Anti-HER2 antibody drug conjugate for treating breast cancer

Abstract

The invention relates to application of an anti-HER2 antibody drug conjugate in preparation of a drug for treating HER2 low-expression breast cancer. The structure of the antibody drug conjugate is shown as a formula (I). # imgabs0 #

Description

Anti-HER2 antibody-drug conjugates for breast cancer treatment

[0001] This disclosure claims priority to the following patent applications: Chinese patent application No. 202310066299X, filed on January 19, 2023; and Chinese patent application No. 2023101211954, filed on February 15, 2023. The entire contents of the foregoing patent applications are incorporated into this disclosure by reference. Technical Field

[0002] The present disclosure belongs to the field of medicine and relates to the use of an anti-HER2 antibody-drug conjugate (ADC) in preparing a drug for treating breast cancer. Background Art

[0003] Breast cancer is the most common malignant tumor worldwide. According to GLOBOCAN 2020 statistics, breast cancer leads the world in both incidence and mortality among female malignancies. Globally, there are approximately 2.26 million new cases of breast cancer and 685,000 deaths each year, ranking first in both incidence and mortality among female malignancies.

[0004] Clinically, approximately 55% of breast cancer patients have low HER2 expression, which refers to an immunohistochemistry (IHC) score of 1+ or IHC 2+ and in situ hybridization (ISH)-. Existing HER2-targeted drugs have failed to show significant benefits. There is a huge, unmet clinical need for HER2-low-expressing metastatic breast cancer. First, for patients with low HER2 expression, previous treatment is equivalent to that of HER2-negative patients, and their options for advanced treatment are limited. Second, for patients with HR+ / HER2-, their disease progresses after resistance to CDK4 / 6 inhibitors or endocrine therapy, and their subsequent options are limited.

[0005] HER2 is a member of the type I transmembrane tyrosine kinase receptor family. It is basically inactive in the monomeric state, but can aggregate 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.

[0006] 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. It then enters the target cell through endocytosis, where it is broken down and releases the cytotoxic drug. Finally, the cytotoxic drug induces cell apoptosis by damaging DNA or acting on microtubules, thereby exerting its anti-tumor effect. If the cytotoxic drug is highly permeable, it may penetrate into the extracellular space after being released from the target cell, killing surrounding HER2-negative cells. This effect is known as the bystander effect. This effect may also occur if the cytotoxic drug is released before ADC endocytosis occurs. WO2020063676A discloses a class of ADCs targeting HER2. Given the excellent efficacy of the approved HER-2 ADC drugs Trastuzumab emtansine (TDM-1) and Trastuzumab Deruxtecan (DS-8201) in the treatment of breast cancer and gastric cancer, it is of great significance to study the indications of the antibody-drug conjugates in WO2020063676A.

[0007] In summary, there is an urgent need to provide safer and more effective clinical treatment options for patients with breast cancer with low HER2 expression.

[0008] Summary of the Invention

[0009] The present disclosure provides a medical use and method of an anti-HER2 antibody-drug conjugate for treating tumors.

[0010] In some embodiments, the present disclosure provides any of the following uses or methods of anti-HER2 antibody drug conjugates:

[0011] (1) Use of anti-HER2 antibody drug conjugates in the preparation of drugs for treating HER2-low-expressing breast cancer,

[0012] (2) Anti-HER2 antibody-drug conjugates for the treatment of HER2-low-expressing breast cancer.

[0013] (3) A method for treating HER2-low expressing breast cancer, comprising administering an anti-HER2 antibody drug conjugate to a subject in need thereof.

[0014] In some embodiments, the structure of the antibody drug conjugate is shown in formula (I):

[0015] in:

[0016] 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.

[0017] Pc is an anti-HER2 antibody.

[0018] In this disclosure, “antibody” is used in the broadest sense to encompass various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, or antigen-binding fragments thereof (also referred to as “antigen-binding portions”), so long as they exhibit the desired antigen-binding activity.

[0019] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof disclosed herein is selected from trastuzumab, or an antigen-binding fragment thereof, and pertuzumab or an antigen-binding fragment thereof.

[0020] In some embodiments, the anti-HER2 antibody or antigen-binding fragment thereof described in the present disclosure is trastuzumab or an antigen-binding fragment thereof.

[0021] In some embodiments, 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.

[0022] The CDR sequences mentioned above are shown in Table 1 below:

[0023] In some specific embodiments, the CDRs are defined according to the Kabat numbering system.

[0024] In some embodiments, the anti-HER2 antibody comprises any one, two, three, four, five, or six of the aforementioned HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3.

[0025] In some embodiments, the anti-HER2 antibody is a humanized antibody. In some specific embodiments, the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 9, or an amino acid sequence having at least 80% sequence identity thereto; and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO: 10, or an amino acid sequence having at least 80% sequence identity thereto.

[0026] Heavy chain variable region:

[0027] Light chain variable region:

[0028] In some embodiments, the anti-HER2 antibody comprises any one or a combination of any two of the aforementioned VH and VL.

[0029] In some embodiments, the anti-HER2 antibody further comprises a heavy chain constant region and / or a light chain constant region. Exemplarily, the above light chain / 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:

[0030] Heavy chain:

[0031] Light chain:

[0032] In some embodiments, 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, or an amino acid sequence having at least 80% sequence identity thereto.

