WO2025149014A1 - Composition pharmaceutique - Google Patents

Composition pharmaceutique

Info

Publication number
WO2025149014A1
WO2025149014A1 PCT/CN2025/071669 CN2025071669W WO2025149014A1 WO 2025149014 A1 WO2025149014 A1 WO 2025149014A1 CN 2025071669 W CN2025071669 W CN 2025071669W WO 2025149014 A1 WO2025149014 A1 WO 2025149014A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
cancer
composition according
adc
conveniently
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/CN2025/071669
Other languages
English (en)
Inventor
Xuesong Li
Gang Qin
Paul H. SONG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Genequantum Healthcare Suzhou Co Ltd
Original Assignee
Genequantum Healthcare Suzhou Co Ltd
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 Genequantum Healthcare Suzhou Co Ltd filed Critical Genequantum Healthcare Suzhou Co Ltd
Publication of WO2025149014A1 publication Critical patent/WO2025149014A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • A61K47/68037—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a camptothecin [CPT] or derivatives
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel Antibody Drug Conjugate (ADC) formulations.
  • the invention relates to pharmaceutical compositions of a particular ADC, to methods of manufacturing the compositions, to kits including the compositions, to containers including the compositions, and to the use of said pharmaceutical compositions as a medicament and for the treatment of diseases, such as cancer.
  • the present application is directed to particular pharmaceutical compositions comprising an antibody drug conjugate targeting trophoblast cell surface antigen 2 (TROP2) .
  • TROP2 trophoblast cell surface antigen 2
  • TROP2 is a cell surface glycoprotein and is highly expressed in a variety of tumours including breast, lung, pancreatic, ovarian, and prostate cancer.
  • the transmembrane protein plays a role in tumour cell proliferation and is a validated oncology target.
  • TROP2 targeting antibody drug conjugates are known and have shown clinical activity in patients with TROP2-expressing tumours.
  • DS-1062 is an ADC originally developed by Daiichi Sankyo using its DXd technology. (sacituzumab govitecan-hziy) was the first FDA-approved anti-TROP2 ADC and is indicated for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who have received two or more prior systemic therapies, at least one of them for metastatic disease. is also approved in the U.S.
  • UC locally advanced or metastatic urothelial cancer
  • PD-1 programmed death receptor-1
  • PD-L1 programmed death-ligand 1
  • A is the anti-TROP2 antibody and each light chain of the antibody is connected by an amide bond at the C-terminus of the light chain to a linker connected to two cytotoxic payload molecules.
  • the ADC therefore consists of an antibody targeting TROP2 (GQhRS7) , wherein a first light chain of the antibody is conjugated via a linker to two cytotoxic payload molecules and a second light chain of the antibody is also conjugated via a separate but identical linker to a further two cytotoxic payload molecules.
  • the pharmaceutical composition according to the first aspect further comprises a surfactant.
  • Suitable surfactants include PEG-35 castor oil ( EL, EL) , PEG-40 hydrogenated castor oil ( RH40, RH40) , D-alpha-tocopheryl PEG-1000 succinate (Vitamin E TPGS) , caprylocaproyl PEG-8 glycerides PEG-32 glyceryl laureate ( 44/14) , poloxamers, and polysorbates.
  • the surfactant is a polysorbate.
  • the surfactant is PEG-60 sorbitan monostearate (polysorbate 60; 60) , PEG-80 sorbitan monooleate (polysorbate 80; 80; PS 80) , or PEG-20 sorbitan monolaurate (polysorbate 20; 20) .
  • the surfactant is polysorbate 80 or polysorbate 20. In terms of minimising insoluble particle formation in the compositions, polysorbate 80 was found to perform slightly better than polysorbate 20. Therefore, in a more convenient embodiment, the surfactant is polysorbate 80.
  • Antioxidants may include ethylenediamine tetraacetic acid (EDTA) , diethylenetriamine pentaacetate (DTPA) , methionine, sodium bisulfite, sodium metabisulfite, monothioglycerol, ascorbic acid, sodium ascorbate, and mixtures thereof.
  • EDTA ethylenediamine tetraacetic acid
  • DTPA diethylenetriamine pentaacetate
  • methionine sodium bisulfite, sodium metabisulfite, monothioglycerol, ascorbic acid, sodium ascorbate, and mixtures thereof.
