Use of anti-HER3 antibody drug conjugates in tumor therapy

Abstract

This disclosure relates to uses and methods for treating tumors with anti-HER3 antibody drug conjugates. Specifically, this disclosure relates to the use of anti-HER3 antibody drug conjugates in the manufacture of drugs for treating EGFR-mutated tumors, wherein the anti-HER3 antibody drug conjugate has the structure shown in formula I below. JPEG2026534220000018.jpg59170

Description

[Technical Field]

[0001] This disclosure claims priority to the patent application filed on September 22, 2023, with application number CN2023112308116, and the patent application filed on May 29, 2024, with application number CN2024106793284. The aforementioned patents are incorporated herein by reference.

[0002] This disclosure relates to the pharmaceutical field and concerns methods and pharmaceutical uses for treating tumors with anti-HER3 antibody drug conjugates. [Background technology]

[0003] HER3 (epidermal growth factor receptor 3, ErbB-3, or HER3) is a member of the epidermal growth factor receptor (EGFR) family. This family includes HER1 (erbB1, EGFR), HER2 (erbB2, NEU), HER3 (erbB3), and HER4 (erbB4). Each of these receptors contains three parts: an extracellular domain, a transmembrane domain, and an intracellular domain. The extracellular domain contains four domains, and the intracellular domain contains one intracellular tyrosine kinase domain for signal transduction and one tail containing a tyrosine phosphorylated residue located in the cytoplasm. Cellular signal transduction is initiated when a ligand binds to extracellular domains I and III. Normally, these receptors mediate cell division, migration, survival, and organ development. When mutations occur in EGFR family members, the resulting abnormal signal transduction stimulates cell survival and is associated with cancer progression. The basic principle by which the HER3 receptor is activated and produces physiological effects is similar to that of other family members, but the difference is that its ligands include neuregulin 1 (NRG-1) and neuregulin 2 (NRG-2), and activated HER3 cannot form homopolymers, but can only form heterodimers with EGFR or HER2. During the process of HER3 heterodimerization, its intracellular domain exhibits high tyrosine phosphorylase activity, and structural analysis revealed that the HER3 intracellular domain has six P85 (PI-3K subunit) binding sites. This specific structure determines that when HER3 interacts with the P85 regulatory subunit, it can recruit up to six PI-3K molecules to the regulatory subunit site, thereby strongly activating the PI-3K signaling pathway. In fact, the HER3 / HER2 dimer is the most active of the HER dimers. EGFR is widely distributed on the cell surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes, and other cells. The EGFR signaling pathway plays a crucial role in physiological processes such as cell growth, proliferation, and differentiation.

[0004] Antibody-drug conjugates (ADCs) covalently link a cytotoxic small molecule drug to an antibody via a single chemical linker, using the antibody as a carrier for targeted delivery of the drug to target cells. This improves the effectiveness of chemotherapy and reduces systemic exposure and toxicity by combining the high targeting ability of the antibody with the strong killing power of the cytotoxic drug against target cells. The endocytosis efficiency of the HER3 receptor is much higher than that of other members of the family, making it even more suitable as a target for ADC drugs.

[0005] Developing safe and effective clinical treatment strategies for HER3 targets is a crucial issue that needs to be addressed in this field. [Overview of the project]

[0006] This disclosure provides methods and pharmaceutical uses for treating tumors with anti-HER3 antibody drug conjugates.

[0007] In some embodiments, this disclosure provides one of the following methods or uses: (1) Uses of anti-HER3 antibody drug conjugates in the manufacture of drugs for treating tumors. (2) A method for treating a subject suffering from a tumor, comprising administering an anti-HER3 antibody drug conjugate to the subject. (3) An anti-HER3 antibody drug conjugate used to treat a subject suffering from a tumor.

[0008] In some embodiments, this disclosure provides one of the following methods or uses: (1) Uses of combination anti-HER3 antibody drug conjugates with tyrosine kinase inhibitors in the manufacture of drugs for treating tumors. (2) Applications of combinations of anti-HER3 antibody drug conjugates and tyrosine kinase inhibitors in the manufacture of drugs for treating tumors. (3) Uses of a pharmaceutical composition comprising an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor in the manufacture of drugs for treating tumors. (4) Uses of pharmaceutical packaging boxes or products containing an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor in the manufacture of drugs for treating tumors. (5) A method for treating a subject suffering from a tumor, comprising administering to the subject an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor. (6) an anti-HER3 antibody drug conjugate used to treat a subject suffering from a tumor, wherein the subject further receives treatment with a tyrosine kinase inhibitor. (7) A tyrosine kinase inhibitor used to treat a subject suffering from a tumor, wherein the subject is further treated with an anti-HER3 antibody drug conjugate. (8) Combination therapy of anti-HER3 antibody drug conjugates with tyrosine kinase inhibitors is used to treat tumors. (9) A pharmaceutical composition comprising an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor is used for the treatment of tumors. (10) A pharmaceutical packaging box or product containing an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor is used for the treatment of tumors.

[0009] In some embodiments, the Disclosure provides a pharmaceutical composition comprising an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor. In some embodiments, the Disclosure provides a pharmaceutical packaging box or product comprising an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor. In some embodiments, the pharmaceutical packaging box or product further comprises one or more containers, each independently comprising an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor. In some embodiments, in any one of the methods or uses described above, the tumor is selected from advanced and / or metastatic solid tumors. In some embodiments, the tumor is a locally advanced or metastatic solid tumor. In some embodiments, the “locally advanced or metastatic solid tumor” is an unresectable locally advanced or metastatic solid tumor. In some embodiments, the tumor is an unresectable locally advanced or metastatic solid tumor, and the solid tumor has failed standard treatment or for which there is no effective standard treatment regimen. In some embodiments, the tumor is non-small cell lung cancer (NSCLC).

[0010] In some specific embodiments, the method or use described above is one in which the tumor is a histologically or cytologically identified unresectable locally advanced or metastatic solid tumor that has recurred or progressed after standard treatment, or for which there is no standard treatment regimen, or for which standard treatment is not currently applicable.

[0011] In some embodiments, the method or use described above, wherein the tumor has brain metastases, bone metastases and / or liver metastases.

[0012] In some embodiments, the tumor is an EGFR-mutated tumor in any of the methods or uses described above. In some embodiments, the tumor is an EGFR-mutated non-small cell lung cancer.

[0013] In some embodiments, the tumor is a locally advanced or metastatic EGFR mutation in any of the methods or uses described above. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer with an EGFR mutation.

[0014] In some embodiments, the terms "EGFR mutation" and "EGFR mutation-positive" can be used interchangeably, which may be a sensitive mutation or an insensitive mutation. In some embodiments, the "EGFR mutation" is confirmed by a histological or blood sample, and comprises at least one EGFR mutation selected from the group consisting of exon 19 deletion (Ex19del), exon 21 substitution mutation (L858R mutation), G719X, and L861Q.

[0015] In some embodiments, in any one of the aforementioned methods or uses, the tumor is a tumor that has failed treatment with a tyrosine kinase inhibitor (TKI). In some embodiments, the tumor is non-small cell lung cancer that has failed treatment with a tyrosine kinase inhibitor (TKI).

[0016] In some embodiments, in any one of the aforementioned methods or uses, the tumor is an EGFR-mutated tumor that has failed treatment with a tyrosine kinase inhibitor (TKI). In some embodiments, the tumor is EGFR-mutated non-small cell lung cancer that has failed treatment with a tyrosine kinase inhibitor (TKI).

[0017] In some embodiments, in any one of the aforementioned methods or uses, the tumor is a locally advanced or metastatic tumor that has failed treatment with a tyrosine kinase inhibitor (TKI). In some embodiments, the tumor is locally advanced or metastatic non-small cell lung cancer that has failed treatment with a tyrosine kinase inhibitor (TKI).

[0018] In some embodiments, in any one of the aforementioned methods or uses, the tumor is an EGFR-mutated locally advanced or metastatic tumor that has failed treatment with a tyrosine kinase inhibitor (TKI). In some embodiments, the tumor is EGFR-mutated locally advanced or metastatic non-small cell lung cancer that has failed treatment with a tyrosine kinase inhibitor (TKI).

[0019] In some embodiments, locally advanced or metastatic is defined as being stage IIIB to IV according to the International Association for Lung Cancer (IASLC) 9th edition TNM classification criteria, and being unsuitable for curative surgery or curative chemoradiotherapy.

[0020] In this disclosure, the terms "failure to treat with TKI," "failure to treat with EGFR-TKI," and "EGFR-TKI resistance" are interchangeable. In some embodiments, "failure to treat" refers to the observation of disease progression on imaging during or after treatment.

[0021] In some embodiments, the tumor is (1) Locally advanced or metastatic solid tumors (e.g., locally advanced or metastatic NSCLC), (2) EGFR mutation-positive non-small cell lung cancer (e.g., EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer, EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer treated as first-line treatment), (3) Non-small cell lung cancer that has failed treatment with EGFR-TKI (for example, locally advanced or metastatic non-small cell lung cancer that has failed treatment with EGFR-TKI, EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer that has failed treatment with EGFR-TKI, (4) Advanced or metastatic solid tumors that have recurred or progressed after standard treatment, for which there is no standard treatment regimen, or for which standard treatment is not currently applicable. (5) This includes, but is not limited to, any one or any combination of, unresectable locally advanced or metastatic solid tumors that have recurred or progressed after standard treatment, for which there is no standard treatment regimen, or for which standard treatment is not currently applicable.

[0022] In some embodiments, subjects with locally advanced or metastatic NSCLC were treated with EGFR TKIs. In some embodiments, subjects with the T790M mutation had to be treated with third-generation EGFR TKIs, and disease progression was observed on imaging during or after treatment. Exemplarily, subjects were (1) Subjects in whom tumor recurrence or metastasis occurred during or within 6 months after discontinuation of EGFR TKI adjuvant therapy; (2) Subjects with non-metastatic tumors who have previously received novel adjuvant / adjuvant chemotherapy or curative chemoradiotherapy in whom tumor recurrence or metastasis occurred at least 6 months after the completion of the above treatment, and who have received EGFR TKI treatment and whose disease progression was observed on imaging during or after the treatment; (3) For locally advanced or metastatic NSCLC, including, but not limited to, cases in which concomitant use of antivascular therapy or targeted therapy (e.g., EGFR / c-MET bispecific antibody, excluding antibody-drug conjugates) is permitted during the EGFR TKI treatment period, but other systemic antitumor treatments other than the above treatments are not permitted.

