 90%, or not less than 95%, or after 1, 3, 5, 7, 14, 20, 21, or 30 days following administration of the antibody-drug conjugate or its pharmaceutically acceptable salt, the tumor volume of the subject decreased by not less than 1.1 times, not less than 1.3 times, not less than 1.5 times, not less than 2 times, not less than 3 times, not less than 5 times, not less than 10 times, not less than 20 times, not less than 22 times, not less than 30 times, not less than 50 times, not less than 100 times, not less than 500 times, not less than 1000 times, or not less than 1500 times.

[0345] The antibody-drug conjugate or its pharmaceutically acceptable salt according to the present invention can have good in vivo safety. In vivo safety can be defined as follows: after administration of the antibody-drug conjugate or its pharmaceutically acceptable salt to a subject, the release rate of free toxin in the subject is not more than 50%, 40%, 30%, 20%, 10%, 7%, 5%, 4%, 3%, 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1.4%, 1.3%, 1.2%, 1.1%, 1.0%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. For example, in vivo safety can be defined as the ability to administer the antibody-drug conjugate or its pharmaceutically acceptable salt at concentrations of not less than 0.5 mg / kg, not less than 1 mg / kg, not less than 2 mg / kg, not less than 3 mg / kg, not less than 4 mg / kg, not less than 5 mg / kg, not less than 10 mg / kg, not less than 20 mg / kg, not less than 30 mg / kg, not less than 50 mg / kg, not less than 70 mg / kg, not less than 100 mg / kg, not less than 200 mg / kg, not less than 500 mg / kg, or not less than 1000 mg / kg without causing toxicity in the subjects.

[0346] Subjects

[0347] In some embodiments, the subjects of the medical uses and treatments according to the present invention may be mammals.

[0348] In some implementations, the subject can be a human being.

[0349] In some implementations, the subjects may alternatively be non-human mammals, including, for example, primates, monkeys, dogs, cats, horses, cattle, sheep, pigs, rabbits, rats, or mice.

[0350] In some implementations, the subject can be a patient, such as a human patient.

[0351] In some implementations, the subject may have and / or have been diagnosed with one or more types of cancer.

[0352] Previously treated subjects

[0353] In some implementations, compounds of formula (I), particularly compound 1, are used in a method of treating metastatic breast cancer in patients with low HER2 expression and positive hormone receptors (HR+) whose disease has progressed on endocrine therapy (ET).

[0354] In some implementations, compounds of formula (I), particularly compound 1, are used in the treatment of breast cancer, especially in HER2-low expressing (IHC 2+ / ISH- and IHC 1+), HR+ patients whose disease has progressed within 6 months after at least two lines of prior ET or first-line ET+CDK4 / 6i in a metastatic setting.

[0355] In a third aspect of the invention, compounds of formula (I), particularly compound 1, are used in a method of treating breast cancer in patients previously treated with anti-HER2 antibodies and / or taxanes.

[0356] In some embodiments of the third aspect of the invention, the anti-HER2 antibody previously used to treat patients is selected from trastuzumab, pertuzumab, and magtuximab, or a biosimilar of any one of them.

[0357] It should be understood that any biosimilar of an antibody described includes any version of that antibody, or a variant thereof.

[0358] In some embodiments of the third aspect of the invention, the anti-HER2 antibody is trastuzumab or a biosimilar thereof.

[0359] It should be understood that trastuzumab is marketed under the brand name Herceptin. ® sell.

[0360] In a third aspect of the invention, the compound of formula (I) is used in a method of treating breast cancer in patients previously treated with trastuzumab and taxane.

[0361] In one respect, the compound of formula (I) is used to treat HER2-positive unresectable / metastatic breast cancer in patients who have been treated with trastuzumab and taxane.

[0362] In some embodiments of the third aspect of the invention, taxane is selected from paclitaxel, docetaxel, cabazitaxel and albumin-bound paclitaxel.

[0363] General terms and definitions

[0364] In its normal sense, the term "treatment cycle" in the field of oncology refers to a period of time during which anticancer drugs are administered, followed by a rest period during which the drugs are no longer used.

[0365] In the context of this disclosure, the term “about” means, as would be understood by one of ordinary skill, an accuracy range that still ensures the technical effect of the feature in question. This term typically indicates a deviation from the indicated numerical value of ±10%, such as ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, and, for example, ±0.01%. As one of ordinary skill will understand, the specific such deviation for a given technical effect will depend on the nature of that technical effect. For example, natural or biotechnological effects may generally have larger such deviations than artificial or engineered technical effects. “About” allows for consideration of uncertainties and variations in technical measurements, such as when referring to a specific amount or concentration.

[0366] The term "polypeptide" is used in its conventional sense to refer to a series of amino acids, usually L-amino acids, linked together, typically by peptide bonds between the α-amino and carboxyl groups of adjacent amino acids. The term "polypeptide" is used interchangeably with the terms "amino acid sequence," "peptide," and / or "protein." The term "residue" is used to refer to an amino acid within an amino acid sequence.

[0367] The term "variant" refers to a polypeptide that has the same function as the amino acid sequence described herein but includes one or more amino acid substitutions, insertions, or deletions.

[0368] The sequence may have one or more amino acid residues that produce a silencing change and result in a functionally equivalent molecule, with deletions, insertions, or substitutions. These sequences are within the scope of this invention. Intentional amino acid substitutions may be made based on similarities in the polarity, charge, solubility, hydrophobicity, hydrophilicity, and / or amphiphilic properties of the residues, as long as activity is preserved.

[0369] For example, negatively charged amino acids include aspartic acid and glutamic acid; positively charged amino acids include lysine and arginine; and amino acids with uncharged polar head groups and similar hydrophilicity values ​​include leucine, isoleucine, valine, glycine, alanine, asparagine, glutamine, serine, threonine, phenylalanine, and tyrosine.

[0370] As used herein, “variant” is synonymous with “mutant” and refers to a polynucleotide or amino acid sequence that differs from the corresponding wild-type sequence. The term “wild-type” is used to refer to a gene or protein that has the same polynucleotide or amino acid sequence as the natural gene or protein.

[0371] Nucleic acid sequences can be RNA or DNA sequences or variants thereof. The term "polynucleotide" includes both RNA and DNA sequences. It can be single-stranded or double-stranded. It can be, for example, genomic DNA, recombinant mRNA, or cDNA.

[0372] The terms "selectively binds" and "specifically binds" are used interchangeably in this article.

[0373] This disclosure is not limited to the exemplary methods and materials disclosed herein, and embodiments of this disclosure may be implemented or tested using any methods and materials similar to or equivalent to those described herein. Numerical ranges include the numbers that define the range. Unless otherwise stated, any nucleic acid sequence is written in a 5' to 3' orientation from left to right; amino acid sequences are written in a left-to-right orientation from amino to carboxyl.

[0374] When providing numerical ranges, it should be understood that, unless the context clearly specifies otherwise, each intermediate value between the upper and lower limits of the range (in tenths of the lower limit unit) is also specifically disclosed. Each smaller range between any stated or intermediate value within the stated range and any other stated or intermediate value within the stated range is included in this disclosure. The upper and lower limits of these smaller ranges may be independently included or excluded from the range, and any limitation in which any, neither, or both are included in the smaller range is also included in this disclosure, subject to any specifically excluded limitation in the stated range. Where a stated range includes one or two limitations, the range excluding any or both of these included limitations is also included in this disclosure.

[0375] It must be noted that, as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly indicates otherwise.

[0376] As used herein, the terms “comprising,” “comprises,” and “comprisedof” are synonymous with “including,” “includes,” or “containing,” and are inclusive or open-ended, not excluding additional, unlisted members, elements, or method steps. The terms “comprising,” “comprises,” and “comprised of” also include the term “consisting of.”

[0377] As used herein, the terms “identity” and “% sequence identity” refer to the percentage (expressed as a percentage) of consecutive nucleotide or amino acid sequences that are identical to a reference sequence between sequences. Identity is calculated by counting the number of identical (matched) aligned nucleotide or amino acids between the sequence of interest and the reference sequence, dividing that number by the total number of nucleotides or amino acids, and multiplying by 100. Therefore, identity percentage = (matches × 100) / length of aligned region. Insertions and deletions are not permitted when calculating the identity percentage. Chemical modifications of nucleotides can be ignored as long as the functional ability to form Watson Crick base pairs is preserved.

[0378] Identity comparisons can be performed visually or, more commonly, with the aid of readily available sequence comparison programs. These commercially available computer programs can calculate the percentage identity between two or more sequences. A suitable computer program for performing such comparisons is the GCG Wisconsin Bestfit software package (University of Wisconsin; Devereux et al., 1984, Nucleotide sequences Research 12:387). Examples of other software that can perform sequence comparisons include, but are not limited to, the BLAST software package (see Ausubel et al., 1999, ibid. – Chapter 18), FASTA (Atschul et al., 1990, J. Mol. Biol., 403-410), and the GNEWORKS comparison tool suite. BLAST and FASTA can be used for both offline and online searches. For example, the percentage identity between two polypeptide sequences can be easily determined using BLAST, which is freely available at http: / / blast.ncbi.nlm.nih.gov.

[0379] Once the software produces the best alignment, the percentage of identity can be calculated. The software typically does this as part of sequence comparisons and generates numerical results.

[0380] The publications discussed herein are provided solely for their publication prior to the filing date of this application. Nothing in this document should be construed as an admission that such publications constitute prior art as claimed herein.

[0381] This disclosure is not limited to the exemplary methods and materials disclosed herein, and embodiments of this disclosure may be implemented or tested using any methods and materials similar to or equivalent to those described herein. Numerical ranges include the numbers that define the range. Unless otherwise stated, any nucleic acid sequence is written in a 5' to 3' orientation from left to right; amino acid sequences are written in a left-to-right orientation from amino to carboxyl.

[0382] The publications discussed herein are provided solely for their publication prior to the filing date of this application. Nothing in this document should be construed as an admission that such publications constitute prior art as claimed herein.

[0383] The invention will now be further described by way of examples, which are intended to help those skilled in the art to implement the invention and are not intended to limit the scope of the invention in any way.

[0384] Example

[0385] Example 1 - Synthesis of Compound 1

[0386] Synthesis of intermediate 1-(1S,3R)-N-((1S,9S)-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1H,12H-benzo[de]pyrano[3',4':6,7]indolazino[1,2-b]quinoline-1-yl)-3-hydroxycyclobutane-1-carboxamide

[0387] Step 1: DIEA (500 mg, 3.87 mmol) was added to a solution of intermediate 1z (900 mg, 1.69 mmol), HATU (691 mg, 1.88 mmol), and intermediate 1a (320 mg, 2.00 mmol) in DMF (18 mL) under a nitrogen atmosphere at 0 °C, and the mixture was stirred at 25 °C for 3 hours. After the starting materials were completely consumed as detected by TLC (EA), the reaction solution was added dropwise to deionized water (320 mL) and filtered to give a gray solid (850 mg, yield: 87%).

[0388] Step 2.

[0389] NaHCO3 (42 mg, 0.50 mmol) as solid was added to a solution of intermediate 1b (100 mg, 0.174 mmol) in MeOH / DCM (1 / 1, 3 mL), and the mixture was stirred at 25 °C for 3 hours. After the reaction was completed as detected by TLC (EA), the reaction solution was filtered, dried by low-temperature rotary evaporation, slurried with aq. HCl (0.5 M, 10 mL), filtered, purified by preparative HPLC (0.1% TFA), and then freeze-dried to give a gray solid (15 mg, yield: 16%).

[0390] MS m / z (ESI): 534 [M+1]

[0391] H-NMR (400 MHz, DMSO-D): 8.45(d, 1H), 7.81 (d, 1H), 7.32 (s, 1H), 6.52 (m, 1H), 5.58-5.56 (m, 1 H), 5.44 (s, 2H), 5.14 (dd, 2 H), 3.96 (m, 1H),3.48 (m, 1H), 3.19 (m, 2H), 2.53-2.28 (m, 3H), 2.48 (s, 3H), 2.20-2.00(m,4H), 1.95-1.80 (m, 2H), 0.89 (t, 3H)

[0392] Synthesis of intermediate 2. (1) R 3 R )-4-((( S )-7-benzyl-19-(2,5-dioxo-2,5-dihydro-1 H -pyrrolo-1-yl)-3,6,9,12,15-pentoxo-2,5,8,11,14-pentazanonadecanyl)oxy)- N -((1 S 9 S )-9-ethyl-5-fluoro-9-hydroxy-4-methyl-10,13-dioxo-2,3,9,10,13,15-hexahydro-1 H 12 H -benzo[ de ]pyrano[3',4':6,7]indolazino[1,2- b Quinoline-1-yl)cyclobutane-1-carboxamide

[0393] Step 1.