  • the pharmaceutical composition according to the first aspect comprises the ADC and a buffer, wherein the pharmaceutical composition is a liquid and has a pH of about 5.4 to 6.5; wherein the buffer is a histidine buffer and the composition further comprises polysorbate 20 or polysorbate 80 as a surfactant, and sucrose or trehalose as a stabiliser.
  • the pharmaceutical composition according to the first aspect comprises the ADC, a pH 5.4 to 6.5 histidine buffer, 0.01 to 0.2 %w/v of polysorbate 20 or polysorbate 80, and 0.5 to 10 %w/v of sucrose or trehalose.
  • the pharmaceutical composition according to the first aspect comprises the ADC at a concentration of 5 to 100 mg/mL, a pH 5.4 to 6.5 histidine buffer, 0.01 to 0.2 %w/v of polysorbate 20 or polysorbate 80, and 0.5 to 10 %w/v of sucrose or trehalose.
  • the pharmaceutical composition according to the first aspect comprises the ADC at a concentration of 5 to 50 mg/mL, a pH 6.0 to 6.2 histidine buffer at a concentration of 5 to 50 mM, 0.02 to 0.05 %w/v of polysorbate 20 or polysorbate 80, and 3 to 8 %w/v of sucrose or trehalose.
  • the pharmaceutical composition according to the first aspect comprises the ADC at a concentration of 15 to 25 mg/mL, a pH 6.0 to 6.2 histidine buffer at a concentration of 10 to 30 mM, 0.02 to 0.05 %w/v polysorbate 80, and 3 to 8 %w/v sucrose.
  • the ADC is physically and/or chemically stable within the pharmaceutical composition for at least four weeks when stored at 2-8°C or -20°C.
  • Chemical stability relates to low levels of impurities being formed over the storage period referred to.
  • impurities related to the ADC may be measured by suitable techniques such as SEC, non-reducing CE-SDS, HIC, or HPLC.
  • Aggregate content may be measured by SEC-HPLC.
  • the pharmaceutical composition contains less than 5%aggregates (such as less than 4%, or less than 3%aggregates) as determined by SEC-HPLC when stored at 2-8°C or -20°C for at least four weeks.
  • the content of acidic peaks in the pharmaceutical composition increases by less than 10% (such as less than 9%, less than 8%, less than 7%, or less than 6%) as determined by CEX-HPLC when stored at 25°C for at least three months.
  • the content of alkaline peaks in the pharmaceutical composition increases by less than 12% (such as less than 11%, less than 10%, less than 9%, or less than 8%) as determined by CEX-HPLC when stored at 25°C for at least three months.
  • the content of free drug in the pharmaceutical composition is less than 0.5 mg/ml (such as less than 0.4 mg/ml, or less than 0.3 mg/ml) as determined by RP-HPLC when stored at 2-8°C or -20°C for at least four weeks. In an embodiment, the content of free drug in the pharmaceutical composition is less than 0.75 mg/ml (such as less than 0.6 mg/ml, or less than 0.5 mg/ml) as determined by RP-HPLC when stored at 25°C for at least four weeks.
  • a process for manufacturing a pharmaceutical composition comprises the steps of mixing together the ADC and the buffer; and optionally any one or more additional components, optionally in any amount, concentration, or form; and optionally adjusting any one or more parameters, such as pH, in relation to the pharmaceutical composition.
  • the process comprises the steps of (i) mixing together the ADC and buffer components; (ii) adding the liquid (e.g. water) to give the desired concentration; (iii) adjusting the pH if necessary to ensure it is within the range 5.4 to 6.5; and (iv) optionally adding one or more pharmaceutically acceptable additional excipients selected from a surfactant, a stabiliser, a tonicity modifier, an antioxidant and a diluent.
  • the liquid e.g. water
  • adjusting the pH if necessary to ensure it is within the range 5.4 to 6.5
  • optionally adding one or more pharmaceutically acceptable additional excipients selected from a surfactant, a stabiliser, a tonicity modifier, an antioxidant and a diluent.
  • the process comprises the steps of (i) dissolving the buffer components in the liquid (e.g. water) to give the desired concentration; (ii) adjusting the pH of the buffer solution if necessary to ensure it is within the range 5.4 to 6.5; (iii) adding the ADC to the buffer solution; and (iv) optionally adding one or more pharmaceutically acceptable additional excipients selected from a surfactant, a stabiliser, a tonicity modifier, an antioxidant and a diluent.
