WO2023198060A1 - Association pharmaceutique d'inhibiteur de protéasome et d'anticorps anti-pd-1 - Google Patents
Association pharmaceutique d'inhibiteur de protéasome et d'anticorps anti-pd-1 Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
Definitions
- the present disclosure belongs to the field of medical technology and relates to a pharmaceutical combination of a proteasome inhibitor and an anti-PD-1 antibody. Specifically, it relates to the pharmaceutical combination of the compound of formula I' of the present disclosure, its prodrug or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or its antigen-binding fragment and its use in the prevention or treatment of solid tumors.
- the ubiquitin-proteasome pathway is an important pathway for degrading intracellular proteins. Proteins are ubiquitinated through interactions with ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin ligases. The ubiquitinated-labeled proteins are catalyzed by 26S protease. recognized and degraded by the body. The 26S proteasome is composed of two parts: the 20S core particle and the 19S regulatory particle. Tumor cells are more sensitive to protein homeostasis due to their proliferation needs. Proteasome inhibitors inhibit the ubiquitin-proteasome pathway, leading to the accumulation of polyubiquitination-labeled proteins and affecting related signaling pathways, ultimately inducing tumor cells. The purpose of apoptosis.
- WO2018157820A1 discloses compounds of formula I and other compounds
- WO2020025037A1 discloses compounds of formula II and other compounds, which are proteasome inhibitors.
- PD-1 programmed death-1, programmed death receptor 1
- PD-L1 Programmed death-ligand1
- CD274 or B7-H1 is a ligand of PD-1.
- the combination of PD-1 and PD-L1 mediates co-inhibitory signals of T cell activation, inhibits the killing function of T cells, and plays a negative regulatory role in the human immune response.
- Chinese patent document CN106977602A discloses an anti-PD-1 monoclonal antibody 14C12H1L1. This monoclonal antibody can very effectively block the combination of PD1 and PDL1 and shows good anti-tumor activity.
- the biggest challenge encountered in the process of tumor immunotherapy is poor efficacy due to tumor immune tolerance and escape.
- the combination of small molecule anti-tumor compounds and anti-PD-1/PD-L1 antibodies is used to try to break the body's already existing
- the established immune tolerance to tumor cells has important theoretical significance and application value.
- the present disclosure provides a pharmaceutical combination comprising a compound of formula I', an ester thereof or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof,
- Ring A is selected from phenyl or 5-10 membered heteroaryl
- Each R 1 is independently selected from halogen, CN, OH, NH 2 , C 1-6 alkyl or C 1-6 heteroalkyl, wherein the C 1-6 alkyl or C 1-6 heteroalkyl is either Optionally substituted with one or more groups selected from halogen, OH or NH ;
- n is selected from 0, 1, 2, 3, 4 or 5;
- R 2 and R 3 are each independently selected from H or C 1-6 alkyl.
- Ring A is selected from phenyl or 5-6 membered heteroaryl. In some embodiments, Ring A is selected from phenyl or pyridyl.
- each R 1 is independently selected from halogen, CN, OH, NH 2 , C 1-3 alkyl, or C 1-3 alkoxy. In some embodiments, each R1 is independently selected from fluorine or CN.
- n is selected from 1 or 2.
- R 2 and R 3 are each independently selected from H.
- the compound of Formula I', its ester or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of Formula I, Formula I-1, Formula I-2 or Formula I-3, its ester or a pharmaceutically acceptable salt thereof. Take it with a grain of salt
- kits comprising a pharmaceutical combination, specifically comprising 1) a compound of formula I', its ester or a pharmaceutically acceptable salt thereof; 2) an anti-PD-1 antibody or its antigen binding fragment,
- the ester of the compound of Formula I' is a prodrug form of the compound of Formula I'.
- the ester of the compound of Formula I' is the malate ester of the compound of Formula I'.
- the ratio of the number of molecules of the compound of formula I' to malic acid in the malic acid ester of the compound of formula I' is selected from 1:1.
- the malate ester of the compound of Formula I' is a prodrug form of the compound of Formula I'.
- ester structure of the compound of Formula I' or the malate ester structure of the compound of Formula I' is selected from the group consisting of compounds of Formula II, Formula II-1, Formula II-2 or Formula II-3
- the present disclosure provides a pharmaceutical combination comprising a compound of Formula I (or Formulas I-1 to I-3), an ester thereof or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof,
- kits which includes a pharmaceutical combination, specifically including 1) a compound of formula I (or formulas I-1 to I-3), an ester thereof or a pharmaceutically acceptable salt thereof; 2 ) anti-PD-1 antibody or antigen-binding fragment thereof,
- the ester of a compound of Formula I is a prodrug form of a compound of Formula I (or Formulas I-1 to I-3).
- the ester of the compound of Formula I (or Formulas I-1 to I-3) is the malate ester of the compound of Formula I (or Formulas I-1 to I-3).
- the molecular number ratio of the compound of Formula I (or Formula I-1 to I-3) and malic acid in the ester of the compound of Formula I (or Formula I-1 to I-3) is selected from 1:1 .
- the malate ester of the compound of Formula I is a prodrug form of the compound of Formula I (or Formulas I-1 to I-3).
- the ester of the compound of Formula I is a compound of Formula II
- the ester of the compound of Formula I-1 is a compound of Formula II-1
- the ester of the compound of Formula I-2 is a compound of Formula II-2
- the ester of the compound of Formula I-3 is a compound of Formula II-3
- the present disclosure provides a pharmaceutical combination comprising a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.
- the present disclosure provides a kit comprising 1) a compound of formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof; 2) an anti-PD-1 antibody or an antigen-binding fragment thereof , and 3) Instructions for use of a compound of formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.
- the anti-PD-1 antibody or antigen-binding fragment thereof comprises light chain complementarity determining regions LCDR1, LCDR2, and LCDR3 and heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, wherein said LCDR1, LCDR2, and LCDR3 Containing the amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3 respectively, the HCDR1, HCDR2 and HCDR3 respectively include SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO: The amino acid sequence shown in 6.
- the anti-PD-1 antibody or antigen-binding fragment thereof comprises light chain complementarity determining regions LCDR1, LCDR2 and LCDR3 and heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3, said light chain complementarity determining regions LCDR1, LCDR2 and LCDR3.
- LCDR2 and LCDR3 are respectively composed of the amino acid sequences shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3.
- the heavy chain complementarity determining regions HCDR1, HCDR2 and HCDR3 are respectively composed of SEQ ID NO:4, SEQ ID NO:4.
- the anti-PD-1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that has more than 85% (including 86%, 87%, 88%, 89%, Light chain variable region and amino acid sequence 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 8
- the amino acid sequence shown has more than 85% (including 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical heavy chain variable region.
- the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain variable region with an amino acid sequence set forth in SEQ ID NO:7 and a heavy chain variable region with an amino acid sequence set forth in SEQ ID NO:8. Change area.
- the anti-PD-1 antibody or antigen-binding fragment thereof comprises an amino acid sequence that has more than 85% (including 86%, 87%, 88%, 89%, A light chain and amino acid sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical to that shown in SEQ ID NO: 10
- the amino acid sequence has more than 85% (including 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%) identical heavy chain.
- the anti-PD-1 antibody or antigen-binding fragment thereof comprises a light chain with an amino acid sequence set forth in SEQ ID NO:9 and a heavy chain with an amino acid sequence set forth in SEQ ID NO:10.
- the anti-PD-1 antibody is 14C12H1L1.
- the anti-PD-1 antibody is Nivolumab, Pembrolizumab, Toripalimab (JS-001), Sintilimab (IBI308), Camrelizumab (Camrelizumab), Tislelizumab (BGB-A317), Balstilimab (Balstilimab), Genosumab (GB226), LZM009, HLX10, AK103 (HX008 ), CS1003, SCT-I10A, F520, SG001 or cepalizumab (GLS-010).
- the pharmaceutical combination includes: a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or an antigen-binding fragment thereof.
- the pharmaceutical combination includes: a compound of Formula I (or Formulas I-1 to I-3) or its malate ester (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or an antigen-binding fragment thereof.
- the pharmaceutical combination includes: a compound of Formula I (or Formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or an antigen-binding fragment thereof.
- the pharmaceutical combination includes: a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof; and 14C12H1L1 or an antigen-binding fragment thereof.
