Use and method of anti-HER3 antibody drug conjugates for treating tumors

Abstract

The present disclosure relates to the use and methods of anti-HER3 antibody drug conjugates for the treatment of tumors. Specifically, the invention relates to application of the anti-HER3 antibody drug conjugate in preparation of drugs for treating EGFR mutation tumors, and the anti-HER3 antibody drug conjugate has a structure as shown in a formula I. The invention further relates to a preparation method of the anti-HER3 antibody drug conjugate.

Description

Use and method of anti-HER3 antibody-drug conjugates for treating tumors

[0001] The present disclosure claims priority from patent application number CN2023112308116 filed on September 22, 2023, and patent application number CN2024106793284 filed on May 29, 2024. The foregoing patents are incorporated herein by reference. Technical Field

[0002] The present disclosure belongs to the field of medicine and relates to a method for treating tumors with an anti-HER3 antibody-drug conjugate and its medical uses. Background Art

[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). These receptors all contain three parts: an extracellular region, a transmembrane region, and an intracellular region. The extracellular region contains four domains, and the intracellular region contains an intracellular tyrosine kinase domain for signal transduction and a tail with tyrosine phosphorylation residues located in the cytoplasm. When ligands bind to extracellular domains I and III, cell signaling is initiated. Under normal circumstances, these receptors mediate cell division, migration, survival, and organ development. When EGFR family members mutate, the resulting abnormal signaling stimulates cell survival and is associated with cancer progression. The basic mechanism by which the HER3 receptor is activated and produces its physiological effects is similar to that of other HER3 family members. However, its ligands include neuregulin 1 (NRG-1) and neuregulin 2 (NRG-2). Furthermore, upon activation, HER3 cannot form homomers, but can only form heterodimers with EGFR or HER2. During heterodimerization, the intracellular domain of HER3 exhibits high tyrosine phosphatase activity. Structural analysis has revealed six P85 (PI-3K) binding sites within the HER3 intracellular domain. This specific structure enables HER3 to recruit up to six PI-3Ks to the P85 regulatory subunit upon interaction, thereby strongly activating the PI-3K signaling pathway. In fact, the HER3 / HER2 dimer is the most active of the HER3 dimers. EGFR is widely distributed on the 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 attach a cytotoxic small molecule drug to an antibody via a chemical linker. Using the antibody as a carrier, the small molecule drug is delivered to target cells. ADCs combine the highly targeted properties of antibodies with the potent killing power of cytotoxic drugs against target cells, thereby improving the effectiveness of chemotherapy and reducing systemic exposure and toxicity. The HER3 receptor has a much higher internalization efficiency than other members of the HER3 receptor family, making it a more suitable target for ADC drugs.

[0005] Developing safe and effective clinical treatment strategies targeting HER3 is an important issue that needs to be addressed in this field.

[0006] Summary of the Invention

[0007] The present disclosure provides methods and medical uses of anti-HER3 antibody-drug conjugates for treating tumors.

[0008] In some embodiments, the present disclosure provides any of the following methods or uses:

[0009] (1) Use of anti-HER3 antibody-drug conjugates in the preparation of drugs for treating tumors.

[0010] (2) A method for treating a subject having a tumor, comprising administering an anti-HER3 antibody drug conjugate to the subject.

[0011] (3) An anti-HER3 antibody drug conjugate for use in treating a subject with a tumor.

[0012] In some embodiments, the present disclosure provides any of the following methods or uses:

[0013] (1) Use of anti-HER3 antibody-drug conjugates combined with tyrosine kinase inhibitors in the preparation of drugs for treating tumors.

[0014] (2) Use of a combination of an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor in the preparation of a drug for treating tumors.

[0015] (3) Use of a pharmaceutical composition in the preparation of a drug for treating tumors; wherein the pharmaceutical composition comprises an anti-HER3 antibody-drug conjugate and a tyrosine kinase inhibitor.

[0016] (4) Use of a drug packaging box or product in the preparation of a drug for treating tumors; wherein the drug packaging box or product comprises an anti-HER3 antibody-drug conjugate and a tyrosine kinase inhibitor.

[0017] (5) A method for treating a subject having a tumor, comprising administering to the subject: an anti-HER3 antibody drug conjugate; and a tyrosine kinase inhibitor.

[0018] (6) An anti-HER3 antibody-drug conjugate for use in treating a subject suffering from a tumor; wherein the subject is also receiving treatment with a tyrosine kinase inhibitor.

[0019] (7) A tyrosine kinase inhibitor for use in treating a subject with a tumor; wherein the subject is also receiving treatment with an anti-HER3 antibody drug conjugate.

[0020] (8) Anti-HER3 antibody-drug conjugates combined with tyrosine kinase inhibitors are used to treat tumors.

[0021] (9) A pharmaceutical composition for treating tumors; wherein the pharmaceutical composition comprises an anti-HER3 antibody-drug conjugate and a tyrosine kinase inhibitor.

[0022] (10) A drug package or product for treating tumors; wherein the drug package or product comprises an anti-HER3 antibody-drug conjugate and a tyrosine kinase inhibitor.

[0023] In some embodiments, the present disclosure provides pharmaceutical compositions comprising an anti-HER3 antibody-drug conjugate and a tyrosine kinase inhibitor. In some embodiments, the present disclosure provides pharmaceutical packaging or articles of manufacture comprising an anti-HER3 antibody-drug conjugate and a tyrosine kinase inhibitor. In some embodiments, the pharmaceutical packaging or articles of manufacture further comprises one or more containers, each independently comprising an anti-HER3 antibody-drug conjugate and a tyrosine kinase inhibitor.

[0024] In some embodiments, any of the foregoing methods or uses, wherein: 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 that has failed standard treatment or has no effective standard treatment options. In some embodiments, the tumor is non-small cell lung cancer (NSCLC).

[0025] In some specific embodiments, any of the aforementioned methods or uses, wherein: the tumor is a patient with an unresectable locally advanced or metastatic solid tumor confirmed by histology or cytology, which has recurred or progressed after standard treatment, or there is no standard treatment option, or standard treatment is not applicable at this stage.

[0026] In some embodiments, any of the aforementioned methods or uses, wherein: the tumor has brain metastases, bone metastases and / or liver metastases.

[0027] In some embodiments, any of the aforementioned methods or uses, wherein: the tumor is an EGFR mutant tumor. In some embodiments, the tumor is an EGFR mutant non-small cell lung cancer.

[0028] In some embodiments, any of the aforementioned methods or uses, wherein: the tumor is a locally advanced or metastatic tumor with an EGFR mutation. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer with an EGFR mutation.

[0029] In some embodiments, the terms "EGFR mutation" and "EGFR mutation positive" are used interchangeably and may refer to either a sensitive or non-sensitive mutation. In some embodiments, the term "EGFR mutation" refers to at least one of the following EGFR mutations, as confirmed by histological or blood specimens: exon 19 deletion (Ex19del), exon 21 substitution mutation (L858R mutation), G719X, or L861Q.

[0030] In some embodiments, any of the aforementioned methods or uses, wherein: the tumor is a tumor that has failed tyrosine kinase inhibitor (TKI) treatment. In some embodiments, the tumor is non-small cell lung cancer that has failed tyrosine kinase inhibitor (TKI) treatment.

[0031] In some embodiments, any of the foregoing methods or uses, wherein: the tumor is an EGFR mutant tumor that has failed tyrosine kinase inhibitor (TKI) treatment. In some embodiments, the tumor is an EGFR mutant non-small cell lung cancer that has failed tyrosine kinase inhibitor (TKI) treatment.

[0032] In some embodiments, any of the foregoing methods or uses, wherein: the tumor is a locally advanced or metastatic tumor that has failed tyrosine kinase inhibitor (TKI) treatment. In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer that has failed tyrosine kinase inhibitor (TKI) treatment.

[0033] In some embodiments, any of the foregoing methods or uses, wherein: the tumor is a locally advanced or metastatic tumor with an EGFR mutation that has failed treatment with a tyrosine kinase inhibitor (TKI). In some embodiments, the tumor is a locally advanced or metastatic non-small cell lung cancer with an EGFR mutation that has failed treatment with a tyrosine kinase inhibitor (TKI).

[0034] In some embodiments, locally advanced or metastatic disease is defined as stage IIIB-IV according to the 9th edition TNM staging criteria of the International Association for the Study of Lung Cancer (IASLC), and is no longer suitable for radical surgery or radical chemoradiotherapy.

[0035] In this disclosure, "TKI treatment failure", "EGFR-TKI treatment failure", and "EGFR-TKI resistance" are used interchangeably. In some embodiments, "treatment failure" refers to radiographic disease progression during or after treatment.

[0036] In some embodiments, the tumor includes, but is not limited to, any one or any combination of the following:

[0037] (1) Locally advanced or metastatic solid tumors (e.g., locally advanced or metastatic NSCLC);

[0038] (2) EGFR mutation-positive non-small cell lung cancer (e.g., EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer, treatment-naive EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer);

[0039] (3) Non-small cell lung cancer that has failed EGFR-TKI treatment (e.g., locally advanced or metastatic non-small cell lung cancer that has failed EGFR-TKI treatment, EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer that has failed EGFR-TKI treatment;

[0040] (4) Advanced or metastatic solid tumors that have relapsed or progressed after standard treatment, or for which there is no standard treatment option or standard treatment is not currently applicable;

[0041] (5) Unresectable locally advanced or metastatic solid tumors that have recurred or progressed after standard treatment, or for which there is no standard treatment option or standard treatment is not currently applicable.