[0023] In some embodiments, “locally advanced or metastatic NSCLC” refers to locally advanced or metastatic non-small cell lung cancer that is histologically or cytologically confirmed to be unresectable. In some specific embodiments, “locally advanced or metastatic NSCLC” refers to locally advanced or metastatic non-small cell lung cancer that is histologically or cytologically confirmed to be unresectable. It is characterized by recurrence or progression after standard treatment, the absence of a standard treatment regimen, or inapplicability of standard treatment at present.

[0024] In some embodiments, "EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer" is histologically or cytologically confirmed unresectable locally advanced or metastatic non-small cell lung cancer, confirmed histologically or by blood specimens, and having an EGFR mutation (sensitive or insensitive mutation). In some embodiments, "EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer" refers to histologically or cytologically confirmed unresectable locally advanced or metastatic non-small cell lung cancer, confirmed histologically or by blood specimens, and having an EGFR exon 19 deletion or L858R mutation or G719X or L861Q. In some embodiments, "EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer" is "EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer that has failed treatment with EGFR-TKIs," or "EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer that is treated as first-line treatment."

[0025] In this disclosure, standard treatment regimens are those well known to those skilled in the art, such as those disclosed in treatment guidelines approved by regulatory authorities. This includes, but is not limited to, detailed and up-to-date information on standard treatment regimens for various cancers provided in, for example, the NCCN guidelines and CSCO guidelines.

[0026] Anti-HER3 antibody drug conjugate In some embodiments, the dose of the anti-HER3 antibody drug conjugate is approximately 0.1 mg / kg to approximately 20 mg / kg, for example, approximately 1.0 mg / kg to approximately 20 mg / kg, approximately 1.0 mg / kg to approximately 12 mg / kg, approximately 1.5 mg / kg to approximately 12 mg / kg, approximately 1.0 mg / kg to approximately 10.5 mg / kg, approximately 1.0 mg / kg to approximately 10 mg / kg, approximately 1.0 mg / kg to approximately 9 mg / kg, approximately The ranges are approximately 1.5 mg / kg to 10.5 mg, approximately 1.5 mg / kg to 9.0 mg / kg, approximately 3.0 mg / kg to 9.0 mg / kg, approximately 4.5 mg / kg to 9.0 mg / kg, approximately 6.0 mg / kg to 9.0 mg / kg, approximately 7.5 mg / kg to 9.0 mg / kg, approximately 1.5 mg / kg to 7.5 mg / kg, approximately 3.0 mg / kg to 7.5 mg / kg, or any range between these values.In some embodiments, the dose of the anti-HER3 antibody drug conjugate is approximately 1.0 mg / kg, approximately 1.1 mg / kg, approximately 1.2 mg / kg, approximately 1.3 mg / kg, approximately 1.4 mg / kg, approximately 1.5 mg / kg, approximately 1.6 mg / kg, approximately 1.7 mg / kg, approximately 1.8 mg / kg, approximately 1.9 mg / kg, approximately 2.0 mg / kg, approximately 2.1 mg / kg, approximately 2.2 mg / kg, approximately 2.3 mg / kg, approximately 2.4 mg / kg, approximately 2.5 mg / kg, approximately 2.6 mg / kg, approximately 2.7 mg / kg kg, approximately 2.8 mg / kg, approximately 2.9 mg / kg, approximately 3.0 mg / kg, approximately 3.1 mg / kg, approximately 3.2 mg / kg, approximately 3.4 mg / kg, approximately 3.5 mg / kg, approximately 3.6 mg / kg, approximately 3.8 mg / kg, approximately 4.0 mg / kg, approximately 4.2 mg / kg, approximately 4.3 mg / kg, approximately 4.5 mg / kg, approximately 4.6 mg / kg, approximately 4.8 mg / kg, approximately 5.0 mg / kg, approximately 5.1 mg / kg, approximately 5.3 mg / kg, approximately 5.5 mg / kg, approximately 5.6 mg / kg, approximately 5.8 mg / kg, approximately 6. 0 mg / kg, approx. 6.1 mg / kg, approx. 6.3 mg / kg, approx. 6.4 mg / kg, approx. 6.5 mg / kg, approx. 6.6 mg / kg, approx. 6.8 mg / kg, approx. 6.9 mg / kg, approx. 7.0 mg / kg, approx. 7.2 mg / kg, approx. 7.4 mg / kg, approx. 7.5 mg / kg, approx. 7.6 mg / kg, approx. 7.7 mg / kg, approx. 7.8 mg / kg, approx. 7.9 mg / kg, approx. 8.0 mg / kg, approx. 8.1 mg / kg, approx. 8.2 mg / kg, approx. 8.3 mg / kg, approx. 8.4 mg / kg, approx. 8.5 mg / kg The dosage can be selected from g, approximately 8.6 mg / kg, approximately 8.7 mg / kg, approximately 8.8 mg / kg, approximately 8.9 mg / kg, approximately 9.0 mg / kg, approximately 9.1 mg / kg, approximately 9.2 mg / kg, approximately 9.3 mg / kg, approximately 9.4 mg / kg, approximately 9.5 mg / kg, approximately 10.0 mg / kg, approximately 10.5 mg / kg, approximately 12 mg / kg, approximately 12.5 mg / kg, approximately 13 mg / kg, approximately 13.5 mg / kg, approximately 14 mg / kg, approximately 16 mg / kg, approximately 18 mg / kg, approximately 19 mg / kg, and approximately 20 mg / kg.

[0027] In some embodiments, the administration frequency of the anti-HER3 antibody drug conjugate is once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every twelve weeks. In some specific embodiments, the administration frequency of the anti-HER3 antibody drug conjugate is once every three weeks.

[0028] In some embodiments, the administration regimen of the anti-HER3 antibody drug conjugate is as follows: (a1) The dosage is approximately 0.1 mg / kg to approximately 20 mg / kg, and the frequency of administration is once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every twelve weeks. (a2) The dosage is approximately 1.0 mg / kg to approximately 13.5 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (a3) The dosage is approximately 1.0 mg / kg to approximately 10.5 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (a4) The dosage is approximately 1.0 mg / kg to approximately 9.0 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (a5) The dosage is approximately 1.5 mg / kg to approximately 10.5 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (a6) The dosage is approximately 1.5 mg / kg to approximately 9.0 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (a7) The dosage is approximately 1.5 mg / kg to approximately 12.0 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (a8) The dosage is approximately 7.5 mg / kg to approximately 9.0 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (a9) The dosage is approximately 1.0 mg / kg, approximately 1.5 mg / kg, approximately 3.0 mg / kg, approximately 4.5 mg / kg, approximately 6.0 mg / kg, approximately 6.5 mg / kg, approximately 7.0 mg / kg, approximately 7.5 mg / kg, approximately 8.0 mg / kg, approximately 8.5 mg / kg, approximately 9.0 mg / kg, approximately 10.5 mg / kg, approximately 12 mg / kg, or approximately 13.5 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (a 10 The dosage is approximately 1.5 mg / kg, approximately 3.0 mg / kg, approximately 4.5 mg / kg, approximately 6.0 mg / kg, approximately 6.5 mg / kg, approximately 7.0 mg / kg, approximately 7.5 mg / kg, approximately 8.0 mg / kg, approximately 8.5 mg / kg, or approximately 9.0 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (a 11 The dose of the aforementioned anti-HER3 antibody drug conjugate is approximately 1.5 mg / kg, and the frequency of administration is once every three weeks. (a 12 The dose of the aforementioned anti-HER3 antibody drug conjugate is approximately 3.0 mg / kg, and the administration frequency is once every three weeks. (a 13 The dose of the aforementioned anti-HER3 antibody drug conjugate is approximately 4.5 mg / kg, and the administration frequency is once every three weeks. (a 14 The dose of the aforementioned anti-HER3 antibody drug conjugate is approximately 6.0 mg / kg, and the administration frequency is once every three weeks. (a15 ) the dosage of the anti-HER3 antibody-drug conjugate is about 7.5 mg / kg, and the administration frequency is once every 3 weeks, (a 16 ) the dosage of the anti-HER3 antibody-drug conjugate is about 8.0 mg / kg, and the administration frequency is once every 3 weeks, (a 17 ) the dosage of the anti-HER3 antibody-drug conjugate is about 8.5 mg / kg, and the administration frequency is once every 3 weeks, (a 18 ) the dosage of the anti-HER3 antibody-drug conjugate is about 9.0 mg / kg, and the administration frequency is once every 3 weeks, is selected from any one of the foregoing.

[0029] In some specific embodiments, in the above (a1) to (a 10 ), in the administration regimen according to any one of the foregoing, the administration frequency of the anti-HER3 antibody-drug conjugate is once every 3 weeks.

[0030] In some embodiments, the anti-HER3 antibody-drug conjugate is an antibody-drug conjugate of any structure disclosed in WO2022078425A1 and WO2020063676A1, and the present disclosure incorporates the relevant contents such as the structure and manufacturing method of the immunoconjugate in the aforementioned patents into the present disclosure by reference.

[0031] In some embodiments, the anti-HER3 antibody-drug conjugate has a structure represented by the following formula, [Chemical Formula] Here, n is 1 to 8, n is a decimal or an integer, and Pc is an anti-HER3 antibody.

[0032] In some embodiments, n is 4.0±0.4.

[0033] In some embodiments, the anti-HER3 antibody-drug conjugate has a structure represented by the following formula, [ka] Here, n is between 1 and 8, is a decimal or an integer, and Pc is an anti-HER3 antibody.

[0034] In some embodiments, n is 4.0 ± 0.4.

[0035] In this disclosure, "antibody" is used in its broadest sense, covering a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, or their antigen-binding fragments ("antigen-binding moieties").

[0036] In some embodiments, the anti-HER3 antibody is from any type of anti-HER3 antibody or its antigen-binding fragment in WO2022078425A1, and this disclosure incorporates, by reference, the relevant content of the above patent, such as the antibody sequence and manufacturing method.

[0037] In some embodiments, the anti-HER3 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 shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, and / or the light chain variable region comprises LCDR1, LCDR2, and LCDR3 shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively.

[0038] The aforementioned CDR sequences are shown in the table below.

[0039] [Table 1]

[0040] The aforementioned CDR is defined based on the Kabat numbering system.

[0041] In some embodiments, the anti-HER3 antibody comprises one, two, three, four, five, or six CDRs selected from HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 shown in SEQ ID NO:1 to SEQ ID NO:6.

[0042] In some embodiments, the anti-HER3 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), where the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO:7, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO:8. The CDRs are defined based on the Kabat, IMGT, Chothia, AbM, or Contact numbering system. In some specific embodiments, the CDRs are defined based on the Kabat numbering system.

