Anti-tumor combination comprising an anti-CEACAM5 antibody-drug conjugate and an anti-VEGFR-2 antibody

Abstract

The present disclosure relates to antibody conjugates comprising an anti-CEACAM5 antibody for use in combination with an anti-VEGFR-2 antibody to treat cancer. The present disclosure further relates to pharmaceutical compositions and kits of parts comprising an anti-CEACAM5 antibody in combination with an anti-VEGFR-2 antibody for use in treating cancer.

Description

[Technical field]

[0001] The present disclosure relates to an antibody-drug conjugate comprising an anti-CEACAM5 antibody for use in combination with an anti-VEGFR-2 antibody to treat cancer. The present disclosure also relates to an anti-VEGFR-2 antibody for use in combination with an antibody-drug conjugate comprising an anti-CEACAM5 antibody to treat cancer. The present disclosure relates to a combination comprising an anti-VEGFR-2 antibody and an antibody-drug conjugate comprising an anti-CEACAM5 antibody for use in treating cancer. The present disclosure further relates to pharmaceutical compositions and kits of parts comprising an anti-CEACAM5 antibody in combination with an anti-VEGFR-2 antibody for use in treating cancer. [Background technology]

[0002] Carcinoembryonic antigen (CEA) is a glycoprotein involved in cell adhesion. CEA was first identified in 1965 as a protein normally expressed by fetal intestine during the first six months of pregnancy (Gold and Freedman, J Exp Med, 121, 439, 1965) and has been found in cancers of the pancreas, liver and colon. The CEA family belongs to the immunoglobulin superfamily. The CEA family, consisting of 18 genes, is subdivided into two subgroups of proteins: the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) subgroup and the pregnancy-specific glycoprotein subgroup (Kammerer & Zimmermann, BMC Biology 2010, 8:12).

[0003] In humans, the CEACAM subgroup consists of seven members: CEACAM1, CEACAM3, CEACAM4, CEACAM5, CEACAM6, CEACAM7 and CEACAM8. Numerous studies have shown that CEACAM5, identical to the first identified CEA, is highly expressed on the surface of colorectal, gastric, lung, breast, prostate, ovarian, cervical and bladder tumor cells and weakly expressed in a few normal epithelial tissues such as columnar and goblet cells of the colon, mucous cervical cells of the stomach and squamous cells of the esophagus and cervix (Hammarstroem et al, 2002, in "Tumor markers, Physiology, Pathobiology, Technology and Clinical Applications" Eds. Diamandis EP et al., AACC Press, Washington pp 375). CEACAM5 may therefore constitute a suitable therapeutic target for tumor-specific targeting approaches such as antibody-drug conjugates (ADCs).

[0004] The extracellular domain of CEACAM family members is composed of repeated immunoglobulin-like (Ig-like) domains classified into three types, A, B and N, according to sequence homology. CEACAM5 contains seven such domains, namely N, A1, B1, A2, B2, A3 and B3. The CEACAM5 A1, A2 and A3 domains on the one hand and the B1, B2 and B3 domains on the other hand show high sequence homology, with the A domain of human CEACAM5 showing 84-87% pairwise sequence similarity and the B domain showing 69-80%. Furthermore, other human CEACAM members presenting A and / or B domains in their structure, namely CEACAM1, CEACAM6, CEACAM7 and CEACAM8, show homology with human CEACAM5. In particular, the A and B domains of human CEACAM6 protein show sequence homology with the A1 and A3 domains and either the B1 to B3 domains of human CEACAM5, respectively, which is even higher than that observed between the A and B domains of human CEACAM5.

[0005] Considering the diagnostic or therapeutic purpose of targeting CEA, a number of anti-CEA antibodies have been generated. Specificity to related antigens has always been mentioned as a concern in the field, for example by Sharkey et al (1990, Cancer Research 50, 2823). Due to the above-mentioned homology, some of the previously described antibodies may demonstrate binding to repeated epitopes of CEACAM5 present in different immunoglobulin domains and / or show cross-reactivity to other CEACAM members such as CEACAM1, CEACAM6, CEACAM7 or CEACAM8, and lack specificity for CEACAM5. The specificity of anti-CEACAM5 antibodies is desirable in terms of CEA-targeting therapy, as they bind to human CEACAM5-expressing tumor cells but not to some normal tissues expressing other CEACAM members.

[0006] The international patent application published as WO 2014 / 079886 discloses an antibody that binds to the A3-B3 domain of human and Macaca fascicularis CEACAM5 proteins and does not significantly cross-react with human CEACAM1, human CEACAM6, human CEACAM7, human CEACAM8, Macaca fascicularis CEACAM1, Macaca fascicularis CEACAM6 and Macaca fascicularis CEACAM8. This antibody was conjugated to a maytansinoid, thereby inhibiting the IC 50 The present invention provides an antibody-drug conjugate having significant cytotoxic activity against MKN45 human gastric cancer cells, with a cytotoxicity value of ≦1 nM.

[0007] Antibody-drug conjugates (ADC) comprise an antibody conjugated to a chemotherapeutic agent, such as a cytotoxic agent or a growth inhibitory agent or a cytostatic agent.

[0008] According to one embodiment, the chemotherapeutic agent is linked to the antibody via a chemical linker. These antibody-drug conjugates (ADCs) have great potential in cancer chemotherapy, allowing selective delivery of potent chemotherapeutic agents to target cancer cells, resulting in improved efficacy, reduced systemic toxicity, and improved pharmacokinetics, pharmacodynamics, and biodistribution compared to conventional chemotherapy. To date, hundreds of different antibody-drug conjugates (ADCs) have been developed for various cancers, and some of them have been approved for human use.

[0009] Vascular endothelial growth factor (VEGF) is considered an important proangiogenic factor that drives tumor angiogenesis. VEGF expression is highly deregulated in primary tumors and metastatic lesions. In tumors, VEGF is expressed at high levels by multiple cell types, including cancer cells, tumor stroma, and infiltrating bone marrow cells, leading to endothelial cell hyperproliferation and loss of induction mechanisms of angiogenic sprouting.

[0010] Activation of vascular endothelial growth factor receptor 2 (VEGFR-2) by VEGF is considered the most important driver of tumor angiogenesis. VEGF has been shown to be expressed at high levels in many different types of carcinomas. Autophosphorylation of VEGFR-2 kinase is one of the earliest events upon VEGF binding and is critical for activation of the kinase and subsequent phosphorylation events on the VEGFR-2 receptor. As a result, antagonist antibodies against VEGFR-2 have been produced and studied. In particular, ramucirumab (CAS number 947687-13-0) is a fully human IgG1 monoclonal antibody that binds to the ligand-binding site of VEGFR-2 and prevents its activation. Ramucirumab has been approved for use as monotherapy for hepatocellular carcinoma, as monotherapy and in combination with chemotherapy in metastatic gastric cancer, gastroesophageal junction adenocarcinoma (GEJ) or metastatic colorectal cancer, and in combination with chemotherapy for metastatic non-small cell lung cancer. Summary of the Invention [Problem to be solved by the invention]

[0011] However, according to the World Health Organization, cancer is the second leading cause of death worldwide, responsible for approximately 9.6 million deaths in 2018. Thus, there is a continuing need to provide improved drug combinations and regimens for the treatment of cancer. [Means for solving the problem]

[0012] The present disclosure relates to antibody-drug conjugates (ADCs) comprising an anti-CEACAM5 antibody conjugated to a cytotoxic maytansinoid agent (DM4) for use in combination with an anti-VEGFR2 antibody to treat cancer.

[0013] The present disclosure relates to antibody-drug conjugates (ADCs) comprising an anti-CEACAM5 antibody and a cytotoxic agent for use in combination with an anti-VEGFR-2 antibody to treat cancer.

[0014] The present disclosure relates to anti-VEGFR-2 antibodies for use in combination with an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody and a cytotoxic agent for treating cancer.

[0015] The present disclosure further relates to pharmaceutical compositions comprising antibody-drug conjugates (ADCs) comprising an anti-CEACAM5 antibody and a cytotoxic agent and / or an anti-VEGFR-2 antibody, as well as uses of the pharmaceutical compositions for treating cancer.

[0016] The present disclosure further relates to a pharmaceutical composition comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody and a cytotoxic agent and / or an anti-VEGFR-2 antibody, and a pharma- ceutically acceptable excipient, as well as the use of the pharmaceutical composition for treating cancer.

[0017] The present disclosure also relates to a kit comprising, in separate or combined formulations, (i) a pharmaceutical composition comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody and a cytotoxic agent, and (ii) a pharmaceutical composition comprising an anti-VEGFR-2 antibody.

[0018] The disclosure also relates to (i) a pharmaceutical composition comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody and a cytotoxic agent and a pharma- ceutically acceptable excipient, and (ii) a kit comprising a pharmaceutical composition comprising an anti-VEGFR-2 antibody and a pharma- ceutically acceptable excipient, in separate or combined formulations.

[0019] The present disclosure also relates to a combination comprising an anti-VEGFR-2 and an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody and a cytotoxic agent for use to treat cancer.

[0020] The present disclosure further relates to the use of the kit for the treatment of cancer.

[0021] The present disclosure further relates to a pharmaceutical composition or a kit as disclosed herein for use in treating cancer.

[0022] The present inventors have determined that antibody-drug conjugates (ADCs) comprising an anti-CEACAM5 antibody and a cytotoxic agent administered in combination with an anti-VEGFR-2 antibody exhibit favorable activity in the treatment of cancer.

[0023] Also, as shown in the Examples section, the inventors have determined that antibody-drug conjugates (ADCs) comprising an anti-CEACAM5 antibody, e.g., an anti-CEACAM5 antibody conjugated to a maytansinoid, e.g., tusamitamaravtansine (huMAb2-3-SPDB-DM4), administered in combination with an anti-VEGFR-2 antibody, e.g., ramucirumab, exhibit synergistic activity in reducing tumor growth and tumor size compared to the effects achieved with the ADC or the anti-VEGFR-2 antibody used alone.

[0024] Moreover, as shown in the Examples section, the inventors have surprisingly found that a dose of about 100 mg / m 2 , about 150mg / m 2 or about 170 mg / m 2It has been observed that administration of an antibody-drug conjugate, ADC, comprising an anti-CEACAM5 antibody and a cytotoxic agent at a dose of 100 mg / kg / day was particularly well tolerated and efficient in the treatment of gastric cancer (GC) or gastroesophageal junction cancer (GEJ) when administered every two weeks.

[0025] The inventors have also surprisingly found that an antibody-drug conjugate, ADC, comprising an anti-CEACAM5 antibody and a cytotoxic agent is effective in treating patients with a cytotoxic agent at a dose of about 100 mg / m in combination with an anti-VEGFR-2 antibody at a dose of about 8 mg / kg or about 10 mg / kg. 2 , about 120mg / m 2 , about 135mg / m 2 , about 150mg / m 2 or about 170 mg / m 2 was observed to be particularly well tolerated and effective in the treatment of gastric cancer (GC) or gastroesophageal junction cancer (GEJ) when administered every 3 weeks.

[0026] In particular, the present inventors have surprisingly found that administration of an antibody-drug conjugate, ADC, comprising an anti-CEACAM5 antibody and a cytotoxic agent results in a dose of approximately 120 mg / m 2 , about 150mg / m 2 or about 170 mg / m 2 in the first cycle, i.e. as a loading or initial dose, followed by administration of about 100 mg / m 2 or 80 mg / m 2 It has been observed that administration of a dose of about 8 mg / kg in said first, second and optionally at least one subsequent (or additional) cycle, i.e. as a subsequent dose, in a second cycle, optionally in at least one subsequent (or additional) cycle, in combination with an anti-VEGFR-2 antibody at a dose of about 8 mg / kg in said first, second and optionally at least one subsequent (or additional) cycle, was particularly well tolerated and efficient in the treatment of gastric cancer (GC) or gastroesophageal junction cancer (GEJ), when said first, second and subsequent cycles last for two weeks, i.e. when said administration occurs every two weeks.

[0027] Within this disclosure, the expression "loading dose" is intended to refer to a dose of a drug used at the beginning of treatment to frontload an adequate plasma concentration of the drug that is maintained by subsequent doses. The loading dose is typically higher than the subsequent doses. "Loading dose" is used interchangeably with "initial dose" or "initial dose". "Subsequent dose" is intended to refer to a dose of a drug that is administered on a regular schedule once a high plasma concentration of the drug has been established by use of a loading dose to maintain a plateau of the plasma drug concentration. The subsequent doses are typically lower than the loading dose. "Subsequent dose" is used interchangeably with "second dose".

[0028] The inventors have surprisingly found that in the first cycle and optionally at least one subsequent cycle, 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 It has been observed that administration of an antibody-drug conjugate, ADC, comprising an anti-CEACAM5 antibody and a cytotoxic agent at a dose of 8 or 10 mg / kg in the first cycle and optionally subsequent cycles, of an anti-VEGFR-2 antibody at a dose of 8 or 10 mg / kg, was particularly well tolerated and efficient in the treatment of gastric cancer (GC), gastroesophageal junction (GEJ) or lung cancer, when the first cycle and additional cycles last for 3 weeks, i.e., when the administration occurs every 3 weeks.