- the pharmaceutical combination contains a compound of formula I (or formula I-1 to I-3), or its ester (for example, formula II (or II-1 to II-3) in the range of 0.5 mg to 8.5 mg. ) compound) or a pharmaceutically acceptable salt thereof.
- the pharmaceutical combination includes 0.5 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg or the compound of formula I (or formula I-1 to I-3) or its ester (for example, the compound of formula II (or II-1 to II-3) within the range formed by any of the above values ) or its pharmaceutically acceptable salt.
- the pharmaceutical combination contains a compound of formula I (or formula I-1 to I-3), its ester (for example, formula II (or II-1 to II-3) in the range of 0.8mg-8.0mg ) compound) or a pharmaceutically acceptable salt thereof.
- the pharmaceutical combination contains 0.8 mg, 1.2 mg, 1.6 mg, 2.0 mg, 2.4 mg, 2.8 mg, 3.2 mg, 3.6 mg, 4.0 mg, 4.4 mg, 4.8 mg, 5.2 mg, 5.6 mg, 6.0 mg, 6.4 mg, 6.8 mg, 7.2 mg, 7.6 mg, 8.0 mg or a compound of formula I (or formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof within the range formed by any of the above values.
- the pharmaceutical combination contains a compound of Formula I (or Formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof in an amount of 4.0 mg to 8 mg. In some embodiments, the pharmaceutical combination contains a compound of Formula I (or Formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof in an amount of 5.0 mg to 6 mg. In some embodiments, the pharmaceutical combination contains a compound of Formula I (or Formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof in an amount of 4.0 mg to 5.6 mg. In some embodiments, the pharmaceutical combination contains a compound of Formula I (or Formulas I-1 to I-3) or a pharmaceutically acceptable salt thereof in an amount of 4.0 mg, 4.8 mg or 5.6 mg.
- the pharmaceutical combination contains a compound of formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof (in the form of formula II (or II-1 to II-3) Compound weight).
- the pharmaceutical combination includes 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0
- the pharmaceutical combination contains a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof in an amount of 5.0 mg to 7.0 mg. In some embodiments, the pharmaceutical combination contains a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof in an amount of 5.0 mg, 6.0 mg or 7.0 mg. In some embodiments, the pharmaceutical combination contains a compound of formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof in an amount of 6.0 mg.
- the pharmaceutical combination contains a compound of Formula II or a pharmaceutically acceptable salt thereof in the range of 1.0 mg to 10 mg (based on the weight of the compound of Formula II).
- the pharmaceutical combination contains approximately 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.1 mg, 6.2mg, 6.3mg, 6.4mg, 6.5mg, 7.0mg, 7.1mg, 7.2mg, 7.3mg, 7.4mg, 7.5mg, 8.0mg, 8.5mg, 8.6mg, 8.7mg, 8.8mg, 8.9mg, 9.0mg , 9.5 mg, 10 mg or a range of the formula II compound or a pharmaceutically acceptable salt thereof (based on the weight of the formula II compound) within the range formed by any of the above values.
- the pharmaceutical combination includes an amount of about 5.5 mg to about 9.5 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II). In some embodiments, the pharmaceutical combination contains a compound of Formula II in an amount of approximately 6.0 mg to 9.0 mg. or a pharmaceutically acceptable salt thereof (based on the weight of the compound of formula II). In some embodiments, the pharmaceutical combination includes an amount of approximately 6.3 mg, 7.5 mg, or 8.8 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II). In some embodiments, the pharmaceutical combination includes an amount of approximately 7.5 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof (based on the weight of the compound of Formula II).
- the pharmaceutical combination contains about 10 mg to about 1000 mg of an anti-PD-1 antibody or antigen-binding fragment thereof.
- the pharmaceutical combination contains about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, approximately 1000 mg, or a range of any of the above values of an anti-PD-1 antibody or antigen-binding fragment thereof.
- the pharmaceutical combination contains approximately 50-350 mg of anti-PD-1 antibody or antigen-binding fragment thereof.
- the pharmaceutical combination contains approximately 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof.
- the pharmaceutical combination of the present disclosure contains: 4.0 mg-5.6 mg of the compound of Formula I (or Formula I-1 to I-3) or its malate ester, or its pharmaceutically acceptable salt; and 50-350 mg of anti-PD-1 antibody or antigen-binding fragment thereof.
- the pharmaceutical combination of the present disclosure includes: 5.0 mg to 7.0 mg (such as 6 mg) of a compound of formula II (or II-1 to II-3); and 50 mg to 350 mg of an anti-PD-1 antibody or its Antigen-binding fragments.
- the pharmaceutical combination of the present disclosure includes: 5.0 mg, 6.0 mg or 7.0 mg of a compound of formula II (or II-1 to II-3); and 100 mg or 200 mg of an anti-PD-1 antibody or its Antigen-binding fragments.
- the pharmaceutical combination of the present disclosure includes a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutical composition thereof.
- the weight ratio of the above acceptable salt and anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of 4 mg: 100 mg, 4.4 mg: 100 mg, 4.8 mg: 100 mg, 5.2 mg: 100 mg, 5.6 mg: 100 mg, 6.0 mg: 100 mg, 4 mg : 200mg, 4.4mg: 200mg, 4.8mg: 200mg, 5.2mg: 200mg, 5.6mg: 200mg, 6.0mg: 200mg or the range formed by any of the above values.
- the pharmaceutical combination of the present disclosure includes a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof (in the form of a compound of Formula II (or II-1 to II-3) By weight) and the anti-PD-1 antibody or antigen-binding fragment thereof (approximately) the weight ratio is selected from 5 mg: 100 mg, 5.5 mg: 100 mg, 6 mg: 100 mg, 6.1 mg: 100 mg, 6.2 mg: 100 mg, 6.3 mg: 100 mg, 6.4 mg: 100mg, 6.5mg: 100mg, 7mg: 100mg, 7.1mg: 100mg, 7.2mg: 100mg, 7.3mg: 100mg, 7.4mg: 100mg, 7.5mg: 100mg, 7.6mg: 100mg, 7.7mg: 100mg, 7.8mg : 100mg, 7.9mg: 100mg, 8.0mg: 100mg, 8.5mg: 100mg, 8.6mg:
- the drug combination is a fixed combination or a non-fixed combination.
- the pharmaceutical combination is a fixed combination.
- the fixed combination is in the form of a solid pharmaceutical composition or a liquid pharmaceutical composition.
- the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable
- the accepted salt and the anti-PD-1 antibody or antigen-binding fragment thereof are present in the same pharmaceutical composition.
- the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof (e.g., 14C12H1L1 or an antigen thereof) in the fixed combination binding fragment) present in the same pharmaceutical composition.
- an anti-PD-1 antibody or an antigen-binding fragment thereof e.g., 14C12H1L1 or an antigen thereof
- the pharmaceutical combination is a non-fixed combination.
- the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutical
- the acceptable salt and the anti-PD-1 antibody or antigen-binding fragment thereof are each in the form of a pharmaceutical composition.
- the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or its Antigen-binding fragments) are each in the form of a pharmaceutical composition.
- an anti-PD-1 antibody or antigen-binding fragment thereof e.g., 14C12H1L1 or its Antigen-binding fragments
- the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutical Acceptable salts and anti-PD-1 antibodies or antigen-binding fragments thereof (e.g., 14C12H1L1 or antigen-binding fragments thereof) are each in the form of pharmaceutical compositions, and compounds of Formula I (or Formulas I-1 to I-3), esters thereof (for example, a pharmaceutical composition of formula II (or compound II-1 to II-3) or a pharmaceutically acceptable salt thereof and a pharmaceutical combination of an anti-PD-1 antibody or an antigen-binding fragment thereof (for example, 14C12H1L1 or an antigen-binding fragment thereof) items may or may not exist in the same medicine bag.
- the present disclosure also aims to at least provide a pharmaceutical package, which contains individually packaged pharmaceutical compositions in independent containers, wherein one container contains a compound of formula I (or formulas I-1 to I-3), A pharmaceutical composition of an ester thereof (such as a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof, and comprising an anti-PD-1 antibody or an antigen-binding fragment thereof in a second container (for example, pharmaceutical compositions of 14C12H1L1 or antigen-binding fragments thereof).
- medicaments of compounds of Formula I or Formulas I-1 to I-3), esters thereof (e.g., compounds of Formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof
- the composition is selected from solid pharmaceutical compositions.
