Use of Anti-her2 antibody-drug conjugate or combination-therapy drug thereof for treating non-small cell lung cancer

Abstract

The present invention belongs to the field of biopharmaceuticals and relates to use of an anti-HER2 antibody-drug conjugate or a combination of the anti-HER2 antibody-drug conjugate and a PD-1 / PD-L1 inhibitor for treating non-small cell lung cancer, or a method for treating non-small cell lung cancer in a subject. The administration of the anti-HER2 antibody-drug conjugate or the combination of the anti-HER2 antibody-drug conjugate and the PD-1 / PD-L1 inhibitor to the subject can produce clinical benefits for the subject with non-small cell lung cancer and have good safety.

Description

Use of anti-HER2 antibody-drug conjugates or their combination with other drugs in the treatment of non-small cell lung cancer Technical Field

[0001] This disclosure pertains to the field of biomedicine and specifically relates to the use of anti-HER2 antibody-drug conjugates for the treatment of non-small cell lung cancer, as well as the use of anti-HER2 antibody-drug conjugates in combination with PD-1 / PD-L1 inhibitors for the treatment of non-small cell lung cancer. Background Technology

[0002] Human epidermal growth factor receptor 2 (HER2) belongs to the human epidermal growth factor receptor family, which includes EGFR (ErbB-1), HER2 / c-neu (ErbB-2), HER3 (ErbB-3), and HER4 (ErbB-4). These receptors are all located on the cell surface and have similar structures. HER2 is a widely expressed receptor protein; abnormal gene amplification leads to protein overexpression, which in turn causes abnormal activation of signaling pathways, a major pathway promoting solid tumor growth. HER2 can form homodimers and readily form heterodimers with other HER family receptors, leading to phosphorylation of receptor tyrosine residues and initiation of multiple signaling pathways, including MPK, PI3K, JAK, STAT3, and PKC, thereby causing cell proliferation and tumorigenesis.

[0003] Anti-HER2 targeted therapy is an important approach to treating non-small cell lung cancer. Therefore, there is an urgent need to explore HER2-targeting drugs to meet the huge clinical demand for non-small cell lung cancer treatment. Summary of the Invention

[0004] Methods and uses

[0005] This disclosure provides a method for treating a subject with non-small cell lung cancer, comprising administering the disclosed anti-HER2 antibody-drug conjugate to the subject. This disclosure also provides a method for first-line treatment of a subject with non-small cell lung cancer, comprising administering the disclosed anti-HER2 antibody-drug conjugate to the subject. This disclosure further provides a method for second-line or later-line treatment of a subject with non-small cell lung cancer, comprising administering the disclosed anti-HER2 antibody-drug conjugate to the subject. In some embodiments, the method involves administering the anti-HER2 antibody-drug conjugate at a therapeutically effective amount.

[0006] This disclosure provides a method for treating a subject with non-small cell lung cancer, comprising administering the drug combination of this disclosure to the subject. This disclosure also provides a method for first-line treatment of a subject with non-small cell lung cancer, comprising administering the drug combination of this disclosure to the subject. This disclosure further provides a method for second-line or later-line treatment of a subject with non-small cell lung cancer, comprising administering the drug combination of this disclosure to the subject. In some embodiments, the drug combination is administered at a therapeutically effective amount. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate and a PD-1 / PD-L1 inhibitor (e.g., an anti-PD-L1 antibody or its antigen-binding fragment).

[0007] This disclosure provides a method for treating a subject with non-small cell lung cancer (NSCLC), comprising administering to the subject an anti-HER2 antibody-drug conjugate and a PD-1 / PD-L1 inhibitor of the present disclosure. This disclosure also provides a method for first-line treatment of a subject with NSCLC, comprising administering to the subject an anti-HER2 antibody-drug conjugate and a PD-1 / PD-L1 inhibitor of the present disclosure. This disclosure also provides a method for second-line or later-line treatment of a subject with NSCLC, comprising administering to the subject an anti-HER2 antibody-drug conjugate and a PD-1 / PD-L1 inhibitor of the present disclosure. In some embodiments, the anti-HER2 antibody-drug conjugate is administered in a therapeutically effective amount. In some embodiments, the PD-1 / PD-L1 inhibitor is administered in a therapeutically effective amount. In some embodiments, the PD-1 / PD-L1 inhibitor is an anti-PD-L1 antibody or an antigen-binding fragment thereof, or an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0008] This disclosure provides a method for treating a subject with non-small cell lung cancer, comprising administering to the subject the disclosed anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or an antigen-binding fragment thereof. This disclosure also provides a method for first-line treatment of a subject with non-small cell lung cancer, comprising administering to the subject the disclosed anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or an antigen-binding fragment thereof. This disclosure further provides a method for second-line or later-line treatment of a subject with non-small cell lung cancer, comprising administering to the subject the disclosed anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-HER2 antibody-drug conjugate is administered in a therapeutically effective amount. In some embodiments, the anti-PD-L1 antibody or an antigen-binding fragment thereof is administered in a therapeutically effective amount.

[0009] This disclosure provides a method for treating a subject with non-small cell lung cancer, comprising administering to the subject the disclosed anti-HER2 antibody-drug conjugate and an anti-PD-1 antibody or an antigen-binding fragment thereof. This disclosure also provides a method for first-line treatment of a subject with non-small cell lung cancer, comprising administering to the subject the disclosed anti-HER2 antibody-drug conjugate and an anti-PD-1 antibody or an antigen-binding fragment thereof. This disclosure also provides a method for second-line or later-line treatment of a subject with non-small cell lung cancer, comprising administering to the subject the disclosed anti-HER2 antibody-drug conjugate and an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the method administers the anti-HER2 antibody-drug conjugate in a therapeutically effective amount. In some embodiments, the method administers the anti-PD-1 antibody or an antigen-binding fragment thereof in a therapeutically effective amount.

[0010] This disclosure also provides the use of the antiHER2 antibody-drug conjugate of this disclosure in the preparation of a medicament for treating non-small cell lung cancer in a subject. This disclosure also provides the use of the antiHER2 antibody-drug conjugate of this disclosure in the preparation of a medicament for first-line treatment of non-small cell lung cancer in a subject. This disclosure further provides the use of the antiHER2 antibody-drug conjugate of this disclosure in the preparation of a medicament for second-line or later-line treatment of non-small cell lung cancer in a subject. In some embodiments, in the use described above, the medicament comprises a therapeutically effective amount of the antiHER2 antibody-drug conjugate.

[0011] This disclosure also provides the use of the pharmaceutical combinations of this disclosure in the preparation of a medicament for treating a subject with non-small cell lung cancer. This disclosure also provides the use of the pharmaceutical combinations of this disclosure in the preparation of a medicament for first-line treatment of a subject with non-small cell lung cancer. This disclosure also provides the use of the pharmaceutical combinations of this disclosure in the preparation of a medicament for second-line or later-line treatment of a subject with non-small cell lung cancer. In some embodiments, in the use of this medicament, the medicament comprises a therapeutically effective amount of the pharmaceutical combination.

[0012] This disclosure also provides the use of the antiHER2 antibody-drug conjugate and PD-1 / PD-L1 inhibitor of this disclosure in the preparation of a medicament for treating non-small cell lung cancer in subjects. This disclosure also provides the use of the antiHER2 antibody-drug conjugate and PD-1 / PD-L1 inhibitor of this disclosure in the preparation of a medicament for first-line treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the antiHER2 antibody-drug conjugate and PD-1 / PD-L1 inhibitor of this disclosure in the preparation of a medicament for second-line or later-line treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the antiHER2 antibody-drug conjugate of this disclosure in the preparation of a medicament in combination with a PD-1 / PD-L1 inhibitor for the treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the antiHER2 antibody-drug conjugate of this disclosure in the preparation of a medicament in combination with a PD-1 / PD-L1 inhibitor for first-line treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the anti-HER2 antibody-drug conjugate of this disclosure in the preparation of a medicament for use in combination with a PD-1 / PD-L1 inhibitor for second-line or later-line treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the PD-1 / PD-L1 inhibitor of this disclosure in the preparation of a medicament for use in combination with an anti-HER2 antibody-drug conjugate for the treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the PD-1 / PD-L1 inhibitor of this disclosure in the preparation of a medicament for use in combination with an anti-HER2 antibody-drug conjugate for first-line treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the PD-1 / PD-L1 inhibitor of this disclosure in the preparation of a medicament for use in combination with an anti-HER2 antibody-drug conjugate for second-line or later-line treatment of non-small cell lung cancer in subjects. In some embodiments, in this use, the anti-HER2 antibody-drug conjugate is administered at a therapeutically effective amount. In some embodiments, in this use, the PD-1 / PD-L1 inhibitor is administered at a therapeutically effective amount. In some embodiments, the PD-1 / PD-L1 inhibitor is an anti-PD-L1 antibody or its antigen-binding fragment, or an anti-PD-1 antibody or its antigen-binding fragment.

[0013] This disclosure also provides the use of the antiHER2 antibody drug conjugate and antiPD-L1 antibody or antigen-binding fragment thereof in the preparation of a medicament for treating non-small cell lung cancer in a subject. This disclosure also provides the use of the antiHER2 antibody drug conjugate and antiPD-L1 antibody or antigen-binding fragment thereof in the preparation of a medicament for first-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the antiHER2 antibody drug conjugate and antiPD-L1 antibody or antigen-binding fragment thereof in the preparation of a medicament for second-line or later-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the antiHER2 antibody drug conjugate in the preparation of a medicament in combination with an antiPD-L1 antibody or antigen-binding fragment thereof for the treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the antiHER2 antibody drug conjugate in the preparation of a medicament in combination with an antiPD-L1 antibody or antigen-binding fragment thereof for first-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the anti-HER2 antibody drug conjugate of this disclosure in the preparation of a medicament for use in combination with an anti-PD-L1 antibody or its antigen-binding fragment for second-line or later-line treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the anti-PD-L1 antibody or its antigen-binding fragment of this disclosure in the preparation of a medicament for use in combination with an anti-HER2 antibody drug conjugate for the treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the anti-PD-L1 antibody or its antigen-binding fragment of this disclosure in the preparation of a medicament for use in combination with an anti-HER2 antibody drug conjugate for first-line treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the anti-PD-L1 antibody or its antigen-binding fragment of this disclosure in the preparation of a medicament for use in combination with an anti-HER2 antibody drug conjugate for second-line or later-line treatment of non-small cell lung cancer in subjects. In some embodiments, in this use, the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount. In some embodiments, in this use, the anti-PD-L1 antibody or its antigen-binding fragment is administered in a therapeutically effective amount.

[0014] This disclosure also provides the use of the antiHER2 antibody drug conjugate and antiPD-1 antibody or antigen-binding fragment thereof in the preparation of a medicament for treating non-small cell lung cancer in a subject. This disclosure also provides the use of the antiHER2 antibody drug conjugate and antiPD-1 antibody or antigen-binding fragment thereof in the preparation of a medicament for first-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the antiHER2 antibody drug conjugate and antiPD-1 antibody or antigen-binding fragment thereof in the preparation of a medicament for second-line or later-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the antiHER2 antibody drug conjugate in the preparation of a medicament in combination with an antiPD-1 antibody or antigen-binding fragment thereof for the treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the antiHER2 antibody drug conjugate in the preparation of a medicament in combination with an antiPD-1 antibody or antigen-binding fragment thereof for first-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the anti-HER2 antibody drug conjugate of this disclosure in the preparation of a medicament for use in combination with an anti-PD-1 antibody or an antigen-binding fragment thereof for second-line or later-line treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the anti-PD-1 antibody or an antigen-binding fragment thereof of this disclosure in the preparation of a medicament for use in combination with an anti-HER2 antibody drug conjugate for the treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the anti-PD-1 antibody or an antigen-binding fragment thereof of this disclosure in the preparation of a medicament for use in combination with an anti-HER2 antibody drug conjugate for first-line treatment of non-small cell lung cancer in subjects. This disclosure also provides the use of the anti-PD-1 antibody or an antigen-binding fragment thereof of this disclosure in the preparation of a medicament for use in combination with an anti-HER2 antibody drug conjugate for second-line or later-line treatment of non-small cell lung cancer in subjects. In some embodiments, in the use, the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount. In some embodiments, in the use, the anti-PD-1 antibody or an antigen-binding fragment thereof is administered in a therapeutically effective amount.

[0015] This disclosure also provides the disclosed anti-HER2 antibody drug conjugate and anti-PD-L1 antibody or antigen-binding fragment thereof for combination therapy of subjects with non-small cell lung cancer. This disclosure also provides the disclosed anti-HER2 antibody drug conjugate and anti-PD-L1 antibody or antigen-binding fragment thereof for combination therapy of subjects with non-small cell lung cancer as first-line treatment. This disclosure also provides the disclosed anti-HER2 antibody drug conjugate and anti-PD-L1 antibody or antigen-binding fragment thereof for combination therapy of subjects with non-small cell lung cancer as second-line or later-line treatment. This disclosure also provides an anti-HER2 antibody drug conjugate in combination with the disclosed anti-PD-L1 antibody or antigen-binding fragment thereof for the treatment of subjects with non-small cell lung cancer. This disclosure also provides an anti-PD-L1 antibody or antigen-binding fragment thereof in combination with the disclosed anti-HER2 antibody drug conjugate for the treatment of subjects with non-small cell lung cancer. This disclosure also provides an anti-HER2 antibody drug conjugate in combination with the disclosed anti-PD-L1 antibody or antigen-binding fragment thereof for the first-line treatment of subjects with non-small cell lung cancer. This disclosure also provides an anti-HER2 antibody-drug conjugate in combination with the anti-PD-L1 antibody or its antigen-binding fragment for use in subjects receiving second-line or later-line treatment of non-small cell lung cancer. This disclosure also provides an anti-PD-L1 antibody or its antigen-binding fragment in combination with the anti-HER2 antibody-drug conjugate for use in first-line treatment of non-small cell lung cancer. This disclosure also provides an anti-PD-L1 antibody or its antigen-binding fragment in combination with the anti-HER2 antibody-drug conjugate for use in second-line or later-line treatment of non-small cell lung cancer. This disclosure also provides the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment of this disclosure in a method of treating a subject with non-small cell lung cancer, wherein the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are administered separately to the subject. This disclosure also provides the anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or antigen-binding fragment thereof of this disclosure in a method for first-line treatment of non-small cell lung cancer in subjects, wherein the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered separately to the subjects. This disclosure also provides the anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or antigen-binding fragment thereof of this disclosure in a method for second-line or later-line treatment of non-small cell lung cancer in subjects, wherein the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or antigen-binding fragment thereof are administered separately to the subjects. In some embodiments, the anti-HER2 antibody-drug conjugate is administered in a therapeutically effective amount. In some embodiments, the anti-PD-L1 antibody or antigen-binding fragment thereof is administered in a therapeutically effective amount.

[0016] This disclosure also provides the use of the anti-HER2 antibody-drug conjugate of this disclosure for treating non-small cell lung cancer in a subject. This disclosure also provides the use of the drug combination of this disclosure for treating non-small cell lung cancer in a subject. This disclosure also provides the use of the anti-HER2 antibody-drug conjugate of this disclosure and a PD-1 / PD-L1 inhibitor for treating non-small cell lung cancer in a subject. This disclosure also provides the use of the anti-HER2 antibody-drug conjugate of this disclosure and an anti-PD-L1 antibody or an antigen-binding fragment thereof for treating non-small cell lung cancer in a subject. This disclosure also provides the use of the anti-HER2 antibody-drug conjugate of this disclosure and an anti-PD-1 antibody or an antigen-binding fragment thereof for treating non-small cell lung cancer in a subject.

[0017] This disclosure also provides the use of the anti-HER2 antibody-drug conjugate of this disclosure for first-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the drug combination of this disclosure for first-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the anti-HER2 antibody-drug conjugate and PD-1 / PD-L1 inhibitor of this disclosure for first-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or antigen-binding fragment thereof of this disclosure for first-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the anti-HER2 antibody-drug conjugate and anti-PD-1 antibody or antigen-binding fragment thereof of this disclosure for first-line treatment of non-small cell lung cancer in a subject.

[0018] This disclosure also provides the use of the anti-HER2 antibody-drug conjugate of this disclosure for second-line or later-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the drug combination of this disclosure for second-line or later-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the anti-HER2 antibody-drug conjugate and PD-1 / PD-L1 inhibitor of this disclosure for second-line or later-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or antigen-binding fragment thereof of this disclosure for second-line or later-line treatment of non-small cell lung cancer in a subject. This disclosure also provides the use of the anti-HER2 antibody-drug conjugate and anti-PD-1 antibody or antigen-binding fragment thereof of this disclosure for second-line or later-line treatment of non-small cell lung cancer in a subject.