[0043] In some embodiments, the anti-HER3 antibody is a mouse-derived antibody, a chimeric antibody, a humanized antibody, a human antibody, or one of the aforementioned antigen-binding fragments. In some specific embodiments, the anti-HER3 antibody is selected from a humanized antibody or its antigen-binding fragment.

[0044] In some embodiments, the VH anti-HER3 antibody comprises the amino acid sequence shown in SEQ ID NO:7, or an amino acid sequence having at least 80% to 90% sequence identity thereto, and the VL comprises the amino acid sequence shown in SEQ ID NO:8, or an amino acid sequence having at least 80% to 90% sequence identity thereto. [ka]

[0045] In some embodiments, the anti-HER3 antibody comprises one or two of the above-mentioned VH and VL.

[0046] In some embodiments, the anti-HER3 antibody further comprises an antibody constant region, for example, the heavy chain constant region of the antibody constant region is selected from human IgG1, IgG2, IgG3, and IgG4 constant regions and their variants, and the light chain constant region of the antibody constant region is selected from human antibody κ and λ chain constant regions and their variants.

[0047] The above light chain variable region and light chain constant region sequences are combined to form the light chain sequence, and each heavy chain variable region and heavy chain constant region are combined to form the heavy chain sequence. An example of a humanized antibody sequence is shown below. [ka]

[0048] In some embodiments, the anti-HER3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence shown in SEQ ID NO:9 or having at least 80% to 90% identity thereto, and the light chain comprises an amino acid sequence shown in SEQ ID NO:10 or having at least 80% to 90% identity thereto.

[0049] In some embodiments, the anti-HER3 antibody comprises one or two of the heavy and light chains described above.

[0050] In the context of this disclosure, “at least 80%” and “at least 90%” cover a numerical range of 80% or more, 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 two of these ranges.

[0051] In some embodiments, the route of administration of the anti-HER3 antibody drug conjugate is oral, parenteral, or transdermal, and parenteral administration includes, but is not limited to, intravenous, subcutaneous, or intramuscular injection. In some specific embodiments, the route of administration of the anti-HER3 antibody drug conjugate is intravenous injection.

[0052] In some embodiments, the anti-HER3 antibody drug conjugate is formulated into an injectable form. Exemplarily, the injectable form of the anti-HER3 antibody drug conjugate is an injection solution or a lyophilized powder injection, which comprises the anti-HER3 antibody drug conjugate and one or more pharmaceutically acceptable excipients.

[0053] In some embodiments, the pharmaceutical composition comprising an anti-HER3 antibody drug conjugate further comprises a buffer, a stabilizer, an osmotic pressure modifier and / or a surfactant. Exemplarily, the buffer is selected from any one of the following buffers: acetate-sodium acetate, succinate-sodium succinate, histidine-hydrochloride, and citrate-sodium citrate. In some specific embodiments, the buffer is acetate-sodium acetate. Examples of surfactants include polysorbates (e.g., polysorbate 20, polysorbate 80), poloxamers, Triton, sodium dodecylsulfonate, sodium laurylsulfonate, sodium octylglucoside, lauryl sulfobetaine, myristyl sulfobetaine, linoleyl sulfobetaine, stearyl sulfobetaine, lauryl sarcosine, myristyl sarcosine, linoleyl sarcosine, stearyl sarcosine, linoleyl betaine, myristyl betaine, cetyl betaine, lauryl sulfobetaine, myristyl betaine, cetyl betaine, lauryl sulfobetaine. Lamidopropyl betaine, cocamidopropyl betaine, linoleidopropyl betaine, myristamidopropyl betaine, palmidopropyl betaine, isostearamidopropyl betaine, myristamidopropyl dimethylamine, palmidopropyl dimethylamine, isostearamidopropyl dimethylamine, methyl cocoyl sodium, methyl oleoyl taurate sodium, polyethylene glycol, polypropylene glycol, and copolymers of ethylene and propylene glycol may be selected. In some specific embodiments, the surfactant is polysorbate. Exemplarily, it is polysorbate 80 or polysorbate 20. In some specific embodiments, the surfactant is polysorbate 80. In some embodiments, the pharmaceutical composition containing the anti-HER3 antibody drug conjugate further comprises sugars. Exemplarily, "sugars" is a general composition (CH2O) nThe sugars include and derivatives thereof, and include monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, etc. The sugars may be selected from glucose, sucrose, trehalose, α,α-trehalose dihydrate, lactose, fructose, maltose, dextran, glycerin, erythritol, propanetriol, arabitol, sylitol, sorbitol, mannitol, melibiose, melegitose, raffinose, manninotriose, stachyose, maltose, lactulose, maltulose, sorbitol, maltitol, lactitol, isomaltulose, etc. In some specific embodiments, "sugar" is sucrose.

[0054] Combination therapy with anti-HER3 antibody drug conjugates and tyrosine kinase inhibitors In some embodiments, the present disclosure provides applications in the manufacture of drugs for treating tumors, using a combination of an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor.

[0055] In some embodiments, a combination of an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor is used to treat tumors.

[0056] In some embodiments, the present disclosure provides a method for treating a subject suffering from a tumor, the method comprising administering to the subject 1) an anti-HER3 antibody drug conjugate and 2) a tyrosine kinase inhibitor.

[0057] In some embodiments, the tyrosine kinase inhibitor is selected from neratinib, lapatinib, tucatinib, gefitinib, erlotinib, icotinib, afatinib, dacomitinib, osimertinib, or ametinib.

[0058] In some embodiments, the tyrosine kinase inhibitor is ametinib.

[0059] In some embodiments, the dosage of the tyrosine kinase inhibitor is approximately 1 mg to approximately 1000 mg, for example, approximately 10 mg to approximately 1000 mg, approximately 10 mg to approximately 900 mg, approximately 10 mg to approximately 800 mg, approximately 10 mg to approximately 500 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 450 mg, approximately 50 mg to approximately 400 mg, approximately 50 mg to approximately 350 mg, approximately 50 mg to approximately 300 mg, approximately 50 mg to approximately 250 mg, approximately 50 mg to approximately 200 mg, approximately 50 mg to approximately 180 mg, approximately 50 mg to approximately 150 mg, approximately 55 mg to approximately 110 mg, approximately 100 mg to approximately 150 mg, approximately 100 mg to approximately 180 mg, or approximately 100 to approximately 200 mg, and any numerical range between any two.

[0060] In some appropriate cases, the dosage of tyrosine kinase inhibitors is approximately 50 mg, 55 mg, 60 mg, 70 mg, 80 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 350 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, and 1000 mg.

[0061] In some embodiments, the frequency of administration of the tyrosine kinase inhibitor is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, or once every five days. In some specific embodiments, the frequency of administration of the tyrosine kinase inhibitor is once a week.

[0062] In some embodiments, the administration regimen of the tyrosine kinase inhibitor is: (b1) The dose of the tyrosine kinase inhibitor is approximately 10 mg to approximately 1000 mg, and the frequency of administration is once a day, twice a day, three times a day, once every two days, once every three days, once every four days, once every five days, or once a week. (b2) The dose of the tyrosine kinase inhibitor is approximately 10 mg to approximately 500 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. (b3) The dose of the tyrosine kinase inhibitor is approximately 50 mg to approximately 200 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. (b4) The dose of the tyrosine kinase inhibitor is approximately 50 mg to approximately 150 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. (b5) The dose of the tyrosine kinase inhibitor is approximately 55 mg to approximately 110 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. (b6) The dose of the tyrosine kinase inhibitor is approximately 100 mg to approximately 200 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. (b7) The dose of the tyrosine kinase inhibitor is approximately 55 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. (b8) The dose of the tyrosine kinase inhibitor is approximately 110 mg, and the frequency of administration is selected from one of the following: once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. In some embodiments, in the administration regimen described in any one of (b1) to (b8) above, the frequency of administration of the tyrosine kinase inhibitor is once a day.

[0063] In some embodiments, the frequency and dosage of administration of the anti-HER3 antibody drug conjugate are as shown in any one of the above.

[0064] For example, the dosage of the anti-HER3 antibody drug conjugate is approximately 0.1 mg / kg to approximately 20 mg / kg, for example, approximately 1.0 mg / kg to approximately 20 mg / kg, approximately 1.0 mg / kg to approximately 13.5 mg / kg, approximately 1.0 mg / kg to approximately 12 mg / kg, approximately 1.5 mg / kg to approximately 12 mg / kg, approximately 1.0 mg / kg to approximately 10.5 mg / kg, approximately 1.0 mg / kg to approximately 10 mg / kg, and approximately 1.0 mg / kg. The values ​​are approximately 9 mg / kg for g / kg, 10.5 mg / kg for 1.5 mg / kg, 9.0 mg / kg for 1.5 mg / kg, 9.0 mg / kg for 3.0 mg / kg, 9.0 mg / kg for 4.5 mg / kg, 9.0 mg / kg for 6.0 mg / kg, 9.0 mg / kg for 7.5 mg / kg, 7.0 mg / kg for 1.5 mg / kg, and 7.5 mg / kg for 3.0 mg / kg. For example, the dosages are approximately 1.5 mg / kg, 3.0 mg / kg, 4.5 mg / kg, 6.0 mg / kg, 6.5 mg / kg, 7.0 mg / kg, 7.5 mg / kg, 8.0 mg / kg, 8.5 mg / kg, 9.0 mg / kg, 9.5 mg / kg, 10.0 mg / kg, 10.5 mg / kg, 12.0 mg / kg, and 13.5 mg / kg. The administration frequency of the anti-HER3 antibody drug conjugate is once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every twelve weeks. For example, once every three weeks.