[0394] Benzyl bromide (11.0 g, 64.6 mmol) was added dropwise to a solution of intermediate 2a (5.00 g, 43.0 mmol) and NaHCO3 (10.9 g, 129 mmol) in DMF (50 mL) under a nitrogen atmosphere, and the mixture was reacted at 25 °C for 17 h. After the reaction was complete as detected by TLC (PE / EA = 2 / 1), the reaction solution was added to water (500 mL), extracted twice with EA (250 mL), separated, and washed with a saturated aqueous solution of sodium chloride (500 mL). The organic phase was dried over anhydrous Na2SO4, concentrated, and purified by column chromatography (PE:EA = 3:2) to give a colorless liquid (5.1 g, yield: 57.1%).

[0395] Step 2.

[0396] Under a nitrogen atmosphere, intermediate 2b (4.50 g, 21.8 mmol) in THF (10 mL) was added dropwise to a solution of intermediate 2z (4.00 g, 10.9 mmol) and TsOH (800 mg, 4.65 mmol) in THF (30 mL), and the mixture was reacted at 25 °C for 2 hours. After the reaction was complete as detected by TLC (PE / EA = 1 / 2), the reaction solution was added to water (200 mL), extracted twice with EA (200 mL), and separated. The organic phase was dried over anhydrous Na₂SO₄, concentrated, and purified by column chromatography (PE / EA = 3 / 2) to give a white solid (1.56 g, yield: 26%).

[0397] Step 3.

[0398] Pd / C (80 mg) was added to a mixed solution of intermediate 2c (800 mg, 1.55 mmol) in EtOH (8 mL) and EA (8 mL) under a hydrogen atmosphere at 0 °C, and the mixture was stirred at 0 °C for 2.5 h. After the reaction was complete as detected by LCMS, the reaction solution was filtered through Celite® and the filter cake was washed with EA (200 mL). The filtrate was concentrated, dissolved in THF (20 mL), and dried by rotary evaporation to give a white solid (600 mg, yield: 91%).

[0399] Step 4.

[0400] DIEA (152 mg, 1.18 mmol) was added to a solution of intermediate 2d (220 mg, 0.515 mmol), intermediate 1z (250 mg, 0.47 mmol), and HATU (214 mg, 0.56 mmol) in DMF (6 mL) under a nitrogen atmosphere at 0 °C, and the mixture was reacted at 0 °C for 2 h. After the reaction was complete as detected by LCMS, the reaction solution was added to an aqueous citric acid solution (pH = 4) (150 mL) and filtered. The filter cake was washed with water (175 mL), dried under filtration, and then dried with an oil pump to give a brown solid (260 mg, yield: 66%).

[0401] Step 5.

[0402] Diethylamine (8 mL) was added dropwise to a solution of intermediate 2e (260 mg, 0.309 mmol) in DCM (30 mL) under a nitrogen atmosphere at 0 °C, and the mixture was reacted at 0 °C for 3 hours. After the reaction was complete as detected by LCMS, the reaction solution was added to a petroleum ether solution (600 mL) at 0 °C, and a solid precipitated. The resulting mixture was allowed to stand until the solid was adsorbed at the bottom of the flask, and the solution was poured off and dried with an oil pump to give a brown solid (90 mg, yield: 47.1%).

[0403] Step 6.

[0404] HATU (74 mg, 0.19 mmol) was added to a solution of intermediate 2f (90 mg, 0.13 mmol), intermediate 2y (92 mg, 0.19 mmol), and DIEA (50 mg, 0.39 mmol) in DMF (2.5 mL) under a nitrogen atmosphere at 0 °C, and the mixture was reacted at 0 °C for 2 hours. After the reaction was complete as detected by LCMS, the reaction mixture was added to an aqueous solution of citric acid at pH 4 (30 mL) at 0 °C, and a flocculent solid precipitated. The resulting mixture was filtered and purified by PTLC (DCM / MeOH = 10 / 1) to give a pale yellow solid (9.2 mg, yield: 6%).

[0405] MS m / z (ESI): 1074 [M+1]

[0406] H-NMR (400 MHz, MeOD): 7.65 (d, 1H), 7.62 (s, 1H), 7.30-7.21 (m, 5H), 6.79 (s, 2H), 5.69-5.65 (m, 1 H), 5.57 (d, 1H), 5.43-5.10 (m, 3H), 4.70 (d,2H), 4.48-4.39 (m, 2H), 4.10-4.05 (m, 1H), 4.01-3.75 (m, 5H), 3.46 (t, 2H), 3.22-3.15 (m, 2H), 3.07-3.00 (m, 1H), 2.75 (m, 1H), 2.62 (m, 1H), 2.45 (s,3H), 2.37-2.20 (m, 6H), 2.10-2.02 (m, 2H), 2.00-1.92 (m, 2H) 1.68-1.57 (m,6H), 1.01 (t, 3H)

[0407] Synthesis of Compound 1

[0408] Compound 1

[0409] Thaw the trastuzumab antibody at room temperature. Add EDTA solution (20 mM) and reduction buffer (20 mM PB, 150 mM NaCl, pH 6.9 ± 0.1) to the antibody solution. Then adjust the pH to 7.0 using 0.5 M Na₂HPO₄ or 0.3 M NaH₂PO₄ buffer. Weigh tris(2-carboxyethyl)phosphine (TCEP) hydrochloride powder and dissolve it in water for injection (WFI) to prepare a TCEP solution. Then add this solution to the antibody solution (TCEP to antibody molar ratio of 8–10). The reduction reaction is allowed to proceed for 2.0–4.0 hours at room temperature. Weigh the adapter-load intermediate 2 powder and dissolve it in dimethyl sulfoxide (DMSO). Then add the adapter-load DMSO solution to the mixing bag reactor. After adding the DMSO solution of intermediate 2, the organic phase concentration is 10% (v / v) and the intermediate 2 / mAb molar ratio is 13. Allow the conjugation reaction to proceed for 2.0–6.0 hours at room temperature. After conjugation, the ADC solution was purified by UF / DF dialysis using 25 mM histidine buffer at pH 5.5. The ADC concentration was 20.2 mg / mL, and the drug-to-antibody ratio (DAR) was determined to be 7.8 by RP-HPLC.

[0410] RP-HPLC method

[0411] The drug-to-antibody ratio (DAR) distribution was detected by reducing ADC molecules to separate heavy and light chains, followed by further separation and quantification of each LC and HC substance with different linker payload numbers using reversed-phase high-performance liquid chromatography (RP-HPLC). Details of the RP-HPLC method are provided in Table 1 below.

[0412] Table 1

[0413] Example 2 – Phase 1 / 2a study of compound 1 in endometrial cancer

[0414] method

[0415] An ongoing Phase 1 / 2a, multicenter, open-label, first-in-human study is evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of compound 1 in subjects with advanced / metastatic solid tumors. The study consists of two parts: Part 1 (Phase 1, dose escalation) uses accelerated titration as the first dose, followed by a classic “3+3” design to determine the maximum tolerated dose (MTD) / recommended Phase 2 dose (RP2D), with seven dose ranges from 2.2 to 12 mg / kg; Part 2 (Phase 2a, dose extension) begins to evaluate safety / tolerability and efficacy in subjects with selected HER2-expressing or HER2-mutant malignant solid tumors. The study includes subjects with HER2-expressing (immunohistochemical [IHC] 1 / 2 / 3+ or in situ hybridization [ISH]+) advanced / unresectable, recurrent, or metastatic endometrial cancer that is refractory to or intolerant of standard therapy, or for whom no standard therapy is available. Compound 1, formulated as Composition 1, shall be administered intravenously every 3 weeks until disease progression, withdrawal of consent, or unacceptable toxicity. Adverse events (AEs) shall be coded using the Medication for Regulatory Activities (MedDRA) and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0). Tumor response shall be assessed according to the Evaluation of Efficacy in Solid Tumors (RECIST, version 1.1).

[0416] result

[0417] As of May 8, 2023, 32 subjects with endometrial cancer had received compound 1 at doses of 7 or 8 mg / kg. The most common histological subtypes were uterine serous papillary carcinoma (USPC, 34.4%), adenocarcinoma (25.0%), and uterine carcinosarcoma (UCS, 18.8%). The median duration of treatment was 2.6 months (range, 0.7–10.4), with 29 subjects (90.6%) still receiving treatment. The median number of prior regimens for metastatic disease was 2 (range, 1–10). Nineteen subjects (59.4%) had previously received immunotherapy. A total of 17 subjects were evaluable for response. According to RECIST 1.1, ten subjects (58.8%) had objective partial tumor responses (4 confirmed, 6 requiring further confirmation): 7 with USPC (87.5%, 7 / 8), 1 with UCS (50.0%, 1 / 2), 1 with mixed adenocarcinoma (50.0%, 1 / 2), and 1 with adenocarcinoma (33.3%, 1 / 3). The objective response rates (ORRs) at 7 and 8 mg / kg doses were 50.0% (2 / 4) and 61.5% (8 / 13), respectively. The overall disease control rate (DCR) was 94.1%. Figure 1 The study demonstrated the efficacy of assessing the best overall tumor change relative to baseline in subjects. Figure 2 The efficacy was demonstrated by assessing the depth and duration of response in subjects. Treatment-emergent adverse events (TEAEs) of any grade occurred in 30 subjects (93.8%), with the most common (≥20%) being nausea (50.0%), fatigue (31.2%), and vomiting (28.1%). Grade ≥3 TEAEs occurred in 10 subjects (31.2%), with the most common (≥5%) being hypokalemia (12.5%), anemia (6.2%), and syncope (6.2%). No TEAEs resulted in discontinuation or death. No interstitial lung disease occurred.

[0418] As of December 14, 2023, 118 subjects with endometrial cancer had received compound 1 at doses of 7 or 8 mg / kg. The most common histological subtypes were adenocarcinoma (30.5%), uterine serous papillary carcinoma (USPC, 25.4%), and uterine carcinosarcoma (UCS, 11.9%). The median duration of treatment was 3.0 (range, 0.7–11.9) months, with 71 subjects (60.2%) still receiving treatment. The median prior regimen for metastatic disease was 2 (range, 1–8). Eighty subjects (67.8%) had previously received immunotherapy. A total of 91 subjects were evaluable for response. One subject achieved a complete response (CR), and thirty-seven subjects achieved a partial response (PR). The confirmed objective response rate (ORR) was 41.8% (38 / 91). The objective responses (ORRs) for HER2-expressing subjects at doses of 7 mg / kg and 8 mg / kg were 50.0% (2 / 4) and 42.9% (36 / 84), respectively. The overall disease control rate (DCR) was 89.0%. Figure 4 The study demonstrated the efficacy of assessing the best overall tumor change relative to baseline in subjects. Figure 5 The efficacy was assessed in terms of the depth and duration of response in subjects. TEAEs of any grade occurred in 107 subjects (90.7%), with the most common (≥20%) being nausea (65.3%), anemia (41.5%), vomiting (37.3%), fatigue (34.7%), decreased platelet count (29.7%), decreased appetite (28.8%), hypokalemia (24.6%), and increased aspartate aminotransferase (21.2%). TEAEs of grade ≥3 occurred in 54 subjects (45.8%), with the most common (≥5%) being anemia (16.1%), decreased platelet count (12.7%), hypokalemia (6.8%), and decreased neutrophil count (6.8%). TEAEs leading to discontinuation occurred in 17 subjects (14.4%). TEAEs leading to death occurred in 4 subjects (3.4%). Interstitial lung disease / pneumonia occurred in 17 subjects (14.4%).

[0419] in conclusion

[0420] Compound 1 exhibits a manageable safety profile and promising antitumor activity, demonstrating high disease control in subjects with advanced / metastatic endometrial cancer.

[0421] Example 3 – Phase 1 / 2a study of compound 1 in HER2-positive breast cancer

[0422] method

[0423] An ongoing Phase 1 / 2a, multicenter, open-label, first-in-human study is evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of compound 1 in subjects with advanced / metastatic solid tumors. The study consists of two parts: Part 1 (Phase 1, dose escalation) employs accelerated titration as the first dose, followed by a classic “3+3” design to determine the MTD / RP2D, with seven dose ranges from 2.2 to 12 mg / kg; Part 2 (Phase 2a, dose extension) begins to evaluate safety / tolerability and efficacy in subjects with selected HER2-expressing or HER2-mutant malignant solid tumors. The study includes subjects with HER2-positive (IHC 3+, or IHC 2+ and ISH+) advanced / unresectable, recurrent, or metastatic breast cancer who are refractory to or intolerant of standard therapy, or for whom no standard therapy is available. Compound 1, formulated as composition 1, will be administered intravenously every 3 weeks until disease progression, withdrawal of consent, or unacceptable toxicity. AEs were coded using MedDRA and graded according to NCI-CTCAE version 5.0. Tumor response was assessed according to RECIST version 1.1.