- the pharmaceutical composition of the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is selected from solid pharmaceutical compositions.
- the solid pharmaceutical composition is selected from tablets or capsules.
- the pharmaceutical composition of an anti-PD-1 antibody or antigen-binding fragment thereof is selected from the group consisting of liquid pharmaceutical compositions.
- the liquid pharmaceutical composition is selected from injectable solutions.
- the compound of Formula I (or Formula I-1 to I-3), its ester (such as the compound of Formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof can Apply once every day, apply twice daily, apply once every two days, apply once every three days, apply once every four days, apply once every five days, apply once every six days, apply once every week, apply every two weeks Apply once, once every three weeks, twice every three weeks, or three times every three weeks.
- the anti-PD-1 antibody or antigen-binding fragment thereof can be administered once every day, once every two days, once every three days, once every four days , apply once every five days, once every six days, once every week, once every two weeks, or once every three weeks.
- the drug combination is treated every 14 days (2 weeks), 21 days (3 weeks), or 28 days (4 weeks). In some embodiments, the drug combination is administered in a treatment cycle every 21 days (3 weeks).
- the pharmaceutical combination is administered 1, 2, 3 or 4 times per treatment cycle with a compound of Formula I (or Formulas I-1 to I-3), its ester (e.g. Formula II ( or compound II-1 to II-3) or a pharmaceutically acceptable salt thereof.
- a compound of Formula I (or Formula I-1 to I-3), or an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)) is administered 2 or 3 times per treatment cycle or a pharmaceutically acceptable salt thereof.
- a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)) or a pharmaceutical thereof is administered twice per treatment cycle. with an acceptable salt.
- the pharmaceutical combination is administered 1, 2, 3 or 4 times per treatment cycle.
- Formula II (or II-1 to II-3) compound or a pharmaceutically acceptable salt thereof is administered two or three times per treatment cycle.
- a compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is administered twice per treatment cycle.
- the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is administered once on day 1 and day 8 of each treatment cycle.
- compounds of Formula I or Formulas I-1 to I-3
- esters thereof e.g., compounds of Formula II (or II-1 to II-3)
- pharmaceutically acceptable salts thereof can be used in the morning. Take orally on an empty stomach; optionally, at least 1 hour before or 2 hours after a meal.
- the anti-PD-1 antibody or antigen-binding fragment thereof is administered once, twice, or three times per treatment cycle. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) is administered once per treatment cycle. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) is administered intravenously on Day 1 (D1) of each treatment cycle, administered once per treatment cycle.
- D1 Day 1
- the anti-PD-1 antibody or antigen-binding fragment thereof is administered intravenously on Day 1 (D1) of each treatment cycle. Note time is 60 ⁇ 10min. In some embodiments, the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof) is administered intravenously on Day 1 (D1) of each treatment cycle. The injection time is 60 ⁇ 10min, and the maximum medication time should not exceed 24 months.
- the administration of a compound of Formula I (or Formula I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof is based on a treatment cycle of 3 weeks (21 days), with administration once on the 1st day and once on the 8th day.
- the administration of the compound of formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is 3 weeks (21 days) as a treatment cycle, with day 1 and day 8 Apply once each.
- the anti-PD-1 antibody or antigen-binding fragment thereof e.g., 14C12H1L1 or antigen-binding fragment thereof
- D1 Anti-PD-1 antibody or antigen-binding fragment thereof is administered intravenously. That is, the anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof) is administered at a frequency of once every 3 weeks (q3w).
- the pharmaceutical combination is suitable for administration in a single treatment cycle, and the drug administered in a single treatment cycle includes: 10 mg to 16 mg of a compound of formula I or formula I', an ester thereof, or a pharmaceutically acceptable salt thereof ; and 10-1000mg anti-PD-1 antibody or antigen-binding fragment thereof.
- the pharmaceutical combination is suitable for administration in a single treatment cycle, which (drug administered in a single treatment cycle) contains approximately: 10-20 mg of Formula I (or Formulas I-1 to I-3)
- the drug combination is suitable for administration in a single treatment cycle, which (drug administered in a single treatment cycle) contains approximately: 10 mg, 10.6 mg, 11.6 mg, 12.3 mg, 12.4 mg, 12.5 mg, 12.6mg, 13.6mg, 14.6mg, 14.7mg, 14.8mg, 14.9mg, 15.0mg, 15.1mg, 15.2mg, 15.3mg, 15.4mg, 15.5mg, 16.6mg, 16.8mg, 17.0mg, 17.2mg, 17.4mg , 17.5 mg, 17.6 mg, 17.8 mg or 18 mg of the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutical Acceptable salts (based on the weight of the compound of Formula II (or Formula II-1 to II-3)); and about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about
- the drug combination is suitable for administration in a single treatment cycle, which (drugs administered in a single treatment cycle) Approximately containing: 12.0 mg-18.0 mg of the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable Salt (based on the weight of the compound of Formula II (or Formula II-1 to II-3)); and 50-350 mg of anti-PD-1 antibody or antigen-binding fragment thereof (eg, 14C12H1L1 or antigen-binding fragment thereof).
- the pharmaceutical combination is suitable for administration in a single treatment cycle, which (drug administered in a single treatment cycle) contains approximately: 12.6 mg, 15 mg or 17.6 mg of Formula I (or Formula I-1 to I-3) compound, its ester (such as formula II (or formula II-1 ⁇ II-3) compound) or its pharmaceutically acceptable salt (based on formula II (or formula II-1 ⁇ II-3) compound weight (calculated); and 100 mg or 200 mg of anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof).
- the pharmaceutical combination is administered each time a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., a compound of Formula II (or II-1 to II-3)) or its
- the pharmaceutically acceptable salt (based on the weight of the compound of formula II (or formula II-1 to II-3)) is 6.0 mg-9 mg (for example, 7.5 mg), each time the anti-PD-1 antibody or antigen-binding fragment thereof is administered ( For example, 14C12H1L1 or its antigen-binding fragment) is 100 mg-200 mg.
- the pharmaceutical combination is suitable for administration within a single treatment cycle, which (drug administered within a single treatment cycle) includes: 10 mg to 16 mg of a compound of formula I (or formulas I-1 to I-3) , its ester (such as formula II (or II-1 ⁇ II-3) compound) or its pharmaceutically acceptable salt; and 10-1000 mg anti-PD-1 antibody or its antigen-binding fragment (such as 14C12H1L1 or its antigen-binding fragment ).
- the pharmaceutical combination is suitable for administration in a single treatment cycle, which (a drug administered in a single treatment cycle) comprises: 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg or 16 mg of Formula I (or Compounds of formulas I-1 to I-3), esters thereof (such as compounds of formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof; and about 100 mg, about 150 mg, about 200 mg, about 250 mg , about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg or an anti-PD-1 antibody or an antigen-binding fragment thereof within a range formed by any of the above values (e.g. 14C12H1L1 or its antigen-binding fragment).
- a drug administered in a single treatment cycle comprises: 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg or 16 mg of Formula I (or Compounds of formulas I-1 to I-3), esters thereof (
- the pharmaceutical combination is suitable for administration within a single treatment cycle, which (drug administered within a single treatment cycle) includes: 10 mg to 14 mg of a compound of formula I (or formulas I-1 to I-3) , its ester (such as formula II (or II-1 ⁇ II-3) compound or its pharmaceutically acceptable salt; and 50-350 mg anti-PD-1 antibody or its antigen-binding fragment (such as 14C12H1L1 or its antigen-binding fragment) .
- the pharmaceutical combination is suitable for administration in a single treatment cycle, which (drug administered in a single treatment cycle) comprises: 10 mg, 11 mg, 12 mg, 13 mg or 14 mg of Formula I (or Formula I-1 to I-3) Compounds, esters thereof (for example, compounds of Formula II (or II-1 to II-3) or pharmaceutically acceptable salts thereof; and 100 mg or 200 mg of anti-PD-1 antibodies or antigen-binding fragments thereof (for example, 14C12H1L1 or Antigen-binding fragments thereof).
- the pharmaceutical combination each time a compound of Formula I (or Formulas I-1 to I-3), its ester (e.g., Formula II (or II-1 to II-3) is administered ) compound or a pharmaceutically acceptable salt thereof is 5 mg-8 mg, and each administration of the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof) is 100 mg-200 mg.
