Use of antibody or antibody-drug conjugate in combination with another therapeutic agent

Abstract

A use of an antibody-drug conjugate and another therapeutic agent in preparation of a drug for treating a tumor or cancer, wherein said another therapeutic agent is selected from one or more of an anti-EGFR antibody and an anti-VEGF antibody.

Description

Use of antibody or antibody drug conjugate in combination with other therapeutic agents

[0001] This application is based on and claims priority to Chinese Patent Application No. 202411369340.1, filed on September 29, 2024, Chinese Patent Application No. 202411890265.3, filed on December 20, 2024, and Chinese Patent Application No. 202511352136.3, filed on September 22, 2025, the disclosures of which are incorporated by reference herein in their entireties.

[0002] SEQUENCE LISTING

[0003] The instant application contains a Sequence Listing which has been submitted in XML format via EFS-Web and is hereby incorporated by reference in its entirety. Said Sequence Listing is entitled IEC250301PCT, was created on September 23, 2025, and is 28.6 KB in size. TECHNICAL FIELD

[0004] The present application relates to the field of targeted therapy, in particular to the use of antibody or antibody drug conjugate in combination with other therapeutic agents. Specifically, the combination of antibody or antibody drug conjugate with other therapeutic agents can be used for the treatment of tumors or cancers. BACKGROUND

[0005] Cancer treatment is a key area of global medical research, and its importance lies in its direct relationship with patient survival rate and quality of life. The main means of cancer treatment include surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, and emerging antibody drug conjugate (ADC) therapy. Each treatment method has its specific indications and advantages.

[0006] Surgical treatment is usually the first choice for early-stage cancer, treating cancer by physically removing tumor tissue. However, the risks of surgery and the impact on the patient's body are factors that must be considered. Radiotherapy uses high-energy rays to damage the DNA of cancer cells, and is suitable for a variety of cancer types, especially those that are not sensitive to chemotherapy, such as nasopharyngeal carcinoma and head and neck tumors. Chemotherapy, on the other hand, uses drugs to interfere with the proliferation of cancer cells, and it is a systemic treatment that can target cancer that has already spread. Targeted therapy and immunotherapy are relatively new treatment methods that work by more precisely targeting cancer cells or activating the patient's own immune system to reduce damage to normal cells.

[0007] Particularly noteworthy is ADC therapy, which combines the targeting of monoclonal antibodies and the killing power of cytotoxic drugs, enabling precise drug delivery to cancer cells. ADC therapy has shown significant efficacy in certain types of cancer, but there are still some challenges to overcome, including improving the specificity of treatment, reducing side effects, and addressing drug resistance.

[0008] Therefore, current cancer treatment drugs have limitations in safety and effectiveness. For example, chemotherapy drugs, while killing cancer cells, can also damage normal cells, leading to a series of side effects. Targeted therapy, although with better specificity, is not effective for all patients, and long-term use can lead to the development of drug resistance. Immunotherapy, although has achieved significant results in some patients, but there are also patients who may not respond to treatment, and can cause the immune system to attack normal tissues, leading to immune-related side effects. Therefore, new drugs and treatment methods need to be developed to improve the safety and effectiveness of treatment. SUMMARY

[0009] In one aspect, the present application provides use of an antibody drug conjugate and other therapeutic agents in the preparation of a medicament for treating a tumor or cancer; the other therapeutic agents are selected from one, two or more of an anti-EGFR antibody and a VEGF antibody.

[0010] In some embodiments, the present application provides use of an antibody drug conjugate and other therapeutic agents in the preparation of a medicament for treating a tumor or cancer; the other therapeutic agents are selected from one or more of an anti-EGFR antibody and a VEGF antibody.

[0011] In another aspect, the present application provides use of a composition of an antibody drug conjugate and other therapeutic agents in the preparation of a medicament for treating a tumor or cancer; the other therapeutic agents are selected from one, two or more of an anti-EGFR antibody and a VEGF antibody.

[0012] In some embodiments, the present application provides use of a composition of an antibody drug conjugate and other therapeutic agents in the preparation of a medicament for treating a tumor or cancer; the other therapeutic agents are selected from one or more of an anti-EGFR antibody and a VEGF antibody.

[0013] In another aspect, the present application provides use of an anti-EGFR antibody and a VEGF antibody in the preparation of a medicament for treating a tumor or cancer.

[0014] In some embodiments, the present application provides use of an anti-EGFR antibody and a VEGF antibody in the preparation of a medicament for treating a tumor or cancer.

[0015] In some embodiments, the anti-VEGF antibody is selected from one, two or more of Bevacizumab, Ranibizumab, Brolucizumab, Faricimab.

[0016] In some embodiments, the anti-VEGF antibody is Bevacizumab.

[0017] In some embodiments, the anti-EGFR antibody is selected from one, two or more of Cetuximab, Panitumumab, Necitumumab, Nimotuzumab, Amivantamab (Rybrevant).

[0018] In some embodiments, the anti-EGFR antibody is Cetuximab.

[0019] In some embodiments, the other therapeutic agent is Bevacizumab and Cetuximab.

[0020] In some embodiments, the antibody drug conjugate is an antibody drug conjugate targeting human Tyrosine Kinase 7 (PTK7).

[0021] In some embodiments, the antibody drug conjugate contains an anti-human Tyrosine Kinase 7 (PTK7) antibody or antigen binding fragment thereof.

[0022] In some embodiments, the antibody or antigen binding fragment thereof comprises:

[0023] (1) a heavy chain variable region (VH) and / or a light chain variable region (VL) as follows:

[0024] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 3 or a variant thereof, CDR-H2 of SEQ ID NO: 4 or a variant thereof, CDR-H3 of SEQ ID NO: 5 or a variant thereof; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6 or a variant thereof, CDR-L2 of SEQ ID NO: 7 or a variant thereof, CDR-L3 of SEQ ID NO: 8 or a variant thereof;

[0025] said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence from which it is derived or said variant has one or several amino acid substitutions, deletions, or additions compared to the sequence from which it is derived (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions); preferably said substitutions are conservative substitutions;

[0026] or,

[0027] (2) the following heavy chain variable region (VH) and / or light chain variable region (VL):

[0028] a heavy chain variable region (VH) comprising the following 3 CDRs: CDR-H1 of SEQ ID NO: 9 or a variant thereof, CDR-H2 of SEQ ID NO: 10 or a variant thereof, CDR-H3 of SEQ ID NO: 5 or a variant thereof; and / or, a light chain variable region (VL) comprising the following 3 CDRs: CDR-L1 of SEQ ID NO: 6 or a variant thereof, CDR-L2 of SEQ ID NO: 7 or a variant thereof, CDR-L3 of SEQ ID NO: 8 or a variant thereof;

[0029] said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence from which it is derived or said variant has one or several amino acid substitutions, deletions, or additions compared to the sequence from which it is derived (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions); preferably said substitutions are conservative substitutions;

[0030] or,

[0031] (3) the following heavy chain variable region (VH) and / or light chain variable region (VL):

[0032] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 16 or a variant thereof, CDR-H2 of SEQ ID NO: 17 or a variant thereof, CDR-H3 of SEQ ID NO: 5 or a variant thereof; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6 or a variant thereof, CDR-L2 of SEQ ID NO: 7 or a variant thereof, CDR-L3 of SEQ ID NO: 8 or a variant thereof;

[0033] said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the sequence from which it is derived or said variant has one or several (e.g. 1, 2 or 3) amino acid substitutions, deletions or additions compared to the sequence from which it is derived; preferably, said substitutions are conservative substitutions;

[0034] or,

[0035] (4) a heavy chain variable region (VH) and / or a light chain variable region (VL) of:

[0036] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 16 or a variant thereof, CDR-H2 of SEQ ID NO: 17 or a variant thereof, CDR-H3 of SEQ ID NO: 5 or a variant thereof; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6 or a variant thereof, CDR-L2 of SEQ ID NO: 7 or a variant thereof, CDR-L3 of SEQ ID NO: 8 or a variant thereof;

[0037] said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the sequence from which it is derived or said variant has one or several (e.g. 1, 2 or 3) amino acid substitutions, deletions or additions compared to the sequence from which it is derived; preferably, said substitutions are conservative substitutions.

[0038] In some embodiments, the antibody or antigen binding fragment thereof comprises:

[0039] (1) a heavy chain variable region (VH) and / or a light chain variable region (VL) in which the CDRs are defined according to the Chothia numbering system:

[0040] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 3 or a variant thereof, CDR-H2 of SEQ ID NO: 4 or a variant thereof, CDR-H3 of SEQ ID NO: 5 or a variant thereof; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6 or a variant thereof, CDR-L2 of SEQ ID NO: 7 or a variant thereof, CDR-L3 of SEQ ID NO: 8 or a variant thereof;

[0041] said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the sequence from which it is derived or said variant has one or several (e.g. 1, 2 or 3) amino acid substitutions, deletions, or additions compared to the sequence from which it is derived; preferably, said substitution is a conservative substitution;

[0042] or,

[0043] (2) a heavy chain variable region (VH) and / or a light chain variable region (VL) in which the CDRs are defined according to the Kabat numbering system:

[0044] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 9 or a variant thereof, CDR-H2 of SEQ ID NO: 10 or a variant thereof, CDR-H3 of SEQ ID NO: 5 or a variant thereof; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6 or a variant thereof, CDR-L2 of SEQ ID NO: 7 or a variant thereof, CDR-L3 of SEQ ID NO: 8 or a variant thereof;

[0045] said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence from which it is derived or said variant has one or several (e.g. 1, 2 or 3) amino acid substitutions, deletions, or additions compared to the sequence from which it is derived; preferably, said substitutions are conservative substitutions;

[0046] or,

[0047] (3) a heavy chain variable region (VH) and / or a light chain variable region (VL) in which the CDRs are defined according to the IMGT numbering system:

[0048] a heavy chain variable region (VH) comprising the following 3 CDRs: CDR-H1 of SEQ ID NO: 1 1 or a variant thereof, CDR-H2 of SEQ ID NO: 12 or a variant thereof, CDR-H3 of SEQ ID NO: 13 or a variant thereof; and / or, a light chain variable region (VL) comprising the following 3 CDRs: CDR-L1 of SEQ ID NO: 14 or a variant thereof, CDR-L2 of SEQ ID NO: 15 or a variant thereof, CDR-L3 of SEQ ID NO: 8 or a variant thereof;

[0049] said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence from which it is derived or said variant has one or several (e.g. 1, 2 or 3) amino acid substitutions, deletions, or additions compared to the sequence from which it is derived; preferably, said substitutions are conservative substitutions;

[0050] or,

[0051] (4) a heavy chain variable region (VH) and / or a light chain variable region (VL) in which the CDRs are defined according to the AbM numbering system:

[0052] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 3, CDR-H2 of SEQ ID NO: 4, CDR-H3 of SEQ ID NO: 5; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6, CDR-L2 of SEQ ID NO: 7, CDR-L3 of SEQ ID NO: 8;

[0053] said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the sequence from which it is derived or said variant has one or several (e.g. 1, 2 or 3) amino acid substitutions, deletions or additions compared to the sequence from which it is derived; preferably said substitution is a conservative substitution.