[0033] In some embodiments, 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.

[0034] In the context of the present disclosure, "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.

[0035] In some embodiments, the anti-HER2 antibody-drug conjugate described above can be prepared according to the method in WO2021190581A. The present disclosure incorporates the relevant contents of ADC structure, antibody sequence and preparation method in WO2021190581A into the present disclosure by reference.

[0036] In some embodiments, the anti-HER2 antibody drug conjugates disclosed herein have a structure as shown in the following formula:

[0037] Here, n is 3 to 8 and is a decimal or an integer.

[0038] In some embodiments, n is 6 ± 0.8. For example, 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.

[0039] In an optional embodiment, n is 6 in the anti-HER2 antibody drug conjugate described in the present disclosure.

[0040] In the present disclosure, the term "HER2-low expressing breast cancer" is not particularly limited, as long as it is recognized as HER2-low expressing breast cancer by a person skilled in the art. Preferred examples of HER2-low expressing breast cancer include IHC 2+ and ISH negative, IHC 1+ and ISH negative, IHC 1+ and ISH undetectable, and 0<IHC<1+.

[0041] In some embodiments, the HER2-low expressing breast cancer is a breast cancer whose HER2 expression is determined to be 1+ by immunohistochemistry, i.e., IHC1+, such as IHC1+ / ISH- or IHC1+ / ISH-undetectable.

[0042] In some embodiments, the HER2-low expressing breast cancer is a breast cancer whose HER2 expression is 2+ as determined by immunohistochemistry and negative as determined by in situ hybridization, i.e., IHC2+ / ISH-.

[0043] In some embodiments, the HER2-low expressing breast cancer is unresectable, recurrent and / or metastatic breast cancer with low HER2 expression.

[0044] In some embodiments, the HER2-low expressing breast cancer is HER2-low expressing unresectable or metastatic breast cancer.

[0045] In some embodiments, the HER2-low expressing breast cancer patient is a patient with HER2-low expressing recurrent or metastatic breast cancer.

[0046] In some embodiments, the breast cancer patient is a HR-positive patient or a HR-negative patient.

[0047] In some embodiments, the breast cancer patient has received at least one line of endocrine therapy.

[0048] In some embodiments, the breast cancer patient has not received or has received prior chemotherapy.

[0049] In some embodiments, the patient with low HER2-expressing breast cancer has previously received treatment with an anti-HER2 drug. In some embodiments, the patient with low HER2-expressing breast cancer has developed resistance or refractory disease after previously receiving treatment with an anti-HER2 drug.

[0050] In the present disclosure, "resistance" or "refractory" refers to the property of not responding to treatment with an anticancer agent, and may also be expressed as "non-responsiveness" or "non-responsiveness."

[0051] In some embodiments, the anti-HER2 antibody-drug conjugates provided herein are used to treat patients with low HER2-expressing breast cancer, and can significantly improve the patients' tumor objective response rate and progression-free survival time. In particular, at a dosage of 6.4 mg / kg, a cORR of 64.9% and an mPFS of 13.8 months can be achieved. Compared with other ADC drugs with the same target, these drugs have significant therapeutic advantages and provide a positive and effective clinical treatment option for patients with low HER2-expressing breast cancer.

[0052] In some embodiments, the anti-HER2 antibody-drug conjugates provided herein 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.

[0053] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with a second therapeutic agent.

[0054] In some embodiments, 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.

[0055] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with a CDK4 / 6 inhibitor.

[0056] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with a SERD (selective estrogen receptor degrader).

[0057] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with a VEGF ligand inhibitor.

[0058] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with an aromatase inhibitor.

[0059] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with a CDK4 / 6 inhibitor and an aromatase inhibitor.

[0060] In some embodiments, 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. In some embodiments, the CDK4 / 6 inhibitor is a compound of formula (II) or a pharmaceutically acceptable salt thereof,

[0061] In some embodiments, the pharmaceutically acceptable salt of the compound represented by Formula II is isethionate.

[0062] In some embodiments, the SERD disclosed herein is selected from fulvestrant, AZD-9496, RAD1901, and ZB-716. In some embodiments, the SERD is fulvestrant.

[0063] In some embodiments, the VEGF ligand inhibitors disclosed herein are selected from bevacizumab, ramucirumab, ranibizumab, aflibercept, conbercept, 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-5 5. OTSGC-A24, PAN-90806, AVA-101, ODM-203, TAS-115, X-82, MP-0250, Sitravatinib, 4SC-2 03, AL-2846, ABT-165, SIM-010603, BI-836880, HL-217, CS-2164, RGX-314, AMC-303 and VXM-01. In some embodiments, the VEGF ligand inhibitor is bevacizumab.

[0064] In some embodiments, 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.

[0065] In some embodiments, the dosage of the anti-HER2 antibody drug conjugates of the present disclosure is 1.0 mg / kg-10.0 mg / kg. In alternative embodiments, the dosage of the anti-HER2 antibody drug conjugates of 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. In one embodiment, the dosage of the anti-HER2 antibody drug conjugate of the present invention 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.