[0065] For example, the administration regimen of the anti-HER3 antibody drug conjugate is (a1)~(a 14 The administration regimen is selected from one of the following:

[0066] In some embodiments, the combined administration regimen of the anti-HER3 antibody drug conjugate and the tyrosine kinase inhibitor is selected from one of the following: (a1) The dose of the anti-HER3 antibody drug conjugate is approximately 0.1 mg / kg to approximately 20 mg / kg, and the frequency of administration is once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every twelve weeks. (b1) The dose of the tyrosine kinase inhibitor is approximately 10 mg to approximately 1000 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. Or, (a2) The dose of the anti-HER3 antibody drug conjugate is approximately 1.0 mg / kg to approximately 20 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (b2) The dose of the tyrosine kinase inhibitor is approximately 10 mg to approximately 500 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. Or, (a3) The dose of the anti-HER3 antibody drug conjugate is approximately 1.0 mg / kg to approximately 13.5 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (b3) The dose of the tyrosine kinase inhibitor is approximately 50 mg to approximately 200 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. Or, (a4) The dose of the anti-HER3 antibody drug conjugate is approximately 1.0 mg / kg to approximately 9.0 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (b3) The dose of the tyrosine kinase inhibitor is approximately 50 mg to approximately 200 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. Or, (a5) The dose of the anti-HER3 antibody drug conjugate is approximately 1.5 mg / kg to approximately 12.5 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (b3) The dose of the tyrosine kinase inhibitor is approximately 50 mg to approximately 200 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. Or, (a5) The dose of the anti-HER3 antibody drug conjugate is approximately 1.5 mg / kg to approximately 10.5 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (b4) The dose of the tyrosine kinase inhibitor is approximately 50 mg to approximately 150 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. Or, (a6) The dose of the anti-HER3 antibody drug conjugate is approximately 7.5 mg / kg to approximately 9.0 mg / kg, and the frequency of administration is selected from once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, or once every ten weeks. (b5) The dose of the tyrosine kinase inhibitor is approximately 55 mg to approximately 110 mg, and the frequency of administration is once daily, twice daily, three times daily, once every two days, once every three days, once every four days, once every five days, or once a week. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 1.5 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 110 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 3.0 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 110 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 4.5 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 110 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 6.0 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 110 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 6.5 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 110 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 7.5 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 110 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 8.0 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 110 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 8.5 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 110 mg, administered once daily. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 9.0 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 110 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 10.5 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 110 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 1.5 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 55 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 3.0 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 55 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 4.5 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 55 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 6.0 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 55 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 6.5 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 55 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 7.5 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 55 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 8.0 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 55 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 8.5 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 55 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 9.0 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 55 mg, administered once a day. Or, The dose of the anti-HER3 antibody drug conjugate is approximately 10.5 mg / kg, administered once every three weeks, and the dose of the tyrosine kinase inhibitor is approximately 55 mg, administered once a day.

[0067] In some embodiments, the anti-HER3 antibody-drug conjugate is an anti-HER3 antibody-drug conjugate of any of the aforementioned structures.

[0068] For example, the anti-HER3 antibody drug conjugate is [ka] It has the structure shown.

[0069] Here, n is between 1 and 8, is a decimal or an integer, and Pc is an anti-HER3 antibody.

[0070] Exemplary, in some embodiments, n is 4.0 ± 0.4.

[0071] Exemplary, in some embodiments, the anti-HER3 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), where the heavy chain variable region comprises HCDR1, HCDR2, and HCDR3 shown in SEQ ID NO:1, SEQ ID NO:2, and SEQ ID NO:3, respectively, and / or the light chain variable region comprises LCDR1, LCDR2, and LCDR3 shown in SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6, respectively.

[0072] Exemplary, in some embodiments, the VH of the anti-HER3 antibody includes the amino acid sequence shown in SEQ ID NO:7, or an amino acid sequence having at least 80% to 90% sequence identity thereto, and the VL includes the amino acid sequence shown in SEQ ID NO:8, or an amino acid sequence having at least 80% to 90% sequence identity thereto.

[0073] Exemplary, in some embodiments, the anti-HER3 antibody comprises a heavy chain and a light chain, wherein the heavy chain variable region comprises an amino acid sequence shown in SEQ ID NO:9 or having at least 80% to 90% identity thereto, and the light chain variable region comprises an amino acid sequence shown in SEQ ID NO:10 or having at least 80% to 90% identity thereto.

[0074] In some embodiments, the route of administration of the tyrosine kinase inhibitor is oral, parenteral, or transdermal, and parenteral administration includes, but is not limited to, intravenous, subcutaneous, or intramuscular injection. In some specific embodiments, the route of administration of the tyrosine kinase inhibitor is oral.

[0075] In some embodiments, the route of administration of the anti-HER3 antibody drug conjugate is oral, parenteral, or transdermal, and parenteral administration includes, but is not limited to, intravenous, subcutaneous, or intramuscular injection. In some specific embodiments, the route of administration of the anti-HER3 antibody drug conjugate is intravenous injection.

[0076] In some embodiments, the administration order of a combination of an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor is the anti-HER3 antibody drug conjugate followed by the tyrosine kinase inhibitor, with both administered at the required time interval (e.g., less than 1 hour, less than 2 hours, etc.).

[0077] In some embodiments, the administration order of a combination of an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor is tyrosine kinase inhibitor followed by the anti-HER3 antibody drug conjugate, with both administered at required time intervals (e.g., less than 1 hour, less than 2 hours, etc.). [Brief explanation of the drawing]

[0078] [Figure 1] This shows the Kaplan-Meier curve of median progression-free survival (PFS) for patients treated with ADC-1.

[0079] term To facilitate understanding of this disclosure, several technical and scientific terms are defined below. All other technical and scientific terms used herein have meanings that are generally understood by those skilled in the art unless they are clearly and explicitly defined herein.

[0080] Unless otherwise explicitly stated in the context, terms such as “include,” “possess,” and “contain” throughout the specification and claims should be understood to have a comprehensive, rather than exclusive, meaning “includes, but not limited to.”

[0081] "Optional" or "optionally" means that the events or environments described later may occur, but are not required to occur, and the description includes cases where the events or environments occur or do not occur.

[0082] "Approximately" or "about" means that a numerical value is within the acceptable margin of error of a specific value measured by a person skilled in the art, and such numerical value is determined in part by how it is measured or measured (i.e., the limits of the measuring system). For example, "approximately" may mean a standard deviation of 1 or more than 1. Alternatively, "approximately" or "substantially included" may mean that it varies within a range of at most 20%, for example between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, or between 0.5% and 1%, and in this disclosure, each instance in which the term "approximately" precedes a number or numerical value also includes a given embodiment of the numerical value. Unless otherwise specified, where a specific value is given in this application and claims, the meaning of "approximately" or "substantially included" should be assumed to be within the acceptable margin of error of that specific value.

[0083] The term "and / or," for example, "X and / or Y," should be understood to mean "X and Y" or "X or Y," and should be used to provide clear support for both meanings or either of them.

[0084] In some embodiments, this disclosure defines the following:

[0085] An antibody-drug conjugate (ADC) refers to a drug in which an antibody or antibody fragment is linked to a biologically active cytotoxin or a small molecule drug with cytotoxic activity via a stable chemical linker compound. It fully utilizes the specificity of the antibody against tumor cells or binding specificity to highly expressed antigens, as well as the high efficiency of the cytotoxin, while avoiding toxic side effects on normal cells. Compared to conventional chemotherapy drugs, antibody-drug conjugates can accurately bind to tumor cells and reduce their impact on normal cells.

[0086] If the antibody-drug conjugate does not exhibit significant chemical changes, the antibody "maintains its chemical stability" in the pharmaceutical formulation. Chemical stability can be evaluated by detecting and quantifying the chemically altered form of the protein. Degradation processes that constantly change the chemical structure of a protein include hydrolysis or cleavage (e.g., evaluated by methods such as size exclusion chromatography and CE-SDS), oxidation (e.g., evaluated by methods such as mass spectrometry or peptide mapping combined with MALDI / TOF / MS), deamidation (e.g., evaluated by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, and isoaspartic acid measurement), and isomerization (e.g., evaluated by measurement of isoaspartic acid content, peptide mapping, etc.).

[0087] If the biological activity of an antibody-drug conjugate within a given time is within a predetermined range of the biological activity exhibited when manufacturing a pharmaceutical product, the antibody-drug conjugate "retains its biological activity" in the pharmaceutical product.

[0088] The three-letter and one-letter amino acid codes used in this disclosure are as described in J.biol.chem, 243, p3558 (1968).

[0089] As used herein, the term “antibody” is used in its broadest sense, covering a variety of 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 regions), as long as they exhibit the desired antigen-binding activity. An antibody may also refer to an immunoglobulin, a tetrapeptide chain structure consisting of two identical heavy chains and two identical light chains linked by interchain disulfide bonds. The constant regions of immunoglobulin heavy chains differ in their amino acid composition and sequence order, and therefore their antigenicity also differs. This allows for the classification of immunoglobulins into five classes, or they may be called immunoglobulin isotypes, namely IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being the μ, δ, γ, α, and ε chains, respectively. Ig of the same class may be divided into various subclasses based on differences in the amino acid composition of its hinge region and the number and position of heavy chain disulfide bonds. For example, IgG may be divided into IgG1, IgG2, IgG3, and IgG4. The light chain is divided into a κ chain or a λ chain based on the constant region. Each of the five classes of Ig may have either a κ chain or a λ chain. Approximately 110 amino acids near the N-terminus of the antibody heavy and light chains are highly variable and constitute the variable region (V region), while other amino acids near the C-terminus have relatively stable sequences and constitute the constant region (C region). The variable region includes three hypervariable regions (HVRs) and four relatively conserved skeletal regions (FRs). The three hypervariable regions determine the specificity of the antibody and are also called complementarity-determining regions (CDRs). Each light chain variable region (VL) and heavy chain variable region (VH) consists of three CDR regions and four FR regions, arranged in the order FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 from the amino group terminus to the carboxyl group terminus. The three CDR regions of the light chain refer to LCDR1, LCDR2, and LCDR3, while the three CDR regions of the heavy chain refer to HCDR1, HCDR2, and HCDR3.

[0090] Regarding the determination or definition of CDRs, a clear description of the CDR and the identification of residues containing the antibody binding site can be achieved by elucidating the structure of the antibody and / or the antibody-ligand complex. This can be accomplished by any one of the various techniques known to those skilled in the art, for example, by X-ray crystallography. Multiple analytical methods can be used to identify CDRs, including, but not limited to, the Kabat numbering system, the Chothia numbering system, the AbM numbering system, the IMGT numbering system, contact definitions, and conformational definitions.

[0091] The amino acid sequence boundaries of CDRs can be determined by various known schemes, such as the "Kabat" numbering rule (see Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD), the "Chothia" numbering rule, the "ABM" numbering rule, the "contact" numbering rule (see Martin, ACR. Protein Sequence and Structure Analysis of Antibody Variable Domains [J]. 2001), and the ImMunoGenTics (IMGT) numbering rule (Lefranc, MP et al., Dev. Comp. Immunol., 27, 55-77 (2003), Front Immunol. 2018 Oct 16;9:2278).

[0092] The terms “antigen-binding fragment,” “functional fragment,” or “antigen-binding moiety” refer to one or more fragments of a complete antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Exemplary examples of binding fragments included in the term “antigen-binding fragment” include: (i) Fab fragments, which are monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab′)2 fragments, which are bivalent fragments containing two Fab fragments linked by disulfide bond crosslinks on a hinge region; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of VH and VL domains of a single arm of the antibody; (v) dsFv, which are stable antigen-binding fragments formed by interchain disulfide bonds in VH and VL; (vi) scFv; (vii) scFv, dsFv, Fab; diaboves, bispecific antibodies, and multispecific antibodies containing such fragments.