[0054] In some embodiments, the antibody or antigen-binding fragment thereof comprises:

[0055] (1 ) a heavy chain variable region (VH) and / or light chain variable region (VL) in which the CDRs are defined according to the Chothia numbering system:

[0056] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 3, CDR-H2 of SEQ ID NO: 4, CDR-H3 of SEQ ID NO: 5; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6, CDR-L2 of SEQ ID NO: 7, CDR-L3 of SEQ ID NO: 8;

[0057] or,

[0058] (2) a heavy chain variable region (VH) and / or light chain variable region (VL) in which the CDRs are defined according to the Kabat numbering system:

[0059] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 9, CDR-H2 of SEQ ID NO: 10, and CDR-H3 of SEQ ID NO: 5; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6, CDR-L2 of SEQ ID NO: 7, and CDR-L3 of SEQ ID NO: 8;

[0060] Alternatively,

[0061] (3) a heavy chain variable region (VH) and / or a light chain variable region (VL), wherein the CDRs are defined according to the IMGT numbering system:

[0062] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 11, CDR-H2 of SEQ ID NO: 12, and CDR-H3 of SEQ ID NO: 13; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 14, CDR-L2 of SEQ ID NO: 15, and CDR-L3 of SEQ ID NO: 8;

[0063] Alternatively,

[0064] (4) a heavy chain variable region (VH) and / or a light chain variable region (VL), wherein the CDRs are defined according to the AbM numbering system:

[0065] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 16, CDR-H2 of SEQ ID NO: 17, and CDR-H3 of SEQ ID NO: 5; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6, CDR-L2 of SEQ ID NO: 7, and CDR-L3 of SEQ ID NO: 8.

[0066] In some embodiments, the antibody or antigen-binding fragment thereof comprises:

[0067] a VH of SEQ ID NO: 1 or a variant thereof, and / or a VL of SEQ ID NO: 2 or a variant thereof;

[0068] wherein said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the sequence from which it is derived, or said variant has one or several amino acid substitutions, deletions or additions (e.g. 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions) compared to the sequence from which it is derived; preferably said substitutions are conservative substitutions.

[0069] In some embodiments, the antibody or antigen-binding fragment thereof comprises:

[0070] a VH as depicted in SEQ ID NO: 1 or a variant thereof, and, a VL as depicted in SEQ ID NO: 2 or a variant thereof;

[0071] wherein said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the sequence from which it is derived, or said variant has one or several amino acid substitutions, deletions or additions (e.g. 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions) compared to the sequence from which it is derived; preferably said substitutions are conservative substitutions.

[0072] In some embodiments, the antibody or antigen-binding fragment thereof comprises:

[0073] a VH as depicted in SEQ ID NO: 1, and, a VL as depicted in SEQ ID NO: 2.

[0074] In some embodiments, the antibody or antigen-binding fragment thereof further comprises:

[0075] (a) a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof having one or more amino acid substitutions, deletions or additions (e.g. up to 20, up to 15, up to 10, or up to 5 amino acid substitutions, deletions or additions; e.g. 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions) compared to the wild-type sequence from which it is derived; and / or

[0076] (b) a light chain constant region (CL) of a human immunoglobulin or a variant thereof having one or more substitutions, deletions, or additions of amino acids as compared to the wild type sequence from which it is derived (e.g., up to 20, up to 15, up to 10, or up to 5 amino acid substitutions, deletions, or additions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions).

[0077] In some embodiments, the antibody or antigen-binding fragment thereof further comprises:

[0078] (a) a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof having one or more substitutions, deletions, or additions of amino acids as compared to the wild type sequence from which it is derived (e.g., up to 20, up to 15, up to 10, or up to 5 amino acid substitutions, deletions, or additions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions); and

[0079] (b) a light chain constant region (CL) of a human immunoglobulin or a variant thereof having one or more substitutions, deletions, or additions of amino acids as compared to the wild type sequence from which it is derived (e.g., up to 20, up to 15, up to 10, or up to 5 amino acid substitutions, deletions, or additions; e.g., 1, 2, 3, 4, or 5 amino acid substitutions, deletions, or additions).

[0080] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) as set forth in SEQ ID NO: 19, and / or, a light chain constant region (CL) as set forth in SEQ ID NO: 18.

[0081] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) as set forth in SEQ ID NO: 19, and, a light chain constant region (CL) as set forth in SEQ ID NO: 18.

[0082] In some embodiments, the antibody or antigen-binding fragment thereof comprises:

[0083] a heavy chain comprising a VH as set forth in SEQ ID NO: 1 and a heavy chain constant region (CH) as set forth in SEQ ID NO: 19, and / or, a light chain comprising a VL as set forth in SEQ ID NO: 2 and a light chain constant region (CL) as set forth in SEQ ID NO: 18.

[0084] In some embodiments, the antibody or antigen-binding fragment thereof comprises:

[0085] a heavy chain comprising a VH of SEQ ID NO: 1 and a heavy chain constant region (CH) of SEQ ID NO: 19, and, a light chain comprising a VL of SEQ ID NO: 2 and a light chain constant region (CL) of SEQ ID NO: 18.

[0086] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain (HC) of SEQ ID NO: 20, and / or, a light chain (LC) of SEQ ID NO: 21.

[0087] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain (HC) of SEQ ID NO: 20, and, a light chain (LC) of SEQ ID NO: 21.

[0088] In some embodiments, the antibody or antigen-binding fragment thereof of the antibody drug conjugate is conjugated to a cytotoxic drug via a linker.

[0089] In some embodiments, the cytotoxic drug is a DNA topoisomerase inhibitor.

[0090] In some embodiments, the DNA topoisomerase inhibitor is a topoisomerase I inhibitor (e.g., camptothecin, hydroxycamptothecin, 9-aminocamptothecin, SN-38, irinotecan, topotecan, belotecan, rubitecan, exatecan, or Dxd, or derivatives thereof), and the following compounds:

[0091] In some embodiments, the cytotoxic drug is a camptothecin compound.

[0092] In some embodiments, the antibody drug conjugate is an antibody drug conjugate that targets human tyrosine kinase 7 (PTK7), and the other therapeutic agent is bevacizumab and cetuximab.

[0093] In some embodiments, the antibody drug conjugate contains an anti-PTK7 antibody or antigen-binding fragment thereof, which comprises:

[0094] (1) a heavy chain variable region (VH) and / or a light chain variable region (VL), wherein the CDRs are defined according to the Chothia numbering system:

[0095] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 9, CDR-H2 of SEQ ID NO: 10, CDR-H3 of SEQ ID NO: 5; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6, CDR-L2 of SEQ ID NO: 7, CDR-L3 of SEQ ID NO: 8;

[0096] or,

[0097] (2) a heavy chain variable region (VH) and / or a light chain variable region (VL) in which the CDRs are defined according to the Kabat numbering system:

[0098] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 9, CDR-H2 of SEQ ID NO: 10, CDR-H3 of SEQ ID NO: 5; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6, CDR-L2 of SEQ ID NO: 7, CDR-L3 of SEQ ID NO: 8;

[0099] or,

[0100] (3) a heavy chain variable region (VH) and / or a light chain variable region (VL) in which the CDRs are defined according to the IMGT numbering system:

[0101] a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 11, CDR-H2 of SEQ ID NO: 12, CDR-H3 of SEQ ID NO: 13; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 14, CDR-L2 of SEQ ID NO: 15, CDR-L3 of SEQ ID NO: 8;

[0102] or,

[0103] (4) a heavy chain variable region (VH) and / or a light chain variable region (VL) in which the CDRs are defined according to the AbM numbering system:

[0104] the heavy chain variable region (VH) comprising the following 3 CDRs: CDR-H1 of SEQ ID NO: 16, CDR-H2 of SEQ ID NO: 17, and CDR-H3 of SEQ ID NO: 5; and / or, the light chain variable region (VL) comprising the following 3 CDRs: CDR-L1 of SEQ ID NO: 6, CDR-L2 of SEQ ID NO: 7, and CDR-L3 of SEQ ID NO: 8; and

[0105] the other therapeutic agent is bevacizumab and cetuximab.

[0106] In some embodiments, the antibody drug conjugate has the following structure: Ab-[M-L-E-D] x

[0107] wherein:

[0108] Ab is an antibody or antigen binding fragment thereof as described in any of the above;

[0109] M is a linker moiety that links to the antibody or antigen binding fragment thereof;

[0110] L is a linker between M and E;

[0111] E is a structural moiety linking L and D;

[0112] D is a cytotoxic drug moiety;

[0113] x is selected from 1 to 10.

[0114] In some embodiments, M is selected from the following structures:

[0115] In some embodiments, M is selected from the following structures:

[0116] In some embodiments, L is selected from the following structures:

[0117] wherein s is selected from an integer from 1 to 20.

[0118] In some embodiments, L is selected from the following structures:

[0119] In some embodiments, L is selected from the following structures:

[0120] In some embodiments, E is a single bond, -NH-CH2-, -NH-CH2-O-CH2-CO-,

[0121] In some embodiments, E is -NH-CH2-,

[0122] In some embodiments, E is -NH-CH2-.

[0123] In some embodiments, D is selected from the following structures:

[0124] In some embodiments, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0125] In some embodiments, the antibody drug conjugate has the following structure:

[0126] wherein HA or HA-(S- is an antibody or antigen binding fragment thereof as described in any of the above, S in HA-(S- is derived from a thiol in the antibody or antigen binding fragment thereof; and x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0127] In some embodiments, the antibody drug conjugate has the following structure:

[0128] wherein HA or HA-(S- is an antibody or antigen binding fragment thereof as described in any of the above, S in HA-(S- is derived from a thiol in the antibody or antigen binding fragment thereof; and x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0129] In some embodiments, the antibody drug conjugate has the following structure:

[0130] wherein HA or HA-(S- is an antibody or antigen binding fragment thereof as described in any of the above, S in HA-(S- is derived from a thiol in the antibody or antigen binding fragment thereof; and x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0131] and the other therapeutic agent is cetuximab.

[0132] In some embodiments, the antibody drug conjugate has the following structure:

[0133] wherein HA-(S- is an antibody or antigen-binding fragment thereof described in any one of the above, S in HA-(S- is derived from a thiol in the antibody or antigen-binding fragment thereof; x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0134] and the other therapeutic agent is bevacizumab.

[0135] In some embodiments, the antibody drug conjugate has the following structure:

[0136] wherein HA-(S- is an antibody or antigen-binding fragment thereof described in any one of the above, S in HA-(S- is derived from a thiol in the antibody or antigen-binding fragment thereof; x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0137] and the other therapeutic agent is cetuximab and bevacizumab.

[0138] In some embodiments, the antibody drug conjugate has the following structure:

[0139] wherein HA-(S- comprises a heavy chain (HC) of the sequence set forth in SEQ ID NO: 20, and a light chain (LC) of the sequence set forth in SEQ ID NO: 21, S in HA-(S- is derived from a thiol in the antibody or antigen-binding fragment thereof; x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0140] In some embodiments, the antibody drug conjugate has the following structure:

[0141] wherein HA-(S- comprises a heavy chain (HC) of the sequence set forth in SEQ ID NO: 20, and a light chain (LC) of the sequence set forth in SEQ ID NO: 21, S in HA-(S- is derived from a thiol in the antibody or antigen-binding fragment thereof; x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0142] and the other therapeutic agent is cetuximab.