[0029] Furthermore, the present inventors have surprisingly found that the antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody and a cytotoxic agent can be administered at a concentration of about 80 mg / m 2 or about 100 mg / m 2 and administration of an anti-VEGFR-2 antibody at a dose of about 8 mg / kg or about 10 mg / kg in the first and second cycles, optionally at least one additional cycle, was observed to be particularly well tolerated and effective for the treatment of lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), when the first, second and additional cycles last for two weeks, i.e., when administration occurs every two weeks.

[0030] The inventors have surprisingly found that 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 It has been observed that administration of an antibody-drug conjugate, ADC, comprising an anti-CEACAM5 antibody and a cytotoxic agent at a dose of about 8 or about 10 mg / kg and administration of an anti-VEGFR-2 antibody at a dose of about 8 or about 10 mg / kg in the first and second cycles, optionally at least one subsequent cycle, was particularly tolerable and efficient in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), when the first cycle, second cycle and subsequent cycles last for three weeks, i.e., when administration occurs every three weeks.

[0031] In some embodiments, the present disclosure relates to an antibody-drug conjugate comprising an anti-CEACAM5 antibody and a cytotoxic agent for use in combination with an anti-VEGFR2 antibody to treat cancer.

[0032] The present disclosure relates to a combination comprising an anti-VEGFR-2 antibody and an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody and a cytotoxic agent for use in the treatment of cancer.

[0033] The cancer is a CEACAM5-expressing cancer. "CEACAM5-expressing cancer" is used interchangeably with "CEACAM5-positive cancer." A CEACAM5-positive cancer may have a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells. Such a cancer may be labeled as a high CEACAM5-expressing cancer. A CEACAM5-positive cancer may have a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more and less than 50% of the cancer cells. Such a cancer may be labeled as a moderate CEACAM5-expressing cancer.

[0034] Cancers with CEACAM5 immunohistochemical intensity of 2+ or higher in less than 1% of cancer cells are cancers with low or negative CEACAM5 expression.

[0035] In some embodiments, the anti-CEACAM5 antibody may comprise a CDR-H1 consisting of SEQ ID NO: 1, a CDR-H2 consisting of SEQ ID NO: 2, a CDR-H3 consisting of SEQ ID NO: 3, a CDR-L1 consisting of SEQ ID NO: 4, a CDR-L2 consisting of the amino acid sequence NTR, and a CDR-L3 consisting of SEQ ID NO: 5.

[0036] In some embodiments, the anti-CEACAM5 antibody can comprise a heavy chain variable domain (VH) consisting of SEQ ID NO:6 and a light chain variable domain (VL) consisting of SEQ ID NO:7.

[0037] In some embodiments, the anti-CEACAM5 antibody can comprise a heavy chain (VH) consisting of SEQ ID NO:8 and a light chain (VL) consisting of SEQ ID NO:9.

[0038] In some embodiments, the antibody-drug conjugate may comprise at least one and at least one cytotoxic agent (also called a chemotherapeutic agent).

[0039] In some embodiments, the chemotherapeutic agent may be selected from the group consisting of a radioisotope, a protein toxin, a small molecule toxin, and combinations thereof.

[0040] In some embodiments, small molecule toxins can be selected from antimetabolites, DNA alkylating agents, DNA crosslinking agents, DNA intercalating agents, anti-microtubule agents, topoisomerase inhibitors, and combinations thereof.

[0041] In some embodiments, the chemotherapeutic agent may be selected from the group consisting of taxanes, vinca alkaloids, maytansinoids, colchicine, podophyllotoxin, gluseofulvin, and combinations thereof.

[0042] In some embodiments, the maytansinoid may be selected from the group consisting of N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N2'-deacetyl-N-2'(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4), and combinations thereof.

[0043] In some embodiments, the anti-CEACAM5 antibody can be covalently attached to at least one chemotherapeutic agent via a cleavable or non-cleavable linker.

[0044] In some embodiments, the linker may be selected from the group consisting of N-succinimidyl pyridyldithiobutyrate (SPDB), 4-(-ylidin-2-yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB) and succinimidyl (N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).

[0045] In some embodiments, the CEACAM5 antibody may comprise a heavy chain (VH) consisting of SEQ ID NO:8 and a light chain (VL) consisting of SEQ ID NO:9 (huMAb2-3), which is covalently linked to N2'-deacetyl-N-2'(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4) via N-succinimidylpyridyldithiobutyrate (SPDB).

[0046] In the following description, an antibody-drug conjugate comprising an anti-CEACAM5 antibody and a cytotoxic agent (also called a chemotherapeutic agent) is referred to as an "antibody-drug conjugate" or an "antibody-drug conjugate comprising a CEACAM5-antibody."

[0047] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody and a cytotoxic agent and an anti-VEGFR2 antibody may be administered separately or sequentially to a patient in need thereof.

[0048] A patient in need thereof is a patient having a CEACAM5-expressing cancer.

[0049] In some embodiments, the antibody-drug conjugate comprising an anti-CEACAM5 antibody and a cytotoxic agent and an anti-VEGFR2 antibody may be formulated into a single pharmaceutical composition comprising the antibody-drug conjugate and the anti-VEGFR2 antibody.

[0050] In some embodiments, the antibody-drug conjugate and the anti-VEGFR2 antibody may be formulated in the form of two separate pharmaceutical compositions, where (i) one pharmaceutical composition may contain the antibody-drug conjugate and (ii) the other pharmaceutical composition may contain the anti-VEGFR2 antibody.

[0051] The antibody-drug conjugate and the anti-VEGFR-2 antibody may be administered simultaneously, separately or sequentially.

[0052] In some embodiments, the antibody-drug conjugate and the anti-VEGFR2 antibody may be administered separately or sequentially to a patient in need thereof.

[0053] In the present disclosure, the phrase "administered sequentially" when used in reference to administration of at least two drugs is intended to mean that the second drug is administered in time with respect to the first drug, i.e., one drug is administered before or after the other drug. The administration may be by the same route or by separate routes. The period between administration of the first drug and administration of the second drug may last from about 5 minutes to about 3 hours, e.g., from 10 minutes to about 2.5 hours, from about 30 minutes to about 2 hours, or from about 1 hour to about 1.5 hours. The period between administration of the first drug and administration of the second drug may last from about 5 minutes, about 10 minutes, about 30 minutes, about 1 hour, 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours.

[0054] In this disclosure, the phrase "administered simultaneously," when used in reference to administration of at least two drugs, is intended to mean that a first drug and a second drug are administered at the same time or simultaneously, optionally by the same route, e.g., when formulated in the same composition.

[0055] In the present disclosure, the phrase "administered separately" when used in reference to administration of at least two drugs is intended to mean that the first and second drugs are administered by separate routes, or by the same route but at different locations in the body, for example, by two intramuscular administrations in different muscles. The administrations can be simultaneous in time or sequential. Usually, the administrations are simultaneous, i.e., usually within a time frame of less than about 5 minutes.

[0056] In some embodiments, the antibody-drug conjugate and the anti-VEGFR-2 antibody are administered sequentially.

[0057] The antibody-drug conjugate may be administered before or after the anti-VEGFR-2 antibody. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody, i.e., after the anti-VEGFR-2 antibody.

[0058] In some embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody.

[0059] In some embodiments, the antibody-drug conjugate and the anti-VEGFR-2 antibody may be administered for at least one cycle of treatment.

[0060] In the present disclosure, the expression "treatment cycle" is intended to refer to a treatment period followed by a rest period (no treatment) that is repeated on a regular schedule. For example, one day of treatment followed by one or more days of rest is one treatment cycle. This cycle repeated multiple times on a regular schedule constitutes a treatment series. For example, within the present disclosure, a treatment cycle can last for a period of 1, 2, 3, 4, 5 or 6 weeks, with the first day of the cycle being the treatment period and the subsequent days being the rest period. A treatment (or course of treatment) can include a first cycle followed by at least one second cycle and optionally at least one additional cycle. A treatment can include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cycles.

[0061] In some embodiments, the antibody-drug conjugate and the anti-VEGFR-2 antibody may be administered for a first cycle of treatment and at least one additional cycle of treatment.

[0062] In some embodiments, the antibody-drug conjugate and the anti-VEGFR-2 antibody may be administered on day 1 of the first cycle of treatment.

[0063] In some embodiments, the antibody-drug conjugate and the anti-VEGFR-2 antibody may be administered on day 1 of at least one additional (or subsequent) cycle of treatment.

[0064] In some embodiments, the treatment cycle may be about two or three weeks.

[0065] In some embodiments, the treatment cycle may be about two weeks.

[0066] In some embodiments, the treatment cycle may be about 3 weeks.

[0067] In some embodiments, the cancer can be a CEACAM5-expressing cancer.

[0068] In some embodiments, the cancer may be a CEACAM5 positive cancer, having a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells as measured by immunohistochemistry. Such CEACAM5 positive or CEACAM5 expressing cancers may be labeled as high CEACAM5 positive cancers.

[0069] In some embodiments, the cancer may be a CEACAM5-positive cancer, with more than 1% and less than 50% of the cancer cells having a CEACAM5 immunohistochemical intensity of 2+ or greater as measured by immunohistochemistry. Such CEACAM5-positive or CEACAM5-expressing cancers may be labeled as moderate CEACAM5-positive cancers.

[0070] In some embodiments, the cancer may be selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, lung cancer, cervical cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0071] In some embodiments, the cancer may be selected from gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, and lung cancer, such as non-squamous non-small cell lung cancer.

[0072] In some embodiments, the cancer is gastric (GC) or gastroesophageal adenocarcinoma (GEJ cancer).

[0073] In some embodiments, the lung cancer can be non-squamous non-small cell lung cancer (NSQ NSCLC).

[0074] In some embodiments, the disclosure provides an antibody-drug conjugate comprising an anti-CEACAM5 antibody and a cytotoxic agent for use in combination with an anti-VEGFR2 antibody to treat cancer, wherein the antibody-drug conjugate is administered at a concentration of 60 mg / m 2 ~210mg / m 2 and the anti-VEGFR-2 antibody may be administered at a dose of 2 mg / kg to 20 mg / kg.

[0075] In some embodiments, the disclosure provides an antibody-drug conjugate comprising an anti-CEACAM5 antibody and a cytotoxic agent for use in combination with an anti-VEGFR2 antibody to treat cancer, the antibody-drug conjugate comprising an anti-CEACAM5 antibody and a cytotoxic agent for use in combination with an anti-VEGFR2 antibody, the antibody-drug conjugate being administered at a dose of about 60 mg / m 2 ~about 210mg / m 2 The present invention relates to an antibody-drug conjugate that can be administered in a dose of

[0076] Dosage may be based on the patient's body surface area. In some embodiments, for patients with a body surface area (BSA) greater than 2.2 m2, the dose of the antibody-drug conjugate may be capped based on 2.2 m2 of BSA.

[0077] The antibody-drug conjugate may be administered at about 60, 80, 100, 120, 135, 150, 170, 180, 190 or about 210 mg / m 2 may be administered at a dose of

[0078] The antibody-drug conjugate is approximately 80 mg / m 2 ~about 170mg / m 2 may be administered at a dose of

[0079] The antibody-drug conjugate is approximately 80 mg / m 2 , about 100mg / m 2 , about 120mg / m 2 , about 150mg / m 2 or about 170 mg / m 2 may be administered at a dose of

[0080] The antibody-drug conjugate is at about 120, 135, 150 or about 170 mg / m 2 may be administered at a dose of

[0081] The antibody-drug conjugate may be administered at a loading or first dose of about 80, 100, 120, 135, 150 or about 170 mg / m 2 may be administered at a dose of

[0082] The antibody-drug conjugate is administered at about 80, 100, 120, 135, 150 or about 170 mg / m as a subsequent or second dose. 2 may be administered at a dose of

[0083] The antibody-drug conjugate is approximately 80 mg / m 2 , about 100mg / m 2 Subsequent doses may be administered at a dose of

[0084] In some embodiments, the antibody-drug conjugate is administered at 80 mg / m on day 1 of the first cycle of treatment. 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2or 170 mg / m 2 may be administered in a dose of

[0085] In some embodiments, the antibody-drug conjugate is administered at about 120 mg / m on day 1 of the first cycle of treatment. 2 , 135 mg / m 2 or 150 mg / m 2 may be administered in a dose of

[0086] In some embodiments, the antibody-drug conjugate is administered at about 80 mg / m on day 1 of the first cycle of treatment. 2 or about 100 mg / m 2 may be administered in a dose of

[0087] In some embodiments, the present disclosure relates to an antibody-drug conjugate comprising an anti-CEACAM5 antibody and a cytotoxic agent for use to treat cancer in combination with an anti-VEGFR2 antibody, wherein the anti-VEGFR-2 antibody may be administered at a dose of about 2 mg / kg to about 20 mg / kg.

[0088] The anti-VEGFR-2 antibody may be administered at a dose of about 2 to about 20 mg / kg, or about 4 to about 15 mg / kg, or about 6 to about 10 mg / kg, or about 8 mg / kg.

[0089] The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg or about 10 mg / kg.

[0090] The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg.

[0091] The anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg.

[0092] In some embodiments, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 , 100 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the treatment cycle may be two weeks.

[0093] In some embodiments, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the treatment cycle may be three weeks.

[0094] In some embodiments, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the treatment cycle may be three weeks.

