WO2024153229A1 - 抗her2抗体药物偶联物治疗乳腺癌 - Google Patents

抗her2抗体药物偶联物治疗乳腺癌 Download PDF

Info

Publication number
WO2024153229A1
WO2024153229A1 PCT/CN2024/073246 CN2024073246W WO2024153229A1 WO 2024153229 A1 WO2024153229 A1 WO 2024153229A1 CN 2024073246 W CN2024073246 W CN 2024073246W WO 2024153229 A1 WO2024153229 A1 WO 2024153229A1
Authority
WO
WIPO (PCT)
Prior art keywords
once
her2
weeks
her2 antibody
drug conjugate
Prior art date
Application number
PCT/CN2024/073246
Other languages
English (en)
French (fr)
Inventor
王泉人
Original Assignee
江苏恒瑞医药股份有限公司
上海盛迪医药有限公司
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 江苏恒瑞医药股份有限公司, 上海盛迪医药有限公司 filed Critical 江苏恒瑞医药股份有限公司
Publication of WO2024153229A1 publication Critical patent/WO2024153229A1/zh

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • 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
    • 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
    • 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 disclosure belongs to the field of medicine and relates to the use of anti-HER2 antibody-drug conjugates (ADC) in the preparation of drugs for treating breast cancer.
  • ADC anti-HER2 antibody-drug conjugates
  • Breast cancer is the most common malignant tumor in the world. According to GLOBOCAN 2020 statistics, the incidence and mortality of breast cancer rank first among female malignant tumors. The number of new cases of breast cancer and 685,000 deaths are about 2.26 million per year, ranking first in the incidence and mortality of female malignant tumors.
  • HER2 expression refers to an immunohistochemistry (IHC) score of 1+ or IHC 2+ and in situ hybridization (ISH)-.
  • IHC immunohistochemistry
  • ISH in situ hybridization
  • HER2 is a member of the type I transmembrane tyrosine kinase receptor family. It is basically inactive in the monomeric state, but can polymerize with the other three transmembrane tyrosine kinase members of the family, HER1, HER3, and HER4, leading to the phosphorylation of receptor tyrosine residues and the activation of multiple signaling pathways (such as MAPK, PI3K/Akt, etc.), thereby promoting cell proliferation and tumor occurrence and development.
  • multiple signaling pathways such as MAPK, PI3K/Akt, etc.
  • ADCs targeting HER2 work in the following ways: first, the antibody in the ADC specifically recognizes and binds to the HER2 receptor on the surface of the target cell, then enters the target cell through endocytosis, and releases the cytotoxic drug after being decomposed inside the cell. Finally, the cytotoxic drug induces cell apoptosis by damaging DNA or acting on tubulin, thereby exerting an anti-tumor effect. If the cytotoxic drug has high membrane permeability, it may penetrate into the extracellular space after being released in the target cell, killing the surrounding HER2-negative cells. This effect is called the bypass killing effect. If the cytotoxic drug is released before the ADC endocytosis occurs, this effect may also occur.
  • WO2020063676A discloses a class of ADCs targeting HER2.
  • TDM-1 Trastuzumab emtansine
  • DS-8201 Trastuzumab Deruxtecan
  • the present invention provides a medical use and method of an anti-HER2 antibody-drug conjugate for treating tumors.
  • the present disclosure provides any of the following uses or methods of anti-HER2 antibody drug conjugates:
  • a method for treating HER2-low expressing breast cancer comprising administering an anti-HER2 antibody drug conjugate to a subject in need thereof.
  • the structure of the antibody-drug conjugate is shown in formula (I):
  • n is 3 to 8, and n is a decimal or an integer; for example, n is 3, 4, 5, 6, 7, 8 or any integer or decimal between any two of the foregoing values.
  • Pc is an anti-HER2 antibody.
  • antibody is used in the broadest sense, which covers various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (such as bispecific antibodies), full-length antibodies or antigen-binding fragments thereof (also referred to as “antigen-binding portions”), as long as they exhibit the desired antigen-binding activity.
  • the anti-HER2 antibody or antigen-binding fragment thereof disclosed herein is selected from Trastuzumab, or an antigen-binding fragment thereof, Pertuzumab or an antigen-binding fragment thereof.
  • the anti-HER2 antibody or antigen-binding fragment thereof described in the present disclosure is trastuzumab or an antigen-binding fragment thereof.
  • the anti-HER2 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL): wherein the heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively.
  • VH heavy chain variable region
  • VL light chain variable region
  • the CDRs are defined according to the Kabat numbering system.
  • the anti-HER2 antibody comprises any 1, 2, 3, 4, 5 or 6 of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3.
  • the anti-HER2 antibody is a humanized antibody.
  • the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 9, or an amino acid sequence having at least 80% sequence identity thereto;
  • the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 10, or an amino acid sequence having at least 80% sequence identity thereto.
  • the anti-HER2 antibody comprises any one or a combination of any two of the aforementioned VH and VL.
  • the anti-HER2 antibody further comprises a heavy chain constant region and/or a light chain constant region.
  • a heavy chain constant region is combined with the variable region of the aforementioned antibody to form a complete antibody, and its light chain/heavy chain sequence is as follows:
  • the heavy chain of the anti-HER2 antibody comprises the amino acid sequence shown in SEQ ID NO: 2, or an amino acid sequence having at least 80% sequence identity thereto;
  • the light chain comprises the amino acid sequence shown in SEQ ID NO: 1 An amino acid sequence, or an amino acid sequence having at least 80% sequence identity thereto.
  • the present disclosure provides an anti-HER2 antibody comprising any one or a combination of any two of the aforementioned heavy chains and light chains.
  • At least 80% encompasses 80% and above, for example at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and any numerical range therebetween.
  • the anti-HER2 antibody-drug conjugate as described above can be prepared by referring to the method in WO2021190581A.
  • the present disclosure incorporates the relevant contents of the ADC structure, antibody sequence and preparation method in WO2021190581A into the present disclosure by reference.
  • the anti-HER2 antibody drug conjugates disclosed herein have a structure as shown in the following formula:
  • n is 3 to 8 and is a decimal or an integer.
  • n is 6 ⁇ 0.8.
  • n is 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8.
  • n is 6 in the anti-HER2 antibody drug conjugate described in the present disclosure.
  • the "HER2 low-expressing breast cancer” is not particularly limited, as long as it is considered to be HER2 low-expressing breast cancer by those skilled in the art.
  • Preferred examples of HER2 low-expressing breast cancer may include IHC2+ and ISH negative, IHC1+ and ISH negative, IHC1+ and ISH undetectable, and 0 ⁇ IHC ⁇ 1+.
  • the HER2 low-expressing breast cancer is a breast cancer whose HER2 expression is determined to be 1+ by immunohistochemistry, that is, IHC1+, such as IHC1+/ISH- or IHC1+/ISH not detected.
  • the HER2 low-expressing breast cancer is a breast cancer in which the expression of HER2 is determined to be 2+ by immunohistochemistry and the expression of HER2 is determined to be negative by in situ hybridization, that is, IHC2+/ISH-.
  • the HER2-low expressing breast cancer is unresectable, recurrent and/or metastatic breast cancer with HER2-low expressing.
  • the HER2-low expressing breast cancer is HER2-low expressing unresectable or metastatic breast cancer.
  • the HER2 low-expressing breast cancer is a patient with HER2 low-expressing recurrent or metastatic breast cancer.
  • the breast cancer patient is a HR-positive patient or a HR-negative patient.
  • the breast cancer patient has received at least one line of endocrine therapy.
  • the breast cancer patient has not received or has received chemotherapy previously.
  • the HER2 low-expressing breast cancer patient has previously been treated with an anti-HER2 drug. In some embodiments, the HER2 low-expressing breast cancer patient has previously been treated with an anti-HER2 drug and has developed resistance or refractory disease.
  • “resistance” or “refractory” means a property of not responding to treatment with an anticancer agent, and may also be expressed as “non-responsiveness” or “non-responsiveness”.
  • the anti-HER2 antibody-drug conjugates provided by the present disclosure are used to treat patients with breast cancer with low HER2 expression, and can significantly improve the patients' tumor objective response rate and progression-free survival time, especially at a dosage of 6.4 mg/kg, a cORR of 64.9% and an mPFS of 13.8 months can be achieved, which has significant therapeutic advantages compared with other ADC drugs with the same target, and provides a positive and effective clinical treatment plan for patients with breast cancer with low HER2 expression.
  • the anti-HER2 antibody-drug conjugates provided by the present disclosure can significantly reduce the incidence of interstitial pneumonia when administered to a subject, have improved clinical safety, and are beneficial for broadening the clinical dosing window.
  • the anti-HER2 antibody drug conjugate is used in combination with a second therapeutic agent.
  • the second therapeutic agent is selected from one or a combination of two or more of a CDK4/6 inhibitor, a SERD, a VEGF ligand inhibitor, an aromatase inhibitor, and a CDK4/6 inhibitor.
  • the anti-HER2 antibody drug conjugate is used in combination with a CDK4/6 inhibitor.
  • the anti-HER2 antibody drug conjugate is used in combination with a SERD (selective estrogen receptor degrader).
  • SERD selective estrogen receptor degrader
  • the anti-HER2 antibody drug conjugate is used in combination with a VEGF ligand inhibitor.
  • the anti-HER2 antibody drug conjugate is used in combination with an aromatase inhibitor.
  • the anti-HER2 antibody drug conjugate is used in combination with a CDK4/6 inhibitor and an aromatase inhibitor.
  • the CDK4/6 inhibitor described in the present disclosure is selected from abemaciclib, ribociclib, palbociclib, alvocidib, trilaciclib, voruciclib, AT-7519, G1T-38, FLX-925, INOC-005, G1T28-1, BPI-1178, gossypin, G1T30-1, GZ-38-1, P-276-00, staurosporine, R-547, PAN-1215, PD-0183812, AG-024322, NSC-625987, CGP-82996, PD-171851 and a compound of formula (II) or a pharmaceutically acceptable salt thereof.
  • the CDK4/6 inhibitor is a compound of formula (II) or a pharmaceutically acceptable salt thereof,
  • the pharmaceutically acceptable salt of the compound of Formula II is isethionate.
  • the SERD disclosed herein is selected from fulvestrant, AZD-9496, RAD1901, and ZB-716. In some embodiments, the SERD is fulvestrant.
  • the VEGF ligand inhibitor described in the present disclosure is selected from bevacizumab, ramucirumab, ranibizumab, aflibercept, conbercept, abipar pegol, brolucizumab, LMG-324, nesvacumab, sevacizumab, tanibirumab, navicixizumab, RG-7716, LHA-510, OPT-302, TK-001, GZ-402663, VGX-100 , PG-545, BI-836880, GNR-011, BR-55, OTSGC-A24, PAN-90806, AVA-101, ODM-203, TAS-115, X-82, MP-0250, Sitravatinib, 4SC-203, AL-2846, ABT-165, SIM-010603, BI-836880, HL-217, CS-2164, RGX-314, AMC-303 and VXM-01.
  • bevacizumab
  • the aromatase inhibitor of the present disclosure is selected from formestane, exemestane, fadrozole, letrozole, vorozole and anastrozole. In some embodiments, the aromatase inhibitor is letrozole or anastrozole.
  • the dosage of the anti-HER2 antibody drug conjugates described in the present disclosure is 1.0 mg/kg-10.0 mg/kg. In optional embodiments, the dosage of the anti-HER2 antibody drug conjugates described in the present disclosure is 1.0 mg/kg, 1.2 mg/kg, 1.4 mg/kg, 1.6 mg/kg, 1.8 mg/kg, 2.0 mg/kg, 2.2 mg/kg, 2.4 mg/kg, 2.6 mg/kg, 2.8 mg/kg, 3.0 mg/kg, 3.2 mg/kg, 3.4 mg/kg, 3.6 mg/kg, 3.8 mg/kg, 4.0 mg/kg, 4.2 mg/kg, 4.4 mg/kg, 4.6 mg/kg, 4.8 mg/kg, 5.0 mg/kg, 5.
  • the dosage of the anti-HER2 antibody drug conjugate described in the present disclosure is 1.0 mg/kg, 2.0 mg/kg, 3.2 mg/kg, 4.8 mg/kg, 5.6 mg/kg, 6.4 mg/kg or 8.0 mg/kg.
  • the anti-HER2 antibody drug conjugates disclosed herein are administered at least once a week, at least once every two weeks, at least once every three weeks, at least once every four weeks, or at least once every six weeks.
  • the administration frequency is once a week, once every two weeks, once every three weeks, or once every four weeks. In an optional embodiment, the administration frequency is once every two weeks or once every three weeks.
  • the dosage of the anti-HER2 antibody drug conjugate described in the present disclosure is 1.0 mg/kg. 2.0 mg/kg, 3.2 mg/kg, 4.8 mg/kg, 5.6 mg/kg, 6.4 mg/kg or 8.0 mg/kg, with a dosing frequency of once every two weeks or once every three weeks.
  • the dosage of the CDK4/6 inhibitor described in the present disclosure is 1-1000 mg.
  • the dosage of the CDK4/6 inhibitor described in the present disclosure can be 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg.
  • the dosage is 100 mg, 125 mg, 150 mg.
  • the administration frequency can be once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, or once a month. In an optional embodiment, the administration frequency is once a day.
  • the dosage of the CDK4/6 inhibitor described in the present disclosure is 75 mg, 100 mg, 125 mg, 150 mg, and the administration frequency is once a day.
  • the dosage of SERD described in the present disclosure is 1-1000mg.
  • the dosage of SERD described in the present disclosure can be 5mg, 10mg, 12.5mg, 15mg, 17.5mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 60mg, 70mg, 75mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 475mg, 500mg, 600mg, 700mg, 750mg, 800mg, 900mg, 1000mg.
  • the dosage of SERD described in the present disclosure is 500mg.
  • the administration frequency of the SERD described in the present disclosure can be once a day, twice a day, three times a day, once a week, once every two weeks, once every three weeks, or once a month. In some embodiments, the administration frequency can be once a day, once a week, once every two weeks, once every three weeks, or once a month, for example, once every two weeks or once a month.
  • the dosage of the SERD disclosed in the present invention is 500 mg, and the administration frequency is once every two weeks or once a month.
  • the dosage of the VEGF ligand inhibitor described in the present disclosure is 0.1-100 mg/kg.
  • the dosage of the VEGF ligand inhibitor described in the present disclosure can be 0.5 mg/kg, 1 mg/kg, 2 mg/kg, 2.5 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 7.5 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 12.5 mg/kg, 12 mg/kg, 15 mg/kg, 17.5 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg.
  • the dosage of the VEGF ligand inhibitor described in the present disclosure is 15 mg/kg.
  • the administration frequency of the VEGF ligand inhibitor described in the present disclosure can be once a day, once a week, once every two weeks, once every three weeks, or once a month. In an optional embodiment, the administration frequency can be once a week, once every two weeks, once every three weeks, or once a month. In an optional embodiment, the administration frequency is once every three weeks.
  • the dosage of the VEGF ligand inhibitor described in the present disclosure is 15 mg/kg, and the administration frequency is once every three weeks.
  • the dosage of the aromatase inhibitor described in the present disclosure is 0.1-50 mg. In optional embodiments, the dosage of the aromatase inhibitor described in the present disclosure can be 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.25 mg, 1.5 mg, 1.75 mg, 2 mg, 2.25 mg, 2.5 mg, 2.75 mg, 3 mg, 3.25 mg, 3.5mg, 3.75mg, 4mg, 4.25mg, 4.5mg, 4.75mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 8.5mg, 9mg, 9.5mg, 10mg, 12.5mg, 15mg, 17.5mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg or 50mg.
  • the dosage of the aromatase inhibitor described in the present disclosure is 0.5mg, 1.0mg, 1.5mg, 2.0mg, 2.5mg, 3.0mg, 3.5mg, 4.0mg, 4.5mg or 5.0mg.
  • the aromatase inhibitor described in the present disclosure is administered once a day or twice a day.
  • the administration frequency is once a day or twice a day.
  • the dosage of the aromatase inhibitor described in the present disclosure is 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0 mg, 4.5 mg or 5.0 mg, and the frequency of administration is once a day or twice a day.
  • the aromatase inhibitor disclosed in the present invention is letrozole, the dosage is 2.5 mg, and the administration frequency is once a day.
  • the aromatase inhibitor disclosed in the present invention is anastrozole, the dosage is 1 mg, and the administration frequency is once a day.
  • the anti-HER2 antibody drug conjugates described in the present disclosure are administered once every two weeks or once every three weeks; the CDK4/6 inhibitors described in the present disclosure are administered once a day, wherein the medication is taken continuously for the first 2 weeks (day 1 to day 14) and then there is a week of rest (no medication) (day 15 to day 21), or the medication is taken continuously for the first 3 weeks and then there is a week of rest.
  • the anti-HER2 antibody drug conjugate described in the present disclosure is administered once every two weeks or once every three weeks; the treatment cycle of the SERD described in the present disclosure is one treatment cycle every 4 weeks, wherein the drug is administered on the 1st and 15th day of the first cycle, and then on the 1st day of each subsequent cycle.
  • the anti-HER2 antibody drug conjugate described in the present disclosure is administered once every two weeks or once every three weeks; the VEGF ligand inhibitor described in the present disclosure is administered once every three weeks.
  • the anti-HER2 antibody drug conjugate described in the present disclosure is administered once every two weeks or once every three weeks; the aromatase inhibitor described in the present disclosure is administered once a day, and the medication is taken continuously.
  • the anti-HER2 antibody drug conjugate described in the present disclosure is administered once every two weeks or once every three weeks; the CDK4/6 inhibitor described in the present disclosure is administered once a day, wherein the medication is taken continuously for the first 2 weeks (day 1 to day 14) and there is a rest (no medication) for the next week (day 15 to day 21), or the medication is taken continuously for the first 3 weeks and there is a rest for the next week; the aromatase inhibitor described in the present disclosure is administered once a day, and the medication is taken continuously.
  • the treatment cycle is one treatment cycle every two weeks, one treatment cycle every three weeks, or one treatment cycle every four weeks.
  • the present disclosure also provides a use of an anti-HER2 antibody-drug conjugate in combination with a second therapeutic agent in the preparation of a drug for treating breast cancer, wherein the structure of the antibody-drug conjugate is shown in formula (I):
  • n 3 to 8, and n is a decimal or an integer
  • Pc is an anti-HER2 antibody or an antigen-binding fragment thereof
  • the second therapeutic agent is selected from one or more of a CDK4/6 inhibitor, a SERD, a VEGF ligand inhibitor and an aromatase inhibitor.
  • the anti-HER2 antibody drug conjugate is used in combination with a CDK4/6 inhibitor.
  • the anti-HER2 antibody drug conjugate is used in combination with a SERD.
  • the anti-HER2 antibody drug conjugate is used in combination with a VEGF ligand inhibitor.
  • the anti-HER2 antibody drug conjugate is used in combination with an aromatase inhibitor.
  • the anti-HER2 antibody drug conjugate is used in combination with a CDK4/6 inhibitor and an aromatase inhibitor.