[0143] In some embodiments, the antibody drug conjugate has the following structure:

[0144] wherein HA-(S- comprises a heavy chain (HC) comprising the sequence of SEQ ID NO: 20, and, a light chain (LC) comprising the sequence of SEQ ID NO: 21, S in HA-(S- is derived from a thiol in the antibody or antigen-binding fragment thereof; x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0145] and the other therapeutic agent is bevacizumab.

[0146] In some embodiments, the antibody drug conjugate has the following structure:

[0147] wherein HA-(S- comprises a heavy chain (HC) comprising the sequence of SEQ ID NO: 20, and, a light chain (LC) comprising the sequence of SEQ ID NO: 21, S in HA-(S- is derived from a thiol in the antibody or antigen-binding fragment thereof; x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0148] and the other therapeutic agent is cetuximab and bevacizumab.

[0149] In some embodiments, the antibody drug conjugate has the following structure:

[0150] wherein HA' is an antibody or antibody-binding fragment thereof of any one of the above, and x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

[0151] In some embodiments, the heavy chain constant region of the antibody or antigen-binding fragment can comprise a C-terminal lysine, or lack a C-terminal lysine or a C-terminal glycine-lysine dipeptide.

[0152] In some embodiments, the N-terminal amino acid of the variable region of the antibody or antigen-binding fragment can be cyclized to pyroglutamic acid.

[0153] In some embodiments, the N-terminal amino acid of the variable region of the antibody or antigen-binding fragment can be cyclized to pyroglutamic acid.

[0154] In some embodiments, the antibodies or antigen-binding fragments described herein include antibodies or antigen-binding fragments that specifically bind to an antigen, and can include post-translational modifications thereof (e.g., C-terminal lysine clipping, pyroglutamic acid groups or pyroglutamic acid resulting from conversion of glutamine or glutamic acid) that can occur while the antibody or antigen-binding fragment is being recombinantly expressed in a host cell (e.g., a CHO cell), or during purification / storage.

[0155] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain (HC) having an amino acid sequence as set forth in SEQ ID NO: 22 and a light chain (LC) having an amino acid sequence as set forth in SEQ ID NO: 21.

[0156] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain (HC) having an amino acid sequence as set forth in SEQ ID NO: 23 and a light chain (LC) having an amino acid sequence as set forth in SEQ ID NO: 21.

[0157] In certain embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain (HC) having an amino acid sequence as set forth in SEQ ID NO: 24 and a light chain (LC) having an amino acid sequence as set forth in SEQ ID NO: 21.

[0158] In certain embodiments, the antibody drug conjugate has the following structure:

[0159] wherein HA-(S- is a heavy chain (HC) comprising a sequence as set forth in SEQ ID NO: 20, 22, 23, or 24, and a light chain (LC) as set forth in SEQ ID NO: 21.

[0160] The other therapeutic agent is cetuximab.

[0161] In certain embodiments, the antibody drug conjugate has the following structure:

[0162] wherein HA-(S- is a heavy chain (HC) comprising a sequence as set forth in SEQ ID NO: 20, 22, 23, or 24, and a light chain (LC) as set forth in SEQ ID NO: 21.

[0163] The other therapeutic agent is bevacizumab.

[0164] In certain embodiments, the antibody drug conjugate has the following structure:

[0165] wherein HA-(S- is a heavy chain (HC) comprising a sequence as set forth in SEQ ID NO: 20, 22, 23, or 24, and a light chain (LC) as set forth in SEQ ID NO: 21.

[0166] The other therapeutic agent is cetuximab and bevacizumab.

[0167] In some embodiments, the composition of antibody drug conjugates comprises one or more ADCs as described herein. The composition has a "drug-to-antibody ratio" (DAR) ranging from 1 to 10. Methods of determining DAR are well known to the skilled artisan, including methods using reverse phase chromatography or HPLC-MS.

[0168] In some embodiments, the composition of antibody drug conjugates has a DAR value (drug-to-antibody ratio) of 1-10, e.g., 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 5-6, 5-7, 5-8, 5-9, 5-10, 6-7, 6-8, 6-9, 6-10, 7-8, 7-9, 7-10, 8-9, 8-10, or 9-10, preferably 1-8, more preferably 3-9, e.g., 3.0-3.5, 3.0-4.0, 3.0-4.5, 3.0-5.0, 3.0-5.5, 3.0-6.0, 3.5-4.0, 3.5-4.5, 3.5-5.0, 3.5-5.5, 3.5-6.0, 3.5-6.5, 3.5-7.0, 3.5-7.5, 3.5-8.0, 4.0-4.5, 4.0-5.0, 4.0-5.5, 4.0-6.0, 4.0-6.5, 4.0-7.0, 4.0-7.5, 4.0-8.0, 4.5-5.0, 4.5-5.5, 4.5-6.0, 4.5-6.5, 4.5-7.0, 4.5-7.5, 4.5-8.0, 5.0-5.5, 5.0-6.0, 5.0-6.5, 5.0-7.0, 5.0-7.5, 5.0-8.0, 5.5-6.0, 5.5-6.5, 5.5-7.0, 5.5-7.5, 5.5-8.0, 6.0-6.5, 6.0-7.0, 6.0-7.5, 6.0-8.0, 6.0-8.5, 6.5-7.0, 6.5-7.5, 6.5-8.0, 6.5-8.5, 7.0-7.5, 7.0-8.0, 7.0-8.5, 7.0-9.0, 7.5-8.0, 7.5-8.5, or 7.5-9.0.

[0169] In some embodiments, the DAR value (drug to antibody ratio) of the composition of the antibody drug conjugate is 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, or 9.0.

[0170] In some embodiments, the DAR value (drug to antibody ratio) of the composition of the antibody drug conjugate is 6.00, 6.01, 6.02, 6.03, 6.04, 6.05, 6.06, 6.07, 6.08, 6.09, 6.10, 6.11, 6.12, 6.13, 6.14, 6.15, 6.16, 6.17, 6.18, 6.19, 6.20, 6.21, 6.22, 6.23, 6.24, 6.25, 6.26, 6.27, 6.28, 6.29, 6.30, 6.31, 6.32, 6.33, 6.34, 6.35, 6.36, 6.37, 6.38, 6.39, 6.40, 6.41, 6.42, 6.43, 6.44, 6.45, 6.46, 6.47, 6.48, 6.49, 6.50, 6.51, 6.52, 6.53, 6.54, 6.55, 6.56, 6.57, 6.58, 6.59, 6.60, 6.61, 6.62, 6.63, 6.64, 6.65, 6.66, 6.67, 6.68, 6.69, 6.70, 6.71, 6.72, 6.73, 6.74, 6.75, 6.76, 6.77, 6.78, 6.79, 6.80, 6.81, 6.82, 6.83, 6.84, 6.85, 6.86, 6.87, 6.88, 6.89, 6.90, 6.91, 6.92, 6.93, 6.94, 6.95, 6.96, 6.97, 6.98, 6.99, 7.00, 7.01, 7.02, 7.03, 7.04, 7.05, 7.06, 7.07, 7.08, 7.09, 7.10, 7.11, 7.12, 7.13, 7.14, 7.15, 7.16, 7.17, 7.18, 7.19, 7.20, 7.21, 7.22, 7.23, 7.24, 7.25, 7.26, 7.27, 7.28, 7.29, 7.30, 7.31, 7.32, 7.33, 7.34, 7.35, 7.36, 7.37, 7.38, 7.39, 7.40, 7.41, 7.42, 7.43, 7.44, 7.45, 7.46, 7.47, 7.48, 7.49, 7.50, 7.51, 7.52, 7.53, 7.54, 7.55, 7.56, 7.57, 7.58, 7.59, 7.60, 7.61, 7.62, 7.63, 7.64, 7.65, 7.66, 7.67, 7.68, 7.69, 7.70, 7.71, 7.72, 7.73, 7.74, 7.75, 7.76, 7.77, 7.78, 7.79, 7.80, 7.81, 7.82, 7.83, 7.84, 7.85, 7.86, 7.87, 7.88, 7.89, 7.90, 7.91, 7.92, 7.93, 7.94, 7.95, 7.96, 7.97, 7.98, 7.99, 8.00, 8.01, 8.02, 8.03, 8.04, 8.05, 8.06, 8.07, 8.08, 8.09, 8.10, 8.11, 8.12, 8.13, 8.14, 8.15, 8.16, 8.17, 8.18, 8.19, 8.20, 8.21, 8.22, 8.23, 8.24, 8.25, 8.26, 8.27, 8.28, 8.29, 8.30, 8.31, 8.32, 8.33, 8.34, 8.35, 8.36, 8.37, 8.38, 8.39, 8.40, 8.41, 8.42, 8.43, 8.44, 8.45, 8.46, 8.47, 8.48, 8.49, 8.50, 8.51, 8.52, 8.53, 8.54, 8.55, 8.56, 8.57, 8.58, 8.59, 8.60, 8.61, 8.62, 8.63, 8.64, 8.65, 8.66, 8.67, 8.68, 8.69, 8.70, 8.71, 8.72, 8.73, 8.74, 8.75, 8.76, 8.77, 8.78, 8.79, 8.80, 8.81, 8.82, 8.83, 8.84, 8.85, 8.86, 8.87, 8.88, 8.89, 8.90, 8.91, 8.92, 8.93, 8.94, 8.95, 8.96, 8.97, 8.98, 8.99, or 9.00.

[0171] In some embodiments, the composition can comprise one or more than two of the antibody drug conjugates described above, wherein each species can independently comprise a C-terminal lysine, a C-terminal lysine deletion, a C-terminal glycine-lysine deletion, and / or comprise a N-terminal glutamine or glutamic acid, or pyroglutamic acid resulting from N-terminal amino acid cyclization.

[0172] In certain embodiments, the predominant antibody drug conjugate species in the composition comprises: (i) an antibody with a C-terminal lysine deletion in the heavy chain; (ii) an antibody with a N-terminal glutamine, glutamic acid, pyroglutamic acid group, or pyroglutamic acid in the heavy chain; or (iii) an antibody with a C-terminal lysine deletion in the heavy chain and a N-terminal glutamine, glutamic acid, pyroglutamic acid group, or pyroglutamic acid in the heavy chain.

[0173] In certain embodiments, the present application further provides a composition comprising an antibody drug conjugate described herein, wherein the predominant antibody drug conjugate species in the composition comprises an antibody with a C-terminal lysine deletion in the heavy chain and a N-terminal pyroglutamic acid group or pyroglutamic acid in the heavy chain.

[0174] In certain embodiments, the composition of the antibody drug conjugate is a pharmaceutical composition of the antibody drug conjugate, optionally containing one or more pharmaceutically acceptable excipients, diluents, or carriers.

[0175] In certain embodiments, the tumor or cancer comprises a solid tumor or a hematological malignancy.