[0019] In some embodiments, in the method or use, the pharmaceutical combination comprises the anti-HER2 antibody-drug conjugate of this disclosure and an anti-PD-L1 antibody or an antigen-binding fragment thereof. In some embodiments, in the method or use, the pharmaceutical combination comprises the anti-HER2 antibody-drug conjugate of this disclosure and an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0020] In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment may be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are administered sequentially. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are administered on the same day. In some embodiments, in the method or use, the anti-PD-L1 antibody or its antigen-binding fragment is administered first on the same day, followed by the anti-HER2 antibody drug conjugate. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are each in the form of a pharmaceutical composition and may be administered simultaneously, sequentially, and / or alternately. In some embodiments, in the method or use, the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are each in the form of a pharmaceutical composition and are administered sequentially. In some embodiments, in the method or use, the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are each in the form of a pharmaceutical composition and are administered on the same day. In some embodiments, in the method or use, the anti-PD-L1 antibody or its antigen-binding fragment is administered first, followed by the anti-HER2 antibody-drug conjugate. In some embodiments, in the method or use, the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are each in the form of a pharmaceutical composition, and the anti-PD-L1 antibody or its antigen-binding fragment is administered first, followed by the anti-HER2 antibody-drug conjugate. In some embodiments, in the method or use, the anti-HER2 antibody-drug conjugate is administered first, followed by the anti-PD-L1 antibody or its antigen-binding fragment. In some embodiments, in the method or use, the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are each in the form of a pharmaceutical composition, and the anti-HER2 antibody-drug conjugate is administered first, followed by the anti-PD-L1 antibody or its antigen-binding fragment. In some embodiments, in the stated use, the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are packaged separately. In some embodiments, in the stated use, the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are each in the form of a pharmaceutical composition and packaged separately.

[0021] In some embodiments, during the method or use, the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are administered using the same or different dosing regimens. In some embodiments, during the method or use, the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are administered using different dosing regimens.

[0022] In some embodiments, the antiHER2 antibody-drug conjugate is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w) in the method or use. In one specific embodiment, the antiHER2 antibody-drug conjugate is administered once every 3 weeks in the method or use. In some embodiments, the antiHER2 antibody-drug conjugate is administered each time at a dose of 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg. In some embodiments, the antiHER2 antibody-drug conjugate is administered each time at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, 9 mg / kg, or a range of any two of the above values. In some embodiments, in the method or use, the anti-HER2 antibody-drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg each time. In some embodiments, in the method or use, the anti-HER2 antibody-drug conjugate is administered at a dose of 6 mg / kg each time. In some embodiments, in the method or use, the anti-HER2 antibody-drug conjugate is administered at a dose of 7.5 mg / kg each time. In some embodiments, in the method or use, the anti-HER2 antibody-drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, at a dose of 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg of the anti-HER2 antibody-drug conjugate each time. In some embodiments, in the method or use, the anti-HER2 antibody-drug conjugate is administered every 3 weeks at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg. In some embodiments, in the method or use, the anti-HER2 antibody-drug conjugate is administered every 3 weeks at a dose of 6 mg / kg or 7.5 mg / kg. In some embodiments, in the method or use, the anti-HER2 antibody-drug conjugate is administered every 3 weeks at a dose of 6 mg / kg. In some embodiments, in the method or use, the anti-HER2 antibody-drug conjugate is administered every 3 weeks at a dose of 7.5 mg / kg.

[0023] In some embodiments, in the method or use, the anti-PD-L1 antibody or its antigen-binding fragment is administered once every 1 week (q1w), every 2 weeks (q2w), every 3 weeks (q3w), or every 4 weeks (q4w). In one specific embodiment, in the method or use, the anti-PD-L1 antibody or its antigen-binding fragment is administered once every 3 weeks. In some embodiments, in the method or use, the anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 600-2400 mg, 600-1800 mg, or 1200-1500 mg each time. In some embodiments, in the method or use, the anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 600 mg, 800 mg, 1000 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg, or any two of the above values. In some embodiments, in the method or use, the anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 1200 mg. In some embodiments, in the method or use, the anti-PD-L1 antibody or its antigen-binding fragment is administered every 3 weeks at a dose of 600-2400 mg, 600-1800 mg, or 1200-1500 mg. In some embodiments, in the method or use, the anti-PD-L1 antibody or its antigen-binding fragment is administered every 3 weeks at a dose of 600 mg, 800 mg, 1000 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg, or any two of the above values. In some embodiments, in the method or use, the anti-PD-L1 antibody or its antigen-binding fragment is administered every 3 weeks at a dose of 1200 mg.

[0024] In some embodiments, the method or use comprises a treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. In some embodiments, the method or use comprises a treatment cycle every 3 weeks. In some embodiments, the method or use comprises a treatment cycle every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks, with the anti-HER2 antibody-drug conjugate administered once per treatment cycle. In some embodiments, the method or use comprises a treatment cycle every 3 weeks, with the anti-HER2 antibody-drug conjugate administered once per treatment cycle. In some embodiments, the method or use comprises a treatment cycle every 3 weeks, with 6 mg / kg or 7.5 mg / kg of the anti-HER2 antibody-drug conjugate administered per treatment cycle. In some embodiments, the method or use comprises a treatment cycle every 3 weeks, with 6 mg / kg or 7.5 mg / kg of the anti-HER2 antibody-drug conjugate administered on day 1 of each treatment cycle. In some embodiments, the method or use comprises a treatment cycle of 3 weeks, with 6 mg / kg of the anti-HER2 antibody-drug conjugate administered in each treatment cycle. In some embodiments, the method or use comprises a treatment cycle of 3 weeks, with 6 mg / kg of the anti-HER2 antibody-drug conjugate administered on day 1 of each treatment cycle. In some embodiments, the method or use comprises a treatment cycle of 3 weeks, with 7.5 mg / kg of the anti-HER2 antibody-drug conjugate administered in each treatment cycle. In some embodiments, the method or use comprises a treatment cycle of 3 weeks, with 7.5 mg / kg of the anti-HER2 antibody-drug conjugate administered on day 1 of each treatment cycle.

[0025] In some embodiments, the method or use comprises a treatment cycle of 1 week, 2 weeks, 3 weeks, or 4 weeks, with an anti-PD-L1 antibody or its antigen-binding fragment administered once during each treatment cycle. In some embodiments, the method or use comprises a treatment cycle of 3 weeks, with 1200 mg of the anti-PD-L1 antibody or its antigen-binding fragment administered during each treatment cycle. In some embodiments, the method or use comprises a treatment cycle of 3 weeks, with 1200 mg of the anti-PD-L1 antibody or its antigen-binding fragment administered on day 1 of each treatment cycle.

[0026] In some embodiments, the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment have the same or different treatment cycles in the method or use. In some specific embodiments, the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment have the same treatment cycle, for example, every 3 weeks as one treatment cycle.

[0027] In some embodiments, in the method or use, a treatment cycle is defined as every 3 weeks, with the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment administered in each treatment cycle. In some embodiments, in the method or use, a treatment cycle is defined as every 3 weeks, with the anti-HER2 antibody-drug conjugate administered once in each treatment cycle, and the anti-PD-L1 antibody or its antigen-binding fragment administered once in each treatment cycle. In some embodiments, in the method or use, a treatment cycle is defined as every 3 weeks, with the anti-HER2 antibody-drug conjugate administered once on day 1 of each treatment cycle, and the anti-PD-L1 antibody or its antigen-binding fragment administered once on day 1 of each treatment cycle.

[0028] In some specific embodiments, in the method or use, a treatment cycle is performed every 3 weeks, with 6 mg / kg or 7.5 mg / kg of the anti-HER2 antibody-drug conjugate administered in each treatment cycle, and 1200 mg of the anti-PD-L1 antibody or its antigen-binding fragment administered in each treatment cycle. In some specific embodiments, in the method or use, a treatment cycle is performed every 3 weeks, with 6 mg / kg of the anti-HER2 antibody-drug conjugate administered in each treatment cycle, and 1200 mg of the anti-PD-L1 antibody or its antigen-binding fragment administered in each treatment cycle. In some specific embodiments, in the method or use, a treatment cycle is performed every 3 weeks, with 7.5 mg / kg of the anti-HER2 antibody-drug conjugate administered in each treatment cycle, and 1200 mg of the anti-PD-L1 antibody or its antigen-binding fragment administered in each treatment cycle. In some specific embodiments, in the method or use, a treatment cycle is defined as 3 weeks, with 6 mg / kg or 7.5 mg / kg of the anti-HER2 antibody-drug conjugate administered on day 1 of each treatment cycle, and 1200 mg of the anti-PD-L1 antibody or its antigen-binding fragment administered on day 1 of each treatment cycle. In some specific embodiments, in the method or use, a treatment cycle is defined as 3 weeks, with 6 mg / kg of the anti-HER2 antibody-drug conjugate administered on day 1 of each treatment cycle, and 1200 mg of the anti-PD-L1 antibody or its antigen-binding fragment administered on day 1 of each treatment cycle. In some specific embodiments, in the method or use, a treatment cycle is defined as 3 weeks, with 7.5 mg / kg of the anti-HER2 antibody-drug conjugate administered on day 1 of each treatment cycle, and 1200 mg of the anti-PD-L1 antibody or its antigen-binding fragment administered on day 1 of each treatment cycle.

[0029] In some embodiments, the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are administered in multiple doses or a single dose during each treatment cycle. In some embodiments, both the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are administered in multiple doses during each treatment cycle.

[0030] Anti-HER2 antibody-drug conjugates can be formulated with one or more pharmaceutically acceptable excipients to form suitable pharmaceutical compositions (or formulations). The pharmaceutical composition can be any suitable dosage form. In some embodiments, the anti-HER2 antibody-drug conjugate is formulated for parenteral administration. In some specific embodiments, the anti-HER2 antibody-drug conjugate is formulated for intravenous administration. In some specific embodiments, the anti-HER2 antibody-drug conjugate can be formulated as an injection. In some specific embodiments, the anti-HER2 antibody-drug conjugate is formulated for intravenous injection or infusion. In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment is formulated for parenteral administration. In some specific embodiments, the anti-PD-L1 antibody or its antigen-binding fragment is formulated for intravenous administration. In some specific embodiments, the anti-PD-L1 antibody or its antigen-binding fragment can be formulated as an injection. In some specific embodiments, the anti-PD-L1 antibody or its antigen-binding fragment is formulated for intravenous injection or infusion.

[0031] In some embodiments, in the method or use, the administration of the anti-HER2 antibody drug conjugate is performed by intravenous injection or intravenous infusion (also known as "intravenous drip"). In some embodiments, in the method or use, the administration of the anti-PD-L1 antibody or its antigen-binding fragment is performed by intravenous injection or intravenous infusion (also known as "intravenous drip").

[0032] In some embodiments, the non-small cell lung cancer is unresectable, refractory, locally advanced, advanced, recurrent, and / or metastatic non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is unresectable. In some embodiments, the non-small cell lung cancer is refractory. In some embodiments, the non-small cell lung cancer is locally advanced. In some embodiments, the non-small cell lung cancer is stage IIIB or IIIC. In some embodiments, the non-small cell lung cancer is advanced. In some embodiments, the non-small cell lung cancer is recurrent and / or metastatic. In some embodiments, the non-small cell lung cancer is stage IV.

[0033] In some embodiments, the non-small cell lung cancer is non-small cell lung cancer with abnormalities in the HER2 gene or other HER family genes (such as the EGFR gene).

[0034] In some embodiments, the non-small cell lung cancer (NSCLC) is NSCLC with HER2 gene abnormalities. In some embodiments, the NSCLC is NSCLC with HER2 overexpression. In some embodiments, the NSCLC is NSCLC with HER2 amplification. In some embodiments, the NSCLC is NSCLC with HER2 mutation. In some embodiments, the NSCLC is NSCLC with HER2 overexpression, HER2 amplification, and / or HER2 mutation. In some embodiments, the NSCLC is NSCLC with HER2 overexpression, HER2 amplification, or HER2 mutation. In some embodiments, the NSCLC is NSCLC with HER2 overexpression or HER2 amplification, but not HER2 mutation. In some embodiments, the NSCLC is NSCLC with HER2 overexpression, but not HER2 mutation. In some embodiments, the NSCLC is NSCLC with HER2 overexpression, but not HER2 mutation. In some embodiments, HER2 overexpression is determined by immunohistochemistry (IHC) to be IHC 3+ or IHC 2+. In some embodiments, the HER2-overexpressing non-small cell lung cancer is non-small cell lung cancer that is determined to be IHC 3+ by HER2 detection via IHC. In some embodiments, the HER2-overexpressing non-small cell lung cancer is non-small cell lung cancer that is determined to be IHC 2+ by HER2 detection via IHC.In some embodiments, the HER2 mutation is selected from at least one of the following groups: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777in sL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S779insG、S779_P780 insVGS, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V30 8M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661 V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, G776C, G776L, S779P, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007*, S1151L, and HER2 exon 20 insertion mutations. In some embodiments, the HER2 mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310Y, and S310F. In some embodiments, the HER2 mutation is a HER2 exon 20 insertion mutation.In some embodiments, the HER2 mutation is selected from at least one of the following groups: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, G776delinsLC, G776delinsAVGC, G776delinsVV, G776_V777insL, G776_V777insVC, G776_V777insVGC, V777_G778insCG, V777_G778insG, G778_S779insG, and S779_P780insVGS. In some embodiments, the HER2 mutation is selected from at least one of the following groups: Y772_A775dup, G778_P780dup, and G776delinsVC. In some embodiments, the HER2 mutation is a single base pair substitution mutation. In some embodiments, the HER2 mutation is at least one selected from the group consisting of: L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R. Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, G776C, G776L, S779P, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L. In some embodiments, the HER2 mutation is selected from at least one of the following groups: L755S, V777L, V659E, G660D, S310Y, and S310F. In some embodiments, the HER2 mutation is S310Y.

[0035] In some embodiments, the non-small cell lung cancer is EGFR-mutated non-small cell lung cancer. In some embodiments, the EGFR mutation is an EGFR exon 19 deletion mutation. In some embodiments, the EGFR mutation is an EGFR exon 21 L858R mutation. In some embodiments, the EGFR mutation is an EGFR exon 20 insertion mutation.

[0036] In some embodiments, the non-small cell lung cancer is non-small cell lung cancer having at least one of the following: HER2 exon 20 insertion mutation, HER2 overexpression (IHC 3+ or IHC 2+), EGFR exon 21L858R mutation, HER2 exon 8S310Y mutation, and HER2 amplification. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer having at least one of the following: HER2 exon 20 insertion mutation, HER2 overexpression (IHC 3+ or IHC 2+), and HER2 amplification.

[0037] In some embodiments, the non-small cell lung cancer (NSCLC) is unresectable NSCLC with HER2 overexpression, HER2 amplification, and / or HER2 mutation. In some embodiments, the NSCLC is locally advanced NSCLC with HER2 overexpression, HER2 amplification, and / or HER2 mutation. In some embodiments, the NSCLC is advanced NSCLC with HER2 overexpression, HER2 amplification, and / or HER2 mutation. In some embodiments, the NSCLC is recurrent and / or metastatic NSCLC with HER2 overexpression, HER2 amplification, and / or HER2 mutation. In some embodiments, the NSCLC is unresectable NSCLC with HER2 overexpression, HER2 amplification, or HER2 mutation. In some embodiments, the NSCLC is locally advanced NSCLC with HER2 overexpression, HER2 amplification, or HER2 mutation. In some embodiments, the NSCLC is advanced NSCLC with HER2 overexpression, HER2 amplification, or HER2 mutation. In some embodiments, the non-small cell lung cancer is recurrent and / or metastatic non-small cell lung cancer with HER2 overexpression, HER2 amplification, or HER2 mutation. In some embodiments, the non-small cell lung cancer is unresectable non-small cell lung cancer with HER2 overexpression. In some embodiments, the non-small cell lung cancer is locally advanced non-small cell lung cancer with HER2 overexpression. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer with HER2 overexpression. In some embodiments, the non-small cell lung cancer is recurrent and / or metastatic non-small cell lung cancer with HER2 overexpression.

[0038] In some embodiments, the non-small cell lung cancer is unresectable non-small cell lung cancer with an EGFR mutation. In some embodiments, the non-small cell lung cancer is locally advanced non-small cell lung cancer with an EGFR mutation. In some embodiments, the non-small cell lung cancer is advanced non-small cell lung cancer with an EGFR mutation. In some embodiments, the non-small cell lung cancer is recurrent and / or metastatic non-small cell lung cancer with an EGFR mutation.