  • the breast cancer is HER2 low-expressing breast cancer.
  • the HER2 low-expressing breast cancer is a breast cancer whose HER2 expression is determined to be 1+ by immunohistochemistry, that is, IHC1+, such as IHC1+/ISH- or IHC1+/ISH not detected.
  • the HER2 low-expressing breast cancer is a breast cancer in which the expression of HER2 is determined to be 2+ by immunohistochemistry and the expression of HER2 is determined to be negative by in situ hybridization, that is, IHC2+/ISH-.
  • the HER2-low expressing breast cancer is unresectable, recurrent and/or metastatic breast cancer with HER2-low expressing.
  • the breast cancer is unresectable or metastatic breast cancer.
  • the breast cancer patient is a HR-positive patient or a HR-negative patient.
  • the breast cancer patient has received at least one line of endocrine therapy.
  • the breast cancer patient has not received or has received chemotherapy previously.
  • the treatment cycle of the present disclosure is one treatment cycle every two weeks, one treatment cycle every three weeks, or one treatment cycle every four weeks, for example, one treatment cycle every three weeks.
  • Another aspect of the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising the aforementioned anti-HER2 antibody-drug conjugate and a second therapeutic agent, and one or more pharmaceutically acceptable carriers, wherein the second therapeutic agent is selected from one or more of a CDK4/6 inhibitor, a SERD, a VEGF ligand inhibitor, and an aromatase inhibitor.
  • Another aspect of the present disclosure provides an anti-HER2 antibody drug couple for treating breast cancer with low HER2 expression. Joint objects.
  • Another aspect of the present disclosure provides the aforementioned anti-HER2 antibody-drug conjugate for use in treating breast cancer, wherein the anti-HER2 antibody-drug conjugate is used in combination with the aforementioned therapeutic agent.
  • compositions, uses and treatment methods disclosed herein can also be used as adjuvant chemotherapy in combination with a surgical procedure.
  • the treatment methods disclosed herein can be administered prior to a surgical procedure for the purpose of reducing tumor size (referred to as preoperative adjuvant chemotherapy or neoadjuvant therapy), or can be administered after a surgical procedure for the purpose of preventing tumor recurrence (referred to as postoperative adjuvant chemotherapy or adjuvant therapy).
  • the method of scoring the degree of HER2 expression by an immunohistochemical method or the method of determining the positivity or negativity of HER2 expression by an in situ hybridization method is not particularly limited as long as it is recognized by those skilled in the art.
  • Antibody drug conjugates are antibodies or antibody fragments connected to biologically active cytotoxins or small molecule drugs with cell-killing activity through stable chemical linker compounds, making full use of the antibody's specificity for tumor cell-specific or highly expressed antigens and the high efficiency of cytotoxins to avoid toxic side effects on normal cells. Compared with traditional chemotherapy drugs, antibody drug conjugates can accurately bind to tumor cells and reduce the impact on normal cells.
  • An antibody "retains its chemical stability" in a pharmaceutical formulation if the antibody drug conjugate does not show significant chemical changes. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein.
  • Degradation processes that often change the chemical structure of a protein include hydrolysis or truncation (assessed by methods such as size exclusion chromatography and CE-SDS), oxidation (assessed by methods such as peptide mapping in combination with mass spectrometry or MALDI/TOF/MS), deamidation (assessed by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, isoaspartate measurement), and isomerization (assessed by measuring isoaspartate content, peptide mapping, etc.).
  • An antibody drug conjugate "retains its biological activity" in a pharmaceutical formulation if the biological activity of the antibody drug conjugate at a given time is within a predetermined range of the biological activity exhibited when the pharmaceutical formulation is prepared.
  • an antibody described in the present disclosure is used in the broadest sense, covering various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (such as bispecific antibodies), full-length antibodies and antibody fragments (or antigen-binding fragments, or antigen-binding portions), as long as they exhibit the desired antigen-binding activity.
  • an antibody may refer to an immunoglobulin, which is a tetrapeptide chain structure in which a complete antibody is composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds. The amino acid composition and arrangement order of the constant region of the heavy chain of immunoglobulins are different, so their antigenicity is also different.
  • immunoglobulins can be divided into five categories, or so-called isotypes of immunoglobulins, namely IgM, IgD, IgG, IgA and IgE, and their corresponding heavy chains are ⁇ chain, ⁇ chain, ⁇ chain, and ⁇ chain, respectively.
  • the same class of Ig can be divided into different subclasses according to the difference in the amino acid composition of its hinge region and the number and position of heavy chain disulfide bonds.
  • IgG can be divided into IgG1, IgG2, IgG3, and IgG4.
  • Light chains are divided into ⁇ chains or ⁇ chains based on the differences in the constant region.
  • Each of the five types of Ig can have ⁇ chains or ⁇ chains.
  • the "antibody or its antigen binding” or “functional fragment” described in the present disclosure refers to the Fab fragment, Fab' fragment, F(ab')2 fragment with antigen binding activity, and the Fv fragment scFv fragment that binds to the antibody.
  • the Fv fragment contains the antibody heavy chain variable region and light chain variable region, but no constant region, and is the smallest antibody fragment with all antigen binding sites.
  • the Fv antibody also contains a polypeptide linker between the VH and VL domains, and is capable of forming the structure required for antigen binding.
  • Two antibody variable regions can also be connected into a polypeptide chain using different connectors, which is called a single-chain antibody (single chain antibody) or single-chain Fv (sFv).
  • linker unit or “linking fragment” or “linking unit” refers to a chemical structure fragment or bond that is connected to an antibody or its antigen-binding fragment at one end and to a drug at the other end, and can also be connected to other linkers before being connected to the drug.
  • the preferred embodiment of the present disclosure is represented by L and L1 to L4 , wherein the L1 end is connected to the antibody, and the L4 end is connected to the structural unit Y and then connected to the compound or toxin.
  • Linkers including extenders, spacers, and amino acid units, can be synthesized by methods known in the art, such as those described in US2005-0238649A1.
  • the linker can be a "cleavable linker" that facilitates release of the drug in the cell.
  • an acid-labile linker e.g., hydrazone
  • a protease-sensitive linker e.g., peptidase-sensitive
  • a photolabile linker e.g., peptidase-sensitive linker
  • a dimethyl linker e.g., a disulfide-containing linker
  • drug loading refers to the average number of cytotoxic drugs loaded on each antibody or antigen-binding fragment thereof in the molecule of formula (I), and can also be expressed as the ratio of the amount of drug to the amount of antibody.
  • the range of drug loading can be 0-12, preferably 1-10, more preferably 3-8, and most preferably 5.3-6.1 cytotoxic drugs (D) connected to each antibody or antigen-binding fragment thereof (Pc).
  • the drug loading is expressed as n, which can be exemplified as the average of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
  • the average number of drugs per ADC molecule after the coupling reaction can be identified by conventional methods such as UV/visible light spectroscopy, mass spectrometry, ELISA experiments, and HPLC characteristics.
  • the cytotoxic drug is coupled to the N-terminal amino group, the ⁇ -amino group of the lysine residue and/or the thiol group of the antibody or its antigen-binding fragment through a linker.
  • the number of drug molecules that can be coupled to the antibody in the coupling reaction will be less than the theoretical maximum value.
  • cytotoxic drugs can be controlled by the following non-limiting methods, including:
  • administering refers to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, a human, a subject, a cell, a tissue, an organ, or a biological fluid.
  • administering can refer to, for example, treatment, pharmacokinetic, diagnostic, research, and experimental procedures.
  • Treatment of cells includes contact of an agent with a cell, and contact of an agent with a fluid, wherein the fluid is in contact with a cell.
  • administering and “treating” also mean the contact of an agent, a diagnostic, a combination of a composition, or another agent.
  • An in vitro and ex vivo treatment of cells such as cells.
  • Treatment when applied to human, veterinary or research subjects refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.
  • Treatment means administering an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient who has one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect.
  • the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the treated patient or population to induce regression of such symptoms or inhibit the development of such symptoms to any clinically measurable degree.
  • the amount of therapeutic agent effective to alleviate any specific disease symptom may vary according to a variety of factors, such as the patient's disease state, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient.
  • Whether the disease symptom has been alleviated can be evaluated by any clinical test method commonly used by physicians or other professional health care personnel to evaluate the severity or progression of the symptom.
  • the embodiments of the present disclosure e.g., treatment methods or products
  • may not be effective in alleviating every target disease symptom they should alleviate the target disease symptoms in a statistically significant number of patients as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test.
  • an "effective amount” includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical disease.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • the effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's general health, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount may be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.
  • n refers to the average number of cytotoxic drugs loaded on each antibody or antigen-binding fragment thereof in the antibody drug conjugate molecule, and can also be expressed as the ratio of the amount of drug to the amount of antibody, which is the average number of drugs per ADC molecule after the coupling reaction is identified by hydrophobic chromatography (HIC) mass spectrometry.
  • HIC hydrophobic chromatography
  • the so-called “combination” is a mode of administration, which includes various situations in which two or more drugs are administered successively or simultaneously.
  • the modes of administration of simultaneous administration, independent preparation and co-administration, or independent preparation and sequential administration all belong to the combined administration described in the present disclosure.
  • the so-called “simultaneous” here refers to the administration of at least one dose of anti-HER2 antibody drug conjugate and other therapeutic agents within a certain time limit, for example, within 2 days, or within 1 day, where both substances show pharmacological effects.
  • the so-called “sequential" administration includes the situation in which anti-HER2 antibody drug conjugate and other therapeutic agents are administered separately in different administration cycles.
  • the time limit can be within a dosing cycle, and can be selected within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, within 24 hours, and within 2 hours. This time limit includes such treatments, in which anti-HER2 antibody drug conjugates and other therapeutic agents are administered by the same administration route or different administration routes.
  • n 6.0, i.e., ADC-32.
  • the underlined sequences are CDR sequences defined according to the Kabat numbering system, and the italicized sequences are constant region sequences.
  • Example 1 The anti-HER2 antibody drug conjugate described in Example 1, lyophilized powder injection, specification: 100 mg/bottle.
  • the dose of anti-HER2 antibody drug conjugates was 1.0 mg/kg, 2.0 mg/kg, 3.2 mg/kg, 4.8 mg/kg, 6.4 mg/kg or 8.0 mg/kg, intravenous drip, once every 3 weeks, and one cycle was 3 weeks (21 days).
  • ORR is shown as % (n/N, 95% CI) or % (n/N).
  • Subjects must undergo efficacy assessment every 6 weeks ( ⁇ 7 days) within the first 48 weeks after the first dose, and every 12 weeks ( ⁇ 7 days) thereafter. Imaging assessment is not affected by dosing interruptions or delays. Subjects who are first evaluated as CR or PR should be confirmed after 4 weeks (the next planned time point).
  • cBOR is the confirmed best overall tumor efficacy
  • cORR is the confirmed objective response rate
  • uORR is the objective response rate to be confirmed.
  • the tumor objective response rate (cORR) of confirmed HER2 low-expressing breast cancer patients can be as high as 64.9% (6.4 mg/kg administration) and 60.6% (5.6 mg/kg administration); and among all HER2 low-expressing breast cancer patients who received different doses, the cORR reached 59.1% and the uORR reached 67.3%.
  • the anti-HER2 antibody drug conjugate provided by the present disclosure can be used to treat HER2 low-expressing breast cancer patients and can exert a significant tumor inhibition effect.
  • PFS progression-free survival
  • mPFS median progression-free survival
  • 06-mo PFS rate is the progression-free survival rate at 6 months
  • 12-mo PFS rate is the progression-free survival rate at 12 months
  • 18-mo PFS rate is the progression-free survival rate at 18 months.
  • mDoR is the median duration of response.
  • the median progression-free survival (mPFS) can be as high as 13.8 months (6.4 mg/kg dosage), and the median duration of remission (mDoR) can be as high as 16.7 months (6.4 mg/kg dosage).
  • the median progression-free survival (mPFS) can reach 10.9 months, and the median duration of remission (mDoR) can reach 12.2 months.
  • the anti-HER2 antibody-drug conjugate provided by the present disclosure is used to treat patients with HER2 low-expressing breast cancer, which can significantly prolong the patient's progression-free survival time and tumor duration, so that patients with breast cancer with low HER2 expression can be effectively treated.
  • Example 4 An open, multicenter phase Ib/II clinical study of an anti-HER2 antibody drug conjugate combined with isethionate of the compound represented by formula (II), fulvestrant, bevacizumab, letrozole/anastrozole for the treatment of unresectable or metastatic breast cancer with low HER2 expression
  • Example 1 The anti-HER2 antibody drug conjugate described in Example 1, lyophilized powder injection, specification: 100 mg/bottle.
  • Fulvestrant injection (Pulahe), injection, specifications: 5ml: 0.25g.
  • Bevacizumab injection (Areto), injection, specifications: 100mg (4ml)/bottle.
  • age ⁇ 60 natural postmenopausal status (defined as spontaneous cessation of regular menstruation for at least 12 consecutive months without other pathological or physiological reasons), estradiol (E2) and follicle-stimulating hormone (FSH) at postmenopausal levels; or
  • Premenopausal or perimenopausal female patients may also be included, but must be willing to receive luteinizing hormone-releasing hormone (LHRH) agonist treatment during the study.
  • LHRH luteinizing hormone-releasing hormone
  • Phase I dose finding: Patients have received at least 1 line of endocrine therapy, and ⁇ 2 lines of chemotherapy are allowed.
  • Phase II (Expansion of Efficacy): Patients who have received ⁇ 1 line of endocrine therapy and have not received chemotherapy during the recurrence/metastasis stage are allowed.
  • Phase I dose finding: Patients have received at least 1 line of chemotherapy.
  • Phase II (expansion of efficacy): Recurrence/metastasis stage with no prior systemic anti-tumor treatment.
  • the dose-finding phase aims to evaluate the safety, tolerability, pharmacokinetic characteristics and immunogenicity of the anti-HER2 antibody-drug conjugate combined with the compound represented by formula (II), isethionate, fulvestrant, and bevacizumab, and to preliminarily observe its anti-tumor efficacy.
  • the dose of anti-HER2 antibody drug conjugate is 2.0 mg/kg, 3.2 mg/kg or 4.8 mg/kg, intravenous drip, once every 3 weeks, and each 3 weeks (21 days) is a cycle;
  • the dosage of the isethionate salt of the compound represented by formula (II) is 100 mg, 125 mg, and 150 mg, taken orally once a day, and one course of treatment is 2 weeks of taking and 1 week of stopping.
  • the administration cycle, administration sequence and dosage of the study drug can be adjusted, including but not limited to: a. adjusting the administration cycle of the anti-HER2 antibody drug conjugate to once every 2 weeks, and adjusting the dosage accordingly; b. adjusting the treatment course of the isethionate salt of the compound represented by formula (II) to take for 3 weeks/stop for 1 week; c. adjusting the administration sequence of the anti-HER2 antibody drug conjugate and the isethionate salt of the compound represented by formula (II), such as administering at intervals of several days.
  • Anti-HER2 antibody-drug conjugate combined with fulvestrant
  • the dose of anti-HER2 antibody drug conjugate was 2.0 mg/kg, 3.2 mg/kg or 4.8 mg/kg, administered once every 3 weeks.
  • the dose of Fulvestrant is 500 mg, and one treatment course is every 4 weeks, with administration on days 1 and 15 of the first treatment course and on day 1 of each subsequent treatment course.
  • the administration cycle, administration sequence and dosage of the study drug may be adjusted, including but not limited to: adjusting the administration cycle of the anti-HER2 antibody drug conjugate to once every 2 weeks and adjusting the dosage accordingly.
  • the dose of anti-HER2 antibody drug conjugate was 2.0 mg/kg, 3.2 mg/kg or 4.8 mg/kg, administered once every 3 weeks.
  • the dose of bevacizumab was fixed at 15 mg/kg, administered once every 3 weeks.
  • the administration cycle, administration sequence and dosage of the study drug may be adjusted, including but not limited to: adjusting the administration cycle of the anti-HER2 antibody drug conjugate to once every 2 weeks and adjusting the dosage accordingly.
  • the efficacy expansion phase aims to observe and evaluate the preliminary efficacy, safety, pharmacokinetic characteristics and immunogenicity of the anti-HER2 antibody drug conjugate combined with the isethionate salt of the compound represented by formula (II) and letrozole/anastrozole, fulvestrant, letrozole/anastrozole, and bevacizumab.
  • At least one dose group of the anti-HER2 antibody drug conjugate and the isethionate of the compound represented by formula (II) combined with letrozole or anastrozole is selected for efficacy expansion.
  • Letrozole is taken orally, once a day, 2.5 mg each time, for continuous medication.
  • Anastrozole is taken orally, once a day, 1 mg each time, for continuous medication.
  • Anti-HER2 antibody-drug conjugate combined with fulvestrant
  • Letrozole is taken orally, once a day, 2.5 mg each time, for continuous medication.
  • Anastrozole is taken orally, once a day, 1 mg each time, for continuous medication.
  • At least one dose group will be selected for efficacy expansion.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