[0176] In certain embodiments, the tumor or cancer comprises a tumor or cancer that overexpresses PTK7.

[0177] In certain embodiments, the tumor or cancer comprises a solid tumor or a hematological malignancy.

[0178] In certain embodiments, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer, or esophageal cancer.

[0179] In certain embodiments, the tumor or cancer is lung cancer.

[0180] In certain embodiments, the tumor or cancer is non-small cell lung cancer.

[0181] Another aspect of the present application provides the use of an antibody drug conjugate as described previously in combination with other therapeutic agents selected from one or more of an anti-EGFR antibody and a VEGF antibody in the preparation of a medicament for treating a tumor or cancer in a subject; the other therapeutic agents, anti-EGFR antibody, and anti-VEGF antibody being as defined in any one of the preceding.

[0182] Another aspect of the present application provides the use of a composition of an antibody drug conjugate in combination with other therapeutic agents selected from one or more of an anti-EGFR antibody and a VEGF antibody in the preparation of a medicament for treating a tumor or cancer in a subject; the tumor or cancer being as described in any one of the preceding. In certain embodiments, the other therapeutic agents, anti-EGFR antibody, and anti-VEGF antibody are as defined in any one of the preceding.

[0183] Another aspect of the present application provides the use of a combination of an anti-EGFR antibody and a VEGF antibody in the preparation of a medicament for treating a tumor or cancer in a subject; the anti-EGFR antibody and VEGF antibody being as described in any one of the preceding, the tumor or cancer being as described in any one of the preceding.

[0184] Another aspect of the present application provides use of the antibody drug conjugate as described above and other therapeutic agent in the manufacture of a medicament for treating a tumor or cancer in a subject; the other therapeutic agent is selected from one, two or more of an anti-EGFR antibody and a VEGF antibody, the tumor or cancer is as described in any of the above. In certain embodiments, the other therapeutic agent, anti-EGFR antibody and anti-VEGF antibody are as defined in any of the above.

[0185] Another aspect of the present application provides use of a composition of the antibody drug conjugate as described above and other therapeutic agent in the manufacture of a medicament for treating a tumor or cancer in a subject; the other therapeutic agent is selected from one, two or more of an anti-EGFR antibody and a VEGF antibody, the tumor or cancer is as described in any of the above. In certain embodiments, the other therapeutic agent, anti-EGFR antibody and anti-VEGF antibody are as defined in any of the above.

[0186] Another aspect of the present application provides use of an anti-EGFR antibody and a VEGF antibody in the manufacture of a medicament for treating a tumor or cancer in a subject; the anti-EGFR antibody and VEGF antibody are as described in any of the above, the tumor or cancer is as described in any of the above. In certain embodiments, the anti-EGFR antibody and anti-VEGF antibody are as defined in any of the above.

[0187] Another aspect of the present application provides use of the antibody drug conjugate as described above in the manufacture of a medicament for treating a tumor or cancer in combination with other therapeutic agent; the other therapeutic agent is selected from one or more of an anti-EGFR antibody and a VEGF antibody, the tumor or cancer is as described in any of the above. In certain embodiments, the other therapeutic agent, anti-EGFR antibody and anti-VEGF antibody are as defined in any of the above.

[0188] Another aspect of the present application provides use of a composition of the antibody drug conjugate as described above in the manufacture of a medicament for treating a tumor or cancer in combination with other therapeutic agent; the other therapeutic agent is selected from one or more of an anti-EGFR antibody and a VEGF antibody, the tumor or cancer is as described in any of the above. In certain embodiments, the other therapeutic agent, anti-EGFR antibody and anti-VEGF antibody are as defined in any of the above.

[0189] Another aspect of the present application provides use of an anti-EGFR antibody in the manufacture of a medicament for treating a tumor or cancer in combination with an anti-VEGF antibody; the anti-EGFR antibody and VEGF antibody are as described in any of the above, the tumor or cancer is as described in any of the above.

[0190] Another aspect of the present application provides use of an anti-VEGF antibody in the manufacture of a medicament for treating a tumor or cancer in combination with an anti-EGFR antibody; the anti-VEGF antibody and the anti-EGFR antibody are as described in any of the preceding aspects, and the tumor or cancer is as described in any of the preceding aspects.

[0191] Another aspect of the present application provides use of an antibody drug conjugate as described in the preceding aspects in the manufacture of a medicament for improving the therapeutic effect of another therapeutic agent in treating a tumor or cancer; the tumor or cancer is as described in any of the preceding aspects.

[0192] Another aspect of the present application provides use of a composition of an antibody drug conjugate as described in the preceding aspects in the manufacture of a medicament for improving the therapeutic effect of another therapeutic agent in treating a tumor or cancer; the tumor or cancer is as described in any of the preceding aspects.

[0193] Another aspect of the present application provides a method for improving the therapeutic effect of a tumor or cancer, comprising administering an antibody drug conjugate as defined in any of the preceding aspects or a composition thereof in combination with an anti-EGFR antibody and / or an anti-VEGF antibody as defined in any of the preceding aspects.

[0194] In some embodiments, the medicament improves the TGI (tumor growth inhibition rate) of the other therapeutic agent in treating a tumor or cancer by 5% or more, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 110% or more, 120% or more, 130% or more, 140% or more, or 150% or more.

[0195] Another aspect of the present application also provides an antibody drug conjugate as described in the preceding aspects and another therapeutic agent as described in the preceding aspects for use in treating a tumor or cancer in a subject; the tumor or cancer is as described in any of the preceding aspects.

[0196] Another aspect of the present application also provides a composition of an antibody drug conjugate as described in the preceding aspects and another therapeutic agent as described in the preceding aspects for use in treating a tumor or cancer in a subject; the tumor or cancer is as described in any of the preceding aspects.

[0197] Another aspect of the present application also provides an anti-EGFR antibody and an anti-VEGF antibody for use in treating a tumor or cancer in a subject; the tumor or cancer is as described in any of the preceding aspects.

[0198] Another aspect of the present application also provides one or more kits comprising an antibody drug conjugate or a composition thereof as described in any of the preceding aspects and another therapeutic agent as described in any of the preceding aspects.

[0199] In some embodiments, the kit comprises the antibody drug conjugate or composition thereof as described in any of the preceding embodiments in one compartment, and another therapeutic agent as described in any of the preceding embodiments selected from one or more of the anti-EGFR antibody and the VEGF antibody in another compartment.

[0200] In some embodiments, the kit further comprises instructions for administering the antibody drug conjugate and the other therapeutic agent.

[0201] In some embodiments, the kit is used for treating a tumor or cancer as described in the preceding.

[0202] Another aspect of the present application also provides one or more kits comprising the anti-EGFR antibody of any of the preceding embodiments and the anti-VEGF antibody of any of the preceding embodiments.

[0203] In some embodiments, the kit comprises the anti-EGFR antibody of any of the preceding embodiments in one compartment, and the anti-VEGF antibody of any of the preceding embodiments in another compartment.

[0204] In some embodiments, the kit further comprises instructions for administering the anti-EGFR antibody and the anti-VEGF antibody.

[0205] In some embodiments, the kit is used for treating a tumor or cancer as described in the preceding.

[0206] Another aspect of the present application also provides a pharmaceutical combination comprising the antibody drug conjugate or composition thereof as described in the preceding and another therapeutic agent as described in any of the preceding embodiments selected from one, two or more of the anti-EGFR antibody and the VEGF antibody. In certain embodiments, the anti-EGFR antibody and the anti-VEGF antibody are as defined in any of the preceding.

[0207] Another aspect of the present application also provides a pharmaceutical combination comprising the anti-EGFR antibody as described in the preceding and the anti-VEGF antibody as described in any of the preceding.

[0208] In some embodiments, the pharmaceutical combination is used for treating a tumor or cancer as described in the preceding.

[0209] Another aspect of the present application also provides a pharmaceutical composition comprising the antibody drug conjugate or composition thereof as described in the preceding and another therapeutic agent as described in any of the preceding embodiments selected from one or more of the anti-EGFR antibody and the VEGF antibody. In certain embodiments, the anti-EGFR antibody and the anti-VEGF antibody are as defined in any of the preceding.

[0210] Another aspect of the present application also provides a pharmaceutical composition comprising the anti-EGFR antibody as described above and the anti-VEGF antibody as described in any one of the above.

[0211] In some embodiments, the pharmaceutical composition is used for treating the tumor or cancer as described above.

[0212] In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, diluents or carriers.

[0213] Another aspect of the present application also provides an antibody drug conjugate or a composition thereof for treating a tumor or cancer, wherein the antibody drug conjugate or the composition is as described in any one of the above and is administered in a combination therapy with other therapeutic agents as described above, and the tumor or cancer is as described in any one of the above.

[0214] Another aspect of the present application also provides an anti-EGFR antibody for treating a tumor or cancer, wherein the anti-EGFR antibody is as described in any one of the above and is administered in a combination therapy with the anti-VEGF antibody as described above, and the tumor or cancer is as described in any one of the above.

[0215] Another aspect of the present application also provides an anti-EGFR antibody for treating a tumor or cancer, wherein the anti-EGFR antibody is as described in any one of the above and is administered in a combination therapy with the anti-VEGF antibody as described above, and the tumor or cancer is lung cancer, preferably non-small cell lung cancer; the anti-VEGF antibody is administered at a dose of 1-10 mg / kg, 1-3 times per week, for 1-10 times; and the anti-EGFR antibody is administered at a dose of 1-10 mg / kg, 1-3 times per week, for 1-10 times.

[0216] Another aspect of the present application also provides an anti-VEGF antibody for treating a tumor or cancer, wherein the anti-VEGF antibody is as described in any one of the above and is administered in a combination therapy with the anti-EGFR antibody as described above, and the tumor or cancer is as described in any one of the above.

[0217] Another aspect of the present application also provides an anti-VEGF antibody for treating a tumor or cancer, wherein the anti-VEGF antibody is as described in any one of the above and is administered in a combination therapy with the anti-EGFR antibody as described above, and the tumor or cancer is lung cancer, preferably non-small cell lung cancer; the anti-VEGF antibody is administered at a dose of 1-10 mg / kg, 1-3 times per week, for 1-10 times; and the anti-EGFR antibody is administered at a dose of 1-10 mg / kg, 1-3 times per week, for 1-10 times.

[0218] The present application provides a method of treating a tumor or cancer described supra using a combination of an antibody drug conjugate described supra or a composition thereof and another therapeutic agent described supra.

[0219] The present application provides a method of treating a tumor or cancer described supra using a combination of an anti-EGFR antibody described supra and an anti-VEGF antibody described supra.

[0220] The present application provides a use of a therapeutic combination for treating a tumor or cancer described supra, and the therapeutic combination comprises an antibody drug conjugate described supra and another therapeutic agent described supra.

[0221] The present application also provides a use of a therapeutic combination for treating a tumor or cancer described supra, and the therapeutic combination comprises an anti-EGFR antibody described supra and an anti-VEGF antibody described supra.

[0222] The present application also provides a method of treating a tumor or cancer described supra, the method comprising administering to a subject in need thereof:

[0223] (a) a therapeutically effective amount of an antibody drug conjugate described supra; and

[0224] (b) a therapeutically effective amount of another therapeutic agent described supra.

