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WO2025054996A1 - Conjugué anticorps-médicament - Google Patents

Conjugué anticorps-médicament Download PDF

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Publication number
WO2025054996A1
WO2025054996A1 PCT/CN2023/119242 CN2023119242W WO2025054996A1 WO 2025054996 A1 WO2025054996 A1 WO 2025054996A1 CN 2023119242 W CN2023119242 W CN 2023119242W WO 2025054996 A1 WO2025054996 A1 WO 2025054996A1
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WO
WIPO (PCT)
Prior art keywords
antibody
pharmaceutically acceptable
acceptable salt
drug conjugate
cancer
Prior art date
Application number
PCT/CN2023/119242
Other languages
English (en)
Inventor
Yang Qiu
Wei Gu
Original Assignee
Duality Biologics (Suzhou) Co., Ltd.
BioNTech SE
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Duality Biologics (Suzhou) Co., Ltd., BioNTech SE filed Critical Duality Biologics (Suzhou) Co., Ltd.
Priority to PCT/CN2023/119242 priority Critical patent/WO2025054996A1/fr
Priority to PCT/EP2024/075631 priority patent/WO2025056748A1/fr
Publication of WO2025054996A1 publication Critical patent/WO2025054996A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell

Definitions

  • the present invention relates to an antibody-drug conjugate that comprises the antibody trastuzumab for use in a method of treating endometrial cancer.
  • the present invention also relates to the antibody-drug conjugate for use in a method of treating cancer, wherein the method comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the range of 2.2 mg/kg to 12.0 mg/kg.
  • the present invention also relates to compositions comprising the antibody-drug conjugate.
  • Epidermal growth factor receptor 2 (EGFR2 or HER2) has shown gene amplification/over-expression in more than 30%of all human cancers, including breast cancer, gastric, colon, salivary gland, bladder, and uterine serous carcinoma and its overexpression in tumours is associated with poor prognosis.
  • HER2-targeted therapy has improved the outcome of HER2-amplified/overexpressing patients.
  • HER2-positive tumour respond well to current therapies.
  • Resistance towards HER2-targeting therapies is common in patients, occurring as either intrinsic or acquired resistance.
  • the present invention is based, at least in part, on the inventors’ development of antibody-drug conjugates which have particularly advantageous and surprising properties.
  • the antibody-drug conjugate according to the invention may be particularly effective at treating cancers, such as HER2-associated cancers.
  • the present invention provides an antibody-drug conjugate having a structure shown as formula (I) :
  • an average connection number N a is an integer or a decimal from 1 to 10;
  • L is -L a -L b -L c -;
  • X 1 is saturated C, and X 1 is substituted with R n ;
  • ring A is selected from the group consisting of: 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A is substituted with 0 or at least 1 substituent R 1a ;
  • L 2 is -R 2 -L 3 -, and R 2 is used for direct or indirect linking of a ligand
  • 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 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N (R a ) (R b ) , -C (O) R, -CO 2 R, -C (O) C (O) R, -C (O) CH 2 C (O) R, -S (O) R, -S (O) 2 R, -C (O) N (R a ) (R b ) , -SO 2 N (R a ) (R b ) , -OC (O) R, -N (R) SO 2 R, or a C 1-6 aliphatic group optionally substituted with R;
  • each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C (O) H, -CO 2 H, -C (O) C (O) H, -C (O) CH 2 C (O) H, -S (O) H, -S (O) 2 H, -C (O) NH 2 , -SO 2 NH 2 , -OC (O) H, -N (H) SO 2 H or a C 1-6 aliphatic group;
  • n and n are each independently selected from the group consisting of integers ⁇ 0, and p is an integer ⁇ 1;
  • the present invention provides an antibody-drug conjugate having a structure shown as formula (I) :
  • an average connection number N a is an integer or a decimal from 1 to 10;
  • L is -L a -L b -L c -;
  • X 1 is saturated C, and X 1 is substituted with R n ;
  • ring A is selected from the group consisting of: 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A is substituted with 0 or at least 1 substituent R 1a ;
  • L 2 is -R 2 -L 3 -, and R 2 is used for direct or indirect linking of a ligand
  • 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 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N (R a ) (R b ) , -C (O) R, -CO 2 R, -C (O) C (O) R, -C (O) CH 2 C (O) R, -S (O) R, -S (O) 2 R, -C (O) N (R a ) (R b ) , -SO 2 N (R a ) (R b ) , -OC (O) R, -N (R) SO 2 R, or a C 1-6 aliphatic group optionally substituted with R;
  • each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C (O) H, -CO 2 H, -C (O) C (O) H, -C (O) CH 2 C (O) H, -S (O) H, -S (O) 2 H, -C (O) NH 2 , -SO 2 NH 2 , -OC (O) H, -N (H) SO 2 H or a C 1-6 aliphatic group;
  • n and n are each independently selected from the group consisting of integers ⁇ 0, and p is an integer ⁇ 1;
  • the method comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the range of 2.2 mg/kg to 12.0 mg/kg.
  • the dose may be in the range of 6.0 mg/kg to 10.0 mg/kg.
  • the patient may have been determined to have a cancer which is a HER2 positive or HER2 overexpressive cancer.
  • the patient may have been determined to have a cancer which is a HER2 low or HER2 negative cancer.
  • the cancer may be selected from the group consisting of lung cancer, kidney cancer, urinary tract carcinoma, colourectal cancer, prostatic cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, esophageal cancer and endometrial cancer.
  • the cancer may be selected from the group consisting of breast cancer, colourectal cancer, endometrial cancer, esophageal carcinoma, ovarian cancer, and vaginal cancer.
  • the cancer may be breast cancer.
  • the cancer may be a HER2 positive breast cancer.
  • the cancer may be a HER2 low or HER2 negative breast cancer.
  • the cancer may be endometrial cancer.
  • the cancer may be a HER2 positive endometrial cancer.
  • the cancer may be a HER2 low or HER2 negative endometrial cancer.
  • ring A may be 4 membered saturated carbocyclyl.
  • ring A may be substituted with 1 L 2 .
  • m may be 0, and L 3 may be a covalent bond.
  • n may be 1, and L 1 may be -C (R 5a ) (R 5b ) -wherein 1 methylene unit of L 1 may be replaced by -C (O) -.
  • the drug moiety may have the following structure I-A:
  • R 2 is as defined in the first or second aspect of the invention.
  • the antibody-drug conjugate may be Compound 1 having the structure below:
  • N a represents an average connection number, and N a is selected from the group consisting of integers or decimals from 7 to 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2.2 mg/kg to 12.0 mg/kg.
  • the dose may be in the range of 6.0 mg/kg to 10.0 mg/kg.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 8.0 mg/kg.
  • the antibody-drug conjugate, or pharmaceutically acceptable salt thereof may be administered once every three weeks.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be formulated as a composition comprising:
  • the present invention also provides a composition comprising:
  • an average connection number N a is an integer or a decimal from 1 to 10;
  • L is -L a -L b -L c -;
  • X 1 is saturated C, and X 1 is substituted with R n ;
  • ring A is selected from the group consisting of: 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A is substituted with 0 or at least 1 substituent R 1a ;
  • L 2 is -R 2 -L 3 -, and R 2 is used for direct or indirect linking of a ligand
  • each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C (O) H, -CO 2 H, -C (O) C (O) H, -C (O) CH 2 C (O) H, -S (O) H, -S (O) 2 H, -C (O) NH 2 , -SO 2 NH 2 , -OC (O) H, -N (H) SO 2 H or a C 1-6 aliphatic group;
  • n and n are each independently selected from the group consisting of integers ⁇ 0, and p is an integer ⁇ 1;
  • pH of the composition is about 5.5.
  • the present invention generally relates to antibody-drug conjugates (ADCs) .