- the Pharmaceutical combination the compound of formula I (or formula I-1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3) or its pharmaceutically acceptable salt) is 5mg-7mg per administration (e.g., 6 mg), the anti-PD-1 antibody or antigen-binding fragment thereof (e.g., 14C12H1L1 or antigen-binding fragment thereof) is 200 mg per administration.
- the pharmaceutical combination is administered every 21 days as a treatment cycle in the following manner: the compound of formula I, its ester (such as the compound of formula II) or its pharmaceutical composition is administered once on day 1 and day 8.
- the above acceptable salts are 5 mg, 5.5 mg, 6 mg, 6.5 mg or 7 mg/time, and the anti-PD-1 antibody or its antigen-binding fragment (such as 14C12H1L1 or its antigen-binding fragment) is administered once on the first day, 200 mg/time.
- the drug combination is administered every 21 days as a treatment cycle in the following manner: the compound of formula I, its ester (for example, the compound of formula II (compound or its pharmaceutical composition) is administered once on day 1 and day 8).
- the above acceptable salts are 5 mg, 6 mg or 7 mg/time, and the anti-PD-1 antibody or its antigen-binding fragment (such as 14C12H1L1 or its antigen-binding fragment) is administered once on the first day, 200 mg/time.
- the pharmaceutical combination, the compound of Formula II is administered at a dosage of 5 mg to 8 mg, and 14C12H1L1 is administered at a dosage of 100 mg to 200 mg.
- the pharmaceutical combination, the compound of Formula II is administered at a dose of 5 mg to 7 mg per administration, and the 14C12H1L1 is administered at a dose of is 200mg.
- the pharmaceutical combination is administered every 21 days as a treatment cycle in the following manner: the compound of formula II or a pharmaceutically acceptable salt thereof is administered once on day 1 and day 8.
- the compound of formula II is administered once on day 1 and day 8.
- Each administration dose is 5 mg-8 mg
- the anti-PD-1 antibody or its antigen-binding fragment (such as 14C12H1L1 or its antigen-binding fragment) is administered once on day 1.
- Each administration dose of 14C12H1L1 is 100 mg-200 mg.
- the pharmaceutical combination is administered every 21 days as a treatment cycle in the following manner: the compound of formula II or a pharmaceutically acceptable salt thereof is administered once on day 1 and day 8.
- the compound of formula II is administered once on day 1 and day 8.
- Each administration dose is 5mg-7mg.
- 14C12H1L1 or its antigen-binding fragment is administered once on day 1.
- Each administration dose of 14C12H1L1 is 200mg.
- the pharmaceutical combination is administered every 21 days as a treatment cycle in the following manner: the compound of formula II is administered once on day 1 and day 8, and the dosage of compound of formula II per administration is 5 mg, 5.5 mg, 6 mg, 6.5 mg or 7 mg, 14C12H1L1 is administered once on Day 1, with 14C12H1L1 administered at a dose of 200 mg.
- the pharmaceutical combination is administered every 21 days as a treatment cycle in the following manner: the compound of formula II is administered once on day 1 and day 8, and the dosage of compound of formula II is 5 mg and 6 mg each time. Or 7 mg, 14C12H1L1 administered once on Day 1, 14C12H1L1 administered at a dose of 200 mg. In some embodiments, the pharmaceutical combination is administered in a dosage of 0.5 mg or 2 mg of a compound of Formula II or a pharmaceutically acceptable salt thereof.
- the anti-PD-1 antibody or antigen-binding fragment thereof is administered in a dosage of 10 mL:100 mg per administration.
- the pharmaceutical combination contains a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable compound thereof.
- the salt and the anti-PD-1 antibody or antigen-binding fragment thereof eg, 14C12H1L1 or antigen-binding fragment thereof
- the pharmaceutical combination contains a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable compound thereof.
- the salt and the anti-PD-1 antibody or antigen-binding fragment thereof are administered separately in a single dose.
- the pharmaceutical combination contains a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable compound thereof.
- the salt and the anti-PD-1 antibody or antigen-binding fragment thereof are administered separately in multiple doses.
- the present disclosure also provides the use of the pharmaceutical combination of the present disclosure in the preparation of a medicament for treating tumors.
- the present disclosure also provides methods of treating tumors comprising administering to an individual in need thereof an effective amount of a pharmaceutical combination of the present disclosure.
- the present disclosure also provides pharmaceutical combinations for treating tumors.
- the present disclosure also provides the use of the pharmaceutical combination of the present disclosure for treating tumors.
- the present disclosure also provides a method of treating a subject suffering from a tumor, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I (or Formulas I-1 to I-3) of the present disclosure, which A pharmaceutical combination of an ester (eg, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.
- a compound of Formula I or Formulas I-1 to I-3 of the present disclosure, which A pharmaceutical combination of an ester (eg, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof.
- the present disclosure provides a kit comprising 1) a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or Pharmaceutically acceptable salts thereof; 2) anti-PD-1 antibodies or antigen-binding fragments thereof (such as 14C12H1L1 or antigen-binding fragments thereof), and 3) compounds of formula I (or formulas I-1 to I-3) and esters thereof Instructions for the use of (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof and an anti-PD-1 antibody or an antigen-binding fragment thereof (for example, 14C12H1L1 or an antigen-binding fragment thereof) for the treatment of tumors .
- a kit comprising 1) a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or Pharmaceutically acceptable salts thereof; 2) anti-PD-1 antibodies or antigen-
- the present disclosure provides compounds of formula I (or formulas I-1 to I-3), esters thereof (such as compounds of formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof, or Use of its pharmaceutical composition in the preparation of drugs for treating solid tumors.
- the present disclosure also provides methods of treating solid tumors, comprising administering to an individual in need thereof an effective amount of a compound of Formula I (or Formulas I-1 to I-3), an ester thereof (e.g., Formula II (or II-1 to II- 3) compound) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.
- the present disclosure also provides compounds of Formula I (or Formulas I-1 to I-3), esters thereof (such as compounds of Formula II (or II-1 to II-3)) or pharmaceutically acceptable compounds thereof for the treatment of solid tumors. salts or pharmaceutical compositions thereof.
- the present disclosure also provides compounds of formula I (or formulas I-1 to I-3), esters thereof (such as compounds of formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof For the treatment of solid tumors way.
- the ester of a compound of Formula I is a prodrug form of a compound of Formula I (or Formulas I-1 to I-3).
- the ester of the compound of Formula I is the malate ester of the compound of Formula I (or Formulas I-1 to I-3).
- the molecular number ratio of the compound of formula I (or formula I-1 to I-3) and malic acid in the ester of the compound of formula I is selected from 1:1.
- the malate ester of the compound of Formula I is a prodrug form of the compound of Formula I (or Formulas I-1 to I-3).
- the ester of the compound of Formula I is a compound of Formula II (or II-1 to II-3)
- the compound of formula I (or formula I-1 to I-3), its ester (for example, the compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof or its
- the dosage of the pharmaceutical composition per administration is selected from the group consisting of 0.5 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5.0 mg, 5.5 mg, 6.0 mg, 6.5 mg, 7.0 mg, 7.5 mg, 8.0 mg, 8.5 mg or any of the above values.
- the compound of formula I (or formula I-1 to I-3), its ester (for example, the compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof or its
- the dosage of the pharmaceutical composition per administration is selected from the group consisting of 0.8 mg, 1.2 mg, 1.6 mg, 2.0 mg, 2.4 mg, 2.8 mg, 3.2 mg, 3.6 mg, 4.0 mg, 4.4 mg, 4.8 mg, 5.2 mg, 5.6 mg, 6.0 mg, 6.4mg, 6.8mg, 7.2mg, 7.6mg, 8.0mg or the range formed by any of the above values.
- the dosage of each administration of the compound of formula II (or II-1 to II-3), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is selected from the group consisting of 1.0 mg, 1.5 mg, 2.0 mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5.0mg, 5.5mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg, 8.0mg, 8.5mg, 9.0mg, 9.5mg, 10mg or any of the above values range of formation.
- the dosage per administration of the compound of formula II (or II-1 to II-3), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is selected from 5 mg to 7 mg.
- the pharmaceutical combination, wherein each dose of the compound of formula II (or II-1 to II-3), or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is selected from 5 mg, 6 mg or 7mg.