[0066] In some embodiments, the anti-HER2 antibody drug conjugates described 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. In alternative embodiments, the administration frequency is once a week, once every two weeks, once every three weeks, or once every four weeks. In alternative embodiments, the administration frequency is once every two weeks or once every three weeks.

[0067] In an optional embodiment, 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, and the administration frequency is once every two weeks or once every three weeks.

[0068] In some embodiments, the dosage of the CDK4 / 6 inhibitors described herein is 1-1000 mg. In alternative embodiments, the dosage of the CDK4 / 6 inhibitors described herein 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. In alternative embodiments, the dosage is 100 mg, 125 mg, 150 mg.

[0069] The frequency of administration 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 frequency of administration is once a day.

[0070] In an optional embodiment, the dosage of the CDK4 / 6 inhibitor described in the present disclosure is 75 mg, 100 mg, 125 mg, or 150 mg, and the administration frequency is once a day.

[0071] In some embodiments, the dosage of the SERD described in the present disclosure is 1-1000 mg. In an optional embodiment, the dosage of the SERD described in the present disclosure can be 5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 600 mg, 700 mg, 750 mg, 800 mg, 900 mg, 1000 mg. In an optional embodiment, the dosage of the SERD described in the present disclosure is 500 mg.

[0072] In some embodiments, the SERD described in the present disclosure can be administered 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.

[0073] In an optional embodiment, the dosage of the SERD disclosed herein is 500 mg, and the administration frequency is once every two weeks or once a month.

[0074] In some embodiments, the VEGF ligand inhibitors described herein are administered at a dosage of 0.1-100 mg / kg. In alternative embodiments, the VEGF ligand inhibitors described herein are administered at a dosage of 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, or 30 mg / kg. In alternative embodiments, the VEGF ligand inhibitors described herein are administered at a dosage of 15 mg / kg.

[0075] In some embodiments, the VEGF ligand inhibitors described herein can be administered once daily, once a week, once every two weeks, once every three weeks, or once a month. In alternative embodiments, the administration frequency can be once a week, once every two weeks, once every three weeks, or once a month. In alternative embodiments, the administration frequency is once every three weeks.

[0076] In an optional embodiment, the dosage of the VEGF ligand inhibitor disclosed herein is 15 mg / kg, and the administration frequency is once every three weeks.

[0077] In some embodiments, the aromatase inhibitors of the present disclosure are administered at a dosage of 0.1-50 mg. In alternative embodiments, the aromatase inhibitors of the present disclosure are administered at a dosage of 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, 3.5 mg, 3.75 mg, 4 mg, 4.25 mg, 4.5 mg, 4.75 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg. In alternative embodiments, the aromatase inhibitors described herein are administered at a dosage of 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.

[0078] In an alternative embodiment, the aromatase inhibitor of the present disclosure is administered once a day or twice a day. In an alternative embodiment, the aromatase inhibitor is administered once a day or twice a day.

[0079] In an optional embodiment, 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 administration frequency is once a day or twice a day.

[0080] In an optional embodiment, the aromatase inhibitor disclosed herein is letrozole, with a dosage of 2.5 mg and a dosing frequency of once a day.

[0081] In an optional embodiment, the aromatase inhibitor disclosed herein is anastrozole, with a dosage of 1 mg and a dosing frequency of once a day.

[0082] In some embodiments, the anti-HER2 antibody drug conjugates described herein are administered once every two weeks or once every three weeks; the CDK4 / 6 inhibitors described herein are administered once a day, with continuous medication for the first two weeks (day 1 to day 14) and a rest (no medication) for the next week (day 15 to day 21), or continuous medication for the first three weeks and a rest for the next week.

[0083] In an optional embodiment, 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 days of the first cycle, and then on the 1st day of each subsequent cycle.

[0084] In an optional embodiment, 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.

[0085] In an optional embodiment, 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.

[0086] In an optional embodiment, 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 two 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 three weeks and then there is a week of rest; the aromatase inhibitor described in the present disclosure is administered once a day, and the medication is taken continuously.

[0087] In some embodiments, the treatment cycle is one treatment cycle every two weeks, one treatment cycle every three weeks, or one treatment cycle every four weeks.

[0088] 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 medicament for treating breast cancer. The structure of the antibody-drug conjugate is shown in formula (I):

[0089] in:

[0090] n is 3 to 8, and n is a decimal or an integer;

[0091] Pc is an anti-HER2 antibody or an antigen-binding fragment thereof,

[0092] 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.

[0093] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with a CDK4 / 6 inhibitor.

[0094] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with a SERD.

[0095] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with a VEGF ligand inhibitor.

[0096] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with an aromatase inhibitor.

[0097] In some embodiments, the anti-HER2 antibody drug conjugate is used in combination with a CDK4 / 6 inhibitor and an aromatase inhibitor.

[0098] In some embodiments, the breast cancer is HER2-low expressing breast cancer.

[0099] In some embodiments, the HER2-low expressing breast cancer is a breast cancer whose HER2 expression is determined to be 1+ by immunohistochemistry, i.e., IHC1+, such as IHC1+ / ISH- or IHC1+ / ISH-undetectable.