[0042] In some embodiments, for locally advanced or metastatic NSCLC, the subject has received EGFR TKI treatment. In some embodiments, the subject with the T790M mutation must have received third-generation EGFR TKI treatment and had radiographic disease progression during or after treatment. Exemplarily:

[0043] (1) Subjects who experience tumor recurrence or metastasis during adjuvant treatment with EGFR TKI or within 6 months of discontinuation of treatment; (2) Subjects who have previously received neoadjuvant / adjuvant chemotherapy or radical chemoradiotherapy for non-metastatic tumors and have experienced tumor recurrence or metastasis at least 6 months after completing the above treatment, and who have received EGFR TKI treatment and have radiographic disease progression during or after treatment; (3) For locally advanced or metastatic NSCLC, combined anti-vascular therapy or targeted therapy (such as EGFR / c-MET bispecific antibodies, excluding antibody-drug conjugates) is allowed during EGFR TKI treatment, but other systemic anti-tumor treatments other than the above treatments are not allowed.

[0044] In some embodiments, "locally advanced or metastatic NSCLC" refers to a subject with histologically or cytologically confirmed unresectable locally advanced or metastatic non-small cell lung cancer. In some specific embodiments, "locally advanced or metastatic NSCLC" refers to a subject with histologically or cytologically confirmed unresectable locally advanced or metastatic non-small cell lung cancer that has relapsed or progressed after standard treatment, or for which there is no standard treatment option or standard treatment is not currently applicable.

[0045] In some embodiments, "EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer" refers to a subject with unresectable locally advanced or metastatic non-small cell lung cancer confirmed by histology or cytology, and histology or blood specimens confirm that the subject has an EGFR mutation (sensitive or non-sensitive mutation). In some embodiments, "EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer" refers to a subject with unresectable locally advanced or metastatic non-small cell lung cancer confirmed by histology or cytology, and histology or blood specimens confirm that the subject has 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 EGFR-TKI treatment", or "first-line EGFR mutation-positive locally advanced or metastatic non-small cell lung cancer".

[0046] In the present disclosure, standard treatment regimens are well known to those skilled in the art, for example, treatment regimens disclosed in treatment guidelines approved by regulatory authorities, including but not limited to detailed and up-to-date information on standard treatment regimens for various cancers provided in the NCCN Guidelines and the CSCO Guidelines.

[0047] Anti-HER3 Antibody Drug Conjugates

[0048] In some embodiments, the anti-HER3 antibody drug conjugate is administered at a dose of about 0.1 mg / kg to about 20 mg / kg, for example, about 1.0 mg / kg to about 20 mg / kg, about 1.0 mg / kg to about 12 mg / kg, about 1.5 mg / kg to about 12 mg / kg, about 1.0 mg / kg to about 10.5 mg / kg, about 1.0 mg / kg to about 10 mg / kg, about 1.0 mg / kg to about 9 mg / kg, about 1.5 mg / kg to about 10.5 mg, about 1.5 mg / kg to about 9.0 mg / kg; about 3.0 mg / kg to about 9.0 mg / kg; about 4.5 mg / kg to about 9.0 mg / kg; about 6.0 mg / kg to about 9.0 mg / kg; about 7.5 mg / kg to about 9.0 mg / kg; about 1.5 mg / kg to about 7.5 mg / kg; about 3.0 mg / kg to about 7.5 mg / kg; or any range therebetween.In some embodiments, the anti-HER3 antibody drug conjugate is administered at a dose selected from about 1.0 mg / kg, about 1.1 mg / kg, about 1.2 mg / kg, about 1.3 mg / kg, about 1.4 mg / kg, about 1.5 mg / kg, about 1.6 mg / kg, about 1.7 mg / kg, about 1.8 mg / kg, about 1.9 mg / kg, about 2.0 mg / kg, about 2.1 mg / kg, about 2.2 mg / kg, about 2.3 mg / kg, about 2.4 mg / kg, about 2.5 mg / kg, about 2.6 mg / kg, about 2.7 mg / kg, about 2.8mg / kg, about 2.9mg / kg, about 3.0mg / kg, about 3.1mg / kg, about 3.2mg / kg, about 3.4mg / kg, about 3.5mg / kg, about 3.6mg / kg, about 3.8mg / kg, about 4.0mg / kg, about 4.2mg / kg, about 4.3mg / kg, about 4.5mg / kg, about 4.6mg / kg, about 4.8mg / kg, about 5.0mg / kg, about 5.1mg / kg, about 5.3mg / kg, about 5.5mg / kg, about 5.6mg / kg, about 5.8mg / kg, about 6. 0mg / kg, about 6.1mg / kg, about 6.3mg / kg, about 6.4mg / kg, about 6.5mg / kg, about 6.6mg / kg, about 6.8mg / kg, about 6.9mg / kg, about 7.0mg / kg, about 7.2mg / kg, about 7.4mg / kg, about 7.5mg / kg, about 7.6mg / kg, about 7.7mg / kg, about 7.8mg / kg, about 7.9mg / kg, about 8.0mg / kg, about 8.1mg / kg, about 8.2mg / kg, about 8.3mg / kg, about 8.4mg / kg, about 8.5mg / kg g / kg, about 8.6mg / kg, about 8.7mg / kg, about 8.8mg / kg, about 8.9mg / kg, about 9.0mg / kg, about 9.1mg / kg, about 9.2mg / kg, about 9.3mg / kg, about 9.4mg / kg, about 9.5mg / kg, about 10.0mg / kg, about 10.5mg / kg, about 12mg / kg, about 12.5mg / kg, about 13mg / kg, about 13.5mg / kg, about 14mg / kg, about 16mg / kg, about 18mg / kg, about 19mg / kg, about 20mg / kg.

[0049] In some embodiments, the anti-HER3 antibody drug conjugate is administered 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 12 weeks. In some specific embodiments, the anti-HER3 antibody drug conjugate is administered once every three weeks.

[0050] In some embodiments, the administration regimen of the anti-HER3 antibody drug conjugate is selected from any one of the following:

[0051] (a1) a dose of about 0.1 mg / kg to about 20 mg / kg, with a dosing frequency of 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;

[0052] (a2) the dosage is about 1.0 mg / kg to about 13.5 mg / kg, and the administration frequency 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;

[0053] (a3) the dosage is about 1.0 mg / kg to about 10.5 mg / kg, and the administration frequency 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;

[0054] (a4) the dosage is about 1.0 mg / kg to about 9.0 mg / kg, and the administration frequency 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;

[0055] (a5) the dosage is about 1.5 mg / kg to about 10.5 mg / kg, and the administration frequency 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;

[0056] (a6) the dosage is about 1.5 mg / kg to about 9.0 mg / kg, and the administration frequency 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;

[0057] (a7) the dosage is about 1.5 mg / kg to about 12.0 mg / kg, and the administration frequency 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;

[0058] (a8) the dosage is about 7.5 mg / kg to about 9.0 mg / kg, and the administration frequency 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;

[0059] (a9) 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, about 8.0 mg / kg, about 8.5 mg / kg, about 9.0 mg / kg, about 10.5 mg / kg, about 12 mg / kg, or about 13.5 mg / kg; with a dosing frequency 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;

[0060] (a 10 ) 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, about 8.0 mg / kg, about 8.5 mg / kg, or about 9.0 mg / kg; with a dosing frequency 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;

[0061] (a 11 ) The dosage of the anti-HER3 antibody drug conjugate is about 1.5 mg / kg, and the administration frequency is once every three weeks.

[0062] (a 12 ) The dosage of the anti-HER3 antibody drug conjugate is about 3.0 mg / kg, and the administration frequency is once every three weeks.

[0063] (a 13 ) The dosage of the anti-HER3 antibody drug conjugate is about 4.5 mg / kg, and the administration frequency is once every three weeks.

[0064] (a 14 ) The dosage of the anti-HER3 antibody drug conjugate is about 6.0 mg / kg, and the administration frequency is once every three weeks.

[0065] (a 15 ) The dosage of the anti-HER3 antibody drug conjugate is about 7.5 mg / kg, and the administration frequency is once every three weeks.

[0066] (a 16 ) The dosage of the anti-HER3 antibody drug conjugate is about 8.0 mg / kg, and the administration frequency is once every three weeks.

[0067] (a 17 ) The dosage of the anti-HER3 antibody drug conjugate is about 8.5 mg / kg, and the administration frequency is once every three weeks.

[0068] (a 18) The dosage of the anti-HER3 antibody drug conjugate is about 9.0 mg / kg, and the administration frequency is once every three weeks.

[0069] In some specific embodiments, in the above (a1)-(a 10 ) In any one of the dosage regimens described above, the anti-HER3 antibody drug conjugate is administered once every three weeks.

[0070] In some embodiments, the anti-HER3 antibody drug conjugate is derived from an antibody drug conjugate of any structure in WO2022078425A1 and WO2020063676A1. The present disclosure incorporates the structures, preparation methods, and other related contents of the immunoconjugates in the above patents into the present disclosure by reference.

[0071] In some embodiments, the anti-HER3 antibody drug conjugate has a structure as shown in the following formula:

[0072] Wherein: n is 1 to 8, n is a decimal or an integer; Pc is an anti-HER3 antibody.

[0073] In some embodiments, n is 4.0±0.4.

[0074] In some embodiments, the anti-HER3 antibody drug conjugate has a structure as shown in the following formula:

[0075] Wherein: n is 1 to 8, n is a decimal or an integer; Pc is an anti-HER3 antibody.

[0076] In some embodiments, n is 4.0±0.4.

[0077] In this disclosure, "antibody" is used in the broadest sense to cover various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies or antigen-binding fragments thereof (also referred to as "antigen-binding portions"), so long as they exhibit the desired antigen-binding activity.

[0078] In some embodiments, the anti-HER3 antibody is derived from any type of anti-HER3 antibody or antigen-binding fragment thereof in WO2022078425A1. The present disclosure incorporates the antibody sequences, preparation methods and other related contents in the above patents into the present disclosure by reference.

[0079] 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 as 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 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively.