[0095] In additional (or subsequent) cycles, the antibody-drug conjugate is administered at a dose of about 100 mg / m 2 may be administered at a dose of

[0096] In some embodiments, the antibody-drug conjugate is administered at 80 mg / m on day 1 of an additional cycle of treatment (at least one cycle following the first cycle). 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 can be administered at a dose of

[0097] In some embodiments, the antibody-drug conjugate is administered at about 100 mg / m on day 1 of an additional cycle of treatment (at least one cycle following the first cycle). 2 can be administered at a dose of

[0098] In some embodiments, the antibody-drug conjugate is administered at about 80 mg / m on day 1 of an additional cycle of treatment (at least one cycle following the first cycle). 2 can be administered at a dose of

[0099] The antibody-drug conjugate is administered at a dose of about 80 mg / m on day 1 of the first cycle of treatment. 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or about 170 mg / m 2 and about 80 mg / m on day 1 of an additional cycle of treatment. 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or about 170 mg / m 2 A cycle may be 2 weeks or 3 weeks.

[0100] The antibody-drug conjugate is administered at a dose of about 80 mg / m on day 1 of the first cycle of treatment. 2 or 100 mg / m 2 and about 80 mg / m on day 1 of an additional cycle of treatment. 2 or 100 mg / m 2 A cycle may be administered for 2 weeks.

[0101] The antibody-drug conjugate is administered at about 120 mg / m on day 1 of the first cycle of treatment. 2 , 135 mg / m 2 , 150 mg / m 2 or about 170 mg / m 2 and about 120 mg / m on day 1 of an additional cycle of treatment. 2 , 135 mg / m 2 , 150 mg / m 2 or about 170 mg / m 2 A cycle may be 3 weeks.

[0102] The antibody-drug conjugate is administered at about 120 mg / m on day 1 of the first cycle of treatment. 2 , 135 mg / m 2 , 150 mg / m 2 or about 170 mg / m 2 and about 80 mg / m on day 1 of an additional cycle of treatment. 2 or about 100 mg / m 2 may be administered at a dose of

[0103] The antibody-drug conjugate is administered at about 120 mg / m on day 1 of the first cycle of treatment. 2 , 135 mg / m 2 or 150 mg / m 2 on day 1 of an additional cycle of treatment at a dose of about 100 mg / m 2 may be administered in a dose of

[0104] The antibody-drug conjugate is administered at about 150 mg / m on day 1 of the first cycle of treatment. 2 or about 170 mg / m 2 and about 80 mg / m on day 1 of an additional cycle of treatment. 2 or about 100 mg / m 2 A cycle may be 2 weeks.

[0105] The antibody-drug conjugate is administered at about 100 mg / m on day 1 of the first cycle of treatment. 2 or about 80 mg / m 2 on day 1 of an additional cycle at a dose of approximately 100 mg / m 2 may be administered in a dose of

[0106] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg or about 10 mg / kg on day 1 of the first cycle of treatment.

[0107] In some embodiments, the anti-VEGFR-2 antibody can be administered at a dose of about 8 mg / kg on day 1 of the first cycle of treatment.

[0108] In some embodiments, the anti-VEGFR-2 antibody can be administered at a dose of about 10 mg / kg on day 1 of the first cycle of treatment.

[0109] The anti-VEGFR-2 antibody may be administered at a dose from 8 mg / kg, and the treatment cycle may be two weeks.

[0110] The anti-VEGFR-2 antibody may be administered at a dose from 10 mg / kg, and the treatment cycle may be three weeks.

[0111] In additional (or subsequent) cycles, the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg or about 10 mg / kg.

[0112] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg or about 10 mg / kg on day 1 of an additional cycle of treatment (at least one cycle following the first cycle).

[0113] In some embodiments, the anti-VEGFR-2 antibody can be administered at a dose of about 8 mg / kg on day 1 of an additional cycle of treatment (at least one cycle following the first cycle).

[0114] In some embodiments, the anti-VEGFR-2 antibody can be administered at a dose of about 10 mg / kg on day 1 of an additional cycle of treatment (at least one cycle following the first cycle).

[0115] In some embodiments, the anti-VEGFR-2 antibody can be administered at a dose of about 8 mg / kg on day 1 of the first cycle of treatment and on day 1 of each additional cycle of treatment (at least one cycle following the first cycle). A cycle can be 2 weeks.

[0116] In some embodiments, the anti-VEGFR-2 antibody can be administered at a dose of about 10 mg / kg on day 1 of the first cycle of treatment and on day 1 of each additional cycle of treatment (at least one cycle following the first cycle). A cycle can be 3 weeks.

[0117] In some embodiments, the cancer may be lung cancer.

[0118] In some embodiments, the cancer may be lung cancer and the antibody-drug conjugate is administered at a concentration of 80 mg / m 2 ~170mg / m 2 may be administered in a dose of

[0119] In some embodiments, the cancer can be lung cancer, such as non-small cell lung cancer, e.g., non-squamous non-small cell lung cancer (NSQ NSCLC), and the antibody-drug conjugate is administered at a dose of about 80 mg / m 2 ~about 170mg / m 2 may be administered at a dose of

[0120] The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg or about 10 mg / kg.

[0121] In some embodiments, the cancer may be lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), and the antibody-drug conjugate is administered at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 may be administered in a dose of

[0122] The lung cancer can be non-squamous non-small cell lung cancer (NSQ NSCLC).

[0123] In some embodiments, the antibody-drug conjugate is administered at 80 mg / m on day 1 of the first cycle of treatment. 2 , 100 mg / m 2 , 120 mg / m 2or 150 mg / m 2 can be administered at a dose of

[0124] In some embodiments, the antibody-drug conjugate is administered at 80 mg / m on day 1 of the first cycle of treatment. 2 or 100 mg / m 2 The anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg.

[0125] In some embodiments, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 or 100 mg / m 2 and the treatment cycle may be two weeks.

[0126] In some embodiments, on day 1 of the first cycle of treatment, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the cycle may be two weeks.

[0127] In some embodiments, the antibody-drug conjugate is administered at about 80 mg / m on day 1 of the first cycle of treatment. 2 The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg. The treatment cycle may last for 2 weeks.

[0128] In some embodiments, the antibody-drug conjugate is administered at about 100 mg / m on day 1 of the first cycle of treatment. 2 The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg. The treatment cycle may last for 2 weeks.

[0129] In some embodiments, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2and the treatment cycle may last for 3 weeks. The anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg.

[0130] In some embodiments, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 120 mg / m 2 or 150 mg / m 2 and the treatment cycle may be three weeks.

[0131] In some embodiments, on day 1 of the first cycle of treatment, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the cycle may be 3 weeks.

[0132] In some embodiments, the antibody-drug conjugate is administered at 80 mg / m on day 1 of at least one additional cycle of treatment. 2 , 100 mg / m 2 , 120 mg / m 2 or 150 mg / m 2 can be administered at a dose of

[0133] In some embodiments, the antibody-drug conjugate is administered at 80 mg / m on day 1 of at least one additional cycle of treatment. 2 or 100 mg / m 2 and the cycle may be two weeks.

[0134] In some embodiments, the antibody-drug conjugate is administered at 80 mg / m on day 1 of at least one further (or subsequent) cycle of treatment. 2 The treatment cycle may last for two weeks.

[0135] In some embodiments, the antibody-drug conjugate is administered at 100 mg / m on day 1 of at least one further (or subsequent) cycle of treatment. 2 The treatment cycle may last for two weeks.

[0136] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg on day 1 of at least one additional cycle of treatment, and the cycle may be two weeks.

[0137] In some embodiments, the antibody-drug conjugate is administered at 120 mg / m on day 1 of at least one additional cycle of treatment. 2 or 150 mg / m 2 and the cycle may last for three weeks.

[0138] In some embodiments, the antibody-drug conjugate is administered at 170 mg / m on day 1 of at least one additional cycle of treatment. 2 can be administered at a dose of

[0139] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg on day 1 of at least one additional cycle of treatment, and the cycle may be 3 weeks.

[0140] In some embodiments, the antibody-drug conjugate is administered at 80 mg / m on day 1 of the first cycle of treatment and on day 1 of at least one additional cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the treatment cycle may be two weeks.

[0141] In some embodiments, the antibody-drug conjugate is administered at 100 mg / m on day 1 of the first cycle of treatment and on day 1 of at least one additional cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the treatment cycle may be two weeks.

[0142] In some embodiments, the antibody-drug conjugate is administered at 120 mg / m on day 1 of the first cycle of treatment and on day 1 of at least one additional cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the treatment cycle may be 3 weeks.

[0143] In some embodiments, the antibody-drug conjugate is administered at 150 mg / m on day 1 of the first cycle of treatment and on day 1 of at least one additional cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the treatment cycle may be 3 weeks.

[0144] In some embodiments, the cancer may be lung cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 80 mg / m 2 on day 1 of the first cycle, and the cycle may be two weeks.

[0145] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 80 mg / m as a subsequent dose on day 1 of an additional cycle. 2 and the cycle may be two weeks.

[0146] In some embodiments, the cancer may be lung cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 100 mg / m 2 on day 1 of the first cycle, and the cycle may be two weeks.

[0147] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg as a subsequent dose, followed by administration of an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 100 mg / m as a subsequent dose on day 1 of an additional cycle. 2 and the cycle may be for several weeks.

[0148] In some embodiments, the cancer may be lung cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 120 mg / m 2 on day 1 of the first cycle, and the cycle may be three weeks.

[0149] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 120 mg / m as a subsequent dose on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0150] In some embodiments, the cancer may be lung cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 150 mg / m 2 on day 1 of the first cycle, and the cycle may be three weeks.

[0151] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by administration of an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a subsequent dose of 150 mg / m on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0152] In some embodiments, the cancer is gastric cancer or gastroesophageal adenocarcinoma (GEJ) cancer.

[0153] In some embodiments, the cancer is gastric cancer or gastroesophageal adenocarcinoma (GEJ) cancer and the antibody-drug conjugate is administered at a concentration of 80 mg / m 2 ~170mg / m 2 is administered at a dose of

[0154] In some embodiments, the cancer may be gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer, and the antibody-drug conjugate is administered at a dose of about 100 mg / m 2 ~about 170mg / m 2 The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg to about 10 mg / kg.

[0155] In some embodiments, the antibody-drug conjugate is at a concentration of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 may be administered in a dose of

[0156] In some embodiments, the antibody-drug conjugate is administered at 80 mg / m on day 1 of the first cycle of treatment. 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 may be administered in a dose of

[0157] On day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of about 120 mg / m 2 , 135 mg / m 2 , about 150mg / m 2 or about 170 mg / m 2 The cycle may be 2 weeks or 3 weeks. The cycle may be 3 weeks.

[0158] The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg to about 10 mg / kg.

[0159] Antibody-drug conjugate at approximately 120 mg / m on day 1 of the first cycle of treatment 2 The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg or about 10 mg / kg. The treatment cycle may last for 2 or 3 weeks.

[0160] Antibody-drug conjugate at approximately 135 mg / m on day 1 of the first cycle of treatment 2 The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg or about 10 mg / kg. The treatment cycle may last for 2 or 3 weeks.

[0161] Antibody-drug conjugate at approximately 150 mg / m on day 1 of the first cycle of treatment 2 The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg to about 10 mg / kg. The treatment cycle may last for 2 or 3 weeks.

[0162] Antibody-drug conjugate at approximately 170 mg / m on day 1 of the first cycle of treatment 2 The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg to about 10 mg / kg. The treatment cycle may last for 2 or 3 weeks.

[0163] In some embodiments, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 120 mg / m 2, 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 A loading dose of 10 mg / kg / day is administered, and the cycle is 2 weeks.

[0164] In some embodiments, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 150 mg / m 2 or 170 mg / m 2 A loading dose of 10 mg / kg / day is administered, and the cycle is 2 weeks.

[0165] In some embodiments, on day 1 of at least one additional cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 or 100 mg / m 2 and subsequent doses are administered in a cycle of two weeks.

[0166] In some embodiments, the antibody-drug conjugate is administered at about 100 mg / m on day 1 of an additional cycle (at least one cycle following the first cycle). 2 The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg or about 10 mg / kg. The treatment cycle may last for 2 or 3 weeks.

[0167] A treatment cycle may last for about 2 weeks. A treatment cycle may last for about 3 weeks.

[0168] In some embodiments, the anti-VEGFR2 antibody may be administered at a dose of 8 mg / kg and the cycle may be two weeks.

[0169] In some embodiments, the anti-VEGFR2 antibody may be administered at a dose of 10 mg / kg and the cycle may be three weeks.

[0170] In some embodiments, the antibody-drug conjugate is administered at 150 mg / m on day 1 of the first cycle. 2and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the antibody-drug conjugate may be administered at 80 mg / m on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the treatment cycle may be two weeks.

[0171] In some embodiments, the antibody-drug conjugate is administered at 170 mg / m on day 1 of the first cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the antibody-drug conjugate may be administered at 100 mg / m on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the treatment cycle may be two weeks.

[0172] In some embodiments, the cancer may be gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg on day 1 of the first cycle, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 150 mg / m 2 and the cycle may be two weeks.

[0173] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 80 mg / m as a subsequent dose on day 1 of an additional cycle. 2 and the cycle may be two weeks.