[0100] In some embodiments, the HER2-low expressing breast cancer is a breast cancer whose HER2 expression is 2+ as determined by immunohistochemistry and negative as determined by in situ hybridization, i.e., IHC2+ / ISH-.

[0101] In some embodiments, the HER2-low expressing breast cancer is unresectable, recurrent and / or metastatic breast cancer with low HER2 expression.

[0102] In an optional embodiment, the breast cancer is unresectable or metastatic breast cancer.

[0103] In alternative embodiments, the breast cancer patient is a HR-positive patient or a HR-negative patient.

[0104] In an optional embodiment, the breast cancer patient has received at least one line of endocrine therapy.

[0105] In an alternative embodiment, the breast cancer patient has not received or has received chemotherapy previously.

[0106] In some embodiments, 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.

[0107] Another aspect of the present disclosure provides 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.

[0108] Another aspect of the present disclosure provides the aforementioned anti-HER2 antibody-drug conjugate for treating HER2-low-expressing breast cancer.

[0109] 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.

[0110] The pharmaceutical compositions, uses, and methods of treatment of the present disclosure can also be used as adjuvant chemotherapy in combination with a surgical procedure. The methods of treatment of the present disclosure can be administered before 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).

[0111] 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.

[0112] the term

[0113] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise explicitly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present disclosure belongs.

[0114] The present disclosure incorporates all the contents of application WO2020063676A into the present application.

[0115] Antibody-drug conjugates (ADCs) link antibodies or antibody fragments to biologically active cytotoxins or small molecule drugs with cell-killing activity via a stable chemical linker. These ADCs leverage the antibody's specificity for tumor cell-specific or highly expressed antigens and the high efficacy of the cytotoxin, while avoiding toxic side effects on normal cells. Compared to traditional chemotherapy drugs, ADCs can precisely bind to tumor cells while minimizing their effects on normal cells.

[0116] An antibody drug conjugate "retains its chemical stability" in a pharmaceutical formulation if the antibody drug conjugate shows no 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.).

[0117] 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.

[0118] The term "antibody" as used herein is used in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., 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. For example, an antibody may refer to an immunoglobulin, which is a tetrapeptide chain structure consisting of two identical heavy chains and two identical light chains connected by interchain disulfide bonds. Immunoglobulins differ in their antigenicity due to the different amino acid composition and arrangement order of their heavy chain constant regions. Accordingly, immunoglobulins can be divided into five classes, or so-called immunoglobulin isotypes, namely IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being μ, δ, γ, α, and ε chains, respectively. Igs of the same class can be further divided into different subclasses based on differences in the amino acid composition of their hinge regions and the number and position of their heavy chain disulfide bonds. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are classified as either kappa or lambda chains based on differences in their constant regions. Each of the five Ig classes can have either kappa or lambda chains.

[0119] The "antibody or its antigen-binding" or "functional fragment" described in this disclosure refers to a Fab fragment, a Fab' fragment, a F(ab')2 fragment, and an Fv fragment scFv fragment that binds to an antibody, which has antigen-binding activity. The Fv fragment contains the variable regions of the heavy and light chains of an antibody, but does not have a constant region, and is the smallest antibody fragment with all antigen-binding sites. Generally, an 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 linked into a single polypeptide chain using different connectors, which is called a single-chain antibody or single-chain Fv (sFv).

[0120] The term "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. It 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 L 1 To L 4 , where L 1 The end is connected to the antibody, L 4 The end is connected to the structural unit Y and then connected to the compound or toxin.

[0121] Linkers, including extenders, spacers, and amino acid units, can be synthesized by methods known in the art, such as those described in US 2005-0238649 A1. The linker can be a "cleavable linker" that facilitates release of the drug in the cell. For example, an acid-labile linker (e.g., a hydrazone), a protease-sensitive (e.g., a peptidase-sensitive) linker, a photolabile linker, a dimethyl linker, or a disulfide-containing linker can be used (Chari et al., Cancer Research 52: 127-131 (1992); U.S. Patent No. 5,208,020).

[0122] The term "drug loading" refers to the average amount of cytotoxic drug loaded per antibody or antigen-binding fragment thereof in a molecule of Formula (I), and can also be expressed as the ratio of the amount of drug to the amount of antibody. The drug loading range can be 0-12, preferably 1-10, more preferably 3-8, and most preferably 5.3-6.1 cytotoxic drugs (D) attached per antibody or antigen-binding fragment thereof (Pc). In embodiments of the present disclosure, the drug loading is expressed as n, which can be an average of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, for example. The average amount of drug per ADC molecule after the conjugation reaction can be determined using conventional methods such as UV / visible spectroscopy, mass spectrometry, ELISA assays, and HPLC characterization.

[0123] In one embodiment of the present disclosure, the cytotoxic drug is coupled to the N-terminal amino group, the ε-amino group of a lysine residue and / or the sulfhydryl group of an antibody or an antigen-binding fragment thereof via a linker. Generally, the number of drug molecules that can be coupled to the antibody in the coupling reaction will be less than the theoretical maximum value.

[0124] Cytotoxic drug loading can be controlled by the following non-limiting methods, including:

[0125] (1) Control the molar ratio of the linker and the monoclonal antibody,

[0126] (2) Control reaction time and temperature,

[0127] (3) Select different reaction reagents.