[0039] In some embodiments, the subject with non-small cell lung cancer is not suitable for surgery and / or radical concurrent chemoradiotherapy to treat non-small cell lung cancer. In some embodiments, the subject with locally advanced non-small cell lung cancer is not suitable for surgery and / or radical concurrent chemoradiotherapy to treat non-small cell lung cancer. In some embodiments, the subject with recurrent and / or metastatic non-small cell lung cancer is not suitable for surgery and / or radical concurrent chemoradiotherapy to treat non-small cell lung cancer.

[0040] In some embodiments, the non-small cell lung cancer (NSCLC) is locally advanced NSCLC that is unsuitable for surgery and radical concurrent chemoradiotherapy. In some embodiments, the NSCLC is advanced NSCLC that is unsuitable for surgery and radical concurrent chemoradiotherapy. In some embodiments, the NSCLC is recurrent and / or metastatic NSCLC that is unsuitable for surgery and radical concurrent chemoradiotherapy. In some embodiments, the subject of the NSCLC is a subject with locally advanced, recurrent, or metastatic NSCLC who is unsuitable for surgery and radical concurrent chemoradiotherapy.

[0041] In some embodiments, the subject with non-small cell lung cancer (NSCLC) has previously been treated for NSCLC (e.g., treatment failure or intolerance). In some embodiments, the subject with NSCLC has previously received at least one first-line treatment for NSCLC (e.g., treatment failure or intolerance). In some embodiments, the subject with NSCLC has previously received standard treatment for NSCLC (e.g., treatment failure or intolerance). In some embodiments, the subject with NSCLC is a subject with locally advanced, recurrent, or metastatic NSCLC who has previously received standard treatment but failed and is unsuitable for surgery and radical concurrent chemoradiotherapy.

[0042] In some implementations, the non-small cell lung cancer subjects are non-small cell lung cancer subjects who have previously received first-line treatment with the following: anti-PD-1 antibody, anti-PD-L1 antibody, anti-VEGF antibody, platinum-based drugs, antimetabolite chemotherapy drugs, EGFR-TKI inhibitors, EGFR inhibitors, BTK inhibitors, or any combination thereof. In some implementations, the non-small cell lung cancer (NSCLC) subjects are NSCLC subjects who have previously received any of the following first-line treatments: (1) sintilimab + bevacizumab + pemetrexed + carboplatin, (2) pemetrexed + nedaplatin + sintilimab / sugmalimab, (3) bevacizumab + pemetrexed + carboplatin, (4) pemetrexed + carboplatin + sintilimab, (5) pemetrexed + carboplatin, (6) vometinib + carboplatin + pemetrexed, (7) amitinib, (8) bevacizumab + pemetrexed + carboplatin + osimertinib, (9) pemetrexed + cisplatin + pembrolizumab + lenvatinib, and (10) pemetrexed + cisplatin + camrelizumab.

[0043] In some implementations, the non-small cell lung cancer (NSCLC) subjects are NSCLC subjects who have previously received second-line therapy with the following: anti-PD-L1 antibody, c-Met inhibitor, taxane antitumor drugs, anti-PD-1 antibody, EGFR inhibitor, antimetabolite chemotherapy drugs, platinum-based drugs, and anti-VEGF antibody. In some implementations, the NSCLC subjects are NSCLC subjects who have previously received any of the following second-line therapies: (1) Ab1 + AL2846, (2) docetaxel + sintilimab, (3) putelilimab + becotatug vedotin, (4) pemetrexed + carboplatin + bevacizumab, and (5) pemetrexed + carboplatin + camrelizumab + bevacizumab.

[0044] Drug combination

[0045] In one aspect, this disclosure provides a pharmaceutical combination comprising an anti-HER2 antibody-drug conjugate and a PD-1 / PD-L1 inhibitor. In some embodiments, the PD-1 / PD-L1 inhibitor is an anti-PD-L1 antibody or an antigen-binding fragment thereof, or an anti-PD-1 antibody or an antigen-binding fragment thereof.

[0046] In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate and an anti-PD-L1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate and an anti-PD-1 antibody or an antigen-binding fragment thereof. In some embodiments, the anti-HER2 antibody-drug conjugate and the PD-1 / PD-L1 inhibitor are each in the form of a pharmaceutical composition and are packaged separately. In some embodiments, the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or an antigen-binding fragment thereof are each in the form of a pharmaceutical composition and are packaged separately. In some embodiments, the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or an antigen-binding fragment thereof are each in the form of a pharmaceutical composition and are each administered separately to the subject.

[0047] In some embodiments, the unit dose of the anti-HER2 antibody-drug conjugate in the drug combination is 50-600 mg, 100-400 mg, or 100-200 mg. In some embodiments, the unit dose of the anti-HER2 antibody-drug conjugate in the drug combination is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg, or a range formed by any two of the above values. In some embodiments, the unit dose of the anti-HER2 antibody-drug conjugate in the drug combination is 100 mg.

[0048] In some embodiments, the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment in the drug combination is 50-1800 mg, 100-1200 mg, or 100-600 mg. In some embodiments, the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment in the drug combination is 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, and / or 1800 mg, or a range formed by any two of the above values. In some embodiments, the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment in the drug combination is 100 mg and / or 600 mg. In some embodiments, the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment in the drug combination is 600 mg.

[0049] In some embodiments, the drug combination includes an anti-HER2 antibody drug conjugate in a unit dose of 50-600 mg, 100-400 mg, or 100-200 mg, and an anti-PD-L1 antibody or its antigen-binding fragment in a unit dose of 50-1800 mg, 100-1200 mg, or 100-600 mg. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at unit doses of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg, or any two of the above values, and an anti-PD-L1 antibody or its antigen-binding fragment at unit doses of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, and / or 1800 mg, or any two of the above values. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at a unit dose of 100 mg and an anti-PD-L1 antibody or its antigen-binding fragment at a unit dose of 600 mg.

[0050] In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at doses of 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at doses of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg, or any two of the above values. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at 6 mg / kg or 7.5 mg / kg. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at 6 mg / kg. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at 7.5 mg / kg.

[0051] In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at doses of 1.5-9 mg / kg / dose, 5-7.5 mg / kg / dose, or 6-7.5 mg / kg / dose. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at doses of 1.5 mg / kg / dose, 3 mg / kg / dose, 4.5 mg / kg / dose, 5 mg / kg / dose, 5.4 mg / kg / dose, 6 mg / kg / dose, 7.5 mg / kg / dose, or 9 mg / kg / dose, or any two of the above values. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at 6 mg / kg / dose or 7.5 mg / kg / dose. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at 6 mg / kg / dose. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at 7.5 mg / kg / dose.

[0052] In some embodiments, the drug combination comprises 600-2400 mg, 600-1800 mg, or 1200-1500 mg of an anti-PD-L1 antibody or its antigen-binding fragment. In some embodiments, the drug combination comprises 600 mg, 800 mg, 1000 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg, or any two of the above values ​​within a range. In some embodiments, the drug combination comprises 1200 mg of an anti-PD-L1 antibody or its antigen-binding fragment.

[0053] In some embodiments, the drug combination comprises an anti-PD-L1 antibody or its antigen-binding fragment at doses of 600-2400 mg / dose, 600-1800 mg / dose, or 1200-1500 mg / dose. In some embodiments, the drug combination comprises an anti-PD-L1 antibody or its antigen-binding fragment at doses of 600 mg / dose, 800 mg / dose, 1000 mg / dose, 1200 mg / dose, 1300 mg / dose, 1400 mg / dose, 1500 mg / dose, 1600 mg / dose, 1800 mg / dose, 2000 mg / dose, 2200 mg / dose, or 2400 mg / dose, or any two of the above values. In some embodiments, the drug combination comprises an anti-PD-L1 antibody or its antigen-binding fragment at doses of 1200 mg / dose.

[0054] In some embodiments, the drug combination includes 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg of an anti-HER2 antibody drug conjugate, and 600-2400 mg, 600-1800 mg, or 1200-1500 mg of an anti-PD-L1 antibody or its antigen-binding fragment. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at a concentration of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg, or any two of the above values, and an anti-PD-L1 antibody or its antigen-binding fragment at a concentration of 600 mg, 800 mg, 1000 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg, or any two of the above values. In some embodiments, the drug combination comprises an anti-HER2 antibody-drug conjugate at a concentration of 6 mg / kg or 7.5 mg / kg, and an anti-PD-L1 antibody or its antigen-binding fragment at a concentration of 1200 mg. In some embodiments, the drug combination comprises 6 mg / kg of an anti-HER2 antibody-drug conjugate and 1200 mg of an anti-PD-L1 antibody or its antigen-binding fragment. In some embodiments, the drug combination comprises 7.5 mg / kg of an anti-HER2 antibody-drug conjugate and 1200 mg of an anti-PD-L1 antibody or its antigen-binding fragment.

[0055] In some embodiments, the drug combination includes an anti-HER2 antibody drug conjugate of 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg, and an anti-PD-L1 antibody or its antigen-binding fragment of 600-2400 mg / kg, 600-1800 mg / kg, or 1200-1500 mg / kg. In some embodiments, the drug combination includes an anti-HER2 antibody-drug conjugate at doses of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg, or any two of the above values, and an anti-PD-L1 antibody or its antigen-binding fragment at doses of 600 mg / kg, 800 mg / kg, 1000 mg / kg, 1200 mg / kg, 1300 mg / kg, 1400 mg / kg, 1500 mg / kg, 1600 mg / kg, 1800 mg / kg, 2000 mg / kg, 2200 mg / kg, or 2400 mg / kg, or any two of the above values. In some embodiments, the drug combination comprises an anti-HER2 antibody drug conjugate at a dose of 6 mg / kg or 7.5 mg / kg, and an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1200 mg / kg. In some embodiments, the drug combination comprises an anti-HER2 antibody drug conjugate at a dose of 6 mg / kg, and an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1200 mg / kg. In some embodiments, the drug combination comprises an anti-HER2 antibody drug conjugate at a dose of 7.5 mg / kg, and an anti-PD-L1 antibody or its antigen-binding fragment at a dose of 1200 mg / kg.

[0056] In some embodiments, the drug combination is suitable for administration over a single treatment cycle (e.g., a 3-week treatment cycle) and comprises an anti-HER2 antibody-drug conjugate at doses of 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg. In some embodiments, the drug combination is suitable for administration over a single treatment cycle (e.g., a 3-week treatment cycle) and comprises an anti-HER2 antibody-drug conjugate at doses of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg, or any range of two of the above values. In some embodiments, the drug combination is suitable for administration over a single treatment cycle (e.g., a 3-week treatment cycle) and comprises an anti-HER2 antibody-drug conjugate at doses of 6 mg / kg or 7.5 mg / kg. In some embodiments, the drug combination is suitable for administration over a single treatment cycle (e.g., a 3-week treatment cycle) and comprises an anti-HER2 antibody-drug conjugate at doses of 6 mg / kg. In some embodiments, the drug combination is suitable for administration over a single treatment cycle (e.g., a 3-week treatment cycle), comprising 7.5 mg / kg of an anti-HER2 antibody-drug conjugate.

[0057] In some embodiments, the drug combination is suitable for administration over a single treatment cycle (e.g., a 3-week treatment cycle) and comprises 600-2400 mg, 600-1800 mg, or 1200-1500 mg of an anti-PD-L1 antibody or its antigen-binding fragment. In some embodiments, the drug combination is suitable for administration over a single treatment cycle (e.g., a 3-week treatment cycle) and comprises 600 mg, 800 mg, 1000 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg, or a range forming any two of the above values, of an anti-PD-L1 antibody or its antigen-binding fragment. In some embodiments, the drug combination is suitable for administration over a single treatment cycle (e.g., a 3-week treatment cycle) and comprises 1200 mg of an anti-PD-L1 antibody or its antigen-binding fragment.

[0058] In some embodiments, the drug combination is suitable for administration over a single treatment cycle (e.g., a 3-week treatment cycle) and comprises 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg of an anti-HER2 antibody drug conjugate, and 600-2400 mg, 600-1800 mg, or 1200-1500 mg of an anti-PD-L1 antibody or its antigen-binding fragment. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises an anti-HER2 antibody-drug conjugate at a concentration of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg, or any two of the above values, and an anti-PD-L1 antibody or its antigen-binding fragment at a concentration of 600 mg, 800 mg, 1000 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg, or any two of the above values. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises an anti-HER2 antibody-drug conjugate at a concentration of 6 mg / kg or 7.5 mg / kg and an anti-PD-L1 antibody or its antigen-binding fragment at a concentration of 1200 mg. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 6 mg / kg of an anti-HER2 antibody-drug conjugate and 1200 mg of an anti-PD-L1 antibody or an antigen-binding fragment thereof. In some embodiments, the drug combination is suitable for administration within a single treatment cycle and comprises 7.5 mg / kg of an anti-HER2 antibody-drug conjugate and 1200 mg of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0059] In some embodiments, the amount of the anti-HER2 antibody drug conjugate in the drug combination is a daily dose. In some embodiments, the amount of the anti-HER2 antibody drug conjugate in the drug combination is a single dose. In some embodiments, the amount of the anti-HER2 antibody drug conjugate in the drug combination is a once-daily dose.

[0060] In some embodiments, the amount of the anti-PD-L1 antibody or its antigen-binding fragment in the drug combination is a daily dose. In some embodiments, the amount of the anti-PD-L1 antibody or its antigen-binding fragment in the drug combination is a single dose. In some embodiments, the amount of the anti-PD-L1 antibody or its antigen-binding fragment in the drug combination is a once-daily dose.

[0061] In some embodiments, the anti-HER2 antibody drug conjugate may be a pharmaceutical composition of anti-HER2 antibody drug conjugates. The pharmaceutical composition of the anti-HER2 antibody drug conjugate may be a single dose or multiple doses, preferably multiple doses. In some embodiments, the multiple doses may consist of a pharmaceutical composition of anti-HER2 antibody drug conjugates with a single dose of 50-600 mg, 100-400 mg, or 100-200 mg. In some embodiments, the multiple doses may consist of a pharmaceutical composition of anti-HER2 antibody drug conjugates with a single dose of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg. In some embodiments, the multiple doses may consist of a pharmaceutical composition of anti-HER2 antibody drug conjugates with a single dose of 100 mg.

[0062] In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment may be a pharmaceutical composition of an anti-PD-L1 antibody or its antigen-binding fragment. The pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment may be a single dose or multiple doses, preferably multiple doses. In some embodiments, the multiple doses may consist of a single dose of 50-1800 mg, 100-1200 mg, or 100-600 mg of the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment. In some embodiments, the multiple doses may consist of a single dose of 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, and / or 1800 mg of the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment. In some embodiments, the multiple doses may consist of a pharmaceutical composition of an anti-PD-L1 antibody or its antigen-binding fragment in a single dose of 100 mg and / or 600 mg. In some embodiments, the multiple doses may consist of a pharmaceutical composition of an anti-PD-L1 antibody or its antigen-binding fragment in a single dose of 600 mg.