[0174] In some embodiments, the cancer may be gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg on day 1 of the first cycle, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 170 mg / m 2 and the cycle may be two weeks.

[0175] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 100 mg / m as a subsequent dose on day 1 of an additional cycle. 2 and the cycle may be two weeks.

[0176] In some embodiments, the antibody-drug conjugate is at a concentration of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the cycle may be three weeks.

[0177] In some embodiments, the antibody-drug conjugate is at a concentration of 120 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the cycle may be three weeks.

[0178] In some embodiments, the anti-VEGFR2 antibody may be administered at a dose of 10 mg / kg and the cycle may be three weeks.

[0179] In some embodiments, the antibody-drug conjugate is administered at 80 mg / m on day 1 of the first cycle of treatment and on day 1 of at least one additional cycle.2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the treatment cycle may be 3 weeks.

[0180] In some embodiments, the antibody-drug conjugate is administered at 100 mg / m on day 1 of the first cycle of treatment and on day 1 of at least one additional cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the treatment cycle may be 3 weeks.

[0181] In some embodiments, the antibody-drug conjugate is administered at 120 mg / m on day 1 of the first cycle of treatment and on day 1 of at least one additional cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the treatment cycle may be 3 weeks.

[0182] In some embodiments, the antibody-drug conjugate is administered at 135 mg / m on day 1 of the first cycle of treatment and on day 1 of at least one additional cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the treatment cycle may be 3 weeks.

[0183] In some embodiments, the antibody-drug conjugate is administered at 150 mg / m on day 1 of the first cycle of treatment and on day 1 of at least one additional cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the treatment cycle may be 3 weeks.

[0184] In some embodiments, the antibody-drug conjugate is administered at 170 mg / m on day 1 of the first cycle of treatment and on day 1 of at least one additional cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the treatment cycle may be 3 weeks.

[0185] In some embodiments, the cancer may be gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg on day 1 of the first cycle, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the cycle may be three weeks.

[0186] In some embodiments, on day 1 of an additional cycle, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the cycle may be three weeks.

[0187] In some embodiments, the cancer may be gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg on day 1 of the first cycle, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 80 mg / m 2 and the cycle may be three weeks.

[0188] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 80 mg / m as a subsequent dose on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0189] In some embodiments, the cancer may be gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg on day 1 of the first cycle, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 100 mg / m 2 and the cycle may be three weeks.

[0190] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by administration of an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a subsequent dose of 100 mg / m on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0191] In some embodiments, the cancer may be gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg on day 1 of the first cycle, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 120 mg / m 2 and the cycle may be three weeks.

[0192] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 120 mg / m as a subsequent dose on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0193] In some embodiments, the cancer may be gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg on day 1 of the first cycle, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 135 mg / m 2 and the cycle may be three weeks.

[0194] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by administration of an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a subsequent dose of 135 mg / m on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0195] In some embodiments, the cancer may be gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg on day 1 of the first cycle, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 150 mg / m 2 and the cycle may be three weeks.

[0196] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a subsequent dose of 150 mg / m on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0197] In some embodiments, the cancer may be gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, the patient having a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg on day 1 of the first cycle, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 170 mg / m 2 and the cycle may be three weeks.

[0198] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a subsequent dose of 170 mg / m on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0199] In some embodiments, an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a cytotoxic agent, such as a maytansinoid (e.g., DM4), e.g., tusamitamabravtansine, can be used in combination with an anti-VEGFR-2 antibody, such as ramucirumab, as disclosed herein to achieve a synergistic effect in the treatment of cancer.

[0200] A synergistic effect may be achieved in reducing tumor growth.

[0201] A synergistic effect may be achieved in reducing tumor size.

[0202] The tumor can be a tumor derived from a cancer, eg, a carcinoma, such as gastric cancer, gastroesophageal adenocarcinoma (GEJ) cancer, or lung cancer, eg, non-squamous non-small cell lung cancer.

[0203] The combinations disclosed herein can be used in the different uses and methods disclosed herein for treating cancer, for example, to achieve a synergistic effect in reducing tumor size or tumor growth.

[0204] The antibody-drug conjugate can be tusamitamaravtansine (huMAb2-3-SPDB-DM4).

[0205] The anti-VEGFR-2 antibody can be ramucirumab.

[0206] In some embodiments, the present disclosure relates to pharmaceutical compositions comprising the antibody-drug conjugates and anti-VEGFR2 antibodies disclosed herein and a pharma- ceutically acceptable excipient.

[0207] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising an antibody-drug conjugate disclosed herein and ramucirumab and a pharma- ceutical acceptable excipient.

[0208] In some embodiments, the present disclosure relates to a pharmaceutical composition comprising tusamitamaravtansine, ramucirumab, and a pharmaceutically acceptable excipient.

[0209] In some embodiments, the disclosure relates to a kit comprising (i) a pharmaceutical composition of an antibody-drug conjugate disclosed herein and a pharma- ceutically acceptable excipient, and (ii) a pharmaceutical composition comprising an anti-VEGFR2 antibody and a pharma- ceutically acceptable excipient.

[0210] In some embodiments, the present disclosure relates to a pharmaceutical composition or a kit disclosed herein for use in treating cancer.

[0211] definition An "antibody" may be a natural or conventional antibody with two heavy chains linked to each other by disulfide bonds and each heavy chain linked to a light chain by a disulfide bond. There are two types of light chains, lambda (l) and kappa (k). There are five major heavy chain classes (or isotypes) that determine the functional activity of the antibody molecule: IgM, IgD, IgG, IgA and IgE. Each chain contains distinct sequence domains. The light chain contains two domains or regions, the variable domain (VL) and the constant domain (CL). The heavy chain contains four domains, the variable domain (VH) and three constant domains (CH1, CH2 and CH3, collectively referred to as CH). The variable regions of both the light (VL) and heavy (VH) chains determine binding recognition and specificity to the antigen. The constant region domains of the light chain (CL) and the heavy chain (CH) confer important biological properties such as antibody chain association, secretion, transplacental mobility, complement binding and binding to Fc receptors (FcR). The Fv fragment is the N-terminal portion of the Fab fragment of an immunoglobulin and consists of the variable portions of one light chain and one heavy chain. The specificity of an antibody resides in the structural complementarity between the antibody binding site and an antigenic determinant. The antibody binding site is composed of residues mainly from the hypervariable or complementarity determining regions (CDRs). Occasionally, residues from non-hypervariable or framework regions (FRs) influence the overall domain structure and thus the binding site. Thus, complementarity determining regions or CDRs refer to amino acid sequences that together define the binding affinity and specificity of the native Fv region of a native immunoglobulin binding site. Each light and heavy chain of an immunoglobulin has three CDRs, designated CDR1-L, CDR2-L, CDR3-L and CDR1-H, CDR2-H, CDR3-H, respectively. Thus, a conventional antibody antigen-binding site contains six CDRs, including a set of CDRs from each of the heavy and light chain V regions.

[0212] "Framework region" (FR) refers to the amino acid sequences intervening between the CDRs, i.e., the portions of the immunoglobulin light and heavy chain variable regions that are relatively conserved among different immunoglobulins of a single species. The light and heavy chains of an immunoglobulin each have four FRs, designated FR1-L, FR2-L, FR3-L, FR4-L and FR1-H, FR2-H, FR3-H, FR4-H, respectively. A human framework region is a framework region that is substantially identical (about 85% or more, particularly 90%, 95%, 97%, 99% or 100%) to the framework regions of naturally occurring human antibodies.

[0213] In the context of the present disclosure, the definition of CDR / FR in an immunoglobulin light or heavy chain should be determined based on the definition of IMGT (Lefranc et al. Dev. Comp. Immunol., 2003, 27(1):55-77; www.imgt.org).

[0214] As used herein, the term "antibody" refers to conventional antibodies and fragments thereof as well as single domain antibodies and fragments thereof, in particular the variable heavy chains of single domain antibodies as well as chimeric, humanized, bispecific or multispecific antibodies.

[0215] As used herein, antibody or immunoglobulin also includes the more recently described "single domain antibodies", which are antibodies whose complementarity determining regions are part of a single domain polypeptide. Examples of single domain antibodies include heavy chain antibodies, antibodies naturally devoid of light chains, single domain antibodies derived from traditional four-chain antibodies, and engineered single domain antibodies. Single domain antibodies can be derived from any species, including but not limited to mouse, human, camel, llama, goat, rabbit, cow. Single domain antibodies can be naturally occurring single domain antibodies known as heavy chain antibodies devoid of light chains. In particular, Camelidae species, such as camel, dromedary, llama, alpaca, and guanaco, produce heavy chain antibodies naturally devoid of light chains. Camel heavy chain antibodies also lack the CH1 domain.

[0216] The variable heavy chains of these single domain antibodies, devoid of light chains, are known in the art as "VHH" or "Nanobodies". Like conventional VH domains, VHHs contain four FRs and three CDRs. VHHs have advantages over conventional antibodies: they are about 10 times smaller than IgG molecules, and as a result, properly folded, functional VHHs can be produced by in vitro expression while achieving high yields. Furthermore, VHHs are very stable and resistant to the action of proteases. The properties and production of VHHs are reviewed in Harmsen and De Haard HJ (Appl. Microbiol. Biotechnol. 2007 Nov;77(1):13-22).

[0217] The term "monoclonal antibody" or "mAb" as used herein refers to an antibody molecule of a single amino acid sequence directed against a particular antigen and should not be construed as requiring production of the antibody by any particular method. A monoclonal antibody may be produced by a single clone of a B cell or hybridoma, but may also be produced recombinantly, i.e., by protein engineering.

[0218] The term "humanized antibody" refers to an antibody that is wholly or partially of non-human origin and that has been modified to substitute certain amino acids, particularly in the framework regions of the VH and VL domains, to avoid or minimize immune responses in humans. The constant domains of a humanized antibody are most often human CH and CL domains.

[0219] A "fragment" of a (conventional) antibody comprises a portion of an intact antibody, in particular the antigen-binding or variable region of the intact antibody. Examples of antibody fragments include Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, diabodies, bispecific and multispecific antibodies formed from antibody fragments. A fragment of a conventional antibody can also be a heavy chain antibody or a single domain antibody such as a VHH.

[0220] "Fab" refers to an antibody fragment with a molecular weight of about 50,000 and antigen-binding activity, in which about half of the N-terminal heavy chain is bound to the entire light chain by a disulfide bond. It is usually obtained between fragments of IgG by treating it with a protease such as papain.

[0221] The term "F(ab')2" refers to an antibody fragment with a molecular weight of about 100,000 and an antigen-binding activity slightly greater than that of two identical Fab fragments linked via disulfide bonds in the hinge region, which is usually obtained between fragments by treating IgG with a protease such as pepsin.

[0222] The term "Fab'" refers to an antibody fragment having a molecular weight of approximately 50,000 and retaining antigen-binding activity, which is obtained by cleaving the disulfide bond in the hinge region of F(ab')2.

[0223] Single-chain Fv ("scFv") polypeptides are VH::VL heterodimers that are typically expressed from gene fusions containing genes encoding VH and VL linked by a covalent peptide-encoding linker. Human scFv fragments of the present disclosure contain the CDRs held in the proper conformation, particularly by using recombinant gene technology. Bivalent and multivalent antibody fragments can form spontaneously by association of monovalent scFvs or can be generated by coupling monovalent scFvs by a peptide linker, such as a bivalent sc(Fv)2. A "dsFv" is a VH::VL heterodimer stabilized by a disulfide bond. "(dsFv)2" indicates two dsFvs coupled by a peptide linker.

[0224] The term "bispecific antibody" or "BsAb" refers to an antibody that combines the antigen-binding sites of two antibodies in a single molecule. Thus, BsAbs can bind two different antigens simultaneously. Genetic engineering is being used more and more frequently to design, modify and produce antibodies or antibody derivatives with a desired set of binding properties and effector functions, as described, for example, in EP 2050 764 A1.

[0225] The term "multispecific antibody" refers to an antibody that combines the antigen-binding sites of more than one antibody in a single molecule.

[0226] The term "diabody" refers to a small antibody fragment with two antigen-binding sites, which comprises a heavy chain variable domain (VH) linked to a light chain variable domain (VL) in the same polypeptide chain (VH-VL). By using a linker that is too short to allow pairing between the two domains in the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites.

[0227] An amino acid sequence that is "at least 85% identical to a reference sequence" is a sequence that has 85% or more, particularly 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity over its entire length to the entire length of the reference amino acid sequence.

[0228] The percentage of "sequence identity" between amino acid sequences can be determined by comparing two optimally aligned sequences over a comparison window, where the portion of the polynucleotide or polypeptide sequence within the comparison window may contain additions or deletions (i.e., gaps) compared to the reference sequence (which does not contain additions or deletions) due to optimal alignment of the two sequences. The percentage is calculated by determining the number of positions where the same nucleic acid base or amino acid residue is present in both sequences to obtain the number of matched positions, dividing the number of matched positions by the total number of positions in the comparison window, and multiplying the result by 100 to obtain the percentage of sequence identity. Optimal alignment of sequences for comparison is performed by global pairwise alignment, for example, using the algorithm of Needleman and Wunsch J. Mol. Biol. 48:443 (1970). The percentage of sequence identity can be easily determined, for example, using the program Needle with the BLOSUM62 matrix and the following parameters: gap-open=10, gap-extend=0.5.