抗HER2抗体药物偶联物在制备治疗HER2低表达乳腺癌的药物中的用途，所述抗体药物偶联物的结构如式（I）所示。

Description

抗HER2抗体药物偶联物治疗乳腺癌
本公开要求如下专利申请的优先权：于2023年01月19日提交，申请号为202310066299X的中国专利申请；于2023年02月15日，申请号为2023101211954的中国专利申请。前述专利申请的全部内容通过引用结合至本公开中。
技术领域
本公开属于医药领域，涉及抗HER2抗体药物偶联物(antibody-drug conjugate，ADC)在制备治疗乳腺癌的药物中的用途。
背景技术
乳腺癌是世界范围内最常见的恶性肿瘤。根据GLOBOCAN2020统计数据，乳腺癌的发病率和死亡率均位居女性恶性肿瘤首位，全球每年乳腺癌新发病例数约226万，死亡68.5万，位居女性恶性肿瘤发病率和死亡率首位。
临床中，大约有55％的乳腺癌患者为HER2低表达，HER2低表达是指免疫组化(IHC)评分1+或IHC 2+且原位杂交(ISH)-。现有的HER2靶向药物未能显示出明显获益。HER2低表达转移性乳腺癌存在巨大的、未被满足的临床需求。首先，针对HER2低表达患者，既往治疗上等同于HER2阴性患者，晚期治疗选择有限；其次、针对HR+/HER2-患者，接受CDK4/6抑制剂或内分泌治疗耐药后出现疾病进展，后续选择有限。
HER2是I型跨膜酪氨酸激酶受体家族的一员，其在单体状态下基本无活性，但可与家族其他3个跨膜酪氨酸激酶成员HER1、HER3、HER4发生聚合作用，导致受体酪氨酸残基的磷酸化、启动多种信号通路(如MAPK、PI3K/Akt等)，从而促进细胞增殖和肿瘤发生发展。
以HER2为靶点的ADCs通过以下方式发挥作用，首先，ADC中的抗体特异性识别并结合靶细胞表面的HER2受体，然后通过内吞作用进入靶细胞，在胞内经分解释放出细胞毒药物，最后细胞毒药物通过破坏DNA或者作用于微管蛋白，诱导细胞的凋亡，从而发挥抗肿瘤作用。若细胞毒药物具有高透膜性，其在靶细胞内被释放后或可穿透至细胞外间隙，杀伤周围的HER2阴性细胞，该作用即被称为旁路杀伤效应。若细胞毒药物在ADC内吞发生之前被释放，也可能产生该效应。WO2020063676A公开了一类以HER2为靶点的ADCs，鉴于已经获批上市的HER-2ADC药物Trastuzumab emtansine(TDM-1)及Trastuzumab Deruxtecan(DS-8201)在乳腺癌、胃癌治疗方面的优异效果，对WO2020063676A中的抗体药物偶联物进行适应症方面的研究具有重大意义。
综上所述，对于HER2低表达的乳腺癌患者，亟需提供更加安全、有效的临床治疗方案。
发明内容
本公开提供一种抗HER2抗体药物偶联物治疗肿瘤的医药用途及方法。
一些实施方案中，本公开提供抗HER2抗体药物偶联物的如下任一用途或方法：
(1)抗HER2抗体药物偶联物在制备治疗HER2低表达乳腺癌的药物中的用途，
(2)抗HER2抗体药物偶联物，用于治疗HER2低表达乳腺癌，
(3)治疗HER2低表达乳腺癌的方法，其包括向有需要的受试者施用抗HER2抗体药物偶联物。
一些实施方案中，所述抗体药物偶联物的结构如式(I)所示：
其中：
n为3至8，n是小数或整数；例如，n为3、4、5、6、7、8或前述任意两个数值之间的任意整数或小数。
Pc为抗HER2抗体。
在本公开中，“抗体”以最广义使用，其涵盖各种抗体结构，包括但不限于单克隆抗体，多克隆抗体，多特异性抗体(例如双特异性抗体)，全长抗体或其抗原结合片段(也称“抗原结合部分”)，只要它们展现出期望的抗原结合活性。”
一些实施方案中，本公开所述抗HER2抗体或其抗原结合片段选自曲妥珠单抗(Trastuzumab)，或其抗原结合片段，帕妥珠单抗(Pertuzumab)或其抗原结合片段。
一些实施方案中，本公开所述抗HER2抗体或其抗原结合片段为曲妥珠单抗或其抗原结合片段。
一些实施方案中，抗HER2抗体包含重链可变区(VH)和轻链可变区(VL)：其中所述重链可变区包含分别如SEQ ID NO：1、SEQ ID NO：2和SEQ ID NO：3所示的HCDR1、HCDR2和HCDR3，所述轻链可变区包含分别如SEQ ID NO：4、SEQ ID NO：5和SEQ ID NO：6所示的LCDR1、LCDR2和LCDR3。
其中，前面所述的各CDR序列如下表1所示：