[0080] The aforementioned CDR sequences are shown in the following table:

[0081] Table 1. CDR sequences obtained by Kabat numbering rules

[0082] The CDRs are defined according to the Kabat numbering system.

[0083] In some embodiments, the anti-HER3 antibody comprises any one, any two, any three, any four, any five, or six CDRs selected from HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 shown in SEQ ID NO: 1 to SEQ ID NO: 6.

[0084] 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, respectively, as shown in SEQ ID NO: 7, and the light chain variable region comprises LCDR1, LCDR2, and LCDR3, respectively, as shown in SEQ ID NO: 8. The CDRs are defined according to the Kabat, IMGT, Chothia, AbM, or Contact numbering systems. In some specific embodiments, the CDRs are defined according to the Kabat numbering system.

[0085] In some embodiments, the anti-HER3 antibody is a murine antibody, a chimeric antibody, a humanized antibody, a human antibody, or an antigen-binding fragment thereof. In some specific embodiments, the anti-HER3 antibody is selected from a humanized antibody or an antigen-binding fragment thereof.

[0086] In some embodiments, the VH of the anti-HER3 antibody comprises the amino acid sequence as shown in SEQ ID NO: 7, or an amino acid sequence having at least 80% or 90% sequence identity thereto; and the VL comprises the amino acid sequence as shown in SEQ ID NO: 8, or an amino acid sequence having at least 80% or 90% sequence identity thereto.

[0087] HER3 heavy chain variable region:

[0088] HER3 light chain variable region:

[0089] In some embodiments, the anti-HER3 antibody comprises any one or two of the above-mentioned VH and VL.

[0090] 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 variants thereof; the light chain constant region of the antibody constant region is selected from human antibody κ and λ chain constant regions and variants thereof.

[0091] The above light chain variable region and light chain constant region sequences are combined to form a light chain sequence, and each heavy chain variable region and heavy chain constant region are combined to form a heavy chain sequence. An exemplary humanized antibody sequence is shown below:

[0092] HER3-29 heavy chain:

[0093] HER3-29 light chain:

[0094] 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 as shown in SEQ ID NO: 9, or at least 80% or 90% identical thereto, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 10, or at least 80% or 90% identical thereto.

[0095] In some embodiments, the anti-HER3 antibody comprises any one or two of the aforementioned heavy and light chains.

[0096] In the context of the present disclosure, "at least 80%" and "at least 90%" encompass 80% and above, for example at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, and any numerical range therebetween.

[0097] In some embodiments, the anti-HER3 antibody drug conjugate is administered orally, parenterally, or transdermally; parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, the anti-HER3 antibody drug conjugate is administered by intravenous injection.

[0098] In some embodiments, the anti-HER3 antibody drug conjugate is formulated in 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.

[0099] In some embodiments, the pharmaceutical composition comprising an anti-HER3 antibody drug conjugate further comprises a buffer, a stabilizer, an osmotic pressure regulator and / or a surfactant. Exemplarily, the buffer is selected from any one of acetic acid-sodium acetate, succinic acid-sodium succinate, histidine-hydrochloride and citric acid-sodium citrate buffer. In some specific embodiments, the buffer is acetic acid-sodium acetate. Exemplarily, the surfactant may be selected from polysorbates (e.g., polysorbate 20, polysorbate 80), polyhydroxyalkylene, Triton, sodium dodecyl sulfate, sodium lauryl sulfate, sodium octyl glucoside, lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine, stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine, stearyl-sarcosine, linoleyl-betaine, myristyl-betaine, spermaceti In some specific embodiments, the surfactant is a polysorbate. Exemplary are polysorbate 80 or polysorbate 20. In some specific embodiments, the surfactant is polysorbate 80. In some embodiments, the pharmaceutical composition comprising an anti-HER3 antibody drug conjugate further comprises a sugar. Exemplary, "sugar" comprises a conventional composition (CHO). n and derivatives thereof, including monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, and the like. The sugar can be selected from glucose, sucrose, trehalose, α,α-trehalose dihydrate, lactose, fructose, maltose, dextran, glycerol, erythritol, glycerol, arabitol, sylitol, sorbitol, mannitol, melibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, sorbitol, maltitol, lactitol, iso-maltulose, and the like. In some specific embodiments, the "sugar" is sucrose.

[0100] Anti-HER3 antibody-drug conjugate combined with tyrosine kinase inhibitor

[0101] In some embodiments, the present disclosure provides use of an anti-HER3 antibody-drug conjugate combined with a tyrosine kinase inhibitor in the preparation of a medicament for treating tumors.

[0102] In some embodiments, an anti-HER3 antibody drug conjugate is combined with a tyrosine kinase inhibitor for treating tumors.

[0103] In some embodiments, the present disclosure provides methods of treating a subject having a tumor, comprising administering to the subject: 1) an anti-HER3 antibody drug conjugate; and, 2) a tyrosine kinase inhibitor.

[0104] In some embodiments, the tyrosine kinase inhibitor is selected from neratinib, lapatinib, tucatinib, gefitinib, erlotinib, icotinib, afatinib, dacomitinib, osimertinib, or ametinib.

[0105] In some embodiments, the tyrosine kinase inhibitor is ametinib.

[0106] In some embodiments, the tyrosine kinase inhibitor is administered at a dosage of about 1 mg to about 1000 mg, for example, about 10 mg to about 1000 mg, about 10 mg to about 900 mg, about 10 mg to about 800 mg, 10 mg to about 500 mg, about 50 mg to about 500 mg, about 50 mg to about 450 mg, about 50 mg to about 400 mg, about 50 mg to about 350 mg, about 50 mg to about 300 mg, about 50 mg to about 250 mg, about 50 mg to about 200 mg, about 50 mg to about 180 mg, about 50 mg to about 150 mg, about 55 mg to about 110 mg, about 100 mg to about 150 mg, about 100 mg to about 180 mg, or about 100 to about 200 mg, and any range therebetween.

[0107] In some embodiments, the tyrosine kinase inhibitor is administered at a dosage of about 50 mg, about 55 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 95 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 220 mg, about 240 mg, about 260 mg, about 280 mg, about 300 mg, about 350 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg.

[0108] In some embodiments, the tyrosine kinase inhibitor is administered once a day, twice a day, three times a day, once every two days, once every three days, once every four days, or once every five days. In some specific embodiments, the tyrosine kinase inhibitor is administered once a week.

[0109] In some embodiments, the dosing regimen of the tyrosine kinase inhibitor is selected from any one of the following:

[0110] (b1) the tyrosine kinase inhibitor is administered in a dose of about 10 mg to about 1000 mg, with a frequency of administration of 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;

[0111] (b2) the tyrosine kinase inhibitor is administered in a dose of about 10 mg to about 500 mg, with a frequency of 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;

[0112] (b3) the tyrosine kinase inhibitor is administered in a dose of about 50 mg to about 200 mg, with a frequency of 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;

[0113] (b4) the tyrosine kinase inhibitor is administered in a dose of about 50 mg to about 150 mg, with a frequency of administration of 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;

[0114] (b5) the tyrosine kinase inhibitor is administered at a dose of about 55 mg to about 110 mg, with a frequency of 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;

[0115] (b6) the tyrosine kinase inhibitor is administered in a dose of about 100 mg to about 200 mg, with a frequency of administration of 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;

[0116] (b7) the tyrosine kinase inhibitor is administered in a dose of about 55 mg, with a frequency of administration of 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;

[0117] (b8) the tyrosine kinase inhibitor is administered in a dosage of about 110 mg, with a frequency of administration of 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;

[0118] In some embodiments, in the dosing regimen described in any one of (b1) to (b8) above, the tyrosine kinase inhibitor is administered once a day.

[0119] In some embodiments, the dosing frequency and dosage of the anti-HER3 antibody drug conjugate are as shown in any one of the above items.

[0120] Exemplarily, the anti-HER3 antibody drug conjugate is administered at a dosage of about 0.1 mg / kg to about 20 mg / kg, for example, about 1.0 mg / kg to about 20 mg / kg, about 1.0 mg / kg to about 13.5 mg / kg, about 1.0 mg / kg to about 12 mg / kg, about 1.5 mg / kg to about 12 mg / kg, about 1.0 mg / kg to about 10.5 mg / kg, about 1.0 mg / kg to about 10 mg / kg, about 1.0 mg / kg to about 10 mg / kg, about 1.0 mg / kg to about 10 mg / kg. / kg to about 9 mg / kg, about 1.5 mg / kg to about 10.5 mg, about 1.5 mg / kg to about 9.0 mg / kg; about 3.0 mg / kg to about 9.0 mg / kg; about 4.5 mg / kg to about 9.0 mg / kg; about 6.0 mg / kg to about 9.0 mg / kg; about 7.5 mg / kg to about 9.0 mg / kg; about 1.5 mg / kg to about 7.5 mg / kg; about 3.0 mg / kg to about 7.5 mg / kg. For example, 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, about 8.0 mg / kg, about 8.5 mg / kg, about 9.0 mg / kg, about 9.5 mg / kg, about 10.0 mg / kg, about 10.5 mg / kg, about 12.0 mg / kg, about 13.5 mg / kg, etc. The anti-HER3 antibody drug conjugate can be administered 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.

[0121] Exemplarily, the administration regimen of the anti-HER3 antibody drug conjugate is selected from (a1)-(a 14 ) in any one of the dosage regimens.