- medicaments of compounds of Formula I or Formulas I-1 to I-3), esters thereof (e.g., compounds of Formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof
- the composition is selected from solid pharmaceutical compositions.
- the pharmaceutical composition of the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is selected from solid pharmaceutical compositions.
- the solid pharmaceutical composition is selected from tablets or capsules.
- the compound of Formula I (or Formula I-1 to I-3), its ester (such as the compound of Formula II (or II-1 to II-3)) or a pharmaceutically acceptable salt thereof can Apply once every day, apply twice daily, apply once every two days, apply once every three days, apply once every four days, apply once every five days, apply once every six days, apply once every week, apply every two weeks Apply once, once every three weeks, twice every three weeks, or three times every three weeks.
- a treatment cycle is every 21 days (3 weeks) or 28 days (4 weeks).
- the compound of Formula I (or Formula I-1 to I-3), its ester (e.g., the compound of Formula II (or II-1 to II-3)), or a pharmaceutically acceptable salt thereof is administered.
- a treatment cycle of 3 weeks (21 days) is used, once on the 1st day and once on the 8th day.
- the application method of salt is: a treatment cycle of 3 weeks (21 days) is used, and it is administered once on the 1st day, the 8th day, and the 15th day.
- the compound of Formula II (or II-1 to II-3) or a pharmaceutically acceptable salt thereof is administered at a dosage of 0.5 mg or 2 mg (based on the weight of the compound of Formula II).
- the pharmaceutical combination contains a compound of formula I (or formula I-1 to I-3), an ester thereof (for example, a compound of formula II (or II-1 to II-3)) or a pharmaceutically acceptable compound thereof.
- the salts are administered in single or multiple doses.
- the tumor is selected from solid tumors. In some embodiments, the tumor is selected from advanced solid tumors. In some embodiments, the tumor or advanced solid tumor is selected from advanced malignant solid tumors. In some embodiments, the tumor, advanced solid tumor or advanced malignant solid tumor is selected from lung cancer. In some embodiments, the tumor, advanced solid tumor or advanced malignant solid tumor is selected from advanced or locally advanced lung cancer. In some embodiments, the tumor, advanced solid tumor or advanced malignant solid tumor is selected from metastatic, recurrent and/or refractory lung cancer. In some embodiments, the tumor, advanced solid tumor, advanced malignant solid tumor or lung cancer is selected from the group consisting of lung cancer with a mutation in the EGFR cancer driver gene.
- the tumor, advanced solid tumor, advanced malignant solid tumor, or lung cancer is selected from tumor in situ of lung cancer. In some embodiments, the tumor, advanced solid tumor, advanced malignant solid tumor or lung cancer is selected from the group consisting of lung cancer in situ with a CC1ORTTA-EGFR-DEL cancer driver gene mutation.
- the tumor is selected from lung adenocarcinoma. In some embodiments, the tumor is selected from EGFR driven lung adenocarcinoma.
- the tumor is selected from the group consisting of advanced progressive/metastatic solid tumors confirmed by histopathology and/or cytology.
- the patient/individual has a tumor for which standard treatment is not available, or has disease progression or is intolerant to standard treatment. In some embodiments, the patient/individual wherein the tumor is demonstrated to have at least one measurable lesion according to RECIST 1.1 criteria.
- the patient/individual has a tumor that has progressed following or is intolerant to targeted therapy.
- the patient/individual whose tumor has progressed after prior treatment with an ALK inhibitor or is intolerant to it is not limited to the following abbreviations:
- the tumor has a patient/individual ECOG score: 0-2 points. In some embodiments, the patient/individual with the tumor is expected to survive for more than 3 months.
- the patient/individual with the tumor has good major organ function and meets the following criteria:
- Routine blood examination standards no blood transfusion, no correction with hematopoietic stimulating factor drugs or other medical support treatment within 14 days before the examination:
- ALT Alanine aminotransferase
- AST aspartate aminotransferase
- CCR Creatinine clearance rate
- Urine routine urine protein ⁇ 2+ (when the baseline urine protein is ⁇ 2+, a 24-hour urine protein quantitative test should be performed within 7 days, and only when the urine protein is ⁇ 1g can be selected);
- the coagulation function test must meet the following requirements: prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) ⁇ 1.5 ⁇ ULN;
- Thyroid function test thyroid stimulating hormone (TSH) ⁇ ULN; if abnormal, T3 and T4 levels should be examined. If T3 and T4 levels are normal, you can be selected;
- LVEF left ventricular ejection fraction
- the compound of formula I has the following structural formula and is prepared by referring to the method disclosed in WO2018157820A1,
- ester of the compound of formula I is the compound of formula II, which is the prodrug form of the compound of formula I and is prepared by referring to the method disclosed in WO2020025037A1:
- the compound of Formula I includes its free compound, its ester form, and its pharmaceutically acceptable salts.
- the non-salt forms or salts are all included in the protection scope of this disclosure.
- the compound of formula I, its ester (eg, the compound of formula II) or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition
- the single dose of the pharmaceutical composition is 0.5 mg to 50 mg of the pharmaceutical composition.
- a pharmaceutical composition with a single dose of 0.5mg-10mg is preferably a pharmaceutical composition with a single dose of 0.5mg-10mg.
- the compound of formula II or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition
- the single dose of the pharmaceutical composition is a pharmaceutical composition of 0.5 mg to 50 mg, preferably a single dose of 0.5 mg, 1 mg , 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg , 27mg, 28mg, 29mg, 30mg, 31mg, 32mg, 33mg, 34mg, 35mg, 36mg, 37mg, 38mg, 39mg, 40mg, 41mg, 42mg, 43mg, 44mg, 45mg, 46mg, 47mg, 48mg, 49m
- the method of administration can be comprehensively determined based on the activity, toxicity and patient tolerance of the drug.
- the pharmaceutical composition of the compound of Formula I, its ester (eg, the compound of Formula II) or a pharmaceutically acceptable salt thereof further contains pharmaceutically acceptable excipients.
- Pharmaceutically acceptable excipients include fillers, absorbents, wetting agents, binders, disintegrating agents agents, lubricants, etc.
- the pharmaceutical compositions include, but are not limited to, formulations suitable for oral, parenteral, topical administration.
- the pharmaceutical composition is a formulation suitable for oral administration.
- the pharmaceutical composition is a solid formulation suitable for oral administration.
- the pharmaceutical compositions include, but are not limited to, tablets and capsules.
- the pharmaceutical composition is a solid pharmaceutical composition.
- the pharmaceutical composition of a compound of Formula I, an ester thereof (e.g., a compound of Formula II), or a pharmaceutically acceptable salt thereof is a compound of Formula I, an ester thereof (e.g., a compound of Formula II), or a pharmaceutical composition thereof.
- Solid pharmaceutical compositions of pharmaceutically acceptable salts are described below.
- the pharmaceutical composition of a compound of Formula I, an ester thereof (e.g., a compound of Formula II), or a pharmaceutically acceptable salt thereof is a compound of Formula I, an ester thereof (e.g., a compound of Formula II), or a pharmaceutical composition thereof.
- Capsules of pharmaceutically acceptable salt is a compound of Formula I, an ester thereof (e.g., a compound of Formula II), or a pharmaceutical composition thereof.
- the pharmaceutical composition of the present disclosure can be manufactured using methods well known in the art, such as conventional mixing methods, dissolving methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.
- Solid oral compositions may be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain tablets or The core of the sugar coating.
- suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
- 14C12H1L1 is an anti-PD-1 monoclonal antibody, and its sequence and structure can be found in the literature (CN106977602A).
- LCDR1 contains the sequence QDINTY (SEQ ID NO: 1)
- LCDR2 contains the sequence RAN (SEQ ID NO: 2)
- LCDR3 contains the sequence LQYDEFPLT (SEQ ID NO: 3)
- HCDR1 contains the sequence GFAFSSYD (SEQ ID NO: 4)
- HCDR2 contains the sequence ISGGGRYT (SEQ ID NO:5)
- HCDR3 contains the sequence ANRYGEAWFAY (SEQ ID NO:6).