在一些具体的实施方案中，所述CDR是根据Kabat编号系统定义的。
在一些实施方案中，抗HER2抗体包含前述HCDR1、HCDR2、HCDR3、LCDR1、LCDR2和LCDR3中的任意1个、2个、3个、4个、5个或6个。
在一些实施方案中，抗HER2抗体为人源化抗体。在一些具体的实施方案中，重链可变区包含如SEQ ID NO：9所示的氨基酸序列，或与之具有至少80％序列同一性的氨基酸序列；轻链可变区包含如SEQ ID NO：10所示的氨基酸序列，或与之具有至少80％序列同一性的氨基酸序列。
重链可变区：
轻链可变区：
在一些实施方案中，抗HER2抗体，其包含前述VH、VL中的任意一个或任意2个的组合。
在一些实施方案中，抗HER2抗体进一步包含重链恒定区和/或轻链恒定区。示例性地，将上述轻链/重链恒定区与前述抗体的可变区组合形成完整的抗体，其轻链/重链序列如下：
重链：
轻链：
一些实施方案中，所述抗HER2抗体的重链包含如SEQ ID NO：2所示的氨基酸序列，或与之具有至少80％序列同一性的氨基酸序列；轻链包含如SEQ ID NO：1所示的 氨基酸序列，或与之具有至少80％序列同一性的氨基酸序列。
在一些实施方案中，本公开提供的抗HER2抗体，其包含前述重链、轻链中的任意一个或任意2个的组合。
在本公开的上下文中，“至少80％”涵盖80％及以上，例如至少80％、至少81％、至少82％、至少83％、至少84％、至少85％、至少86％、至少87％、至少88％、至少89％、至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％，以及任意两者之间的数值范围。
一些实施方案中，如上所述的抗HER2抗体-药物偶联物可以参照WO2021190581A中的方法制备。本公开通过引用将WO2021190581A中ADC结构、抗体序列及制备方法的相关内容并入本公开。
一些实施方案中，本公开所述的抗HER2抗体药物偶联物具有如下式所示的结构：
其中，n为3至8，n是小数或整数。
一些实施方案中，n为6±0.8。例如，n为5.2、5.3、5.4、5.5、5.6、5.7、5.8、5.9、6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、或6.8。
可选的实施方案中，本公开所述的抗HER2抗体药物偶联物中n为6。
在本公开中，所述的“HER2低表达乳腺癌”没有特别限制，只要其被本领域技术人员认为是HER2低表达乳腺癌即可。HER2低表达乳腺癌的优选实例可以包括IHC2+且ISH阴性，IHC1+且ISH阴性，IHC1+且ISH未测，0＜IHC＜1+。
一些实施方案中，所述的HER2低表达乳腺癌是通过免疫组织化学法判定HER2的表达为1+的乳腺癌。也即，IHC1+，例如IHC1+/ISH-或IHC1+/ISH未测。
一些实施方案中，所述的HER2低表达乳腺癌是通过免疫组织化学法判定HER2的表达为2+，且通过原位杂交法判定HER2的表达为阴性的乳腺癌。也即，IHC2+/ISH-。
一些实施方案中，所述的HER2低表达乳腺癌为HER2低表达的不可切除、复发和/或转移性乳腺癌。
一些实施方案中，所述的HER2低表达乳腺癌为HER2低表达不可切除或转移性乳腺癌。
一些实施方案中，所述的HER2低表达乳腺癌为HER2低表达复发或转移性乳腺癌患者。
一些实施方案中，乳腺癌患者为HR阳性患者或HR阴性患者。
一些实施方案中，乳腺癌患者至少接受过1线内分泌治疗。
一些实施方案中，乳腺癌患者既往未接受或接受过化疗。
一些实施方案中，所述的HER2低表达乳腺癌患者既往接受抗HER2药物的治疗。在一些实施方案中，所述HER2低表达乳腺癌患者既往接受抗HER2药物的治疗后产生耐性或难治性。
在本公开中，“耐性”或“难治性”表示对于基于抗癌剂的治疗而无应答的性质，也可表达为“无应答性”、“无反应性”。
在一些实施方案中，本公开提供的抗HER2抗体药物偶联物用于治疗HER2低表达乳腺癌患者，可以显著提高患者的肿瘤客观缓解率和无进展生存时间，特别是在6.4mg/kg的给药剂量下，可达到64.9％的cORR，和13.8个月的mPFS，与同靶点其他ADC药物相比具有显著治疗优势，为HER2低表达乳腺癌患者提供了积极有效的临床治疗方案。
在一些实施方案中，本公开提供的抗HER2抗体药物偶联物施用于受试者，能够显著降低间质性肺炎发生率，具有提高的临床安全性，有利于拓宽临床给药窗口。
一些实施方案中，所述抗HER2抗体药物偶联物与第二治疗剂联用。
一些实施方案中，所述第二治疗剂选自CDK4/6抑制剂、SERD、VEGF配体抑制剂、芳香化酶抑制剂和CDK4/6抑制剂中的一种或两种以上的组合。
一些实施方案中，所述抗HER2抗体药物偶联物与CDK4/6抑制剂联用。
一些实施方案中，所述抗HER2抗体药物偶联物与SERD(选择性雌激素受体降解剂)联用。
一些实施方案中，所述抗HER2抗体药物偶联物与VEGF配体抑制剂联用。
一些实施方案中，所述抗HER2抗体药物偶联物与芳香化酶抑制剂联用。
一些实施方案中，所述抗HER2抗体药物偶联物与CDK4/6抑制剂以及芳香化酶抑制剂联用。
一些实施方案中，本公开所述的CDK4/6抑制剂选自abemaciclib、ribociclib、palbociclib、alvocidib、trilaciclib、voruciclib、AT-7519、G1T-38、FLX-925、INOC-005、G1T28-1、BPI-1178、gossypin、G1T30-1、GZ-38-1、P-276-00、staurosporine、R-547、PAN-1215、PD-0183812、AG-024322、NSC-625987、CGP-82996、PD-171851和式(II)所示化合物或其可药用盐。一些实施方案中，所述的CDK4/6抑制剂为式(II)所示化合物或其可药用盐，
一些实施方案中，所述式II所示化合物的可药用盐为羟乙基磺酸盐。
一些实施方案中，本公开所述的SERD选自氟维司群、AZD-9496、RAD1901和ZB-716。一些实施方案中，所述的SERD为氟维司群。
一些实施方案中，本公开所述的VEGF配体抑制剂选自贝伐珠单抗、雷莫芦单抗、雷珠单抗、阿柏西普、康柏西普、Abicipar pegol、Brolucizumab、LMG-324、Nesvacumab、Sevacizumab、Tanibirumab、Navicixizumab、RG-7716、LHA-510、OPT-302、TK-001、GZ-402663、VGX-100、PG-545、BI-836880、GNR-011、BR-55、OTSGC-A24、PAN-90806、AVA-101、ODM-203、TAS-115、X-82、MP-0250、Sitravatinib、4SC-203、AL-2846、ABT-165、SIM-010603、BI-836880、HL-217、CS-2164、RGX-314、AMC-303和VXM-01。一些实施方案中，所述的VEGF配体抑制剂为贝伐珠单抗。
一些实施方案中，本公开所述的芳香化酶抑制剂选自福美坦、依西美坦、法倔唑、来曲唑、伏氯唑和阿那曲唑。一些实施方案中，所述的芳香化酶抑制剂为来曲唑或阿那曲唑。
一些实施方案中，本公开所述的抗HER2抗体药物偶联物的给药剂量为1.0mg/kg-10.0mg/kg。可选的实施方案中，本公开所述的抗HER2抗体药物偶联物的给药剂量为1.0mg/kg、1.2mg/kg、1.4mg/kg、1.6mg/kg、1.8mg/kg、2.0mg/kg、2.2mg/kg、2.4mg/kg、2.6mg/kg、2.8mg/kg、3.0mg/kg、3.2mg/kg、3.4mg/kg、3.6mg/kg、3.8mg/kg、4.0mg/kg、4.2mg/kg、4.4mg/kg、4.6mg/kg、4.8mg/kg、5.0mg/kg、5.2mg/kg、5.4mg/kg、5.6mg/kg、5.8mg/kg、6.0mg/kg、6.2mg/kg、6.4mg/kg、6.6mg/kg、6.8mg/kg、7.0mg/kg、7.2mg/kg、7.4mg/kg、7.6mg/kg、7.8mg/kg、8.0mg/kg、8.2mg/kg、8.4mg/kg、8.6mg/kg、8.8mg/kg、9.0mg/kg、9.2mg/kg、9.4mg/kg、9.6mg/kg、9.8mg/kg或10.0mg/kg。可选的实施方案中，本公开所述的抗HER2抗体药物偶联物的给药剂量为1.0mg/kg，2.0mg/kg，3.2mg/kg，4.8mg/kg，5.6mg/kg、6.4mg/kg或8.0mg/kg。
一些实施方案中，本公开所述的抗HER2抗体药物偶联物的给药频次为每一周至少一次，每二周至少一次，每三周至少一次，每四周至少一次或每六周至少一次。可选的实施方案中，给药频次为每一周一次，每二周一次，每三周一次或每四周一次。可选的实施方案中，给药频次为每二周一次或每三周一次。
可选的实施方案中，本公开所述的抗HER2抗体药物偶联物的给药剂量为1.0mg/kg， 2.0mg/kg，3.2mg/kg，4.8mg/kg，5.6mg/kg，6.4mg/kg或8.0mg/kg，给药频次为每二周一次或每三周一次。
一些实施方案中，本公开所述的CDK4/6抑制剂的给药剂量为1-1000mg。可选的实施方案中，本公开所述的CDK4/6抑制剂的给药剂量可以是5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、100mg、125mg、150mg、175mg、200mg、250mg、300mg、350mg、400mg、450mg、500mg，600mg、700mg、750mg、800mg、900mg、1000mg。可选的实施方案中，剂量为100mg、125mg、150mg。
给药频次可以是一日一次、一日二次、一日三次、一周一次、二周一次、三周一次或一月一次。可选的实施方案中，给药频次为一日一次。
可选的实施方案中，本公开所述的CDK4/6抑制剂的给药剂量为75mg、100mg、125mg、150mg，给药频次为一日一次。
一些实施方案中，本公开所述的SERD的给药剂量为1-1000mg。可选的实施方案中，本公开所述的SERD的给药剂量可以是5mg、10mg、12.5mg、15mg、17.5mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、60mg、70mg、75mg、80mg、90mg、100mg、125mg、150mg、175mg、200mg、225mg、250mg、275mg、300mg、325mg、350mg、375mg、400mg、425mg、450mg、475mg、500mg、600mg、700mg、750mg、800mg、900mg、1000mg。可选的实施方案中，本公开所述的SERD的给药剂量为500mg。
一些实施方案中，本公开所述的SERD的给药频次可以是一日一次、一日二次、一日三次、一周一次、二周一次、三周一次或一月一次。一些实施方案中，给药频次可以是一日一次、一周一次、二周一次、三周一次或一月一次，例如二周一次或一月一次。
可选的实施方案中，本公开所述的SERD的给药剂量为500mg，给药频次为二周一次或一月一次。
一些实施方案中，本公开所述的VEGF配体抑制剂的给药剂量为0.1-100mg/kg。可选的实施方案中，本公开所述的VEGF配体抑制剂的给药剂量可以是0.5mg/kg、1mg/kg、2mg/kg、2.5mg/kg、3mg/kg、4mg/kg、5mg/kg、6mg/kg、7mg/kg、7.5mg/kg、8mg/kg、9mg/kg、10mg/kg、12.5mg/kg、12mg/kg、15mg/kg、17.5mg/kg、20mg/kg、25mg/kg、30mg/kg。可选的实施方案中，本公开所述的VEGF配体抑制剂的给药剂量为15mg/kg。
一些实施方案中，本公开所述的VEGF配体抑制剂的给药频次可以是一日一次、一周一次、二周一次、三周一次或一月一次。可选的实施方案中，给药频次可以是一周一次、二周一次、三周一次或一月一次。可选的实施方案中，给药频次为三周一次。
可选的实施方案中，本公开所述的VEGF配体抑制剂的给药剂量为15mg/kg，给药频次为三周一次。
一些实施方案中，本公开所述的芳香化酶抑制剂的给药剂量为0.1-50mg。可选的实施方案中，本公开所述的芳香化酶抑制剂的给药剂量可以是0.1mg、0.25mg、0.5mg、0.75mg、1mg、1.25mg、1.5mg、1.75mg、2mg、2.25mg、2.5mg、2.75mg、3mg、3.25mg、 3.5mg、3.75mg、4mg、4.25mg、4.5mg、4.75mg、5mg、5.5mg、6mg、6.5mg、7mg、7.5mg、8mg、8.5mg、9mg、9.5mg、10mg、12.5mg、15mg、17.5mg、20mg、25mg、30mg、35mg、40mg、45mg或50mg。可选的实施方案中，本公开所述的芳香化酶抑制剂的给药剂量为0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg或5.0mg。
可选的实施方案中，本公开所述的芳香化酶抑制剂给药频次为一日一次、一日两次。可选的实施方案中，给药频次为一日一次、一日两次。
可选的实施方案中，本公开所述的芳香化酶抑制剂的给药剂量为0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg或5.0mg，给药频次为一日一次、一日两次。
可选的实施方案中，本公开所述的芳香化酶抑制剂为来曲唑，给药剂量为2.5mg，给药频次为一日一次。
可选的实施方案中，本公开所述的芳香化酶抑制剂为阿那曲唑，给药剂量为1mg，给药频次为一日一次。