[0063] In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-HER2 antibody-drug conjugate and a pharmaceutical composition of an anti-PD-L1 antibody or its antigen-binding fragment. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-HER2 antibody-drug conjugate and a pharmaceutical composition of an anti-PD-L1 antibody or its antigen-binding fragment, wherein the pharmaceutical composition of the anti-HER2 antibody-drug conjugate is prepared to be suitable for administering a single or multiple dose of 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg of the anti-HER2 antibody-drug conjugate to a patient per treatment cycle, and the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment is prepared to be suitable for administering a single or multiple dose of 600-2400 mg, 600-1800 mg, or 1200-1500 mg of the anti-PD-L1 antibody or its antigen-binding fragment to a patient per treatment cycle. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-HER2 antibody-drug conjugate and a pharmaceutical composition of an anti-PD-L1 antibody or its antigen-binding fragment thereof, wherein the pharmaceutical composition of the anti-HER2 antibody-drug conjugate is prepared to be administered to a patient in a single or multiple dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg per treatment cycle, and the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment thereof is prepared to be administered to a patient in a single or multiple dose of 600 mg, 800 mg, 1000 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg or 2400 mg per treatment cycle. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-HER2 antibody-drug conjugate and a pharmaceutical composition of an anti-PD-L1 antibody or an antigen-binding fragment thereof, wherein the pharmaceutical composition of the anti-HER2 antibody-drug conjugate is prepared to be administered to a patient in a single or multiple dose of 6 mg / kg or 7.5 mg / kg of the anti-HER2 antibody-drug conjugate per treatment cycle, and the pharmaceutical composition of the anti-PD-L1 antibody or an antigen-binding fragment thereof is prepared to be administered to a patient in a single or multiple dose of 1200 mg of the anti-PD-L1 antibody or an antigen-binding fragment thereof per treatment cycle.In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-HER2 antibody-drug conjugate and a pharmaceutical composition of an anti-PD-L1 antibody or its antigen-binding fragment, wherein the pharmaceutical composition of the anti-HER2 antibody-drug conjugate is prepared to be administered to a patient in a single or multiple dose of 6 mg / kg of the anti-HER2 antibody-drug conjugate per treatment cycle, and the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment is prepared to be administered to a patient in a single or multiple dose of 1200 mg of the anti-PD-L1 antibody or its antigen-binding fragment per treatment cycle. In some embodiments, the drug combination comprises a pharmaceutical composition of an anti-HER2 antibody-drug conjugate and a pharmaceutical composition of an anti-PD-L1 antibody or its antigen-binding fragment, wherein the pharmaceutical composition of the anti-HER2 antibody-drug conjugate is prepared to be administered to a patient in a single or multiple dose of 7.5 mg / kg of the anti-HER2 antibody-drug conjugate per treatment cycle, and the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment is prepared to be administered to a patient in a single or multiple dose of 1200 mg of the anti-PD-L1 antibody or its antigen-binding fragment per treatment cycle. In some of these implementations, a treatment cycle lasts for 3 weeks.

[0064] In some embodiments, the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment can be packaged separately or together in the drug combination. The anti-HER2 antibody drug conjugate can be packaged in single or multiple portions, and the anti-PD-L1 antibody or its antigen-binding fragment can be packaged in single or multiple portions. In some embodiments, the anti-HER2 antibody drug conjugate can be packaged in single or multiple equal portions (e.g., 2, 3, 4, 5, 6, 7, 8 or more portions), and the anti-PD-L1 antibody or its antigen-binding fragment can be packaged in single or multiple equal portions (e.g., 2 or other equal portions).

[0065] In some embodiments, the drug combination is packaged in the same kit; optionally, the kit further includes instructions for using the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment in combination to treat tumors. In other embodiments, the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment in the drug combination are packaged separately in their respective kits; optionally, the kits further include instructions for using the anti-HER2 antibody-drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment in combination to treat tumors.

[0066] In some implementations, the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are formulated separately (i.e., each is in the form of a pharmaceutical composition).

[0067] In some embodiments, the drug combination is a non-fixed combination. In some embodiments, in the non-fixed combination, the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are each in the form of a pharmaceutical composition.

[0068] In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of the anti-HER2 antibody drug conjugate is a solid pharmaceutical composition. In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of the anti-HER2 antibody drug conjugate is a lyophilized formulation. In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of the anti-HER2 antibody drug conjugate is a powder for injection.

[0069] In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment is a liquid pharmaceutical composition. In some specific embodiments, in the non-fixed combination, the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment is an injectable preparation.

[0070] In another aspect, this disclosure provides a kit comprising a pharmaceutical composition of an anti-HER2 antibody-drug conjugate and a pharmaceutical composition of an anti-PD-L1 antibody or an antigen-binding fragment thereof, optionally further comprising instructions for using the pharmaceutical composition of the anti-HER2 antibody-drug conjugate and the pharmaceutical composition of the anti-PD-L1 antibody or an antigen-binding fragment thereof in combination to treat tumors. In some embodiments, the kit is used to treat tumors. In some embodiments, the pharmaceutical composition of the anti-HER2 antibody-drug conjugate and the pharmaceutical composition of the anti-PD-L1 antibody or an antigen-binding fragment thereof are in separate, individual kits.

[0071] In another aspect, this disclosure also provides a pharmaceutical package containing individually packaged pharmaceutical compositions in separate containers, wherein the first container contains a pharmaceutical composition of an anti-HER2 antibody-drug conjugate, and the second container contains a pharmaceutical composition of an anti-PD-L1 antibody or an antigen-binding fragment thereof. In some embodiments, the pharmaceutical package is used to treat tumors.

[0072] In some embodiments, the anti-HER2 antibody drug conjugate pharmaceutical composition in the kit or drug package is a solid pharmaceutical composition. In some embodiments, the anti-HER2 antibody drug conjugate pharmaceutical composition in the kit or drug package is a lyophilized formulation. In some embodiments, the anti-HER2 antibody drug conjugate pharmaceutical composition in the kit or drug package is a powder for injection.

[0073] In some specific embodiments, the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment in the kit or drug package is a liquid pharmaceutical composition. In some specific embodiments, the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment in the kit or drug package is an injectable preparation.

[0074] In some implementations, the tumor is non-small cell lung cancer.

[0075] Anti-HER2 antibody-drug conjugates

[0076] The anti-HER2 antibody-drug conjugates used in this disclosure are formed by linking a drug-linker of the structure shown in Formula Ia to an antigen-binding construct targeting HER2.

[0077] in,

[0078] The 3-position of -(succinimide-3-yl-N)- in formula Ia (i.e., with The connection point is linked to the antigen-binding construct targeting HER2.

[0079] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment. The first antigen-binding fragment comprises: a heavy chain CDR1 (HCDR1) containing the amino acid sequence shown in SEQ ID NO:1, an HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, an HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, a light chain CDR1 (LCDR1) containing the amino acid sequence shown in SEQ ID NO:4, an LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and an LCDR3 containing the amino acid sequence shown in SEQ ID NO:6. The second antigen-binding fragment comprises: an HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, an HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, an HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, an LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, an LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and an LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

[0080] In some embodiments, the 3-position of the -(succinimide-3-yl-N)- is linked to the antigen-binding construct targeting HER2 via a thioether bond.

[0081] In some embodiments, the average number of drug-connectors for each HER2-targeting antigen-binding construct in the anti-HER2 antibody drug conjugate is 2 to 8. In some embodiments, the average number of drug-connectors for each HER2-targeting antigen-binding construct in the anti-HER2 antibody drug conjugate is 4 to 7. In some embodiments, the average number of drug-connectors for each HER2-targeting antigen-binding construct in the anti-HER2 antibody drug conjugate is 5 to 6. In some embodiments, the average number of drug-connectors for each HER2-targeting antigen-binding construct in the anti-HER2 antibody drug conjugate is 5.5 to 6. In some embodiments, the average number of drug-connectors for each HER2-targeting antigen-binding construct in the anti-HER2 antibody drug conjugate is 5.8 to 6.

[0082] Table 1. Exemplary CDR sequences of antigen-binding constructs targeting HER2

[0083] Those skilled in the art will understand that, unless otherwise specified, the term "CDR" or "complementarity-determining region" for a given antibody or its antigen-binding fragment or its region (e.g., variable region) should be understood to encompass complementarity-determining regions defined by any known scheme. While the CDRs claimed in this disclosure are based on the sequences shown in Table 1 (one definition), the amino acid sequences corresponding to other CDR definition rules (e.g., combinations of one or more of the definitions of AbM, CCG, Kabat, Chothia, IMGT, or Contact, as well as those known in the art) should also fall within the scope of this disclosure.

[0084] In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 7. In some embodiments, the first antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 8. In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 7, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 8. In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:7 and a light chain variable region having the amino acid sequence shown in SEQ ID NO:8. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the first antigen-binding fragment is as shown in SEQ ID NO:7, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:8. In some embodiments, the first antigen-binding fragment comprises: HCDR1, HCDR2, and HCDR3 in the heavy chain variable region having the amino acid sequence shown in SEQ ID NO:7, and LCDR1, LCDR2, and LCDR3 in the light chain variable region having the amino acid sequence shown in SEQ ID NO:8.

[0085] In some embodiments, the first antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 having the amino acid sequence shown in SEQ ID NO:1, HCDR2 having the amino acid sequence shown in SEQ ID NO:2, and HCDR3 having the amino acid sequence shown in SEQ ID NO:3; the light chain variable region comprises LCDR1 having the amino acid sequence shown in SEQ ID NO:4, LCDR2 having the amino acid sequence shown in SEQ ID NO:5, and LCDR3 having the amino acid sequence shown in SEQ ID NO:6; and the heavy chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:7; and the light chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 89%, 99%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:7; and the light chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:7; NO:8 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical.

[0086] In some embodiments, the different amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:7 or SEQ ID NO:8 are located in the frame region (FR).

[0087] In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 15. In some embodiments, the second antigen-binding fragment comprises a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO: 16. In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:15, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:16. In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:15 and a light chain variable region having the amino acid sequence shown in SEQ ID NO:16. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the second antigen-binding fragment is as shown in SEQ ID NO:15, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:16. In some embodiments, the second antigen-binding fragment comprises: HCDR1, HCDR2, and HCDR3 in the heavy chain variable region having the amino acid sequence shown in SEQ ID NO:15, and LCDR1, LCDR2, and LCDR3 in the light chain variable region having the amino acid sequence shown in SEQ ID NO:16.

[0088] In some embodiments, the second antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises HCDR1 having the amino acid sequence shown in SEQ ID NO:9, HCDR2 having the amino acid sequence shown in SEQ ID NO:10, and HCDR3 having the amino acid sequence shown in SEQ ID NO:11; the light chain variable region comprises LCDR1 having the amino acid sequence shown in SEQ ID NO:12, LCDR2 having the amino acid sequence shown in SEQ ID NO:13, and LCDR3 having the amino acid sequence shown in SEQ ID NO:14; and the heavy chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:15; and the light chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 89%, 99%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:15; and the light chain variable region comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 95%, 96%, 97%, 98%, 99%, or 100% identity with SEQ ID NO:15. NO:16 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical.

[0089] In some embodiments, the differing amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:15 or SEQ ID NO:16 are located in FR.

[0090] In some embodiments, the HER2-targeting antigen-binding construct may further comprise a constant region of an immunoglobulin, or a fragment, analog, variant, or derivative of said constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is derived from the heavy chain of human immunoglobulins, such as IgG1, IgG2, IgG3, and IgG4, or the heavy chain of other classes of immunoglobulins, preferably the heavy chain of IgG1. In some embodiments, the light chain constant region is derived from the light chain of human immunoglobulins, such as the κ or λ light chain of human immunoglobulins. In some embodiments, the constant region may contain any modifications described herein, such as the insertion, deletion, substitution, or chemical modification of amino acids. In some embodiments, the C-terminal lysine of the heavy chain constant region may be present or absent; the deletion of the C-terminal lysine of the heavy chain constant region typically occurs during recombinant expression. In some embodiments, the constant region contains mutations that alter effector function. In some embodiments, any amino acid residue of the constant region may be substituted with any allotype amino acid residue.

[0091] In some embodiments, the HER2-targeting antigen-binding construct comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:17. In some embodiments, the HER2-targeting antigen-binding construct comprises a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:18. In some embodiments, the HER2-targeting antigen-binding construct comprises a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:19. In some embodiments, the HER2-targeting antigen-binding construct comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17. The amino acid sequence shown in SEQ ID NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity. In some embodiments, the HER2-targeting antigen-binding construct comprises a first polypeptide chain having the amino acid sequence shown in SEQ ID NO:17, a second polypeptide chain having the amino acid sequence shown in SEQ ID NO:18, and a third polypeptide chain having the amino acid sequence shown in SEQ ID NO:19.In some specific embodiments, the antigen-binding construct targeting HER2 consists of three polypeptide chains, wherein the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19.

[0092] In some embodiments, the HER2-targeting antigen-binding construct comprises a first polypeptide chain, a second polypeptide chain, and a third polypeptide chain. The first polypeptide chain comprises HCDR1 having the amino acid sequence shown in SEQ ID NO:1, HCDR2 having the amino acid sequence shown in SEQ ID NO:2, HCDR3 having the amino acid sequence shown in SEQ ID NO:3, LCDR1 having the amino acid sequence shown in SEQ ID NO:4, LCDR2 having the amino acid sequence shown in SEQ ID NO:5, and LCDR3 having the amino acid sequence shown in SEQ ID NO:6. The second polypeptide chain comprises HCDR1 having the amino acid sequence shown in SEQ ID NO:9, HCDR2 having the amino acid sequence shown in SEQ ID NO:10, and HCDR3 having the amino acid sequence shown in SEQ ID NO:11. The third polypeptide chain comprises LCDR1 having the amino acid sequence shown in SEQ ID NO:12, LCDR2 having the amino acid sequence shown in SEQ ID NO:13, and LCDR3 having the amino acid sequence shown in SEQ ID NO:14. Furthermore, the first polypeptide chain comprises [the amino acid sequence shown in SEQ ID NO:1]. The amino acid sequence shown in NO:17 has at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:18. The second polypeptide chain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:18. The third polypeptide chain comprises an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 100% identity with the amino acid sequence shown in SEQ ID NO:18. The amino acid sequence shown in NO:19 has an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical.

[0093] In some embodiments, the different amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 17, 18, or 19 are located in the FR or constant region.

[0094] In some embodiments, the C-terminal lysine residue of the amino acid sequence shown in SEQ ID NO:17 is deleted, as shown in SEQ ID NO:20. In some embodiments, the C-terminal lysine residue of the amino acid sequence shown in SEQ ID NO:18 is deleted, as shown in SEQ ID NO:21. In some embodiments, the C-terminal lysine residues of the first and second polypeptide chains are deleted, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:20, and the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:21.

[0095] In some embodiments, the HER2-targeting antigen-binding construct is selected from Expi Her2-1, Expi Her2-3, Expi Her2-4, Expi Her2-5, 23C2 Her2-1, 23C2 Her2-3, 23C2 Her2-4, or 23C2 Her2-5 (see WO2021219046 or CN115279791A). In some other embodiments, the HER2-targeting antigen-binding construct is selected from Zanidatamab (ZW25), KN026, MBS301, KM257, or BCD-147.

[0096] The anti-HER2 antibody-drug conjugate used in this disclosure can also be represented by the structure shown in Formula II:

[0097] The HER2-targeting antigen-binding construct is as described above. In some embodiments, the drug-connector is linked to the HER2-targeting antigen-binding construct via a thioether bond. n has the same meaning as DAR, representing the average number of cytotoxic drug connections per HER2-targeting antigen-binding construct. In some embodiments, n is 2 to 8. In some embodiments, n is 4 to 7. In some embodiments, n is 5 to 6. In some embodiments, n is 5.5 to 6. In some embodiments, n is 5.8 to 6.

[0098] The antibody-drug conjugates preferred in this disclosure are formed by linking a drug-linker of the structure shown in Formula Ia to an antigen-binding construct targeting HER2.

[0099] in,

[0100] In formula Ia, the 3-position of -(succinimide-3-yl-N)- is linked to the antigen-binding construct targeting HER2.

[0101] The HER2-targeting antigen-binding construct comprises three polypeptide chains: the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17 or a variant with a C-terminal lysine deletion; the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18 or a variant with a C-terminal lysine deletion; and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19 (for example, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19; or the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:20, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:21, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19; or the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:20, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19; or the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17, and the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:19). As shown in NO:21, the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO:19, and

[0102] For a single antigen-binding construct targeting HER2, the average number of drug-connector linkages is 5 to 6.

[0103] In some embodiments, the 3-position of -(succinimide-3-yl-N)- in Formula Ia is linked to an antigen-binding construct targeting HER2 via a thioether bond.

[0104] The antibody-drug conjugates preferred in this disclosure can also be represented by the structure shown in Formula II:

[0105] Where n is between 5 and 6,

[0106] The HER2-targeting antigen-binding construct comprises three polypeptide chains: the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17 or a variant with a C-terminal lysine deletion; the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18 or a variant with a C-terminal lysine deletion; and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19 (for example, the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19; or the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:20, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:21, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19; or the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:20, the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:18, and the amino acid sequence of the third polypeptide chain is shown in SEQ ID NO:19; or the amino acid sequence of the first polypeptide chain is shown in SEQ ID NO:17, and the amino acid sequence of the second polypeptide chain is shown in SEQ ID NO:19). As shown in NO:21, the amino acid sequence of the third polypeptide chain is as shown in SEQ ID NO:19. In some embodiments, the drug-connector is linked to the antigen-binding construct targeting HER2 via a thioether bond.

[0107] In other specific embodiments, the anti-HER2 antibody-drug conjugates disclosed herein are selected from... MRG002, ARX788, A166, SHR-A1811, BB-1701, SYD985, FS-1502 or BAT8001.