[0424] result

[0425] As of July 26, 2023, 93 subjects with multiple tumor types (2.2 mg / kg, n=1; 4.4 mg / kg, n=5; 6.0 mg / kg, n=15; 7.0 mg / kg, n=29; 8.0 mg / kg, n=31; and 10.0 mg / kg, n=12) were recruited and received ≥1 dose of compound 1 in dose escalation and 40 subjects with HER2-positive breast cancer (8.0 mg / kg) in dose extension. The median follow-up period was 7.8 months (range, 0.7–16.2) for dose-escalation subjects and 4.6 months (range, 0.7–6.4) months for dose-expansion subjects with HER2-positive breast cancer. The median duration of treatment was 4.5 months (range, 0.7–13.3) and 4.2 months (range, 0.7–5.9), respectively, with median prior regimens of 7.0 (range, 1–27) and 4.0 (range, 1–9), respectively. In the 89 efficacy-evaluable subjects in the dose-escalation phase, the ORR according to RECIST v1.1 was 52.8% (47 / 89; 35 confirmed and 3 pending), the DCR was 89.9% (80 / 89), and 73 (82.0%) subjects showed a reduction in tumor size from baseline. Figure 3A) The median time to response (TTR) was 1.6 months (range, 1.2–4.0), the median duration of response (DoR) was 9.7 months (95% CI, 5.6–non-evaluable), and the median progression-free survival (PFS) was 8.4 months (95% CI, 5.5–10.9). In the dose extension study, among 39 efficacy-evaluable subjects with HER2-positive breast cancer, the ORR according to RECIST v1.1 was 66.7% (26 / 39, 17 confirmed and 9 pending), the DCR was 97.4% (38 / 39), and 38 (97.4%) subjects showed a reduction in tumor size from baseline. Figure 3 (B) The median TTR was 1.4 months (range, 1.1–2.7), and the 3-month PFS rate was 97.1% (95% CI, 81.4–99.6). Subgroup analysis of ORR in subjects with HER2-positive breast cancer during dose extension is shown in Table 1. All subjects (n = 133) experienced TEAEs, of which 39.1% were ≥ grade 3 (G3); the five most common TEAEs were nausea (64.7%, 3.0% ≥ G3), decreased platelet count (57.9%, 16.5% ≥ G3), anemia (53.4%, 6.0% ≥ G3), vomiting (50.4%, 1.5% ≥ G3), and elevated aspartate aminotransferase (46.6%, 0.0% ≥ G3). Notably, a small number of subjects experienced ≥G3 neutropenia (3.8%, G3; 0.0%, G4) and alopecia (9.8%, G1; 0.8%, G2). TEAEs leading to drug discontinuation were reported only during dose escalation (2 subjects [1.5%], 1 drug-related investigator-assessed), TEAEs leading to death (1 [0.8%], 7 mg / kg group, pneumonia, unrelated investigator-assessed), and interstitial lung disease (ILD, 6 subjects [4.5%], 4 G1 and 2 G2; 5 drug-related investigator-assessed and 1 unrelated investigator-assessed). ≥G3 ILDs were not reported during the study. No dose-limiting toxicities occurred in this study and no MTD was reached.

[0426] Table 2. Subgroup analysis of ORR in subjects with HER2-positive breast cancer during dose extension.

[0427] a Data on the previous lines of treatment for the four patients are unknown.

[0428] As of December 14, 2023, 93 subjects with multiple tumor types (2.2 mg / kg, n=1; 4.4 mg / kg, n=5; 6.0 mg / kg, n=15; 7.0 mg / kg, n=29; 8.0 mg / kg, n=31; and 10.0 mg / kg, n=12) were recruited and received ≥1 dose of compound 1 in dose escalation and 40 subjects with HER2-positive breast cancer (8.0 mg / kg) in dose extension. The median follow-up period for dose-escalation subjects was 13.4 (range, 6.3–22.4) months, and for dose-expansion subjects with HER2-positive breast cancer, the median follow-up period was 9.2 (range, 6.9–11.0) months, the median duration of treatment was 5.6 (range, 0.7–17.7) months and 8.0 (range, 0.7–10.7) months, and the median number of prior regimens was 5.0 (range, 1–24) and 3.0 (range, 1–8), respectively. In 93 efficacy-evaluable subjects in dose escalation, the confirmed ORR according to RECIST v1.1 was 40.9% (38 / 93), DCR was 87.1% (81 / 93), median time to response (TTR) was 1.5 (range, 1.2–4.0) months, median duration of response (DoR) was 8.97 (95% CI, 5.78–non-evaluable) months, and median progression-free survival (PFS) was 8.31 (95% CI, 5.45–8.54) months. In the dose extension study, among 40 evaluable subjects with HER2-positive breast cancer, the confirmed ORR according to RECIST v1.1 was 67.5% (27 / 40), the DCR was 95.0% (38 / 40), the median TTR was 1.5 months (range, 1.1–5.3), and the median PFS was 8.97 months (95% CI, 8.18–non-evaluable). In the dose escalation study, among 93 subjects, all experienced TEAEs, of which 57.0% were ≥ grade 3 (G3); the five most common TEAEs were nausea (69.9%, 3.2% ≥ G3), anemia (57.0%, 12.9% ≥ G3), decreased platelet count (53.8%, 15.1% ≥ G3), vomiting (52.7%, 2.2% ≥ G3), and elevated aspartate aminotransferase (44.1%, 1.1% ≥ G3). It is noteworthy that a small number of subjects experienced ≥G3 neutrophil count reduction (11.8%, G3; 0.0%, G4) and hair loss (12.9%, G1; 1.1%, G2).During dose escalation, TEAEs leading to drug discontinuation were reported (9 subjects [9.7%], 7 drug-related investigator assessments), TEAEs leading to death (1 [1.1%], 7 mg / kg group, pneumonia, drug-unrelated investigator assessments), and interstitial lung disease (ILD, 7 [7.5%], 4 G1, 3 G2 and 1 G3; 6 drug-related investigator assessments and 1 drug-unrelated investigator assessment). In the dose-expansion study of 40 subjects with HER2-positive breast cancer (8.0 mg / kg), all subjects experienced TEAEs, of which 55.0% were ≥ grade 3 (G3). The five most common TEAEs were decreased platelet count (85.0%, 27.5% ≥ G3), increased aspartate aminotransferase (67.5%, 0.0% ≥ G3), nausea (62.5%, 2.5% ≥ G3), vomiting (62.5%, 2.5% ≥ G3), and anemia (60.0%, 7.5% ≥ G3). Notably, a small number of subjects experienced ≥ G3 neutropenia (12.5%, G3; 0.0%, G4) and alopecia (5.0%, G1). No TEAEs leading to death occurred. In dose-expansion studies, TEAEs leading to drug discontinuation (5 subjects [12.5%], all assessed by drug-related investigators) and ILD (6 subjects [15.0%], 3 G1 and 3 G2; assessed by 4 drug-related investigators and 2 by drug-unrelated investigators) were reported in subjects with HER2-positive breast cancer (8.0 mg / kg). No dose-limiting toxicities occurred in this study and the MTD was not reached.

[0429] in conclusion

[0430] Compound 1 demonstrated manageable safety profile and promising antitumor activity in subjects with advanced / metastatic solid tumors, particularly in HER2-positive breast cancer.

[0431] Example 4 - Dosage Range Discovery Study

[0432] reason

[0433] The optimal dosage of compound 1, specifically 8 mg / kg, was determined based on all evidence derived from the efficacy and safety summary. This is supported by clinical data from 217 subjects in ongoing clinical studies of compound 1 (data cutoff date: May 29, 2023), including data from Phase 1 (dose escalation, 2.2 to 10 mg / kg Q3W in solid tumors) and Phase 2a (dose extension, 8 mg / kg Q3W in subjects with endometrial cancer, HER2-low breast cancer, and HER2-positive breast cancer). A summary of the dosage justification based on clinical efficacy and safety data is provided below.

[0434] method

[0435] An ongoing Phase 1 / 2a, multicenter, open-label, first-in-human study is evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of compound 1 in subjects with advanced / metastatic solid tumors. The study consists of two parts: Part 1 (Phase 1, dose escalation) employs accelerated titration as the first dose, followed by a classic “3+3” design to determine the MTD / RP2D, with seven doses ranging from 2.2 to 12 mg / kg; Part 2 (Phase 2a, dose extension) begins to evaluate safety / tolerability and efficacy in subjects with selected HER2-expressing or HER2-mutant malignant solid tumors. This study included subjects with advanced / unresectable, recurrent, or metastatic solid tumors (including endometrial cancer, HER2-low [IHC2+ and ISH-negative, or IHC1+] breast cancer, HER2-positive [IHC3+, or IHC2+ and ISH+] breast cancer, etc.) expressing HER2 (IHC 1 / 2 / 3+ or ISH+) or HER2 mutations, who were refractory to or intolerant of standard therapy, or for whom no standard therapy was available. Compound 1, formulated as composition 1, was administered intravenously every 3 weeks until disease progression, withdrawal of consent, or unacceptable toxicity. AEs were coded using MedDRA and graded according to NCI-CTCAE version 5.0. Tumor response was assessed according to RECIST version 1.1.

[0436] result

[0437] Overall clinical efficacy in solid tumors (as of May 29, 2023)

[0438] As of May 29, 2023, a total of 217 subjects across all tumor types and doses received at least one dose of compound 1, and 186 subjects were included in the efficacy analysis set. Of these 186 subjects, 1 subject (0.5%) achieved a complete response (CR), 88 subjects (47.3%) achieved a partial response (PR), with an unconfirmed ORR of 47.8% (95% CI: 40.49, 55.28); of these, 31 subjects had PRs that were too early to be confirmed, with a confirmed ORR of 28.0% (95% CI: 21.64, 34.99) and a median DoR of 5.78 months (95% CI: 4.27, NE). Eighty-one (81) subjects had stable disease, with an overall DCR of 91.4% (95% CI: 86.41, 95.00). The median TTR was 1.38 months (95% CI: 1.12, 4.04), corresponding to the first scheduled tumor assessment. The median PFS was 8.11 months (95% CI: 5.42, NE), and OS was limited by the immature follow-up duration of 3.81 months (see Table 3).

[0439] A total of 14 subjects were treated with compound 1 at 6 mg / kg. Nine subjects achieved partial response (PR), with an unconfirmed objective response rate (ORR) of 64.3% (95% CI: 35.14, 87.24) and a confirmed ORR of 50.0% (95% CI: 23.04, 76.96). Four subjects had stable disease, with an overall disease control rate (DCR) of 92.9% (95% CI: 66.13, 99.82). The median duration of response (DoR) was 5.78 months (95% CI: 5.55, NE), the median time to recovery (TTR) was 2.60 months (95% CI: 1.22, 2.83), and the median progression-free survival (PFS) was 5.45 months (95% CI: 3.94, NE) (see Table 3).

[0440] A total of 28 subjects were treated with compound 1 at 7 mg / kg. Of these, 17 subjects achieved a partial response (PR), with an unconfirmed objective response rate (ORR) of 60.7% (95% CI: 40.58, 78.50). Two subjects achieved a PR too early to be confirmed, resulting in a confirmed ORR of 46.4% (95% CI: 27.51, 66.13). Ten subjects had stable disease, with an overall disease control rate (DCR) of 96.4% (95% CI: 81.65, 99.91). The median disease response rate (DoR) was not reached. The median time to recovery (TTR) was 1.38 months (95% CI: 1.18, 2.69), and the median progression-free survival (PFS) was 8.38 months (95% CI: 4.27, NE) (see Table 3).

[0441] A total of 136 subjects were treated with compound 1 at 8 mg / kg. Of these, 59 subjects achieved a partial response (PR), with an unconfirmed objective response rate (ORR) of 44.1% (95% CI: 35.62, 52.88). Twenty-eight subjects achieved a PR too early to be confirmed, resulting in a confirmed ORR of 22.1% (95% CI: 15.41, 29.97). Sixty-six subjects had stable disease, with an overall disease control rate (DCR) of 92.6% (95% CI: 86.89, 96.42). The median time to response (TTR) was 1.35 months (95% CI: 1.12, 4.04). The median disease response rate (DoR) and median progression-free survival (PFS) were not reached (see Table 3).