一些实施方案中，本公开所述的抗HER2抗体药物偶联物每二周给药一次或每三周给药一次；本公开所述的CDK4/6抑制剂一日给药一次，其中前2周(第1天至第14天)连续服药，后1周(第15天至第21天)休息(不服药)，或前3周连续服药，后1周休息。
可选的实施方案中，本公开所述的抗HER2抗体药物偶联物的每二周给药一次或每三周给药一次；本公开所述的SERD的治疗周期为每4周为一个治疗周期，其中第一周期第1天和第15天给药，随后每个周期的第1天给药。
可选的实施方案中，本公开所述的抗HER2抗体药物偶联物的每二周给药一次或每三周给药一次；本公开所述的VEGF配体抑制剂每三周给药一次。
可选的实施方案中，本公开所述的抗HER2抗体药物偶联物的每二周给药一次或每三周给药一次；本公开所述的芳香化酶抑制剂一日给药一次，连续服药。
可选的实施方案中，本公开所述的抗HER2抗体药物偶联物每二周给药一次或每三周给药一次；本公开所述的CDK4/6抑制剂一日给药一次，其中前2周(第1天至第14天)连续服药，后1周(第15天至第21天)休息(不服药)，或前3周连续服药，后1周休息；本公开所述的芳香化酶抑制剂一日给药一次，连续服药。
一些实施方案中，治疗周期为每两周一个治疗周期，每三周一个治疗周期或每四周一个治疗周期。
本公开还提供一种抗HER2抗体药物偶联物联合第二治疗剂在制备治疗乳腺癌的药物中的用途，所述抗体药物偶联物的结构如式(I)所示：
其中：
n为3至8，n是小数或整数；
Pc为抗HER2抗体或其抗原结合片段，
所述第二治疗剂选自CDK4/6抑制剂、SERD、VEGF配体抑制剂和芳香化酶抑制剂中的一种或多种。
一些实施方案中，所述抗HER2抗体药物偶联物与CDK4/6抑制剂联用。
一些实施方案中，所述抗HER2抗体药物偶联物与SERD联用。
一些实施方案中，所述抗HER2抗体药物偶联物与VEGF配体抑制剂联用。
一些实施方案中，所述抗HER2抗体药物偶联物与芳香化酶抑制剂联用。
一些实施方案中，所述抗HER2抗体药物偶联物与CDK4/6抑制剂以及芳香化酶抑制剂联用。
一些实施方案中，所述的乳腺癌为HER2低表达乳腺癌。
一些实施方案中，所述的HER2低表达乳腺癌是通过免疫组织化学法判定HER2的表达为1+的乳腺癌。也即，IHC1+，例如IHC1+/ISH-或IHC1+/ISH未测。
一些实施方案中，所述的HER2低表达乳腺癌是通过免疫组织化学法判定HER2的表达为2+，且通过原位杂交法判定HER2的表达为阴性的乳腺癌。也即，IHC2+/ISH-。
一些实施方案中，所述的HER2低表达乳腺癌为HER2低表达的不可切除、复发和/或转移性乳腺癌。
可选的实施方案中，所述的乳腺癌为不可切除或转移性乳腺癌。
可选的实施方案中，乳腺癌患者为HR阳性患者或HR阴性患者。
可选的实施方案中，乳腺癌患者至少接受过1线内分泌治疗。
可选的实施方案中，乳腺癌患者既往未接受或接受过化疗。
在一些实施方式中，本公开的治疗周期为每两周一个治疗周期，每三周一个治疗周期或每四周一个治疗周期，例如是每三周一个治疗周期。
本公开另一方面提供一种药物组合物，包含前述抗HER2抗体药物偶联物和第二治疗剂，以及一种或多种药学上可接受的载体，其中所述第二治疗剂选自CDK4/6抑制剂、SERD、VEGF配体抑制剂和芳香化酶抑制剂中的一种或多种。
本公开另一方面提供一种用于治疗HER2低表达乳腺癌的前述抗HER2抗体药物偶 联物。
本公开另一方面提供一种用于治疗乳腺癌的前述抗HER2抗体药物偶联物，所述抗HER2抗体药物偶联物与前述治疗剂联合使用。
本公开的药物组合物、用途和治疗方法还可以作为辅助化学疗法与手术程序组合使用。本公开的治疗方法可以在手术程序之前施用以用于减小肿瘤大小的目的(称为手术前辅助化学疗法或新辅助疗法)，或者可以在手术程序之后施用以用于预防肿瘤复发的目的(称为手术后辅助化学疗法或辅助疗法)。
通过免疫组织化学方法对HER2表达的程度进行评分的方法或通过原位杂交方法确定HER2表达的阳性或阴性的方法没有特别限制，只要其被本领域技术人员认识到即可。
术语
为了更容易理解本公开，以下具体定义了某些技术和科学术语。除非在本文中另有明确定义，本文使用的所有其它技术和科学术语都具有本公开所属领域的一般技术人员通常理解的含义。
本公开将申请WO2020063676A中的全部内容引入本申请。
“抗体药物偶联物(antibody drug conjugate，ADC)”是把抗体或者抗体片段通过稳定的化学接头化合物与具有生物活性的细胞毒素或具有细胞杀伤活性的小分子药物相连，充分利用了抗体对肿瘤细胞特异或高表达抗原结合的特异性和细胞毒素的高效性，避免对正常细胞的毒副作用。与以往传统的化疗药物相比，抗体药物偶联物能精准地结合肿瘤细胞并降低对正常细胞的影响。
如果抗体药物偶联物没有显示出显著的化学改变，那么所述抗体在药物制剂中“保留它的化学稳定性”。通过检测和定量化学上改变的形式的蛋白，可以评估化学稳定性。经常改变蛋白化学结构的降解过程包括水解或截短(通过诸如尺寸排阻色谱法和CE-SDS等方法来评价)、氧化(通过诸如与质谱法或MALDI/TOF/MS结合的肽谱法等方法来评价)、脱酰胺作用(通过诸如离子交换色谱法、毛细管等电聚焦、肽谱法、异天冬氨酸测量等方法来评价)和异构化(通过测量异天冬氨酸含量、肽谱法等来评价)。
如果抗体药物偶联物在给定时间的生物活性是在制备药物制剂时表现出的生物活性的预定范围内，那么所述抗体药物偶联物在药物制剂中“保留它的生物活性”。
本公开所述的“抗体”以最广义使用，涵盖各种抗体结构，包括但不限于单克隆抗体，多克隆抗体；单特异性抗体，多特异性抗体(例如双特异性抗体)，全长抗体和抗体片段(或抗原结合片段，或抗原结合部分)，只要它们展现出期望的抗原结合活性。例如，抗体可以指免疫球蛋白，是完整抗体由两条相同的重链和两条相同的轻链通过链间二硫键连接而成的四肽链结构。免疫球蛋白重链恒定区的氨基酸组成和排列顺序不同，故其抗原性也不同。据此，可将免疫球蛋白分为五类，或称为免疫球蛋白的同种型，即IgM、IgD、IgG、IgA和IgE，其相应的重链分别为μ链、δ链、γ链、α链、和ε链。同一类Ig根据其铰链区氨基酸组成和重链二硫键的数目和位置的差别，又可分为不同的亚类， 如IgG可分为IgG1、IgG2、IgG3、IgG4。轻链通过恒定区的不同分为κ链或λ链。五类Ig中每类Ig都可以有κ链或λ链。
本公开中所述的“抗体或其抗原结合”或“功能片段”，指具有抗原结合活性的Fab片段，Fab’片段，F(ab’)2片段，以及与抗体结合的Fv片段scFv片段。Fv片段含有抗体重链可变区和轻链可变区，但没有恒定区，并具有全部抗原结合位点的最小抗体片段。一般地，Fv抗体还包含在VH和VL结构域之间的多肽接头，且能够形成抗原结合所需的结构。也可以用不同的连接物将两个抗体可变区连接成一条多肽链，称为单链抗体(single chain antibody)或单链Fv(sFv)。
术语“接头单元”或“连接片段”或“连接单元”是指一端与抗体或其抗原结合片段连接而另一端与药物相连的化学结构片段或键，也可以连接其他接头后再与药物相连。本公开的优选方案表示为L和L1至L4，其中L1端与抗体相连，L4端与结构单元Y相连后与化合物或毒素相连。
接头，包括延伸物、间隔物和氨基酸单元，可以通过本领域已知方法合成，诸如US2005-0238649A1中所记载的。接头可以是便于在细胞中释放药物的“可切割接头”。例如，可使用酸不稳定接头(例如腙)、蛋白酶敏感(例如肽酶敏感)接头、光不稳定接头、二甲基接头、或含二硫化物接头(Chari等,Cancer Research 52:127-131(1992)；美国专利No.5,208,020)。
术语“载药量”是指式(I)分子中每个抗体或其抗原结合片段上加载的细胞毒性药物平均数量，也可以表示为药物量和抗体量的比值，药物载量的范围可以是每个抗体或其抗原结合片段(Pc)连接0-12个，优选1-10个，更优选3-8个，最优选5.3-6.1个细胞毒性药物(D)。在本公开的实施方式中，载药量表示为n，示例性的可以为1，2，3，4，5，6，7，8，9，10的均值。可用常规方法如UV/可见光光谱法，质谱，ELISA实验和HPLC特征鉴定偶联反应后每个ADC分子的药物品均数量。
本公开的一个实施方式中，细胞毒性药物通过连接单元偶联在抗体或其抗原结合片段的N端氨基、赖氨酸残基的ε-氨基和/或巯基上，一般地，偶联反应中能与抗体偶联的药物分子数将小于理论上的最大值。
可以用以下非限制性方法控制细胞毒性药物的载量，包括：
(1)控制连接试剂和单抗的摩尔比，
(2)控制反应时间和温度，
(3)选择不同的反应试剂。
常规的药物组合物的制备见中国药典。
“给予”和“处理”当应用于动物、人、实验受试者、细胞、组织、器官或生物流体时，是指外源性药物、治疗剂、诊断剂或组合物与动物、人、受试者、细胞、组织、器官或生物流体的接触。“给予”和“处理”可以指例如治疗、药物代谢动力学、诊断、研究和实验方法。细胞的处理包括试剂与细胞的接触，以及试剂与流体的接触，其中所述流体与细胞接触。“给予”和“处理”还意指通过试剂、诊断、结合组合物或通过另 一种细胞体外和离体处理例如细胞。“处理”当应用于人、兽医学或研究受试者时，是指治疗处理、预防或预防性措施，研究和诊断应用。
“治疗”意指给予患者内用或外用治疗剂，例如包含本公开的任一种结合化合物的组合物，所述患者具有一种或多种疾病症状，而已知所述治疗剂对这些症状具有治疗作用。通常，在受治疗患者或群体中以有效缓解一种或多种疾病症状的量给予治疗剂，以诱导这类症状退化或抑制这类症状发展到任何临床可测量的程度。有效缓解任何具体疾病症状的治疗剂的量(也称作“治疗有效量”)可根据多种因素变化，例如患者的疾病状态、年龄和体重，以及药物在患者产生需要疗效的能力。通过医生或其它专业卫生保健人士通常用于评价该症状的严重性或进展状况的任何临床检测方法，可评价疾病症状是否已被减轻。尽管本公开的实施方案(例如治疗方法或制品)在缓解每个目标疾病症状方面可能无效，但是根据本领域已知的任何统计学检验方法如Student t检验、卡方检验、依据Mann和Whitney的U检验、Kruskal-Wallis检验(H检验)、Jonckheere-Terpstra检验和Wilcoxon检验确定，其在统计学显著数目的患者中应当减轻目标疾病症状。
“有效量”包含足以改善或预防医学疾病的症状或病症的量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：例如，待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。
本公开抗HER2抗体药物偶联物中“n”是指抗体药物偶联物分子中每个抗体或其抗原结合片段上加载的细胞毒性药物平均数量，也可以表示为药物量和抗体量的比值，为经疏水色谱法(HIC)质谱鉴定偶联反应后每个ADC分子的药物平均数量。
本公开中，所谓“联合”是一种给药方式，其包括两种或多种药物先后，或同时给药的各种情况。同时给药、独立地配制并共给药或独立地配制并相继给药的给药方式，均属于本公开所述的联合给药。此处所谓“同时”是指一定时间期限内给予至少一种剂量的抗HER2抗体药物偶联物和其他治疗剂，例如在2天内，或1天内给予两种药物，其中两种物质都显示药理学作用。所谓“先后”给药，则包括在不同给药周期内分别给予抗HER2抗体药物偶联物和其他治疗剂的情况。所述的时间期限可以是一个给药周期内，可选4周内，3周内，2周内，1周内，24小时以内，2小时以内。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予抗HER2抗体药物偶联物和其他治疗剂。
具体实施方式
以下结合实施例进一步描述本公开，但这些实施例并非是对本公开范围的限制。本公开实施例中未注明具体条件的实验方法，通常按照常规条件，如参照冷泉港实验室出版的《抗体技术实验手册》，《分子克隆手册》；或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。
实施例1.抗HER2抗体药物偶联物的制备
根据WO2021190581A中描述的生产方法，使用了Trastuzumab(抗HER2抗体)与依喜替康类似物制备如下结构所示的抗HER2抗体-药物偶合物，HIC方法计算平均值：n＝6.0，即ADC-32。
以下为Trastuzumab的序列：
轻链：
重链：
注：下划线为根据Kabat编号系统定义的CDR序列，斜体为恒定区序列。
实施例2.抗HER2抗体药物偶联物在HER2低表达乳腺癌(BC)患者中的临床研究
一、试验药物
实施例1所述的抗HER2抗体药物偶联物，冻干粉针，规格：100mg/瓶。
二、入组受试者
1.年龄≥18岁。
2.经病理学或细胞学确诊的HER2低表达(IHC2+且ISH阴性，IHC1+且ISH阴性，或IHC1+且ISH未测)复发或转移性乳腺癌患者。
三、给药方式
经筛选合格的受试者给予相应的抗HER2抗体药物偶联物。抗HER2抗体药物偶联物的剂量为1.0mg/kg，2.0mg/kg，3.2mg/kg，4.8mg/kg，6.4mg/kg或8.0mg/kg，静脉滴注，每3周给药一次，每3周(21天)为一个周期。
四、试验结果
部分疗效数据如表2所示。共入组患者77例，其中，HER2-低表达BC患者的ORR为55.8％(43/77，95％CI 44.1-67.2)。
表2.ORR亚组分析
ORR显示为％(n/N，95％CI)或％(n/N)。
*ORR是使用先前在晚期/转移性环境中接受过抗HER2癌症治疗的受试者数量作为分母来计算的；使用Clopper-Pearson方法估计双边95％CIs。
**包括RC48-ADC、A166、DP303c、MRG002、ARX788、TAA013、DX126-262、PF-06804103和BAT8001。
临床试验后续继续入组110例可评估的HER2低表达乳腺癌患者，其疗效评价结果如表3和表4所示。
表3.HER2低表达乳腺癌患者接受抗HER2抗体药物偶联物的肿瘤反应