  • the buffer components in the liquid e.g. water
  • the pH of the buffer solution if necessary to ensure it is within the range 5.4 to 6.5
  • adding the ADC to the buffer solution
  • optionally adding one or more pharmaceutically acceptable additional excipients selected from a surfactant, a stabiliser, a tonicity modifier, an antioxidant and a diluent.
  • the process comprises dialysis. Therefore, in an embodiment, the process comprises the steps of (i) dissolving the buffer components in the liquid (e.g. water) to give the desired concentration, and optionally adding a stabiliser to the buffer solution; (ii) adjusting the pH of the buffer solution if necessary to ensure it is within the range 5.4 to 6.5; (iii) adding a dialysis bag containing the ADC to the buffer solution; (iv) carrying out dialysis with one or more changes of the buffer solution; and (v) optionally adding to the resultant composition one or more pharmaceutically acceptable additional excipients selected from a surfactant, a tonicity modifier, an antioxidant and a diluent.
  • the buffer components e.g. water
  • a stabiliser e.g. water
  • the process comprises the steps of (i) dissolving the buffer components in the liquid (e.g. water) to give the desired concentration, and adding a stabiliser selected from sucrose and trehalose to the buffer solution; (ii) adjusting the pH of the buffer solution if necessary to ensure it is within the range 5.4 to 6.5; (iii) adding a dialysis bag containing the ADC to the buffer solution; (iv) carrying out dialysis with one or more changes of the buffer solution; and (v) adding to the resultant composition surfactant selected from polysorbate 20 and polysorbate 80, and optionally adding one or more pharmaceutically acceptable additional excipients selected from a tonicity modifier, an antioxidant and a diluent.
  • a stabiliser selected from sucrose and trehalose
  • a lyophilized formulation comprising the ADC and a buffer, wherein the formulation can be reconstituted to form the pharmaceutical composition according to the first aspect.
  • the composition may be stored as a dried, lyophilized formulation, prior to reconstitution as a liquid immediately prior to use (e.g. for intravenous infusion) .
  • the lyophilized formulation further comprises a stabilizer and/or a surfactant and optionally one or more pharmaceutically acceptable excipients, such as a tonicity modifier, an antioxidant, or a bulking agent.
  • the bulking agent may include mannitol, sorbitol, glucose, glycine, hydroxyethyl starch, polyvinyl pyrrolidone (PVP) , or a mixture thereof.
  • the lyophilized formulation is a sterile powder.
  • a process for manufacturing a lyophilized according to the third aspect comprises the step of lyophilizing or freeze-drying the pharmaceutical composition according to the first aspect.
  • a container comprising a pharmaceutical composition according to the first aspect, or a lyophilized formulation according to the third aspect, wherein the container can be a vial, single-use vial, light-protected vial, ampoule, syringe, pre-filled syringe, injection pen or intravenous infusion bag.
  • the container is a transparent, amber or brown container.
  • the container is a vial, ampoule, or syringe made from glass; conveniently the glass is borosilicate glass.
  • the container is made from plastic; conveniently the plastic is polyethylene, polypropylene, a polyolefin, polyethylene terephthalate, polyethylene vinyl acetate, or polyvinyl chloride.
  • a container comprising a pharmaceutical composition according to the first aspect, wherein the container is a vial, single-use vial, light-protected vial, ampoule, syringe, pre-filled syringe, injection pen, or intravenous infusion bag.
  • a container comprising a lyophilized formulation according to the third aspect, wherein the container is a vial, single-use vial, light-protected vial, or ampoule.
  • a pharmaceutical composition according to the first aspect or a lyophilized formulation according to the third aspect, for use as a medicament.
  • a pharmaceutical composition according to the first aspect or a lyophilized formulation according to the third aspect, for use in the treatment of cancer, or an autoimmune disease.
  • the cancer is a TROP2-associated tumour.
  • the TROP2-associated tumour includes a tumour overexpressing TROP2 (e.g. a tumour marked as ++ or +++ using immunohistochemistry) or a tumour with one or more TROP2 gene mutations.