  • ADCs are a class of targeted therapeutics that improves both the selectivity and the cytotoxic activity of drugs, such as cancer drugs, by targeting the drugs to specific targets such as cancer cells.
  • ADCs comprise three main components: (i) an antibody (such as a monoclonal antibody) conjugated to (ii) a linker, which in turn is also conjugated to (iii) a cargo or payload (such as a cytotoxic or chemotherapeutic drug) .
  • the cytotoxic or chemotherapeutic drug refers to a drug that reduces or eliminates the viability of a cell. Suitable cytotoxic or chemotherapeutic drugs will be known in the art.
  • the present inventors have surprisingly found that the antibody-drug conjugates according to the invention are particularly effective at treating cancers, such as HER2-associated cancers.
  • an antibody-drug conjugate having a structure shown as formula (I) :
  • an average connection number N a is an integer or a decimal from 1 to 10;
  • L is -L a -L b -L c -;
  • X 1 is saturated C, and X 1 is substituted with R n ;
  • ring A is selected from the group consisting of: 3-10 membered saturated or partially unsaturated heterocyclyl and 3-10 membered saturated or partially unsaturated carbocyclyl, wherein ring A is substituted with 0 or at least 1 substituent R 1a ;
  • L 2 is -R 2 -L 3 -, and R 2 is used for direct or indirect linking of a ligand
  • 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 are each independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OR, -SR, -N (R a ) (R b ) , -C (O) R, -CO 2 R, -C (O) C (O) R, -C (O) CH 2 C (O) R, -S (O) R, -S (O) 2 R, -C (O) N (R a ) (R b ) , -SO 2 N (R a ) (R b ) , -OC (O) R, -N (R) SO 2 R, or a C 1-6 aliphatic group optionally substituted with R;
  • each R, each R a and each R b are each independently hydrogen, protium, deuterium, tritium, halogen, -NO 2 , -CN, -OH, -SH, -NH 2 , -C (O) H, -CO 2 H, -C (O) C (O) H, -C (O) CH 2 C (O) H, -S (O) H, -S (O) 2 H, -C (O) NH 2 , -SO 2 NH 2 , -OC (O) H, -N (H) SO 2 H or a C 1-6 aliphatic group;
  • n and n are each independently selected from the group consisting of integers ⁇ 0, and p is an integer ⁇ 1;
  • an antibody-drug conjugate having a structure shown as formula (I) as defined above, either in its broadest aspect or a preferred aspect, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer, wherein the method comprises administering the antibody-drug conjugate or pharmaceutically acceptable salt thereof to a patient at a dose in the range of 6.0 mg/kg to 10.0 mg/kg.
  • the term “average connection number N a ” in the context of antibody-drug conjugates refers to the average number of drug molecules connected (e.g. conjugated) to the antibody.
  • the “average connection number N a ” can be considered as the average number of linked payload (e.g. cytotoxic. drugs) per antibody.
  • the average connection number N a can affect the safety and therapeutic effectiveness of the antibody-drug conjugate.
  • the number of drug molecules per antibody molecule can be characterized by conventional methods such as UV/visible spectroscopy, mass spectrometry, ELISA assays and HPLC.
  • connection number N a is an integer or a decimal from 1 to 10.
  • the average connection number N a may be an integer or a decimal selected from the list of ranges selected from: 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.
  • the average connection number N a may be an integer or a decimal selected from the list of ranges selected from: 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.
  • the average connection number N a may be an integer or a decimal selected from the list of ranges selected from: 1 to 8, 2 to 8, 3 to 8, 4 to 8, 5 to 8, 6 to 8, or 7 to 8.
  • the average connection number N a may be selected from the group of integers of: 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • the average connection number N a may be selected from the group of integers or decimals of: 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, 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
  • the average connection number N a may be an integer or a decimal selected from the range of about 7 to about 8. In some embodiments, the average connection number N a may be an integer or a decimal selected from the range of about 7.5 to about 8. In some embodiments, the average connection number N a may be an integer or a decimal selected from the range of about 7.6 to about 8. In some embodiments, the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may 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 connection number N a may be an integer or a decimal selected from the range of about 7.6 to about 8.
  • the antibody-drug conjugate or a pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the term “pharmaceutically acceptable salt” has the generally known meaning of an ionic assembly of anions and cations, where one of the ions is the compound used in the present invention and the other ion is a non-toxic counter-ion.
  • the pharmaceutically acceptable salt may be a sodium salt or a potassium salt.
  • the antibody component, the drug component, and/or if present, the linker component may take the structures shown herein.
  • the antibody component, the drug component, and/or if present, the linker component of the antibody-drug conjugate for use in the present invention may take the form of a tautomer, a mesomer, a racemate, an enantiomer or a diastereoisomer of any of the structures shown, or a mixture thereof.
  • N a represents an average connection number, and N a is selected from the group consisting of integers or decimals from 7 to 8.
  • Compound 1 is disclosed as compound ADC-II-9 and general and specific methods for its synthesis are disclosed in WO2022/068878 and published national applications derived therefrom.
  • the antibody-drug conjugate according to the invention may have (but is not limited to) one or more of the following features:
  • the antibody-drug conjugate according to the invention comprises an antibody which is trastuzumab.
  • binding to binds to binds
  • targeting targets
  • antibody refers to a protein or polypeptide having an antigen-binding domain which comprises at least one complementarity determining region (CDR) .
  • CDR complementarity determining region
  • CDR complementarity determining region
  • “Complementarity determining region” or “CDR” with regard to antigen-binding domain or antibody refers to a hypervariable region or a highly variable loop in the variable region of the heavy chain of the light chain of an antibody, which contribute primarily to antigen binding. CDRs can interact with the antigen conformation and largely determine binding to the antigen (although some framework regions are known to be involved in binding) .
  • the heavy chain variable region and the light chain variable region each contain 3 CDRs (heavy chain CDRs 1, 2 and 3 and light chain CDRs 1, 2 and 3, numbered from the amino to the carboxy terminus) .
  • Each CDR may, for example, have one, two or three amino acid mutations.
  • the CDRs of the variable regions of a heavy and light chain of an antigen-binding domain or antibody can be predicted from the heavy and light chain variable region sequences of the antibody, using prediction software available in the art, e.g. using the Abysis algorithm, or using the IMGT/V-QUEST software, e.g. the IMGT algorithm (ImMunoGeneTics) which can be found at www. IMGT. org, (see for example Lefranc et al, 2009 NAR 37: D1006-D1012 and Lefranc 2003, Leukemia 17: 260-266) . CDR regions identified by either algorithm are considered to be equally suitable for use in the invention.
  • CDRs may vary in length, depending on the antigen-binding domain or antibody from which they are predicted and between the heavy and light chains.
  • the three heavy chain CDRs of an intact antigen-binding domain or antibody may be of different lengths (or may be of the same length) and the three light chain CDRs of an intact antigen-binding domain or antibody may be of different lengths (or may be of the same length) .
  • a CDR for example, may range from 2 or 3 amino acids in length to 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 amino acids in length.
  • a CDR may be from 3-14 amino acids in length, e.g. at least 3 amino acids and less than 15 amino acids.
  • Heavy chain variable region refers to the fragment of the heavy chain of an antigen-binding domain or antibody that contains three CDRs interposed between flanking stretches known as framework regions, which are more highly conserved than the CDRs and form a scaffold to support the CDRs.
  • Light chain variable region refers to the fragment of the light chain of an antigen-binding domain or antibody that contains three CDRs interposed between framework regions.
  • chimeric antibody generally refers to an antibody obtained by fusing a variable region of a murine antibody and a constant region of a human antibody, which can reduce an immune response induced by the murine antibody.
  • a hybridoma secreting murine specific monoclonal antibody can be established, and a variable region gene is cloned from the mouse hybridoma cells; then a constant region gene of human antibody can be cloned as required, and the mouse variable region gene and the human constant region gene are connected to form a chimeric gene; then the chimeric gene is inserted into an expression vector, wherein chimeric antibody molecules can be expressed in a eukaryotic system or a prokaryotic system.