[0093] The terms "specific binding," "selective binding," "selectively binding," and "specifically binding" refer to the binding of an antibody to a pre-defined epitope on an antigen. Typically, antibodies bind to approximately 10 -8 Less than M, for example, about 10 -9 Less than M, 10 -10 Less than M, 10 -11 It binds with an affinity (KD) of less than M or smaller.

[0094] The term "KD" refers to the dissociation equilibrium constant of a particular antibody-antigen interaction. Typically, the antibodies in this disclosure have a KD of approximately 10. -7 Less than M, for example, about 10 -8 Less than M, 10 -9 Less than M or 10 -10 These molecules are coupled to IL-5 with a dissociation equilibrium constant (KD) less than or equal to M, and were measured, for example, using surface plasmon resonance (SPR) techniques with a BIACORE instrument.

[0095] "Homologousity" or "identity" refers to the sequence similarity between two polynucleotide sequences or two polypeptides. The molecules are homologous at a given position if the positions in both comparison sequences are occupied by the same base or amino acid monomer subunit—for example, if the positions in each of two DNA molecules are occupied by adenine. The percentage of homology between two sequences is a function of (number of matching or homologous positions shared by the two sequences divided by the number of positions being compared) × 100. For example, if 6 out of 10 positions in two sequences match or are homologous in the optimal alignment of the sequences, the two sequences are 60% homologous; if 95 out of 100 positions in two sequences match or are homologous, the two sequences are 95% homologous. Typically, a comparison is performed when the two sequences are aligned to give the maximum percentage of homology. For example, the comparison may be performed using the BLAST algorithm, where the algorithm's parameters are chosen to give the maximum agreement between each sequence over the entire length of each reference sequence. The following references relate to the BLAST algorithm, which is commonly used in sequence analysis: Altschul, SF et al., (1990) J.Mol.Biol.215:403-410; Gish, W. et al., (1993) Nature Genet.3:266-272; Madden, TL et al., (1996) Meth.Enzymol.266:131-141; Altschul, SF et al., (1997) Nucleic Acids Res.25:3389-3402; Zhang, J. et al., (1997) Genome Res.7:649-656. Other common BLAST algorithms using NCBI BLAST are also known to those skilled in the art.

[0096] When applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, “giving” and “processing” refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid. “Giving” and “processing” may also refer to, for example, therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Treatment of cells includes contact between a reagent and cells, and contact between a reagent and a body fluid, where the body fluid is in contact with the cells. “Giving” and “processing” are further intended to refer to the treatment of cells, for example, in vitro and ex vivo, with a reagent, diagnostic, binding composition, or another cell. When applied to humans, veterinary, or research subjects, “processing” refers to therapeutic treatment, preventive or prophylactic measures, research, and diagnostic applications.

[0097] "Treatment" means administering a therapeutic agent to a patient, either orally or topically, such as a composition containing any one of the conjugate compounds of the present disclosure, the patient having one or more disease symptoms, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, the therapeutic agent is administered to a patient or population to treat in a dose that effectively alleviates one or more disease symptoms, thereby inducing degeneration of such symptoms or preventing them from progressing to any clinically measurable degree. The amount of therapeutic agent that effectively alleviates any specific disease symptom (also called the "therapeutic dose") can vary depending on several factors, such as the patient's disease state, age and weight, and the drug's ability to produce the desired therapeutic effect in the patient. A physician or other healthcare professional may assess whether the disease symptoms have been alleviated by any clinical detection method typically used to assess the severity or progression of the symptoms. Embodiments of this disclosure (e.g., treatment methods or products) may be ineffective in alleviating each target disease symptom, but this can be determined based on any statistical test known in the art, such as the Student t-test, chi-squared test, Mann and Whitney U test, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test, and should alleviate the target disease symptoms in a statistically significant number of patients.

[0098] The “effective dose” encompasses the amount sufficient to improve or prevent a medical disease or condition. The effective dose also means the amount sufficient to enable or facilitate a diagnosis. The effective dose for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the patient’s overall health, the method, route, and dosage of administration, and the severity of side effects. The effective dose may be the maximum dose or administration protocol that avoids significant side effects or toxic effects.

[0099] The terms "subject" and "patient" are intended to refer to mammals, especially primates, and especially humans.

[0100] The “combination” as described in this disclosure refers to a single administration method in which at least one dose of an anti-HER3 antibody drug conjugate and at least one dose of a tyrosine kinase inhibitor are administered within a certain period of time, wherein both drugs exhibit pharmacological effects. The period may be within a single administration cycle and is preferably within 4 weeks, 3 weeks, 2 weeks, 1 week, 24 hours, or 12 hours. The anti-HER2 antibody drug conjugate or a pharmaceutically acceptable salt thereof and the tyrosine kinase inhibitor may be administered concurrently or sequentially. Such a period may include treatment in which the anti-HER3 antibody drug conjugate and the tyrosine kinase inhibitor are administered via the same or different routes of administration. The combination administration methods described in this disclosure may be selected from concurrent administration, independently prepared and administered together, or independently prepared and administered sequentially.

[0101] In the anti-HER3 antibody-drug conjugates of this disclosure, "n" refers to the average number of cytotoxic drugs loaded onto each antibody or its antigen-binding fragment in the antibody-drug conjugate molecule, which may be expressed as a ratio of drug amount to antibody amount, or the average number of drugs in each ADC molecule after the conjugation reaction as identified by hydrophobic chromatography (HIC) mass spectrometry.

[0102] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs with other chemical components, the other components being, for example, physiologically / pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to a living organism, to facilitate the absorption of the active ingredient, and to further exert biological activity. [Modes for carrying out the invention]

[0103] The present disclosure will be further described below with reference to examples, but these examples will not limit the scope of the present disclosure. Experimental methods for which specific conditions are not specified in the examples of this disclosure will generally follow conventional conditions, such as the "Antibody Technology Manual" and "Molecular Cloning Manual" published by Cold Spring Harbor Laboratory, or conditions proposed by the raw material or product manufacturer. Reagents for which the specific source is not specified are common reagents purchased on the market.

[0104] Example 1. Production of anti-HER3 antibody drug conjugates The anti-HER3 antibody drug conjugates are those described in Examples 3-1 (n=4.19), 3-2 (n=2.91), and 3-3 (n=7.27) of WO2022078425A1 (which is incorporated into this disclosure as a whole by reference), and their structures are as follows. [ka] Here, n is between 1 and 8, preferably between 3 and 5.

[0105] The structure of the anti-HER3 antibody-drug conjugate is abbreviated as ADC-1, as shown in the following structural formula. [ka] Here, n (DAR value) is approximately 4.0, which corresponds to 4.0 ± 0.4.

[0106] The HER3 antibody is derived from antibody HER3-29 of WO2022078425A1, and its CDR sequence is shown in Table 1. The full-length heavy chain of antibody HER3-29 is shown in SEQ ID NO:9, and the full-length light chain is shown in SEQ ID NO:10.

[0107] ADC-1 was prepared as an injectable solution (sterile powder for injection) with a specification of 100 mg / vial. The injectable solution was prepared using research-grade drugs filled in disposable vials. The vial containing 100 mg of the research drug was redissolved in 5 mL of sterile water for injection to a concentration of 20 mg / mL, and then further diluted to the target concentration with 0.9% sodium chloride or 5% glucose solution.

[0108] Example 2. Study on the safety, tolerance, pharmacokinetics, and therapeutic effects of ADC-1 for injection in patients with advanced solid tumors. 1. Test drug 1) ADC-1 manufactured in Example 1.

[0109] 2. Participating subjects 1) Ages 18 to 75 (including both extremes), gender unspecified. 2) Patients with locally advanced or metastatic solid tumors that are histologically or cytologically confirmed to be unresectable and have recurred or progressed after standard treatment, or for whom there is no standard treatment regimen, or for whom standard treatment is not currently applicable. 3) According to RECIST v1.1, patients with at least one measurable tumor lesion (in the dose-escalation phase, patients with only non-target lesions are allowed to participate), 4) Subjects participating in dose-extension and efficacy-extension phases must provide tumor tissue samples for detection of HER3 expression, etc. Tumor tissue samples must be adequately fresh or stored, consisting of neutral formalin-fixed, paraffin-embedded [FFPE] tissue blocks, or at least six unstained tumor tissue sections, with fresh samples being preferable. Subjects unable to provide newly collected tissue may provide stored tumor tissue samples taken within 12 months prior to the start of the initial study treatment. 5) ECOG health status scoring: 0-1 point, 6) Predicted survival period ≥ 12 weeks, 7) The patient must have sufficient bone marrow and organ function, and the following test results must be completed within 7 days prior to the initial study treatment.

[0110] Complete blood count (no blood transfusions or hematopoietic stimulating agent treatments within 14 days prior to the test): Neutrophil count (ANC) ≥ 1.5 × 10⁹ / L (1,500 / mm³), platelets ≥ 100 × 10⁹ / L (100,000 / mm³) Hemoglobin (Hgb) ≥ 9.0 g / dL (90 g / L), Liver function tests: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN (in patients with confirmed liver metastasis, ALT and AST ≤ 5 × ULN), total bilirubin ≤ 1.5 × ULN (in patients with confirmed Gilbert syndrome, total bilirubin ≤ 3 mg / dL). Renal function test: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL / min (Cockcroft-Gault formula used). Coagulation function tests: Prothrombin time and activated partial thromboplastin time ≤ 1.5 × ULN.

[0111] 3. Clinical regimens The "i3+3" design was used for dose escalation of ADC-1 to determine the maximum tolerated dose (MTD) or maximum dose (MAD). For patients with advanced solid tumors participating in dose escalation, the dose was increased from low to high. ADC-1 was administered intravenously once every three weeks (Q3W), and the observation period for DLT (dose-limiting toxicity) was 21 days after the first dose. Based on preclinical study data, six doses were pre-defined: 1.5 mg / kg, 3.0 mg / kg, 4.5 mg / kg, 6.0 mg / kg, 7.5 mg / kg, and 9.0 mg / kg.

[0112] Primary study endpoints: 1) Maximum tolerated dose (MTD) or maximum dose (MAD) was determined to provide a recommended dose (RP2D) for subsequent studies. 2) Incidence and severity of adverse events / serious adverse events (assessed based on CTCAEv5.0).