  • the cancer is selected from fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, thyroid cancer, endometrial cancer, melanoma, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, bile duct cancer, choriocarcino
  • a pharmaceutical composition according to the first aspect, or a lyophilized formulation according to the third aspect in the manufacture of a medicament for the treatment of cancer, or an autoimmune disease.
  • a pharmaceutical composition according to the first aspect, or a lyophilized formulation according to the third aspect in the manufacture of a medicament for the treatment of cancer.
  • the cancer is a TROP2-associated tumour.
  • the TROP2-associated tumour includes a tumour overexpressing TROP2 or a tumour with one or more TROP2 gene mutations.
  • the cancer is selected from fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, thyroid cancer, endometrial cancer, melanoma, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, bile duct cancer, choriocarcino
  • a method of treating cancer, or an autoimmune disease, in a subject in need thereof comprising the steps of (i) reconstituting a lyophilized formulation according to the third aspect; and (ii) administering to the subject a therapeutically effective amount of the reconstituted formulation from step (i) .
  • the cancer is a TROP2-associated tumour.
  • the TROP2-associated tumour includes a tumour overexpressing TROP2 or a tumour with one or more TROP2 gene mutations.
  • the cancer is selected from fibrosarcoma, myosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, thyroid cancer, endometrial cancer, melanoma, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, bile duct cancer, choriocarcino
  • the route of administration for the pharmaceutical compositions according to the present invention may be parenteral, for example, by injection or infusion, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; or by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.
  • the route of administration for the pharmaceutical compositions according to the present invention is intravenous infusion.
  • the method of treatment typically comprises administering a therapeutically effective amount of a pharmaceutical composition according to the present invention, to a subject.
  • Appropriate dosages of the pharmaceutical compositions according to the present invention can vary from patient to patient. Determining the optimal dosage will generally involve balancing the level of therapeutic benefit against any risk or deleterious side effects.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other active agents, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient.
  • the dosage and route of administration will ultimately be at the discretion of the clinician, although generally the dosage will be selected to achieve concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • kits of parts comprising a pharmaceutical composition according to the first aspect, or the lyophilized formulation according to the third aspect, in a container and, optionally, a set of instructions with directions regarding the administration (e.g. by way of intravenous infusion) of the pharmaceutical composition or the lyophilized formulation.
  • a kit of parts comprising a lyophilized formulation according to the third aspect in a container, a diluent for reconstituting the lyophilized formulation and, optionally, a set of instructions with directions regarding the administration (e.g. by way of intravenous infusion) of the reconstituted formulation.
  • the diluent is an aqueous sodium chloride solution.
  • the diluent is sterile water.
  • the diluent is bacteriostatic water.
  • Sample purity was tested by cation exchange high-performance liquid chromatography (CEX-HPLC) .
  • the chromatographic column was YMC BioPro IEX SF (4.6*100 mm) cation exchange chromatography column.
  • the mobile phase composition was A: 40 Mm (N-morpholino) ethanesulfonic acid (MES) (pH 6.0)
  • B 40 Mm MES + 100 mM NaCl (pH 6.0) .
  • the test sample was diluted with ultrapure water to approximately 2 mg per 1 mL.
  • the chromatographic parameters were set as follows: column temperature was 45°C, sample chamber temperature was 8°C, flow rate was 0.8 mL/min, injection volume was 50 ⁇ L, detection wavelength was 280 nm, elution time was 40 minutes.
  • the elution gradient is shown in the table below.
  • the area normalization method was used to calculate the relative percentages of acidic components, main peaks and basic components. Purity (R CE-SDS)
  • NR-CE-SDS Purity by NR-CE-SDS was detected using a capillary electrophoresis instrument (Beckman Coulte PA800 Plus) .
  • the test sample was diluted with ultrapure water to 10 mg/ml, and to 10 ⁇ L of the diluted sample solution was added 85 ⁇ L of pH 6.2 sample buffer (citric acid-phosphate buffer) , and 5 ⁇ L of 500 mmol/L iodoacetamide (IAM) , and the sample was vortex-mixed. After homogenization, and heating at 70°C for 5 minutes, the sample was cooled to room temperature, and centrifuged at 13,000 rpm for 10 minutes before loading. The purity of the main peak was calculated as the percentage of the calibrated area of the IgG main peak to the total calibrated peak area.
  • the instrument parameters are shown in the table below: DAR Value
  • Hydrophobic interaction chromatography was used to detect the drug-antibody ratio (DAR) value.