注：受试者须在首次给药后前48周内每6周(±7天)进行1次疗效评估，之后每12周(±7天)评估1次。影像学评估不受给药中断或延迟的影响。首次评价为CR或PR的受试者应在4周后(计划的下一个时间点)予以确认。
cBOR为经确认的肿瘤最佳总体疗效，cORR是经确认的客观缓解率，uORR为待确认的客观缓解率。
由表3结果可知，在各给药剂量组中，经确认的HER2低表达乳腺癌患者的肿瘤客观缓解率(cORR)可高达64.9％(6.4mg/kg给药)，60.6％(5.6mg/kg给药)；并且，在所有接受不同剂量给药的HER2低表达乳腺癌患者中，cORR达到59.1％，uORR达67.3％。说明本公开提供的抗HER2抗体药物偶联物用于治疗HER2低表达乳腺癌患者，能够发挥显著的肿瘤抑制效果。
表4.HER2低表达乳腺癌患者接受抗HER2抗体药物偶联物的PFS和DoR
注：PFS为无进展生存期，mPFS为中位无进展生存期，06-mo PFS rate为6个月时无进展生存发生率，12-mo PFS rate为12个月时无进展生存发生率，18-mo PFS rate为18个月时无进展生存发生率。mDoR为中位缓解持续时间。
由表4结果可知，在抗HER2抗体药物偶联物治疗的HER2低表达乳腺癌患者中，中位无进展生存期(mPFS)可以高达13.8个月(6.4mg/kg给药剂量)，中位缓解持续时间(mDoR)可以高达16.7个月(6.4mg/kg给药剂量)。并且，在110例接受抗HER2抗体药物偶联物治疗的HER2低表达乳腺癌患者中，中位无进展生存期(mPFS)可达10.9个月，中位缓解持续时间(mDoR)可达到12.2个月。说明本公开提供的抗HER2抗体药物偶联物，用于治疗HER2低表达乳腺癌患者，能够显著延长患者的无进展生存时间及肿瘤持续患者时间，使HER2低表达的乳腺癌患者能够得到有效的治疗。
实施例3.抗HER2抗体药物偶联物的临床I期研究
在抗HER2抗体药物偶联物的I期临床研究中，243名晚期实体瘤患者(97.2％)报告了治疗相关不良事件(TRAEs)。分别有131例(52.4％)、31例(12.4％)和3例(1.2％)患者报告了≥3级TRAEs、严重TRAEs和治疗相关死亡。据报告，8例(3.2％)受试者出现间质性肺病(AESI)。抗HER2抗体药物偶联物、总抗体和有效载荷的暴露量一般与3.2至8.0mg/kg的剂量成正比。所有患者的ORR为61.6％(154/250，95％CI 55.3-67.7)。
实施例4.抗HER2抗体药物偶联物联合式(II)所示化合物羟乙基磺酸盐、氟维司群、贝伐珠单抗、来曲唑/阿那曲唑治疗HER2低表达不可切除或转移性乳腺癌的开放、多中心Ⅰb/Ⅱ期临床研究
一、试验药物
实施例1所述的抗HER2抗体药物偶联物，冻干粉针，规格：100mg/瓶。
式(II)所示化合物羟乙基磺酸盐，片剂，规格：25mg/片、50mg/片、125mg/片、150mg/片。
氟维司群注射液(普来和)，注射剂，规格：5ml:0.25g。
来曲唑片(芙瑞)，片剂，规格：2.5mg。
阿那曲唑片(伊舒致)，片剂，规格：1mg。
贝伐珠单抗注射液(艾瑞妥)，注射剂，规格：100mg(4ml)/瓶。
二、入组受试者
1. 18岁至75岁(含两端值)的女性。
2.经组织学或细胞学证实的HER2低表达(IHC2+/ISH-、IHC1+/ISH-或未测)不可切除或转移性乳腺癌；复发/转移阶段需明确雌激素受体/孕激素受体(ER/PR)状态[ER阳性和/或PR阳性定义需符合美国临床肿瘤学协会/美国病理医师学院(ASCO/CAP)指南]。HER2低表达需经本研究参研中心病理科核实确认。
3.对于HR阳性受试者，需满足以下任一条：
a)既往进行过双侧卵巢切除术，或年龄≥60岁；或
b)年龄<60，自然绝经后状态(定义为连续至少12个月规律月经自发性停止且无其他病理或生理原因)，雌二醇(E2)和促卵泡生成素(FSH)在绝经后水平；或
c)绝经前或围绝经期女性患者也可以入选，但在研究期间必须愿意接受促黄体生成激素释放激素(LHRH)激动剂治疗。
4.在开始研究治疗前的末次全身治疗中或治疗后，有影像学或客观疾病进展证据。
5.既往治疗如下：
HR阳性受试者：
a)第一阶段(剂量探索)：至少接受过1线内分泌治疗，允许≤2线化疗。
b)第二阶段(疗效拓展)：允许接受过≤1线内分泌治疗，复发/转移阶段未接受过化疗。
HR阴性受试者：
c)第一阶段(剂量探索)：至少接受过1线化疗。
d)第二阶段(疗效拓展)：复发/转移阶段未接受过系统性抗肿瘤治疗。
e)辅助内分泌治疗后前24个月内疾病复发被认为是一个线数的治疗；(新)辅助化疗后6个月内出现复发，算作一线的化疗方案。
三、给药方式
经筛选合格的受试者给予相应的药物。
第一阶段(剂量探索阶段)：
剂量探索阶段旨在评价抗HER2抗体药物偶联物联合式(II)所示化合物羟乙基磺酸盐、氟维司群、贝伐珠单抗的安全性、耐受性、药代动力学特征和免疫原性，并初步观察其抗肿瘤疗效。
抗HER2抗体药物偶联物联合式(II)所示化合物羟乙基磺酸盐：
抗HER2抗体药物偶联物的剂量为2.0mg/kg、3.2mg/kg或4.8mg/kg，静脉滴注，每3周给药一次，每3周(21天)为一个周期；
式(II)所示化合物羟乙基磺酸盐的剂量为100mg、125mg、150mg，口服，每天1次，服用2周/停1周为一个治疗疗程。
若相关剂量组不耐受，可调整研究药物的给药周期、给药时序和用法用量，包括但不限于：a.调整抗HER2抗体药物偶联物的给药周期为每2周一次，并对应调整给药剂量；b.调整式(II)所示化合物羟乙基磺酸盐的治疗疗程为服用3周/停1周；c.调整抗HER2抗体药物偶联物和式(II)所示化合物羟乙基磺酸盐给药时序，如间隔几天给药等。
抗HER2抗体药物偶联物联合氟维司群：
抗HER2抗体药物偶联物的剂量为2.0mg/kg、3.2mg/kg或4.8mg/kg，每3周给药1次。
氟维司群的剂量为500mg，每4周为一个治疗疗程，其中第一疗程第1天和第15天给药，随后每个疗程的第1天给药。
若相关剂量组不耐受，可调整研究药物的给药周期、给药时序和用法用量，包括但不限于：调整抗HER2抗体药物偶联物的给药周期为每2周一次，并对应调整给药剂量等。
抗HER2抗体药物偶联物联合贝伐珠单抗：
抗HER2抗体药物偶联物的剂量为2.0mg/kg、3.2mg/kg或4.8mg/kg，每3周给药1次。
贝伐珠单抗的剂量固定为15mg/kg，每3周给药1次。
若相关剂量组不耐受，可调整研究药物的给药周期、给药时序和用法用量，包括但不限于：调整抗HER2抗体药物偶联物的给药周期为每2周一次，并对应调整给药剂量等。
第二阶段(疗效拓展阶段)：
疗效拓展阶段旨在观察和评价抗HER2抗体药物偶联物联合式(II)所示化合物羟乙基磺酸盐和来曲唑/阿那曲唑、氟维司群、来曲唑/阿那曲唑、贝伐珠单抗的初步有效性、安全性、药代动力学特征和免疫原性。
抗HER2抗体药物偶联物和式(II)所示化合物羟乙基磺酸盐联合来曲唑/阿那曲唑：
抗HER2抗体药物偶联物联合式(II)所示化合物羟乙基磺酸盐完成第一阶段剂量探索后，选择至少1个剂量组的抗HER2抗体药物偶联物和式(II)所示化合物羟乙基磺酸盐联合来曲唑或者阿那曲唑进行疗效拓展。
来曲唑为口服，每天一次，每次2.5mg，连续服药。
阿那曲唑为口服，每天一次，每次1mg，连续服药。
抗HER2抗体药物偶联物联合氟维司群：
抗HER2抗体药物偶联物联合氟维司群完成第一阶段剂量探索后，选择1～2个剂量进行疗效拓展。筛选合格的受试者将进入抗HER2抗体药物偶联物联合氟维司群进行疗效拓展。
抗HER2抗体药物偶联物联合来曲唑/阿那曲唑：
抗HER2抗体药物偶联物联合氟维司群完成第一阶段剂量探索后，将参考该剂量组安全性，选择1～2个剂量进行抗HER2抗体药物偶联物和来曲唑/阿那曲唑进行疗效拓展。
来曲唑为口服，每天一次，每次2.5mg，连续服药。
阿那曲唑为口服，每天一次，每次1mg，连续服药。
抗HER2抗体药物偶联物联合贝伐珠单抗：
抗HER2抗体药物偶联物联合贝伐珠单抗完成第一阶段剂量探索后，选择至少1个剂量组进行疗效拓展。