[0225] In some embodiments, the antibody conjugate drug described supra and the other therapeutic agent described supra are administered simultaneously.

[0226] In some embodiments, the antibody conjugate drug described supra and the other therapeutic agent described supra are administered separately.

[0227] In some embodiments, the antibody conjugate drug described supra and the other therapeutic agent described supra are administered sequentially.

[0228] In some embodiments, the antibody conjugate drug is administered first, and the other therapeutic agent described supra is administered later.

[0229] The present application also provides a method of treating a tumor or cancer described supra, the method comprising administering to a subject in need thereof:

[0230] (a) a therapeutically effective amount of an anti-VEGF antibody described supra; and

[0231] (b) a therapeutically effective amount of an anti-EGFR antibody described supra.

[0232] In some embodiments, the anti-VEGF antibody described supra and the anti-EGFR antibody described supra are administered simultaneously.

[0233] In some embodiments, the anti-VEGF antibody described supra and the anti-EGFR antibody described supra are administered separately.

[0234] In some embodiments, the anti-VEGF antibody described supra and the anti-EGFR antibody described supra are administered sequentially.

[0235] In some embodiments, the anti-VEGF antibody described supra is administered at a frequency of 1 to 20 times within a period of 1 to 4 weeks; for example, 1 time per week, 2 times per week, 3 times per week, 1 time per 2 weeks, 3 times per 2 weeks, 1 time per 3 weeks, 2 times per 3 weeks, 1 time per 4 weeks, or 3 times per 4 weeks.

[0236] In some embodiments, the anti-EGFR antibody described supra is administered at a frequency of 1 to 20 times within a period of 1 to 4 weeks; for example, 1 time per week, 2 times per week, 3 times per week, 1 time per 2 weeks, 3 times per 2 weeks, 1 time per 3 weeks, 2 times per 3 weeks, 1 time per 4 weeks, or 3 times per 4 weeks.

[0237] In some embodiments, the anti-VEGF antibody described supra is administered at a frequency of 1 to 20 times within a period of 1 to 4 weeks; for example, 1 time per week, 2 times per week, 3 times per week, 1 time per 2 weeks, 3 times per 2 weeks, 1 time per 3 weeks, 2 times per 3 weeks, 1 time per 4 weeks, or 3 times per 4 weeks.

[0238] In some embodiments, the antibody drug conjugate is administered at a dose per administration selected from the group consisting of 0.1-100 mg / kg, preferably 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg, based on the body weight of the subject to be administered. In some embodiments, the antibody drug conjugate is administered at a dose per administration of 6 mg / kg.

[0239] In some embodiments, the anti-VEGF antibody is administered at a dose per administration selected from the group consisting of 0.1-100 mg / kg, preferably 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg, based on the body weight of the subject to be administered.

[0240] In some embodiments, the anti-VEGF antibody is administered at a dose per administration of 4 mg / kg.

[0241] In some embodiments, the anti-VEGF antibody is administered at a dose of 1.5 mg / kg per administration.

[0242] In some embodiments, the anti-EGFR antibody is administered at a dose per administration selected from 0.1-100 mg / kg, preferably 1 mg / kg, 1.5 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, or 10 mg / kg, based on the body weight of the subject.

[0243] In some embodiments, the anti-EGFR antibody is administered at a dose of 1 mg / kg per administration.

[0244] In some embodiments, the anti-EGFR antibody is administered at a dose of 1.5 mg / kg per administration.

[0245] In some embodiments, the method reduces the ability of tumor growth and stabilizes the disease.

[0246] In some embodiments, the antibody drug conjugate is administered at a dose selected from 0.1-2000 mg, such as 0.1-1900 mg, 0.1-1800 mg, 0.1-1700 mg, 0.1-1600 mg, 0.1-1500 mg, 0.1-1400 mg, 0.1-1300 mg, 0.1-1200 mg, 0.1-1100 mg, 0.1-900 mg, 0.1-900 mg, 0.1-800 mg, 0.1-700 mg, 0.1-600 mg, 0.1-500 mg, 0.1-400 mg, 0.1-300 mg, 0.1-200 mg, 0.1-100 mg, 0.1-50 mg, 0.1-30 mg, 0.1-20 mg, 0.1-10 mg; and for example 0.1 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg.

[0247] In some embodiments, the dose of the anti-EGFR antibody is selected from the group consisting of 0.1-2000 mg, such as 0.1-1900 mg, 0.1-1800 mg, 0.1-1700 mg, 0.1-1600 mg, 0.1-1500 mg, 0.1-1400 mg, 0.1-1300 mg, 0.1-1200 mg, 0.1-1100 mg, 0.1-900 mg, 0.1-900 mg, 0.1-800 mg, 0.1-700 mg, 0.1-600 mg, 0.1-500 mg, 0.1-400 mg, 0.1-300 mg, 0.1-200 mg, 0.1-100 mg, 0.1-50 mg, 0.1-30 mg, 0.1-20 mg, 0.1-10 mg; and for example 0.1 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg.

[0248] In some embodiments, the dose of the anti-VEGF antibody is selected from the group consisting of 0.1-2000 mg, e.g., 0.1-1900 mg, 0.1-1800 mg, 0.1-1700 mg, 0.1-1600 mg, 0.1-1500 mg, 0.1-1400 mg, 0.1-1300 mg, 0.1-1200 mg, 0.1-1100 mg, 0.1-900 mg, 0.1-900 mg, 0.1-800 mg, 0.1-700 mg, 0.1-600 mg, 0.1-500 mg, 0.1-400 mg, 0.1-300 mg, 0.1-200 mg, 0.1-100 mg, 0.1-50 mg, 0.1-30 mg, 0.1-20 mg, 0.1-10 mg; and, e.g., 0.1 mg, 1.0 mg, 2.0 mg, 3.0 mg, 4.0 mg, 5.0 mg, 6.0 mg, 7.0 mg, 8.0 mg, 9.0 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg.

[0249] In some embodiments, the method is for treating lung cancer, the method comprising administering to a subject in need thereof:

[0250] (a) a therapeutically effective amount of an anti-VEGF antibody as described hereinabove; and

[0251] (b) a therapeutically effective amount of an anti-EGFR antibody as described hereinabove;

[0252] the anti-VEGF antibody is administered at a dose of 1-10 mg / kg, 1-3 times per week, for 1-10 administrations; and the anti-EGFR antibody is administered at a dose of 1-10 mg / kg, 1-3 times per week, for 1-10 administrations.

[0253] In some embodiments, the lung cancer is non-small cell lung cancer.

[0254] In some embodiments, the method has a tumor growth inhibition (TGI) percentage of 50% or more, for example, 60% or more, 70% or more, 80% or more, 90% or more, 100% or more, 110% or more, 120% or more, 130% or more, 140% or more, 150% or more, 160% or more, 170% or more, 180% or more.

[0255] In the above, embodiments formed by the combination of individual embodiments, or embodiments formed by the combination of technical features or preferred technical features in one embodiment with technical features or preferred technical features in another embodiment, are also included in the scope of the present application.

[0256] Definitions

[0257] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. References to techniques employed herein are intended to refer to the techniques as commonly understood in the art, including variations thereto or substitutions therefor that would be apparent to those of ordinary skill in the art. Also, the practice of the present application employs, unless otherwise indicated, conventional techniques of genomics, nucleic acid chemistry, molecular biology and the like, which are all within the ordinary skill of the art. Although it is believed that the following terms are well understood by those of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the application.

[0258] The term "antibody" refers to an immunoglobulin molecule that is generally composed of two pairs of polypeptide chains (each pair having one light (LC) and one heavy (HC) chain). Antibody light chains can be classified as kappa (kappa) and lambda (lambda) light chains. Heavy chains can be classified as mu, delta, gamma, alpha, or epsilon, and define a different class of antibodies, as IgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, and the heavy chain also contains a "D" region of about 3 or more amino acids. Each heavy chain is composed of a heavy chain variable region (VH) and a heavy chain constant region (CH). The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is composed of a light chain variable region (VL) and a light chain constant region (CL). The light chain constant region is comprised of one domain, CL. The constant domains are not involved directly in binding of an antibody to an antigen, but exhibit various effector functions, such as mediating immunoglobulin- host tissue or factor, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy chain / light chain pair (VH and VL) form the antigen binding site. Assignment of amino acids to each region or domain can follow various numbering systems known in the art.

[0259] The term "complementarity determining region" or "CDR" refers to amino acid residues in the variable region of an antibody that are responsible for antigen binding. There are three CDRs in each of the variable regions of the heavy and light chains, designated CDR1, CDR2, and CDR3. The precise boundaries of these CDRs can be defined according to various numbering systems known in the art, e.g., as defined by the Rabat numbering system (Rabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md., 1991), the Chothia numbering system (Chothia & Lesk (1987) J. Mol. Biol. 196:901-917; Chothia et al. (1989) Nature 342:878-883), the IMGT numbering system (Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003), or the AbM numbering system (Martin ACR, Cheetham JC, Rees AR (1989) Modelling antibody hypervariable loops: A combined algorithm. Proc Natl Acad Sci USA 86:9268-9272). For a given antibody, one of skill in the art will readily be able to identify the CDRs defined by each numbering system. Moreover, the correspondence between different numbering systems is well known to those skilled in the art (see, e.g., Lefranc et al., Dev. Comparat. Immunol. 27:55-77, 2003).

[0260] In the present application, the CDRs contained by an antibody or antigen-binding fragment thereof can be determined according to various numbering systems known in the art, e.g., by the Rabat, Chothia, IMGT, or AbM numbering system. In certain embodiments, the CDRs contained by an antibody or antigen-binding fragment thereof are defined by the Chothia numbering system.

[0261] The entire amino acid sequence of the VH is typically numbered according to Rabat, while the three CDRs within the variable region can be defined according to any of the numbering systems described above. In certain embodiments, the amino acid positions in the VH can be sequentially numbered from amino acid position 1 through to the end of the sequence, or can be numbered according to Rabat. Unless otherwise specified, the amino acid positions in the VH and VL described herein are defined according to sequential numbering.

[0262] The numbering of the amino acid positions in the heavy chain constant region can be sequentially numbered, starting with amino acid position 1, through to the end of the sequence, or can be numbered according to Eu. The amino acid sequence of the IgGl heavy chain constant region has 330 amino acids, numbered sequentially as 1 through 330. The corresponding sequence numbered according to Eu starts with position 118 and ends with position 447. Unless otherwise specified, the amino acid positions of the heavy and light chains described herein are defined according to the sequential numbering.

[0263] The term "framework region" or "FR" residues refer to those amino acid residues in a variable region of an antibody that are not CDR residues as defined above.