[0108] The anti-HER2 antibody drug conjugates described in this disclosure also include isomers of the anti-HER2 antibody drug conjugate, pharmaceutically acceptable salts, or solvates of the anti-HER2 antibody drug conjugate, its isomers, or pharmaceutically acceptable salts.

[0109] Pharmaceutical compositions of anti-HER2 antibody drug conjugates

[0110] In some embodiments, the anti-HER2 antibody drug conjugate is formulated for parenteral administration. In some specific embodiments, the anti-HER2 antibody drug conjugate is formulated for intravenous administration, such as for injection or infusion.

[0111] In some embodiments, the anti-HER2 antibody drug conjugate is formulated with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition. Pharmaceutically acceptable excipients include, for example, excipients, diluents, encapsulating materials, fillers, buffers, or other reagents.

[0112] In some embodiments, the unit dose of the anti-HER2 antibody drug conjugate pharmaceutical composition is 50-600 mg, 100-400 mg, or 100-200 mg of anti-HER2 antibody drug conjugate, for example, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg, or any two of the above values ​​forming a range of anti-HER2 antibody drug conjugates.

[0113] In some specific embodiments, the pharmaceutical composition of the anti-HER2 antibody drug conjugate is an injectable formulation. In some specific embodiments, the pharmaceutical composition of the anti-HER2 antibody drug conjugate is an aqueous injectable formulation, which includes, but is not limited to, an aqueous formulation that has not been lyophilized or an aqueous formulation reconstituted from lyophilized powder.

[0114] In some specific embodiments, the pharmaceutical composition of the anti-HER2 antibody drug conjugate is a powder for injection. In some specific embodiments, the pharmaceutical composition of the anti-HER2 antibody drug conjugate is a lyophilized formulation (e.g., a lyophilized powder for injection). The lyophilized formulation refers to a formulation prepared by lyophilizing an aqueous solution, in which the substance is first frozen, then the solvent quantity is reduced by sublimation (primary drying process), and then by desorption (secondary drying process), until the solvent quantity is at a value that no longer supports biological activity or chemical reaction. The lyophilized formulation of this disclosure can also be dried by other methods known in the art, such as spray drying and bubble drying.

[0115] Anti-PD-L1 antibody or its antigen-binding fragment

[0116] In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:22, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:23, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:24, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:25, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:26, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:27. The CDR sequences of the anti-PD-L1 antibody or its antigen-binding fragment are provided in Table 2 below.

[0117] Table 2. CDR sequences of anti-PD-L1 antibodies or their antigen-binding fragments

[0118] Those skilled in the art will understand that, unless otherwise specified, the term "CDR" or "complementarity-determining region" for a given antibody or its antigen-binding fragment or its region (e.g., variable region) should be understood to encompass complementarity-determining regions defined by any known scheme. While CDR regions are shown in Table 2, when referring to antibodies defined by a specific CDR sequence, the scope of said antibodies encompasses antibodies defined by a CDR sequence of any numbering system (e.g., a combination of one or more of the definitions of AbM, CCG, Kabat, Chothia, IMGT, or Contact, as is known in the art).

[0119] In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:28, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:29. In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy chain variable region having the amino acid sequence shown in SEQ ID NO:28 and a light chain variable region having the amino acid sequence shown in SEQ ID NO:29. In some specific embodiments, the amino acid sequence of the heavy chain variable region of the anti-PD-L1 antibody or its antigen-binding fragment is as shown in SEQ ID NO:28, and the amino acid sequence of the light chain variable region is as shown in SEQ ID NO:29. In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment comprises HCDR1, HCDR2, and HCDR3 in the heavy chain variable region having the amino acid sequence shown in SEQ ID NO:28, and LCDR1, LCDR2, and LCDR3 in the light chain variable region having the amino acid sequence shown in SEQ ID NO:29.

[0120] In some embodiments, the differing amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:28 or 29 are located in FR.

[0121] In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment may further comprise a constant region of an immunoglobulin, or a fragment, analog, variant, or derivative of the constant region. In some embodiments, the constant region comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region is derived from the heavy chain of human immunoglobulins, such as IgG1, IgG2, IgG3, and IgG4, or the heavy chain of other classes of immunoglobulins, preferably the heavy chain of IgG1. In some embodiments, the light chain constant region is derived from the light chain of human immunoglobulins, such as the κ or λ light chain of human immunoglobulins. In some embodiments, the constant region may contain any modifications described herein, such as the insertion, deletion, substitution, or chemical modification of amino acids. In some embodiments, the constant region contains mutations that alter effector function. In some embodiments, any amino acid residue of the constant region may be substituted with any allotype amino acid residue, preferably with G1m(3) and / or nG1m(1) amino acid residues.

[0122] In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:30, and a light chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:31. In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy chain of the amino acid sequence shown in SEQ ID NO:30 and a light chain of the amino acid sequence shown in SEQ ID NO:31. In some specific embodiments, the heavy chain amino acid sequence of the anti-PD-L1 antibody or its antigen-binding fragment is as shown in SEQ ID NO:30, and the light chain amino acid sequence is as shown in SEQ ID NO:31. The terminal amino acid K in SEQ ID NO:30 may or may not be present.

[0123] In some embodiments, the different amino acids in the amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO: 30 or 31 are located in the FR or constant region.

[0124] The anti-PD-L1 antibodies or antigen-binding fragments thereof disclosed herein include, but are not limited to, the 13C5, 5G11, ch13C5-hIgG1, ch13C5-hIgG4, ch5G11-hIgG1, ch5G11-hIgG4, hu13C5-hIgG1, hu13C5-hIgG4, hu5G11-hIgG1 or hu5G11-hIgG4 monoclonal antibodies or antigen-binding fragments thereof described in the patent applications with publication numbers WO2016022630 or CN107001463.

[0125] Pharmaceutical compositions of anti-PD-L1 antibodies or their antigen-binding fragments

[0126] In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment is formulated as a preparation for parenteral administration. In some specific embodiments, the anti-PD-L1 antibody or its antigen-binding fragment is formulated as a preparation for intravenous, intramuscular, or other parenteral administration routes, such as for injection or infusion.

[0127] In some embodiments, the anti-PD-L1 antibody or its antigen-binding fragment is formulated with one or more pharmaceutically acceptable excipients to form a suitable pharmaceutical composition. Pharmaceutically acceptable excipients include, for example, excipients, diluents, encapsulating materials, fillers, buffers, or other reagents.

[0128] In some embodiments, the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment is 50-1800 mg, 100-1200 mg, or 100-600 mg, for example, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, or 1800 mg, or any two of the above values ​​forming a range of anti-PD-L1 antibody or its antigen-binding fragment.

[0129] In some embodiments, the concentration of the anti-PD-L1 antibody or its antigen-binding fragment in the pharmaceutical composition is 1-200 mg / mL, 2-150 mg / mL, 4.5-100 mg / mL, 5-80 mg / mL, 10-60 mg / mL, 10-50 mg / mL, or 10-30 mg / mL. In some specific embodiments, the concentration of the anti-PD-L1 antibody or its antigen-binding fragment is 4.8 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 25 mg / mL, 30 mg / mL, 35 mg / mL, 40 mg / mL, 45 mg / mL, 50 mg / mL, 55 mg / mL, 60 mg / mL, 80 mg / mL, 100 mg / mL, or 120 mg / mL. In some embodiments, the concentration of the anti-PD-L1 antibody or its antigen-binding fragment is 4.8 mg / mL. In some embodiments, the concentration of the anti-PD-L1 antibody or its antigen-binding fragment is 10 mg / mL. In some embodiments, the concentration of the anti-PD-L1 antibody or its antigen-binding fragment is 30 mg / mL. In some embodiments, the concentration of the anti-PD-L1 antibody or its antigen-binding fragment is 60 mg / mL.

[0130] In some embodiments, the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment comprises: 1-150 mg / mL of the anti-PD-L1 antibody or its antigen-binding fragment, 3-50 mM buffer, 2-150 mg / mL of isotonic adjuster / stabilizer, and 0.01-0.8 mg / mL of surfactant, and the pH is 4.5-6.8.

[0131] In one specific embodiment, the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment comprises: (a) 10 mg / mL or 30 mg / mL anti-PD-L1 antibody, (b) 80 mg / mL sucrose, (c) 0.2 mg / mL polysorbate 80, (d) 10 mM histidine, and the pH of the pharmaceutical composition is 5.5.

[0132] In some specific embodiments, the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment is an injectable formulation. In some specific embodiments, the pharmaceutical composition of the anti-PD-L1 antibody or its antigen-binding fragment is an aqueous injectable formulation, which includes, but is not limited to, an aqueous formulation that has not been lyophilized or an aqueous formulation reconstituted from lyophilized powder.

[0133] Anti-PD-1 antibody or its antigen-binding fragment

[0134] The anti-PD-1 antibody or its antigen-binding fragment in this application is selected from pembrolizumab, nivolumab, pembrolizumab, toripalimab, sintilimab, camrelizumab, tislelizumab, zimberelimab, balstilimab, geptanolimab, and Lipustobart (LZM) from Livzon Pharmaceutical Group. -009), cimiplimab, serplulimab, prolgolimab, pucotetenlimab, nofazinlimab, finotonlimab, dostarlimab, cetrelimab, Qilu Pharmaceutical's QL1604, spartalizumab, retifanlimab, sasanlimab, Shandong New Era Pharmaceutical's rulonilimab (F520), or Shangjian Bio's Enlonstobart (SG001).

[0135] Technical effect

[0136] The application of the anti-HER2 antibody-drug conjugate disclosed herein has one or more of the following effects:

[0137] (1) It provides benefit to subjects with non-small cell lung cancer, wherein the non-small cell lung cancer is preferably locally advanced, recurrent and / or metastatic non-small cell lung cancer, more preferably locally advanced, recurrent and / or metastatic non-small cell lung cancer with HER2 overexpression, HER2 amplification or HER2 mutation, and / or EGFR mutation;

[0138] (2) It has good security;

[0139] (3) It was well tolerated by the subjects.

[0140] The combined administration of the disclosed anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment has one or more of the following effects:

[0141] (1) It provides benefit to subjects with non-small cell lung cancer, wherein the non-small cell lung cancer is preferably locally advanced, recurrent and / or metastatic non-small cell lung cancer, more preferably locally advanced, recurrent and / or metastatic non-small cell lung cancer with HER2 overexpression, HER2 amplification or HER2 mutation, and / or EGFR mutation, for example, the ORR may be greater than 50%.

[0142] (2) It has good security;

[0143] (3) It was well tolerated by the subjects;

[0144] (4) Reduce the size of the tumor target lesion;

[0145] (5) Achieving partial remission in non-small cell lung cancer subjects, who may be locally advanced (stage IIIB / IIIC), metastatic or recurrent (stage IV) patients who are not eligible for surgical treatment and cannot receive radical concurrent chemoradiotherapy.

[0146] Definitions and Explanations

[0147] Unless otherwise stated, the following terms as used in this disclosure have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When trade names appear in this disclosure, they are intended to refer to the corresponding product or its active ingredient.

[0148] As used in this article, the structure of "-(succinimide-3-yl-N)-" is as follows:

[0149] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration representing the center of a solid.

[0150] Unless otherwise specified, when a group has a connectable site, the connection between that site and other groups can be indicated by a wavy line. express.

[0151] The “HER2 mutation” used in this article includes, but is not limited to, HER2 exon 20 insertion mutations and single base pair substitution mutations.

[0152] "HER2 exon 20 insertion mutation" refers to a HER2 mutation caused by the insertion of a base pair into exon 20 of the HER2 gene. Specific examples include, but are not limited to: the repeat of the YVMA sequence at positions 772 to 775 of the HER2 protein (Y772_A775dup, also named A775_G776insYVMA, i.e., the insertion of the amino acid sequence YVMA between position A at 775 and position G at 776 of the HER2 protein), and the repeat of the GSP sequence at positions 778 to 780 of the HER2 protein (G778_P780dup, also named P780_Y781insGSP, i.e., the insertion of the amino acid sequence YVMA between position P at 780 and position G at 776 of the HER2 protein). The following amino acid sequences are inserted: GSP between position 81 (Y); G at position 776 of the HER2 protein is replaced with VC (G776 delins VC or G776>VC); AYVM between position 770 (E) and position 771 (A) of the HER2 protein (E770_A771 in AYVM); YVMA between position 771 (A) and position 772 (Y) of the HER2 protein (A771_Y772 in YVMA); AYVM between position 774 (M) and position 775 (A) of the HER2 protein (M774_A775 in AYVM); and G at position 776 of the HER2 protein is replaced with LC (G776d). elinsLC (also named G776>LC), replacing the G at position 776 of the HER2 protein with AVGC (G776delinsAVGC, also named G776>AVGC), replacing the G at position 776 of the HER2 protein with VV (G776delinsVV, also named G776>VV), inserting a leucine between the G at position 776 and the V at position 777 of the HER2 protein (G776_V777insL), inserting VC between the G at position 776 and the V at position 777 of the HER2 protein (G776_V777insVC), and inserting the amino acid sequence VGC between the G at position 776 and the V at position 777 of the HER2 protein. Insert CG between V at position 777 and G at position 778 of the HER2 protein (V777_G778insCG), insert glycine between V at position 777 and G at position 778 of the HER2 protein (V777_G778insG), insert glycine between G at position 778 and S at position 779 of the HER2 protein (G778_S779insG), or insert the amino acid sequence VGS between S at position 779 and P at position 780 of the HER2 protein (S779_P780insVGS), preferably Y772_A775dup, G778_P780dup, or G776delinsVC.

[0153] "Single base pair substitution mutation" refers to a HER2 mutation caused by the substitution of one base pair by another in the HER2 gene. Specific examples include, but are not limited to: L replaced by S at position 775 of the HER2 protein (L755S), V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L. , Q711H, G727A, T733I, E744G, N745D, L755P, L755A, L755F, S760F, D769H, D769N, D769Y, G776C, G776L, S779P, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S The preferred mutations are 819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, deletion of W at position 906 of the HER2 protein (W906*), T917S, Q943*, S1007*, and S1151L, preferably L755S, V777L, V659E, G660D, S310Y, or S310F. "S310Y" refers to the HER2 exon 8S310Y mutation.

[0154] The term "antigen-binding construct" refers to any reagent capable of binding to an antigen, such as a polypeptide or polypeptide complex. In some aspects, an antigen-binding construct is a polypeptide that specifically binds to a target antigen. Antigen-binding constructs can be monomers, dimers, polymers, proteins, peptides, protein or peptide complexes, antibodies, or antigen-binding fragments thereof. Antigen-binding constructs can be single-specific, bispecific, or multispecific polypeptide constructs. In some aspects, antigen-binding constructs may include, for example, one or more antigen-binding fragments (e.g., Fab or scFv) linked to one or more Fc cells.

[0155] An antibody's "antigen-binding fragment" refers to one or more fragments of an antibody that retain the function of specifically binding to an antigen (e.g., the HER2 protein). It has been demonstrated that the antigen-binding function of an antibody can be exercised through fragments of a full-length antibody. Examples encompassed in the term "antigen-binding fragment" of an antibody include: (i) Fab fragments: monovalent fragments consisting of VL, VH, CL, and CH1 domains; (ii) F(ab')2 fragments, bivalent fragments comprising two Fab fragments connected by a disulfide bridge in the hinge region; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of the VL and VH domains of a single arm of the antibody; (v) dAb fragments consisting of the VH domain (see Ward et al., Nature. 341:544-546 (1989)); and (vi) nanobodies, an antibody comprising a single variable domain and two constant domains. Furthermore, although the two domains VL and VH of the Fv fragment are encoded by different genes, VH and VL can be linked into a single protein chain via a linker using recombination methods. VL and VH pair to form a monovalent molecule called a single-chain Fv (scFv) (see Bird et al., Science. 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. 85:5879-5883 (1988)). These single-chain antibodies are also covered under the term antigen-binding fragment. These antibody fragments can be obtained by those skilled in the art using known conventional techniques, and the fragments can be functionally screened using the same methods as full-length antibodies.

[0156] The term "identity," also known as consistency, refers to the percentage of amino acid residues in the sequence to be aligned that are identical to those in the specific amino acid sequence shown herein, after aligning the sequence to be aligned with it and, if necessary, introducing vacancies to achieve the maximum percentage of sequence identity, and without considering any conservative substitutions as part of the sequence identity. Amino acid sequence alignment for identity can be performed in various ways within the scope of the art. Those skilled in the art can determine the appropriate parameters for the aligned sequences, including any algorithm required to achieve the maximum alignment across the full length of the compared sequences.