[0442] Overall clinical efficacy in solid tumors (as of December 14, 2023)

[0443] As of December 14, 2023, a total of 310 subjects across all tumor types and doses received at least one dose of compound 1, and 270 subjects were included in the efficacy analysis set. Of these 270 subjects, 3 subjects (1.1%) achieved complete response (CR), 138 subjects (51.1%) achieved partial response (PR), with an unconfirmed ORR of 52.2% (95% CI: 46.08, 58.31); of these, 9 subjects had PRs that were too early to be confirmed, with a confirmed ORR of 42.6% (95% CI: 36.62, 48.73), with a median DoR of 8.71 months (95% CI: 6.74, NE). Ninety-seven (97) subjects had stable disease, with an overall DCR of 88.1% (95% CI: 83.68, 91.75). The median TTR was 1.45 months (95% CI: 1.12, 5.42), corresponding to the first scheduled tumor assessment. The median PFS was 8.18 months (95% CI: 6.77, 8.41), and OS was limited by the immature follow-up duration of 9.49 months.

[0444] A total of 15 subjects were treated with compound 1 at 6 mg / kg. Nine subjects achieved partial response (PR), with an unconfirmed objective response rate (ORR) of 60.0% (95% CI: 32.29, 83.66) and a confirmed ORR of 46.7% (95% CI: 21.27, 73.41). Four subjects had stable disease, with an overall disease control rate (DCR) of 86.7% (95% CI: 59.54, 98.34). The median duration of response (DoR) was 9.72 months (95% CI: 5.55, NE), the median time to recovery (TTR) was 2.60 months (95% CI: 1.22, 2.83), and the median progression-free survival (PFS) was 5.45 months (95% CI: 2.43, 10.91).

[0445] A total of 29 subjects were treated with compound 1 at 7 mg / kg. Of these, 1 subject achieved complete remission (CR) and 16 subjects achieved partial remission (PR), with an unconfirmed objective response rate (ORR) of 58.6% (95% CI: 38.94, 76.48) and a confirmed ORR of 48.3% (95% CI: 29.45, 67.47). Ten subjects had stable disease, with an overall disease control rate (DCR) of 93.1% (95% CI: 77.23, 99.15). The median duration of response (DoR) was 6.90 months (95% CI: 3.19, NE). The median time to recovery (TTR) was 1.41 months (95% CI: 1.18, 2.99), and the median progression-free survival (PFS) was 5.59 months (95% CI: 3.02, 8.41).

[0446] A total of 202 subjects were treated with compound 1 at 8 mg / kg. Of these, 103 subjects achieved partial response (PR), with an unconfirmed objective response rate (ORR) of 52.0% (95% CI: 44.86, 59.04). PR was too early to be confirmed in six subjects, resulting in a confirmed ORR of 44.1% (95% CI: 37.10, 51.20). Seventy-six subjects had stable disease, with an overall disease control rate (DCR) of 89.6% (95% CI: 84.55, 93.45). The median duration of response (DoR) was 8.71 months (95% CI: 6.74, NE). The median time to recovery (TTR) was 1.48 months (95% CI: 1.12, 5.42), and the median progression-free survival (PFS) was 8.18 months (95% CI: 7.06, 8.64).

[0447] The above evidence suggests that compound 1, when administered at a dose range of 6 to 8 mg / kg, provides clinical benefit in subjects with solid tumors.

[0448] Clinical efficacy in endometrial cancer (as of May 29, 2023)

[0449] • As of May 29, 2023, eight subjects were enrolled in the dose-escalation efficacy assessment. Four subjects received 7 mg / kg of compound 1, while the other subjects received 8 mg / kg. The median follow-up times were 6.92 months and 5.29 months, respectively. At DCO, two subjects in the 7 mg / kg group achieved PR, with an unconfirmed ORR of 50.0% (confirmed ORR: 50%, 2 / 4). All subjects in the 8 mg / kg group achieved an objective response, with an unconfirmed ORR of 100.0% (confirmed ORR: 100.0%, 4 / 4), including one CR and three PRs. The median DoR and PFS were not reached (see Table 4).

[0450] A total of 28 subjects with endometrial cancer were treated with compound 1 at 8 mg / kg. One subject achieved complete remission (CR), and 16 subjects achieved partial remission (PR), with an unconfirmed objective response rate (ORR) of 60.7% (95% CI: 40.58, 78.50). Eight subjects had PRs that were too early to be confirmed, resulting in a confirmed ORR of 28.6% (95% CI: 13.22, 48.67). Nine subjects had stable disease, with an overall disease control rate (DCR) of 92.9% (95% CI: 76.50, 99.12). Median doremia, progression-free survival (PFS), and overall survival (OS) were not achieved (see Table 4).

[0451] • A total of 10 patients with HER2-expressing endometrial cancer who received compound 1 at 8 mg / kg were followed up for ≥13 weeks from the first dose. Among them, the confirmed ORR was 70.0% (1 CR, 6 PR) and the DCR was 100.0%, which did not reach the median DoR. 4 patients were followed up for ≥19 weeks from the first dose. Among them, the confirmed ORR was 100.0% (1 CR, 3 PR) and the DCR was 100.0%, which did not reach the median DoR.

[0452] • During dose escalation, 2 subjects (50.0%, 2 / 4) in the 7 mg / kg group discontinued the study drug, while all subjects (100.0%, 4 / 4) in the 8 mg / kg group remained in study treatment. The median follow-up time in the 7 mg / kg group was slightly longer than that in the 8 mg / kg group (6.92 months vs. 5.29 months).

[0453] Clinical efficacy in endometrial cancer (as of December 14, 2023)

[0454] As of December 14, 2023, eight subjects were enrolled in the dose-escalation efficacy assessment. Four subjects received 7 mg / kg of compound 1, while the other subjects received 8 mg / kg. The median follow-up times were 13.45 months and 11.83 months, respectively. At DCO, two subjects in the 7 mg / kg group achieved PR, with an unconfirmed ORR of 50.0% (confirmed ORR: 50%, 2 / 4). All subjects in the 8 mg / kg group achieved an objective response, with an unconfirmed ORR of 100.0% (confirmed ORR: 100.0%, 4 / 4), including four PRs. The median DoR and PFS were not reached.

[0455] A total of 84 subjects with endometrial cancer were treated with compound 1 at 8 mg / kg. Two subjects achieved complete remission (CR), and 41 subjects achieved partial remission (PR), with an unconfirmed objective response rate (ORR) of 51.2% (95% CI: 40.04, 62.26). Five subjects had PR too early to be confirmed, resulting in a confirmed ORR of 42.9% (95% CI: 32.11, 54.12). Thirty-one subjects had stable disease, with an overall disease control rate (DCR) of 88.1% (95% CI: 79.19, 94.14). The median progression-free survival (PFS) was 6.70 months (95% CI: 5.45, 8.31). Median doper remission (DoR) and overall survival (OS) have not yet been reached.

[0456] A total of 76 HER2-expressing endometrial cancer patients who received compound 1 at 8 mg / kg were followed for ≥13 weeks from the first dose. Among them, the confirmed ORR was 47.4% (1 CR, 35 PR) and the DCR was 89.5%, which did not reach the median DoR. Among them, 66 patients were followed for ≥19 weeks from the first dose. Among them, the confirmed ORR was 53.0% (1 CR, 34 PR) and the DCR was 89.4%, which did not reach the median DoR.

[0457] The above evidence suggests that compound 1, when administered at a dose of 8 mg / kg, provides clinical benefit in subjects with endometrial cancer.

[0458] Clinical efficacy of HER2-low breast cancer (as of May 29, 2023)

[0459] As of May 29, 2023, in the dose-escalation phase of the Compound 1 clinical study, most subjects with HER2-low breast cancer were treated with Compound 1 at doses of 7 mg / kg (7 subjects) and 8 mg / kg (10 subjects), with median follow-up times of 6.90 months and 5.65 months, respectively. At DCO, one subject in the 7 mg / kg group and four subjects in the 8 mg / kg group achieved confirmed PRs, with confirmed ORRs of 14.3% and 40.0%, respectively (Table 5). The median DoR was not reached. The median PFS was 4.27 months in the 7 mg / kg group, while it has not yet been reached in the 8 mg / kg group (Table 5).

[0460] To further confirm the benefit of 8 mg / kg Q3W, ORR data for all subjects with HER2-low breast cancer during dose escalation and dose extension in the compound 1 clinical study were summarized, with two different follow-up durations: 33 subjects with HER2-low breast cancer followed for ≥13 weeks from first dose had an unconfirmed ORR of 45.5% (30.3% confirmed response and 9.1% pending response). Meanwhile, 10 subjects followed for ≥19 weeks from first dose had an unconfirmed ORR of 50.0% (40.0% confirmed response).

[0461] • In addition, during dose escalation, subjects with HER2-low breast cancer who received 8 mg / kg Q3W maintained treatment for longer periods compared to those who received 7 mg / kg Q3W, with 40.0% (8 mg / kg Q3W) and 0% (7 mg / kg Q3W) of subjects still receiving more than 8 cycles of treatment.

[0462] Clinical efficacy of HER2-low breast cancer (as of December 14, 2023)

[0463] As of December 14, 2023, in the dose-escalation phase of the Compound 1 clinical trial, most subjects with HER2-low breast cancer were administered Compound 1 at doses of 7 mg / kg (7 subjects), 8 mg / kg (10 subjects), and 10 mg / kg (9 subjects), with median follow-up times of 13.44 months, 12.19 months, and 6.74 months, respectively. At DCO, two subjects in the 7 mg / kg group, four subjects in the 8 mg / kg group, and three subjects in the 10 mg / kg group achieved confirmed PRs, with confirmed ORRs of 28.6%, 40.0%, and 33.3%, respectively. The median DoR was not reached. The median PFS was 4.24 months in the 7 mg / kg group, 11.14 months in the 8 mg / kg group, and not yet reached in the 10 mg / kg group.

[0464] The above evidence suggests that compound 1, when administered at a dose of 8 mg / kg, provides clinical benefit in subjects with HER2-low expression breast cancer.

[0465] Clinical safety

[0466] • During the dose-escalation clinical study of compound 1, compound 1 was well tolerated at all doses from 2.2 mg / kg to 10 mg / kg, the MTD of compound 1 was not reached at doses up to 10 mg / kg, and no DLT was observed during the DLT assessment period (day 1 to day 21 of cycle 1).

[0467] The incidence of TEAEs, ≥ grade 3 TEAEs, SAEs, TEAEs leading to dose reduction, TEAEs leading to dose interruption, TEAEs leading to permanent discontinuation, and adverse events of particular concern (AESIs) was similar among subjects receiving 8 mg / kg (N=159) of compound 1 during dose escalation and dose extension periods compared with subjects receiving 7 mg / kg (N=29) and 6 mg / kg (N=15) during dose escalation periods (Table 6). To date, the safety profile of compound 1 has been acceptable in subjects treated with 6 to 8 mg / kg Q3W.

[0468] Table 3. Overall clinical efficacy of compound 1 in clinical studies (efficacy analysis set)

[0469] ORR was calculated using the Clopper-Pearson method. DoR, PFS, and OS were calculated using the Kaplan-Meier method. TTR was calculated using subjects with confirmed responses.

[0470] CI = Confidence Interval, DCR = Disease Control Rate, DoR = Duration of Response, NE = Not Evaluable, NR = Not Achieved, OS = Overall Survival, PFS = Progression-Free Survival.

[0471] Table 4. Overall clinical efficacy of compound 1 in subjects with endometrial cancer during clinical trials (efficacy analysis set).

[0472] ORR was calculated using the Clopper-Pearson method. DoR, PFS, and OS were calculated using the Kaplan-Meier method. TTR was calculated using subjects with confirmed responses.

[0473] CI = Confidence Interval, DCR = Disease Control Rate, DoR = Duration of Response, NE = Not Evaluable, NR = Not Achieved, OS = Overall Survival, PFS = Progression-Free Survival.

[0474] Table 5. Overall clinical efficacy of compound 1 in subjects with HER2-low expression breast cancer in clinical studies (efficacy analysis set).

[0475] ORR was calculated using the Clopper-Pearson method. DoR, PFS, and OS were calculated using the Kaplan-Meier method. TTR was calculated using subjects with confirmed responses.

[0476] CI = Confidence Interval, DCR = Disease Control Rate, DoR = Duration of Response, NE = Not Evaluable, NR = Not Achieved, OS = Overall Survival, PFS = Progression-Free Survival.

[0477] Table 6. Overview of treatment-related adverse events observed in clinical studies of Compound 1 (safety analysis set)

[0478] DLT = Dose-limiting toxicity, TEAE = Treatment-related adverse events, TRAE = Treatment-related adverse events.