[0122] In some embodiments, the administration regimen of the anti-HER3 antibody drug conjugate combined with the tyrosine kinase inhibitor is selected from any one of the following:

[0123] (a1) the anti-HER3 antibody drug conjugate is administered at a dose of about 0.1 mg / kg to about 20 mg / kg, with a dosing frequency of 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;

[0124] (b1) the tyrosine kinase inhibitor is administered in a dose of about 10 mg to about 1000 mg, with a frequency of administration of 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;

[0125] or,

[0126] (a2) the anti-HER3 antibody drug conjugate is administered at a dose of about 1.0 mg / kg to about 20 mg / kg, with a dosing frequency 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;

[0127] (b2) the tyrosine kinase inhibitor is administered in a dose of about 10 mg to about 500 mg, with a frequency of 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;

[0128] or,

[0129] (a3) the anti-HER3 antibody drug conjugate is administered at a dose of about 1.0 mg / kg to about 13.5 mg / kg, with a dosing frequency 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;

[0130] (b3) the tyrosine kinase inhibitor is administered in a dose of about 50 mg to about 200 mg, with a frequency of 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;

[0131] or

[0132] (a4) the anti-HER3 antibody drug conjugate is administered at a dose of about 1.0 mg / kg to about 9.0 mg / kg, with a dosing frequency 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;

[0133] (b3) the tyrosine kinase inhibitor is administered in a dose of about 50 mg to about 200 mg, with a frequency of 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;

[0134] or

[0135] (a5) the anti-HER3 antibody drug conjugate is administered at a dose of about 1.5 mg / kg to about 12.5 mg / kg, with a dosing frequency 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;

[0136] (b3) the tyrosine kinase inhibitor is administered in a dose of about 50 mg to about 200 mg, with a frequency of 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;

[0137] or

[0138] (a5) the anti-HER3 antibody drug conjugate is administered at a dose of about 1.5 mg / kg to about 10.5 mg / kg, with a dosing frequency 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;

[0139] (b4) the tyrosine kinase inhibitor is administered in a dose of about 50 mg to about 150 mg, with a frequency of administration of 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;

[0140] or

[0141] (a6) the anti-HER3 antibody drug conjugate is administered at a dose of about 7.5 mg / kg to about 9.0 mg / kg, with a dosing frequency 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;

[0142] (b5) the tyrosine kinase inhibitor is administered at a dose of about 55 mg to about 110 mg, with a frequency of 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;

[0143] or,

[0144] The dosage of the anti-HER3 antibody drug conjugate is about 1.5 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 110 mg, and the administration frequency is once a day.

[0145] or,

[0146] The dosage of the anti-HER3 antibody drug conjugate is about 3.0 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 110 mg, and the administration frequency is once a day.

[0147] or,

[0148] The dosage of the anti-HER3 antibody drug conjugate is about 4.5 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 110 mg, and the administration frequency is once a day.

[0149] or,

[0150] The dosage of the anti-HER3 antibody drug conjugate is about 6.0 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 110 mg, and the administration frequency is once a day.

[0151] or,

[0152] The dosage of the anti-HER3 antibody drug conjugate is about 6.5 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 110 mg, and the administration frequency is once a day.

[0153] or,

[0154] The dosage of the anti-HER3 antibody drug conjugate is about 7.5 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 110 mg, and the administration frequency is once a day.

[0155] or,

[0156] The dosage of the anti-HER3 antibody drug conjugate is about 8.0 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 110 mg, and the administration frequency is once a day.

[0157] or,

[0158] The dosage of the anti-HER3 antibody drug conjugate is about 8.5 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 110 mg, and the administration frequency is once a day.

[0159] or,

[0160] The dosage of the anti-HER3 antibody drug conjugate is about 9.0 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 110 mg, and the administration frequency is once a day.

[0161] or,

[0162] The dosage of the anti-HER3 antibody drug conjugate is about 10.5 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 110 mg, and the administration frequency is once a day.

[0163] or,

[0164] The dosage of the anti-HER3 antibody drug conjugate is about 1.5 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 55 mg, and the administration frequency is once a day.

[0165] or,

[0166] The dosage of the anti-HER3 antibody drug conjugate is about 3.0 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 55 mg, and the administration frequency is once a day.

[0167] or,

[0168] The dosage of the anti-HER3 antibody drug conjugate is about 4.5 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 55 mg, and the administration frequency is once a day.

[0169] or,

[0170] The dosage of the anti-HER3 antibody drug conjugate is about 6.0 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 55 mg, and the administration frequency is once a day.

[0171] or,

[0172] The dosage of the anti-HER3 antibody drug conjugate is about 6.5 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 55 mg, and the administration frequency is once a day.

[0173] or,

[0174] The dosage of the anti-HER3 antibody drug conjugate is about 7.5 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 55 mg, and the administration frequency is once a day.

[0175] or,

[0176] The dosage of the anti-HER3 antibody drug conjugate is about 8.0 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 55 mg, and the administration frequency is once a day.

[0177] or,

[0178] The dosage of the anti-HER3 antibody drug conjugate is about 8.5 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 55 mg, and the administration frequency is once a day.

[0179] or,

[0180] The dosage of the anti-HER3 antibody drug conjugate is about 9.0 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 55 mg, and the administration frequency is once a day.

[0181] or,

[0182] The dosage of the anti-HER3 antibody drug conjugate is about 10.5 mg / kg, and the administration frequency is once every three weeks; the dosage of the tyrosine kinase inhibitor is about 55 mg, and the administration frequency is once a day.

[0183] In some embodiments, the anti-HER3 antibody-drug conjugate is an anti-HER3 antibody-drug conjugate of any of the aforementioned structures.

[0184] Exemplarily, the anti-HER3 antibody drug conjugate has the following structure:

[0185] Wherein: n is 1 to 8, n is a decimal or an integer; Pc is an anti-HER3 antibody.

[0186] Illustratively, in some embodiments, n is 4.0±0.4.

[0187] Exemplarily, 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 as 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 as shown in SEQ ID NO: 4, SEQ ID NO: 5, and SEQ ID NO: 6, respectively.

[0188] Illustratively, in some embodiments, the VH of the anti-HER3 antibody comprises the amino acid sequence shown in SEQ ID NO: 7, or an amino acid sequence having at least 80% or 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% or 90% sequence identity thereto.

[0189] Exemplarily, 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 as shown in SEQ ID NO: 9, or at least 80%, 90% identical thereto, and the light chain variable region comprises an amino acid sequence as shown in SEQ ID NO: 10, or at least 80%, 90% identical thereto.

[0190] In some embodiments, the tyrosine kinase inhibitor is administered orally, parenterally, or transdermally; parenteral administration includes but is not limited to intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, the tyrosine kinase inhibitor is administered orally.

[0191] In some embodiments, the anti-HER3 antibody drug conjugate is administered orally, parenterally, or transdermally; parenteral administration includes, but is not limited to, intravenous injection, subcutaneous injection, and intramuscular injection. In some specific embodiments, the anti-HER3 antibody drug conjugate is administered by intravenous injection.

[0192] In some embodiments, the order of administration of the anti-HER3 antibody drug conjugate combined with the tyrosine kinase inhibitor is: anti-HER3 antibody drug conjugate, then the tyrosine kinase inhibitor, with the required time interval between the two administrations (e.g., no more than 1 hour, no more than 2 hours, etc.).

[0193] In some embodiments, the order of administration of the anti-HER3 antibody drug conjugate combined with the tyrosine kinase inhibitor is: tyrosine kinase inhibitor, anti-HER3 antibody drug conjugate, with the required time interval between the two administrations (e.g., no more than 1 hour, no more than 2 hours, etc.). BRIEF DESCRIPTION OF THE DRAWINGS

[0194] FIG1 shows the Kaplan-Meier curve of the median progression-free survival (PFS) of patients treated with ADC-1.

[0195] the term

[0196] In order to make the present disclosure more easily understood, certain technical and scientific terms are specifically defined below. Unless otherwise explicitly defined herein, all other technical and scientific terms used herein have the meanings commonly understood by those skilled in the art to which the present disclosure belongs.

[0197] Unless the context clearly requires otherwise, throughout the specification and claims, the words "comprising," "having," "including," etc. should be construed to have an inclusive sense rather than an exclusive or exhaustive sense; that is, in the sense of "including but not limited to."

[0198] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0199] "About" and "approximately" refer to values ​​within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which value depends in part on how it is measured or determined (i.e., the limits of the measurement system). For example, "about" can mean within 1 or more than 1 standard deviation. Alternatively, "about" or "substantially comprising" can mean a range of up to 20%, such as between 1% and 15%, between 1% and 10%, between 1% and 5%, between 0.5% and 5%, between 0.5% and 1%, and in this disclosure, each instance of a number or numerical range preceded by the term "about" also includes embodiments of the given number. Unless otherwise stated, when a specific value appears in the application and claims, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for that specific value.

[0200] The term "and / or," such as "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 meaning.

[0201] In some embodiments, the present disclosure defines:

[0202] Antibody-drug conjugates (ADCs) link antibodies or antibody fragments to biologically active cytotoxins or small molecule drugs with cell-killing activity via a stable chemical linker. These ADCs leverage the antibody's specificity for tumor cell-specific or highly expressed antigens and the high efficacy of the cytotoxin, while avoiding toxic side effects on normal cells. Compared to traditional chemotherapy drugs, ADCs can precisely bind to tumor cells while minimizing their effects on normal cells.

[0203] An antibody drug conjugate "retains its chemical stability" in a pharmaceutical formulation if the antibody drug conjugate shows no significant chemical changes. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. Degradation processes that often change the chemical structure of a protein include hydrolysis or truncation (assessed by methods such as size exclusion chromatography and CE-SDS), oxidation (assessed by methods such as peptide mapping in combination with mass spectrometry or MALDI / TOF / MS), deamidation (assessed by methods such as ion exchange chromatography, capillary isoelectric focusing, peptide mapping, isoaspartate measurement), and isomerization (assessed by measuring isoaspartate content, peptide mapping, etc.).

[0204] An antibody drug conjugate "retains its biological activity" in a pharmaceutical formulation if the biological activity of the antibody drug conjugate at a given time is within a predetermined range of the biological activity exhibited when the pharmaceutical formulation is prepared.