[0157] The term "treatment" means administering the compounds described in this disclosure to improve or eliminate a disease or one or more symptoms associated with said disease, and includes, but is not limited to:

[0158] (i) Suppress the disease or disease state, that is, curb its development;

[0159] (ii) Relieve the disease or disease state, even if the disease or disease state subsides;

[0160] (iii) To reduce any direct or indirect pathological consequences of disease or disease state.

[0161] The term "therapeutic effective amount" means (i) the amount of the disclosed compound used to treat a particular disease, condition, or disorder, or (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder. The amount of the disclosed compound constituting a "therapeutic effective amount" can vary depending on factors such as the compound and its ability to elicit the desired response in an individual, the disease state and its severity, the route of administration, and the age, sex, and weight of the mammal to be treated.

[0162] The terms “application,” “administration,” or “giving” indicate the physical introduction of a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those skilled in the art.

[0163] Antibody-drug conjugates (e.g., anti-HER2 antibody-drug conjugates) can be administered via intravenous, intramuscular, intraperitoneal, spinal, or other parenteral routes. As used herein, the term "parenteral administration" refers to non-enteral administration methods typically performed by injection, including but not limited to intravenous, intramuscular, intra-arterial, intrathecal, intralymphatic, intralesional, intracystic, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, intra-articular, subcapsular, subarachnoid, spinal, epidural, and intrasternal injections and infusions, as well as intracorporeal electroporation. Administration can also be performed, for example, once, multiple times, and / or over one or more extended time periods.

[0164] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0165] The term "pharmaceutically acceptable salt" refers to a salt of a compound (such as the antibody-drug conjugate of this disclosure) that is safe and effective when used in mammals and has the intended biological activity. For example, it can be a metal salt, an ammonium salt, a salt formed with an organic base, a salt formed with an inorganic acid, a salt formed with an organic acid, a salt formed with a basic or acidic amino acid, etc.

[0166] The term "excipient" refers to any component other than the active ingredient (e.g., the antibody-drug conjugate of this disclosure). The selection of excipients will largely depend on factors such as the specific route of administration, the efficacy of the excipient in terms of solubility and stability, and the nature of the dosage form.

[0167] The term "solvent" refers to a substance formed by the association of a compound with solvent molecules.

[0168] In this disclosure, "HER2 overexpressing" non-small cell lung cancer is not specifically limited as long as it is recognized by those skilled in the art as HER2 overexpressing non-small cell lung cancer. Preferably, for example, non-small cell lung cancer that is determined to be IHC 3+ or IHC 2+ by HER2 detection using immunohistochemistry (IHC).

[0169] In this document, the terms “subject,” “patient,” or “subject” are used interchangeably. “Subject,” “patient,” or “subject” includes any human or non-human animal. The term “non-human animal” includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject, patient, or subject is a mammal. In some embodiments, the subject, patient, or subject is a mouse. In some embodiments, the subject, patient, or subject is a human.

[0170] The term "pharmaceutical composition" refers to a mixture of one or more active ingredients (such as the anti-HER2 antibody drug conjugate of this disclosure) and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the active ingredient to a subject. In this document, the terms "pharmaceutical composition" and "formulation" have the same meaning and are used interchangeably.

[0171] The terms “drug combination” and “combination drugs” are used interchangeably to cover situations where two or more active ingredients or drugs are packaged separately (e.g., in different boxes or different units of the same box) or packaged together, and when the two or more active ingredients or drugs are administered to the patient separately, simultaneously or at intervals, they can work together to treat the disease in the patient.

[0172] As used herein, “combined use” or “conjunctive use” means that two or more active substances may be administered to an individual simultaneously, sequentially, or in any order as individual formulations.

[0173] "Simultaneous" administration of drug A with one or more other drugs means that drug A is administered on the same day as treatment with the one or more other drugs during the same treatment cycle. For example, in a cancer therapy administered every 3 weeks, the multiple drugs administered simultaneously are each administered on day 1 of the 3-week dosing cycle.

[0174] The words “comprise,” “comprise,” or “comprise,” and their English variations such as comprises or comprising, should be understood in an open, non-exclusive sense, meaning “including but not limited to.”

[0175] In this document, unless the context clearly indicates otherwise, singular terms encompass plural referents, and vice versa.

[0176] As used herein, “about” means within an acceptable range of error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” may, in accordance with art practice, mean within one or more standard deviations. Alternatively, “about” may mean a range of up to ±5%, such as fluctuations within ±2%, ±1%, or ±0.5% of a given specific numerical range. When a particular value is given in this disclosure or claims, unless otherwise stated, “about” shall be understood to mean within an acceptable range of error for that particular value. In this document, unless otherwise stated, all values ​​for dosage, time, procedure parameters, or conditions of the medicine are implicitly modified by “about”.

[0177] For purposes of description and disclosure, all patents, patent applications, and other identified publications are expressly incorporated herein by reference. These publications are provided solely because their publications predate the filing date of this disclosure. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any acknowledgment of the accuracy of the dates or contents of these documents. Furthermore, in any country, any reference to these publications herein does not constitute an endorsement that such publications are part of the general knowledge in the art.

[0178] This disclosure also provides the following specific implementation schemes, but the scope of protection of this disclosure is not limited thereto:

[0179] Implementation Scheme 1. A method for treating a subject with non-small cell lung cancer, comprising administering an anti-HER2 antibody-drug conjugate to the subject, wherein the anti-HER2 antibody-drug conjugate is composed of a drug-linker of the structure shown in Formula Ia linked to an antigen-binding construct targeting HER2.

[0180] In formula Ia, the 3-position of -(succinimide-3-yl-N)- is linked to the antigen-binding construct targeting HER2.

[0181] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment. The first antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6. The second antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

[0182] Implementation Scheme 2. The method according to Implementation Scheme 1, wherein the average number of drug-connectors in each HER2-targeting antigen-binding construct is 4 to 7.

[0183] Implementation Scheme 3. The method according to Implementation Scheme 2, wherein the average number of drug-connectors for each HER2-targeting antigen-binding construct is 5 to 6.

[0184] Implementation Scheme 4. The method according to Implementation Scheme 3, wherein the average number of drug-connectors for each HER2-targeting antigen-binding construct is 5.5 to 6.

[0185] Implementation Scheme 5. The method according to any one of Implementation Schemes 1-4, wherein,

[0186] (i) The first antigen-binding fragment comprises a heavy chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:7;

[0187] (ii) The first antigen-binding fragment comprises a light chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:8;

[0188] (iii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:8;

[0189] (iv) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:15;

[0190] (v) The second antigen-binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16;

[0191] (vi) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 16; or

[0192] (vii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8. The amino acid sequence shown in NO:15 has a heavy chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16, and a light chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16.

[0193] Implementation Scheme 6. The method according to any one of Implementation Schemes 1-5, wherein,

[0194] (i) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:17 or 20;

[0195] (ii) The antigen-binding construct targeting HER2 comprises a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 18 or 21;

[0196] (iii) The antigen-binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:19;

[0197] (iv) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 17 or 20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 18 or 21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 18 or 21; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 17 or 20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0198] (v) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0199] (vi) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0200] (vii) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:21; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity; or

[0201] (viii) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0202] Implementation Scheme 7. The method according to any one of Implementation Schemes 1-6, wherein the unit dose of the anti-HER2 antibody drug conjugate is 50-600 mg, 100-400 mg, or 100-200 mg; preferably, the unit dose of the anti-HER2 antibody drug conjugate is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg; more preferably, the unit dose of the anti-HER2 antibody drug conjugate is 100 mg.

[0203] Implementation Scheme 8. The method according to any one of Implementation Schemes 1-7, wherein the anti-HER2 antibody drug conjugate is administered in a therapeutically effective amount.

[0204] Implementation Scheme 9. The method according to any one of Implementation Schemes 1-8, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6-7.5 mg / kg each time.

[0205] Implementation Scheme 10. The method according to Implementation Scheme 9, wherein the anti-HER2 antibody drug conjugate is administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg each time.

[0206] Implementation Scheme 11. The method according to any one of Implementation Schemes 1-10, wherein the anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks.

[0207] Implementation Scheme 12. The method according to any one of Implementation Schemes 1-11, wherein the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 6 mg / kg or 7.5 mg / kg each time; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 7.5 mg / kg each time.

[0208] Implementation Scheme 13. The method according to any one of Implementation Schemes 1-12, wherein the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0209] Implementation Scheme 14. The method according to any one of Implementation Schemes 1-13, wherein the administration of the anti-HER2 antibody drug conjugate is performed by intravenous infusion.

[0210] Implementation Scheme 15. The method according to any one of Implementation Schemes 1-14, wherein the method comprises further administering a PD-1 / PD-L1 inhibitor to the subject.

[0211] Implementation Scheme 16. The method according to Implementation Scheme 15, wherein the PD-1 / PD-L1 inhibitor is an anti-PD-L1 antibody or its antigen-binding fragment or an anti-PD-1 antibody or its antigen-binding fragment; preferably, the PD-1 / PD-L1 inhibitor is an anti-PD-L1 antibody or its antigen-binding fragment.

[0212] Implementation Scheme 17. The method according to Implementation Scheme 16, wherein the anti-PD-L1 antibody or its antigen-binding fragment comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:22, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:23, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:24, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:25, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:26, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:27.

[0213] Implementation Scheme 18. The method according to Implementation Scheme 17, wherein the anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:28, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:29.

[0214] Implementation Scheme 19. The method according to Implementation Scheme 17 or 18, wherein the anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:30, and a light chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:31.

[0215] Implementation Scheme 20. The method according to any one of Implementation Schemes 16-19, wherein the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment is 50-1800 mg, 100-1200 mg, or 100-600 mg; preferably, the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment is 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, and / or 1800 mg; more preferably, the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment is 600 mg.

[0216] Implementation Scheme 21. The method according to any one of Implementation Schemes 16-20, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered in a therapeutically effective amount.

[0217] Implementation Scheme 22. The method according to any one of Implementation Schemes 16-21, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 600-2400 mg, 600-1800 mg, or 1200-1500 mg each time; preferably, the anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 600 mg, 800 mg, 1000 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg each time; more preferably, the anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 1200 mg each time.

[0218] Implementation Scheme 23. The method according to any one of Implementation Schemes 16-22, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-PD-L1 antibody or its antigen-binding fragment is administered once every 3 weeks.

[0219] Implementation Scheme 24. The method according to any one of Implementation Schemes 16-23, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered once every 3 weeks at a dose of 1200 mg each time.

[0220] Implementation Scheme 25. The method according to any one of Implementation Schemes 16-24, wherein the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment may be administered simultaneously, sequentially and / or alternately; and / or the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are administered on the same day.

[0221] Implementation Scheme 26. The method according to any one of Implementation Schemes 1-25, wherein each treatment cycle is 3 weeks.

[0222] Implementation Scheme 27. The method according to any one of Implementation Schemes 1-26, wherein the non-small cell lung cancer is locally advanced non-small cell lung cancer.

[0223] Implementation Scheme 28. The method according to any one of Implementation Schemes 1-26, wherein the non-small cell lung cancer is stage IIIB or stage IIIC non-small cell lung cancer.

[0224] Implementation Scheme 29. The method according to any one of Implementation Schemes 1-26, wherein the non-small cell lung cancer is recurrent and / or metastatic non-small cell lung cancer.

[0225] Implementation Scheme 30. The method according to any one of Implementation Schemes 1-26, wherein the non-small cell lung cancer is stage IV non-small cell lung cancer.

[0226] Implementation Scheme 31. The method according to any one of Implementation Schemes 1-30, wherein the non-small cell lung cancer is HER2 overexpression, HER2 amplification and / or HER2 mutation non-small cell lung cancer.

[0227] Implementation Scheme 32. The method according to Implementation Scheme 31, wherein the HER2 overexpression is determined by HER2 detection by IHC as IHC 3+ or IHC 2+.

[0228] Implementation Scheme 33. The method according to Implementation Scheme 31, wherein the HER2 mutation is a HER2 exon 20 insertion mutation or a single base pair substitution mutation.

[0229] Implementation Scheme 34. The method according to Implementation Scheme 31, wherein the HER2 mutation is selected from at least one of the following groups: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, G776delinsLC, G776delinsAVGC, G776delin sVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S77 9insG, S779_P780insVGS, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I6 54V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755 A. L755F, S760F, D769H, D769N, D769Y, G776C, G776L, S779P, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L;

[0230] Preferably, the HER2 mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310Y, and S310F.

[0231] Implementation Scheme 35. The method according to any one of Implementation Schemes 1-35, wherein the non-small cell lung cancer is EGFR-mutant non-small cell lung cancer.

[0232] Implementation Scheme 36. The method according to Implementation Scheme 36, wherein the EGFR mutation is selected from at least one of the following: EGFR exon 19 deletion mutation, EGFR exon 21 L858R mutation and EGFR exon 20 insertion mutation.

[0233] Implementation Scheme 37. The method according to any one of Implementation Schemes 1-37, wherein the subject with non-small cell lung cancer has previously been treated for non-small cell lung cancer.

[0234] Implementation Scheme 38. The method according to Implementation Scheme 38, wherein the subject with non-small cell lung cancer has previously received standard treatment for non-small cell lung cancer.

[0235] Implementation Scheme 39. The method according to any one of Implementation Schemes 1-39, wherein the subject with non-small cell lung cancer is not suitable for surgery and / or radical concurrent chemoradiotherapy to treat non-small cell lung cancer.

[0236] Implementation Scheme 40. The method according to any one of Implementation Schemes 1-40, wherein,

[0237] The anti-HER2 antibody-drug conjugate is used as a first-line treatment for non-small cell lung cancer in subjects; or the anti-HER2 antibody-drug conjugate is used as a second-line or later-line treatment for non-small cell lung cancer in subjects.

[0238] Implementation Scheme 41. The method according to any one of Implementation Schemes 15-40, wherein,

[0239] The anti-HER2 antibody-drug conjugate and PD-1 / PD-L1 inhibitor are used in combination for first-line treatment of non-small cell lung cancer in subjects; or the anti-HER2 antibody-drug conjugate and PD-1 / PD-L1 inhibitor are used in combination for second-line or later-line treatment of non-small cell lung cancer in subjects.

[0240] Implementation Scheme 42. Use of an anti-HER2 antibody drug conjugate in the preparation of a medicament for treating non-small cell lung cancer in a subject, wherein the anti-HER2 antibody drug conjugate is formed by linking a drug-linker of the structure shown in Formula Ia to an antigen-binding construct targeting HER2.

[0241] In formula Ia, the 3-position of -(succinimide-3-yl-N)- is linked to the antigen-binding construct targeting HER2.

[0242] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment. The first antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6. The second antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

[0243] Implementation Scheme 43. The use according to Implementation Scheme 42, wherein the average number of drug-connectors in each HER2-targeting antigen-binding construct is 4 to 7.

[0244] Implementation Scheme 44. The use according to Implementation Scheme 43, wherein the average number of drug-connectors in each HER2-targeting antigen-binding construct is 5 to 6.

[0245] Implementation Scheme 45. The use according to Implementation Scheme 44, wherein the average number of drug-connectors in each HER2-targeting antigen-binding construct is 5.5 to 6.

[0246] Implementation Scheme 46. The use according to any one of Implementation Schemes 42-45, wherein,

[0247] (i) The first antigen-binding fragment comprises a heavy chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:7;

[0248] (ii) The first antigen-binding fragment comprises a light chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:8;

[0249] (iii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:8;

[0250] (iv) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:15;

[0251] (v) The second antigen-binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16;

[0252] (vi) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 16; or

[0253] (vii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8. The amino acid sequence shown in NO:15 has a heavy chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16, and a light chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16.

[0254] Implementation Scheme 47. The use according to any one of Implementation Schemes 42-46, wherein,

[0255] (i) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:17 or 20;

[0256] (ii) The antigen-binding construct targeting HER2 comprises a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 18 or 21;

[0257] (iii) The antigen-binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:19;

[0258] (iv) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 17 or 20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 18 or 21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 18 or 21; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 17 or 20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0259] (v) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0260] (vi) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0261] (vii) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:21; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity; or

[0262] (viii) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0263] Implementation Scheme 48. The use according to any one of Implementation Schemes 42-47, wherein the unit dose of the anti-HER2 antibody drug conjugate is 50-600 mg, 100-400 mg, or 100-200 mg; preferably, the unit dose of the anti-HER2 antibody drug conjugate is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg; more preferably, the unit dose of the anti-HER2 antibody drug conjugate is 100 mg.

[0264] Implementation Scheme 49. The use according to any one of Implementation Schemes 42-48, wherein the drug comprises a therapeutically effective amount of the anti-HER2 antibody-drug conjugate.