[0264] The term "antigen-binding fragment" of an antibody refers to a polypeptide of a fragment of an antibody, e.g., a polypeptide of a fragment of a full-length antibody, that retains the ability to specifically bind to the same antigen bound by the full-length antibody, and / or competes with the full-length antibody for specific binding to the antigen, which is also referred to as an "antigen-binding portion". See generally, Fundamental Immunology, Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)), which is incorporated herein by reference in its entirety for all purposes. Antigen-binding fragments of an antibody can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. Non-limiting examples of antigen-binding fragments include Fab fragments, Fab' fragments, F(ab)'2 fragments, F(ab)'3 fragments, Fd, Fv, scFv, di-scFv, (scFv)2, disulfide stabilized Fv proteins ("dsFv"), single domain antibodies (sdAbs, nanobodies), and polypeptides comprising at least a portion of an antibody that is sufficient to confer specific antigen binding ability to the polypeptide. Engineered antibody variants are reviewed in Holliger et al., 2005; Nat Biotechnol, 23: 1126-1136.

[0265] The term "Fd" means an antibody fragment consisting of the VH and CHI domains; the term "dAb fragment" means an antibody fragment that consists of a VH domain (Ward et al., Nature 341:544 546 (1989)); the term "Fab fragment" means an antibody fragment consisting of the VL, VH, CL and CHI domains; the term "F(ab')2 fragment" means an antibody fragment that comprises two Fab fragments linked by disulfide bridges on the hinge region; the term "Fab' fragment" means the fragment obtained by reducing the disulfide bonds in a F(ab')2 fragment, consisting of an intact light chain and a Fd fragment of a heavy chain (consisting of VH and CHI domains).

[0266] The term "Fv" means an antibody fragment consisting of the VL and VH domains of a single arm of an antibody. The Fv fragment is commonly considered the smallest fragment of an antibody that is capable of forming a complete antigen binding site. It is generally considered that the six CDRs confer antigen binding specificity to an antibody. However, even a single variable domain (e.g., an Fd fragment, which contains only three CDRs specific for an antigen) is capable of recognizing and binding antigen, although at a lower affinity than the entire binding site.

[0267] The term "Fc" means an antibody fragment formed by disulfide bonds between the second, third constant regions of the first heavy chain and the second, third constant regions of the second heavy chain of an antibody. The Fc fragment of an antibody has a variety of different functions, but does not participate in antigen binding.

[0268] The term "scFv" refers to a single polypeptide chain comprising a VL and a VH domain, wherein the VL and VH are connected by a linker (see, e.g., Bird et al., Science 242:423-426 (1988); Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); and Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994)). Such scFv molecules can have the general structure: NH2-VL-linker-VH-COOH or NH2-VH-linker-VL-COOH. Suitable prior art linkers consist of repeating GGGGS (SEQ ID NO: 55) amino acid sequences or variants thereof. For example, a linker having the amino acid sequence (GGGGS)4(SEQ ID NO: 56) can be used, but variants thereof can also be used (Holliger et al. (1993), Proc. Natl. Acad. Sci. USA 90:6444-6448). Other linkers useful in the present application are described by Alfthan et al. (1995), Protein Eng. 8:725-731, Choi et al. (2001), Eur. J. Immunol. 31:94-106, Hu et al. (1996), Cancer Res. 56:3055-3061, Kipriyanov et al. (1999), J. Mol. Biol. 293:41-56, and Roovers et al. (2001), Cancer Immunol. In some cases, a disulfide bond can also be present between the VHand VLof the scFv. In certain embodiments, the VHand VLdomains can be positioned relative to each other in any suitable arrangement. For example, scFv comprising NH2-VH-VH-COOH, NH2-VH-VL-COOH, NH2-VL-VH-COOH, or NH2-VL-VL-COOH are contemplated. 2- VL-VL-COOH.

[0269] The term "single-domain antibody (sdAb)" has the meaning generally understood by those skilled in the art and refers to an antibody fragment consisting of a single monomeric variable antibody domain, such as a single heavy chain variable region, that retains the ability to specifically bind the same antigen to which a full-length antibody binds (Holt, L. et al., Trends in Biotechnology, 21(11):484-490, 2003). Single-domain antibodies are also known as nanobodies.

[0270] Each of the above antibody fragments maintains the ability to specifically bind to the same antigen bound by the full-length antibody from which they are derived, and / or competes with the full-length antibody for specific binding to the antigen.

[0271] In the present context, the term "antibody" when used in reference to a term "antibody" includes not only intact antibodies, but also antigen binding fragments of antibodies, unless otherwise clearly indicated by context.

[0272] Antigen binding fragments of antibodies (e.g., the above antibody fragments) can be obtained using conventional techniques known to those of skill in the art (e.g., recombinant DNA technology or enzymatic or chemical cleavage methods) from a given antibody (e.g., an antibody provided herein) and screened for specificity in the same manner as is used for intact antibodies.

[0273] The term "murine antibody" refers to an antibody obtained by fusing B cells of an immunized mouse with myeloma cells, screening for murine hybridoma cells that both proliferate indefinitely and secrete antibody, followed by screening, antibody production, and antibody purification, or refers to an antibody secreted by a plasma cell that developed from a B cell that proliferated in response to an antigen invading a mouse.

[0274] The term "humanized antibody" refers to a non-human antibody that has been genetically engineered to have an amino acid sequence that is modified to increase homology to the sequence of a human antibody. Typically, a humanized antibody has all or a portion of the CDR regions from a non-human antibody (donor antibody) and all or a portion of the non-CDR regions (e.g., variable region FR and / or constant region) from a human immunoglobulin (acceptor antibody). A humanized antibody typically retains the desired properties of the donor antibody, including but not limited to, antigen specificity, affinity, reactivity, ability to increase immune cell activity, ability to enhance an immune response, and the like. The donor antibody can be a mouse, rat, rabbit, or non-human primate (e.g., cynomolgus monkey) antibody that has the desired properties (e.g., antigen specificity, affinity, reactivity, ability to increase immune cell activity, and / or ability to enhance an immune response).

[0275] The term "identity" is used in reference to the matching of sequences between two polypeptides or between two nucleic acids. When a position in each sequence that is being compared is occupied by the same base or amino acid monomer subunit (e.g., a position in each of two DNA molecules that is occupied by adenine, or a position in each of two polypeptides that is occupied by lysine), then the molecules are identical at that position. The "percentage of identity" between two sequences is the function of the number of matching positions shared by the two sequences divided by the number of positions compared x 100. For example, if 6 of 10 positions in two sequences are matched then the two sequences have 60% identity. For example, the DNA sequences CTGACT and CAGGTT share 50% identity (3 of 6 positions are matched). Typically, the comparison is made over the full length of the two sequences. Such a comparison can be conveniently accomplished by use of the method of Needleman et al. (1970) J. Mol. Biol. 48:443-453, as implemented in the computer program Align (DNAstar, Inc.), or by use of the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4:11-17 (1988)) as integrated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. In addition, the percentage of identity between two amino acid sequences can be determined using the algorithm of Needleman and Wunsch (J MoI Biol. 48:444-453 (1970)) as implemented in the GAP program, using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a gap length weight of 1, 2, 3, 4, 5, or 6, as incorporated into the GCG software package (available at www.gcg.com).

[0276] The term "conservative substitution" means an amino acid substitution that does not adversely affect or alter the intended properties of a protein / polypeptide comprising the amino acid sequence. For example, conservative substitutions can be introduced by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions include substitutions of amino acid residues with residues having similar side chains, e.g., substitutions that take place within a family of amino acid residues that are physicochemically or functionally similar, e.g., substitutions having similar size, shape, charge, chemical properties, including ability to form covalent or hydrogen bonds, etc. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, and histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a preference for substitution of a corresponding amino acid residue with another amino acid residue from the same side chain family. Methods for identifying amino acid conservative substitutions are well known in the art (see, e.g., Brummell et al., Biochem. 32: 1180-1187 (1993); Kobayashi et al. Protein Eng. 12(10):879-884 (1999); and Burks et al. Proc. Natl Acad. Set USA 94:412-417 (1997), which are incorporated herein by reference).

[0277] The nomenclature used herein for the twenty conventional amino acids follows the conventional usage. See, e.g., Immunology - A Synthesis (2nd Edition, E.S. Golub and D.R. Gren, Eds., Sinauer Associates, Sunderland, Mass. (1991)), which is incorporated herein by reference. In the present application, amino acids are generally referred to by the one-letter and three-letter abbreviations well known in the art. For example, alanine can be represented by A or Ala.

[0278] The terms "comprising," "including," "having," "containing," or "involving," and other variants as well as "comprises," "includes," "has," "contains," or "involves," and other variants thereof are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. DETAILED DESCRIPTION

[0279] The present application is further described below by way of specific embodiments, but this is not a limitation of the present application. Based on the teachings of the present application, those skilled in the art will be able to make various modifications or improvements, without departing from the basic idea and scope of the present application.

[0280] Information of the sequences involved herein is described in the following table:

[0281] Example 1

[0282] 1. Drugs and reagents used in the experiment

[0283] PTK-ADC A-05: obtained from Sichuan Kelun Botai Biopharmaceutical Co., Ltd., prepared according to the preparation method of "101A6HZm-A-05" described in WO2024078586, and configured into a solution with 0.9% sodium chloride injection before administration.

[0284] Cetuximab: obtained from Sichuan Kelun Botai Biopharmaceutical Co., Ltd. The heavy chain and light chain amino acid sequences of the antibody are described on page 3, lines 1-6 of the specification and Figures 3 and 4 of WO2004085474A2. The antibody is configured into a solution with 0.9% sodium chloride injection before administration.

[0285] Bevacizumab: full name is bevacizumab injection (trade name: Avastin), active ingredient is bevacizumab (humanized anti-VEGF monoclonal antibody), purchased from Roche, stored at 2-8°C.

[0286] NCI-H292 cells: purchased from Nanjing Kebai Company.

[0287] 2. Experimental procedures and results

[0288] NCI-H292 lung cancer cells were cultured in monolayer in vitro, and the culture conditions were as follows: 10% fetal bovine serum was added to RPMI 1640 medium, and the cells were cultured in a 37°C incubator containing 5% CO2. The cells were trypsinized and passaged once or twice a week. When the cells were in the exponential growth phase, the culture medium was taken for mycoplasma detection. After passing the detection, the cells were collected and counted.

[0289] Female BALB / c Nude mice were used, and about 3x10 6 NCI-H292 cells were subcutaneously inoculated in the right axillary of each mouse, suspended in 0.1ml PBS+50% Matrigel. When the average tumor volume grew to about 100-200mm 3Mice with tumors that were too small or too large were removed, and the remaining mice were randomly divided into 8 groups of 6 mice each according to tumor volume and animal weight, and were administered the drugs intravenously according to the dosage and frequency in Table 1.

[0290] Table 1. Dosing Regimen

[0291] Regularly measure the long and short diameters of the tumor using calipers. The formula for calculating tumor volume (V) is: V = 0.5 × a × b 2 Where a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of a drug is evaluated using the tumor growth inhibition rate (TGI) (%), calculated using the formula: TGI (%) (瘤体积) =[1-(T) Vt -T V0 ) / (C Vt -C V0 )]×100%, T V0 T represents the average tumor volume of the test compound group when administered in groups. Vt The mean tumor volume of the test compound group on day t after administration; C V0 C represents the average tumor volume in the solvent group during the grouped drug administration. Vt The mean tumor volume in the solvent group is shown on day t after drug administration. TGI (%) is the percentage of tumor regression observed. (瘤体积) =100% - (T) Vt -T V0 ) / T V0 ×100%.