  • the chromatographic column was Sepex Proteomix HIC Butyl NP5, 4.6 ⁇ 35 mm, particle size 5 ⁇ m.
  • the test sample was diluted with pure water to approximately 5 mg per 1 mL.
  • the chromatographic parameters were set as follows: column temperature was 35°C, sample chamber temperature was 5 ⁇ 3°C, flow rate was 0.8 mL/min, injection volume was 5 ⁇ L, detection wavelength was 280 nm, elution time was 20 minutes.
  • the sample DAR0, DAR2, and DAR4 peak area percentages were calculated through the area normalization method, and finally the DAR value of the test product was calculated.
  • the elution gradient was as follows: Free Drug (RP-HPLC)
  • Free Drug detection was performed by reversed-phase high-performance liquid chromatography (RP-HPLC) .
  • the chromatographic column was Waters Xbridge C18, 4.6 ⁇ 150 mm, particle size 3.5 ⁇ m.
  • Mobile phase A was 20 mM KH 2 PO 4 solution (pH 5.0)
  • mobile phase B was acetonitrile solution.
  • the protein was precipitated using acetone aqueous solution and the supernatant was taken for Free Drug determination.
  • the chromatographic conditions were set as follows: the flow rate was 0.8 mL/min, the injection volume was 10 ⁇ L, the column temperature was 25°C, the sample chamber temperature was 4°C, the detection wavelength was 264 nm, and the analysis time was 20 min.
  • the content in the sample was calculated by use of an external standard.
  • the elution gradient was as follows: Binding Activity (ELISA)
  • Binding activity was determined by enzyme-linked immunosorbent assay (ELISA) .
  • Antigen GR1002T
  • GR1002T Antigen
  • the reference product and test solution were added respectively, and the plate was incubated with shaking at 25°C for 1 hour.
  • horseradish peroxidase-labelled Goat anti-human IgG-Fc antibody solution was added and the enzyme plate was incubated with shaking at 25°C for 1 hour.
  • TMB was added for color development and to protect from light. After 10 minutes the reaction was stopped with stop solution, and the absorbance was measured at a wavelength of 450 nm.
  • Y (A-D) / (1+ (X/C) ⁇ B) + D) with the concentration as the abscissa and the OD 450 value as the ordinate.
  • R 2 curve fitting correlation coefficient
  • R 2 the EC 50 of the standard and sample, in order to calculate the relative binding activity of the sample.
  • Detection was carried out using an Osmomat 3000 osmotic pressure detector. Before sample detection, a calibration solution (300 mOsm/L, 500 mOsm/L) was used to calibrate the detector. Materials Abbreviations Example 1: Formation of Antibody Drug Conjugate (ADC)
  • the Antibody Drug Conjugate has the following structure: 1.1 Preparation of Payload –Scheme A Scheme A: Synthetic Route to Payload 1.1.1 Formation of N- (2-bromo-5-fluorophenyl) acetamide (Compound 2)
  • the deprotection of Compound 17 was conducted twice by adding 10 mL of 20%piperidine/DMF solution and reacting for 10 minutes for each time. After the reaction was complete, the solution was removed by vacuum suction. The resin was washed with DMF twice, methanol once, DMF once, methanol once and DMF twice in sequence, with a volume of 10 mL and a time length of 1 minute for each wash. The solvent was removed by vacuum suction. A small amount of dry resin was taken for ninhydrin detection. Both the resin and solution were dark blue.
  • the deprotection of Compound 19 was conducted twice by adding 10 mL 20%piperidine/DMF solution and reacting for 10 minutes for each time. After the reaction was complete, the solution was removed by vacuum suction. The resin was washed with DMF twice, methanol once, DMF once, methanol once and DMF twice in sequence, with a volume of 10 mL and a time length of 1 minute for each wash. The solvent was removed by vacuum suction. A small amount of dry resin was taken for ninhydrin detection. Both the resin and solution were dark blue. Then 462 mg MC-OSu was placed in a 50 mL centrifuge tube, and 10 mL DMF was added. The solid was dissolved by shaking.
  • Plasmids encoding the light and heavy chains of GQhRS7 were paired and mixed at a mass ratio of 2: 1.