[0205] The three letter and one letter codes for amino acids used in this disclosure are as described in J. biol. chem, 243, p3558 (1968).

[0206] As used herein, the term "antibody" is used in the broadest sense to encompass various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies; monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), full-length antibodies, and antibody fragments (or antigen-binding fragments, or antigen-binding portions), as long as they exhibit the desired antigen-binding activity. An antibody may refer to an immunoglobulin, which is a tetrapeptide chain structure composed of two identical heavy chains and two identical light chains connected by interchain disulfide bonds. The amino acid composition and arrangement order of the constant regions of immunoglobulins' heavy chains differ, resulting in different antigenicity. Accordingly, immunoglobulins can be divided into five classes, or so-called immunoglobulin isotypes: IgM, IgD, IgG, IgA, and IgE, with their corresponding heavy chains being μ, δ, γ, α, and ε, respectively. Igs of the same class can be further divided into different subclasses based on differences in the amino acid composition of their hinge regions and the number and location of heavy chain disulfide bonds. For example, IgG can be divided into IgG1, IgG2, IgG3, and IgG4. Light chains are classified as either kappa or lambda chains based on differences in their constant regions. Each of the five classes of Ig can have either kappa or lambda chains. The approximately 110 amino acids near the N-terminus of both the heavy and light chains of antibodies vary greatly in sequence and constitute the variable region (V region); the remaining amino acid sequences near the C-terminus are relatively stable and constitute the constant region (C region). The variable region consists of three hypervariable regions (CDRs) and four framework regions (FRs) whose sequences are relatively conserved. These three hypervariable regions determine the specificity of the antibody and are also known as complementarity-determining regions (CDRs). Each light chain variable region (VL) and heavy chain variable region (VH) consists of three CDRs and four FRs, arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The three CDRs of the light chain are referred to as LCDR1, LCDR2, and LCDR3; the three CDRs of the heavy chain are referred to as HCDR1, HCDR2, and HCDR3.

[0207] For the determination or definition of CDRs, the definitive delineation of CDRs and the identification of residues comprising the binding site of the antibody can be accomplished by resolving the structure of the antibody and / or resolving the structure of the antibody-ligand complex. This can be accomplished by any of the various techniques known to those skilled in the art, such as X-ray crystallography. A variety of 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.

[0208] The amino acid sequence boundaries of CDRs can be determined by various well-known schemes, for example: "Kabat" numbering convention (see Kabat et al. (1991), "Sequences of Proteins of Immunological Interest", 5th edition, Public Health Service, National Institutes of Health, Bethesda, MD), "Chothia" numbering convention, "ABM" numbering convention, "contact" numbering convention (see Martin, ACR. Protein Sequence and Structure Analysis of Antibody Variable Domains [J]. 2001) and ImMunoGenTics (IMGT) numbering convention (Lefranc, MP et al., Dev. Comp. Immunol., 27, 55-77 (2003); Front Immunol. 2018 Oct 16; 9: 2278), etc.

[0209] The term "antigen-binding fragment" or "functional fragment" or "antigen-binding portion" refers to one or more fragments of an intact antibody that retains the ability to specifically bind to an antigen. It has been shown that fragments of a full-length antibody can be used to perform the antigen-binding function of an antibody. Exemplary binding fragments encompassed by the term "antigen-binding fragment" include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VH and VL domains of a single arm of an antibody; (v) a dsFv, a stable antigen-binding fragment formed by an interchain disulfide bond between VH and VL; (vi) scFv; (vii) diabodies, bispecific antibodies, and multispecific antibodies comprising fragments such as scFv, dsFv, and Fab.

[0210] The terms "specific binding", "selective binding", "selectively binds" and "specifically binds" refer to the binding of an antibody to a predetermined epitope on an antigen. -8 M, for example, less than approximately 10 -9 M, 10 -10 M, 10 -11 Binds with an affinity (KD) of M or less.

[0211] The term "KD" refers to the dissociation equilibrium constant for a particular antibody-antigen interaction. Typically, the antibodies of the present disclosure exhibit dissociation equilibrium constants of less than about 10-7 M, for example, less than about 10-7 M. -8 M, 10 -9 M or 10 -10 The IL-5 binding protein binds to IL-5 with a dissociation equilibrium constant (KD) of M or less, e.g., as determined using surface plasmon resonance (SPR) technology in a BIACORE instrument.

[0212] "Homology" or "identity" refers to the sequence similarity between two polynucleotide sequences or between two polypeptides. When a position in the two compared sequences is occupied by the same base or amino acid monomer subunit, for example, if every position in two DNA molecules is occupied by adenine, then the molecules are homologous at that position. The percentage homology between two sequences is a function of the number of matching or homologous positions shared by the two sequences divided by the number of positions compared × 100. For example, if 6 out of 10 positions in the two sequences match or are homologous when the sequences are optimally aligned, then the two sequences are 60% homologous; if 95 out of 100 positions in the two sequences match or are homologous, then the two sequences are 95% homologous. Typically, when two sequences are aligned, the comparison is made to give the maximum percentage homology. For example, the comparison can be performed using the BLAST algorithm, where the parameters of the algorithm are selected to give the maximum match between each sequence over the entire length of each reference sequence. The following references relate to the BLAST algorithm commonly used for sequence analysis: BLAST ALGORITHMS: 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 conventional BLAST algorithms, such as those provided by NCBI BLAST, are also well known to those skilled in the art.

[0213] "Administering" and "treating" as applied to an animal, a human, a laboratory subject, a cell, a tissue, an organ or a biological fluid, refers to the contacting of an exogenous drug, therapeutic agent, diagnostic agent or composition with an animal, a human, a subject, a cell, a tissue, an organ or a biological fluid. "Administering" and "treating" can refer to, for example, therapeutic, pharmacokinetics, diagnostics, research and experimental procedures. Treatment of cells includes contacting an agent with a cell, and contacting an agent with a fluid, wherein the fluid is in contact with the cell. "Administering" and "treating" also mean treating, for example, a cell in vitro and ex vivo, by an agent, a diagnostic, a binding composition or by another cell. "Treatment" as applied to a human, veterinary or research subject, refers to therapeutic treatment, prophylactic or preventative measures, research and diagnostic applications.

[0214] "Treatment" means administering an internal or external therapeutic agent, such as a composition comprising any of the binding compounds of the present disclosure, to a patient who has one or more symptoms of a disease for which the therapeutic agent is known to have a therapeutic effect. Typically, the therapeutic agent is administered in an amount effective to alleviate one or more symptoms of the disease in the patient or population being treated, to induce regression of such symptoms or to inhibit the progression of such symptoms to any clinically measurable degree. The amount of a therapeutic agent effective to alleviate any specific disease symptom (also referred to as a "therapeutically effective amount") can vary according to a variety of factors, such as the patient's disease state, age, and weight, and the ability of the drug to produce the desired therapeutic effect in the patient. Whether the symptoms of the disease have been alleviated can be assessed by any clinical test method commonly used by a physician or other health care professional to assess the severity or progression of the symptoms. Although embodiments of the present disclosure (e.g., methods of treatment or articles of manufacture) may not be effective in alleviating every symptom of the target disease, they should alleviate the target disease symptoms in a statistically significant number of patients as determined by any statistical test known in the art, such as Student's t-test, chi-square test, U test according to Mann and Whitney, Kruskal-Wallis test (H test), Jonckheere-Terpstra test, and Wilcoxon test.

[0215] An "effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also means an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0216] The terms "subject" and "patient" refer to mammals, particularly primates, and especially humans.

[0217] The "combination" described in the present disclosure is a mode of administration, which refers to the administration of at least one dose of an anti-HER3 antibody drug conjugate and at least one dose of a tyrosine kinase inhibitor within a certain time limit, wherein both drugs show a pharmacological effect. The time limit can be within a dosing cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours, or within 12 hours. The anti-HER2 antibody drug conjugate or a pharmaceutically acceptable salt thereof and the tyrosine kinase inhibitor can be administered simultaneously or sequentially. This period includes treatments in which the anti-HER3 antibody drug conjugate and the tyrosine kinase inhibitor are administered by the same route of administration or different routes of administration. The combined mode of administration described in the present disclosure is selected from simultaneous administration, independent formulation and co-administration, or independent formulation and sequential administration.

[0218] In the anti-HER3 antibody drug conjugates disclosed herein, "n" refers to the average number of cytotoxic drugs loaded on each antibody or antigen-binding fragment thereof in the antibody drug conjugate molecule, and can also be expressed as the ratio of the amount of drug to the amount of antibody, which is the average number of drugs per ADC molecule after the coupling reaction as determined by hydrophobic chromatography (HIC) mass spectrometry.

[0219] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity. DETAILED DESCRIPTION

[0220] The present disclosure is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present disclosure. Experimental methods in the examples herein where specific conditions are not specified generally follow conventional conditions, such as those in the Cold Spring Harbor Laboratory's "Antibody Techniques Laboratory Manual" and "Molecular Cloning Manual," or according to the conditions recommended by the raw material or product manufacturer. Reagents where the specific source is not specified are commercially available.

[0221] Example 1. Preparation of anti-HER3 antibody drug conjugates

[0222] The anti-HER3 antibody drug conjugates are Example 3-1 (n=4.19), Example 3-2 (n=2.91), and Example 3-3 (n=7.27) in WO2022078425A1 (incorporated herein by reference in its entirety), and have the following structures:

[0223] wherein n is 1 to 8, preferably 3 to 5.

[0224] The structure of the anti-HER3 antibody drug conjugate is abbreviated as the following structural formula ADC-1:

[0225] Here, n (DAR value) is about 4.0, which is equivalent to 4.0±0.4.