[0229] A "conservative amino acid substitution" is one in which an amino acid residue is replaced with another amino acid residue having a side chain R group with similar chemical properties (e.g., charge, size, or hydrophobicity). In general, conservative amino acid substitutions do not substantially change the functional properties of a protein. Examples of groups of amino acids with side chains with similar chemical properties include: 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, histidine; 6) acidic side chains: aspartic acid and glutamic acid; and 7) sulfur-containing side chains: cysteine ​​and methionine. Conservative amino acid substitutions can also be defined based on amino acid size.

[0230] "Purified" and "isolated", when referring to a polypeptide (i.e., an antibody of the present disclosure) or nucleotide sequence, mean that the indicated molecule is present in the substantial absence of other biological macromolecules of the same type. As used herein, the term "purified" specifically means that at least 75%, 85%, 95% or 98% (by weight) of the same type of biological macromolecules is present. An "isolated" nucleic acid molecule encoding a particular polypeptide refers to a nucleic acid molecule that is substantially free of other nucleic acid molecules that do not encode the subject polypeptide. However, the molecule may contain some additional bases or moieties that do not adversely affect the basic characteristics of the composition.

[0231] As used herein, the term "subject" or "patient" refers to mammals, such as rodents, cats, dogs, and primates. In particular, subjects according to the present disclosure are humans.

[0232] Antibody-drug conjugates including anti-CEACAM5 antibodies The present disclosure relates to antibody-drug conjugates (ADCs) comprising an anti-CEACAM5 antibody used in combination with an anti-VEGFR-2 antibody for the treatment of cancer.

[0233] An antibody-drug conjugate typically comprises an anti-CEACAM5 antibody and at least one chemotherapeutic agent. An antibody-drug conjugate (ADC) comprises an anti-CEACAM5 antibody conjugated to at least one chemotherapeutic agent. In particular, in an antibody-drug conjugate, an anti-CEACAM5 antibody is covalently linked to at least one chemotherapeutic agent via a cleavable or non-cleavable linker.

[0234] Anti-CEACAM5 antibody According to one embodiment, the antibody-drug conjugate comprises a humanized anti-CEACAM5 antibody.

[0235] According to one embodiment, the antibody-drug conjugate comprises an anti-CEACAM5 antibody, which comprises a CDR-H1 consisting of SEQ ID NO: 1, a CDR-H2 consisting of SEQ ID NO: 2, a CDR-H3 consisting of SEQ ID NO: 3, a CDR-L1 consisting of SEQ ID NO: 4, a CDR-L2 consisting of the amino acid sequence NTR, and a CDR-L3 consisting of SEQ ID NO: 5.

[0236] In a further embodiment, the antibody-drug conjugate comprises an anti-CEACAM5 antibody, the anti-CEACAM5 antibody comprising a heavy chain variable domain (VH) consisting of SEQ ID NO:6 and a light chain variable domain (VL) consisting of SEQ ID NO:7.

[0237] The antibody-drug conjugate, in a further embodiment, comprises an anti-CEACAM5 antibody, the anti-CEACAM5 antibody being - a sequence in which FR1-H spans amino acid positions 1 to 25, CDR1-H spans amino acid positions 26 to 33 (SEQ ID NO: 1), FR2-H spans amino acid positions 34 to 50, CDR2-H spans amino acid positions 51 to 58 (SEQ ID NO: 2), FR3-H spans amino acid positions 59 to 96, CDR3-H spans amino acid positions 97 to 109 (SEQ ID NO: 3), and FR4-H spans amino acid positions 110 to 120; [ka] (SEQ ID NO:6, CDRs are shown in bold), and - a sequence in which FR1-L spans amino acid positions 1 to 26, CDR1-L spans amino acid positions 27 to 32 (SEQ ID NO: 4), FR2-L spans amino acid positions 33 to 49, CDR2-L spans amino acid positions 50 to 52, FR3-L spans amino acid positions 53 to 88, CDR3-L spans amino acid positions 89 to 97 (SEQ ID NO: 5), and FR4-L spans amino acid positions 98 to 107 [ka] (SEQ ID NO:7, CDRs are shown in bold) Includes.

[0238] In a further embodiment, the antibody-drug conjugate comprises an anti-CEACAM5 antibody, the anti-CEACAM5 antibody comprising a heavy chain variable domain (VH) having at least 90% identity to SEQ ID NO: 6 and a light chain variable domain (VL) having at least 90% identity to SEQ ID NO: 7, wherein CDR1-H consists of SEQ ID NO: 2, CDR2-H consists of SEQ ID NO: 3, CDR3-H consists of SEQ ID NO: 4, CDR1-L consists of SEQ ID NO: 6, CDR2-L consists of the amino acid sequence NTR, and CDR3-L consists of SEQ ID NO: 7.

[0239] In a further embodiment, the antibody-drug conjugate comprises an anti-CEACAM5 antibody, the anti-CEACAM5 antibody comprising a heavy chain variable domain (VH) having at least 92%, at least 95%, at least 98% identity to SEQ ID NO: 6 and a light chain variable domain (VL) having at least 92%, at least 95%, at least 98% identity to SEQ ID NO: 7, wherein CDR1-H consists of SEQ ID NO: 2, CDR2-H consists of SEQ ID NO: 3, CDR3-H consists of SEQ ID NO: 4, CDR1-L consists of SEQ ID NO: 6, CDR2-L consists of the amino acid sequence NTR, and CDR3-L consists of SEQ ID NO: 7.

[0240] In a further embodiment, the antibody-drug conjugate comprises an anti-CEACAM5 antibody, the anti-CEACAM5 antibody comprising a heavy chain (HC) consisting of SEQ ID NO:8 and a light chain (LC) consisting of SEQ ID NO:9.

[0241] In a further embodiment, the antibody-drug conjugate comprises an anti-CEACAM5 antibody, the anti-CEACAM5 antibody comprising a heavy chain (HC) having at least 90% sequence identity to SEQ ID NO: 8 and a light chain (LC) having at least 90% sequence identity to SEQ ID NO: 9, wherein CDR1-H consists of SEQ ID NO: 2, CDR2-H consists of SEQ ID NO: 3, CDR3-H consists of SEQ ID NO: 4, CDR1-L consists of SEQ ID NO: 6, CDR2-L consists of the amino acid sequence NTR, and CDR3-L consists of SEQ ID NO: 7.

[0242] In a further embodiment, the antibody-drug conjugate comprises an anti-CEACAM5 antibody, wherein the anti-CEACAM5 antibody comprises a heavy chain (HC) having at least 92%, at least 95%, at least 98% identity to SEQ ID NO: 8 and a light chain (LC) having at least 92%, at least 95%, at least 98% identity to SEQ ID NO: 9, wherein CDR1-H consists of SEQ ID NO: 2, CDR2-H consists of SEQ ID NO: 3, CDR3-H consists of SEQ ID NO: 4, CDR1-L consists of SEQ ID NO: 6, CDR2-L consists of the amino acid sequence NTR, and CDR3-L consists of SEQ ID NO: 7.

[0243] The anti-CEACAM5 antibody contained in the antibody-drug conjugate can also be a single domain antibody or a fragment thereof. In particular, the single domain antibody fragment can consist of a variable heavy chain (VHH) comprising the CDR1-H, CDR2-H and CDR3-H of the above antibody. The antibody can also be a heavy chain antibody, i.e. an antibody lacking a light chain, which may or may not include a CH1 domain.

[0244] A single domain antibody or fragment thereof may comprise a camelid single domain antibody framework region and optionally also a camelid single domain antibody constant domain.

[0245] The anti-CEACAM5 antibody contained in the antibody-drug conjugate may also be an antibody fragment, particularly a humanized antibody fragment, selected from the group consisting of Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2 and diabody.

[0246] The antibody may also be a bispecific or multispecific antibody formed from antibody fragments, at least one of the antibody fragments being an antibody fragment according to the present disclosure. Multispecific antibodies are multivalent protein complexes, e.g. as described in EP 2050764 A1 or US 2005 / 0003403 A1.

[0247] The anti-CEACAM5 antibodies and fragments thereof contained in the antibody-drug conjugates can be produced by any technique known in the art. In particular, the antibodies are produced by the techniques described below.

[0248] The anti-CEACAM5 antibodies and fragments thereof contained in the antibody-drug conjugates can be isolated (eg, purified) from or contained in a vector, such as a membrane or lipid vesicle (eg, liposome).

[0249] The anti-CEACAM5 antibodies and fragments thereof contained in the antibody-drug conjugates may be produced by any technique known in the art, including, but not limited to, any chemical, biological, genetic or enzymatic technique, either alone or in combination.

[0250] By knowing the amino acid sequence of the desired sequence, the skilled artisan can easily produce anti-CEACAM5 antibodies and fragments thereof by standard techniques for producing polypeptides. For example, they can be synthesized using well-known solid-phase methods, in particular using commercially available peptide synthesizers (such as those manufactured by Applied Biosystems, Foster City, California), following the manufacturer's instructions. Alternatively, anti-CEACAM5 antibodies and fragments thereof can be synthesized by recombinant DNA techniques, as is well known in the art. For example, these fragments can be obtained as DNA expression products after incorporating a DNA sequence encoding the desired (poly)peptide into an expression vector and introducing such a vector into a suitable eukaryotic or prokaryotic host that expresses the desired polypeptide, from which they can be subsequently isolated using well-known techniques.

[0251] The anti-CEACAM5 antibodies and fragments thereof are suitably separated from the culture medium by conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxylapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0252] Methods for producing humanized antibodies based on conventional recombinant DNA and gene transfection techniques are well known in the art (see Riechmann L. et al. 1988; Neuberger MS. et al. 1985). Antibodies may be humanized using various techniques known in the art, such as those disclosed in WO 2009 / 032661, CDR grafting (EP 239,400; WO 91 / 09967; U.S. Pat. Nos. 5,225,539; 5,530,101; and 5,585,089), veneering or resurfacing (EP 592,106; EP 519,596; Padlan EA (1991); Studnicka GM et al. (1994); Roguska MA.et al. (1994)) and chain shuffling (U.S. Pat. No. 5,565,332). General recombinant DNA techniques for preparing such antibodies are also known (see EP 125023 and WO 96 / 02576).

[0253] The Fab of the anti-CEACAM5 antibody can be obtained by treating an antibody that specifically reacts with CEACAM5 with a protease such as papain. Alternatively, the Fab of the anti-CEACAM5 antibody can be produced by inserting a DNA sequence encoding both chains of the Fab of the anti-CEACAM5 antibody into a vector for prokaryotic or eukaryotic expression, introducing the vector into a prokaryotic or eukaryotic cell (as necessary), and expressing the Fab of the anti-CEACAM5 antibody.

[0254] F(ab')2 of anti-CEACAM5 antibody can be obtained by treating an antibody that specifically reacts with CEACAM5 with a protease, pepsin. Alternatively, F(ab')2 of anti-CEACAM5 antibody can be produced by binding to the following Fab' via a thioether bond or disulfide bond.

[0255] The Fab' of the anti-CEACAM5 antibody can be obtained by treating F(ab')2 that specifically reacts with CEACAM5 with a reducing agent such as dithiothreitol. Alternatively, the Fab' of the anti-CEACAM5 antibody can be produced by inserting a DNA sequence encoding the Fab' chain of the antibody into a prokaryotic expression vector or a eukaryotic expression vector, and introducing the vector into a prokaryotic or eukaryotic cell (as necessary) to express the antibody.

[0256] The scFv of the anti-CEACAM5 antibody can be produced by obtaining the sequence of the CDR or VH and VL domains as described above, constructing DNA encoding the scFv fragment, inserting the DNA into a prokaryotic or eukaryotic expression vector, and then introducing the expression vector (as required) into a prokaryotic or eukaryotic cell to express the scFv. To generate a humanized scFv fragment, a well-known technique called CDR grafting can be used, which involves selecting the complementarity determining regions (CDRs) according to the present disclosure and grafting them onto a human scFv fragment framework of known three-dimensional structure (e.g., WO 98 / 45322; WO 87 / 02671; U.S. Pat. No. 5,859,205; U.S. Pat. No. 5,585,089; U.S. Pat. No. 4,816,567; EP 0173494).

[0257] In one embodiment, the anti-CEACAM5 antibody is tusamitamab (CAS[2349294-95-5].

[0258] Chemotherapeutic agents Antibody-drug conjugates for use according to the present disclosure typically include at least one chemotherapeutic agent (also referred to herein as a cytotoxic agent). A chemotherapeutic agent as used herein refers to an agent that kills cells, including cancer cells. Such agents preferably stop the division and growth of cancer cells and reduce the size of tumors. The term "chemotherapeutic agent" is used interchangeably herein with the terms "cytotoxic agent", "growth inhibitory agent" or "cytostatic agent".

[0259] The term "chemotherapeutic agent" as used herein refers to a substance that inhibits or prevents the function of cells and / or causes the destruction of cells. The term "chemotherapeutic agent" is intended to include toxins such as radioisotopes, enzymes, antibiotics and small molecule or enzymatically active toxins of bacterial, fungal, plant or animal origin (including fragments and / or variants thereof), as well as various antitumor or anticancer agents disclosed below. In some embodiments, the chemotherapeutic agent is an antimetabolite.