[0292] Data processing was performed using GraphPad Prism 9.5.1 software (or other statistical analysis software).

[0293] The in vivo combination index (CI) of the two drugs in the Bliss independent model was calculated using the invivoSyn method. CI < 1 indicates a synergistic effect, CI = 1 indicates an additive effect, and CI > 1 indicates an antagonistic effect.

[0294] The experimental results are shown in Table 2 below.

[0295] Table 2. Tumor volume measurement results Note: "N / A" indicates that it is not applicable;

[0296] Table 2 shows that on day 28 after administration, the tumor volume in each administration group (G2-G8) was significantly reduced compared with the G1 saline group.

[0297] According to the data results of G2-G6, G8 groups, the tumor inhibition effects of the two-drug combination groups (G5, G6) and the three-drug combination group (G8) including PTK-ADC A-05 have significant differences compared with the PTK-ADC A-05 single-drug group (G2) (p<0.01). And the tumor inhibition effects of the two-drug combination groups (G5, G6) and the three-drug combination group (G8) including PTK-ADC A-05 also have significant advantages compared with the cetuximab single-drug group (G3) or the bevacizumab single-drug group (G4). Among them, the tumor inhibition effect of the three-drug combination group (G8) including PTK-ADC A-05 is the best. And the tumors of the 6 mice in G5, G6, G8 groups all present partial regression. The above results show that the anti-tumor effect of the combination of PTK-ADC A-05 is significantly better than that of single drug. The in vivo combination index (CI) of the two drugs is calculated by invivoSyn method, and the CI value of PTK-ADC A-05 and cetuximab is 0.606, and the CI value of PTK-ADC A-05 and bevacizumab is 0.532, indicating that there is a synergistic effect between PTK-ADC A-05 and cetuximab and between PTK-ADC A-05 and bevacizumab.

[0298] According to the data results of G3, G4, G7 groups, the tumor inhibition effect of the combination of cetuximab and bevacizumab (G7) is better than that of the cetuximab single-drug group (G3) or the bevacizumab single-drug group (G4). The combination of cetuximab and bevacizumab has an additive effect compared with the single-drug group.

[0299] During the test period, no animal died in each group, and the animals in each experimental group had good tolerance. Among them, the G1 group had body weight decrease at the end of the test, which was 9.64% lower than the average at the time of grouping, and the rest of the groups had no obvious body weight change. This shows that each drug combination group (G5-G8) has good safety and tolerance.

[0300] Example 2

[0301] 1. The drugs and reagents used in the experiment

[0302] Cetuximab: from Sichuan Kelun Botai Biopharmaceutical Co., Ltd. The heavy chain and light chain amino acid sequences of the antibody are recorded on page 3, lines 1-6 of the specification WO2004085474A2 and specification figures 3, 4. The antibody is configured into a solution using 0.9% sodium chloride injection before administration.

[0303] Bevacizumab: full name is bevacizumab injection (trade name: Avastin), active ingredient is bevacizumab (humanized anti-VEGF monoclonal antibody), purchased from Roche Company, stored at 2-8°C.

[0304] HCC827 cells: purchased from Nanjing Kebai Company.

[0305] 2. Experimental Procedures and Results

[0306] HCC827 cells were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum at 37°C in an incubator containing 5% CO2. Female BALB / c Nude mice were used, with approximately 5 × 10⁵ cells subcutaneously injected into the right axilla of each mouse. 6 One HCC827 cell. Develop until the average tumor volume reaches approximately 100–250 mm. 3 Mice with tumors that were too small or too large were removed, and the remaining mice were randomly grouped according to tumor volume and animal weight, and administered the drugs via tail vein injection according to the dosage and frequency shown in Table 3 below.

[0307] Table 3. Dosing Regimen Note: "N / A" indicates that it is not applicable;

[0308] Regularly measure the long and short diameters of the tumor using calipers. The formula for calculating tumor volume (V) is: V = 0.5 × a × b 2 Where a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the drug is evaluated using the tumor growth inhibition rate (TGI) (%), calculated using the formula: TGI (%) (瘤体积) =[1-(T) Vt -T V0 ) / (C Vt -C V0 )]×100%, T V0 T represents the average tumor volume of the test compound group when administered in groups. Vt The mean tumor volume of the test compound group on day t after administration; C V0 C represents the average tumor volume in the solvent group during the grouped drug administration. Vt The mean tumor volume in the solvent group is shown on day t after drug administration. TGI (%) is the percentage of tumor regression observed. (瘤体积) =100% - (T) Vt -T V0 ) / T V0 ×100%.

[0309] Data processing was performed using GraphPad Prism 9.5.1 software (or other statistical analysis software), and the experimental results are shown in Table 4 below.

[0310] Table 4. Tumor volume measurement results Note: "N / A" indicates that it is not applicable;

[0311] The results of Table 4 show that group 4, which is administered with cetuximab and bevacizumab, has a good tumor inhibition effect at the 28th day after administration, and has a significant difference compared with group 1 (p<0.001). And the tumor inhibition effect of cetuximab and bevacizumab is also obviously better than that of group 2 and group 3 which are administered with cetuximab or bevacizumab alone, and the mice have good tolerance. According to the Bliss independence model, the in vivo combination index (CI) of the two drugs is calculated by the invivoSyn method, and the CI value of bevacizumab and cetuximab is 0.678, indicating that there is a synergistic effect between bevacizumab and cetuximab.

[0312] Although the specific embodiments of the present application have been described in detail, those skilled in the art will understand that various modifications and substitutions can be made to those details based on all the teachings disclosed, and these changes are within the scope of protection of the present application. The entire scope of the present application is given by the appended claims and any equivalents thereof.

Claims

Use of the antibody drug conjugate and other therapeutic agents in the preparation of a medicament or a combination of medicaments for treating a tumor or cancer; the other therapeutic agents are selected from one, two or more of an anti-EGFR antibody and a VEGF antibody. Use according to claim 1, wherein: The anti-VEGF antibody is selected from one, two or more of Bevacizumab, Ranibizumab, Brolucizumab, Faricimab. Use according to claim 1 or 2, wherein: The anti-VEGF antibody is Bevacizumab. Use according to any one of claims 1 to 3, wherein: The anti-EGFR antibody is selected from one, two or more of Cetuximab, Panitumumab, Necitumumab, Nimotuzumab, Amivantamab. Use according to any one of claims 1 to 4, wherein: The anti-EGFR antibody is Cetuximab. Use according to any one of claims 1 to 5, wherein: The antibody drug conjugate contains an antibody or antigen-binding fragment thereof that specifically binds to human tyrosine kinase 7 (PTK7). Use according to claim 6, wherein: The antibody or antigen-binding fragment thereof comprises: (1) a heavy chain variable region (VH) and / or a light chain variable region (VL), wherein the CDRs are defined according to the Chothia numbering system: a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 with the sequence of SEQ ID NO: 3 or a variant thereof, CDR-H2 with the sequence of SEQ ID NO: 4 or a variant thereof, and CDR-H3 with the sequence of SEQ ID NO: 5 or a variant thereof; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 with the sequence of SEQ ID NO: 6 or a variant thereof, CDR-L2 with the sequence of SEQ ID NO: 7 or a variant thereof, and CDR-L3 with the sequence of SEQ ID NO: 8 or a variant thereof; the variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity to the sequence from which it is derived, or the variant has one or several amino acid substitutions, deletions, or additions (e.g., 1, 2, or 3 amino acid substitutions, deletions, or additions) compared to the sequence from which it is derived; preferably, the substitutions are conservative substitutions; or, (2) a heavy chain variable region (VH) and / or a light chain variable region (VL), wherein the CDRs are defined according to the Kabat numbering system: a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 9 or a variant thereof, CDR-H2 of SEQ ID NO: 10 or a variant thereof, CDR-H3 of SEQ ID NO: 5 or a variant thereof; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6 or a variant thereof, CDR-L2 of SEQ ID NO: 7 or a variant thereof, CDR-L3 of SEQ ID NO: 8 or a variant thereof; said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the sequence from which it is derived or said variant has one or several amino acid substitutions, deletions or additions compared to the sequence from which it is derived (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions); preferably said substitutions are conservative substitutions; or, (3) a heavy chain variable region (VH) and / or a light chain variable region (VL) in which the CDRs are defined according to the IMGT numbering system: a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 11 or a variant thereof, CDR-H2 of SEQ ID NO: 12 or a variant thereof, CDR-H3 of SEQ ID NO: 13 or a variant thereof; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 14 or a variant thereof, CDR-L2 of SEQ ID NO: 15 or a variant thereof, CDR-L3 of SEQ ID NO: 8 or a variant thereof; said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the sequence from which it is derived or said variant has one or several amino acid substitutions, deletions or additions compared to the sequence from which it is derived (e.g. 1, 2 or 3 amino acid substitutions, deletions or additions); preferably said substitutions are conservative substitutions; or, (4) a heavy chain variable region (VH) and / or a light chain variable region (VL) in which the CDRs are defined according to the AbM numbering system: a heavy chain variable region (VH) comprising 3 CDRs: CDR-H1 of SEQ ID NO: 16 or a variant thereof, CDR-H2 of SEQ ID NO: 17 or a variant thereof, and CDR-H3 of SEQ ID NO: 5 or a variant thereof; and / or, a light chain variable region (VL) comprising 3 CDRs: CDR-L1 of SEQ ID NO: 6 or a variant thereof, CDR-L2 of SEQ ID NO: 7 or a variant thereof, and CDR-L3 of SEQ ID NO: 8 or a variant thereof; said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the sequence from which it is derived or has one or several (e.g. 1, 2 or 3) amino acid substitutions, deletions, or additions compared to the sequence from which it is derived; preferably, said substitutions are conservative substitutions. Use according to claim 6 or 7, wherein: said antibody or antigen binding fragment thereof comprises: a VH comprising the sequence of SEQ ID NO: 1 or a variant thereof, and / or, a VL comprising the sequence of SEQ ID NO: 2 or a variant thereof; said variant has at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the sequence from which it is derived or has one or several (e.g. 1, 2, 3, 4 or 5) amino acid substitutions, deletions, or additions compared to the sequence from which it is derived; preferably, said substitutions are conservative substitutions. Use according to any one of claims 6-8, wherein: said antibody or antigen binding fragment thereof comprises a VH of the sequence of SEQ ID NO: 1, and, a VL of the sequence of SEQ ID NO:

2. Use according to any one of claims 6-9, wherein: said antibody or antigen binding fragment thereof further comprises a constant region from or derived from a human immunoglobulin. Use according to any one of claims 6-10, wherein: said antibody or antigen binding fragment thereof comprises: (a) a heavy chain constant region (CH) of a human immunoglobulin or a variant thereof having one or more amino acid substitutions, deletions or additions compared to the wild type sequence from which it is derived (e.g. up to 20, up to 15, up to 10, or up to 5 amino acid substitutions, deletions or additions; e.g. 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions); and (b) a light chain constant region (CL) of a human immunoglobulin or a variant thereof having one or more amino acid substitutions, deletions or additions compared to the wild type sequence from which it is derived (e.g. up to 20, up to 15, up to 10, or up to 5 amino acid substitutions, deletions or additions; e.g. 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions). (b) a light chain constant region (CL) of a human immunoglobulin or a variant thereof having one or more substitutions, deletions or additions of amino acids compared to the wild type sequence from which it is derived (e.g., up to 20, up to 15, up to 10, or up to 5 amino acid substitutions, deletions or additions; e.g., 1, 2, 3, 4 or 5 amino acid substitutions, deletions or additions). Use according to any one of claims 6-11, wherein: The antibody or antigen-binding fragment thereof comprises a heavy chain constant region (CH) as set forth in SEQ ID NO: 19, and / or a light chain constant region (CL) as set forth in SEQ ID NO:

18. Use according to any one of claims 6-12, wherein: The antibody or antigen-binding fragment thereof comprises a heavy chain having a sequence as set forth in SEQ ID NO: 20, and a light chain having a sequence as set forth in SEQ ID NO:

21. Use according to any one of claims 1 to 13, wherein: The antibody or antigen binding fragment thereof of the antibody drug conjugate is conjugated to a cytotoxic drug, which is a DNA topoisomerase inhibitor, such as camptothecin, hydroxy camptothecin, 9-aminocamptothecin, SN-38, irinotecan, topotecan, belotecan, rubitecan, exatecan, or Dxd or derivatives thereof, and the following compounds: Use according to any one of claims 1 to 14, wherein: The antibody drug conjugate has the following structure: wherein HA-(S- is an antibody or antigen-binding fragment thereof as defined in any one of claims 6-13, S in HA-(S- is derived from a thiol in the antibody or antigen-binding fragment thereof; x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. Use according to any one of claims 1 to 15, wherein: The antibody drug conjugate has the following structure: wherein HA-(S- is an antibody or antigen-binding fragment thereof as defined in any one of claims 6-13, S in HA-(S- is derived from a thiol in the antibody or antigen-binding fragment thereof; x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. The additional therapeutic agent is cetuximab. Use according to any one of claims 1 to 15, wherein: The antibody drug conjugate has the following structure: wherein HA-(S- is an antibody or antigen-binding fragment thereof as defined in any one of claims 6-13, S in HA-(S- is derived from a thiol in the antibody or antigen-binding fragment thereof; x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10. The additional therapeutic agent is bevacizumab. Use according to any one of claims 1 to 15, wherein: The antibody drug conjugate has the following structure: wherein HA-(S- is an antibody or antigen-binding fragment thereof as defined in any one of claims 6-13, S in HA-(S- is derived from a thiol in the antibody or antigen-binding fragment thereof; x is 1-10, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; and The additional therapeutic agent is cetuximab and bevacizumab. Use according to any one of claims 15 to 18, wherein: HA-(S- comprises a heavy chain (HC) having a sequence as set forth in SEQ ID NO: 20, and a light chain (LC) having a sequence as set forth in SEQ ID NO:

21. Use according to any one of claims 6-19, wherein: The antibody or antigen-binding fragment thereof has a heavy chain N-terminal glutamine that is cyclized to form pyroglutamic acid or a pyroglutamate salt. Use according to any one of claims 6-20, wherein: The antibody or antigen-binding fragment thereof has a heavy chain N-terminal glutamine that is cyclized to form pyroglutamic acid or a pyroglutamate salt. and / or The antibody or antigen-binding fragment thereof has a heavy chain C-terminal lysine that is lacking. Use according to any one of claims 6 to 21, wherein: The antibody that specifically binds to human tyrosine kinase 7 comprises a heavy chain having a sequence as set forth in SEQ ID NO: 20, 22, 23 or 24, and a light chain having a sequence as set forth in SEQ ID NO:

21. Use of a composition of antibody drug conjugates in the manufacture of a medicament or a combination of medicaments for treating a tumor or a cancer; said composition of antibody drug conjugates comprising one or more antibody drug conjugates as defined in any one of claims 6-22; said medicament or combination of medicaments further comprising another therapeutic agent as defined in any one of claims 1-5. Preferably, the DAR value (drug to antibody ratio) of the composition of antibody drug conjugates is 1-10; further preferably, the DAR value is 1-8; further preferably, the DAR value is 3-9; for example: the DAR value is 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, or 9.

0. Further preferably, the composition of antibody drug conjugates is a pharmaceutical composition of antibody drug conjugates, optionally comprising one or more pharmaceutically acceptable excipients, diluents or carriers. The use according to any one of claims 1-23, wherein the tumor or cancer comprises a solid tumor or a hematological malignancy. Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; further preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer. Preferably, the tumor or cancer overexpresses PTK7. Use of an antibody drug conjugate as defined in any one of claims 6-22 or a composition as defined in claim 23 in the manufacture of a medicament or a combination of medicaments for enhancing the therapeutic effect of another therapeutic agent in treating a tumor or a cancer; said another therapeutic agent being as defined in any one of claims 1-5. Preferably, the tumor or cancer comprises a solid tumor or a hematological malignancy. Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; further preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer. Preferably, the tumor or cancer overexpresses PTK7. A method for enhancing the therapeutic effect of a tumor or a cancer, comprising administering an antibody drug conjugate as defined in any one of claims 6-22 or a composition as defined in claim 23 in combination with an anti-EGFR antibody and / or an anti-VEGF antibody as defined in any one of claims 1-5. Preferably, the tumor or cancer comprises a solid tumor or a hematological malignancy. Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; further preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer; Preferably, the tumor or cancer overexpresses PTK7. Use of a combination of an anti-EGFR antibody and an anti-VEGF antibody in the manufacture of a medicament or a pharmaceutical combination for the treatment of a tumor or cancer; each of the anti-EGFR antibody and the anti-VEGF antibody is independently defined in any one of claims 1-5; Preferably, the anti-EGFR antibody is cetuximab, and the anti-VEGF antibody is bevacizumab. Use according to claim 27, wherein: The tumor or cancer comprises a solid tumor or a hematological malignancy; for example, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; preferably, the tumor or cancer overexpresses PTK7. A pharmaceutical combination comprising an antibody drug conjugate as defined in any one of claims 6-22 or a composition as defined in claim 23, and a further therapeutic agent as defined in any one of claims 1-5; optionally, the pharmaceutical combination is for use in the treatment of a tumor or cancer; Preferably, the tumor or cancer comprises a solid tumor or a hematological malignancy; Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; further preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer; Preferably, the tumor or cancer overexpresses PTK7. A pharmaceutical combination comprising an anti-EGFR antibody as defined in any one of claims 1-5 and an anti-VEGF antibody as defined in any one of claims 1-5; optionally, the pharmaceutical combination is for use in the treatment of a tumor or cancer; Preferably, the tumor or cancer comprises a solid tumor or a hematological malignancy; Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; further preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer. The antibody drug conjugate of any one of claims 6-22 or the composition as defined in claim 23 for use in the treatment of a tumor or cancer, wherein the antibody drug conjugate is administered in a combination therapy with a further therapeutic agent as defined in any one of claims 1-5; Preferably, the tumor or cancer comprises a solid tumor or a hematological malignancy; Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; further preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer. Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; further preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer; Preferably, the tumor or cancer is high expression of PTK7. The anti-EGFR antibody as defined in any one of claims 1-5 for use in the treatment of a tumor or cancer, wherein the anti-EGFR antibody is administered in a combination therapy with the anti-VEGF antibody as defined in any one of claims 1-5; Preferably, the tumor or cancer comprises a solid tumor or a hematological malignancy; Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; further preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer; Preferably, the tumor or cancer is high expression of PTK7. The anti-VEGF antibody as defined in any one of claims 1-5 for use in the treatment of a tumor or cancer, wherein the anti-VEGF antibody is administered in a combination therapy with the anti-EGFR antibody as defined in any one of claims 1-5; Preferably, the tumor or cancer comprises a solid tumor or a hematological malignancy; Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; further preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer; Preferably, the tumor or cancer is high expression of PTK7. A method of treating a tumor or cancer, the method comprising administering to a subject in need thereof: (a) a therapeutically effective amount of an antibody drug conjugate as defined in any one of claims 6-22 or a composition as defined in claim 23; and (b) a therapeutically effective amount of a further therapeutic agent as defined in any one of claims 1-5; Preferably, the tumor or cancer comprises a solid tumor or a hematological malignancy; Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; further preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer; Preferably, the tumor or cancer is high expression of PTK7. A method of treating a tumor or cancer, the method comprising administering to a subject in need thereof: (a) a therapeutically effective amount of an anti-VEGF antibody as defined in any one of claims 1-5; and (b) a therapeutically effective amount of an anti-EGFR antibody as defined in any one of claims 1-5; Preferably, the tumor or cancer comprises a solid tumor or a hematological malignancy; Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; further preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer; Preferably, the tumor or cancer is high expression of PTK7. Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; more preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer. A pharmaceutical composition comprising the antibody drug conjugate as defined in any one of claims 6-22 or the composition as defined in claim 23 and the additional therapeutic agent as defined in any one of claims 1-5. A pharmaceutical composition comprising the anti-EGFR antibody as defined in any one of claims 1-5 and the anti-VEGF antibody as defined in any one of claims 1-5. The pharmaceutical composition of claim 36 or 37, wherein: The pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients, diluents or carriers. The pharmaceutical composition of any one of claims 36-38 for use in the treatment of a tumor or cancer; Preferably, the tumor or cancer comprises a solid tumor or a hematological malignancy; Preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; more preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer; Preferably, the tumor or cancer overexpresses PTK7. One or more kits comprising the antibody drug conjugate as defined in any one of claims 6-22 or the composition as defined in claim 23 and the additional therapeutic agent as defined in any one of claims 1-5. The kit of claim 40, comprising the antibody drug conjugate or the composition thereof in one compartment and the additional therapeutic agent selected from one or more of the anti-EGFR antibody and the anti-VEGF antibody in another compartment; Optionally, the kit further comprises instructions for administering the antibody drug conjugate and the additional therapeutic agent; Optionally, the kit is for use in the treatment of a tumor or cancer; preferably, the tumor or cancer comprises a solid tumor or a hematological malignancy; preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; more preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer; preferably, the tumor or cancer overexpresses PTK7. One or more kits comprising the anti-EGFR antibody as defined in any one of claims 1-5 and the anti-VEGF antibody as defined in any one of claims 1-5. The kit of claim 42, comprising the anti-EGFR antibody in one compartment and the anti-VEGF antibody in another compartment; Optionally, the kit further comprises instructions for administering the anti-EGFR antibody and the anti-VEGF antibody; Optionally, the kit is for use in the treatment of a tumor or cancer; preferably, the tumor or cancer comprises a solid tumor or a hematological malignancy; preferably, the tumor or cancer is lung cancer, renal cancer, colorectal cancer, gastric cancer, gastro-esophageal junction cancer, liver cancer, pancreatic cancer, brain cancer, breast cancer, epidermal cancer, ovarian cancer, head and neck cancer, prostate cancer or esophageal cancer; further preferably, the tumor or cancer is lung cancer, more preferably non-small cell lung cancer.

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