  • the plasmid pair and the PEIMAX (Polyscience) transfection reagent were separately diluted in HEK293F basic medium and then mixed evenly. Transfection was performed by electroporation using Transfection system. The mixture was let stand at room temperature and added to the HEK293F seed cell culture. The cell was cultured at 32 for 24 h and sampled for cell density and viability analysis and supplemented with 10%volume of HEK293F feed medium. Then the culture temperature was shifted to 32°C for the following culture. At 72 h of incubation, the cell culture was sampled again for cell density and viability analysis. At 144 h of incubation, the cell culture was sampled for cell density and viability analysis. 1.4.3 Purification of antibody
  • GQhRS7 was purified by affinity chromatography following the manufacturer’s instruction. Briefly, the chromatography column (BestChrom, Shanghai, China) was packed with the MabSelect SureLX resin (GE Healthcare) and equilibrated with 50 mM Tris, 150 mM NaCl, pH 7.4. Then the supernatant of the cell culture was obtained and applied onto the column. The column was washed with 50 mM Tris, 150 mM NaCl, pH 7.4 to remove non-specifically bound proteins. Then the antibody was eluted by 50 mM citrate Buffer, pH 3.5 and the antibody-containing eluate was adjusted to pH 6.5 using 1 M Tris-HCl, pH 9.0. Finally, the buffer of the antibody was exchanged to 50 mM Tris, 150 mM NaCl, pH 7.4 by an Anicon Ultra-15 centrifugal Filter (Merk Millipore) . 1.5 Preparation ofADC
  • the antibody GQhRS7 was treated by ultrafiltration, dialysis or desalting column.
  • the storage solution was replaced with a ligase buffer.
  • ADC was prepared by coupling reaction of GQhRS7 with the Linker-Payload (described in Example 1.3 above) , under the catalysis of a wild type Sortase A or a mutant ligase optimized and engineered based thereon.
  • the modified antibody and linker-payload were thoroughly mixed at a molar ratio of 1: 1 to 1: 100, and added to a solid phase coupling system.
  • the solid phase coupling system comprised a ligase immobilized on the matrix of the solid phase coupling system.
  • the DAR (drug-to-antibody ratio) distribution of the ADC was analysed by HIC-HPLC.
  • the coupled product was found to mainly contain ADC with DAR of 3.4-3.5.
  • Example 2 Biological Activity of ADC 2.1 Human Trop 2 Binding Affinity
  • Human Trop 2 ECD at concentration of 0.5 ⁇ g/mL was coated on 96-well plates and incubated at 4°C overnight. The plates were then blocked with 3%BSA-PBST for 1 h at room temperature. After washing with PBST (0.05%Tween) , ADC, (comparative Trop 2 ADC) or antibody (GQhRS7) at different concentrations were added onto the 96-well plates, and then incubated at room temperature for 60 min. After incubation goat anti-human FC secondary antibody (HRP) (Sinobiological, SSA001) was added at a ratio of 1: 100000 and incubated at room temperature for 60 min. Following the wash, the plate was treated with TMB solution (Sigma, T0440) as an HRP substrate, and the reaction was stopped with 1 M H 2 SO 4 . The absorbance for each well was detected at 450 nm wavelength.
  • TMB solution Sigma, T0440
  • Figure 1 shows the Trop 2 binding affinity curves for ADC, and GQhRS7. The results demonstrate that ADC has similar Trop 2 binding affinity to GQhRS7 and 2.2 Effect on Tumour Cell Proliferation
  • Trop 2 positive cancer cells BxPC-3, FaDu, and NCI-N87 (3000 to 5000 cells) were plated in 96-well plates, and cells were able to attach overnight.
  • Cells were treated with ADC, DS1062a (comparative Trop 2 ADC –as described in US 2016/0297890A) , or antibody (GQhRS7) at various concentrations for 168 h.
  • Cell viabilities were examined by Luminescent Cell Viability Assay, and percentage of cell viability was calculated.
  • Figures 2 to 4 show the cell viability curves for ADC, DS1062a, and GQhRS7 on BxPC-3, FaDu and NCI-N87 cells respectively.
  • ADC exhibited IC 50 values of 0.226 nM, 0.128 nM, and 0.742 nM respectively
  • DS1062a exhibited IC 50 values of 0.692 nM, 0.170 nM, and 2.101 nM respectively.
  • Antibody alone (GQhRS7) did not show any significant effect on cell viability at the concentrations tested.