[0260] In further embodiments, the chemotherapeutic agent may be selected from the group consisting of a radioisotope, a protein toxin, a small molecule toxin, and combinations thereof.

[0261] The radioisotopes include those suitable for treating cancer. Such radioisotopes generally emit primarily beta radiation. In a further embodiment, the radioisotope is At 211 , Bi 212 , Er 169 , I 131 , I 125 , Y 90 , In 111 , P 32 , Re 186 , Re 188 , Sm 153 , Sr 89 In one embodiment, the radioisotope is selected from the group consisting of an alpha-emitting isotope, more specifically Th. 227 , which emits alpha radiation.

[0262] In further embodiments, the small molecule toxin is selected from antimetabolites, DNA alkylating agents, DNA cross-linking agents, DNA intercalating agents, anti-microtubule agents, topoisomerase inhibitors, and combinations thereof.

[0263] In further embodiments, the anti-microtubule agent is selected from the group consisting of taxanes, vinca alkaloids, maytansinoids, colchicine, podophyllotoxin, gluseofulvin, and combinations thereof.

[0264] In some embodiments, the cytotoxic agent can be a maytansinoid.

[0265] According to one embodiment, the maytansinoid is selected from maytansinol, maytansinol analogues, and combinations thereof.

[0266] Examples of suitable maytansinol analogs include those with modified aromatic rings and those with modifications at other positions. Such suitable maytansinoids are described in U.S. Patent Nos. 4,424,219; 4,256,746; 4,294,757; 4,307,016; 4,313,946; 4,315,929; 4,331,598; 4,361,650; and 4,371,651. Nos. 4,362,663; 4,364,866; 4,450,254; 4,322,348; 4,371,533; 6,333,410; 5,475,092; 5,585,499; and 5,846,545.

[0267] Specific examples of suitable analogues of maytansinol having modified aromatic rings include the following: (1) C-19-dechloro (U.S. Pat. No. 4,256,746) (prepared by LAH reduction of ansamitocin P2); (2) C-20-hydroxy (or C-20-demethyl) + / - C-19-dechloro (U.S. Pat. Nos. 4,361,650 and 4,307,016) (prepared by demethylation with Streptomyces or Actinomyces or by dechlorination with LAH); and (3) C-20-demethoxy, C-20-acyloxy (-OCOR), + / -dechloro (U.S. Pat. No. 4,294,757) (prepared by acylation using acyl chlorides).

[0268] Specific examples of suitable analogues of maytansinol having modifications at other positions include the following: (1) C-9-SH (U.S. Pat. No. 4,424,219) (prepared by reaction of maytansinol with H2S or P2S5); (2) C-14-alkoxymethyl(demethoxy / CH2OR) (U.S. Pat. No. 4,331,598); (3) C-14-hydroxymethyl or acyloxymethyl (CHOH or CHOAc) (U.S. Pat. No. 4,450,254) (prepared from Nocardia); (4) C-15-hydroxy / acyloxy (U.S. Pat. No. 4,364,866) (prepared by conversion of maytansinol by Streptomyces sp.); (5) C-15-methoxy (U.S. Pat. Nos. 4,313,946 and 4,315,929) (isolated from Trewia nudiflora); (6) C-18-N-demethyl (U.S. Pat. Nos. 4,362,663 and 4,322,348) (prepared by demethylation of maytansinol by Streptomyces sp.); and (7) 4,5-deoxy (U.S. Pat. No. 4,371,533) (prepared by titanium trichloride / LAH reduction of maytansinol).

[0269] In a further embodiment, the cytotoxic conjugates of the present disclosure utilize as the cytotoxic agent a thiol-containing maytansinoid, formally referred to as N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine (DM1), which has the following structural formula (I): [ka] It is represented by:

[0270] In a further embodiment, the cytotoxic conjugates of the present disclosure utilize as the cytotoxic agent the thiol-containing maytansinoid DM4, formally referred to as N2'-deacetyl-N-2'(4-methyl-4-mercapto-1-oxopentyl)-maytansine. DM4 has the following structural formula (II): [ka] It is represented by:

[0271] In further embodiments of the disclosure, other maytansines can be used, including thiol- and disulfide-containing maytansinoids with mono- or di-alkyl substitutions on the carbon atom bearing the sulfur atom. These include maytansinoids with acylated amino acid side chains having an acyl group bearing a hindered sulfhydryl group at C-3, C-14 hydroxymethyl, C-15 hydroxy, or C-20 desmethyl, where the carbon atom of the acyl group bearing the thiol functionality bears one or two substituents, said substituents being CH. 3 , C 2 H 5 , linear or branched alkyl or alkenyl having 1 to 10 reagents and any aggregates that may be present in the solution.

[0272] Examples of these cytotoxic agents and methods of conjugation are further provided in WO 2008 / 010101, which is incorporated by reference.

[0273] Immunoconjugates according to the present disclosure can be prepared as described in WO 2004 / 091668, the contents of which are incorporated herein by reference in their entirety.

[0274] Thus, in a further embodiment, the maytansinoid is selected from the group consisting of N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N2'-deacetyl-N-2'(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4), and combinations thereof.

[0275] In a further embodiment, in the antibody-drug conjugate, the anti-CEACAM5 antibody is covalently attached to at least one cytotoxic agent via a cleavable or non-cleavable linker.

[0276] In further embodiments, the linker is selected from the group consisting of N-succinimidyl pyridyldithiobutyrate (SPDB), 4-(pyridin-2-yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB) and succinimidyl (N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).

[0277] In a further embodiment, the linker is attached to a lysine or cysteine ​​residue in the Fc region of the anti-CEACAM5 antibody, hi a further embodiment, the linker forms a disulfide bond or a thioether bond with maytansine.

[0278] In particular, the anti-CEACAM5 antibody-drug conjugate may be selected from the group consisting of: i) an anti-CEACAM5-SPDB-DM4-antibody-drug conjugate of formula (III) [ka] ii) an anti-CEACAM5-sulfo-SPDB-DM4-antibody-drug conjugate of formula (IV) [ka] , and iii) an anti-CEACAM5-SMCC-DM1 antibody-drug conjugate of formula (V): [ka]

[0279] In formulas (III), (IV) and (V) above, "n" corresponds to the number of molecules of chemotherapeutic agent conjugated per antibody molecule. This corresponds to the "drug-to-antibody ratio" (or "DAR"), defined below, and can range from 1 to 10.

[0280] In a further embodiment, an antibody-drug conjugate of the disclosure comprises an anti-CEACAM5 antibody (tusamitamab) comprising a heavy chain (VH) of SEQ ID NO:8 and a light chain (VL) of SEQ ID NO:9, wherein tusamitamab is covalently linked to N2'-deacetyl-N-2'(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4) via N-succinimidylpyridyldithiobutyrate (SPDB), resulting in the antibody-drug conjugate tusamitamab ravtansine (huMAb2-3-SPDB-DM4).

[0281] In one embodiment, the antibody-drug conjugate of the disclosure is tusamitamaravtansine (CAS [2254086-60-5]).

[0282] "Linker," as used herein, means a chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches an antibody to a chemotherapeutic moiety (e.g., a cytostatic, cytotoxic, or growth inhibitory agent). Suitable linkers are well known in the art and include disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups, and esterase labile groups.

[0283] Conjugates can be prepared by in vitro methods. Linking groups are used to link drugs or prodrugs to antibodies, such as chemotherapeutic agents. Suitable linking groups are well known in the art and include disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups and esterase labile groups. Conjugation of an antibody to a chemotherapeutic agent of the disclosure, such as a cytotoxic agent, can be accomplished using, but is not limited to, N-succinimidyl pyridyldithiobutyrate (SPDB), butanoic acid 4-[(5-nitro-2-pyridinyl)dithio]-2,5-dioxo-1-pyrrolidinyl ester (nitro-SPDB), 4-(pyridin-2-yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB), N-succinimidyl (2-pyridyldithio)propionate (SPDP), succinimidyl (N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), iminothiolane (IM), or combinations thereof. A variety of bifunctional protein coupling agents may be used to generate immunotoxins, including bifunctional derivatives of imidoesters (such as dimethyladipimidate HCL), active esters (such as subtilimidyl diserate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl)-hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)-ethylenediamine), diisocyanates (e.g., toluene 2,6-diisocyanate), and bis-active fluorine compounds (e.g., 1,5-difluoro-2,4-dinitrobenzene). For example, ricin immunotoxins can be prepared as described in Vitetta et al. (1987). Carbon-labeled 1-isothiocyanatobenzylmethyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotides to antibodies (WO 94 / 11026).

[0284] The linker may be a "cleavable linker" that facilitates the release of the chemotherapeutic agent in cells. For example, an acid-labile linker, a peptidase-sensitive linker, an esterase-labile linker, a photolabile linker, or a disulfide-containing linker (see, for example, U.S. Pat. No. 5,208,020) may be used. The linker may also be a "non-cleavable linker" (e.g., an SMCC linker), which may provide better tolerance in some cases.

[0285] Generally, the conjugates are prepared by the following steps: (i) contacting an optionally buffered aqueous solution of a cell-binding agent (e.g., an antibody according to the present disclosure) with a solution of a linker and a chemotherapeutic agent, e.g., a cytotoxic compound (or drug); (ii) then, optionally, separating the conjugate formed in (i) from unreacted cell-binding agent (e.g., an antibody of the present disclosure) and unreacted chemotherapeutic agent, e.g., unreacted cytotoxic compound (or drug). The method can be obtained by a method comprising the steps of:

[0286] The aqueous solution of the cell-binding agent can be buffered with a buffer such as, for example, potassium phosphate, acetate, citrate, or N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (Hepes buffer). The buffer depends on the nature of the cell-binding agent (e.g., an antibody of the present disclosure). The chemotherapeutic agent, such as a cytotoxic compound (or drug), is dissolved in an organic polar solvent, such as dimethylsulfoxide (DMSO) or dimethylacetamide (DMA).

[0287] The reaction temperature is usually comprised between 20°C and 40°C. The reaction time can vary from 1 hour to 24 hours. The reaction between the cell-binding agent and the chemotherapeutic agent, e.g., a cytotoxic agent, can be monitored by refractometry and / or size-exclusion chromatography (SEC) using a UV detector. If the conjugate yield is too low, the reaction time can be increased.

[0288] To carry out the separation of step (ii), several different chromatographic methods can be used by those skilled in the art. The conjugate can be purified, for example, from aggregates by SEC, adsorption chromatography (ion exchange chromatography, IEC, etc.), hydrophobic interaction chromatography (HIC), affinity chromatography, mixed support chromatography such as hydroxyapatite chromatography, or high performance liquid chromatography (HPLC). Purification by dialysis or diafiltration can also be used.

[0289] As used herein, the term "aggregate" refers to an association that can be formed between two or more cell-binding agents, the agents being modified or not modified by conjugation. Aggregates can be formed under the influence of a number of parameters, such as high concentration of cell-binding agent (e.g., an antibody of the present disclosure) in solution, pH of the solution, high shear force, number of bound dimers and their hydrophobicity, temperature (see Wang & Gosh, 2008, J. Membrane Sci., 318:311-316 and references cited therein). It should be noted that the relative influence of some of these parameters has not been clearly established. In the case of proteins and antibodies, those skilled in the art are referred to Cromwell et al. (2006, AAPS Journal, 8(3):E572-E579). The content in aggregates can be determined using techniques well known to those skilled in the art, such as SEC (Walter et al., 1993, Anal. Biochem., 212(2):469-480).

[0290] After step (i) or (ii), the conjugate-containing solution may be subjected to a further step (iii) of chromatography, ultrafiltration and / or diafiltration.

[0291] The conjugate is recovered at the end of these steps in aqueous solution.

[0292] In further embodiments, antibody-drug conjugates according to the present disclosure are characterized by a "drug-to-antibody ratio" (or "DAR") ranging from 1 to 10, or from 2 to 5, or from 3 to 4. This is generally the case for conjugates that include a maytansinoid molecule.

[0293] This DAR number may vary depending on the experimental conditions used for conjugation (like chemotherapeutic agent (e.g. growth inhibitory agent) / antibody ratio, reaction time, nature of the solvent and co-solvent if any) as well as the nature of the antibody and drug (i.e. chemotherapeutic agent, e.g. cytotoxic agent or growth inhibitory agent) used. Thus, contact between an antibody and a chemotherapeutic agent, e.g. cytotoxic agent or growth inhibitory agent, results in a mixture comprising several conjugates differing from each other in different drug to antibody ratios, optionally naked antibody; optionally aggregate ratios. The determined DAR is therefore an average value.

[0294] A method that can be used to determine the DAR consists of measuring the ratio of the absorbance of a solution of the substantially purified conjugate at λD and 280 nm with a spectrophotometer. 280 nm is a wavelength commonly used to measure protein concentrations, such as antibody concentrations. The wavelength λD is selected to be able to distinguish the drug from the antibody, i.e., λD is a wavelength at which the drug (i.e., chemotherapeutic agent) has high absorbance, and λD is sufficiently far from 280 nm to avoid substantial overlap of the absorbance peaks of the drug and the antibody, as is readily known to those skilled in the art. λD can be selected as 252 nm for maytansinoid molecules. Methods for calculating the DAR can be obtained from Antony S. Dimitrov (ed), LLC, 2009, Therapeutic Antibodies and Protocols, vol 525, 445, Springer Science.