[0265] Implementation Scheme 50. The use according to any one of Implementation Schemes 42-49, wherein the drug is formulated to be administered at a dose of 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg per administration; preferably, the drug is formulated to be administered at a dose of 6-7.5 mg / kg per administration.

[0266] Implementation Scheme 51. The use according to Implementation Scheme 50, wherein the drug is formulated to be administered at a dose of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg or 9 mg / kg per administration; preferably, the drug is formulated to be administered at a dose of 6 mg / kg or 7.5 mg / kg per administration.

[0267] Implementation Scheme 52. The use according to any one of Implementation Schemes 42-51, wherein the anti-HER2 antibody drug conjugate is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks.

[0268] Implementation Scheme 53. The use according to any one of Implementation Schemes 42-52, wherein the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 6 mg / kg or 7.5 mg / kg; preferably, the anti-HER2 antibody drug conjugate is administered once every 3 weeks at a dose of 7.5 mg / kg.

[0269] Implementation Scheme 54. The use according to any one of Implementation Schemes 42-53, wherein the anti-HER2 antibody drug conjugate is formulated as a preparation for intravenous injection or infusion.

[0270] Implementation Scheme 55. The use according to any one of Implementation Schemes 42-54, wherein the administration of the anti-HER2 antibody drug conjugate is by intravenous infusion.

[0271] Implementation Scheme 56. Use of an anti-HER2 antibody drug conjugate in the preparation of a medicament for use in combination with a PD-1 / PD-L1 inhibitor to treat a subject with non-small cell lung cancer, wherein the anti-HER2 antibody drug conjugate is as described in any one of Implementation Schemes 42-55.

[0272] Implementation Scheme 57. Use of a PD-1 / PD-L1 inhibitor in the preparation of a medicament for use in combination with an anti-HER2 antibody drug conjugate for the treatment of a subject with non-small cell lung cancer, wherein the anti-HER2 antibody drug conjugate is as described in any one of Implementation Schemes 42-55.

[0273] Implementation Scheme 58. The use according to Implementation Scheme 56 or 57, wherein the PD-1 / PD-L1 inhibitor is an anti-PD-L1 antibody or its antigen-binding fragment or an anti-PD-1 antibody or its antigen-binding fragment; preferably, the PD-1 / PD-L1 inhibitor is an anti-PD-L1 antibody or its antigen-binding fragment.

[0274] Implementation Scheme 59. The use according to Implementation Scheme 58, wherein the anti-PD-L1 antibody or its antigen-binding fragment comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:22, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:23, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:24, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:25, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:26, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:27.

[0275] Implementation Scheme 60. The use according to Implementation Scheme 59, wherein the anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:28, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:29.

[0276] Implementation Scheme 61. The use according to Implementation Scheme 59 or 60, wherein the anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy chain having an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:30, and a light chain having an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:31.

[0277] Implementation Scheme 62. The use according to any one of Implementation Schemes 58-61, wherein the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment is 50-1800 mg, 100-1200 mg, or 100-600 mg; preferably, the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment is 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, and / or 1800 mg; more preferably, the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment is 600 mg.

[0278] Implementation Scheme 63. The use according to any one of Implementation Schemes 58-62, wherein the medicament comprises a therapeutically effective amount of the anti-PD-L1 antibody or its antigen-binding fragment.

[0279] Implementation Scheme 64. The use according to any one of Implementation Schemes 58-63, wherein the medicament is formulated to be administered at a dose of 600-2400 mg, 600-1800 mg, or 1200-1500 mg per administration; preferably, the medicament is formulated to be administered at a dose of 600 mg, 800 mg, 1000 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg per administration; more preferably, the medicament is formulated to be administered at a dose of 1200 mg per administration.

[0280] Implementation Scheme 65. The use according to any one of Implementation Schemes 58-64, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered once every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks; preferably, the anti-PD-L1 antibody or its antigen-binding fragment is administered once every 3 weeks.

[0281] Implementation Scheme 66. The use according to any one of Implementation Schemes 58-65, wherein the anti-PD-L1 antibody or its antigen-binding fragment is administered once every 3 weeks at a dose of 1200 mg each time.

[0282] Implementation Scheme 67. The use according to any one of Implementation Schemes 58-66, wherein the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment may be administered simultaneously, sequentially and / or alternately; and / or the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment may be administered on the same day.

[0283] Implementation Scheme 68. The use according to any one of Implementation Schemes 42-67, wherein each treatment cycle is 3 weeks.

[0284] Implementation Scheme 69. The use according to any one of Implementation Schemes 42-68, wherein the non-small cell lung cancer is locally advanced non-small cell lung cancer.

[0285] Implementation Scheme 70. The use according to any one of Implementation Schemes 42-68, wherein the non-small cell lung cancer is stage IIIB or stage IIIC non-small cell lung cancer.

[0286] Implementation Scheme 71. The use according to any one of Implementation Schemes 42-68, wherein the non-small cell lung cancer is recurrent and / or metastatic non-small cell lung cancer.

[0287] Implementation Scheme 72. The use according to any one of Implementation Schemes 42-68, wherein the non-small cell lung cancer is stage IV non-small cell lung cancer.

[0288] Implementation Scheme 73. The use according to any one of Implementation Schemes 42-72, wherein the non-small cell lung cancer is HER2 overexpressing, HER2 amplified and / or HER2-mutated non-small cell lung cancer.

[0289] Implementation Scheme 74. According to the use described in Implementation Scheme 73, wherein the HER2 overexpression is determined by HER2 detection via IHC to be IHC 3+ or IHC 2+.

[0290] Implementation Scheme 75. The use according to Implementation Scheme 73, wherein the HER2 mutation is a HER2 exon 20 insertion mutation or a single base pair substitution mutation.

[0291] Implementation Scheme 76. According to the use described in Implementation Scheme 72, wherein the HER2 mutation is selected from at least one of the following groups: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, G776delinsLC, G776delinsAVGC, G776delin sVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_S77 9insG, S779_P780insVGS, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I6 54V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L755 A. L755F, S760F, D769H, D769N, D769Y, G776C, G776L, S779P, R784C, R784H, L785R, L786V, T791I, G804S, L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L;

[0292] Preferably, the HER2 mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310Y, and S310F.

[0293] Implementation Scheme 77. The use according to any one of Implementation Schemes 42-76, wherein the non-small cell lung cancer is EGFR-mutant non-small cell lung cancer.

[0294] Implementation Scheme 78. The use according to Implementation Scheme 77, wherein the EGFR mutation is selected from at least one of the following: EGFR exon 19 deletion mutation, EGFR exon 21 L858R mutation and EGFR exon 20 insertion mutation.

[0295] Implementation Scheme 79. The use according to any one of Implementation Schemes 42-78, wherein the subject with non-small cell lung cancer has previously been treated for non-small cell lung cancer;

[0296] Preferably, the subject with non-small cell lung cancer has previously received standard treatment for non-small cell lung cancer.

[0297] Implementation Scheme 80. The use according to any one of Implementation Schemes 42-80, wherein the subject with non-small cell lung cancer is not suitable for surgery and / or radical concurrent chemoradiotherapy to treat non-small cell lung cancer.

[0298] Implementation Scheme 81. The use according to any one of Implementation Schemes 42-81, wherein,

[0299] The anti-HER2 antibody-drug conjugate is used as a first-line treatment for non-small cell lung cancer in subjects; or the anti-HER2 antibody-drug conjugate is used as a second-line or later-line treatment for non-small cell lung cancer in subjects.

[0300] Implementation Scheme 82. The use according to any one of Implementation Schemes 56-81, wherein,

[0301] The anti-HER2 antibody-drug conjugate and PD-1 / PD-L1 inhibitor are used in combination for first-line treatment of non-small cell lung cancer in subjects; or the anti-HER2 antibody-drug conjugate and PD-1 / PD-L1 inhibitor are used in combination for second-line or later-line treatment of non-small cell lung cancer in subjects.

[0302] Implementation Scheme 83. A drug combination comprising an anti-HER2 antibody-drug conjugate and a PD-1 / PD-L1 inhibitor, wherein the anti-HER2 antibody-drug conjugate is formed by linking a drug-linker of the structure shown in Formula Ia to an antigen-binding construct targeting HER2.

[0303] In formula Ia, the 3-position of -(succinimide-3-yl-N)- is linked to the antigen-binding construct targeting HER2.

[0304] The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment. The first antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:6. The second antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:14.

[0305] Implementation Scheme 84. The drug combination according to Implementation Scheme 83, wherein the average number of drug-connectors in each HER2-targeting antigen-binding construct is 4 to 7.

[0306] Implementation Scheme 85. The drug combination according to Implementation Scheme 84, wherein the average number of drug-connectors in each HER2-targeting antigen-binding construct is 5 to 6.

[0307] Implementation Scheme 86. The drug combination according to Implementation Scheme 85, wherein the average number of drug-connectors for each HER2-targeting antigen-binding construct is 5.5 to 6.

[0308] Implementation Scheme 87. The drug combination according to any one of Implementation Schemes 83-86, wherein,

[0309] (i) The first antigen-binding fragment comprises a heavy chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:7;

[0310] (ii) The first antigen-binding fragment comprises a light chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:8;

[0311] (iii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:8;

[0312] (iv) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:15;

[0313] (v) The second antigen-binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16;

[0314] (vi) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 16; or

[0315] (vii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8. The amino acid sequence shown in NO:15 has a heavy chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16, and a light chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16.

[0316] Implementation Scheme 88. The drug combination according to any one of Implementation Schemes 83-87, wherein,

[0317] (i) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:17 or 20;

[0318] (ii) The antigen-binding construct targeting HER2 comprises a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 18 or 21;

[0319] (iii) The antigen-binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:19;

[0320] (iv) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 17 or 20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 18 or 21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 18 or 21; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 17 or 20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0321] (v) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0322] (vi) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0323] (vii) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:21; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity; or

[0324] (viii) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity.

[0325] Implementation Scheme 89. The drug combination according to any one of Implementation Schemes 83-88, wherein the PD-1 / PD-L1 inhibitor is an anti-PD-L1 antibody or its antigen-binding fragment or an anti-PD-1 antibody or its antigen-binding fragment; preferably, the PD-1 / PD-L1 inhibitor is an anti-PD-L1 antibody or its antigen-binding fragment.

[0326] Implementation Scheme 90. The drug combination according to Implementation Scheme 89, wherein the anti-PD-L1 antibody or its antigen-binding fragment comprises: HCDR1 comprising the amino acid sequence shown in SEQ ID NO:22, HCDR2 comprising the amino acid sequence shown in SEQ ID NO:23, HCDR3 comprising the amino acid sequence shown in SEQ ID NO:24, LCDR1 comprising the amino acid sequence shown in SEQ ID NO:25, LCDR2 comprising the amino acid sequence shown in SEQ ID NO:26, and LCDR3 comprising the amino acid sequence shown in SEQ ID NO:27.

[0327] Implementation Scheme 91. The drug combination according to Implementation Scheme 90, wherein the anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:28, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:29.

[0328] Implementation Scheme 92. The drug combination according to Implementation Scheme 90 or 91, wherein the anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:30, and a light chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:31.

[0329] Implementation Scheme 93. The drug combination according to any one of Implementation Schemes 83-92, wherein the unit dose of the anti-HER2 antibody drug conjugate is 50-600 mg, 100-400 mg, or 100-200 mg; preferably, the unit dose of the anti-HER2 antibody drug conjugate is 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, and / or 600 mg; more preferably, the unit dose of the anti-HER2 antibody drug conjugate is 100 mg.

[0330] Implementation Scheme 94. The drug combination according to any one of Implementation Schemes 89-93, wherein the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment is 50-1800 mg, 100-1200 mg, or 100-600 mg; preferably, the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment is 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, and / or 1800 mg; more preferably, the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment is 600 mg.

[0331] Implementation Scheme 95. A drug combination according to any one of Implementation Schemes 83-94, wherein the drug combination comprises an anti-HER2 antibody drug conjugate at doses of 1.5-9 mg / kg, 5-7.5 mg / kg, or 6-7.5 mg / kg; preferably, the drug combination comprises an anti-HER2 antibody drug conjugate at doses of 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg; more preferably, the drug combination comprises an anti-HER2 antibody drug conjugate at doses of 6 mg / kg or 7.5 mg / kg.

[0332] Implementation Scheme 96. A drug combination according to any one of Implementation Schemes 89-95, wherein the drug combination comprises 600-2400 mg, 600-1800 mg, or 1200-1500 mg of an anti-PD-L1 antibody or an antigen-binding fragment thereof; preferably, the drug combination comprises 600 mg, 800 mg, 1000 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg, or 2400 mg of an anti-PD-L1 antibody or an antigen-binding fragment thereof; more preferably, the drug combination comprises 1200 mg of an anti-PD-L1 antibody or an antigen-binding fragment thereof.

[0333] Implementation Scheme 97. The drug combination according to any one of Implementation Schemes 83-96, wherein each treatment cycle is 3 weeks.

[0334] Implementation Scheme 98. The drug combination according to any one of Implementation Schemes 83-97, wherein the drug combination is used to treat non-small cell lung cancer.

[0335] Implementation Scheme 99. The drug combination according to Implementation Scheme 98, wherein the non-small cell lung cancer is locally advanced non-small cell lung cancer.

[0336] Implementation Scheme 100. The drug combination according to Implementation Scheme 98, wherein the non-small cell lung cancer is stage IIIB or stage IIIC non-small cell lung cancer.

[0337] Implementation Scheme 101. The drug combination according to Implementation Scheme 98, wherein the non-small cell lung cancer is recurrent and / or metastatic non-small cell lung cancer.

[0338] Implementation Scheme 102. The drug combination according to Implementation Scheme 98, wherein the non-small cell lung cancer is stage IV non-small cell lung cancer.

[0339] Implementation Scheme 103. The drug combination according to any one of Implementation Schemes 98-102, wherein the non-small cell lung cancer is HER2 overexpression, HER2 amplification and / or HER2 mutation non-small cell lung cancer.

[0340] Implementation Scheme 104. The drug combination according to Implementation Scheme 103, wherein the HER2 overexpression is determined by HER2 detection by IHC as IHC 3+ or IHC 2+.

[0341] Implementation Scheme 105. The drug combination according to Implementation Scheme 103, wherein the HER2 mutation is a HER2 exon 20 insertion mutation or a single base pair substitution mutation.

[0342] Implementation Scheme 106. The drug combination according to Implementation Scheme 103, wherein the HER2 mutation is selected from at least one of the following groups: Y772_A775dup, G778_P780dup, G776delinsVC, E770_A771insAYVM, A771_Y772insYVMA, M774_A775insAYVM, G776delinsLC, G776delinsAVGC, G776de linsVV、G776_V777insL、G776_V777insVC、G776_V777insVGC、V777_G778insCG、V777_G778insG、G778_ S779insG, S779_P780insVGS, L755S, V777L, V659E, G660D, S310F, A20T, A21S, R143Q, K200N, A242V, D277 Y, A293P, N302K, V308M, S310Y, N319Y, S335C, R340P, S418T, W452C, V541M, I613V, P627H, A644V, R647G, I654V, I655V, I661V, R678Q, Q680H, V697L, G704R, Q709L, Q711H, G727A, T733I, E744G, N745D, L755P, L75 5A, L755F, S760F, D769H, D769N, D769Y, G776C, G776L, S779P, R784C, R784H, L785R, L786V, T791I, G804S , L807F, S819F, I829T, V842I, L846F, T862I, R868W, L869R, T875I, W906*, T917S, Q943*, S1007* and S1151L.

[0343] Implementation Scheme 107. The drug combination according to Implementation Scheme 106, wherein the HER2 mutation is at least one selected from the group consisting of: Y772_A775dup, G778_P780dup, G776delinsVC, L755S, V777L, V659E, G660D, S310Y, and S310F.

[0344] Implementation Scheme 108. The drug combination according to any one of Implementation Schemes 98-107, wherein the non-small cell lung cancer is EGFR-mutant non-small cell lung cancer.

[0345] Implementation Scheme 109. The drug combination according to Implementation Scheme 108, wherein the EGFR mutation is selected from at least one of the following: EGFR exon 19 deletion mutation, EGFR exon 21 L858R mutation and EGFR exon 20 insertion mutation.

[0346] Implementation Scheme 110. The drug combination according to any one of Implementation Schemes 98-109, wherein the subject with non-small cell lung cancer has previously been treated for non-small cell lung cancer.

[0347] Implementation Scheme 111. The drug combination according to Implementation Scheme 110, wherein the subject with non-small cell lung cancer has previously received standard treatment for non-small cell lung cancer.