  • a negative control group was set: 3 mL of 45%RPMI-1640 + 45%DMEM + 10%FBS medium was added to each well. After the treatment, the cells were moved to the incubator and incubated for 96 h. After the incubation, cells were digested, and washed once with 1X PBS, then transferred to a flow tube, and centrifuged at 2000 rpm for 3 min. The supernatant was then discarded, and the cell amount and cell viability were detected. A certain amount of cells were washed with 1X PBS, the supernatant was discarded after centrifugation, 200 ⁇ L of 100 nM anti-human Trop2 antibody was added, and the cells were mixed and incubated at 4°C for 30 min.
  • T/C% T RTV /C RTV ⁇ 100 % (T RTV : RTV of the treatment group; C RTV : RTV of the vehicle control group) .
  • TGI (%) [1 - (average tumor volume at the end of administration of a treatment group -average tumor volume at the beginning of administration of the treatment group) / (average tumor volume at the end of treatment of the vehicle control group -the average tumor volume at the beginning of treatment of the vehicle control group) ] ⁇ 100%.
  • Table B1 [1 - (average tumor volume at the end of administration of a treatment group -average tumor volume at the beginning of administration of the treatment group) / (average tumor volume at the end of treatment of the vehicle control group -the average tumor volume at the beginning of treatment of the vehicle control group) ] ⁇ 100%.
  • Table B1 average
  • the MDA-MB-468 Trop-2 positive human breast cancer cells; ATCC, HTB-132 cells were maintained in vitro as a monolayer culture in L-15 medium supplemented with 10%fetal bovine serum and 1%Antibiotic-Antimycotic at 37 °C in an atmosphere of 0%CO 2 in air. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. 10x10 6 MDA-MB-468 cells in 0.2 mL of PBS with Matrigel (1: 1) were inoculated subcutaneously in the right flank in BALB/c Nude mice.
  • tumor bearing mice were assigned and administrated intravenously of ADC at 0.5 mg/kg, 1.5 mg/kg and 4.5 mg/kg, at 4.5 mg/kg, or DS1062a at 4.5 mg/kg.
  • the tumor volume was measured twice weekly with a caliper. T/C and TGI values were calculated using tumor volume as described in Example 2.4.
  • the formulations 1-12 were aseptically filled into 2R vials (1.0 ml/bottle) on a clean bench and plugged and capped.
  • Formulations 1-12 were then stored under various conditions (-20 °C, 2-8 °C, 25 °C, and 40 °C) for up to 4 weeks and analysed periodically as described in section 3.2.
  • Table C Summary of initial formulations 3.2 Analysis of ADC buffer formulations 1-12
  • Formulations 4 and 6 produced fine, visible particles after being stored at 40°C for 4 weeks, indicating that the ADC is more likely to produce particles in the citrate buffer system.
  • Formulations 1 to 6 were taken out and thawed at -20°C and left to stand for 4 hours. After visual inspection, a large number of small bubbles appeared, which did not disappear after four hours of standing.
  • Table F1 Percentage aggregate contents (SEC-HPLC) of Formulations 1-12 at different temperatures and times
  • Table F2 Percentage monomer contents (SEC-HPLC) of Formulations 1-12 at different temperatures and times
  • Table F3 Percentage fragment contents (SEC-HPLC) of Formulations 1-12 at different temperatures and times
  • Table I1 shows that at 2-8° C and -20 °C the Linker-Payload falls off relatively slowly. Under the conditions of 20 °C and 40 °C, the Linker-Payload fell off relatively quickly, but there was no significant difference in the shedding rate of the Linker-Payload among Formulations 1-12. However, the shedding rate of Linker-Payload is clearly related to the pH value of the buffer. A low pH value will accelerate the shedding of Linker-Payload, while a higher pH value can slow down the shedding of Linker-Payload.
  • Table I1 Content of Linker-Payload (mg/ml) of Formulations 1-12 at different temperatures and times
  • Table I2 The data in Table I2 show a similar trend; the free drug content of the formulations increases at higher temperatures and lower pH values.