- CDR complementarity determining region
- amino acid sequence of the light chain variable region of 14C12H1L1 is:
- amino acid sequence of the heavy chain variable region of 14C12H1L1 is:
- amino acid sequence of the light chain of 14C12H1L1 is:
- amino acid sequence of the heavy chain of 14C12H1L1 is:
- the 14C12H1L1 is in the form of a pharmaceutical composition
- the single dose of the pharmaceutical composition is a pharmaceutical composition of 50 mg to 500 mg
- the preferred single dose is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg. , 450mg, 500mg or a pharmaceutical composition within the range formed by any of the above values.
- the 14C12H1L1 is in the form of a pharmaceutical composition, and a single dose of the pharmaceutical composition is 100 mg of the pharmaceutical composition.
- the 14C12H1L1 is in the form of a pharmaceutical composition comprising 14C12H1L1, a buffer, an isotonicity regulator/stabilizer, and a surfactant.
- the 14C12H1L1 is in the form of a pharmaceutical composition comprising 14C12H1L1, sodium acetate trihydrate, glacial acetic acid, sorbitol, and polysorbate 80.
- the pharmaceutical composition of 14C12H1L1 is a water-soluble injection
- the water-soluble injection includes but is not limited to a water-soluble preparation that has not been lyophilized or a water-soluble preparation reconstituted with lyophilized powder.
- the pharmaceutical composition of 14C12H1L1 is a lyophilized formulation.
- the freeze-dried preparation refers to a preparation prepared by an aqueous solution undergoing a freeze-drying process. Freeze-drying is a stabilization process in which the substance is first frozen, then the amount of solvent is reduced by sublimation (primary drying process), and then the amount of solvent is reduced by desorption. (secondary drying process) until the amount of solvent no longer supports biological activity or chemical reactions.
- the present disclosure also includes a technical solution in which the "compound of formula I (or formula I-1 to I-3)" is replaced by a “compound of formula I'", as well as It includes a technical solution of replacing the "compound of formula II (or II-1 to II-3)" with "ester of the compound of formula I'".
- the weight of the corresponding compound is based on the weight of the free acid compound, such as the weight of the compound of formula I (or formula I-1 to I-3), further such as formula I (or formula I-
- Each dose of the compound 1 to I-3), its ester (such as the compound of formula II (or II-1 to II-3)) or its pharmaceutically acceptable salt or its pharmaceutical composition is selected from 0.5 mg, 1.5 mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg, 5.0mg, 5.5mg, 6.0mg, 6.5mg, 7.0mg, 7.5mg, 8.0mg, 8.5mg or the range formed by any of the above values , wherein the dosage is based on the weight of the compound of Formula I (or Formula I-1 to I-3); for another example, in some embodiments, the pharmaceutical combination, the dosage of the compound of Formula II is 5mg-8mg each time, and the dosage of 14C12H1L1 is
- antibody refers to an antigen-binding protein having at least one antigen-binding domain.
- Antibodies and fragments thereof of the present disclosure may be whole antibodies or any fragments thereof.
- the antibodies and fragments thereof of the present disclosure include monoclonal antibodies or fragments thereof and antibody variants or fragments thereof.
- Examples of antibodies and antigen-binding fragments thereof include monospecific antibodies, bispecific antibodies, multispecific antibodies, Fab fragments, Fab' fragments, F(ab)' 2 fragments, Fv fragments, isolated CDR regions, single chain Fv molecules (scFv) and other antibody fragments known in the art.
- Anti-PD-1 antibodies or antigen-binding fragments thereof of the present disclosure may be of the IgG1, IgG2, IgG3, or IgG4 isotype.
- the term "isotype" refers to the class of antibody encoded by the heavy chain constant region genes.
- the anti-PD-1 antibodies or antigen-binding fragments thereof of the present disclosure are of the IgG1 or IgG4 isotype.
- Anti-PD-1 antibodies or antigen-binding fragments thereof of the present disclosure can be derived from any species, including, but not limited to, mouse, rat, rabbit, primate, llama, and human.
- the anti-PD-1 antibodies or antigen-binding fragments thereof of the present disclosure may be murine antibodies, chimeric antibodies, humanized antibodies, or fully human antibodies.
- “antibodies” in this disclosure include entire antibodies and any antigen-binding fragments (or “antigen-binding portions") or single chains thereof.
- a conventional "whole antibody” is a glycoprotein containing two heavy (H) chains and two light (L) chains linked by disulfide bonds. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region (CH).
- the heavy chain constant region consists of three domains, namely CH1, CH2 and CH3.
- Each light chain consists of a light chain variable region (VL) and a light chain constant region (CL).
- the light chain constant region consists of one domain, CL.
- VH and VL can also be divided into hypervariable regions, namely complementarity determining regions (CDR), and framework regions (FR) with relatively conserved sequences.
- CDR complementarity determining regions
- FR framework regions
- Each VH and VL are composed of three CDRs and four FRs respectively, from the amino end to the carboxyl end: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.
- the variable regions of the heavy and light chains contain binding domains that interact with the antigen.
- the constant region of an antibody can mediate binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system. Meanwhile, as is understood by those skilled in the art, special “whole antibodies", such as Nanobodies, have only heavy (H) chains and no light (L) chains.
- an “antigen-binding fragment” or “antibody-binding portion” of an antibody refers to one or more fragments of an antibody that retain the function of specifically binding an antigen (eg, PD-1). It has been demonstrated that the antigen-binding function of an antibody can be performed by fragments of the entire antibody.
- Examples encompassed by the term "antigen-binding portion/fragment" of an antibody include: (i) Fab fragments: monovalent fragments consisting of VL, VH , CL and CH1 domains; ( ii) F(ab') 2 fragments , a bivalent fragment containing two Fab fragments connected by a disulfide bridge in the hinge region; (iii) Fd fragment consisting of VH and CH1 domains; (iv) Fv consisting of VL and VH domains of an antibody single arm Fragments; (v) dAb fragments consisting of VH domains (see Ward et al., Nature.
- antigen-binding portion/fragment single chain antibodies are also encompassed by the term antigen-binding portion/fragment.
- recombinant polypeptides, fusion proteins and immunoconjugates comprising such antigen-binding portions/fragments are also encompassed by the term antigen-binding portions/fragments.
- humanized antibody refers to an antibody in which the antigen-binding site is derived from a non-human species and the variable region framework is derived from human immunoglobulin sequences. Humanized antibodies may contain substitutions in the framework regions such that the framework may not be an exact copy of the expressed human immunoglobulin or germline gene sequence.
- isolated antibody means an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody that specifically binds PD-1/PD-L1 is substantially free of other antibodies that specifically bind other than Antibodies to antigens other than PD-1/PD-L1).
- an isolated antibody that specifically binds PD-1/PD-L1 may have cross-reactivity with other antigens, such as PD-1/PD-L1 molecules from different species.
- isolated antibodies may be substantially free of other cellular material and/or chemicals.
- sequence identity or “percent identity” in the comparison of two nucleic acids or polypeptides means that when measured using a nucleotide or amino acid residue sequence comparison algorithm or by visual inspection, Maximum correspondence is compared and aligned when they are similar or have a specific percentage of identical sequences. That is to say, the identity of nucleotide or amino acid sequences can be defined by the ratio that maximizes the number of identical nucleotides or amino acids when comparing two or more nucleotide or amino acid sequences. , and gaps are added as necessary to achieve a consistent ratio of the number of nucleotides or amino acids in the alignment to the total number of nucleotides or amino acids in the alignment.
- sequence identity between two or more polynucleotides or polypeptides can be determined by aligning the nucleotide or amino acid sequences of the polynucleotides or polypeptides and aligning the aligned The number of positions in a polynucleotide or polypeptide that contain the same nucleotide or amino acid residue is scored and compared to the number of positions in the aligned polynucleotide or polypeptide that contain different nucleotides or amino acid residues. Polynucleotides may differ at one position, for example, by containing different nucleotides or deleting nucleotides.
- Polypeptides may differ at one position, for example, by containing a different amino acid or missing an amino acid.
- Sequence identity can be calculated by dividing the number of positions containing identical nucleotides or amino acid residues by the total number of amino acid residues in the polynucleotide or polypeptide. For example, it can be divided by the number of positions containing the same nucleotide or amino acid residue. Percent identity is calculated as the total number of nucleotides or amino acid residues in a polynucleotide or polypeptide multiplied by 100.
- two or more sequences or subsequences have at least 40%, 50%, 60% when compared and aligned with maximum correspondence using sequence comparison algorithms or as measured by visual inspection. , 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% "sequence identity” of nucleotide or amino acid residues sex” or “percent identity”.