[0128] The preparation of conventional pharmaceutical compositions can be found in the Chinese Pharmacopoeia.

[0129] "Administering" and "treating" as applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ or a biological fluid, refers to the contacting 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" and "treating" can refer to, for example, therapeutic, pharmacokinetics, diagnostics, research and experimental procedures. Treatment of cells includes contacting an agent with a cell, and contacting an agent with a fluid, wherein the fluid is in contact with the cell. "Administering" and "treating" also mean treating, for example, a cell in vitro and ex vivo, by an agent, a diagnostic, a binding composition or by another cell. "Treatment" as applied to a human, veterinary or research subject, refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.

[0130] "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. Typically, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the patient or population being treated, to induce regression of such symptoms or to inhibit the progression of such symptoms to any clinically measurable degree. The amount of a therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") can 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 symptoms of the disease have been alleviated can be assessed by any clinical test method commonly used by a physician or other health care professional to assess the severity or progression of the symptoms. Although embodiments of the present disclosure (e.g., methods of treatment or articles of manufacture) may not be effective in alleviating every symptom of the target disease, 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.

[0131] An "effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to permit 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 overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0132] In the anti-HER2 antibody drug conjugates disclosed herein, "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 as determined by hydrophobic chromatography (HIC) mass spectrometry.

[0133] In the present disclosure, the so-called "combination" is a mode of administration, which includes various situations in which two or more drugs are administered sequentially or simultaneously. Modes of administration such as simultaneous administration, independent formulation and co-administration, or independent formulation 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, the administration of two drugs within 2 days, or within 1 day, where both substances show pharmacological effects. The so-called "sequential" administration includes the situation in which the anti-HER2 antibody drug conjugate and other therapeutic agents are administered separately in different dosing cycles. The time limit can be within one dosing cycle, optionally within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, within 24 hours, or within 2 hours. This time limit includes such treatments, in which the anti-HER2 antibody drug conjugate and other therapeutic agents are administered by the same route of administration or different routes of administration. DETAILED DESCRIPTION

[0134] The present disclosure is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present disclosure. Experimental methods in the examples herein where specific conditions are not specified generally follow conventional conditions, such as those in the Cold Spring Harbor Laboratory's "Antibody Techniques Laboratory Manual" and "Molecular Cloning Manual," or according to the conditions recommended by the raw material or product manufacturer. Reagents where the specific source is not specified are commercially available.

[0135] Example 1. Preparation of anti-HER2 antibody drug conjugates

[0136] According to the production method described in WO2021190581A, trastuzumab (anti-HER2 antibody) and isotecan analogs were used to prepare the anti-HER2 antibody-drug conjugate shown in the following structure. The average value was calculated by the HIC method: n = 6.0, i.e., ADC-32.

[0137] The following is the sequence of Trastuzumab:

[0138] Light chain:

[0139] Heavy chain:

[0140] Note: The underlined sequences are CDR sequences defined according to the Kabat numbering system, and the italicized sequences are constant region sequences.

[0141] Example 2. Clinical study of anti-HER2 antibody drug conjugates in patients with HER2-low expressing breast cancer (BC)

[0142] 1. Investigational Drugs

[0143] The anti-HER2 antibody drug conjugate described in Example 1, lyophilized powder injection, specification: 100 mg / bottle.

[0144] II. Enrolled Subjects

[0145] 1. Age ≥ 18 years old.

[0146] 2. Patients with recurrent or metastatic breast cancer confirmed by pathology or cytology with low HER2 expression (IHC2+ and ISH-negative, IHC1+ and ISH-negative, or IHC1+ and ISH-undetectable).

[0147] 3. Dosage

[0148] Qualified subjects were given the corresponding anti-HER2 antibody-drug conjugate at a dose of 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 via intravenous drip every 3 weeks, with each 3-week (21-day) cycle serving as one treatment.

[0149] 4. Test Results

[0150] Some efficacy data are shown in Table 2. A total of 77 patients were enrolled, among whom the ORR of patients with HER2-low expression BC was 55.8% (43 / 77, 95% CI 44.1-67.2).

[0151] Table 2. ORR subgroup analysis

[0152] ORR is shown as % (n / N, 95% CI) or % (n / N).

[0153] *ORR was calculated using the number of subjects who had previously received anti-HER2 cancer therapy in the advanced / metastatic setting as the denominator; two-sided 95% CIs were estimated using the Clopper-Pearson method.

[0154] **Includes RC48-ADC, A166, DP303c, MRG002, ARX788, TAA013, DX126-262, PF-06804103, and BAT8001.

[0155] The clinical trial subsequently enrolled 110 evaluable patients with HER2-low-expressing breast cancer, and the efficacy evaluation results are shown in Tables 3 and 4.

[0156] Table 3. Tumor Responses in Patients with HER2-Low Expressing Breast Cancer Received Anti-HER2 Antibody Drug Conjugates

[0157] Note: Subjects must undergo efficacy assessments every 6 weeks (±7 days) for the first 48 weeks after the first dose, and every 12 weeks (±7 days) thereafter. Radiographic assessments are not affected by dosing interruptions or delays. Subjects with a CR or PR at the first evaluation should have their response confirmed 4 weeks later (at the next scheduled time point).