[0295] The absorbance of the conjugate at λD (AλD) and 280 nm (A280) is measured either by size exclusion chromatography (SEC) analysis of the monomer peak (allowing for the calculation of the "DAR(SEC)" parameter) or by a classical spectrophotometer device (allowing for the calculation of the "DAR(UV)" parameter). The absorbance can be expressed as follows: AλD=(cD×εDλD)+(cA×εAλD) A280=(cD×εD280)+(cA×εA280) During the ceremony, cD and cA are the concentrations of the drug (i.e., chemotherapeutic agent) and antibody in solution, respectively; εDλD and εD280 are the molar extinction coefficients of the drug at λD and 280 nm, respectively; εAλD and εA280 are the molar extinction coefficients of the antibody at λD and 280 nm, respectively.

[0296] Resolution of these two equations with two unknowns results in the following equation: cD=[(εA280×AλD)-(εAλD×A280)] / [(εDλD×εA280)-(εAλD×εD280)] cA = [A280-(cD × εD280)] / εA280

[0297] The average DAR is then calculated from the ratio of the drug concentration to the antibody drug concentration. DAR = cD / cA.

[0298] Anti-VEGFR-2 antibody Antibody-drug conjugates (ADCs) containing anti-CEACAM5 antibodies will be used in combination with anti-VEGFR-2 antibodies for the treatment of cancer.

[0299] In one embodiment, the anti-VEGFR-2 antibody is a monoclonal antibody or a fragment thereof having antagonist activity against VEGFR-2, hi one embodiment, the anti-VEGFR-2 antibody is an IgG.

[0300] The anti-VEGFR-2 antibody is preferably matched to the patient. For example, it is preferred to use an anti-mouse VEGFR-2 antibody, such as DC-101, in mice and an anti-human VEGFR-2 antibody in humans.

[0301] In one embodiment, the anti-VEGFR-2 antibody is ramucirumab (CAS number 947687-13-0), which is a fully human monoclonal IgG1 antibody against human VEGFR-2.

[0302] In one embodiment, the anti-VEGFR-2 antibody comprises the light and heavy chain CDRs of ramucirumab.

[0303] In one embodiment, the anti-VEGFR-2 antibody comprises the heavy chain variable domain (VH) and light chain variable domain (VL) of -ramucirumab.

[0304] In further embodiments, the anti-VEGFR-2 antibody comprises a heavy chain (HC) having at least 92%, at least 95%, or at least 98% identity to SEQ ID NO:10 and a light chain (LC) having at least 92%, at least 95%, or at least 98% identity to SEQ ID NO:11.

[0305] The included anti-VEGFR-2 antibody can also be a single domain antibody or a fragment thereof. In particular, the single domain antibody fragment can consist of a variable heavy chain (VHH) comprising the CDR1-H, CDR2-H and CDR3-H of the above antibody. The antibody can also be a heavy chain antibody, i.e. an antibody lacking a light chain, which may or may not include a CH1 domain.

[0306] A single domain antibody or fragment thereof may comprise a camelid single domain antibody framework region and optionally also a camelid single domain antibody constant domain.

[0307] The anti-VEGFR-2 antibody can also be an antibody fragment, particularly a humanized antibody fragment, selected from the group consisting of Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, and diabody.

[0308] The antibody may also be a bispecific or multispecific antibody formed from antibody fragments, at least one of which is an antibody fragment according to the present disclosure. Anti-VEGFR-2 antibodies and fragments thereof may be produced by any technique known in the art. In particular, the antibodies are produced by techniques such as those already described.

[0309] Anti-VEGFR-2 antibodies and fragments thereof can be used isolated (eg, purified) from or contained within a vector, such as a membrane or lipid vesicle (eg, liposome).

[0310] Anti-VEGFR-2 antibodies and fragments thereof may be produced by any technique known in the art, including, but not limited to, any chemical, biological, genetic or enzymatic technique, either alone or in combination.

[0311] Combination Treatment According to the present disclosure, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is for use in combination with the anti-VEGFR-2 antibody to treat cancer. The present disclosure also relates to the anti-VEGFR-2 antibody for use in combination with the antibody-drug conjugate comprising the anti-CEACAM5 antibody to treat cancer.

[0312] As used herein, the term "in combination with" means that an anti-VEGFR-2 antibody is administered before, after, or simultaneously with an antibody-drug conjugate comprising an anti-CEACAM5 antibody. In some embodiments, the term "in combination with" includes sequential or simultaneous administration of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody. A method of treating cancer (GC, GEJ cancer, NSQ NSCLC) includes administering an antibody-drug conjugate comprising an anti-CEACAM5 antibody (e.g., tusamitamaravtansine) in combination with an anti-VEGFR-2 antibody for additive or synergistic activity.

[0313] For example, when administered "before" an antibody-drug conjugate comprising an anti-CEACAM5 antibody, the anti-VEGFR-2 antibody can be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes before administration of the antibody-drug conjugate comprising the anti-CEACAM5 antibody. When administered "after" administration of an antibody-drug conjugate comprising an anti-CEACAM5 antibody, the anti-VEGFR-2 antibody can be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after administration of the antibody-drug conjugate comprising the anti-CEACAM5 antibody. "Concurrent" administration, including ADC, means that the anti-VEGFR-2 antibody is administered to the patient in a separate dosage form within less than 5 minutes (before, after, or simultaneously) of administration of the antibody-drug conjugate comprising the anti-CEACAM5 antibody, or is administered to the patient as a single combined dosage formulation containing both the anti-VEGFR-2 antibody and the antibody-drug conjugate comprising the anti-CEACAM5 antibody, or as separate formulations, one containing the antibody-drug conjugate comprising the anti-CEACAM5 antibody and the other containing the anti-VEGFR-2 antibody.

[0314] In some embodiments, the method of treating cancer is administering to a patient in need thereof an effective amount of an antibody-drug conjugate comprising an anti-CEACAM5 antibody prior to administering an anti-VEGFR-2 antibody.

[0315] In some embodiments, a method of treating cancer is administering to a patient in need thereof an effective amount of an antibody-drug conjugate comprising an anti-CEACAM5 antibody, after administration of an anti-VEGFR-2 antibody.

[0316] The present disclosure also relates to a method of treating cancer in a patient in need thereof, comprising administering an antibody-drug conjugate comprising an anti-CEACAM5 antibody and administering an anti-VEGFR-2 antibody to a patient in need thereof.

[0317] The present disclosure also relates to a combination comprising an anti-VEGFR-2 antibody and an antibody-drug conjugate comprising an anti-CEACAM5 antibody for use in treating cancer.

[0318] The treatment methods or uses disclosed herein may achieve a synergistic effect in reducing tumor size.

[0319] The treatment methods or uses as disclosed herein may achieve a synergistic effect in inhibiting tumor growth.

[0320] The present disclosure also relates to a combination comprising an anti-VEGFR-2 antibody and an antibody-drug conjugate comprising an anti-CEACAM5 antibody for the manufacture of a medicament for treating cancer.

[0321] In one embodiment, the combination allows for the simultaneous, separate or sequential administration of an antibody-drug conjugate comprising an anti-VEGFR-2 antibody and an anti-CEACAM5 antibody.

[0322] In one embodiment, the combination allows for the simultaneous administration of an anti-VEGFR-2 antibody and an antibody-drug conjugate comprising an anti-CEACAM5 antibody.

[0323] In one embodiment, the combination allows for separate administration of an anti-VEGFR-2 antibody and an antibody-drug conjugate comprising an anti-CEACAM5 antibody.

[0324] In one embodiment, the combination allows for sequential administration of an antibody-drug conjugate comprising an anti-VEGFR-2 antibody and an anti-CEACAM5 antibody.

[0325] In a further embodiment, the combination according to the present disclosure is a pharmaceutical combination.

[0326] The present disclosure also relates to an antibody-drug conjugate comprising an anti-CEACAM5 antibody for use to treat cancer in a patient in need thereof who simultaneously, separately or sequentially receives an anti-VEGFR-2 antibody.

[0327] In one embodiment, the cancer is a carcinoma, a sarcoma, or a blastoma. In a further embodiment, the cancer is a carcinoma.

[0328] According to one embodiment, the cancer is a CEACAM5 expressing cancer.

[0329] According to one embodiment, the cancer is selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, lung cancer (e.g., non-squamous non-small cell lung cancer), cervical cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer (e.g., cholangiocarcinoma), prostate cancer, or skin cancer.

[0330] According to one embodiment, the cancer is gastric cancer or gastroesophageal junction adenocarcinoma (GEJ).

[0331] According to one embodiment, the cancer is gastric cancer.

[0332] According to one embodiment, the cancer is lung cancer. The lung cancer may be non-squamous non-small cell lung cancer (NSQ NSCLC).

[0333] According to one embodiment, the patient is a patient with a malignant tumor, in particular a malignant solid tumor, more particularly a locally advanced or metastatic solid malignant tumor. The metastatic solid malignant tumor may be a metastatic cancer, for example a metastatic carcinoma. The cancer or carcinoma may be as described above.

[0334] In some embodiments, the cancer is a CEACAM5-positive cancer. A CEACAM5-positive cancer is defined as a cancer in which the immunohistochemical [IHC] intensity of CEACAM5 is 2+ or higher in 50% or more of the cancer cells, or 1% or more but less than 50% of the tumor cells (or cancer cells) have an intensity of 2+ or higher.

[0335] In certain embodiments, the patient has a cancer with negative or low CEACAM5 expression on tumor cells, defined as an intensity of 2+ or greater in less than 1% of cells as measured by immunohistochemistry (IHC).

[0336] In certain embodiments, the patient has a cancer with moderate CEACAM5 expression on tumor cells. Moderate CEACAM5 expression on tumor cells can be defined as 2+ or higher intensity in more than 1% and less than 50% of cancer cells when measured by immunohistochemistry.

[0337] In certain embodiments, the patient has a cancer with high CEACAM5 expression on tumor cells. High CEACAM5 expression on tumor cells can be defined as 2+ or higher intensity in 50% or more of cancer cells as measured by immunohistochemistry.

[0338] In some embodiments, the patient has a cancer with CEACAM5 expression defined as a CEACAM5 immunohistochemistry (IHC) intensity of at least about 2+ in at least about 50% of tumor cells.

[0339] According to some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody is administered simultaneously, separately or sequentially to a patient in need thereof.

[0340] According to one embodiment, the antibody-drug conjugate comprising anti-CEACAM5 antibody and anti-VEGFR-2 antibody is administered simultaneously to a patient in need thereof. For example, the antibody-drug conjugate comprising anti-CEACAM5 antibody and anti-VEGFR2 antibody is administered approximately simultaneously on day 1 of a cycle. The simultaneous administration of the antibody-drug conjugate comprising anti-CEACAM5 antibody and anti-VEGFR-2 antibody can be by the same route.

[0341] According to one embodiment, the antibody-drug conjugates comprising anti-CEACAM5 antibody and anti-VEGFR-2 antibody are administered separately to a patient in need thereof. For example, the antibody-drug conjugates comprising anti-CEACAM5 antibody and anti-VEGFR2 antibody are administered by separate routes or at separate locations in the patient's body on day 1 of a cycle. The separate administration of the antibody-drug conjugates comprising anti-CEACAM5 antibody and anti-VEGFR-2 antibody can be simultaneous or close in time, for example, within 5 minutes.

[0342] According to one embodiment, the antibody-drug conjugates comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody are administered sequentially to a patient in need thereof. For example, the antibody-drug conjugates comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody are administered at different times on day 1 of a cycle, for example, the anti-CEACAM5 antibody is administered 1 to 3 hours after the anti-VEGFR-2 antibody. The sequential administration of the antibody-drug conjugates comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody can be by separate routes or the same route. The sequential administration of the antibody-drug conjugates comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody can include administering the anti-CEACAM5 antibody after the anti-VEGFR-2 antibody. The anti-CEACAM5 antibody can be administered about 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or about 6 hours after the anti-VEGFR-2 antibody. The anti-CEACAM5 antibody can be administered about 1 hour after the anti-VEGFR-2 antibody.

[0343] In a further embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody is formulated in the form of (i) a single pharmaceutical composition comprising the antibody-drug conjugate and the anti-VEGFR-2 antibody, or (ii) two separate pharmaceutical compositions, one pharmaceutical composition comprising the antibody-drug conjugate comprising the anti-CEACAM5 antibody and the other pharmaceutical composition comprising the anti-VEGFR-2 antibody.

[0344] In a further embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody is formulated in the form of (i) a single pharmaceutical composition comprising the antibody-drug conjugate and the anti-VEGFR-2 antibody and at least one pharma- ceutically acceptable excipient, or (ii) two separate pharmaceutical compositions, one pharmaceutical composition comprising the antibody-drug conjugate comprising the anti-CEACAM5 antibody and at least one pharma- ceutically acceptable excipient, and the other pharmaceutical composition comprising the anti-VEGFR-2 antibody and at least one pharma- ceutically acceptable excipient.

[0345] When the antibody-drug conjugate and the anti-VEGFR-2 antibody are formulated in two separate pharmaceutical compositions, the two separate pharmaceutical compositions may be administered simultaneously, separately or sequentially to a patient in need thereof. In some embodiments, the two separate pharmaceutical compositions may be administered sequentially to a patient in need thereof.