  • humanized antibody also referred to as CDR-grafted antibody, generally refers to an antibody produced by grafting mouse CDR sequences into a human antibody variable region framework, i.e., an antibody produced in a different type of human germline antibody framework sequence. Therefore, the heterogeneous reaction induced by the presence of a large number of mouse protein components in the chimeric antibody can be overcome.
  • framework sequences can be obtained from public DNA databases or disclosed references that include germline antibody gene sequences. For example, germline DNA sequences of human heavy and light chain variable region genes can be obtained from the "VBase" human germline sequence database.
  • Fully humanized antibody may have both humanized variable region and constant region so as to eliminate immunogenicity and toxic side effects.
  • monoclonal antibodies has four stages, namely murine 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.
  • Relevant technologies for the preparation of fully human antibodies may be: human hybridoma technology, EBV-transformed B-lymphocyte technology, phage display technology, transgenic mouse antibody preparation technology, single B-cell antibody preparation technology, and the like.
  • sequence of the antibody may be defined using Kabat numbering (Kabat E.A. et al., (1991) ) .
  • Antibodies may be obtained by techniques comprising immunizing an animal with a target antigen and isolating the antibody from serum.
  • Monoclonal antibodies may be made by the hybridoma method first described by Kohler et al., Nature 256: 495 (1975) , or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567) .
  • the monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al., Nature 352: 624-628 (1991) and Marks et al., J. Mol. Biol. 222: 581-597 (1991) , for example.
  • the antibody may be a chimeric or humanized antibody.
  • Binding affinity (e.g. a KD value) may be quantitatively determined or measured using methods know in the art, such as by surface plasmon resonance (SPR) , for example by using the system (e.g. Biacore T200) .
  • SPR surface plasmon resonance
  • Binding affinity may be quantitatively determined or measured using methods know in the art, such as by surface plasmon resonance (SPR) , for example by using the system (e.g. Biacore T200) .
  • SPR surface plasmon resonance
  • Kd dissociation rate constant
  • Binding affinity can also be determined using methods such as fluorescence quenching, isothermal titration calorimetry.
  • HER2 Human epidermal growth factor receptor 2
  • ERBB2 Receptor tyrosine-protein kinase erbB-2
  • CD340 Receptor tyrosine-protein kinase erbB-2
  • the antibody of the antibody-drug conjugate is trastuzumab.
  • the antibody specifically binds to HER2.
  • the antibody of the antibody-drug conjugate is trastuzumab.
  • the antibody specifically binds to HER2.
  • trastuzumab is sold under the brand name
  • the antibody may comprise a trastuzumab light chain amino acid sequence according to SEQ ID NO: 2 or an amino acid sequence with 80%, 85%, 90%, 95%, 96%, 97%, 98%or 99%sequence identity thereto.
  • the antibody may comprise (i) a trastuzumab heavy chain amino acid sequence according to SEQ ID NO: 1 or an amino acid sequence with 80%, 85%, 90%, 95%, 96%, 97%, 98%or 99%sequence identity thereto; and (ii) a trastuzumab light chain amino acid sequence according to SEQ ID NO: 2 or an amino acid sequence with 80%, 85%, 90%, 95%, 96%, 97%, 98%or 99%sequence identity thereto.
  • the antibody may comprise a trastuzumab heavy chain amino acid sequence according to SEQ ID NO: 1 and a trastuzumab light chain amino acid sequence according to SEQ ID NO: 2.
  • SEQ ID NO: 2 amino acid sequence of the light chain of trastuzumab
  • the moiety of the antibody-drug conjugate of formula (I) above comprises a linker L, which is a chemical structural fragment, which is linked to the antibody trastuzumab at one end and linked to a cytotoxic drug at the other end, or linked to other linkers and then linked to the cytotoxic drug.
  • the direct or indirect linking of a ligand may mean that the group is directly linked to the ligand via a covalent bond, and may also be linked to the ligand via a linker structure.
  • the moiety of the antibody-drug conjugate of formula (I) above contains a drug linked to the antibody trastuzumab Ab via linker L.
  • the remaining moieties of the antibody-drug conjugate i.e. all those structures including L 2 and all structures to the right of it in formula (I) , are termed “the drug moiety” or “the payload moiety” .
  • the bond between L and L 2 is cleaved, and L 2 and all structures to the right of it are released in vivo.
  • X 1 is saturated C.
  • ring A is 3-10 membered saturated carbocyclyl.
  • ring A is 3-6 membered saturated carbocyclyl.
  • ring A is a 4 membered saturated carbocyclyl.
  • ring A is cis-1, 3-cyclobutyl.
  • n is 1, and L 1 is -C (R 5a ) (R 5b ) -.
  • n is 1, and 1 methylene unit of L 1 is replaced by -C (O) -.
  • R 2 is selected from the group consisting of: -O-, - (R 2a ) N-and –S-.
  • R 2 is -O-.
  • p is 1.
  • R 1a is H.
  • R 1b is H.
  • R 2a is H.
  • R 3a and R 3b are each independently H.
  • R 4 is H.
  • R 5a and R 5b are each independently H.
  • R 6 is H.
  • R n is H.
  • R is H.
  • R a is H.
  • R b is H.
  • ring A is substituted with 1 L 2 .
  • m is 0, and L 3 is a covalent bond.
  • n is 1, and L 1 is -C (R 5a ) (R 5b ) -wherein 1 methylene unit of L 1 may be replaced by -C (O) -.
  • the drug moiety may have the following partial structure I-A:
  • R 2 is as defined above, either in its brodest aspect or a preferred aspect.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at any dose.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 2.2 mg/kg to 12.0 mg/kg.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is preferably Compound 1 or a pharmaceutically acceptable salt thereof.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.5 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may 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 pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose in the range of 6.0 mg/kg to 10.0 mg/kg.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is preferably Compound 1 or a pharmaceutically acceptable salt thereof.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.5 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may 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 pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered to a patient at a dose in the range of 2.2 mg/kg to 12.0 mg/kg.
  • the antibody-drug conjugate is preferably Compound 1 or a pharmaceutically acceptable salt thereof.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.5 to about 8.
  • the antibody-drug conjugate is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.6 to about 8.
  • the antibody-drug conjugate is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 6.0 mg/kg to 10.0 mg/kg.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is preferably Compound 1 or a pharmaceutically acceptable salt thereof.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.5 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may 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 pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 2.0 mg/kg to 12.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 2.5 mg/kg to 11.5 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 3.0 mg/kg to 11.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 3.5 mg/kg to 10.5 mg/kg.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is preferably Compound 1 or a pharmaceutically acceptable salt thereof.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.5 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.6 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 4.0 mg/kg to 10.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 4.5 mg/kg to 9.5 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 5.0 mg/kg to 9.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 5.5 mg/kg to 8.5 mg/kg.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 6.0 mg/kg to 8.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 6.5 mg/kg to 7.5 mg/kg. In each of these embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof is preferably Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.5 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may 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 pharmaceutically acceptable salt thereof is Compound 1 or pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 2.0 mg/kg to 3.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 3.0 mg/kg to 4.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 4.0 mg/kg to 5.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 5.0 mg/kg to 6.0 mg/kg.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 6.0 mg/kg to 7.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 7.0 mg/kg to 8.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 8.0 mg/kg to 9.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 9.0 mg/kg to 10.0 mg/kg.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 10.0 mg/kg to 11.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a patient at a dose in the range of 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 pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.5 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may 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 pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 2.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 2.1 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 2.2 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 2.3 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 2.4 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 2.5 mg/kg.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may 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 pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.6 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 3.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 3.5 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 4.0 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 4.4 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 4.5 mg/kg. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a dose of 5.0 mg/kg.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may 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 pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may 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 pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 1 treatment cycle. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 2 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 3 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 4 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 5 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 6 treatment cycles.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 7 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 8 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 9 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 10 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 11 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 12 treatment cycles.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 13 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in at least 14 treatment cycles. In these embodiments, the antibody-drug conjugate is preferably administered once 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 connection number N a may be an integer or a decimal selected from the range of about 7.5 to about 8.