[0479] Other considerations

[0480] Exposure-response (ER) analysis showed a positive correlation between optimal overall response (BOR) and the level of compound 1 exposure in cycle 1 in patients with HER2-low expression breast cancer (not shown). Therefore, based on increased exposure levels, a dose of ≥7 mg / kg was considered to maximize the efficacy of compound 1 treatment. Furthermore, patients receiving compound 1 at 8 mg / kg Q3W had a longer clinically observed DoR compared to patients receiving 7 mg / kg Q3W; this suggests that ≥8 mg / kg Q3W is a more advantageous dosing regimen.

[0481] Although a peak concentration of compound 1 (C) was observed max A dose-dependent increase in the area under the concentration-time curve was observed, but increased clearance (i.e., a shorter half-life) was observed in a subset of patients in the 6 mg / kg cohort (likely due to target-mediated drug disposition), while no such increase was observed at dose levels ≥7 mg / kg. Therefore, at lower dose levels <7 mg / kg, there may be patients with suboptimal pharmacokinetic outcomes due to increased clearance.

[0482] in conclusion

[0483] All evidence generated from efficacy and safety data supports that 6 to 8 mg / kg Q3W is the optimal dosage regimen for Compound 1. The 6 to 8 mg / kg Q3W dose was well tolerated. Notably, compared to lower dose levels tested in clinical studies of Compound 1, the 8 mg / kg Q3W dose demonstrated a more favorable efficacy profile in subjects with endometrial cancer and HER2-low-expressing breast cancer, thus providing optimal treatment outcomes in these populations.

[0484] Example 5 - Safety characteristics of compound 1 from a Phase 1 / 2a study, and comparison with trastuzumab derushetacan (Enhertu®).

[0485] method

[0486] An ongoing Phase 1 / 2a, multicenter, open-label, first-in-human study is evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of compound 1 in subjects with advanced / metastatic solid tumors. The study consists of two parts: Part 1 (Phase 1, dose escalation) employs accelerated titration as the first dose, followed by a classic “3+3” design to determine the MTD / RP2D, with seven dose ranges from 2.2 to 12 mg / kg; Part 2 (Phase 2a, dose extension) begins to evaluate safety / tolerability and efficacy in selected subjects with HER2-expressing or HER2-mutant malignant solid tumors. The study includes subjects with HER2-positive (IHC 3+, or IHC 2+ and ISH+) advanced / unresectable, recurrent, or metastatic breast cancer who are refractory to or intolerant of standard therapy, or for whom no standard therapy is available. Compound 1, formulated as composition 1, will be administered intravenously every 3 weeks until disease progression, withdrawal of consent, or unacceptable toxicity. AEs were coded using MedDRA and graded according to NCI-CTCAE version 5.0. Tumor response was assessed according to RECIST version 1.1.

[0487] Security discovery

[0488] As of December 14, 2023, a total of 310 subjects across all tumor types and doses received at least one dose of compound 1, including 93 subjects in the dose escalation portion and 217 subjects in the dose extension portion. The median duration of treatment for all doses was 4.6 months (range: 0.7 to 17.7 months). 192 subjects (62.0%) had a treatment duration >3 months; 136 subjects (43.9%) were still receiving treatment at the time of disease control and prevention (DCO).

[0489] For an overview of combined 8 mg and total TEAEs, please refer to Table 7. Compound 1 was generally well tolerated when examining the safety data presented to all subjects. Overall, most subjects experienced at least one TEAE (295 / 310 subjects, 95.2%). 81 / 310 subjects (26.1%) experienced a serious AE (TESAE) occurring during treatment, 51 / 310 subjects (16.5%) experienced a treatment-related TESAE, and 129 / 310 subjects (41.6%) experienced a treatment-related TEAE of grade ≥3. 38 / 310 subjects (12.3%) had TEAEs leading to treatment discontinuation, and 73 / 310 subjects (23.5%) had TEAEs leading to dose reduction.

[0490] Compound 1 was well tolerated at all test doses ranging from 2.2 mg / kg to 10 mg / kg (data not shown). Some differences were observed in the overall safety profile observed in subjects treated with Compound 1 at 6 mg / kg, 8 mg / kg, and 10 mg / kg. The proportion of ≥ Grade 3 TEAEs increased with dose level, with 31.3% (5 / 16 subjects), 49.4% (116 / 235 subjects), and 54.2% (13 / 24 subjects) experiencing ≥ Grade 3 TEAEs in the 6 mg / kg, 8 mg / kg, and 10 mg / kg dose groups, respectively. Similar trends were observed for associated ≥ Grade 3 TEAEs and TEAEs of particular concern. However, there was no significant difference in the proportion of TESAEs between the treatment groups, with 25.0% (4 / 16 subjects), 26.8% (63 / 235 subjects), and 8.3% (2 / 24 subjects) experiencing TESAEs in the 6 mg / kg, 8 mg / kg, and 10 mg / kg dose groups, respectively.

[0491] In the dose escalation phase, the MTD of compound 1 was not reached at doses up to 10 mg / kg, and no DLT was observed during the dose-limiting toxicity (DLT) assessment period (days 1 to 21 of cycle 1).

[0492] A total of 295 / 310 subjects (95.2%) experienced at least one TEAE, most of which were gastrointestinal or hematological (i.e., nausea, decreased platelet count, vomiting, decreased appetite).

[0493] Table 7 Overview of treatment-induced adverse events (TEAEs) in clinical studies of compound 1 (safety analysis set) - pooled at 8 mg / kg and total.

[0494]

[0495] N = total number; n = subset of total number; TEAE = adverse events that occurred during treatment; TESAE = serious adverse events that occurred during treatment.

[0496] A comparative analysis of TEAE was performed, with data from trastuzumab derutecan (Enhertu®) - results are shown in Table 8.

[0497] For compound 1, the combined TEAE of 8 mg / kg and total was compared with the TEAE of the approved drug trastuzumab derutecan (Enhertu®) at a dose of 5.4 mg / kg – the results are shown in Table 8. Data for trastuzumab derutecan (Enhertu®) were obtained from the Destiny-Breast03 study (Hurvitz SA et al.). Lancet , 2023 Jan 14; 401(10371): 105-117). The TEAE (any level and ≥3) of compound 1 was less than that of trastuzumab delutecan (Enhertu®).

[0498] Table 8. Overview of adverse events observed during treatment in clinical studies of Compound 1 compared to those of trastuzumab / delutec (Enhertu®) (Safety Analysis Set)

[0499] For alopecia and GI events, a similar trend was observed when comparing TRAEs (treatment-related adverse events), as shown in Table 9, where TRAEs were reported relatively less frequently for compound 1. TRAE data for trastuzumab derutecan (Enhertu®) are taken from the last revised USPI (April 2024) for trastuzumab derutecan (Enhertu®), specifically from the table of common adverse events (≥10% of all grades or ≥2% of grade 3-4) in patients treated with trastuzumab derutecan (Enhertu®) in the DESTINY-Breast03 trial.

[0500] Table 9. Overview of adverse events related to treatment in clinical studies of Compound 1 compared with those of trastuzumab / drutecan (Enhertu®) (safety analysis set). -Including PT abdominal pain, abdominal discomfort, lower abdominal pain and upper abdominal pain #-Including PT stomatitis, aphthous ulcer, mouth ulceration, oral mucosal erosion, and oral mucosal eruption.

[0501] in conclusion

[0502] As of the data cutoff date of December 14, 2013, compound 1 demonstrated a well-tolerated and manageable safety profile in subjects with advanced / metastatic solid tumors. For certain adverse events, such as gastrointestinal events and alopecia (and possibly other adverse events), compound 1 appeared to show better safety than trastuzumab (delutec), or Enhertu®. Based on the latest preliminary data, a similar trend in the safety profile for these adverse events is expected for specific indications, such as endometrial cancer and / or breast cancer.

[0503] Example 6 - A Phase III, Randomized, Multicenter, Open-Label Trial of Compound 1 and Investigator-Selected Chemotherapy in Previously Treated Patients with HER2-Expressing Recurrent or Metastatic Endometrial Cancer

[0504] HER2, a member of the cell surface transmembrane receptor with tyrosine kinase activity, has received widespread attention in the medical field in recent years. The HER2 gene is known to be overexpressed in over 30% of all human cancers, including serous carcinomas of the breast, stomach, colon, salivary glands, bladder, and uterus (Grabsch et al., 2010; Buza et al., 2013; Cocco et al., 2019), and its overexpression in tumors is associated with poor prognosis. The clinical application of HER2-targeted therapy has improved outcomes for patients with HER2-amplified / overexpressing cancers (Oh et al., 2020). However, not all patients with HER2-positive tumors respond well to current therapies. Resistance to HER2-targeted therapies is common, manifesting as intrinsic or acquired resistance (Ogitani et al., 2016). For HER2-positive cancers other than breast and gastric cancer, including heavily treated patients, no HER2-targeted drugs have been approved, and effective treatment remains lacking.

[0505] In this phase III trial, the safety and efficacy of compound 1 will be compared with investigator-selected single-agent chemotherapy in patients with recurrent or metastatic endometrial cancer (including HER2 1+, 2+ or 3+ scores according to immunohistochemical analysis) whose disease has progressed after at least one line of platinum-based therapy and exposure to immunotherapy.

[0506] The primary objective of this trial was to evaluate the efficacy of compound 1 in progression-free survival (PFS) in a blinded, independent central review (BICR) setting compared to investigator-selected chemotherapy in a patient with endometrial cancer. Following the earliest priority date of this application, the applicant has received Breakthrough Therapy designation for compound 1 in endometrial cancer from the FDA.

[0507] This is an open-label, randomized, multicenter, phase III, interventional trial designed to determine the efficacy and safety of compound 1 compared with investigator-selected single-agent chemotherapy in patients with previously treated recurrent or metastatic endometrial cancer.

[0508] Approximately 390 patients will be randomized in a 2:1 ratio to receive either compound 1 or investigator-selective single-agent chemotherapy (doxorubicin or docetaxel) until disease progression (PD) (according to RECIST 1.1), unless there is unacceptable toxicity, withdrawal of consent, or other criteria for discontinuation are met. Randomization will be stratified by human epidermal growth factor receptor 2 (HER2) expression (IHC score 1+ vs 2+ vs 3+) and prior lines of treatment (1 vs 2+).

[0509] The trial consisted of a screening period, a treatment period, a safety follow-up period, and a long-term survival follow-up period. The screening period lasted 28 days.

[0510] Unless specific treatment discontinuation criteria are met or the patient withdraws consent, all patients will continue treatment until disease progression (PD) as defined in RECIST 1.1. Following discontinuation of trial treatment, all patients will have a post-treatment end-of-operation (EOT) visit (scheduled within 7 days of treatment completion) and a safety follow-up visit (scheduled on day 35 + 7 days after their last dose of trial treatment). If treatment end occurs >35 days after the last dose of trial treatment, the EOT assessment may serve as a safety follow-up. Patients who discontinue treatment for reasons other than PD will also continue to undergo tumor assessment until radiographic progression (or death). All randomized patients will be followed for survival unless trial consent is withdrawn. Long-term / survival follow-up visits will be conducted every 3 months (±14 days) from the date of the safety follow-up visit until death, withdrawal of consent, or trial closure (whichever occurs first).

[0511] Compound 1 will be formulated as Composition 1 and administered intravenously once every 21 days at a dose of 6 or 8 mg / kg (i.e., Q3W) until PD, unacceptable adverse events, or patient withdrawal of consent.

[0512] Doxorubicin will be administered at 60 mg / m² 2 The dose is administered as an intravenous bolus every 3 weeks until PD, unacceptable adverse events, or patient withdrawal of consent.

[0513] Docetaxel will be at 80mg / m 2 The dose is administered as an intravenous infusion on days 1, 8, and 15 of a 28-day cycle until PD, unacceptable adverse events, or patient withdrawal of consent.

[0514] Example 7 - A phase III, randomized, multicenter, open-label study of compound 1 versus investigator-selected chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-low, hormone receptor-positive (HR+) metastatic breast cancer whose disease had progressed on endocrine therapy (ET).

[0515] HER2 expression profiles exist within what is traditionally classified as HER2-negative breast cancer. This category includes IHC 2+ / ISH-negative and IHC 1+ cancers (collectively defined as HER2-low in this study), in addition to tumors without detectable HER2 staining (classified as IHC score 0 in clinical guidelines).