[0113] 4.Results By the data collection deadline, a total of 42 patients participated (83.3% had an ECOG score of 1, 100% were stage IV, 85.7% had non-small cell lung cancer (NSCLC), and 31.0% had brain metastases). The median number of treatment lines prior to systemic therapy was 3 (range, 1-11). Of the 36 NSCLC patients, 34 (94.4%) had EGFR mutations, and all of these patients were resistant to EGFR-TKIs. Of these, 85.3% (29 / 34) had previously received treatment with third-generation drugs. No dose-limiting toxicities (DLTs) were observed at the maximum dose of 10.5 mg / kg. Treatment-related adverse events (TRAEs) of ≥3 grade were reported in 13 patients (31.0%), with a hematological toxicity incidence of ≥5%. In evaluable patients, the objective response rate (ORR) for all tumor types was 25.0% (9 / 36, 95% CI 12.1–42.2), and for NSCLC, the ORR was 30.0% (9 / 30, 95% CI 14.7–49.4), with a median duration of response (DoR) of 7.0 months (range, 2.8–8.5) in all cases. Table 1 shows the responses to different doses for different tumors. The 6-month progression-free survival (PFS) for all tumors was 46.4% (95% CI 27.0–63.8), and for NSCLC it was 49.8% (95% CI 28.8–67.8). After single or multiple doses of 1.5–9.0 mg / kg, systemic exposure to ADC-1, total antibody, and free toxins increased approximately proportionally to the dose, while plasma toxin exposure remained low at all dose levels.

[0114] [Table 2]

[0115] 5. Conclusion ADC-1 demonstrated tolerable safety and invigorating antitumor activity in treated patients with severe, advanced solid tumors.

[0116] Example 3. Study on the safety, tolerance, pharmacokinetics, and therapeutic effects of ADC-1 for injection in patients with advanced solid tumors. 1. Test drug 1) ADC-1 manufactured in Example 1.

[0117] 2. Participating subjects 1) Ages 18 to 75 (including both extremes), gender unspecified. 2) Patients with locally advanced or metastatic solid tumors that are histologically or cytologically confirmed to be unresectable and have recurred or progressed after standard treatment, or for whom there is no standard treatment regimen, or for whom standard treatment is not currently applicable. 3) According to RECIST v1.1, patients with at least one measurable tumor lesion (in the dose-escalation phase, patients with only non-target lesions are allowed to participate), 4) Subjects participating in dose-extension and efficacy-extension phases must provide tumor tissue samples for detection of HER3 expression, etc. Tumor tissue samples must be adequately fresh or stored, consisting of neutral formalin-fixed, paraffin-embedded [FFPE] tissue blocks, or at least six unstained tumor tissue sections, with fresh samples being preferable. Subjects unable to provide newly collected tissue may provide stored tumor tissue samples taken within 12 months prior to the start of the initial study treatment. 5) ECOG health status scoring: 0-1 point, 6) Predicted survival period ≥ 12 weeks, 7) The patient must have sufficient bone marrow and organ function, and the following test results must be completed within 7 days prior to the initial study treatment.

[0118] Complete blood count (no blood transfusions or hematopoietic stimulating agent treatments within 14 days prior to the test): Neutrophil count (ANC) ≥ 1.5 × 10⁹ / L (1,500 / mm³), platelets ≥ 100 × 10⁹ / L (100,000 / mm³), hemoglobin (Hgb) ≥ 9.0 g / dL (90 g / L), Liver function tests: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN (in patients with confirmed liver metastasis, ALT and AST ≤ 5 × ULN), total bilirubin ≤ 1.5 × ULN (in patients with confirmed Gilbert syndrome, total bilirubin ≤ 3 mg / dL). Renal function test: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL / min (Cockcroft-Gault formula used). Coagulation function tests: Prothrombin time and activated partial thromboplastin time ≤ 1.5 × ULN,

[0119] 3. Clinical regimens The "i3+3" design was used for dose escalation of ADC-1 to determine the maximum tolerated dose (MTD) or maximum dose (MAD). For patients with advanced solid tumors participating in dose escalation, the dose was increased from low to high. ADC-1 was administered intravenously at doses of 1.5–12.0 mg / kg, once every three weeks (Q3W), with a 21-day observation period for dose-limiting toxicity (DLT) following the initial dose. One of the expanded indication matrices evaluated patients with epidermal growth factor receptor (EGFR) mutant NSCLC.

[0120] Primary study endpoints: 1) Maximum tolerated dose (MTD) or maximum dose (MAD) was determined to provide a recommended dose (RP2D) for subsequent studies. 2) Incidence and severity of adverse events / serious adverse events (assessed based on CTCAEv5.0).

[0121] 4.Results Study Results: By the data collection deadline (March 30, 2024), a total of 103 EGFR-mutated NSCLC patients participated in and received treatment. The median follow-up period was 8.6 months. The median number of patients with prior systemic treatment was 2 (1–7). All patients received treatment with epidermal growth factor receptor-TKIs, of which 88.3% received treatment with third-generation epidermal growth factor receptor-TKIs, and 64.1% received chemotherapy, of which 59.2% received platinum-based chemotherapy (PBC). Among patients receiving an extended dose of 9.0 mg / kg (n=52), the ORR in the evaluable group was 46.9% (23 / 49, 95% CI 32.5–61.7), and the DCR was 93.9% (46 / 49, 95% CI 83.1–98.7), indicating a sustained response to ADC-1 (Table 2). Table 2 shows the tumor response for all dose groups. Among all treated patients, the median PFS in the 9.0 mg / kg group was 9.6 months (95% CI 5.7–12.4), and the median PFS for all dose groups was 6.7 months (95% CI 4.8–9.7).

[0122] [Table 3] DoR is the duration of sustained response.

[0123] 5. Conclusion In patients with EGFR-mutated NSCLC whose disease progressed after treatment with EGFR-TKIs, ADC-1 demonstrated invigorating antitumor activity and tolerable safety.

[0124] Example 4. Study on the safety, tolerance, pharmacokinetics, and therapeutic effects of ADC-1 for injection in patients with advanced solid tumors. 1. Test drug 1) ADC-1 manufactured in Example 1.

[0125] 2. Key Eligibility Criteria Recurrent / refractory advanced solid tumors (no applicable standard treatment).

[0126] ECOG health status scoring: 0-1.

[0127] Measurable lesions as defined by RECIST v1.1.

[0128] 3. Patient baseline characteristics By the data collection deadline (July 25, 2024), a total of 130 EGFR-mutated NSCLC patients had participated in and received treatment, with 97 patients receiving ADC-1 at doses of 7.5–9.0 mg / kg. The median overall follow-up period was 7.2 months.

[0129] All patients had previously received treatment with EGFR-TKIs, with 89.2% using third-generation EGFR-TKIs, 70.0% receiving chemotherapy, and 64.6% receiving platinum-based chemotherapy (see Table 4).

[0130] [Table 4]

[0131] 4. Safety and efficacy data Among patients treated with ADC-1 at doses of 7.5–9.0 mg / kg, the objective remission rate (ORR) in the evaluable group was 40.4% (38 / 94, 95% CI 30.4%–51.0%), and the disease control rate (DCR) was 93.6% (88 / 94, 95% CI 86.6%–97.6%), indicating a sustained response to ADC-1 (see Table 5 and Figure 2). For tumor responses in each dose group (7.5–9.0 mg / kg and all dose groups), see Table 5.

[0132] In the full analysis set, the median progression-free survival (PFS) for patients treated with 7.5–9.0 mg / kg was 9.6 months (95% CI 5.7–12.3), while the median PFS for all dose groups was 6.9 months (95% CI 5.4–9.7) (see Figure 1).

[0133] Among patients treated with ADC-1 at a dose of 7.5–9.0 mg / kg, 60.8% reported grade 3 or higher treatment-related adverse events (TRAEs), and all events with an incidence of ≥5% were hematological toxicities. According to investigator assessments, 7.2% of patients developed treatment-related interstitial lung disease, of which 2.1% experienced grade 3 or higher events.

[0134] [Table 5]

[0135] 5. Conclusion ADC-1 demonstrated invigorating antitumor activity and tolerable safety characteristics in NSCLC patients with EGFR mutations and disease progression after treatment with EGFR-TKIs.

[0136] Example 5. Study on the safety, tolerance, and efficacy of injectable ADC-1 in combination with antitumor therapy in patients with advanced solid tumors. 1. Test drug 1) ADC-1 manufactured in Example 1. 2) Ametinib.

[0137] 2. Participating subjects 1) Ages 18 to 75 (including both extremes), gender unspecified. 2) Part A1: Subjects with histologically or cytologically confirmed unresectable locally advanced or metastatic non-small cell lung cancer who have an EGFR mutation (sensitive or insensitive mutation) confirmed by histological or blood specimens; Part A2: Subjects with histologically or cytologically confirmed unresectable locally advanced or metastatic non-small cell lung cancer who have an EGFR exon 19 deletion or L858R mutation confirmed by histological or blood specimens. 3) Part A1: Subjects with EGFR-sensitive mutations who have experienced disease progression on imaging after EGFR-TKI treatment and have previously received ≤2 lines of chemotherapy; subjects with EGFR-insensitive mutations who have relapsed or progressed after standard treatment, or who have no standard treatment regimen, or for whom standard treatment is not currently applicable; Part A2: Subjects who have not received systemic treatment for locally advanced / metastatic NSCLC, who are deemed suitable for first-line treatment with ametinib by the researchers, and who have previously received adjuvant or new adjuvant therapy (chemotherapy other than EGFR-TKI, radiotherapy, etc.); 4) According to RECIST v1.1, subjects must have at least one measurable tumor lesion (in Phase IB, subjects with only non-target lesions are allowed to participate). 5) All participating subjects must provide tumor tissue samples for detection of HER3 expression, etc. (Participation of subjects unable to provide tumor tissue samples is permitted in Phase IB). Tumor tissue samples must be either fresh or preserved, consisting of neutral formalin-fixed, paraffin-embedded [FFPE] tissue blocks, or at least six unstained tumor tissue sections, with fresh samples being preferable. Subjects unable to provide newly collected tissue may provide preserved tumor tissue samples taken within 12 months prior to the start of the initial study treatment. Subjects unable to provide tumor tissue samples that meet the above requirements must be discussed with the sponsor to determine whether or not they will participate. 6) ECOG health status scoring: 0-1 point, 7) Predicted survival period ≥ 12 weeks, 8. The patient must have sufficient bone marrow and organ function, and the following test results must be completed within 7 days prior to the initial study treatment. a) Complete blood count (no blood transfusions or hematopoietic stimulating agent treatments within 14 days prior to the test): Neutrophil count (ANC) ≥ 1.5 × 10 9 / L(1,500 / mm 3 ), platelets ≥ 100 × 10 9 / L(100,000 / mm 3 ), hemoglobin (Hgb) ≥ 9.0 g / dL (90 g / L), b) Liver function tests (in subjects who have not received hepatoprotective agent treatment within 7 days prior to the test): Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN (in subjects with confirmed liver metastasis, ALT and AST ≤ 5 × ULN), total bilirubin ≤ 1.5 × ULN (in subjects with confirmed Gilbert syndrome, total bilirubin ≤ 3 mg / dL), c) Renal function test: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL / min (Cockcroft-Gault formula used) d) Coagulation function tests: Prothrombin time and activated partial thromboplastin time ≤ 1.5 × ULN.