  • the antibody-drug conjugate is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.6 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 2 to 14 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 3 to 13 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 4 to 12 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 5 to 11 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 6 to 10 treatment cycles. In some embodiments of the invention, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in from 7 to 9 treatment cycles.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered in 8 treatment cycles. In these embodiments, the antibody-drug conjugate is preferably administered once 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 connection number N a may 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 connection number N a may be an integer or a decimal selected from the range of about 7.6 to about 8.
  • the antibody-drug conjugate is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the dose should be selected based on considerations of age, body weight, disease symptoms, disease progression and/or severity, sex, and/or any other factors which may interfere with the therapeutic effects the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention.
  • the form of administration of the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be, for example, in a form suitable for oral, parenteral, intraperitoneal, systemic, intravenous (such as intravenous infusion or intravenous drip) , intramuscular, subcutaneous, topical, inhalative, rectal, sublingual, transdermal, or vaginal administration.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered intravenously (e.g. by being injected into a subject) .
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a subject once (i.e. as a one-off treatment) .
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a subject once over a continuous period of hours or days.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a subject on multiple, separate occasions (e.g. as part of an on-going treatment) .
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered to a subject on multiple, separate occasions over a total period of hours, days, weeks, months or years.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered once every day. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered more than once every day.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered once every week. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered more than once every week.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered once every two weeks. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered more than once every two weeks.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered once every three weeks. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered more than once every three weeks.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered once every four weeks. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered more than once every four weeks.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered once every five weeks. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered more than once every five weeks.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered once every six weeks. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered more than once every six weeks.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered once every month. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered more than once every month.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered once every year. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered more than once every year.
  • the present invention provides a pharmaceutical composition comprising the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention.
  • the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, diluent, excipient or adjuvant, salt, and optionally one or more further pharmaceutically active polypeptides and/or compounds.
  • compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • the pharmaceutical composition may comprise an aqueous diluent or solvent.
  • the aqueous diluent or solvent may be a phosphate buffered saline solution, such as a sterile phosphate buffered saline solution.
  • the pharmaceutical composition may be in a form suitable for intravenous infusion. In some embodiments, the pharmaceutical composition may be administered intravenously.
  • the composition may comprise the antibody-drug conjugate according to the invention at a concentration of 1 to 100 mg/ml. In some embodiments, the composition may comprise the antibody-drug conjugate according to the invention at a concentration of10-50 mg/ml. In some embodiments, the composition may comprise the antibody-drug conjugate according to the invention at a concentration of 10-30 mg/ml., In some embodiments, the composition may comprise the antibody-drug conjugate according to the invention at a concentration of 30-50 mg/ml. In some embodiments, the composition may comprise the antibody-drug conjugate according to the invention at a concentration of 15-25 mg/ml.
  • the composition may comprise the antibody-drug conjugate according to the invention at a concentration of 17.5-22.5 mg/ml. In some embodiments, the composition may comprise the antibody-drug conjugate according to the invention at a concentration of about 20 mg/ml.
  • the composition may comprise 1 to 100 mM histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise 10-50 mg/ml histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise 10-20 mg/ml histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise 20-30 mg/ml histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise 30-50 mg/ml histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise about 10 mg/ml histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise about 20 mg/ml histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise about 25 mg/ml histidine or a pharmaceutically acceptable salt thereof. In some embodiments, the composition may comprise about 30 mg/ml histidine or a pharmaceutically acceptable salt thereof.
  • the composition may comprise 1 to 20% (w/v) sucrose. In some embodiments, the composition may comprise 5-10 % (w/v) sucrose. In some embodiments, the composition may comprise 8-10 % (w/v) sucrose. In some embodiments, the composition may comprise about 5% (w/v) sucrose. In some embodiments, the composition may comprise about 6% (w/v) sucrose. In some embodiments, the composition may comprise about 7% (w/v) sucrose. In some embodiments, the composition may comprise about 8% (w/v) sucrose. In some embodiments, the composition may comprise about 9% (w/v) sucrose. In some embodiments, the composition may comprise about 10 % (w/v) sucrose.
  • the composition may comprise 0.01 to 0.5 % (w/v) polysorbate 80. In some embodiments, the composition may comprise 0.05-0.1% (w/v) polysorbate 80. In some embodiments, the composition may comprise 0.01-0.05% (w/v) polysorbate 80. In some embodiments, the composition may comprise 0.015-0.045% (w/v) polysorbate 80. In some embodiments, the composition may comprise about 0.02% (w/v) polysorbate 80. In some embodiments, the composition may comprise about 0.03% (w/v) polysorbate 80.
  • the pH of the composition may be 5 to 8 . In some embodiments, the pH of the composition may be 5 to 7. In some embodiments, the pH of the composition may be 5 to 6. In some embodiments, the pH of the composition may be 5.3 to 5.7. In some embodiments, the pH of the composition may be about 5.5.
  • the pH of the composition may be about 5.5.
  • Formulation 1 This formulation is referred to below as “Formulation 1” .
  • the present invention also provides a composition comprising:
  • pH of the composition is about 5.5.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is preferably Compound 1 or a pharmaceutically acceptable salt thereof.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.5 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.6 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is for use as a medicament in the treatment of endometrial cancer.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is for use in a method of treating endometrial cancer.
  • the present invention also provides a method for treating and/or preventing endometrial cancer, comprising administering an antibody-drug conjugate, or pharmaceutically acceptable salt thereof according to the first aspect of the invention to a subject in need thereof.
  • the present invention also provides a method for treating and/or preventing cancer, comprising administering an antibody-drug conjugate, or pharmaceutically acceptable salt thereof according to the second aspect of the invention to a subject in need thereof.
  • the present invention also provides a use of an antibody-drug conjugate, or pharmaceutically acceptable salt thereof according to the first aspect of the invention in the manufacture of a medicament for the treatment and/or prevention of endometrial cancer, in a subject.
  • the present invention also provides a use of an antibody-drug conjugate, or pharmaceutically acceptable salt thereof according to the second aspect of the invention in the manufacture of a medicament for the treatment and/or prevention of a cancer in a subject.
  • the patient may have been determined to have a cancer which is a HER2 positive cancer. In some embodiments of the second aspect of the present invention, the patient may have been determined to have a cancer which is a HER2 overexpressive cancer.
  • a “HER2 positive cancer” or “HER2 overexpressive cancer” is a cancer that is associated with increased expression of HER2, wherein the levels of expression of HER2 are considered to be increased compared to the expression of HER2 in, for example, a non-cancerous cell or tissue, which may not express HER2, or may express HER2 at baseline levels.
  • the patient may have been determined to have a cancer which is a HER2 low cancer. In some embodiments of the second aspect of the present invention, the patient may have been determined to have a cancer which is a HER2 negative cancer. It will be understood that a “HER2 low cancer” or “HER2 negative cancer” is a cancer that is not associated with expression of HER2 or is associated with low levels of expression of HER2, wherein the low levels of expression of HER2 are considered to be reduced compared to the expression of HER2 in, for example, a non-cancerous cell or tissue.
  • the cancer may be selected from the group consisting of lung cancer, kidney cancer, urinary tract carcinoma, colourectal cancer, prostatic cancer, glioblastoma multiforme, ovarian cancer, pancreatic cancer, breast cancer, melanoma, liver cancer, bladder cancer, stomach cancer, esophageal cancer, uterine cancer, and endometrial cancer.