- sequence identity of nucleotide or amino acid residues sex
- percent identity The determination/calculation of "sequence identity” or “percent identity” can be based on any suitable region of the sequence.
- sequences are substantially identical throughout the entire length of either or both compared biopolymers (that is, nucleic acids or polypeptides).
- treating means administering a compound or formulation of the present disclosure to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
- prevention means the administration of a compound or formulation of the present disclosure to prevent a disease or one or more symptoms associated with said disease, and includes: preventing a disease or disease state from occurring in a mammal, particularly when Such mammals are susceptible to the disease state but have not yet been diagnosed as having the disease state.
- systemic treatment refers to treatment in which drug substances are delivered through the bloodstream to reach and affect cells throughout the body.
- the term "subject” includes mammals such as rodents, felines, canines, and primates.
- the subject according to the present disclosure is a human.
- administering means the physical introduction of a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art.
- an "adverse event” is any adverse and generally unintentional or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment.
- adverse events may be associated with activation of the immune system or expansion of immune system cells (eg, T cells) in response to treatment.
- a medical treatment can have one or more associated AEs, and each AE can have the same or different severity levels.
- References to methods that "modify adverse events" refer to treatment embodiments that reduce the incidence and/or severity of one or more AEs associated with the use of different treatment embodiments.
- Dosing interval refers to the amount of time that elapses between each administration of a formulation disclosed herein to a subject (which may be two consecutive administrations or two administrations separated by two administrations). Dosing intervals can thus be indicated as ranges.
- the fixed dose means that two or more different antibodies in a single composition are present in said composition in a specific (fixed) ratio to each other.
- the fixed dose is based on the weight of the antibody (eg, mg).
- the fixed dose is based on the concentration of the antibody (eg, mg/ml).
- the ratio of mg first antibody:mg second antibody is at least about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1: 6.
- a 3:1 ratio of primary antibody to secondary antibody may mean that the vial may contain approximately 240 mg of primary antibody and 80 mg of secondary antibody, or approximately 3 mg/ml of primary antibody and 1 mg/ml of secondary antibody. .
- PD-1 Programmed death receptor-1
- PD-1 is mainly expressed on previously activated T cells in the body and binds two ligands, PD-L1 and PD-L2.
- the term "PD-1” as used herein includes human PD-1 (hPD-1), variants, isoforms and species homologs of hPD-1, and analogs that share at least one epitope in common with hPD-1.
- P-L1 Programmed death ligand-1 (PD-L1) is one of two cell surface glycoprotein ligands for PD-1 (the other is PD-L2), which downregulates T cells after binding to PD-1 Activation and cytokine secretion.
- Subject includes any human or non-human animal.
- non-human animals includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs.
- the subject is a human.
- the terms "subject,” “subject,” and “patient” are used interchangeably in certain contexts herein.
- a “therapeutically effective amount” or “therapeutically effective dose” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject from the onset of a disease or promotes regression of a disease Regression is evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free phases, or the prevention of impairment or disability caused by disease afflictions.
- the ability of therapeutic agents to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by in vitro assays to determine the activity of the agent.
- a therapeutically effective amount of an anti-cancer agent may inhibit cell growth or tumor growth by at least About 10%, at least about 20%, at least about 40%, at least about 60%, or at least about 80%.
- tumor regression may be observed for a period of at least about 7 days, at least about 10 days, at least about 14 days, at least about 20 days, at least about 40 days, or at least about 60 days.
- Immunotherapeutic response patterns refer to clinical response patterns frequently observed in cancer patients treated with immunotherapeutic agents that produce anti-tumor effects by inducing cancer-specific immune responses or by altering innate immune processes. This response pattern is characterized by a beneficial therapeutic effect after an initial increase in tumor burden or the appearance of new lesions, which in the evaluation of conventional chemotherapeutic agents would be classified as disease progression and would be synonymous with drug failure. Therefore, appropriate evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on the target disease.
- a therapeutically effective amount of a drug includes a "prophylactically effective amount" which is when administered alone or in combination with an antineoplastic agent to a subject at risk of developing cancer (e.g., a subject with a premalignant condition) or a subject at risk of recurrence of cancer
- the amount of any drug that inhibits the occurrence or recurrence of cancer In certain embodiments, the prophylactically effective amount completely prevents the development or recurrence of cancer.
- “Inhibiting" the occurrence or recurrence of cancer means reducing the likelihood of the occurrence or recurrence of cancer, or completely preventing the occurrence or recurrence of cancer.
- a “recurrent” cancer is a cancer that grows back at the original site or at a distant site after responding to initial treatment, such as surgery.
- a “locally recurrent” cancer is a cancer that appears after treatment in the same location as a previously treated cancer.
- Metalstatic cancer is cancer that has spread from one part of the body, such as the lungs, to another part of the body.
- the terms “about,” “approximately,” or “substantially comprise” mean a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined or composition, that is, the limitations of the measurement system. For example, “about,” “approximately,” or “substantially including” may mean within 1 or more than 1 standard deviation as is practiced in the art. Alternatively, “about” or “substantially comprising” may refer to a range that differs by up to 10% or 20% (ie, ⁇ 10% or ⁇ 20%) from the parameter or value modified thereby.
- about 3 mg may include any number between 2.7 mg and 3.3 mg (for 10%) or between 2.4 mg and 3.6 mg (for 20%).
- the term may refer up to an order of magnitude or up to 5 times a numerical value.
- a dosing interval of about every 6 weeks or about every 12 weeks means that the first dose can be administered on any day of the first week, and then on any day of the sixth or twelfth week, respectively.
- a dosing interval of about every 6 weeks or about every 12 weeks means administering the first dose on a specific day of the first week (e.g., Monday), and then on a specific day of the first week or 12 weeks, respectively.
- the second dose is administered on the same day at twelve weeks (i.e., Monday). Similar principles apply to phrases including, but not limited to, "about once every 2 weeks,”"about once a month,” etc.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salts includes salts of a base ion with a free acid or an acid ion with a free base.
- prodrug is intended to include any covalently bound carrier that releases the active parent drug of the invention in vivo when such prodrug is administered to a mammalian subject.
- the prodrugs of the present invention are prepared by modifying functional groups present in the compound in such a manner that the modification is cleaved to the parent compound during routine manipulation or in vivo.
- fixed combination means that the active components (eg, anti-PD-1 antibody or compound of formula I) are administered simultaneously to a subject in a fixed total dose or dose ratio, or in the form of a single entity, pharmaceutical composition or preparation.
- active components eg, anti-PD-1 antibody or compound of formula I
- non-fixed combination refers to the administration of two or more active components as independent entities (such as pharmaceutical compositions, preparations) to a subject simultaneously, concurrently or sequentially without specific time limits, wherein the administration to the subject The active ingredient reaches a therapeutically effective dose level.
- non-fixed combinations include cocktail therapy, for example, administration of three or more active ingredients.
- the individual active ingredients may be packaged, sold or administered as entirely separate pharmaceutical compositions.
- the "non-fixed combination” also includes the combined use of "fixed combinations” between “fixed combinations” or “fixed combinations” with any one or more independent entities of the active ingredients.
- “combination” or “used in combination” means that two or more active substances may be administered to a subject together in a mixture, simultaneously as a single formulation, or sequentially in any order as a single formulation.
- pharmaceutical composition refers to a mixture of one or more active ingredients of the present disclosure (eg, anti-PD-1 antibody or compound of Formula I) or a pharmaceutical combination thereof and pharmaceutically acceptable excipients.
- active ingredients of the present disclosure eg, anti-PD-1 antibody or compound of Formula I
- pharmaceutically acceptable excipients e.g., pharmaceutically acceptable excipients.
- the purpose of pharmaceutical compositions is to facilitate administration to a subject of a compound of the present disclosure or a pharmaceutical combination thereof.
- the term "synergistic effect” refers to the effect produced by two or more components (e.g., an anti-PD-1 antibody or a compound of Formula I) (e.g., inhibition or alleviation of lung or colon cancer (symptoms), specifically, for example, inhibition of colon cancer growth, or Alleviating colon cancer symptoms, inhibiting lung cancer growth, or alleviating lung cancer symptoms) is a simple additive effect greater than the effects of the ingredients administered alone.