[0516] Currently, patients with HR+, HER2- low advanced or metastatic breast cancer follow the same treatment paradigm as those with HR+, HER2-negative breast cancer. Estrogen therapy (ET) is generally considered the preferred option for HR+, HER2-negative breast cancer. The optimal treatment sequence is considered to be first-line ET plus a CDK4 / 6 inhibitor, followed by subsequent ET plus targeted therapy (e.g., mTOR or PI3-K inhibitors [for PI3-K-mutant tumors]) (Cardoso et al., 2020). Chemotherapy may be appropriate in patients whose disease has progressed after multiple ET lines (with or without targeted therapy) (Cardoso et al., 2018). Furthermore, chemotherapy may also be appropriate as a continuation of treatment for patients with primary endocrine resistance (i.e., disease progression within the first 6 months after initiation of first-line ET in advanced breast cancer), as the benefit of continuing endocrine therapy after ET plus CDK4 / 6 inhibitor progression has been shown to be minimal (Rossi et al., 2019; Sledge et al., 2020; Turner et al., 2018). In the DESTINY-Breast04 trial, trastuzumab derutecan (T-DXd, Enhertu®) demonstrated superior activity compared to standard chemotherapy options in patients with HER2-low advanced breast cancer. This highlights the clinical relevance of the HER2-low patient population and supports the need to redefine subgroups within HER2-negative breast cancer (Modi S et al., 2022). Prior to this trial, few clinical trials were conducted specifically in patients with HER2-low metastatic breast cancer as defined in this article. Although T-DXd is approved for the treatment of HER2+ and HR+ / HER2-low metastatic breast cancer, most patients experience disease progression, necessitating the use of additional treatment options to overcome resistance. The best approach is to investigate newer, much safer and more effective drugs to further optimize treatment and outcomes for this patient population.

[0517] In the Phase 1 clinical trial described in Example 3 above, as of May 29, 2023, compound 1 showed promising antitumor activity in HER2-low expressing breast cancer, with an unconfirmed ORR of 40.3% (95% CI: 28.49%–53.00%), in which most patients experienced tumor shrinkage and durable response. Data from this study suggest that the antitumor activity of compound 1 has the potential to provide meaningful clinical benefit to patients with HER2-low expression and warrants further evaluation.

[0518] Therefore, in this phase 3 study, compound 1 will be compared with investigator-selected single-agent chemotherapy to determine whether compound 1 can improve outcomes in HER2-low expressing (IHC 2+ / ISH- and IHC 1+), HR+ breast cancer patients (N=466) whose disease has progressed on at least two previous lines of ET or within 6 months after first-line ET+CDK4 / 6i in a metastatic setting.

[0519] To identify subjects who may benefit from HER2-targeted therapy, validated companion diagnostic devices are needed to characterize HER2 expression / amplification in this setting. The prevalence of low HER2 expression in breast cancer has been characterized in the scientific literature.

[0520] Subjects recruited by this trial based on HER2-low expression tumor status are expected to maximize the likelihood of obtaining clinical benefit from the investigational treatment, based on the mechanism of action of HER2-targeted therapy and clinical experience to date in using targeted therapy in the breast oncology setting.

[0521] This study is an open-label, multicenter, randomized trial in patients with HER2-low expression, HR+ breast cancer whose disease has progressed in a metastatic setting after at least two lines of prior ET or within 6 months of first-line ET plus a CDK4 / 6 inhibitor. The primary objective of the study is to determine the efficacy and safety of compound 1 in the target population compared to investigator-selected single-agent chemotherapy. Approximately 466 participants will be randomized 1:1 at approximately 180 centers worldwide to receive either 6 or 8 mg / kg of compound 1 every 3 weeks or investigator-selected single-agent chemotherapy (paclitaxel, albumin-bound paclitaxel, or capecitabine) until disease progression (PD) as defined by RECIST 1.1, unless unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met.

[0522] This study will compare PFS, OS and other efficacy measures among the treatment groups, and further characterize the safety and tolerability of compound 1.

[0523] Random grouping will be stratified as follows: • Previous use of CDK4 / 6 inhibitors (yes vs. no) • HER2 IHC expression (IHC 2+ / ISH- vs IHC 1+) • Previous use of taxanes in non-transfer environments (yes vs. no) The stratification factor status must be known when the subjects are randomly assigned to the study.

[0524] CDK4 / 6 inhibitors are increasingly being used as part of the standard of care for HR+ breast cancer patients. To ensure that the majority of subjects in the HER2-low expression population had received prior CDK4 / 6 inhibitor therapy, no more than 228 subjects (49% of the 466 subjects) who had not received prior CDK4 / 6 inhibitor therapy (e.g., palbociclib, abeciclib, or ribociclib) were randomized.

[0525] Based on all available information, a compound 1 dose of 8 mg / kg Q3W has been selected for this study. For each chemotherapeutic active ingredient, the following doses were selected: Paclitaxel: will be administered at 80 mg / m² 2 The standard care dose of paclitaxel is administered once a week.

[0526] Albumin-bound paclitaxel: Subjects will receive 100 mg / m² on days 1, 8, and 15 of each 28-day cycle. 2 Albumin-bound paclitaxel.

[0527] Capecitabine: Subjects will have the option to receive 1250 mg / m² as indicated on the label. 2 Capecitabine dose or 1000 mg / m² 2 Capecitabine dosage.

[0528] Example 8 - Composition Study

[0529] This embodiment summarizes the results of the lyophilized composition validation study and the reconstitution stability study of Compound 1. The purpose of the lyophilized composition validation study of Compound 1 was to confirm the stability of Compound 1 in the selected composition. The purpose of the reconstitution stability study of Compound 1 was to study the stability of the reconstituted Compound 1 composition in the liquid state.

[0530] Based on previous composition development studies, the composition 1 (composition 1) was selected, consisting of 20.0 mg / mL compound 1, 25 mM histidine, 9% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and pH 5.5. The stability of the lyophilized composition was evaluated at three different temperatures: 2–8 °C, 25 °C, and 40 °C, representing long-term storage conditions, accelerated storage conditions, and stress conditions, respectively.

[0531] Table 10. Compositions of Compound 1

[0532] Example 8a - Validation Study of the Lyophilized Composition

[0533] Sample information: Compound 1 was prepared using 20.0 mg / mL of Compound 1, 25 mM histidine, 9% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and pH 5.5.

[0534] Sample preparation: The drug solution was aseptically filtered, filled into glass vials, partially plugged, and freeze-dried in a lyophilizer. All procedures were performed within a biosafety enclosure.

[0535] Research Plan: The sampling and testing plan for the lyophilized composition validation study is shown in Table 8. Samples were incubated at 2–8°C, 25°C, and 40°C for long-term, accelerated, and stress-condition storage, respectively. T0 samples without any stress treatment were used as controls. Tests performed in this study included appearance (before and after reconstitution), pH, protein concentration, SEC-HPLC, cIEF, and HIAC (highly visible particles). Samples were retrieved and analyzed promptly at each sampling point.

[0536] Table 11: Sampling and Testing Plan for Validation Studies of Lyophilized Compositions

[0537] Results and discussion

[0538] Appearance, pH and protein concentration : The appearance of all samples, including clarity, color, and visible particles, was visually observed against a black and white background using a YB-2 clarity detector with a light intensity of 1000-1500 Lux.

[0539] The pH of the samples was measured using a pH meter with a glass electrode. The pH meter was calibrated using standard solutions at pH 4.01, 7.00, and 9.21. Each sample was measured twice (100 μL each time), and the average value was used in the report.

[0540] Protein concentration was determined using absorbance measurements at 280 nm and 370 nm using a SoloVPE spectrophotometer. The extinction coefficient of compound 1 mAb protein was 1.52 (mg / mL). -1 ·cm -1 .

[0541] The SoloVPE system relies on variable path length spectrophotometry. According to Beer's Law equation: A = ε L C, where A = absorbance, ε = extinction coefficient, L = path length, C = concentration, and the slope m = A / L can be obtained by measuring absorbance at 10 different path lengths. The slope m can be calculated from the path length and absorbance curve. Since C = m / ε, the concentration can be calculated given ε and m.

[0542] The results are shown in Table 9. Regarding the appearance of the freeze-dried cake, no significant changes were observed in any of the stress-treated samples compared to T0. After reconstitution, the composition was colorless, slightly opalescent, and free of visible particles. Furthermore, there were no significant changes in pH or protein concentration.

[0543] Table 12: Summary of data on appearance, pH, and protein concentration in the lyophilized composition validation study

[0544] WLC = White freeze-dried cake; CL = Colorless; SO = Slightly opalescent; FP = Free of visible particles

[0545] SEC-HPLC: The sample was diluted to 10.0 mg / mL with the mobile phase, and then 100 μg of sample was injected into a TSK gel G3000SWXL column (7.8 × 300 mm, 5 μm Steel / TOSOH). Analysis was performed on an Agilent 1260 HPLC system equipped with MWD detectors (detection wavelengths: 280 nm and 370 nm). The chromatographic program was performed at a flow rate of 1.0 mL / min with an isogradient for 20 min, where the mobile phase (50 mM phosphate buffer, 300 mM NaCl, pH 6.8 ± 0.1):ACN = 9:1 (v / v).

[0546] The results are shown in Table 13. SEC-HPLC results showed no substantial changes in the stability studies.

[0547] Table 13: Results of SEC-HPLC in the lyophilized composition validation study

[0548] CIEF: The compound 1 sample is mixed with the master mixture to produce a loading mixture containing 2.0 μL Pharmalyte 8-10.5, 2.0 μL Pharmalyte 3-10, 35 μL 1% MC, 0.5 μL pI-labeled 7.05, 0.5 μL pI-labeled 9.46, 37.5 μL 8M urea solution, 0.15 μL glacial acetic acid, and 2.35 μL ultrapure water, resulting in a final protein concentration of 0.4 mg / mL. The loading mixture is placed in a refrigerator at 2–8°C or a heating block at 5°C for more than 48 hours. Testing must be completed within 96 hours of mixing the sample with the master mixture; otherwise, the sample should be prepared again. The loading mixture is loaded into an FC-coated capillary and analyzed using an iCE3 capillary isoelectric focusing analyzer equipped with a full-column detection camera. After analysis, the raw data are processed using Empower 3.

[0549] The results of CIEF are shown in Table 14. The results of CIEF indicate that no substantial changes were observed in the stability study.

[0550] Table 14: Results of CIEF in the lyophilized composition validation study

[0551] Particulate matter (HIAC): Subvisible particle size and count were measured using a HACH particle analyzer in a laminar flow hood. To avoid introducing air bubbles and interference during the test, all samples were held in the hood for at least 0.5 hours before testing. Each sample was tested four times consecutively, 0.45 mL each time. Results are expressed as the average number of particles ≥10 μm and ≥25 μm per mL (method conforms to USP). <788> (Particulate matter in injections).

[0552] The subvisible particle data measured by HIAC in the lyophilized composition validation study are summarized in Table 15. No substantial change in subvisible particles was observed after storage at 2–8°C / 25°C / 40°C compared to T0.

[0553] Table 15: Results of subvisible particles measured by HIAC in the lyophilized composition validation study

[0554] The following additional studies were conducted at the indicated time points: - Moisture content and reconstitution time study: No significant increase in moisture content or reconstitution time was observed after storage.

[0555] -DAR and free drug stability studies: No substantial changes were observed in the stability studies.

[0556] -Potential assays after storage and reconstitution: No substantial changes in biological activity were observed in the stability studies.

[0557] In summary, in this study, the protein of compound 1 was lyophilized using a final lyophilization process, and its stability was investigated after storage at 40°C for 4 weeks or at 25°C / 2-8°C for 12 weeks. These results indicate that compound 1 is stable in the selected lyophilized composition.

[0558] Stability study of reconstitution

[0559] Materials: Compound 1 used in the reconstitution stability study was prepared in the lyophilized composition confirmation study and stored at 5°C.

[0560] Research Design: The research plan is shown in Table 16.

[0561] Table 16: Reconstitution Stability Study Plan

[0562] X = Appearance (visible particles), pH, protein concentration, SEC-HPLC, cIEF, DAR, HIAC

[0563] Note: In this study, the T0 data of the lyophilized composition confirmation study were used as T0.

[0564] Sample preparation: The drug product was taken out at 5°C and reconstituted with ultrapure water. The reconstituted drug product was then placed under the corresponding conditions listed in Table 17 to study its stability.

[0565] Methods: The same methods as those used in the freeze-drying confirmation study described above were used in this study.

[0566] Appearance, pH, and protein concentration: As this study demonstrates, for the reconstituted Compound 1 drug product, no substantial changes in appearance, pH, and protein concentration were observed compared to T0 after storage at room temperature for 6 hours or at 2–8°C for 24 hours.

[0567] Table 17: Summary of data on appearance, pH, and protein concentration in the reconstitution stability study

[0568] SEC-HPLC: The results of SEC-HPLC are shown in Table 18. For the reconstituted compound 1 DP, no substantial changes were observed in SEC-HPLC compared to T0 after storage at room temperature for 6 hours or at 2–8°C for 24 hours.