Claims (17)

  1. 抗HER2抗体药物偶联物在制备治疗HER2低表达乳腺癌的药物中的用途，所述抗体药物偶联物的结构如式(I)所示：
    其中：
    n为3至8，n是小数或整数；
    Pc为抗HER2抗体。
  2. 根据权利要求1所述的用途，所述抗HER2抗体选自曲妥珠单抗、帕妥珠单抗，或其抗原结合片段；优选为曲妥珠单抗或其抗原结合片段。
  3. 根据权利要求1或2所述的用途，所述抗HER2抗体包含重链可变区和轻链可变区，其中，所述重链可变区包含分别如SEQ ID NO:3、4、5所示的HCDR1、HCDR2和HCDR3，和分别如SEQ ID NO:6、7、8所示的LCDR1、LCDR2和LCDR3；
    优选地，所述重链可变区包含SEQ ID NO:9所示或与之具有至少90％同一性的氨基酸序列，和所述轻链可变区包含SEQ ID NO:10所示或与之具有至少90％同一性的氨基酸序列；
    优选地，所述抗HER2抗体包含重链和轻链，所述重链包含SEQ ID NO:2所示或与之具有至少90％同一性的氨基酸序列，和所述轻链包含SEQ ID NO:1所示或与之具有至少90％同一性的氨基酸序列。
  4. 根据权利要求1-3任一项所述的用途，所述的抗HER2抗体药物偶联物具有如下式所示的结构：