[0226] The HER3 antibody is derived from the antibody HER3-29 of WO2022078425A1, and the CDR sequences are shown in Table 1. The full length of the heavy chain of the antibody HER3-29 is shown in SEQ ID NO: 9, and the full length of the light chain is shown in SEQ ID NO: 10.

[0227] ADC-1 was formulated as an injection (sterile powder for injection) at a strength of 100 mg / vial. The injection was prepared using study drug in single-use vials. The vial containing 100 mg of study drug was reconstituted with 5 mL of sterile water for injection to a concentration of 20 mg / mL and then diluted to the target concentration with 0.9% sodium chloride or 5% dextrose solution.

[0228] Example 2. Study on the safety, tolerability, pharmacokinetics and efficacy of ADC-1 for injection in patients with advanced solid tumors

[0229] 1. Trial Drug

[0230] 1) ADC-1 prepared in Example 1.

[0231] 2. Enrollment of subjects

[0232] 1) Age range: 18 to 75 years old (inclusive), gender is not limited;

[0233] 2) Patients with unresectable locally advanced or metastatic solid tumors confirmed by histology or cytology, who have relapsed or progressed after standard treatment, or have no standard treatment options, or are not currently suitable for standard treatment;

[0234] 3) at least one measurable tumor lesion according to RECIST v1.1 (patients with only non-target lesions were allowed to be enrolled in the dose escalation phase);

[0235] 4) Subjects enrolled in the dose escalation and efficacy expansion phases must provide tumor tissue samples for HER3 expression and other testing. Tumor tissue samples must be either fresh or archived, with fresh samples being preferred. Subjects unable to provide fresh tissue may provide archived tumor tissue samples obtained within 12 months prior to the first study treatment.

[0236] 5) ECOG performance score 0-1;

[0237] 6) Estimated survival time ≥12 weeks;

[0238] 7) Have adequate bone marrow and organ function. The following test results must be completed within 7 days before the first study treatment:

[0239] Routine blood test (no blood transfusion or hematopoietic stimulating factor treatment within 14 days before the examination): neutrophil count (ANC) ≥ 1.5 × 109 / L (1,500 / mm3), platelet ≥ 100 × 109 / L (100,000 / mm3), hemoglobin (Hgb) ≥ 9.0 g / dL (90 g / L);

[0240] Liver function tests: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN (for patients with confirmed liver metastasis, ALT and AST ≤ 5 × ULN), total bilirubin ≤ 1.5 × ULN (for patients with confirmed Gilbert syndrome, total bilirubin ≤ 3 mg / dL);

[0241] Renal function test: serum creatinine ≤1.5×ULN or creatinine clearance ≥60 mL / min (using the Cockcroft-Gault formula);

[0242] Coagulation function tests: prothrombin time and partial thromboplastin time ≤1.5×ULN.

[0243] 3. Clinical plan

[0244] The ADC-1 dose escalation will use an "i3+3" design to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD). The dose escalation group will enroll patients with advanced solid tumors, with the dose increasing sequentially from low to high. ADC-1 is administered by intravenous drip once every 3 weeks (Q3W), and the DLT (dose-limiting toxicity) observation period is 21 days after the first dose. Based on preclinical trial data, 6 doses are preset: 1.5mg / kg, 3.0mg / kg, 4.5mg / kg, 6.0mg / kg, 7.5mg / kg and 9.0mg / kg.

[0245] The primary endpoints of the study were: 1) the maximum tolerated dose (MTD) or maximum administered dose (MAD), which provides the recommended dose (RP2D) for subsequent studies; and 2) the incidence and severity of adverse events / serious adverse events (rated based on CTCAE v5.0).

[0246] 4. Results

[0247] As of the data collection date, a total of 42 patients were enrolled (ECOG grade 1, 83.3%; stage IV, 100%; non-small cell lung cancer (NSCLC), 85.7%; brain metastases, 31.0%); the median number of lines of systemic treatment before was 3 (range, 1-11). Among the 36 NSCLC patients, 34 (94.4%) carried EGFR mutations; all of these patients were resistant to EGFR-TKI, and 85.3% (29 / 34) of them had previously received third-generation drugs. No dose-limiting toxicity (DLT) was observed at the highest dose of 10.5 mg / kg. 13 (31.0%) patients reported treatment-related adverse events (TRAEs) of grade ≥3, of which the incidence of hematologic toxicity was ≥5%. Among evaluable patients, the objective response rate (ORR) was 25.0% (9 / 36; 95% CI 12.1-42.2) across all tumor types and 30.0% (9 / 30; 95% CI 14.7-49.4) in NSCLC; the median duration of response (DoR) was 7.0 months (range, 2.8-8.5). Tumor responses at different doses are listed in Table 1. The 6-month progression-free survival (PFS) rate was 46.4% (95% CI 27.0-63.8) for all tumor types and 49.8% (95% CI 28.8-67.8) for NSCLC. Systemic exposure to ADC-1, total antibody, and free toxin increased approximately dose-proportionally following single and multiple doses of 1.5-9.0 mg / kg; plasma toxin exposure was low at all dose levels.

[0248] Table 2. Dose-related tumor responses

[0249] Analyses were performed on patients assessed after baseline. *Includes unconfirmed responses. n = 2 (PR, n = 1; SD, n = 1). NE, not evaluable.

[0250] 5. Conclusion

[0251] ADC-1 demonstrated a tolerable safety profile and encouraging antitumor activity in patients with advanced, pre-treated solid tumors.

[0252] Example 3. Study on the safety, tolerability, pharmacokinetics and efficacy of ADC-1 for injection in patients with advanced solid tumors

[0253] 1. Trial Drug

[0254] 1) ADC-1 prepared in Example 1.

[0255] 2. Enrollment of subjects

[0256] 1) Age range: 18 to 75 years old (inclusive), gender is not limited;

[0257] 2) Patients with unresectable locally advanced or metastatic solid tumors confirmed by histology or cytology, who have relapsed or progressed after standard treatment, or have no standard treatment options, or are not currently suitable for standard treatment;

[0258] 3) at least one measurable tumor lesion according to RECIST v1.1 (patients with only non-target lesions were allowed to be enrolled in the dose escalation phase);

[0259] 4) Subjects enrolled in the dose escalation and efficacy expansion phases must provide tumor tissue samples for HER3 expression and other testing. Tumor tissue samples must be either fresh or archived, with fresh samples being preferred. Subjects unable to provide fresh tissue may provide archived tumor tissue samples obtained within 12 months prior to the first study treatment.

[0260] 5) ECOG performance score 0-1;

[0261] 6) Estimated survival time ≥12 weeks;

[0262] 7) Have adequate bone marrow and organ function. The following test results must be completed within 7 days before the first study treatment:

[0263] Routine blood test (no blood transfusion or hematopoietic stimulating factor treatment within 14 days before the examination): neutrophil count (ANC) ≥ 1.5 × 109 / L (1,500 / mm3), platelet ≥ 100 × 109 / L (100,000 / mm3), hemoglobin (Hgb) ≥ 9.0 g / dL (90 g / L);

[0264] Liver function tests: alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN (for patients with confirmed liver metastasis, ALT and AST ≤ 5 × ULN), total bilirubin ≤ 1.5 × ULN (for patients with confirmed Gilbert syndrome, total bilirubin ≤ 3 mg / dL);

[0265] Renal function test: serum creatinine ≤1.5×ULN or creatinine clearance ≥60 mL / min (using the Cockcroft-Gault formula);

[0266] Coagulation function tests: prothrombin time and partial thromboplastin time ≤ 1.5 × ULN;

[0267] 3. Clinical plan

[0268] The ADC-1 dose escalation will use an "i3+3" design to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD). The dose escalation group will enroll patients with advanced solid tumors, with the dose increasing sequentially from low to high doses. ADC-1 is administered by intravenous drip at a dose of 1.5-12.0 mg / kg once every 3 weeks (Q3W), and the DLT (dose-limiting toxicity) observation period is 21 days after the first dose. One of the indication expansion cohorts evaluated NSCLC patients with epidermal growth factor receptor (EGFR) mutations.

[0269] The primary endpoints of the study were: 1) the maximum tolerated dose (MTD) or maximum administered dose (MAD), which provides the recommended dose (RP2D) for subsequent studies; and 2) the incidence and severity of adverse events / serious adverse events (rated based on CTCAE v5.0).

[0270] 4. Results

[0271] Study results: As of the data collection date (March 30, 2024), a total of 103 patients with EGFR-mutated NSCLC were enrolled and treated. The median follow-up time was 8.6 months. The median number of patients who had previously received systemic treatment was 2 (1-7). All patients had received prior EGFR-TKI treatment, of which 88.3% had received third-generation EGFR-TKI treatment; 64.1% had received chemotherapy, of which 59.2% had received platinum-based chemotherapy (PBC). In patients with an expanded 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); the response to ADC-1 was durable (Table 2). Table 2 lists the tumor responses in all dose groups. Among all treated patients, the median PFS was 9.6 months (95% CI, 5.7-12.4) in the 9.0 mg / kg group and 6.7 months (95% CI, 4.8-9.7) across all dose groups.

[0272] Table 3. Tumor response (evaluable group) * Including unconfirmed reactions (n=3). method. DoR is the duration of response.

[0273] 5. Conclusion

[0274] ADC-1 showed encouraging antitumor activity and a tolerable safety profile in patients with EGFR-mutant NSCLC whose disease progressed after EGFR-TKI therapy.

[0275] Example 4. Study on the safety, tolerability, pharmacokinetics and efficacy of ADC-1 for injection in patients with advanced solid tumors

[0276] 1. Trial Drug

[0277] 1) ADC-1 prepared in Example 1.

[0278] 2. Key inclusion criteria

[0279] Relapsed / refractory advanced solid tumors (no standard treatment available).

[0280] ECOG performance status score 0-1.

[0281] Measurable lesions according to RECIST v1.1.