[0569] Table 18: Results of SEC-HPLC in the reconstitution stability study

[0570] cIEF: The results for cIEF are shown in Table 19. For the reconstituted compound 1DP, no substantial change in cIEF was observed compared to T0 after storage at room temperature for 6 hours or at 2–8 °C for 24 hours.

[0571] Table 19: Results of cIEF in the reconstitution stability study

[0572] HIAC: Results are shown in Table 20. For the reconstituted Compound 1 drug product, no substantial increase in subvisible particles was observed compared to T0 after storage at room temperature for 6 hours or at 2–8°C for 24 hours.

[0573] Table 20: Results of HIAC in the reconstitution stability study

[0574] Drug-Antibody Ratio (DAR): The results of the DAR are shown in Table 21. For the reconstituted Compound 1 drug product, no substantial change in DAR was observed compared to T0 after storage at room temperature for 6 hours or at 2–8°C for 24 hours.

[0575] Table 21: Results of DAR in the reconstitution stability study

[0576] The following additional studies were conducted at the indicated time points: - Free drug stability study: No substantial changes in the free drug were observed in the reconstituted compound 1 drug product after a specified time period.

[0577] -Potential assays after storage and reconstitution: No substantial changes in biological activity were observed in the reconstitution stability study after a specified period of time.

[0578] Example 8b - Stability Study of the Lyophilized Composition

[0579] Sample information: Compound 1 was prepared using 20.0 mg / mL of Compound 1, 25 mM histidine, 9% (w / v) sucrose, 0.03% (w / v) polysorbate 80, and pH 5.5.

[0580] Sample preparation: The drug solution was aseptically filtered, filled into glass vials, partially plugged, and freeze-dried in a lyophilizer. All procedures were performed within a biosafety enclosure.

[0581] Research Plan: The sampling and testing plan for the lyophilized composition validation study is shown in Table 22. Samples were incubated at 2–8°C, 25°C, and 40°C for long-term, accelerated, and stress-condition storage, respectively. T0 samples without any stress treatment were used as controls. Tests performed in this study included appearance (before and after reconstitution), pH, protein concentration, SEC-HPLC, cIEF, and high-visibility ionization (HIAC). Samples were recovered and analyzed promptly at each sampling point.

[0582] Table 22: Sampling and Testing Plan for Validation Studies of Lyophilized Compositions

[0583] X = Appearance (before and after reconstitution), pH, protein concentration, SEC HPLC, cIEF, DAR; Y = Subvisible particles.

[0584] Results and discussion

[0585] Appearance, pH, and protein concentration: The appearance of all samples, including clarity, color, and visible particles, was visually observed against a black and white background using a YB-2 clarity detector with a light intensity of 1000-1500 Lux.

[0586] The pH of the samples was measured using a pH meter with a glass electrode. The pH meter was calibrated using standard solutions at pH 4.01, 7.00, and 9.21. Each sample was measured twice (100 μL of sample each time), and the average value was used in the report.

[0587] Protein concentration was determined using absorbance measurements at 280 nm and 370 nm using a SoloVPE spectrophotometer. The extinction coefficient of compound 1 mAb protein was 1.52 (mg / mL). -1 ·cm -1 .

[0588] The SoloVPE system relies on variable path length spectrophotometry. According to Beer's Law equation: A = ε L C, where A = absorbance, ε = extinction coefficient, L = path length, C = concentration, and the slope m = A / L can be obtained by measuring absorbance at 10 different path lengths. The slope m can be calculated from the path length and absorbance curve. Since C = m / ε, the concentration can be calculated given ε and m.

[0589] SEC-HPLC: The sample was diluted to 10.0 mg / mL with the mobile phase, and then 100 μg of sample was injected into a TSK gel G3000SWXL column (7.8 × 300 mm, 5 μm Steel / TOSOH). Analysis was performed on an Agilent 1260 HPLC system equipped with MWD detectors (detection wavelengths: 280 nm and 370 nm). The chromatographic program was performed at a flow rate of 1.0 mL / min with an isogradient for 20 min, where the mobile phase (50 mM phosphate buffer, 300 mM NaCl, pH 6.8 ± 0.1):acetonitrile (can) = 9:1 (v / v).

[0590] CIEF: The compound 1 sample was mixed with the master mixture to produce a loading mixture containing 2.0 μL Pharmalyte 8-10.5, 2.0 μL Pharmalyte 3-10, 35 μL 1% MC, 0.5 μL pI-labeled 7.05, 0.5 μL pI-labeled 9.46, 37.5 μL 8M urea solution, 0.15 μL glacial acetic acid, and 2.35 μL ultrapure water, resulting in a final protein concentration of 0.4 mg / mL. The loading mixture was placed in a refrigerator at 2–8°C or a heating block at 5°C for more than 48 hours. Testing must be completed within 96 hours of mixing the sample with the master mixture; otherwise, the sample should be prepared again. The loading mixture was loaded into an FC-coated capillary and analyzed using an iCE3 capillary isoelectric focusing analyzer equipped with a full-column detection camera. After analysis, the raw data were processed using Empower 3.

[0591] Subvisible particulate matter (HIAC): Subvisible particle size and count were measured using a HACH particle analyzer in a laminar flow hood. To avoid introducing air bubbles and interference during the test, all samples were held in the hood for at least 0.5 hours before testing. Each sample was tested four times consecutively, 0.45 mL each time. Results are expressed as the average number of particles ≥10 μm and ≥25 μm per mL (method conforms to USP). <788> (Particulate matter in injections).

[0592] The results are shown in Tables 23 to 25. Regarding the appearance of the freeze-dried cake, no substantial changes in appearance, pH, visible particles, subvisible particles, charge variants, SEC, DAR, or protein concentration were observed under any conditions, including 2–8 °C, 25 °C, and 40 °C.

[0593] Table 23 Stability data at 2-8℃

[0594] Table 24 Stability data at 25℃

[0595] Table 25 Stability data at 40℃

[0596] In summary, in this study, the protein of compound 1 was lyophilized using a final lyophilization process, and its stability was investigated after storage at 2-8°C for 24 months, at 25°C for 6 months, or at 40°C for 1 month. These results indicate that compound 1 is stable in the selected lyophilized compositions.

[0597] Summarize

[0598] In this study, the stability of the reconstituted Compound 1 drug product was investigated. After reconstituted Compound 1 drug product and stored at 25°C for 6 hours or at 2–8°C for 24 hours, no substantial changes in the tested items were observed compared to T0.

[0599] Based on the above results, the reconstituted compound 1 drug product is stable for 6 hours at room temperature and for 24 hours at 2-8°C.

[0600] All samples were colorless, slightly opalescent, and free of visible particles. During the lyophilized composition validation study, no substantial changes in protein concentration, pH, or sub-visible particles were observed in any of the tested samples.

[0601] No substantial changes were observed in any of the key quality attributes after incubation for 12 weeks at 2–8°C / 25°C or for 4 weeks at 40°C.

[0602] During the testing period, no substantial quality change was observed in the Compound 1 drug product after reconstitution.

[0603] In summary, the stability of compound 1 in the selected composition has been confirmed.

[0604] Example 9a - Comparison of Compound 1 and Trastuzumab Emtasine (T-DM1, Kadcyla) ® A phase III, multicenter, open-label, randomized study in patients with HER2-positive unresectable / metastatic breast cancer who had previously received trastuzumab and taxane therapy.

[0605] This is a randomized, controlled, two-arm, open-label, multicenter, phase III study designed to evaluate the efficacy and safety of compound 1 versus trastuzumab emtansine (T-DM1) in patients with HER2-positive unresectable / metastatic breast cancer who have previously received trastuzumab and taxane therapy. Approximately 224 participants with unresectable or metastatic HER2-positive breast cancer will be randomized 1:1 to receive either compound 1 or trastuzumab emtansine.

[0606] Table 26: Arm and Interventions

[0607] Result measurement

[0608] Main results measurement: 1. Progression-free survival (PFS) assessed by blinded independent central review (BICR) according to the efficacy evaluation criteria in solid tumors version 1.1 (RECIST 1.1) - defined as the time from randomization to the first recorded disease progression or death from any cause as assessed by BICR according to RECIST 1.1 (whichever comes first) [time range: up to approximately 24 months].

[0609] Secondary outcome measurement: 2. Overall survival (OS) - defined as the time from randomization to death from any cause. [Time range: up to approximately 24 months].

[0610] 3. Progression-free survival (PFS) as assessed by the investigator according to RECIST 1.1 – defined as the time from randomization to the first recorded disease progression or death from any cause as assessed by the investigator according to RECIST 1.1 (whichever comes first). [Time range: up to approximately 24 months].

[0611] 4. Objective response rate (ORR) assessed by BICR and investigators according to RECIST 1.1 – defined as the percentage of patients who achieved a complete response (CR) or partial response (PR) as assessed by BICR and investigators according to RECIST 1.1. [Time range: up to approximately 24 months].

[0612] 5. Duration of Response (DoR) as assessed by BICR and investigators according to RECIST 1.1 – defined as the time from the first remission (CR or PR) to subsequent disease progression or death from any cause as assessed by BICR and investigators according to RECIST 1.1 (whichever comes first). [Time range: up to approximately 24 months].

[0613] 6. PK parameter: Maximum observed concentration (C max The maximum observed concentrations (C1) of compound 1 and free compound 2, etc., after application of compound 1. max [Time range: up to approximately 24 months].

[0614] 7. PK parameter: Time to reach maximum concentration (T) max The time (T) for compound 1 and free compound 2 to reach their maximum concentrations after application of compound 1. max [Time range: up to approximately 24 months].

[0615] 8. Adverse Events (AEs) - Number and percentage of patients reporting serious adverse events (SAEs), treatment-related adverse events (TEAEs), TEAEs leading to discontinuation of the study drug, and adverse events of special concern (AESIs) (according to the National Cancer Institute Common Terminology Standard for Adverse Events version 5.0 [NCI-CTCAE v5.0] classification) [Time range: up to approximately 24 months.]

[0616] 9. Patient-Reported Outcomes (PRO): Changes from baseline in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30-EORTC QLQ-C30's Functional / Symptom / Global QoL scales. Scale scores range from 0 to 100. For the Functional and Global QoL scales, higher scores indicate better functioning or overall health. For the Symptom scale, higher scores indicate a greater symptom burden. [Time range: up to approximately 24 months.]

[0617] 10. Patient-Reported Outcomes (PRO): EORTC QLQ-BR45 – Changes in the EORTC QLQ-BR45's functional / symptom scales from baseline. Scale scores range from 0 to 100. For the functional scale, higher scores indicate better functioning. For the symptom scale, higher scores indicate a greater symptom burden. [Time range: up to approximately 24 months.]

[0618] 11. Patient-Reported Outcomes (PRO): Changes from baseline in the European Five-Dimensional, Five-Point Quality of Life Scale (EQ-5D-5L) – EQ-5D-5L Health Status Utility Index score and Visual Analogue Scale (VAS). VAS scores range from 0 to 100, with higher scores indicating better health. [Time range: up to approximately 24 months.]

[0619] 12. European Quality of Life Five-Dimensional Five-Point Scale (EQ-5D-5L) EQ-5D-5L Health Status Utility Index score and Visual Analogue Scale (VAS) score. Changes from baseline will be reported. [Time range: up to approximately 24 months.]

[0620] 13. Antidrug Antibodies (ADA) - Number and percentage of patients producing antidrug antibodies (ADA) against compound 1. [Time range: up to approximately 24 months.]

[0621] qualifications

[0622] Minimum age: 18 years old

[0623] Maximum age: None

[0624] • Gender: All

[0625] • Based on gender: All

[0626] • Accepting healthy volunteers: No

[0627] Inclusion criteria

[0628] • Male or female adults aged 18 or older at the time of voluntarily signing the informed consent form.

[0629] • Pathologically confirmed unresectable or metastatic HER2-positive breast cancer previously treated with trastuzumab and taxane.

[0630] • Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

[0631] • At least one measurable lesion is present according to RECIST v1.1.

[0632] • Expected survival time ≥ 12 weeks.

[0633] • Participants must give informed consent to this study and voluntarily sign a written informed consent form before the study begins.

[0634] Exclusion criteria

[0635] • Previous anti-HER2 ADC treatment.

[0636] • A history of ILD / non-infectious pneumonia / radiation pneumonia requiring steroid treatment.

[0637] • Severe allergic reactions are known to occur to the active ingredient of the study drug, the inactive ingredient in the composition, or other antibody drugs.

[0638] • Multiple primary malignant tumors within 3 years, except for fully excised non-melanoma skin cancer, radically treated in situ tumors, or contralateral breast cancer.