    其中，n为3至8，n是小数或整数；优选为6±0.8。
  5. 根据权利要求1-4任一项所述的用途，其中，所述HER2低表达乳腺癌是通过免疫组织化学法判定HER2的表达为1+的乳腺癌，或，
    通过免疫组织化学法判定HER2的表达为2+，且通过原位杂交法判定HER2的表达为阴性的乳腺癌。
  6. 根据权利要求1-5任一项所述的用途，其中所述的HER2低表达乳腺癌为HER2低表达的不可切除、复发和/或转移性乳腺癌。
  7. 根据权利要求1-6任一项所述的用途，其中所述HER2低表达乳腺癌既往接受过抗HER2药物的治疗；优选为既往接受过抗HER2药物的治疗后产生耐性或难治性的HER2低表达乳腺癌。
  8. 根据权利要求7所述的用途，其中，所述抗HER2药物选自曲妥珠单抗、帕妥珠单抗、吡咯替尼、拉帕提尼、T-DM1组成的组中至少一种。
  9. 根据权利要求1-8任一项所述的用途，其中，所述用途为抗HER2抗体药物偶联物联合第二治疗剂在制备治疗HER2低表达乳腺癌的药物中的用途。
  10. 根据权利要求9所述的用途，其中，所述第二治疗剂为CDK4/6抑制剂；
    优选地，所述的CDK4/6抑制剂选自abemaciclib、ribociclib、palbociclib、alvocidib、trilaciclib、voruciclib、AT-7519、G1T-38、FLX-925、INOC-005、G1T28-1、BPI-1178、gossypin、G1T30-1、GZ-38-1、P-276-00、staurosporine、R-547、PAN-1215、PD-0183812、AG-024322、NSC-625987、CGP-82996、PD-171851和式(II)所示化合物或其可药用盐，更优选式(II)所示化合物或其可药用盐，最优选式(II)所示化合物的羟乙基磺酸盐，
    优选地，所述的CDK4/6抑制剂的给药剂量为1-1000mg，优选100mg、125mg、 150mg，优选给药频次可以是一日一次、一日二次、一日三次、一周一次、二周一次、三周一次或一月一次；
    优选地，所述的抗HER2抗体药物偶联物每二周给药一次或每三周给药一次；所述的CDK4/6抑制剂一日给药一次，其中前2周连续服药，后1周休息，或前3周连续服药，后1周休息。
  11. 根据权利要求9所述的用途，其中所述第二治疗剂为芳香化酶抑制剂；优选地，所述的芳香化酶抑制剂选自福美坦、依西美坦、法倔唑、来曲唑、伏氯唑和阿那曲唑，更优选来曲唑或阿那曲唑；
    优选地，所述的芳香化酶抑制剂的给药剂量为0.1-50mg，优选0.5mg、1.0mg、1.5mg、2.0mg、2.5mg、3.0mg、3.5mg、4.0mg、4.5mg或5.0mg，优选给药频次为一日一次、一日两次；
    优选地，所述的抗HER2抗体药物偶联物每二周给药一次或每三周给药一次；所述的芳香化酶抑制剂一日给药一次，连续服药。
  12. 根据权利要求9-11任一项所述的用途，其中所述第二治疗剂为CDK4/6抑制剂和芳香化酶抑制剂。
  13. 根据权利要求9所述的用途，其中，所述第二治疗剂为SERD，所述SERD优选为氟维司群、AZD-9496、RAD1901或ZB-716，更优选为氟维司群；
    优选地，所述的SERD的给药剂量为1-1000mg，优选500mg，优选给药频次为一日一次、一日二次、一日三次、一周一次、二周一次、三周一次或一月一次；
    优选地，所述的抗HER2抗体药物偶联物的每二周给药一次或每三周给药一次；所述的SERD的治疗周期为每4周为一个治疗周期，其中第一周期第1天和第15天给药，随后每个周期的第1天给药。
  14. 根据权利要求9所述的用途，其中所述第二治疗剂为VEGF配体抑制剂，所述VEGF配体抑制剂优选自贝伐珠单抗、雷莫芦单抗、雷珠单抗、阿柏西普、康柏西普、Abicipar pegol、Brolucizumab、LMG-324、Nesvacumab、Sevacizumab、Tanibirumab、Navicixizumab、RG-7716、LHA-510、OPT-302、TK-001、GZ-402663、VGX-100、PG-545、BI-836880、GNR-011、BR-55、OTSGC-A24、PAN-90806、AVA-101、ODM-203、TAS-115、X-82、MP-0250、Sitravatinib、4SC-203、AL-2846、ABT-165、SIM-010603、BI-836880、HL-217、CS-2164、RGX-314、AMC-303或VXM-01，更优选贝伐珠单抗；
    优选地，所述的VEGF配体抑制剂的给药剂量为0.1-100mg/kg，优选15mg/kg，优选给药频次为一日一次、一周一次、二周一次、三周一次或一月一次；
    优选地，其中所述的抗HER2抗体药物偶联物的每二周给药一次或每三周给药一次；所述的VEGF配体抑制剂每三周给药一次。
  15. 根据权利要求1-14任一项所述的用途，其中所述抗HER2抗体药物偶联物的单次给药剂量为1.0mg/kg-10.0mg/kg，优选1.0mg/kg、2.0mg/kg、3.2mg/kg、4.8mg/kg、5.6mg/kg、6.4mg/kg或8.0mg/kg，优选给药频次为每一周一次，每二周一次，每三周一次或每四周一次。
  16. 一种治疗HER2低表达乳腺癌的方法，包括向有需要的受试者施用抗HER2抗体药物偶联物；所述抗HER2抗体药物偶联物的结构如式(I)所示：
    其中：
    n为3至8，n是小数或整数；
    Pc为抗HER2抗体，所述抗HER2抗体药物偶联物如权利要求1-4和15任一项所定义，所述HER2低表达乳腺癌如权利要求5-8任一项所定义；
    优选地，所述方法包括向有需要的受试者施用抗HER2抗体药物偶联物和第二治疗剂；其中，所述第二治疗剂选自CDK4/6抑制剂、SERD、VEGF配体抑制剂和芳香化酶抑制剂中的一种或多种。
  17. 药物组合物，包含抗HER2抗体药物偶联物和第二治疗剂，以及一种或多种药学上可接受的载体；所述抗HER2抗体药物偶联物的结构如式(I)所示：
    其中：
    n为3至8，n是小数或整数；
    Pc为抗HER2抗体，所述抗HER2抗体药物偶联物优选如权利要求1-4和15任一项所定义，所述第二治疗剂优选如权利要求9-14任一项所定义。
PCT/CN2024/073246 2023-01-19 2024-01-19 抗her2抗体药物偶联物治疗乳腺癌 WO2024153229A1 (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202310066299.X 2023-01-19
CN202310066299 2023-01-19
CN202310121195.4 2023-02-15
CN202310121195 2023-02-15

Publications (1)

Publication Number Publication Date
WO2024153229A1 true WO2024153229A1 (zh) 2024-07-25

Family

ID=91955328

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/073246 WO2024153229A1 (zh) 2023-01-19 2024-01-19 抗her2抗体药物偶联物治疗乳腺癌

Country Status (1)

Country Link
WO (1) WO2024153229A1 (zh)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102223897A (zh) * 2008-11-22 2011-10-19 霍夫曼-拉罗奇有限公司 抗-vegf抗体与化学治疗联合用于治疗乳腺癌的应用
CN107137408A (zh) * 2016-03-01 2017-09-08 江苏恒瑞医药股份有限公司 一种cdk4/6抑制剂与芳香化酶抑制剂联合在制备治疗乳腺癌的药物中的用途
CN107137409A (zh) * 2016-03-01 2017-09-08 江苏恒瑞医药股份有限公司 一种cdk4/6抑制剂与雌激素受体拮抗剂联合在制备治疗乳腺癌的药物中的用途
WO2020063676A1 (zh) * 2018-09-26 2020-04-02 江苏恒瑞医药股份有限公司 依喜替康类似物的配体-药物偶联物及其制备方法和应用
WO2021190581A1 (zh) * 2020-03-25 2021-09-30 江苏恒瑞医药股份有限公司 一种含抗体药物偶联物的药物组合物及其用途
WO2021190602A1 (zh) * 2020-03-25 2021-09-30 江苏恒瑞医药股份有限公司 一种抗体药物偶联物的制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102223897A (zh) * 2008-11-22 2011-10-19 霍夫曼-拉罗奇有限公司 抗-vegf抗体与化学治疗联合用于治疗乳腺癌的应用
CN107137408A (zh) * 2016-03-01 2017-09-08 江苏恒瑞医药股份有限公司 一种cdk4/6抑制剂与芳香化酶抑制剂联合在制备治疗乳腺癌的药物中的用途
CN107137409A (zh) * 2016-03-01 2017-09-08 江苏恒瑞医药股份有限公司 一种cdk4/6抑制剂与雌激素受体拮抗剂联合在制备治疗乳腺癌的药物中的用途
WO2020063676A1 (zh) * 2018-09-26 2020-04-02 江苏恒瑞医药股份有限公司 依喜替康类似物的配体-药物偶联物及其制备方法和应用
WO2021190581A1 (zh) * 2020-03-25 2021-09-30 江苏恒瑞医药股份有限公司 一种含抗体药物偶联物的药物组合物及其用途
WO2021190602A1 (zh) * 2020-03-25 2021-09-30 江苏恒瑞医药股份有限公司 一种抗体药物偶联物的制备方法

Similar Documents

Publication Publication Date Title
US11168144B2 (en) Activatable anti-PDL1 antibodies, and methods of use thereof
KR20200142542A (ko) Cd73 길항제 항체 및 pd-1/pd-l1 축 길항제 항체에 의한 항암 조합 요법
US20230279096A1 (en) Combination therapy with anti-il-8 antibodies and anti-pd-1 antibodies for treating cancer
US20210030888A1 (en) Anti-tissue factor antibody-drug conjugates and their use in the treatment of cancer
EP3768325A1 (en) Methods of treating cancer with a combination of a platinum-based agent and an anti-tissue factor antibody-drug conjugate
US20230140694A1 (en) Combination treatment for cancer involving anti-icos and anti-pd1 antibodies, optionally further involving anti-tim3 antibodies
JPWO2021180205A5 (zh)
WO2024153229A1 (zh) 抗her2抗体药物偶联物治疗乳腺癌
US20230034186A1 (en) Methods of treating cancer using multi-specific binding proteins that bind nkg2d, cd16 and a tumor-associated antigen
JP2023531090A (ja) 腫瘍を治療するための薬物
WO2023061472A1 (zh) 抗her2抗体药物偶联物和酪氨酸激酶抑制剂联合在制备治疗肿瘤的药物中的用途
JP2019505516A (ja) インターロイキン−１７（ｉｌ−１７）アンタゴニストを使用してざ瘡を治療する方法
WO2023208001A1 (zh) 抗pd-1抗体和抗egfr抗体组合及其在治疗头颈部鳞癌中的用途
CN116712539A (zh) 抗her2抗体药物偶联物和抗pd-1抗体联合在制备治疗肿瘤的药物中的用途
CN117427186A (zh) 抗her2抗体药物偶联物联合抗pd-l1抗体在制备治疗肺癌的药物中的用途
CN114845738A (zh) 使用位点特异性her2抗体-药物缀合物的治疗
WO2023232100A1 (zh) 用于治疗子宫恶性肿瘤的药物组合
WO2023192478A1 (en) Combination therapy with anti-il-8 antibodies and anti-pd-1 antibodies for treating cancer
WO2024118587A1 (en) Methods of treating cancer with anti-pd-1-antibodies
CN117042795A (zh) 通过施用pd-1抑制剂治疗免疫抑制或免疫受损患者的癌症的方法
BR112019019505A2 (pt) Anticorpo anti-dr5 e a utilização do mesmo

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24744398

Country of ref document: EP

Kind code of ref document: A1