  • the cancer may be a carcinoma. In some embodiments, the cancer may be an adenocarcinoma.
  • the endometrial and/or uterine cancer may be uterine serous endometrial carcinoma.
  • the cancer may be breast cancer.
  • the cancer may be a HER2 positive breast cancer.
  • the cancer may be a HER2 low or HER2 negative breast cancer. In some embodiments of the second aspect of the present invention, the cancer may be a HER2 low breast cancer. In some embodiments of the second aspect of the present invention, the cancer may be a HER2 negative breast cancer.
  • the cancer may be endometrial cancer.
  • the cancer may be a HER2 positive endometrial cancer.
  • the cancer may be a HER2 low or HER2 negative endometrial cancer. In some embodiments of the second aspect of the present invention, the cancer may be a HER2 low endometrial cancer. In some embodiments of the second aspect of the present invention, the cancer may be a HER2 negative endometrial cancer.
  • the cancer may be advanced endometrial cancer. In some embodiments, the cancer may be metastatic endometrial cancer.
  • the cancer may be a solid tumour.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is preferably Compound 1 or a pharmaceutically acceptable salt thereof.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.5 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be an integer or a decimal selected from the range of about 7.6 to about 8.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof is Compound 1 or a pharmaceutically acceptable salt thereof, and the average connection number N a may be selected from the group of integers or decimals of: 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0.
  • Cancer is a well known term that refer to a disease or group of diseases involving abnormal cell growth.
  • cancer may be used interchangeably with “tumour” or “cancerous disease” .
  • disease and “disorder” may be used interchangeably herein, referring to an abnormal condition especially an abnormal medical condition such as an illness or injury, wherein a cell, a tissue, an organ, or an individual is not able to efficiently fulfil its function anymore.
  • a disease is associated with specific symptoms or signs indicating the presence of such disease. The presence of such symptoms or signs may thus, be indicative for a cell, a tissue, an organ, or an individual suffering from a disease. An alteration of these symptoms or signs may be indicative for the progression of such a disease.
  • a progression of a disease is typically characterised by an increase or decrease of such symptoms or signs which may indicate a "worsening" or “bettering" of the disease.
  • the "worsening" of a disease is characterised by a decreasing ability of a cell, tissue, organ or individual/patient to fulfil its function efficiently, whereas the “bettering" of a disease is typically characterised by an increase in the ability of a cell, tissue, an organ or an individual/patient to fulfil its function efficiently.
  • treat refers to lessening, reducing or improving at least one symptom associated with an existing disease or condition and/or to slow down, reduce or block the progression of the disease or condition and/or to delay or prevent the onset of symptoms (such as further symptoms) of the disease or condition.
  • prevention refers to preventing the onset of symptoms of a disease or condition, and as such encompasses prophylactic treatment.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention may result in a lowered incidence of disease or symptoms, delayed onset of disease or symptoms, and/or reduced severity of disease or symptoms, compared to other therapies that are known in the art.
  • the medical uses and methods of treatment described herein may be used in combination with additional treatments and/or medicaments.
  • the medical uses and methods of treatment described herein may be combined with known chemotherapeutic, immunomodulatory and/or radiotherapy treatments in the form of a combination therapy or treatment.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention may be used for the purpose of diagnostics, i.e. to diagnose HER2 cancers and/or test for HER2 expression in tissue samples such as a tissue biopsy.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention may be used in any diagnostic assay, including (but not limited to) diagnostic assays involving ELISA, flow cytometry, immunohistochemistry and histology.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be used to provide a prognosis on disease progression. In some embodiments, the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be used to determine suitability for further anti-cancer therapy.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be used in a method of diagnosis on a biopsy.
  • the biopsy may be a breast biopsy.
  • the biopsy may be a uterine and/or an endometrial biopsy.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention may have inhibitory activity against in vitro proliferation of tumour cells.
  • the inhibitory activity may be that: compared with in a culture medium of tumour cells to which a negative control or a control drug is added, the proliferation capacity of the tumour cells is reduced by no less than 1%, no less than 2%, no less than 4%, no less than 5%, no less than 8%, no less than 10%, no less than 15%, no less than 18%, no less than 20%, no less than 25%, no less than 40%, no less than 50%, no less than 60%, no less than 70%, no less than 80%, no less than 90%or no less than 95%in a culture medium to which the antibody-drug conjugate or pharmaceutically acceptable salt thereof is added.
  • the inhibitory activity may be an IC 50 value (nM) for tumour cells of no more than 10000, no more than 5000, no more than 4000, no more than 3000, no more than 2000, no more than 1000, no more than 500, no more than 400, no more than 300, no more than 200, no more than 150, no more than 120, no more than 110, no more than 100, no more than 99, no more than 98, no more than 97, no more than 95, no more than 90, no more than 80, no more than 75, no more than 70, no more than 65, no more than 62, no more than 60, no more than 50, no more than 40, no more than 30, no more than 25, no more than 23, no more than 22, no more than 20, no more than 19, no more than 18, no more than 18.5, no more than 17, no more than 15, no more than 12, no more than 10, no more than 9, no more than 8.5, no more than 7, no more than 6.7, no more than 6, no more than 5.9, no more than 5.5, no more than 5.0,
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention may have targeting inhibition.
  • the targeting inhibition may be that: compared with in a culture medium of tumour cells with high expression of a specific target point to which a negative control or a control drug is added, the proliferation capacity of the tumour cells with high expression of a specific target point is reduced by no less than 1%, no less than 2%, no less than 4%, no less than 5%, no less than 8%, no less than 10%, no less than 15%, no less than 18%, no less than 20%, no less than 25%, no less than 40%, no less than 50%, no less than 60%, no less than 70%, no less than 80%, no less than 90%or no less than 95%in a culture medium to which the compound disclosed herein is added.
  • the targeting inhibition may be an IC50 value (nM) , for tumour cells with high expression of a specific target point, of no more than 10000, no more than 5000, no more than 4000, no more than 3000, no more than 2000, no more than 1000, no more than 500, no more than 400, no more than 300, no more than 200, no more than 185, no more than 150, no more than 120, no more than 110, no more than 100, no more than 99, no more than 98, no more than 97, no more than 95, no more than 91, no more than 80, no more than 74, no more than 70, no more than 65, no more than 62, no more than 60, no more than 50, no more than 40, no more than 30, no more than 25, no more than 23, no more than 22, no more than 20, no more than 19, no more than 18, no more than 18.5, no more than 17, no more than 15, no more than 12, no more than 10, no more than 9, no more than 8.5, no more than 7, no more than 6.7, no more than IC
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention may have plasma stability.
  • the plasma stability may be that: the antibody-drug conjugate or pharmaceutically acceptable salt thereof releases no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 7%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1.9%, no more than 1.8%, no more than 1.7%, no more than 1.6%, no more than 1.5%, no more than 1.4%, no more than 1.3%, no more than 1.2%, no more than 1.1%, no more than 1.0%, no more than 0.9%, no more than 0.8%, no more than 0.7%, no more than 0.6%, no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%or no more than 0.1%of the cytotoxic drug 1 day, 3 days, 5 days, 7 days, 14 days, 20 days or 30 days after the compound is added to plasma.
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention may have in vivo tumour-inhibiting effect.
  • the tumour-inhibiting effect may be that: compared with the case where a negative control or a control drug is administered to a subject, the tumour of the subject is reduced in volume by no less than 1%, no less than 2%, no less than 4%, no less than 5%, no less than 8%, no less than 10%, no less than 15%, no less than 18%, no less than 20%, no less than 25%, no less than 40%, no less than 50%, no less than 55%, no less than 60%, no less than 70%, no less than 73%, no less than 75%, no less than 80%, no less than 90%or no less than 95%1 day, 3 days, 5 days, 7 days, 14 days, 20 days, 21 days or 30 days after the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered, or the tumour of the subject is reduced in volume by no less than 1.1 fold, no less than 1.3 fold, no less than 1.5
  • the antibody-drug conjugate or pharmaceutically acceptable salt thereof according to the invention may have good in vivo safety.