[0348] Implementation Scheme 112. The drug combination according to any one of Implementation Schemes 98-111, wherein the subject with non-small cell lung cancer is not suitable for surgery and / or radical concurrent chemoradiotherapy to treat non-small cell lung cancer.

[0349] Implementation Scheme 113. The drug combination according to any one of Implementation Schemes 98-112, wherein the anti-HER2 antibody drug conjugate is used as first-line treatment of a subject for non-small cell lung cancer; or

[0350] The anti-HER2 antibody-drug conjugate is used for second-line or later-line treatment of non-small cell lung cancer in subjects.

[0351] Implementation Scheme 114. The drug combination according to any one of Implementation Schemes 98-112, wherein,

[0352] The drug combination was used as first-line treatment for non-small cell lung cancer in the subjects; or

[0353] The drug combination is used as a second-line or later-line treatment for non-small cell lung cancer in subjects.

[0354] Implementation Scheme 115. The drug combination according to any one of Implementation Schemes 98-114, wherein the anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment are packaged separately.

[0355] Implementation Scheme 116. A method of treating a subject with non-small cell lung cancer, comprising administering to the subject the combination of drugs described in any one of Implementation Schemes 83-115. Example

[0356] For clarity, this disclosure is further illustrated by examples, but the examples are not intended to limit the scope of this disclosure.

[0357] The entire contents of patent application documents WO2022033578 or CN115702008A are incorporated herein by reference. The anti-HER2 antibody drug conjugate in the following examples is an anti-HER2 antibody drug conjugate (hereinafter referred to as ADC1) prepared according to the preparation method described in WO2022033578, represented by the following formula:

[0358] In this process, the drug-connector is linked to the HER2-targeting antigen-binding construct via a thioether bond, where n is 5 to 6. In short, the nucleic acid sequences of the three polypeptide chains (amino acid sequences shown in SEQ ID NO: 17, 18, and 19, respectively) encoding the HER2-targeting antigen-binding construct are cloned into the pcDNA3.1 expression vector, co-transfected into FUT8-knockout CHO-S cells for expression, and purified by protein A to obtain the HER2-targeting antigen-binding construct. The HER2-targeting antigen-binding construct is treated with tris(2-carboxyethyl)phosphonic acid hydrochloride, and then reacted with a adapter-payload selected from the structure shown below to finally obtain ADC1:

[0359] The entire contents of patent application documents WO2016022630A1 or CN107001463A are incorporated herein by reference. The heavy chain amino acid sequence of the anti-PD-L1 antibody (hereinafter referred to as Ab1) in the following examples is shown in SEQ ID NO:30 of this disclosure, and the light chain amino acid sequence is shown in SEQ ID NO:31 of this disclosure.

[0360] Example 1: Clinical trial of non-small cell lung cancer with HER2 gene and other HER family gene abnormalities

[0361] 1. Research Objective:

[0362] 1.1 Phase A

[0363] To evaluate the preliminary efficacy, safety, and immunogenicity of ADC1 and ADC1 combined with Ab1 in non-small cell lung cancer with HER2 gene or other HER family gene abnormalities.

[0364] 1.2 Phase B

[0365] To evaluate the objective response rate (ORR), duration of response (DOR), progression-free survival (FPS), overall survival (OS), safety, and immunogenicity of ADC1 in non-small cell lung cancer with HER2 gene abnormalities.

[0366] 2. Experimental Design

[0367] 2.1 Phase A

[0368] Cohort 1: Subjects receiving ADC1 alone, carrying the HER2 mutation, numbering no more than 40;

[0369] Cohort 2: Subjects who received ADC1 alone and carried HER2 amplification or overexpression but did not have HER2 mutations;

[0370] Cohort 3: Subjects who received ADC1 alone carried EGFR mutations;

[0371] Cohort 4: Subjects who received combined administration of ADC1 and Ab1 carried HER2 mutations, HER2 amplification, or HER2 overexpression.

[0372] Phase 2.2B

[0373] This was conducted based on the results of the Phase A clinical trial.

[0374] 3. Selection Criteria

[0375] Subjects who meet all of the following inclusion criteria are eligible to be enrolled in this trial:

[0376] (1) The participants voluntarily joined the study, signed informed consent forms, and had good compliance;

[0377] (2) Age: 18-75 years old (at the time of signing the informed consent form); ECOGPS score: 0-1; expected survival period of more than 3 months;

[0378] (3) Patients with locally advanced (stage IIIB / IIIC), metastatic or recurrent (stage IV) NSCLC who are cytologically or histologically confirmed to be untreatable and ineligible for radical concurrent chemoradiotherapy according to the 8th edition of the TNM staging system for lung cancer by the International Association for the Study of Lung Cancer and the Joint Committee on Cancer Classification of Cancer of the United States.

[0379] (4) Previous standard treatment has failed;

[0380] (5) Cohort 1, Cohort 2 and Cohort 4 require that the subjects have HER2 mutation or overexpression (IHC 2+ or IHC 3+) in their samples within 2 years, and Cohort 3 requires that the subjects carry EGFR mutation;

[0381] (6) There must be at least one measurable lesion according to RECIST 1.1 criteria. Lesions that have previously received radiotherapy cannot be considered as target lesions unless there is clear progression of the lesion after radiotherapy (except for those with only skin and / or brain lesions as measurable lesions).

[0382] (7) Major organ functions are good, and blood routine, biochemical tests, and coagulation function tests meet the standards:

[0383] (8) Female participants of childbearing age should agree to use contraception (such as intrauterine device, birth control pill or condom) during the study and for 6 months after the study ends; have a negative serum pregnancy test within 7 days before the study enrollment and be a non-lactating participant; male participants should agree to use contraception during the study and for 6 months after the study ends.

[0384] 4. Test drug

[0385] ADC1 for injection (specification: 100mg / vial) was developed and supplied by Nanjing Shunxin Pharmaceutical Co., Ltd., a subsidiary of Chia Tai Tianqing Pharmaceutical Group.

[0386] Ab1 injection (specification: 600mg / 20mL / vial) was developed and supplied by Nanjing Shunxin Pharmaceutical Co., Ltd., a subsidiary of Chia Tai Tianqing Pharmaceutical Group.

[0387] 5. Treatment Plan

[0388] 5.1 Queues 1, 2, and 3:

[0389] ADC1 was administered intravenously at a dose of 7.5 mg / kg, with each treatment cycle consisting of 3 weeks (21 days). ADC1 was administered once per treatment cycle (the dosing window was ±3 days of the planned dosing time) until clinical benefit was lost, toxicity became intolerable, or the investigator deemed it unsuitable to continue treatment.

[0390] 5.2 Queue 4:

[0391] ADC1 and Ab1 were administered in combination via intravenous infusion, with Ab1 administered first, followed by ADC1, and both were given on the same day. The ADC1 dosage was 6.0 mg / kg or 7.5 mg / kg, administered once every 3 weeks (21 days) as one treatment cycle; the Ab1 dosage was 1200 mg, administered once every 3 weeks (21 days) as one treatment cycle. The dosing window for both ADC1 and Ab1 was ±3 days from the planned dosing time, and treatment continued until clinical benefit was lost, toxicity became intolerable, or the investigator deemed it unsuitable to continue treatment.

[0392] Adjustments can be made based on the severity of the disease, the disease response, any treatment-related toxicities, the patient's age, and health status.

[0393] 6. Evaluation Criteria

[0394] Effectiveness evaluation: The disease status was determined using the RECIST 1.1 criteria.

[0395] Safety assessment: The severity of adverse events was determined using the NCI-CTC AE 5.0 standard.

[0396] 7. Endpoint Indicators

[0397] 7.1 Phase A

[0398] (1) Primary endpoint:

[0399] ORR as assessed by researchers.

[0400] (2) Secondary endpoint:

[0401] Other efficacy metrics include duration of response (DOR), progression-free survival (PFS), and overall survival (OS);

[0402] Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), as well as abnormal laboratory test results;

[0403] Immunogenicity: such as the incidence of ADA.

[0404] 7.2 Phase B

[0405] (1) Primary endpoint:

[0406] ORR assessed by an independent image review committee.

[0407] (2) Secondary endpoint:

[0408] Other effectiveness metrics assessed by researchers, such as ORR, DOR, PFS, and OS;

[0409] Incidence and severity of AE and SAE, as well as abnormal laboratory test results;

[0410] Immunogenicity: such as the incidence of ADA.

[0411] 8. Results

[0412] As of the data collection date, in Cohort 1, 36 subjects reached evaluable status, of which 23 achieved partial remission (PR), with an ORR of 63.89%; in Cohort 2, 11 subjects reached evaluable status, of which 5 achieved PR, with an ORR of 45.45%; in Cohort 3, 36 subjects reached evaluable status, of which 18 achieved PR, with an ORR of 50%; and in Cohort 4, 12 subjects reached evaluable status, of which 6 achieved PR, with an ORR of 50%.

[0413] The specific results of a representative subset of the participants are shown in the table below:

[0414] The results show that the anti-HER2 antibody-drug conjugate disclosed herein, or the anti-HER2 antibody-drug conjugate combined with anti-PD-L1 antibody, has good efficacy in patients with non-small cell lung cancer (especially non-small cell lung cancer with HER2 mutation, HER2 amplification, HER2 overexpression and / or EGFR mutation), exhibits low immunogenicity, and demonstrates the expected safety in clinical trials.

Claims

An anti-HER2 antibody-drug conjugate and an anti-PD-L1 antibody or their antigen-binding fragment for combination therapy in subjects with non-small cell lung cancer, wherein, The anti-HER2 antibody-drug conjugate is formed by linking a drug-linker of the structure shown in Formula Ia with an antigen-binding construct targeting HER2. In formula Ia, the 3-position of -(succinimide-3-yl-N)- is linked to the antigen-binding construct targeting HER2. The HER2-targeting antigen-binding construct comprises a first antigen-binding fragment and a second antigen-binding fragment. The first antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:1, HCDR2 containing the amino acid sequence shown in SEQ ID NO:2, HCDR3 containing the amino acid sequence shown in SEQ ID NO:3, LCDR1 containing the amino acid sequence shown in SEQ ID NO:4, LCDR2 containing the amino acid sequence shown in SEQ ID NO:5, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:

6. The second antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:9, HCDR2 containing the amino acid sequence shown in SEQ ID NO:10, HCDR3 containing the amino acid sequence shown in SEQ ID NO:11, LCDR1 containing the amino acid sequence shown in SEQ ID NO:12, LCDR2 containing the amino acid sequence shown in SEQ ID NO:13, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:

14. And among them, The anti-PD-L1 antibody or its antigen-binding fragment comprises: HCDR1 containing the amino acid sequence shown in SEQ ID NO:22, HCDR2 containing the amino acid sequence shown in SEQ ID NO:23, HCDR3 containing the amino acid sequence shown in SEQ ID NO:24, LCDR1 containing the amino acid sequence shown in SEQ ID NO:25, LCDR2 containing the amino acid sequence shown in SEQ ID NO:26, and LCDR3 containing the amino acid sequence shown in SEQ ID NO:

27. According to claim 1, the anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for the combined treatment of non-small cell lung cancer in subjects, wherein, The average number of drug-linkers for each HER2-targeting antigen-binding construct is 4 to 7, 5 to 6, or 5.5 to 6. According to claim 1 or 2, the anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects, wherein, (i) The first antigen-binding fragment comprises a heavy chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:7; (ii) The first antigen-binding fragment comprises a light chain variable region having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity with the amino acid sequence shown in SEQ ID NO:8; (iii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:8; (iv) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:15; (v) The second antigen-binding fragment comprises a light chain variable region having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16; (vi) The second antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 15, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 16; or (vii) The first antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:7, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:8; and the second antigen-binding fragment comprises an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:

8. The amino acid sequence shown in NO:15 has a heavy chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:16, and a light chain variable region that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:

16. The anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects according to any one of claims 1-3, wherein, (i) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO:17 or 20; (ii) The antigen-binding construct targeting HER2 comprises a second polypeptide chain having an amino acid sequence that is at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence shown in SEQ ID NO: 18 or 21; (iii) The antigen-binding construct targeting HER2 comprises a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with the amino acid sequence shown in SEQ ID NO:19; (iv) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 17 or 20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 18 or 21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 18 or 21; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO: 17 or 20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity. (v) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:

18. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity. (vi) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:

20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity. (vii) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:17; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:21; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:21; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:

17. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity; or (viii) The antigen-binding construct targeting HER2 comprises a first polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:18; and a second polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:20; and a third polypeptide chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:

20. The amino acid sequence shown in NO:19 has a third polypeptide chain with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity. The anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects according to any one of claims 1-4, wherein, The anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:28, and a light chain variable region having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:

29. The anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects according to any one of claims 1-5, wherein, The anti-PD-L1 antibody or its antigen-binding fragment comprises a heavy chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:30, and a light chain having an amino acid sequence identity of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% with respect to the amino acid sequence shown in SEQ ID NO:

31. The anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects according to any one of claims 1-6, wherein, The unit dose of the anti-HER2 antibody-drug conjugate is preferably 50-600 mg, 100-400 mg, 100-200 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg; and / or the unit dose of the anti-PD-L1 antibody or its antigen-binding fragment is preferably 50-1800 mg, 100-1200 mg, 100-600 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1600 mg, or 1800 mg. The anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects according to any one of claims 1-7, wherein, The anti-HER2 antibody-drug conjugate is administered at doses of 1.5-9 mg / kg, 5-7.5 mg / kg, 6-7.5 mg / kg, 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 5 mg / kg, 5.4 mg / kg, 6 mg / kg, 7.5 mg / kg, or 9 mg / kg; preferably, the anti-HER2 antibody-drug conjugate is administered at a dose of 6 mg / kg or 7.5 mg / kg; and / or the anti-PD-L...

1. The antibody or its antigen-binding fragment is administered at a dose of 600-2400 mg, 600-1800 mg, 1200-1500 mg, 600 mg, 800 mg, 1000 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1800 mg, 2000 mg, 2200 mg or 2400 mg each time; preferably, the anti-PD-L1 antibody or its antigen-binding fragment is administered at a dose of 1200 mg each time. The anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects according to any one of claims 1-8, wherein, The anti-HER2 antibody-drug conjugate is administered once every 1 week, 2 weeks, 3 weeks, or 4 weeks; preferably, the anti-HER2 antibody-drug conjugate is administered once every 3 weeks; and / or the anti-PD-L1 antibody or its antigen-binding fragment is administered once every 1 week, 2 weeks, 3 weeks, or 4 weeks; preferably, the anti-PD-L1 antibody or its antigen-binding fragment is administered once every 3 weeks. The anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects according to any one of claims 1-9, wherein, The anti-HER2 antibody drug conjugate is administered via intravenous infusion; and / or the anti-PD-L1 antibody or its antigen-binding fragment is administered via intravenous injection or intravenous infusion. The anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects according to any one of claims 1-10, wherein, The anti-HER2 antibody drug conjugate and the anti-PD-L1 antibody or its antigen-binding fragment can be administered simultaneously, sequentially, and / or alternately. The anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects according to any one of claims 1-11, wherein, The non-small cell lung cancer mentioned is locally advanced non-small cell lung cancer; The non-small cell lung cancer mentioned is stage IIIB or IIIC non-small cell lung cancer: The non-small cell lung cancer mentioned refers to recurrent and / or metastatic non-small cell lung cancer; The non-small cell lung cancer mentioned is stage IV non-small cell lung cancer: The non-small cell lung cancer mentioned is non-small cell lung cancer with abnormalities in the HER2 gene or EGFR gene: The non-small cell lung cancer referred to is non-small cell lung cancer with HER2 overexpression, HER2 amplification, HER2 mutation, and / or EGFR mutation. According to claim 12, the anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects, wherein, The HER2 mutation is either an insertion mutation in HER2 exon 20 or a single base pair substitution mutation. The anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects according to any one of claims 1-13, wherein, The subjects had previously received standard treatment for non-small cell lung cancer; The subject was not suitable for surgery and / or radical concurrent chemoradiotherapy to treat non-small cell lung cancer; or The subjects were locally advanced, recurrent, or metastatic non-small cell lung cancer patients who were not suitable for surgery and radical concurrent chemoradiotherapy. The anti-HER2 antibody-drug conjugate and anti-PD-L1 antibody or their antigen-binding fragment for combination therapy of non-small cell lung cancer in subjects according to any one of claims 1-14, wherein, The treatment mentioned is first-line treatment, second-line treatment, or later-line treatment.

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