[0639] • Uncontrolled infections requiring intravenous antibiotics, antiviral or antifungal agents; autoimmune diseases requiring treatment; uncontrolled diabetes, hypertension or other systemic diseases that make it difficult to adhere to research procedures.

[0640] • Unrecovered toxicity from previous anticancer treatment, defined as toxicity that has not recovered to ≤ grade 1 (NCI-CTCAE v5.0) or baseline (excluding hair loss).

[0641] Inclusion / exclusion criteria specified in other protocols may apply.

[0642] Example 9b - Further Information - A Phase III, multicenter, open-label, randomized controlled study evaluating compound 1 in combination with trastuzumab emtansine (T-DM1) in patients with HER2-positive unresectable / metastatic breast cancer previously treated with trastuzumab and taxane.

[0643] 1. Purpose of the test

[0644] Primary objective: To compare the progression-free survival (PFS) benefit of compound 1 versus trastuzumab emtansine (T-DM1) in patients with HER2-positive unresectable / metastatic breast cancer who had previously received trastuzumab and taxane therapy. Secondary objectives: To compare the efficacy and safety of compound 1 versus T-DM1, analyze the pharmacokinetic profile of compound 1, evaluate improvements in disease symptoms and quality of life compared to trastuzumab emtansine (T-DM1), and assess the immunogenicity of compound 1.

[0645] 2. Experimental Design

[0646] 3. Subject Information

[0647] Age: 18 years old (minimum age), no upper limit (maximum age)

[0648] Gender: Male + Female

[0649] Healthy subjects: No

[0650] Table 27: Inclusion Criteria

[0651] Table 28: Exclusion Criteria

[0652] 4. Test Grouping

[0653] Research drug: Compound 1

[0654] Dosage form: Lyophilized powder for injection

[0655] Specification: 100mg / bottle

[0656] Dosage: Intravenous infusion, 8 mg / kg

[0657] Dosing schedule: Subjects will continue to receive compound 1 treatment according to the Q3W (1 cycle) dosing regimen until unacceptable toxicity, death, PD, withdrawal of consent, or other criteria for discontinuation occur.

[0658] Comparative agent: Trastuzumab emtansine

[0659] Dosage form: Lyophilized powder for injection

[0660] Specification: 100mg / bottle

[0661] Dosage: Intravenous infusion, 3.6 mg / kg

[0662] Dosage regimen: Subjects will continue to receive T-DM1 treatment according to the Q3W (1 cycle) dosing regimen until unacceptable toxicity, death, PD, withdrawal of consent, or other criteria for discontinuation occur.

[0663] 5. Endpoint Indicators

[0664] Table 29: Key Endpoints and Assessment Time

[0665] Table 30: Secondary endpoint indicators and assessment time

[0666] All publications mentioned herein are incorporated herein by reference. It will be apparent to those skilled in the art that various modifications and variations to the methods and systems described herein will be apparent without departing from the scope and spirit of the invention. Although the invention has been described with reference to specific preferred embodiments, it should be understood that the invention as claimed in the claims should not be unduly limited to these specific embodiments. In fact, various modifications to the described modes of carrying out the invention that will be apparent to those skilled in the art are intended to fall within the scope of the appended claims.

Claims

1. An antibody-drug conjugate having the structure shown in formula (I): ， Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; It is used in the treatment of endometrial cancer.

2. An antibody-drug conjugate having the structure shown in formula (I): ， Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; Or its pharmaceutically acceptable salt. It is used in methods of treating cancer, wherein the method involves administering an antibody-drug conjugate or a pharmaceutically acceptable salt thereof to a patient at a dose ranging from 2.2 mg / kg to 12.0 mg / kg.

3. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to claim 2, wherein the dose is in the range of 6.0 mg / kg to 10.0 mg / kg.

4. The antibody-drug conjugate or its pharmaceutically acceptable salt used according to claim 2 or claim 3, wherein the patient has been diagnosed with cancer, said cancer being HER2-positive or HER2-overexpressing.

5. The antibody-drug conjugate or its pharmaceutically acceptable salt used according to claim 2 or claim 3, wherein the patient has been diagnosed with cancer, said cancer being HER2-low or HER2-negative cancer.

6. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to any one of claims 2-5, wherein the cancer is selected from lung cancer, kidney cancer, urinary tract cancer, colorectal cancer, prostate cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, gastric cancer, esophageal cancer, and endometrial cancer.

7. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to claim 6, wherein the cancer is breast cancer.

8. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to claim 7, wherein the cancer is HER2-positive breast cancer.

9. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to claim 7, wherein the cancer is HER2-low or HER2-negative breast cancer.

10. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to claim 6, wherein the cancer is endometrial cancer.

11. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to claim 10, wherein the cancer is HER2-positive endometrial cancer.

12. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to claim 10, wherein the cancer is HER2-low or HER2-negative endometrial cancer.

13. An antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; It is used in the treatment of breast cancer in patients who have previously been treated with anti-HER2 antibodies and / or taxanes.

14. The antibody-drug conjugate used in claim 13, or a pharmaceutically acceptable salt thereof, wherein the anti-HER2 antibody is selected from trastuzumab, pertuzumab, and magtuximab, or a biosimilar of any one thereof.

15. The antibody-drug conjugate used in claim 14, or a pharmaceutically acceptable salt thereof, wherein the anti-HER2 antibody is trastuzumab or a biosimilar thereof.

16. The antibody-drug conjugate used in any one of claims 13-15, or a pharmaceutically acceptable salt thereof, wherein the taxane is selected from paclitaxel, docetaxel, cabazitaxel, and albumin-bound paclitaxel.

17. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used in any one of claims 13-16, wherein the cancer is HER2-positive breast cancer.

18. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used in any one of claims 13-17, wherein the cancer is unresectable breast cancer.

19. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used in any one of claims 13-18, wherein the cancer is metastatic breast cancer.

20. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used in any one of claims 13-16, wherein the cancer is HER2-positive unresectable or metastatic breast cancer.

21. The antibody-drug conjugate used in any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein ring A is a 4-membered saturated carbocyclic group.

22. The antibody-drug conjugate used according to any one of claims 1-21, or a pharmaceutically acceptable salt thereof, wherein ring A is surrounded by 1 L 2 replace.

23. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to any one of claims 1-22, wherein m is 0 and L 3 It is a covalent bond.

24. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to any one of claims 1-23, wherein n is 1 and L 1 It is -C(R) 5a (R) 5b )-, where L 1 One methylene unit is replaced by -C(O)-.

25. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to any one of claims 1-24, wherein the drug moiety has the following structure IA: I-A Where R 2 As defined in claim 1.

26. The antibody-drug conjugate used according to any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein the antibody-drug conjugate is compound 1 having the following structure: Compound 1, Or a pharmaceutically acceptable salt thereof, wherein N a N represents the number of connections, and N a Integers selected from 7 to 8.

27. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to claim 1, wherein the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose ranging from 2.2 mg / kg to 12.0 mg / kg.

28. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to claim 27, wherein the dose is in the range of 6.0 mg / kg to 10.0 mg / kg.

29. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to any one of claims 1-28, wherein the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is administered at a dose of 8.0 mg / kg.

30. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used in any one of claims 1-29, wherein the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is administered once every three weeks.

31. The antibody-drug conjugate or a pharmaceutically acceptable salt thereof used according to any one of claims 1-30, wherein the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is formulated into a composition comprising: Approximately 20 mg / ml of antibody-drug conjugate or its pharmaceutically acceptable salt; Approximately 25 mM histidine or a pharmaceutically acceptable salt thereof; Approximately 9% (w / v) sucrose; and Approximately 0.03% (w / v) polysorbate 80, Furthermore, the pH of the composition is approximately 5.

5.

32. A composition comprising: An antibody-drug conjugate having the structure shown in formula (I) at a concentration of approximately 20 mg / ml: ， Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c -is-CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; Approximately 25 mM histidine or a pharmaceutically acceptable salt thereof; Approximately 9% (w / v) sucrose; and Approximately 0.03% (w / v) polysorbate 80, The pH of the composition is approximately 5.

5.

33. A composition comprising: An antibody-drug conjugate having the structure shown in formula (I) at a concentration of approximately 20 mg / ml: , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; Approximately 0.82 mg / ml L-histidine; Approximately 4.14 mg / ml of L-histidine hydrochloride monohydrate; Approximately 90 mg / ml sucrose; and Approximately 0.3 mg / ml of polysorbate 80.

34. A lyophilized composition comprising: (a) Approximately 100 mg of an antibody-drug conjugate having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 SO2-, -SO2N(R) 6 -, -C(=S)-, -C(=NR) 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; (b) Approximately 4.1 mg of L-histidine; (c) Approximately 20.7 mg of L-histidine hydrochloride monohydrate; (d) Approximately 450 mg of sucrose; and (e) Approximately 1.5 mg of polysorbate 80.

35. A lyophilized composition comprising: (a) Antibody-drug conjugates having the structure shown in formula (I): , Or its pharmaceutically acceptable salt, wherein: Ab is trastuzumab; Number of connections N a It is an integer from 1 to 10; L is -L a -L b -L c -; -L a -yes ; -L b -yes ; -L c - is –CH2-; X 1 It is saturated C, and X 1 R n replace; Ring A is selected from: 3-10 member saturated or partially unsaturated heterocyclic groups and 3-10 member saturated or partially unsaturated carbocyclic groups, wherein ring A is substituented by 0 or at least 1 R. 1a replace; When ring A is a 3-10 nucleotide saturated or partially unsaturated carbon ring group, ring A is divided by p L groups. 2 Replace, and L 2 Not R n ; Alternatively, when ring A is a 3-10 saturated or partially unsaturated heterocyclic group, ring A is divided by p L 2 replace; L 2 Yes -R 2 -L 3 - and R 2 For direct or indirect ligand linkage; L 3 It is -(C(R) 3a (R) 3b )) m -, where L 3 When containing a methylene unit, L 3 Zero or at least one methylene unit is independently separated by -N(R) 4 )C(O)-、-C(O)N(R 4 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 4 -, -O-, -S-, -SO-, -SO2-, -P(R 4 )-、-P(=O)(R 4 )-、-N(R 4 SO2-, -SO2N(R) 4 -, -C(=S)-, -C(=NR) 4 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; R 2 Selected from: -O-, -(R 2a N-, -S- and -P(=O)(R 2a )-; L 1 It is -(C(R) 5a (R) 5b )) n -, where L 1 When containing a methylene unit, L 1 Zero or at least one methylene unit is independently separated by -N(R) 6 )C(O)-、-C(O)N(R 6 )-, -C(O)-, -OC(O)-, -C(O)O-, -NR 6 -, -O-, -S-, -SO-, -SO2-, -P(R 6 )-、-P(=O)(R 6 )-、-N(R 6 )SO2-, -SO2N(R6)-, -C(=S)-, -C(=NR 6 -, -N=N-, -C=N-, -N=C- or -C(=N2)- can be substituted; Each R 1a Each R 2a Each R 3a Each R 3b Each R 4 Each R 5a Each R 5b Each R 6 and each R n Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OR, -SR, and -N(R). a (R) b ), -C(O)R, -CO2R, -C(O)C(O)R, -C(O)CH2C(O)R, -S(O)R, -S(O)2R, -C(O)N(R a (R) b -SO2N(R) a (R) b -OC(O)R, -N(R)SO2R, or C optionally replaced by R 1-6 Aliphatic groups; Where each R, each R a and each R b Each of these elements independently represents hydrogen, protium, deuterium, tritium, halogens, -NO2, -CN, -OH, -SH, -NH2, -C(O)H, -CO2H, -C(O)C(O)H, -C(O)CH2C(O)H, -S(O)H, -S(O)2H, -C(O)NH2, -SO2NH2, -OC(O)H, -N(H)SO2H, or C 1-6 Aliphatic groups; m and n are each independently selected from integers ≥ 0, and p is an integer ≥ 1; It exists in an amount of approximately 100 parts by weight; (b) L-histidine, present in an amount of about 4.1 parts by weight relative to 100 parts by weight (a); (c) L-histidine hydrochloride monohydrate; present in an amount of about 20.7 parts by weight relative to 100 parts by weight of (a); (d) Sucrose, present in an amount of about 450 parts by weight relative to 100 parts by weight of (a); and (e) Polysorbate 80, present in an amount of about 1.5 parts by weight relative to 100 parts by weight of (a).

36. A method for preparing the composition of claim 31, 32 or 33, the method comprising reconstituted the lyophilized composition of claim 34 or 35 with a diluent.

37. The method of claim 36, wherein the diluent is water.

38. The method of claim 37, wherein the water is water for injection (WFI).

39. A method for preparing the lyophilized composition of claim 34 or 35, the method comprising lyophilizing the composition of claim 31, 32 or 33.

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