[0282] 3. Patient baseline characteristics

[0283] As of the data cutoff date (July 25, 2024), a total of 130 patients with EGFR-mutated NSCLC were enrolled and treated, of whom 97 received ADC-1 at a dose of 7.5-9.0 mg / kg. The overall median follow-up time was 7.2 months.

[0284] All patients had previously received EGFR-TKI treatment, of which 89.2% had used third-generation EGFR-TKI; 70.0% had received chemotherapy, of which 64.6% had received platinum-based chemotherapy (see Table 4).

[0285] Table 4. Baseline Characteristics

[0286] 4. Safety and efficacy data

[0287] Among patients treated with 7.5-9.0 mg / kg ADC-1, the objective response rate (ORR) in the evaluable population 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%). ADC-1 responses were durable (see Table 5 and Figure 2). Tumor responses across dose groups (7.5-9.0 mg / kg and all dose groups) are shown in Table 5.

[0288] In the full analysis set, the median progression-free survival (PFS) for patients receiving 7.5-9.0 mg / kg was 9.6 months (95% CI 5.7-12.3), and the median PFS across all dose groups was 6.9 months (95% CI 5.4-9.7) (see Figure 1).

[0289] Among patients treated with ADC-1 at doses of 7.5-9.0 mg / kg, 60.8% reported Grade 3 or higher treatment-related adverse events (TRAEs); all events with a frequency of ≥5% were hematologic toxicities. Treatment-related interstitial lung disease, as assessed by the investigator, occurred in 7.2% of patients, of whom 2.1% experienced Grade 3 or higher events.

[0290] Table 5. Tumor response *Unconfirmed responses exist because the data cutoff date predated the confirmatory scan. CR, complete response; DCR, disease control rate; DoR, duration of response; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

[0291] 5. Conclusion

[0292] ADC-1 showed encouraging antitumor activity and a tolerable safety profile in patients with EGFR-mutated NSCLC who had progressed after EGFR-TKI therapy.

[0293] Example 5. Study on the safety, tolerability and efficacy of ADC-1 for injection combined with anti-tumor therapy in patients with advanced solid tumors

[0294] 1. Trial Drug

[0295] 1) ADC-1 prepared in Example 1.

[0296] 2) Ametinib.

[0297] 2. Enrollment of subjects

[0298] 1) Age range: 18 to 75 years old (inclusive), gender is not limited;

[0299] 2) Part A1: Subjects with unresectable locally advanced or metastatic non-small cell lung cancer confirmed by histology or cytology, and EGFR mutations (sensitive or non-sensitive mutations) confirmed by histology or blood specimens; Part A2: Subjects with unresectable locally advanced or metastatic non-small cell lung cancer confirmed by histology or cytology, and EGFR exon 19 deletion or L858R mutation confirmed by histology or blood specimens;

[0300] 3) Part A1: Subjects with EGFR-sensitive mutations who have had radiographic progression 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 have no standard treatment options, or are not currently suitable for standard treatment; Part A2: Subjects with locally advanced / metastatic NSCLC who have not received systemic treatment and are judged by the investigator to be suitable for first-line treatment with ametinib, are allowed to have received previous adjuvant or neoadjuvant therapy (chemotherapy, radiotherapy, etc. other than EGFR-TKI);

[0301] 4) at least one measurable tumor lesion according to RECIST v1.1 (subjects with only non-target lesions are allowed to be enrolled in stage IB);

[0302] 5) All enrolled subjects must provide tumor tissue samples for HER3 expression and other tests (subjects who are unable to provide tumor tissue samples are allowed to be enrolled in the Phase IB stage). The requirements for tumor tissue samples are: neutral formalin-fixed, paraffin-embedded [FFPE] tissue blocks or at least 6 unstained tumor tissue sections, fresh or archived, with fresh samples being preferred. Subjects who are unable to provide freshly obtained tissues may provide archived tumor tissue samples within 12 months before the first study treatment. For subjects who are unable to provide tumor tissue samples that meet the above requirements, it is necessary to discuss with the sponsor to determine whether to enroll;

[0303] 6) ECOG performance score 0-1;

[0304] 7) Expected survival time ≥12 weeks;

[0305] 8. Have adequate bone marrow and organ function. The following test results must be completed within 7 days before the first study treatment:

[0306] a) Routine blood test (no blood transfusion or hematopoietic stimulating factor treatment within 14 days before 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);

[0307] b) Liver function tests (no liver-protective medication within 7 days before the test): alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN (for subjects with confirmed liver metastasis, ALT and AST ≤ 5 × ULN), total bilirubin ≤ 1.5 × ULN (for subjects with confirmed Gilbert syndrome, total bilirubin ≤ 3 mg / dL);

[0308] c) Renal function test: serum creatinine ≤1.5×ULN or creatinine clearance ≥60 mL / min (using the Cockcroft-Gault formula);

[0309] d) Coagulation function test: prothrombin time and partial thromboplastin time ≤ 1.5×ULN.

[0310] 3. Dosage regimen

[0311] Part A is a clinical trial of ADC-1 combined with ametinib for the treatment of EGFR mutation-positive locally advanced / metastatic non-small cell lung cancer. Part A is divided into Part A1 and Part A2. Part A1 is for ADC-1 combined with ametinib for the treatment of EGFR mutation-positive locally advanced / metastatic NSCLC who have failed EGFR-TKI treatment, while Part A2 is for ADC-1 combined with ametinib for the treatment of previously untreated EGFR mutation-positive locally advanced / metastatic NSCLC. The study process includes a screening period, a treatment period, and a follow-up period. The treatment period includes Phase IB and Phase II.

[0312] Part A1 is the treatment of ADC-1 combined with ametinib for EGFR mutation-positive locally advanced / metastatic NSCLC that has failed EGFR-TKI treatment.

[0313] Phase IB:

[0314] 1) Part A1, dose group 1: ADC-1 9.0 mg / kg once every 3 weeks (Q3W) combined with ametinib 110 mg once daily (QD);

[0315] 2) Part A1, dose group 2: ADC-1 7.5 mg / kg once every 3 weeks (Q3W) combined with ametinib 110 mg once daily (QD);

[0316] 3) Part A1, dose group 3: ADC-1 9.0 mg / kg once every 3 weeks (Q3W) combined with ametinib 55 mg once daily (QD).

[0317] ADC-1 is administered by intravenous infusion every 3 weeks, and ametinib is administered orally every 24 hours, with a treatment cycle of 21 days. To determine the recommended dose of ADC-1 combined with ametinib in patients with EGFR mutation-positive locally advanced / metastatic non-small cell lung cancer who have failed EGFR-TKI therapy.

[0318] Phase II:

[0319] Arm 1 received the recommended dose of ADC-1 combined with ametinib until disease progression or other discontinuation criteria were met; Arm 2 received ADC-1 monotherapy at the recommended Phase 2 dose (RP2D) until disease progression or other discontinuation criteria were met. The study evaluated the anti-tumor efficacy of ADC-1 combined with ametinib versus ADC-1 monotherapy in EGFR mutation-positive locally advanced / metastatic NSCLC patients who had failed EGFR-TKI therapy.

[0320] Part A2 is the combination of ADC-1 and ametinib for the treatment of first-line EGFR mutation-positive locally advanced / metastatic NSCLC.

[0321] Phase IB:

[0322] 4) Part A2, Cohort 1: Receive ADC-1 6.0 mg / kg Q3W combined with ametinib 110 mg QD until disease progression or meet other discontinuation criteria;

[0323] 5) Part A2, Cohort 2: Receive 6 cycles of ADC-1 6.0 mg / kg Q3W combined with ametinib 110 mg QD, and then continue to receive ametinib 110 mg QD monotherapy until disease progression or meet other discontinuation criteria.

[0324] ADC-1 is administered by intravenous infusion at 6.0 mg / kg every three weeks; ametinib is administered orally at 110 mg every day, with a 21-day treatment cycle. To determine the recommended dose and duration of ADC-1 plus ametinib combination therapy in patients with previously untreated EGFR mutation-positive locally advanced / metastatic non-small cell lung cancer.

[0325] Phase II:

[0326] Arm 1 received the recommended dose of ADC-1 combined with ametinib; Arm 2 received ametinib 110mg QD monotherapy to evaluate the anti-tumor efficacy of ADC-1 combined with ametinib compared with ametinib monotherapy in the treatment of first-line EGFR mutation-positive advanced NSCLC.

[0327] 4. Results Evaluation

[0328] Efficacy indicators include: ORR, DCR, DoR, PFS and OS assessed by investigators.

[0329] Safety Assessment: Tumor assessments were performed using RECIST v1.1 criteria, and all subjects underwent baseline tumor imaging during the screening period. The safety of the study drug was evaluated through adverse event records (including serious adverse events), laboratory tests, vital signs and physical examinations, electrocardiograms, blood oxygen saturation, and echocardiography / multiple gated acquisition (MUGA).

[0330] Example 6. A randomized, controlled, open-label, multicenter phase III study of ADC-1 versus platinum-based chemotherapy in patients with advanced or metastatic non-small cell lung cancer with EGFR mutations who have failed EGFR tyrosine kinase inhibitor (TKI) therapy

[0331] 1. Trial Drug

[0332] 1) ADC-1 prepared in Example 1.

[0333] 2) Pemetrexed disodium for injection, injection, specification: 0.5g.

[0334] 3) Carboplatin for injection, injection, specification is 0.1g.

[0335] 4) Cisplatin injection, injection, specifications are 6ml: 30mg.

[0336] 2. Inclusion criteria

[0337] (1) Age range: 18-75 years old (inclusive), gender is not limited.

[0338] (2) Subjects with locally advanced or metastatic non-squamous non-small cell lung cancer confirmed by histology or cytology.