  • the in vivo safety may be that: after the antibody-drug conjugate or pharmaceutically acceptable salt thereof is administered to a subject, the release rate of in vivo free toxin in the subject is no more than 50%, no more than 40%, no more than 30%, no more than 20%, no more than 10%, no more than 7%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1.9%, no more than 1.8%, no more than 1.7%, no more than 1.6%, no more than 1.5%, no more than 1.4%, no more than 1.3%, no more than 1.2%, no more than 1.1%, no more than 1.0%, no more than 0.9%, no more than 0.8%, no more than 0.7%, no more than 0.6%, no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%or no more than 0.1%.
  • the in vivo safety may be that: the antibody-drug conjugate or pharmaceutically acceptable salt thereof may be administered at a concentration of no less than 0.5 mg/kg, no less than 1 mg/kg, no less than 2 mg/kg, no less than 3 mg/kg, no less than 4 mg/kg, no less than 5 mg/kg, no less than 10 mg/kg, no less than 20 mg/kg, no less than 30 mg/kg, no less than 50 mg/kg, no less than 70 mg/kg, no less than 100 mg/kg, no less than 200 mg/kg, no less than 500 mg/kg or no less than 1000 mg/kg without causing toxic manifestation in the subject.
  • the subject of the medical uses and methods of treatment according to the present invention may be a mammal.
  • the subject may be a human.
  • the subject may alternatively be a non-human mammal, including for example, a primate, a monkey, a dog, a cat, a horse, a cow, a sheep, a pig, a rabbit, a rat, or a mouse.
  • the subject may be a patient, such as a human patient.
  • the subject may suffer from and/or have been diagnosed with one or more cancer (s) .
  • polypeptide is used in the conventional sense to mean a series of amino acids, typically L-amino acids, connected one to the other, typically by peptide bonds between the ⁇ -amino and carboxyl groups of adjacent amino acids.
  • polypeptide is used interchangeably with the terms “amino acid sequence” , “peptide” and/or “protein” .
  • amino acid sequence typically L-amino acids
  • protein typically amino acid sequence
  • residues is used to refer to amino acids in an amino acid sequence.
  • variant refers to a polypeptide that has an equivalent function to the amino acid sequences described herein, but which includes one or more amino acid substitutions, insertions or deletions.
  • sequence may have one or more deletions, insertions or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent molecule. These sequences are encompassed by the present invention. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues as long as the activity is retained.
  • 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 having similar hydrophilicity values include leucine, isoleucine, valine, glycine, alanine, asparagine, glutamine, serine, threonine, phenylalanine, and tyrosine.
  • variant is synonymous with “mutant” and refers to a polynucleotide or amino acid sequence which differs in comparison to the corresponding wild-type sequence.
  • wild-type is used to mean a gene or protein having a polynucleotide or amino acid sequence respectively, which is identical with the native gene or protein respectively.
  • the nucleic acid sequence may be an RNA or DNA sequence or a variant thereof.
  • polynucleotide includes an RNA or DNA sequence. It may be single or double stranded. It may, for example, be genomic, recombinant, mRNA or cDNA.
  • identity and “%sequence identity” as used herein, may refer to the proportion of nucleotides or amino acids (expressed in percent) of a contiguous nucleotide sequence or contiguous amino acid sequence respectively which across the sequence, are identical to a reference sequence.
  • Identity comparisons can be conducted by eye, or more usually, with the aid of readily available sequence comparison programs. These commercially available computer programs can calculate %identity between two or more sequences.
  • a suitable computer program for carrying out such an alignment is the GCG Wisconsin Bestfit package (University of Wisconsin, U.S.A.; Devereux et al., 1984, Nucleotide sequences Research 12: 387) .
  • Examples of other software than can perform sequence comparisons include, but are not limited to, the BLAST package (see Ausubel et al., 1999 ibid –Chapter 18) , FASTA (Atschul et al., 1990, J. Mol. Biol., 403-410) and the GENEWORKS suite of comparison tools.
  • BLAST and FASTA are available for offline and online searching. For example, the percentage identity between two polypeptide sequences may be readily determined by BLAST which is freely available at http: //blast. ncbi. nlm. nih. gov
  • the software typically does this as part of the sequence comparison and generates a numerical result.
  • the drug to antibody ratio (DAR) distribution is detected by reducing ADC molecules to separated heavy chain and light chain, then further separating and quantifying each LC and HC species of different linker payload numbers with reversed phase high performance liquid chromatography (RP-HPLC) .
  • RP-HPLC reversed phase high performance liquid chromatography
  • the Compound 1 demonstrated a manageable safety profile and promising antitumour activity, with high disease control in subjects with advanced/metastatic endometrial cancer.
  • the Phase 1/2a, multicenter, open-label, first in human study is ongoing to assess the safety, tolerability, pharmacokinetics, and preliminary antitumour activity of the Compound 1 in subjects with advanced/metastatic solid tumours.
  • the study consists of two parts: Part 1 (Phase 1, dose-escalation) adopts an accelerated titration at first dose followed by classic “3+3” design to identify the MTD/RP2D with seven doses ranging from 2.2 to 12 mg/kg; Part 2 (Phase 2a, dose-expansion) is initiated to assess safety/tolerability and efficacy in subjects with selected HER2-expressing or HER2-mutant malignant solid tumours.
  • 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 intolerable to standard treatment, or for which no standard treatment is available.
  • Compound 1, formulated as Formulation 1 is administered intravenously once every 3 weeks until disease progression, withdrawal of consent, or unacceptable toxicity.
  • AEs are coded using MedDRA and graded according to the NCI-CTCAE version 5.0. Tumour responses are assessed according to the RECIST version 1.1.
  • TEAEs leading to drug discontinuation (2 subjects [1.5%] , 1 drug-related per investigator assessment)
  • TEAEs leading to death (1 [0.8%] , 7 mg/kg group, pneumonia, not drug-related per investigator assessment)
  • interstitial lung disease ILD, 6 [4.5%] , 4 G1 and 2 G2; 5 drug-related and 1 not drug-related per investigator assessment
  • the 6 to 8 mg/kg once every 3 weeks (Q3W) doses, especially 8 mg/kg for the Compound 1 were determined based on the totality of evidence generated from efficacy and safety summary. It is supported by clinical data (data cutoff on May 29, 2023) collected from 217 subjects in the ongoing Compound 1clinical study which comprised data from the Phase 1 (dose-escalation, 2.2 to 10 mg/kg Q3W in solid tumour) , as well as data from Phase 2a (dose-expansion, 8 mg/kg Q3W in subjects with endometrial cancer, HER-low breast cancer, and HER2-positive breast cancer.
  • Phase 1 dose-escalation, 2.2 to 10 mg/kg Q3W in solid tumour
  • Phase 2a dose-expansion, 8 mg/kg Q3W in subjects with endometrial cancer, HER-low breast cancer, and HER2-positive breast cancer.
  • the Phase 1/2a, multicenter, open-label, first in human study is ongoing to assess the safety, tolerability, pharmacokinetics, and preliminary antitumour activity of the Compound 1 in subjects with advanced/metastatic solid tumours.
  • the study consists of two parts: Part 1 (Phase 1, dose-escalation) adopts an accelerated titration at first dose followed by classic “3+3” design to identify the MTD/RP2D with seven doses ranging from 2.2 to 12 mg/kg; Part 2 (Phase 2a, dose-expansion) is initiated to assess safety/tolerability and efficacy in subjects with selected HER2-expressing or HER2-mutant malignant solid tumours.