[0138] 3. Dosage regimen Part A is a clinical trial to treat EGFR mutation-positive locally advanced / metastatic non-small cell lung cancer with the combination of ADC-1 and ametinib, and Part A is divided into Part A1 and Part A2. Part A1 treats EGFR mutation-positive locally advanced / metastatic NSCLC that has failed EGFR-TKI treatment with the combination of ADC-1 and ametinib, and Part A2 treats EGFR mutation-positive locally advanced / metastatic NSCLC that is being treated as first-line therapy with the combination of ADC-1 and ametinib. The study process includes a screening phase, a treatment phase, and a follow-up phase. The treatment phase includes Phase IB and Phase II.

[0139] Part A1 involves treating EGFR mutation-positive locally advanced / metastatic NSCLC that has failed EGFR-TKI treatment with the combination of ADC-1 and ametinib.

[0140] Phase IB: 1) Part A1, Dose Group 1: ADC-1 is administered at 9.0 mg / kg once every 3 weeks (Q3W), and ametinib is administered at 110 mg once daily (QD) in combination. 2) Part A1, Dose Group 2: ADC-1 is administered at 7.5 mg / kg once every 3 weeks (Q3W), and ametinib is administered at 110 mg once daily (QD) in combination. 3) Part A1, Dose Group 3: ADC-1 was administered at 9.0 mg / kg once every three weeks (Q3W), and ametinib was administered at 55 mg once daily (QD) in combination.

[0141] ADC-1 was administered intravenously as Q3W, and ametinib was administered orally as QD, with each treatment cycle lasting 21 days. The recommended dose of ADC-1 and ametinib in combination was determined for EGFR mutation-positive locally advanced / metastatic non-small cell lung cancer patients who had failed EGFR-TKI therapy.

[0142] Phase II: Arm 1 received treatment with the recommended dose of ADC-1 and ametinib in combination until disease progression or other treatment termination criteria were met, while Arm 2 received treatment with ADC-1 monotherapy at the RP2D (Recommended Phase 2 dose) until disease progression or other treatment termination criteria were met. The antitumor effect of the combination of ADC-1 and ametinib compared to ADC-1 monotherapy was evaluated in EGFR mutation-positive locally advanced / metastatic NSCLC that had failed treatment with EGFR-TKIs.

[0143] Part A2 involves treating EGFR mutation-positive locally advanced / metastatic NSCLC as a first-line treatment with the combination of ADC-1 and ametinib.

[0144] Phase IB: 4) Part A2, Matrix 1: Treatment with ADC-1 6.0 mg / kg Q3W and ametinib 110 mg QD in combination is received until disease progression or other treatment termination criteria are met. 5) Part A2, Matrix 2: The patient received treatment with a combination of ADC-1 6.0 mg / kg Q3W and ametinib 110 mg QD for 6 cycles, followed by ametinib 110 mg QD monotherapy until disease progression or other treatment termination criteria were met.

[0145] ADC-1 was administered intravenously at a dose of 6.0 mg / kg Q3W, and ametinib was administered orally at a dose of 110 mg QD, with one treatment cycle lasting 21 days. The recommended dose and combination therapy cycles for ADC-1 and ametinib in first-line treatment of locally advanced / metastatic non-small cell lung cancer were determined.

[0146] Phase II: Arm 1 was treated with the recommended dose of ADC-1 in combination with ametinib, and Arm 2 was treated with ametinib 110 mg QD monotherapy. The antitumor effect of the combination of ADC-1 and ametinib compared to ametinib monotherapy was evaluated in first-line treatment of EGFR mutation-positive advanced NSCLC.

[0147] 4. Evaluation of Results Efficacy indicators include ORR, DCR, DoR, PFS, and OS as assessed by researchers.

[0148] Safety Assessment: Tumor assessment was performed using the RECIST v1.1 standard, and all subjects were evaluated by baseline tumor imaging during the screening phase. The safety of the drugs in this study was assessed by adverse event recording (including serious adverse events), laboratory tests, vital signs and physical examination, electrocardiogram, blood oxygen saturation, and echocardiogram / multigate acquisition (MUGA).

[0149] Example 6. A randomized, controlled, open-label, multicenter Phase III study comparing the treatment of EGFR-mutated advanced or metastatic non-small cell lung cancer that has failed treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with ADC-1, compared to platinum-containing chemotherapy. 1. Test drug 1) ADC-1 manufactured in Example 1. 2) Pemetrexed disodium for injection, injection formulation, specified 0.5g. 3) The injectable carboplatin, injection formulation, was specified as 0.1 g. 4) The cisplatin injection solution had a specification of 6 ml:30 mg.

[0150] 2. Eligibility Criteria (1) Ages 18-75 (including both extremes), gender is not specified. (2) Subjects with locally advanced or metastatic non-squamous non-small cell lung cancer confirmed histologically or cytologically. Locally advanced or metastatic disease is defined as being classified as stage IIIB to IV according to the International Association for Lung Cancer (IASLC) 9th edition TNM classification criteria, and is unsuitable for curative surgery or curative chemoradiotherapy. (3) Has an EGFR exon 19 deletion or exon 21 (L858R) substitution mutation confirmed by histological or blood specimen, and does not have any driver gene mutations (e.g., ALK fusion, ROS1 fusion, BRAF V600 mutation, etc.) that have not been treated with other known approved targeted drugs. (4) For locally advanced or metastatic NSCLC, the patient must have received treatment with an EGFR TKI, and subjects with the T790M mutation must have received treatment with a third-generation EGFR TKI, and disease progression was observed on imaging during or after treatment. - Subjects who experience tumor recurrence or metastasis during EGFR TKI adjuvant therapy or within 6 months after discontinuation of the drug are eligible to participate. - Subjects with non-metastatic tumors who have previously received novel adjuvant / adjuvant chemotherapy or curative chemoradiotherapy are eligible to participate if they have experienced tumor recurrence or metastasis at least 6 months after the completion of the above treatment, and have received EGFR TKI treatment, with disease progression observed on imaging during or after the treatment period. - For locally advanced or metastatic NSCLC, concomitant use of antivascular therapy or targeted therapy (e.g., EGFR / c-MET bispecific antibodies, excluding antibody-drug conjugates) is permitted during the treatment period with EGFR TKIs, but other systemic antitumor therapies are not permitted. (5) Having at least one measurable lesion that meets the definition according to the RECIST v1.1 standard. (6) The ECOG score is 0 or 1. (7) Predicted survival time ≥ 12 weeks.

[0151] 3. Dosage regimen In the test group, ADC-1 was administered intravenously at a dose of 8.0 mg / kg, and the total dose of ADC-1 was calculated based on the weight measurement of the subjects before each administration.

[0152] Control group: All subjects received dual chemotherapy including a platinum-based agent, with Q3W (week 3) and one cycle lasting 21 days. All drugs were administered on the first day of each cycle. Administration order: Pemetrexed → Carboplatin / Cisplatin. (a) Pemetrexed: Intravenous infusion, 500 mg / m² 2 , (b) Cisplatin: Intravenous infusion, 75 mg / m² 2 , Body surface area calculation formula: Body surface area (m 2 ) = 0.0061 × height (cm) + 0.0128 × weight (kg) - 0.1529, (c) Carboplatin: Intravenous infusion, AUC 5 mg / mL / min (Calvert formula) Carboplatin dose (mg) = (Target AUC) × [Creatinine clearance (mL / min) + 25]. The Cockcroft-Gault formula was used to calculate creatinine clearance.

[0153] 4. Efficacy and Safety Evaluation The primary outcome measure is PFS as assessed by BICR, and secondary outcome measures include OS, PFS as assessed by researchers, ORR (CR+PR), DoR, and DCR (CR+PR+SD) as assessed by researchers and BICR.

[0154] During the study, the safety of the subjects was continuously evaluated. This included the incidence and grade of adverse events (AEs), serious adverse events (SAEs) (as judged according to the NCI-CTCAE V5.0 standard), changes in vital signs, abnormal laboratory test indicators, and the incidence of dose suspension, dose downregulation, and dose discontinuation due to toxicity related to the research drug during the study.

Claims

1. An application of an anti-HER3 antibody drug conjugate in the manufacture of a drug for treating EGFR-mutated tumors, wherein the anti-HER3 antibody drug conjugate has the structure shown in the following formula, 【Chemistry 1】 Here, n is 1 to 8, and Pc is an anti-HER3 antibody. The EGFR-mutated tumor is preferably an EGFR-mutated non-small cell lung cancer.

2. The EGFR-mutated tumor is an EGFR-mutated tumor that has failed treatment with a tyrosine kinase inhibitor (TKI), and is preferably an EGFR-mutated non-small cell lung cancer that has failed treatment with a tyrosine kinase inhibitor (TKI). The EGFR-mutated tumor is an EGFR-mutated locally advanced or metastatic tumor, preferably an EGFR-mutated locally advanced or metastatic non-small cell lung cancer. Or, The use according to claim 1, wherein the EGFR-mutated tumor is an EGFR-mutated locally advanced or metastatic tumor that has failed treatment with TKI, and preferably an EGFR-mutated locally advanced or metastatic non-small cell lung cancer that has failed treatment with TKI.

3. The use according to claim 1 or 2, wherein the EGFR mutation includes at least one of the following: exon 19 deletion (Ex19del), L858R mutation, G719X mutation, and L861Q mutation.

4. The use according to any one of claims 1 to 3, wherein the EGFR-mutated tumor has brain metastases, bone metastases and / or liver metastases.