- single dose refers to the smallest packaging unit containing a certain amount of medicine. For example, if there are seven capsules in a box of medicine, each capsule is a single dose; or each bottle of injection is a single dose.
- multiple doses consists of a plurality of single doses.
- the components in the pharmaceutical combination of the present disclosure may be formulated separately, or part or all of them may be formulated together.
- the pharmaceutical combinations of the present disclosure may be formulated into pharmaceutical compositions suitable for single or multiple administration.
- the components in the pharmaceutical combination of the present disclosure may be administered individually, or part or all thereof may be administered together.
- the components of the pharmaceutical combinations of the present disclosure may be administered substantially simultaneously, or some or all thereof may be administered substantially simultaneously.
- the components of the pharmaceutical combinations of the present disclosure may be administered individually, or part or all thereof, together, by any suitable route, including, but not limited to, oral or parenteral (by intravenous, intramuscular, topical or subcutaneous routes). ). In some embodiments, the components of the pharmaceutical combinations of the present disclosure may be administered individually, or part or all of them may be administered together orally or by injection, such as intravenously or intraperitoneally.
- the components in the pharmaceutical combination of the present disclosure may be suitable dosage forms each independently, or part or all of them together, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, etc.). capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersions and for oral or parenteral administration dosage form of sustained-release preparations.
- suitable dosage forms each independently, or part or all of them together, including but not limited to tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric capsules, etc.). capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispers
- the components in the pharmaceutical combination of the present disclosure may be each independently, or some or all of them may together contain pharmaceutically acceptable carriers and/or excipients.
- compositions of the present disclosure may also include additional therapeutic agents.
- the additional therapeutic agent may be a cancer therapeutic agent known in the art.
- the compounds of formula I′ (specifically, formula I, etc.), their esters (such as compounds of formula II (or II-1 to II-3)) or pharmaceutically acceptable salts thereof disclosed in the present disclosure can exert therapeutic effects on solid tumors such as lung cancer. , has good pharmacokinetic properties, small adverse reactions, good tolerance, and good medicinal value.
- the drug combination of the present disclosure can exert curative effect on solid tumors such as lung cancer; and compared with single drugs, the drug combination of the present disclosure shows an enhanced effect, has a synergistic effect, has good pharmacokinetic properties, has small adverse reactions, and is tolerant. It has good receptivity and good medicinal value.
- the “clinical benefits” of the disclosed drug combination include, but are not limited to: prolongation of progression-free survival (PFS), prolongation of overall survival (OS), improvement of objective response rate (ORR), disease control rate ( DCR) is improved, the number and/or severity of adverse reactions is reduced, the distant metastasis rate and local control rate are reduced, etc.
- 14C12H1L1 injection refers to an injectable medical preparation containing the monoclonal antibody 14C12H1L1, which is usually administered to patients via intravenous infusion.
- the expression "14C12H1L1 injection, 200 mg/time” can be understood in the usual manner in the art as a water-soluble injection medical preparation containing 200 mg of 14C12H1L1 administered to the patient each time.
- CC10RTTA-EGFR-DEL transgenic mice (hereinafter referred to as EGFR-DEL mice) were used for treatment.
- EGFR-DEL mice CC10RTTA-EGFR-DEL transgenic mice
- DOX doxycycline
- mice Before treatment, the size and severity of tumors in EGFR-DEL mice were recorded by computer tomography (CT). And the mice with lung tumors were divided into four groups, namely the normal saline control group (vehicle), the formula II compound treatment group, the 14C12H1L1 treatment group, and the formula II compound + 4C12H1L1 combined treatment group.
- CT computer tomography
- a two-week drug treatment was carried out simultaneously according to the aforementioned administration method and dosage.
- the changes in the lung tumors of the mice were recorded through computed tomography.
- mice After the treatment, the mice were euthanized, and the lung tissues were dissected and paraffin sections were prepared. HE staining of paraffin sections and microscopic observation of pathological changes in mouse lung cancer tissues after drug treatment were performed.
- the lung tumors have almost completely disappeared. It shows that the compound of formula II has a significant therapeutic effect on mouse lung cancer orthotopic tumors with EGFR-DEL driver gene mutation (EGFR gene exon 19 deletion), and combined with 14C12H1L1 can further enhance the therapeutic effect (see Figure 1 for details) .
- Age ⁇ 18 years old (when signing the informed consent form); gender is not limited;
- the expected survival period is more than 3 months;
- Routine blood examination standards no blood transfusion, no correction with hematopoietic stimulating factor drugs or other medical support treatment within 14 days before the examination:
- ALT Alanine aminotransferase
- AST aspartate aminotransferase
- CCR Creatinine clearance rate
- Urine routine urine protein ⁇ 2+ (when the baseline urine protein is ⁇ 2+, a 24-hour urine protein quantitative test should be performed within 7 days, and only when the urine protein is ⁇ 1g can be selected);
- the coagulation function test must meet the following requirements: prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) ⁇ 1.5 ⁇ ULN;
- Thyroid function test thyroid stimulating hormone (TSH) ⁇ ULN; if abnormal, T3 and T4 levels should be examined. If T3 and T4 levels are normal, you can be selected;
- LVEF left ventricular ejection fraction
- Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine devices, birth control pills or condoms) during the study period and within 6 months after the end of the study; have a negative serum pregnancy test within 7 days before study enrollment , and must be non-lactating subjects; women of childbearing age include premenopausal women and women within 2 years after menopause. Male subjects should agree to use birth control measures during the study period and for 6 months after the end of the study period.
- contraceptive measures such as intrauterine devices, birth control pills or condoms
- Formula II compound capsules specifications 0.5mg, 2mg, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
- Capsules of compound of formula II administered once on the 1st and 8th days of each treatment cycle, 5 mg each time (based on the weight of compound of formula I), every 3 weeks is a treatment cycle, taken orally in the morning on an empty stomach (before meals) Take at least 1 hour or at least 2 hours after eating);
- 14C12H1L1 injection administered once every 3 weeks (i.e. administered once on the first day of each cycle), every 3 weeks is a treatment cycle, 200mg/time, administered by intravenous infusion.
- the infusion time is 60 ⁇ 10min.
- Capsules of compound of formula II administered once on the 1st and 8th days of each treatment cycle, 6 mg (based on the weight of compound of formula I) each time, every 3 weeks is a treatment cycle, taken orally in the morning on an empty stomach (before meals) Take at least 1 hour or at least 2 hours after eating);
- 14C12H1L1 injection administered once every 3 weeks (i.e. administered once on the first day of each cycle), every 3 weeks is a treatment cycle, 200mg/time, administered by intravenous infusion.
- the infusion time is 60 ⁇ 10min.
- Capsules of compound of formula II administered once on the 1st and 8th days of each treatment cycle, 7 mg (based on the weight of compound of formula I) each time, every 3 weeks is a treatment cycle, taken orally in the morning on an empty stomach (before meals) Take at least 1 hour or at least 2 hours after eating);
- 14C12H1L1 injection administered once every 3 weeks (i.e. administered once on the first day of each cycle), every 3 weeks is a treatment cycle, 200mg/time, administered by intravenous infusion.
- the infusion time is 60 ⁇ 10min.
- the patient's efficacy evaluation criteria are based on RECIST1.1 (Response Evaluation Criteria for Solid Tumors).
- Efficacy evaluation indicators include but are not limited to: objective response rate (ORR), disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
- ORR objective response rate
- DCR disease control rate
- DOR duration of response
- PFS progression-free survival
- OS overall survival
- AEs adverse events
- the compound of Formula II combined with 14C12H1L1 can safely and effectively treat solid tumors (especially lung cancer), improve the clinical benefits of patients, relieve and control the patient's condition, and slow down the progression of the disease.
- solid tumors especially lung cancer
- Specific exemplary results are as follows:
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Abstract
La présente demande appartient au domaine technique des médicaments et concerne une association pharmaceutique d'un inhibiteur de protéasome et d'un anticorps anti-PD-1. Spécifiquement, la présente demande concerne une association pharmaceutique de composés de formule (I') de la présente divulgation, des promédicaments de ceux-ci ou des sels pharmaceutiquement acceptables de ceux-ci et un anticorps anti-PD-1 ou un fragment de liaison à l'antigène de ceux-ci, ainsi que leur utilisation dans la prévention ou le traitement de tumeurs solides.
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