  • Exposure-response (E-R) analysis indicated a positive relationship between best overall response (BOR) and Cycle 1 Compound 1 exposure levels in HER2-low breast cancer patients (not shown) . Therefore, doses ⁇ 7 mg/kg were considered to maximize efficacy of Compound 1 treatment based on increased exposure levels. Furthermore, the clinically observed DoR was longer in patients who received 8 mg/kg Q3W Compound 1 compared to those who received 7 mg/kg Q3W Compound 1; suggesting that ⁇ 8 mg/kg Q3W is the more favorable dosing regimen.
  • the totality of evidence generated based on efficacy and safety data supports 6 to 8 mg/kg Q3W being optimal dose regimens for Compound 1.
  • the doses of 6 to 8 mg/kg Q3W were well tolerated.
  • the dose of 8 mg/kg Q3W has demonstrated a more favourable efficacy profiles in subjects with endometrial cancer and HER2-low breast cancer over lower dose levels tested in the Compound 1clinical study and thus, provides the optimal treatment outcome in these populations.
  • EXAMPLE 5 A Phase III, randomized, multi-center, open-label trial of Compound 1 versus investigator’s choice chemotherapy in previously treated patients with HER2-expressing recurrent or metastatic endometrial cancer
  • HER2 which has received widespread attention in the medical field in recent years, is a member of cell-surface transmembrane receptors with tyrosine kinase activities.
  • the HER2 gene is known to be overexpressed in more than 30%of all human cancers, including breast cancer, gastric, colon, salivary gland, bladder, and uterine serous carcinoma (Grabsch et al. 2010; Buza et al. 2013; Cocco et al. 2019) , and its overexpression in tumours is associated with poor prognoses.
  • the clinical application of HER2-targeted therapy has improved the outcome of patients with HER2 amplified/overexpressing cancers (Oh et al. 2020) .
  • HER2-positive tumours respond well to current therapies. Resistance towards HER2-targeting therapies is common, occurring as either intrinsic or acquired resistance (Ogitani et al. 2016) . For HER2-positive cancers beyond breast cancer and gastric cancer including heavily treated patients, there is no HER2-targeting drug approved and still lacks effective treatment.
  • the primary objective of this trial is to assess the efficacy of Compound 1 compared with investigator’s choice chemotherapy in terms of progression-free survival (PFS) by Blinded Independent Central Review (BICR) in the endometrial cancer population.
  • PFS progression-free survival
  • BICR Blinded Independent Central Review
  • Randomization will be stratified by human epidermal growth factor receptor 2 (HER2) expression (IHC score 1+ vs 2+ vs 3+) and number of prior lines of therapy (1 vs 2+) .
  • HER2 human epidermal growth factor receptor 2
  • the trial consists of a screening period, a treatment period, a safety follow-up period, and a long-term survival follow-up.
  • the screening period is up to 28 days.
  • EOT post-end of treatment
  • safety follow-up visit scheduled at 35 days +7 days after their last dose of trial treatment
  • EOT assessments can function as safety follow-up.
  • Patients who have discontinued treatment for reasons other than PD will also be followed up with tumour assessments until radiological progression (or death) . All patients randomized should be followed up for survival unless trial consent was withdrawn. Long-term/survival follow-up visits will be performed 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.
  • Compound 1 will be formulated as Formulation 1 and administered at a dose of 6 or 8mg/kg intravenously every 21 days (i.e., Q3W) until PD, unacceptable adverse event, or withdrawal of patient’s consent.
  • Doxorubicin will be administered at a dose of 60 mg/m 2 as an intravenous bolus Q3W until PD, unacceptable adverse event, or withdrawal of patient’s consent.
  • Paclitaxel will be administered at a dose of 80 mg/m 2 as an intravenous infusion on Days 1, 8, and 15 in 28-day cycles until PD, unacceptable adverse event, or withdrawal of patient’s consent.
  • EXAMPLE 6 A Phase III, Randomized, Multi-center, Open-label Study of Compound 1 Versus Investigator’s Choice Chemotherapy in Human Epidermal Growth Factor Receptor 2 (HER2) -low, Hormone Receptor Positive (HR+) Metastatic Breast Cancer Patients whose Disease has progressed on Endocrine Therapy (ET)
  • HER2 Human Epidermal Growth Factor Receptor 2
  • HR+ Hormone Receptor Positive
  • HER2-negative Within breast cancers traditionally classified as HER2-negative, there exists a spectrum of HER2 expression. In addition to tumours with no detectable HER2 staining (classified by an IHC score of 0 in clinical guidelines) , the category encompasses IHC 2+/ISH negative and IHC 1+ cancers (defined in this study collectively as HER2-low) .
  • ET is considered the preferred option for HR+, HER2-negative breast cancer.
  • the optimal treatment sequence is considered to be the use of ET + CDK4/6 inhibitors first line, followed by subsequent ET with targeted therapies (e.g., mTOR or PI3-K inhibitors [for PI3-K mutant tumours] ) (Cardoso et al 2020) .
  • therapies e.g., mTOR or PI3-K inhibitors [for PI3-K mutant tumours]
  • chemotherapy may be appropriate (Cardoso et al 2018) .
  • Enrolling subjects for this trial of Compound 1 based on HER2-low tumour status is expected to maximize the likelihood of clinical benefit from the study treatment based on the mode of action of HER2 targeted therapies and clinical experience to date using targeted therapies in the breast oncology setting.
  • the study is an open-label, multi-center, randomized study in HER2-low, HR+ breast cancer patients with disease progression on at least 2 lines of prior ET or within 6 months of first line ET + CDK4/6 inhibitor in the metastatic setting.
  • the primary purpose of the study is to determine the efficacy and safety of Compound 1 compared with investigator’s choice single agent chemotherapy in the target population. Approximately 466 subjects will be randomized 1: 1 across approximately 180 centers globally to receive either 6 or 8 mg/kg Compound 1 Q3W or investigator’s choice single agent chemotherapy (paclitaxel, nab-paclitaxel or capecitabine) until RECIST 1.1 defined progressive disease (PD) , unless there is unacceptable toxicity, withdrawal of consent, or another criterion for discontinuation is met.
  • the study will compare PFS, OS and other measures of efficacy between the study treatment groups and further characterize the safety and tolerability profile of Compound 1. The randomization will be stratified as follows:
  • CDK4/6 inhibitors are being increasingly utilized as part of standard of care for patients with HR+ breast cancer. To ensure that majority of subjects have received prior CDK4/6 inhibitor therapy in the HER2-low population, no more than 228 subjects (49%of 466 subjects) who have not received prior therapy with CDK 4/6 inhibitors (e.g., palbociclib, abemaciclib, or ribociclib) will be randomized.
  • CDK 4/6 inhibitors e.g., palbociclib, abemaciclib, or ribociclib
  • Paclitaxel will be administered at a standard of care dose of 80 mg/m 2 every week.
  • Nab-paclitaxel Subjects will receive 100 mg/m 2 nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle.
  • Capecitabine Subjects will have the option to receive either the 1250 mg/m 2 capecitabine dose as indicated in the label or the 1000 mg/m 2 capecitabine dose.
  • This Example summarizes the results of a lyophilized formulation confirmation study and reconstitution stability study of Compound 1.
  • the purpose of the Compound 1 lyophilized formulation confirmation study was to confirm the stability of Compound 1 in the selected formulation.
  • the purpose of Compound 1 reconstitution stability study was to investigate the stability of reconstituted Compound 1 formulation in liquid state.
  • Compound 1 was formulated with 20.0 mg/mL Compound 1, 25 mM histidine, 9% (w/v) sucrose, 0.03% (w/v) polysorbate 80, pH 5.5.
  • Sample preparation Drug substance solution was aseptically filtered, filled into glass vials, semi-stoppered and freeze-dried in a lyophilizer. All procedures were carried out in a bio-safety hood.
  • X Appearance (before and after reconstitution) , pH, protein concentration, SEC HPLC,
  • Sample pH was measured by a pH meter with a glass electrode.