[0339] Definition of locally advanced or metastatic disease: According to the 9th edition TNM staging criteria of the International Association for the Study of Lung Cancer (IASLC), the stage is stage IIIB-IV and is no longer suitable for radical surgery or radical chemoradiotherapy.

[0340] (3) Histological or blood specimens confirm the presence of EGFR exon 19 deletion or exon 21 (L858R) substitution mutation, and there are no other known driver gene mutations that are approved for targeted drug treatment (such as ALK fusion, ROS1 fusion, BRAF V600 mutation, etc.).

[0341] (4) For locally advanced or metastatic NSCLC, patients must have received EGFR TKI treatment. Subjects with T790M mutation must have received third-generation EGFR TKI treatment and have experienced radiographic disease progression during or after treatment.

[0342] - Subjects who experience tumor recurrence or metastasis during adjuvant EGFR TKI treatment or within 6 months of discontinuation of treatment are eligible for enrollment;

[0343] - Patients who have previously received neoadjuvant / adjuvant chemotherapy or radical chemoradiotherapy for non-metastatic tumors and have experienced tumor recurrence or metastasis at least 6 months after completing these treatments and who have also received EGFR TKI treatment and have experienced radiographic disease progression during or after treatment are eligible for enrollment;

[0344] -For locally advanced or metastatic NSCLC, combined anti-vascular therapy or targeted therapy (such as EGFR / c-MET bispecific antibodies, excluding antibody-drug conjugates) during EGFR TKI treatment is allowed. Other systemic anti-tumor treatments other than the above are not allowed.

[0345] (5) At least one measurable lesion as defined by RECIST v1.1 criteria.

[0346] (6) ECOG score of 0 or 1.

[0347] (7) Expected survival period ≥12 weeks.

[0348] 3. Dosage regimen

[0349] Experimental group: ADC-1: intravenous drip administration, 8.0 mg / kg. The total amount of ADC-1 administered was calculated based on the subject's body weight before each administration.

[0350] Control group: All subjects received platinum-based doublet chemotherapy every 3 weeks, with each cycle consisting of 21 days. All drugs were administered on the first day of each cycle. The order of administration was: pemetrexed → carboplatin / cisplatin.

[0351] (a) Pemetrexed: intravenous infusion, 500 mg / m 2 ;

[0352] (b) Cisplatin: intravenous drip, 75 mg / m 2 ;

[0353] Body surface area calculation formula: Body surface area (m 2 ) = 0.0061 × height (cm) + 0.0128 × weight (kg) - 0.1529;

[0354] (c) Carboplatin: intravenous infusion, AUC 5 mg / mL / min (Calvert formula);

[0355] Carboplatin dose (mg) = (target AUC) × [creatinine clearance (mL / min) + 25]. Creatinine clearance was calculated using the Cockcroft-Gault formula.

[0356] 4. Effectiveness and Safety Evaluation

[0357] The primary evaluation indicator was PFS assessed by BICR, and the secondary evaluation indicators included OS, PFS assessed by the investigator, ORR (CR+PR), DoR, and DCR (CR+PR+SD) assessed by the investigator and BICR.

[0358] The safety of the subjects was continuously assessed throughout the study, including the incidence and severity of adverse events (AEs), serious adverse events (SAEs) (assessed according to NCI-CTCAE V5.0 criteria), changes in vital signs, abnormal laboratory test indicators, and the incidence of dose suspension, dose reduction, and dose termination due to study drug-related toxicity during the trial.

Claims

1. Use of an anti-HER3 antibody-drug conjugate in the preparation of a drug for treating EGFR-mutated tumors, wherein: The anti-HER3 antibody drug conjugate has a structure as shown in the following formula: Wherein: n is 1 to 8, Pc is an anti-HER3 antibody; The EGFR mutated tumor is preferably EGFR mutated non-small cell lung cancer.

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

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 metastasis, bone metastasis and / or liver metastasis.

5. The use according to any one of claims 1 to 4, wherein 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, the VH comprises an amino acid sequence as shown in SEQ ID NO: 7 or having at least 80%, 90% identity thereto, and the VL comprises an amino acid sequence as shown in SEQ ID NO: 8 or having at least 80%, 90% identity thereto; Preferably, the anti-HER3 antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises an amino acid sequence as shown in SEQ ID NO: 9 or having at least 80%, 90% identity thereto, and the light chain comprises an amino acid sequence as shown in SEQ ID NO: 10 or having at least 80%, 90% identity thereto.

6. The use according to any one of claims 1 to 5, wherein: The dosage of the anti-HER3 antibody drug conjugate is about 0.1 mg / kg to about 20 mg / kg; preferably 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, about 8.0 mg / kg, about 8.5 mg / kg, about 9.0 mg / kg, about 10.5 mg / kg, about 12 mg / kg, or about 13.5 mg / kg; and / or, The anti-HER3 antibody drug conjugate is administered 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 12 weeks; preferably, about once every three weeks.

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

8. Any of the following uses (1) to (5): (1) Use of an anti-HER3 antibody-drug conjugate combined with a tyrosine kinase inhibitor in the preparation of a drug for treating tumors; (2) Use of a combination of an anti-HER3 antibody drug conjugate and a tyrosine kinase inhibitor in the preparation of a drug for treating tumors; (3) Use of the pharmaceutical composition in the preparation of a drug for treating tumors; wherein: The pharmaceutical composition comprises an anti-HER3 antibody-drug conjugate; and a tyrosine kinase inhibitor; (4) an anti-HER3 antibody-drug conjugate for use in treating a subject with a tumor, wherein the subject is also administered a tyrosine kinase inhibitor; (5) A tyrosine kinase inhibitor for treating a subject with a tumor, wherein the subject is also administered an anti-HER3 antibody drug conjugate; Wherein, the anti-HER3 antibody drug conjugate has a structure as shown in the following formula: Wherein: n is 1 to 8, 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), the VH comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, respectively, and the VL comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6, respectively; more preferably, the VH comprises an amino acid sequence as shown in SEQ ID NO: 7 or having at least 80%, 90% identity thereto, and the VL comprises an amino acid sequence as shown in SEQ ID NO: 8 or having at least 80%, 90% identity thereto; More preferably, the anti-HER3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 9 or having at least 80%, 90% identity thereto, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 10 or having at least 80%, 90% identity thereto.

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

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

11. The use according to any one of claims 8 to 10, wherein: The dosage of the anti-HER3 antibody drug conjugate is about 0.1 mg / kg to about 20 mg / kg; preferably 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, about 8.0 mg / kg, about 8.5 mg / kg, about 9.0 mg / kg, about 10.5 mg / kg, about 12 mg / kg, or about 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 12 weeks; preferably once every three weeks; and / or, The dosage 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, 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; The administration frequency 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 anti-HER3 antibody drug conjugate has a structure as shown in the following formula: in: n is 1 to 8, 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), the VH comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 1, SEQ ID NO: 2 and SEQ ID NO: 3, and the VL comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; more preferably, the VH comprises an amino acid sequence as shown in SEQ ID NO: 7 or having at least 80%, 90% identity thereto, and the VL comprises an amino acid sequence as shown in SEQ ID NO: 8 or having at least 80%, 90% identity thereto; More preferably, the anti-HER3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 9 or having at least 80%, 90% identity thereto, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 10 or having at least 80%, 90% identity thereto.

13. A method for treating a tumor, comprising administering to a subject in need thereof: (1) an anti-HER3 antibody-drug conjugate; or, (2) an anti-HER3 antibody-drug conjugate and a tyrosine kinase inhibitor; The anti-HER3 antibody drug conjugate has a structure as shown in the following formula: in: n is 1 to 8, Pc is an anti-HER3 antibody; The anti-HER3 antibody drug conjugate is administered at a dosage of about 0.1 mg / kg to about 20 mg / kg; Preferably, the dosage 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, about 8.0 mg / kg, about 8.5 mg / kg, about 9.0 mg / kg, about 10.5 mg / kg, about 12 mg / kg, or about 13.5 mg / kg; and / or, the administration frequency of the anti-HER3 antibody drug conjugate is once a week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 10 weeks, or once every 12 weeks; preferably once every 3 weeks; Preferably, the tyrosine kinase inhibitor is administered at a dosage of about 1 mg to about 1000 mg, preferably about 10 mg to about 1000 mg, about 10 mg to about 800 mg, 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 tyrosine kinase inhibitor is administered once a day, twice a day, three times a day, once every 2 days, once every 3 days, once every 4 days, once every 5 days or once a week, preferably once a day; Preferably, the tyrosine kinase inhibitor is ametinib.

14. The method according to claim 13, wherein: 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, and the VL comprises LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 4, SEQ ID NO: 5 and SEQ ID NO: 6; more preferably, the VH comprises an amino acid sequence as shown in SEQ ID NO: 7 or having at least 80%, 90% identity thereto, and the VL comprises an amino acid sequence as shown in SEQ ID NO: 8 or having at least 80%, 90% identity thereto; More preferably, the anti-HER3 antibody comprises a heavy chain and a light chain, the heavy chain comprising an amino acid sequence as shown in SEQ ID NO: 9 or having at least 80%, 90% identity thereto, and the light chain comprising an amino acid sequence as shown in SEQ ID NO: 10 or having at least 80%, 90% identity thereto.

15. The method according to claim 13 or 14, wherein: 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 to be treated with a tyrosine kinase inhibitor (TKI); preferably, it is an EGFR mutated non-small cell lung cancer that has failed to be treated with a tyrosine kinase inhibitor (TKI); The EGFR mutated tumor is a locally advanced or metastatic tumor with EGFR mutation, preferably a locally advanced or metastatic non-small cell lung cancer with EGFR mutation; or, The EGFR mutated tumor is a locally advanced or metastatic tumor with EGFR mutation that has failed TKI treatment, preferably a locally advanced or metastatic non-small cell lung cancer with EGFR mutation that has failed TKI treatment.

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

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