[0158] cBOR is the confirmed best overall tumor response rate, cORR is the confirmed objective response rate, and uORR is the unconfirmed objective response rate.

[0159] As shown in Table 3, the objective response rate (cORR) for confirmed HER2-low expressing breast cancer patients in each dose group was as high as 64.9% (6.4 mg / kg dose) and 60.6% (5.6 mg / kg dose). Furthermore, among all patients with HER2-low expressing breast cancer who received different doses, the cORR reached 59.1% and the uORR reached 67.3%. This demonstrates that the anti-HER2 antibody-drug conjugates provided herein can exert significant tumor inhibitory effects in the treatment of HER2-low expressing breast cancer patients.

[0160] Table 4. PFS and DoR in patients with HER2-low expressing breast cancer receiving anti-HER2 antibody drug conjugates

[0161] Note: PFS is progression-free survival, mPFS is median progression-free survival, 06-mo PFS rate is the 6-month progression-free survival rate, 12-mo PFS rate is the 12-month progression-free survival rate, and 18-mo PFS rate is the 18-month progression-free survival rate. mDoR is the median duration of response.

[0162] As can be seen from the results in Table 4, in patients with HER2-low-expressing breast cancer treated with anti-HER2 antibody-drug conjugates, 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). Moreover, in 110 patients with HER2-low-expressing breast cancer treated with anti-HER2 antibody-drug conjugates, the median progression-free survival (mPFS) can reach 10.9 months, and the median duration of remission (mDoR) can reach 12.2 months. This shows that the anti-HER2 antibody-drug conjugate provided by the present disclosure is used to treat patients with HER2-low-expressing breast cancer, and can significantly prolong the patient's progression-free survival time and tumor duration, so that patients with HER2-low-expressing breast cancer can be effectively treated.

[0163] Example 3. Phase I clinical study of anti-HER2 antibody drug conjugates

[0164] In a Phase I clinical study of an anti-HER2 antibody-drug conjugate, 243 patients (97.2%) with advanced solid tumors reported treatment-related adverse events (TRAEs). Grade ≥ 3 TRAEs, severe TRAEs, and treatment-related deaths were reported in 131 (52.4%), 31 (12.4%), and 3 (1.2%) patients, respectively. Interstitial lung disease (AESI) was reported in 8 (3.2%) subjects. Exposure to the anti-HER2 antibody-drug conjugate, total antibody, and payload was generally proportional to the dose of 3.2 to 8.0 mg / kg. The ORR for all patients was 61.6% (154 / 250, 95% CI 55.3-67.7).

[0165] 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, and letrozole / anastrozole for the treatment of unresectable or metastatic breast cancer with low HER2 expression

[0166] 1. Investigational Drugs

[0167] The anti-HER2 antibody drug conjugate described in Example 1, lyophilized powder injection, specification: 100 mg / bottle.

[0168] Isethionate salt of the compound represented by formula (II), tablets, specifications: 25 mg / tablet, 50 mg / tablet, 125 mg / tablet, 150 mg / tablet.

[0169] Fulvestrant injection (Pulihe), injection, specifications: 5ml: 0.25g.

[0170] Letrozole tablets (Fure), tablets, specifications: 2.5 mg.

[0171] Anastrozole tablets (Yishuzhi), tablets, specifications: 1mg.

[0172] Bevacizumab injection (Areto), injection, specifications: 100mg (4ml) / bottle.

[0173] II. Enrolled Subjects

[0174] 1. Women aged 18 to 75 years (inclusive).

[0175] 2. Unresectable or metastatic breast cancer with histologically or cytologically confirmed low HER2 expression (IHC2+ / ISH-, IHC1+ / ISH-, or undetectable); estrogen receptor / progesterone receptor (ER / PR) status must be determined at the recurrent / metastatic stage (ER-positive and / or PR-positive definitions must conform to the American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) guidelines). Low HER2 expression must be verified and confirmed by the pathology department of the participating research center.

[0176] 3. For HR-positive subjects, any of the following must be met:

[0177] a) Previous bilateral oophorectomy, or age ≥ 60 years; or

[0178] b) 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

[0179] c) 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.

[0180] 4. There is imaging or objective evidence of disease progression during or after the last systemic treatment before the start of study treatment.

[0181] 5. Previous treatment as follows:

[0182] HR-positive subjects:

[0183] a) Phase I (dose-finding): Patients have received at least 1 line of endocrine therapy, and ≤ 2 lines of chemotherapy are allowed.

[0184] b) 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.

[0185] HR-negative subjects:

[0186] c) Phase I (dose-finding): Patients have received at least one line of chemotherapy.

[0187] d) Phase II (expansion of efficacy): Recurrence / metastasis stage with no prior systemic anti-tumor treatment.

[0188] e) Disease recurrence within the first 24 months after adjuvant endocrine therapy is considered as one line of treatment; recurrence within 6 months after (neo)adjuvant chemotherapy is counted as a first-line chemotherapy regimen.

[0189] 3. Dosage

[0190] Qualified subjects were given corresponding drugs.

[0191] Phase I (dose-finding phase):

[0192] 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.