  • Table I2 Content of Free Drug (mg/ml) of Formulations 1-12 at different temperatures and times
  • Table J shows the binding activity test results as determined by ELISA of Formulations 7 to 9 after storage under different conditions. This data shows that the binding activity of the ADC in the histidine buffer system does not significantly change after being placed for 4 weeks in the pH range of 5.4 to 6.2 at all temperatures investigated. Table J: Percentage binding activity (ELISA) test results of Formulations 7-9 at different temperatures and times 3.4 Conclusions of Initial Formulation Screening
  • Free Drug analysis shows that the shedding rate of payload is obviously related to the pH value of the buffer. A low pH value will accelerate the shedding of payload, and a higher pH value can slow down the shedding of payload.
  • the pH range of acetate buffer (pH 4.8 to 5.4) is relatively low.
  • formulations 13-24 were aseptically filled into 2R vials (1.0 ml/bottle) on a clean bench and plugged and capped. Formulations 13-24 were then stored under various conditions (-20 °C, 2-8 °C, 25 °C, and 40 °C) for up to 3 months and analysed periodically as described in section 4.2.
  • Osmotic pressure of the samples was determined using an Osmomat 3000 osmotic pressure detector. Before sample detection, a calibration solution (300 mOsm/L, 500 mOsm/L) was used. 4.3 Results of Initial Formulation Screening
  • formulation 14 performed slightly better than formulation 13. In terms of freeze-thaw cycling and shaking, formulation 14 performed slightly better than formulation 16.
  • the only difference between formulation 14 and formulation 13 is the surfactant component (surfactant in formulation 14 is 0.03%polysorbate 80; surfactant in formulation 13 is 0.03%polysorbate 20) and the only difference between formulation 14 and formulation 16 is the stabilizer component (stabilizer in formulation 14 is 6%sucrose; stabilizer in formulation 16 is 6%trehalose) .

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Abstract

La présente invention concerne des compositions pharmaceutiques comprenant un conjugué anticorps-médicament. L'invention concerne également des procédés de fabrication des compositions pharmaceutiques, des kits comprenant les compositions, des récipients comprenant les compositions, et l'utilisation desdites compositions pharmaceutiques en tant que médicament et pour le traitement de maladies, telles que le cancer.
PCT/CN2025/071669 2024-01-12 2025-01-10 Composition pharmaceutique Pending WO2025149014A1 (fr)

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WO2015165413A1 (fr) 2014-04-29 2015-11-05 秦刚 Nouveau conjugué anticorps-médicament stable, procédé pour le préparer, et son utilisation
US20160297890A1 (en) 2013-12-25 2016-10-13 Daiichi Sankyo Company, Limited Anti-trop2 antibody-drug conjugate
WO2021136475A1 (fr) * 2019-12-31 2021-07-08 Genequantum Healthcare (Suzhou) Co., Ltd. Conjugué de médicament et ses utilisations
WO2023088235A1 (fr) * 2021-11-16 2023-05-25 Genequantum Healthcare (Suzhou) Co., Ltd. Dérivés d'exatécan, lieur-charge utile et leurs conjugués
WO2023232144A1 (fr) * 2022-06-02 2023-12-07 启德医药科技（苏州）有限公司 Lieur oligosaccharidique, matériau porté par un lieur comprenant un lieur oligosaccharidique, conjugué anticorps-médicament présentant un remodelage de chaîne de sucre, son procédé de préparation et son utilisation
WO2024012569A1 (fr) * 2022-07-15 2024-01-18 Genequantum Healthcare (Suzhou) Co., Ltd. Lieurs, conjugués et leurs applications
WO2024012566A2 (fr) * 2022-07-15 2024-01-18 Genequantum Healthcare (Suzhou) Co., Ltd. Anticorps, lieurs, charge utile, conjugués et leurs applications
WO2024207177A1 (fr) * 2023-04-04 2024-10-10 Genequantum Healthcare (Suzhou) Co., Ltd. Anticorps, lieurs, charge utile, conjugués et leurs applications
WO2024213091A1 (fr) * 2023-04-13 2024-10-17 Genequantum Healthcare (Suzhou) Co., Ltd. Combinaison d'un conjugué anticorps-médicament et d'un anticorps anti-pd-1, et son utilisation

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WO2003074566A2 (fr) 2002-03-01 2003-09-12 Immunomedics, Inc. Anticorps rs7
US20160297890A1 (en) 2013-12-25 2016-10-13 Daiichi Sankyo Company, Limited Anti-trop2 antibody-drug conjugate
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