  • the pH meter was calibrated by standard solutions of pH 4.01, 7.00 and 9.21. Each sample was determined twice (100 ⁇ L sample each) and the average value was adopted in the report.
  • Protein concentration was determined by the absorbance of 280 nm and 370 nm using SoloVPE spectrophotometer.
  • the extinction coefficient of Compound 1 mAb protein is 1.52 (mg/mL) -1 ⁇ cm -1 .
  • WLC White lyophilized cake
  • CL Colourless
  • SO Slight Opalescence
  • FP Free of visible particles
  • SEC-HPLC The sample was diluted to 10.0 mg/mL with mobile phase, and 100 ⁇ g of sample was then injected into a TSKgel G3000SWXL column (7.8 ⁇ 300 mm, 5 ⁇ m Steel /TOSOH) .
  • the analysis was performed on the Agilent 1260 HPLC system with a MWD detector (detection wavelength: 280 nm and 370 nm) .
  • CIEF Compound 1 samples were mixed with master mixture to generate loading mixture, which contains 2.0 ⁇ L Pharmalyte 8-10.5, 2.0 ⁇ L Pharmalyte 3-10, 35 ⁇ L 1%MC, 0.5 ⁇ L pI marker 7.05, 0.5 ⁇ L pI marker 9.46, 37.5 ⁇ L 8M Urea solution, 0.15 ⁇ L Glacial Acetic Acid, 2.35 ⁇ L ultrapure water at a final protein concentration of 0.4 mg/mL. Place loading mixture in a 2 ⁇ 8 °C refrigerator or a 5°C heat block for more than 48 h. The test need to be completed within 96 h after the samples being mixed with the master mix, otherwise the samples should be re-prepared.
  • the loading mixture was loaded into a FC-Coated capillary, and analyzed with iCE3 Capillary Isoelectric Focusing Analyzer equipped with whole-column detection camera. After the analysis, the raw data were processed with Empower 3.
  • the CIEF results are shown in Table 10. The CIEF results indicated that no substantial change was observed in the stability study.
  • HACH Particulate matter A HACH Particulate Analyzer was utilized to measure the sub-visible particle size and counts under a laminar flow cabinet. To avoid introducing air bubbles and interference during examination, all samples were held in the cabinet for at least 0.5 hour before testing. Each sample was tested for four consecutive runs, 0.45 mL each. The results were presented as average number of particles of ⁇ 10 ⁇ m and ⁇ 25 ⁇ m per mL (method conforms to USP ⁇ 788> Particulate matter in injections) .
  • Sub-visible particles data measured by HIAC in lyophilized formulation confirmation study are summarized in Table 11. Compared to T0, no substantial change of sub-visible particles was observed after storage at 2 ⁇ 8 °C/25 °C/40 °C.
  • X Appearance (visible particle) , pH, protein concentration, SEC-HPLC, cIEF, DAR, HIAC
  • T0 data of lyophilized formulation confirmation study was used as T0 in this study.
  • Sample preparation the Drug Product from 5°C was taken out and reconstituted with ultrapure water, the reconstituted Drug Product placed under corresponding conditions listed in Table 19 to investigate their stability.
  • SEC-HPLC The SEC-HPLC results are shown in Table 14. For the reconstituted Compound 1 DP, after 6 hours of storage at room temperature or 24 hours of storage at 2-8°C, no substantial change of SEC-HPLC was observed compared with T0.
  • cIEF The cIEF results are shown in Table 15. For the reconstituted Compound 1 DP, after 6 hours of storage at room temperature or 24 hours of storage at 2-8°C, no substantial change of cIEF was observed compared to T0.
  • HIAC The results are shown in Table 16. For the reconstituted Compound 1 Drug Product, after 6 hours of storage at room temperature or 24 hours of storage at 2-8°C, no substantial increase of sub-visible particles was observed compared with T0.
  • DAR Drug-Antibody Ratio

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Abstract

La présente invention concerne un conjugué anticorps-médicament qui comprend l'anticorps trastuzumab destiné à être utilisé dans une méthode de traitement du cancer de l'endomètre. La présente invention concerne également le conjugué anticorps-médicament destiné à être utilisé dans une méthode de traitement du cancer, la méthode comprenant l'administration du conjugué anticorps-médicament ou d'un sel pharmaceutiquement acceptable de celui-ci à un patient à une dose dans la plage de 2,2 mg/kg à 12,0 mg/kg. La présente invention concerne également des compositions comprenant le conjugué anticorps-médicament.
PCT/CN2023/119242 2023-09-15 2023-09-15 Conjugué anticorps-médicament WO2025054996A1 (fr)

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Citations (8)

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Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US20160333112A1 (en) * 2014-01-31 2016-11-17 Daiichi Sankyo Company, Limited Anti-her2 antibody-drug conjugate
WO2019219891A1 (fr) * 2018-05-18 2019-11-21 Daiichi Sankyo Co., Ltd. Conjugué anticorps-médicament anti-muc1
EP3828206A1 (fr) * 2018-07-25 2021-06-02 Daiichi Sankyo Company, Limited Procédé efficace de fabrication d'un conjugué anticorps-médicament
WO2021260578A1 (fr) * 2020-06-24 2021-12-30 Astrazeneca Uk Limited Combinaison d'un conjugué anticorps-médicament et d'un inhibiteur de cdk9
WO2022011075A1 (fr) * 2020-07-10 2022-01-13 VelosBio Inc. Nouveaux immunoconjugués d'anticorps ror1
WO2022068878A1 (fr) 2020-09-30 2022-04-07 映恩生物制药（苏州）有限公司 Composé antitumoral, son procédé de préparation et son utilisation
WO2023061472A1 (fr) * 2021-10-14 2023-04-20 江苏恒瑞医药股份有限公司 Utilisation d'un conjugué médicament-anticorps anti-her2 en combinaison avec un inhibiteur de tyrosine kinase dans la préparation d'un médicament pour le traitement de tumeurs

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US20160333112A1 (en) * 2014-01-31 2016-11-17 Daiichi Sankyo Company, Limited Anti-her2 antibody-drug conjugate
WO2019219891A1 (fr) * 2018-05-18 2019-11-21 Daiichi Sankyo Co., Ltd. Conjugué anticorps-médicament anti-muc1
EP3828206A1 (fr) * 2018-07-25 2021-06-02 Daiichi Sankyo Company, Limited Procédé efficace de fabrication d'un conjugué anticorps-médicament
WO2021260578A1 (fr) * 2020-06-24 2021-12-30 Astrazeneca Uk Limited Combinaison d'un conjugué anticorps-médicament et d'un inhibiteur de cdk9
WO2022011075A1 (fr) * 2020-07-10 2022-01-13 VelosBio Inc. Nouveaux immunoconjugués d'anticorps ror1
WO2022068878A1 (fr) 2020-09-30 2022-04-07 映恩生物制药（苏州）有限公司 Composé antitumoral, son procédé de préparation et son utilisation
WO2023061472A1 (fr) * 2021-10-14 2023-04-20 江苏恒瑞医药股份有限公司 Utilisation d'un conjugué médicament-anticorps anti-her2 en combinaison avec un inhibiteur de tyrosine kinase dans la préparation d'un médicament pour le traitement de tumeurs

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KOHLER ET AL., NATURE, vol. 256, 1975, pages 495
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MARKS ET AL., J. MOL. BIOL., vol. 222, 1991, pages 581 - 597
SAITO AYUMI ET AL: "Human epidermal growth factor receptor 2 targeted therapy in endometrial cancer: Clinical and pathological perspectives", WORLD JOURNAL OF CLINICAL ONCOLOGY, vol. 12, no. 10, 24 October 2021 (2021-10-24), US, pages 868 - 881, XP093129160, ISSN: 2218-4333, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8546653/pdf/WJCO-12-868.pdf> DOI: 10.5306/wjco.v12.i10.868 *

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