5. The anti-HER3 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2, and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and the VL comprises LCDR1, LCDR2, and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively. Preferably, VH comprises an amino acid sequence shown in SEQ ID NO: 7 or having at least 80% to 90% identity thereto, and VL comprises an amino acid sequence shown in SEQ ID NO: 8 or having at least 80% to 90% identity thereto. Preferably, the anti-HER3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence shown in SEQ ID NO: 9 or having at least 80% to 90% identity thereto, and the light chain comprising an amino acid sequence shown in SEQ ID NO: 10 or having at least 80% to 90% identity thereto, the use according to any one of claims 1 to 4.

6. The dosage of the anti-HER3 antibody drug conjugate is approximately 0.1 mg / kg to approximately 20 mg / kg, preferably approximately 1.5 mg / kg to approximately 12 mg / kg, or approximately 7.5 mg / kg to approximately 9.0 mg / kg, preferably approximately 1.0 mg / kg, approximately 1.5 mg / kg, approximately 3.0 mg / kg, approximately 4.5 mg / kg, approximately 6.0 mg / kg, approximately 6.5 mg / kg, approximately 7.0 mg / kg, approximately 7.5 mg / kg, approximately 8.0 mg / kg, approximately 8.5 mg / kg, approximately 9.0 mg / kg, approximately 10.5 mg / kg, approximately 12 mg / kg, or approximately 13.5 mg / kg. and / or, The use according to any one of claims 1 to 5, wherein the frequency of administration of the anti-HER3 antibody drug conjugate is once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every twelve weeks, preferably once every three weeks.

7. The use according to any one of claims 1 to 6, wherein the method of administration of the anti-HER3 antibody drug conjugate is by injection, preferably by intravenous injection.

8. (1) Uses of the combination of anti-HER3 antibody drug conjugates and tyrosine kinase inhibitors in the manufacture of drugs for treating tumors, (2) Applications of combinations of anti-HER3 antibody drug conjugates and tyrosine kinase inhibitors in the manufacture of drugs for treating tumors, (3) Uses of a pharmaceutical composition comprising an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor in the manufacture of a drug for treating tumors, (4) The anti-HER3 antibody drug conjugate is used to treat a subject suffering from a tumor, wherein the subject is further administered a tyrosine kinase inhibitor. (5) In any one of the uses shown in (1) to (5), a tyrosine kinase inhibitor is used to treat a subject suffering from a tumor, wherein the subject is further administered an anti-HER3 antibody drug conjugate. The aforementioned anti-HER3 antibody drug conjugate has the structure shown in the following formula, 【Chemistry 2】 Here, n is 1 to 8, and Pc is an anti-HER3 antibody. Preferably, the tyrosine kinase inhibitor is ametinib. Preferably, the anti-HER3 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2, and HCDR3 shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, respectively, and the VL comprises LCDR1, LCDR2, and LCDR3 shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively, and more preferably, the VH comprises an amino acid sequence shown in SEQ ID NO: 7 or having at least 80% to 90% identity thereto, and the VL comprises an amino acid sequence shown in SEQ ID NO: 8 or having at least 80% to 90% identity thereto. More preferably, the anti-HER3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence shown in SEQ ID NO: 9 or having at least 80% to 90% identity thereto, and the light chain comprises an amino acid sequence shown in SEQ ID NO: 10 or having at least 80% to 90% identity thereto.

9. The tumor is an EGFR-mutated tumor, preferably an EGFR-mutated non-small cell lung cancer. Preferably, the EGFR-mutated tumor is an EGFR-mutated tumor that has failed treatment with a tyrosine kinase inhibitor (TKI), and more preferably, an EGFR-mutated non-small cell lung cancer that has failed treatment with a tyrosine kinase inhibitor (TKI). The EGFR-mutated tumor is an EGFR-mutated locally advanced or metastatic tumor, preferably an EGFR-mutated locally advanced or metastatic non-small cell lung cancer. Or, The use according to claim 8, wherein the EGFR-mutated tumor is an EGFR-mutated locally advanced or metastatic tumor that has failed treatment with TKI, and preferably an EGFR-mutated locally advanced or metastatic non-small cell lung cancer that has failed treatment with TKI.

10. The use according to claim 8 or 9, wherein the EGFR mutation includes at least one of exon 19 deletion (Ex19del), L858R mutation, G719X mutation, and L861Q mutation.

11. The dosage of the anti-HER3 antibody drug conjugate is approximately 0.1 mg / kg to approximately 20 mg / kg, preferably approximately 1.5 mg / kg to approximately 12 mg / kg, or approximately 7.5 mg / kg to approximately 9.0 mg / kg, preferably approximately 1.0 mg / kg, approximately 1.5 mg / kg, approximately 3.0 mg / kg, approximately 4.5 mg / kg, approximately 6.0 mg / kg, approximately 6.5 mg / kg, approximately 7.0 mg / kg, approximately 7.5 mg / kg, approximately 8.0 mg / kg, approximately 8.5 mg / kg, approximately 9.0 mg / kg, approximately 10.5 mg / kg, approximately 12 mg / kg, or approximately 13.5 mg / kg. The administration frequency of the anti-HER3 antibody drug conjugate is once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every twelve weeks, preferably once every three weeks. and / or, The dosage of the tyrosine kinase inhibitor is approximately 1 mg to approximately 1000 mg, preferably approximately 10 mg to approximately 1000 mg, approximately 10 mg to approximately 800 mg, approximately 10 mg to approximately 500 mg, approximately 50 mg to approximately 500 mg, approximately 50 mg to approximately 200 mg, approximately 50 mg to approximately 150 mg, or approximately 55 mg to approximately 110 mg, preferably approximately 50 mg, approximately 55 mg, approximately 100 mg, approximately 110 mg, approximately 120 mg, approximately 160 mg, approximately 200 mg, approximately 300 mg, approximately 400 mg, or approximately 500 mg. The use according to any one of claims 8 to 10, wherein the frequency of administration of the tyrosine kinase inhibitor is once a day, twice a day, three times a day, once every two days, once every three days, once every four days, once every five days, or once a week, preferably once a day.

12. A pharmaceutical composition comprising an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor, The aforementioned anti-HER3 antibody drug conjugate has the structure shown in the following formula, 【Transformation 3】 Here, n is 1 to 8, and Pc is an anti-HER3 antibody. Preferably, the tyrosine kinase inhibitor is ametinib. Preferably, the anti-HER3 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2, and HCDR3 shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and the VL comprises LCDR1, LCDR2, and LCDR3 shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, and more preferably, the VH comprises an amino acid sequence shown in SEQ ID NO: 7 or having at least 80% to 90% identity thereto, and the VL comprises an amino acid sequence shown in SEQ ID NO: 8 or having at least 80% to 90% identity thereto. A pharmaceutical composition wherein the anti-HER3 antibody comprises a heavy chain and a light chain, the heavy chain comprises an amino acid sequence shown in SEQ ID NO: 9 or having at least 80% to 90% identity thereto, and the light chain comprises an amino acid sequence shown in SEQ ID NO: 10 or having at least 80% to 90% identity thereto.

13. A method for treating a tumor, comprising administering to a subject in need of such treatment (1) an anti-HER3 antibody drug conjugate, or (2) an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor. The aforementioned anti-HER3 antibody drug conjugate has the structure shown in the following formula, 【Chemistry 4】 Here, n is 1 to 8, and Pc is an anti-HER3 antibody. The dosage of the aforementioned anti-HER3 antibody drug conjugate is approximately 0.1 mg / kg to approximately 20 mg / kg. Preferably, the dose of the anti-HER3 antibody drug conjugate is about 1.5 mg / kg to about 12 mg / kg, or about 7.5 mg / kg to about 9.0 mg / kg, preferably about 1.0 mg / kg, about 1.5 mg / kg, about 3.0 mg / kg, about 4.5 mg / kg, about 6.0 mg / kg, about 6.5 mg / kg, about 7.0 mg / kg, about 7.5 mg / kg, or about 8.0 mg / kg. The dosage is approximately 8.5 mg / kg, approximately 9.0 mg / kg, approximately 10.5 mg / kg, approximately 12 mg / kg, or approximately 13.5 mg / kg, and / or the frequency of administration of the anti-HER3 antibody drug conjugate is once a week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, once every eight weeks, once every ten weeks, or once every twelve weeks, preferably once every three weeks. Preferably, the dose of the tyrosine kinase inhibitor is about 1 mg to about 1000 mg, preferably about 10 mg to about 1000 mg, about 10 mg to about 800 mg, about 10 mg to about 500 mg, about 50 mg to about 500 mg, about 50 mg to about 200 mg, about 50 mg to about 150 mg, or about 55 mg to about 110 mg, preferably about 50 mg, about 55 mg, about 100 mg, about 110 mg, about 120 mg, about 160 mg, about 200 mg, about 300 mg, about 400 mg, or about 500 mg, and / or the frequency of administration of the tyrosine kinase inhibitor is once a day, twice a day, three times a day, once every two days, once every three days, once every four days, once every five days, or once a week, preferably once a day. Preferably, the tyrosine kinase inhibitor is ametinib, a method for treating a tumor.

14. The anti-HER3 antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises HCDR1, HCDR2, and HCDR3 shown in SEQ ID NO: 1, SEQ ID NO: 2, and SEQ ID NO: 3, and the VL comprises LCDR1, LCDR2, and LCDR3 shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, more preferably the VH comprises an amino acid sequence shown in SEQ ID NO: 7 or having at least 80% to 90% identity thereto, and the VL comprises an amino acid sequence shown in SEQ ID NO: 8 or having at least 80% to 90% identity thereto. The method according to claim 13, more preferably, the anti-HER3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence shown in SEQ ID NO: 9 or having at least 80% to 90% identity thereto, and the light chain comprises an amino acid sequence shown in SEQ ID NO: 10 or having at least 80% to 90% identity thereto.

15. The tumor is an EGFR-mutated tumor, preferably an EGFR-mutated non-small cell lung cancer. Preferably, the EGFR-mutated tumor is an EGFR-mutated tumor that has failed treatment with a tyrosine kinase inhibitor (TKI), and more preferably, an EGFR-mutated non-small cell lung cancer that has failed treatment with a tyrosine kinase inhibitor (TKI). The EGFR-mutated tumor is an EGFR-mutated locally advanced or metastatic tumor, preferably an EGFR-mutated locally advanced or metastatic non-small cell lung cancer. Or, The method according to claim 13 or 14, wherein the EGFR-mutated tumor is an EGFR-mutated locally advanced or metastatic tumor that has failed treatment with TKI, and preferably an EGFR-mutated locally advanced or metastatic non-small cell lung cancer that has failed treatment with TKI.

16. The method according to any one of claims 13 to 15, wherein the EGFR mutation includes at least one of exon 19 deletion (Ex19del), L858R mutation, G719X mutation, and L861Q mutation.

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