[0193] Anti-HER2 antibody drug conjugate combined with isethionate salt of compound represented by formula (II):

[0194] The dose of the anti-HER2 antibody drug conjugate is 2.0 mg / kg, 3.2 mg / kg, or 4.8 mg / kg, administered by intravenous drip, once every 3 weeks, with each 3-week (21-day) cycle as one cycle;

[0195] 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, with a treatment course of 2 weeks on and 1 week off.

[0196] If the relevant dose group is not tolerated, the administration cycle, administration sequence, and usage and dosage of the study drug may 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 3 weeks on / 1 week off; 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 them at intervals of several days.

[0197] Anti-HER2 antibody drug conjugate combined with fulvestrant:

[0198] The dose of anti-HER2 antibody drug conjugate is 2.0 mg / kg, 3.2 mg / kg, or 4.8 mg / kg, administered once every 3 weeks.

[0199] The dose of fulvestrant is 500 mg, administered on days 1 and 15 of the first cycle and on day 1 of each subsequent cycle.

[0200] If the relevant dose group is not tolerated, the administration cycle, administration sequence, and usage 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 administration dosage accordingly.

[0201] Anti-HER2 antibody-drug conjugate combined with bevacizumab:

[0202] The dose of anti-HER2 antibody drug conjugate is 2.0 mg / kg, 3.2 mg / kg, or 4.8 mg / kg, administered once every 3 weeks.

[0203] The dose of bevacizumab was fixed at 15 mg / kg, administered once every 3 weeks.

[0204] If the relevant dose group is not tolerated, the administration cycle, administration sequence, and usage 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 administration dosage accordingly.

[0205] Phase II (Efficacy Expansion Phase):

[0206] 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 compound represented by formula (II) isethionate and letrozole / anastrozole, fulvestrant, letrozole / anastrozole, and bevacizumab.

[0207] Anti-HER2 antibody drug conjugate and isethionate of the compound represented by formula (II) combined with letrozole / anastrozole:

[0208] After the first phase of dose exploration of the anti-HER2 antibody drug conjugate combined with the isethionate salt of the compound represented by formula (II) is completed, at least one dose group of the anti-HER2 antibody drug conjugate and the isethionate salt of the compound represented by formula (II) combined with letrozole or anastrozole is selected for efficacy expansion.

[0209] Letrozole is taken orally, once a day, 2.5 mg each time, for continuous administration.

[0210] Anastrozole is taken orally, once a day, 1 mg each time, for continuous administration.

[0211] Anti-HER2 antibody drug conjugate combined with fulvestrant:

[0212] After the first phase of dose exploration of the anti-HER2 antibody drug conjugate combined with fulvestrant is completed, 1-2 doses will be selected for efficacy expansion. Qualified subjects will enter the efficacy expansion phase of the anti-HER2 antibody drug conjugate combined with fulvestrant.

[0213] Anti-HER2 antibody drug conjugate combined with letrozole / anastrozole:

[0214] After the first phase of dose exploration of the anti-HER2 antibody drug conjugate combined with fulvestrant is completed, 1 to 2 doses will be selected for efficacy expansion of the anti-HER2 antibody drug conjugate and letrozole / anastrozole based on the safety of this dose group.

[0215] Letrozole is taken orally, once a day, 2.5 mg each time, for continuous administration.

[0216] Anastrozole is taken orally, once a day, 1 mg each time, for continuous administration.

[0217] Anti-HER2 antibody-drug conjugate combined with bevacizumab:

[0218] After completing the first phase of dose exploration of the anti-HER2 antibody-drug conjugate combined with bevacizumab, at least one dose group will be selected for efficacy expansion.

Claims

1. Use of an anti-HER2 antibody-drug conjugate in the preparation of a drug for treating HER2-low-expressing breast cancer, wherein the structure of the antibody-drug conjugate is shown in formula (I): Wherein: n is from 3 to 8, and n is a decimal or an integer; Pc is an anti-HER2 antibody.

2. The use according to claim 1, wherein the anti-HER2 antibody is selected from trastuzumab, pertuzumab, or an antigen-binding fragment thereof; preferably trastuzumab or an antigen-binding fragment thereof.

3. The use according to claim 1 or 2, wherein the anti-HER2 antibody comprises a heavy chain variable region and a light chain variable region, and wherein, The heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 shown in SEQ ID NO: 3, 4, and 5 respectively, and LCDR1, LCDR2, and LCDR3 shown in SEQ ID NO: 6, 7, and 8 respectively; Preferably, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 9 or having at least 90% identity thereto, and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 10 or having at least 90% identity thereto; Preferably, the anti-HER2 antibody comprises a heavy chain and a light chain, the heavy chain comprises the amino acid sequence shown in SEQ ID NO: 2 or having at least 90% identity thereto, and the light chain comprises the amino acid sequence shown in SEQ ID NO: 1 or having at least 90% identity thereto.

4. According to the use described in any one of claims 1-3, the anti-HER2 antibody-drug conjugate has the structure shown in the following formula: Among them, n is from 3 to 8, and n is a decimal or an integer; preferably 6 ± 0.

8.

5. Use according to any one of claims 1 - 4, wherein, The HER2-low-expression breast cancer is a breast cancer determined by immunohistochemistry to have a HER2 expression of 1+, or a breast cancer determined by immunohistochemistry to have a HER2 expression of 2+ and determined by in situ hybridization to have a negative HER2 expression.

6. The use according to any one of claims 1-5, wherein the HER2-low-expression breast cancer is an unresectable, recurrent, and / or metastatic breast cancer with low HER2 expression.

7. The use according to any one of claims 1-6, wherein the HER2-low-expression breast cancer has been previously treated with an anti-HER2 drug; preferably a HER2-low-expression breast cancer that has developed resistance or refractoriness after being previously treated with an anti-HER2 drug.

8. The use according to claim 7, wherein, The anti-HER2 drug is selected from at least one of the group consisting of trastuzumab, pertuzumab, pyrotinib, lapatinib, and T-DM1.

9. Use according to any one of claims 1 - 8, wherein, The use is the use of an anti-HER2 antibody-drug conjugate combined with a second therapeutic agent in the preparation of a drug for treating HER2-low-expression breast cancer.

10. The use according to claim 9, wherein, The second therapeutic agent is a CDK4 / 6 inhibitor; Preferably, the CDK4 / 6 inhibitor 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 the compound shown in formula (II) or a pharmaceutically acceptable salt thereof, more preferably the compound shown in formula (II) or a pharmaceutically acceptable salt thereof, and most preferably the hydroxyethylsulfonate of the compound shown in formula (II). Preferably, the dosage of the CDK4 / 6 inhibitor is 1-1000 mg, preferably 100 mg, 125 mg, 150 mg, and preferably 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; Preferably, the anti-HER2 antibody-drug conjugate is administered once every two weeks or once every three weeks; the CDK4 / 6 inhibitor is administered once a day, wherein it is taken continuously for the first 2 weeks and then rested for 1 week, or taken continuously for the first 3 weeks and then rested for 1 week.

11. The use according to claim 9, wherein the second therapeutic agent is an aromatase inhibitor; preferably, the aromatase inhibitor is selected from formestane, exemestane, fadrozole, letrozole, vorozole, and anastrozole, more preferably letrozole or anastrozole; Preferably, the dosage of the aromatase inhibitor is 0.1 - 50 mg, preferably 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 preferred dosing frequency is once a day or twice a day; Preferably, the anti-HER2 antibody-drug conjugate is administered once every two weeks or once every three weeks; the aromatase inhibitor is administered once a day and taken continuously.

12. The use according to any one of claims 9 - 11, wherein the second therapeutic agent is a CDK4 / 6 inhibitor and an aromatase inhibitor.

13. The use according to claim 9, wherein, The second therapeutic agent is a SERD, and the SERD is preferably fulvestrant, AZD-9496, RAD1901, or ZB-716, more preferably fulvestrant; Preferably, the dosage of the SERD is 1 - 1000 mg, preferably 500 mg, and the preferred dosing frequency is 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; Preferably, the anti-HER2 antibody-drug conjugate is administered once every two weeks or once every three weeks; the treatment cycle of the SERD is one treatment cycle every 4 weeks, wherein it is administered on the 1st day and the 15th day of the first cycle, and then on the 1st day of each subsequent cycle.

14. The use according to claim 9, wherein the second therapeutic agent is a VEGF ligand inhibitor, and the VEGF ligand inhibitor is preferably selected from bevacizumab, ramucirumab, ranibizumab, aflibercept, conbercept, 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, or VXM-01, more preferably bevacizumab; Preferably, the dosage of the VEGF ligand inhibitor is 0.1 - 100 mg / kg, preferably 15 mg / kg, and the preferred dosing frequency is once a day, once a week, once every two weeks, once every three weeks, or once a month; Preferably, the anti-HER2 antibody-drug conjugate is administered once every two weeks or once every three weeks; the VEGF ligand inhibitor is administered once every three weeks.

15. The use according to any one of claims 1 - 14, wherein the single-dose of the anti-HER2 antibody-drug conjugate is 1.0 mg / kg - 10.0 mg / kg, preferably 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, and the preferred dosing frequency is once a week, once every two weeks, once every three weeks, or once every four weeks.

16. 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 anti-HER2 antibody-drug conjugate is shown in formula (I): Wherein: n is from 3 to 8, and n is a decimal or an integer; Pc is an anti-HER2 antibody, the anti-HER2 antibody-drug conjugate is defined as in any one of claims 1 - 4 and 15, and the HER2-low-expressing breast cancer is defined as in any one of claims 5 - 8; Preferably, the method comprises administering an anti-HER2 antibody-drug conjugate and a second therapeutic agent to a subject in need thereof; 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.

17. A pharmaceutical composition comprising an anti-HER2 antibody-drug conjugate and a second therapeutic agent, and one or more pharmaceutically acceptable carriers; the structure of the anti-HER2 antibody-drug conjugate is shown in formula (I): Wherein: n is from 3 to 8, and n is a decimal or an integer; Pc is an anti-HER2 antibody, the anti-HER2 antibody-drug conjugate is preferably defined as in any one of claims 1 - 4 and 15, and the second therapeutic agent is preferably defined as in any one of claims 9 - 14.

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