[0346] In sequential administration, the period between administration of the anti-VEGFR-2 antibody and the antibody-drug conjugate comprising the anti-CEACAM5 antibody may last from about several minutes to about several hours, days, or weeks. In some embodiments, the period may range from about 5 minutes to about 3 hours, e.g., from 10 minutes to about 2.5 hours, from about 30 minutes to about 2 hours, or from about 1 hour to about 1.5 hours. The period may last for about 5 minutes, about 10 minutes, about 30 minutes, about 1 hour, 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours.

[0347] In some embodiments, the anti-VEGFR-2 is administered over a period of 1 hour.

[0348] In some embodiments, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered for 1.5 hours.

[0349] In some embodiments, in consecutive administrations on the same day of a cycle, the period between administration of an anti-VEGFR-2 antibody and an antibody-drug conjugate comprising an anti-CEACAM5 antibody can range from about 5 minutes to about 3 hours, e.g., 10 minutes to about 2.5 hours, about 30 minutes to about 2 hours, or about 1 hour to about 1.5 hours. In consecutive administrations on the same day of a cycle, the period between can last about 5 minutes, about 10 minutes, about 30 minutes, about 1 hour, 1.5 hours, about 2 hours, about 2.5 hours, or about 3 hours.

[0350] In one embodiment, in consecutive administrations on the same day of a cycle, the period between administration of the anti-VEGFR-2 antibody and the antibody-drug conjugate comprising an anti-CEACAM5 antibody can be at least 1 hour.

[0351] In sequential administration, an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody can be administered after or before the anti-VEGFR-2 antibody.

[0352] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered prior to the anti-VEGFR-2 antibody.

[0353] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered after the anti-VEGFR-2 antibody.

[0354] In some embodiments, the order of administration of the antibody-drug conjugate comprising an anti-CEACAM5 antibody and the anti-VEGFR-2 antibody can be the same for all treatment cycles.

[0355] In some embodiments, the administration sequence of the antibody-drug conjugate comprising an anti-CEACAM5 antibody and the anti-VEGFR-2 antibody may vary along the cycle of treatment. In some embodiments, one or more cycles of treatment may include a first administration sequence, and one or more cycles of treatment may include a second administration sequence, and the first and second sequences are different.

[0356] In some embodiments, for example in use to treat cancer, in the first cycle of treatment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered after the anti-VEGFR-2 antibody, and then in additional cycles of treatment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered after the anti-VEGFR-2 antibody.

[0357] In some embodiments, for example in use to treat cancer, in a first cycle of treatment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered after an anti-VEGFR-2 antibody, and then in additional cycles of treatment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered before the anti-VEGFR-2 antibody.

[0358] In some embodiments, for example in use to treat cancer, in the first cycle of treatment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered before the anti-VEGFR-2 antibody, and then in additional cycles of treatment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered before the anti-VEGFR-2 antibody.

[0359] In some embodiments, for example in use to treat cancer, in a first cycle of treatment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered before an anti-VEGFR-2 antibody, and then in additional cycles of treatment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered after the anti-VEGFR-2 antibody.

[0360] In some embodiments, for example, in use to treat cancer such as gastric cancer, GEJ cancer or lung cancer, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered after an anti-VEGFR-2 antibody for any additional cycles of treatment.

[0361] A treatment or series of treatments may include at least one cycle of treatment.

[0362] In some embodiments, the treatment may include a first cycle of treatment, i.e., cycle 1, and at least one additional cycle of treatment, i.e., cycles 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or more.

[0363] The first cycle and the additional cycles can be the same or different.

[0364] For example, a first cycle can include administration of a loading dose (or first dose) and additional cycles can include administration of a subsequent dose (or second), i.e., different doses for the loading and subsequent doses.

[0365] Alternatively, the first cycle and the additional cycles may involve administration of the same dose, i.e., the same dose for the loading and subsequent doses.

[0366] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered at a loading dose in a first cycle and subsequent doses in additional cycles, i.e., at different doses for the loading and subsequent doses.

[0367] In some embodiments, the antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered at the same dose in the first cycle and in additional cycles, i.e., the same dose for loading and subsequent doses.

[0368] In some embodiments, the anti-VEGFR-2 antibody may be administered at a loading dose in the first cycle and at subsequent doses in additional cycles, i.e., at different doses for the loading and subsequent doses.

[0369] In some embodiments, the anti-VEGFR-2 antibody may be administered at the same dose in the first cycle and in the additional cycles, ie, the same dose for the loading and subsequent doses.

[0370] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered at a different dose for the loading dose in the first cycle and the subsequent doses in additional cycles, i.e., the loading and subsequent doses, and an anti-VEGFR-2 antibody may be administered at the same dose in the first cycle and the additional cycles, i.e., the same dose for the loading and subsequent doses.

[0371] In some embodiments, the antibody-drug conjugate comprising the anti-CEACAM5 antibody may be administered at the same dose in the first cycle and in additional cycles, and the anti-VEGFR-2 antibody may be administered at the same dose in the first cycle and in additional cycles, i.e., the same dose as the loading and subsequent doses.

[0372] A treatment cycle may last from about 1 to about 6 weeks, from 1 to 4 weeks, or from 1 to 3 weeks.

[0373] In some embodiments, a treatment cycle can last for at least about two weeks.

[0374] In some embodiments, a treatment cycle can last for at least about three weeks.

[0375] In some embodiments, a cycle of treatment may include a treatment period on at least the first day of the cycle, such as the first, second, third, fourth, fifth or sixth day, and a rest period that continues until the completion of the cycle. The treatment period and the rest period may be the same or different between the first cycle and at least one additional cycle. In some embodiments, the treatment period and the rest period may be the same between the first cycle and at least one additional cycle.

[0376] In some embodiments, a cycle of treatment, i.e., the first cycle and any additional cycles, may include a treatment period on day 1 of the cycle and a rest period continuing until the completion of said cycle.

[0377] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be administered on day 1 of a first cycle of treatment and on day 1 of at least one additional cycle of treatment.

[0378] An antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR2 antibody can be administered on day 1 of each cycle of treatment.

[0379] The treatment (or course of treatment) may include at least a first cycle (cycle 1) and at least one further (subsequent) cycle of treatment. The treatment may include 2 to 16, 3 to 15, 4 to 14, 5 to 13, 6 to 12, 7 to 11, 8 to 10 or about 9 cycles. The treatment may include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or more cycles.

[0380] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody and a cytotoxic agent for use in combination with an anti-VEGFR-2 antibody to treat cancer is provided, the antibody-drug conjugate comprising an anti-CEACAM5 antibody and a cytotoxic agent for use in combination with an anti-VEGFR-2 antibody, the antibody-drug conjugate being administered at a dose of 60 mg / m 2 ~210mg / m 2 , or about 80 to about 170 mg / m 2 , or about 100 to about 170 mg / m 2, or about 120 to about 170 mg / m 2 , or about 135 to about 170 mg / m 2 , or about 150 to about 170 mg / m 2 Disclosed is an antibody-drug conjugate administered at a dose of

[0381] The anti-VEGFR-2 antibody is administered at a dose of 2 mg / kg to 20 mg / kg, or about 4 to about 15 mg / kg, or about 6 to about 10 mg / kg, or about 8 mg / kg, or about 10 mg / kg.

[0382] In some embodiments, the antibody-drug conjugate is at a concentration of about 60 to about 210 mg / m 2 , or about 80 to about 170 mg / m 2 , or about 100 to about 150 mg / m 2 is administered at a dose of

[0383] In various embodiments, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 60, 70, 80, 90, 100, 110, 120, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, or about 210 mg / m 2 is administered at a dose of

[0384] In various embodiments, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a concentration of about 60, 80, 100, 120, 135, 150, 170, 180, 190, or about 210 mg / m 2 is administered at a dose of

[0385] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a concentration of about 80 mg / m 2 is administered at a dose of

[0386] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a concentration of about 100 mg / m 2 is administered at a dose of

[0387] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a concentration of about 120 mg / m 2 is administered at a dose of

[0388] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a concentration of about 135 mg / m 2 is administered at a dose of

[0389] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a concentration of about 150 mg / m 2 is administered at a dose of

[0390] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a concentration of about 170 mg / m 2 is administered at a dose of

[0391] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose (or first dose) of about 80, 100, 120, 135, 150 or about 170 mg / m 2 is administered at a dose of

[0392] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 120, 135, 150 or about 170 mg / m 2 is administered at a dose of

[0393] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody has a loading dose of about 120, 150 or about 170 mg / m 2 is administered at a dose of

[0394] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 80 mg / m 2 is administered at a dose of

[0395] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 100 mg / m 2is administered at a dose of

[0396] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody has a loading dose of about 120 mg / m 2 is administered at a dose of

[0397] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody has a loading dose of about 135 mg / m 2 is administered at a dose of

[0398] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 150 mg / m 2 is administered at a dose of

[0399] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody has a loading dose of about 170 mg / m 2 is administered at a dose of

[0400] According to one embodiment, the loading dose is for a two-week cycle of treatment.

[0401] According to one embodiment, the loading dose is for a three week cycle of treatment.

[0402] The loading dose may be administered on day 1 of the first cycle.

[0403] On day 1 of the first cycle, an antibody-drug conjugate containing an anti-CEACAM5 antibody was administered at approximately 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or about 170 mg / m 2 can be administered at a dose of

[0404] On day 1 of the first cycle, an antibody-drug conjugate containing an anti-CEACAM5 antibody was administered at approximately 120 mg / m 2, 150 mg / m 2 or about 170 mg / m 2 can be administered at a dose of

[0405] On day 1 of the first cycle, an antibody-drug conjugate containing an anti-CEACAM5 antibody was administered at approximately 80 mg / m 2 or about 100 mg / m 2 can be administered at a dose of

[0406] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a concentration of about 80, 100, 120, 135, 150 or about 170 mg / m 2 may be administered as a subsequent dose (or second dose) at a dose of

[0407] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a subsequent dose of about 80 mg / m 2 may be administered at a dose of

[0408] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a subsequent dose of about 100 mg / m 2 may be administered at a dose of

[0409] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a subsequent dose of about 120 mg / m 2 may be administered at a dose of

[0410] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a subsequent dose of about 135 mg / m 2 may be administered at a dose of

[0411] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a subsequent dose of about 150 mg / m 2 may be administered in a dose of

[0412] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a subsequent dose of about 170 mg / m 2 may be administered at a dose of

[0413] The subsequent dose may be administered on day 1 of the cycle following the first cycle (subsequent or additional cycles).

[0414] On day 1 of an additional cycle (at least one cycle following the first cycle), an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 80 mg / m 2 can be administered at a dose of

[0415] On day 1 of an additional cycle (at least one cycle following the first cycle), an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 100 mg / m 2 can be administered at a dose of

[0416] On day 1 of an additional cycle (at least one cycle following the first cycle), an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 120 mg / m 2 can be administered at a dose of

[0417] On day 1 of an additional cycle (at least one cycle following the first cycle), an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 135 mg / m 2 can be administered at a dose of

[0418] On day 1 of an additional cycle (at least one cycle following the first cycle), an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 150 mg / m 2 can be administered at a dose of

[0419] On day 1 of an additional cycle (at least one cycle following the first cycle), an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 170 mg / m 2 can be administered at a dose of

[0420] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 80, 100, 120, 135, 150 or about 170 mg / m 2 on day 1 of the first cycle of treatment, and then about 80, 100, 120, 135, 150 or about 170 mg / m 2 is administered, for example, on day 1 for an additional cycle.

[0421] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 100, 120, 135, 150 or about 170 mg / m 2 on day 1 of the first cycle of treatment, and then about 80 or about 100 mg / m 2 is administered, for example, on day 1 for an additional cycle.

[0422] The antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of about 80 mg / m on day 1 of the first cycle of treatment. 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or about 170 mg / m 2 on day 1 of an additional cycle at a dose of approximately 80 mg / m 2 or about 100 mg / m 2 may be administered in a dose of

[0423] On day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of about 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or about 170 mg / m 2 and the treatment cycle may be two weeks.

[0424] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of about 80 mg / m on day 1 of the first cycle of treatment. 2 and the cycle may be about two weeks.

[0425] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of about 100 mg / m on day 1 of the first cycle of treatment. 2 and the cycle may be about two weeks.

[0426] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of about 120 mg / m on day 1 of the first cycle of treatment. 2 and the cycle may be about two weeks.

[0427] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 135 mg / m on day 1 of the first cycle of treatment. 2 and the cycle may be about two weeks.

[0428] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of about 150 mg / m on day 1 of the first cycle of treatment. 2 and the cycle may be about two weeks.

[0429] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of about 170 mg / m on day 1 of the first cycle of treatment. 2 and the cycle may be about two weeks.

[0430] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 80 mg / m2 on day 1 of the first cycle of treatment. 2 and subsequent doses of about 80 mg / m 2 An additional cycle may be administered, for example on day 1. The cycle may be about 2 weeks.

[0431] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 100 mg / m2 on day 1 of the first cycle of treatment. 2 and subsequent doses of about 100 mg / m 2 An additional cycle may be administered, for example on day 1. The cycle may be about 2 weeks.

[0432] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 150 mg / m2 on day 1 of the first cycle of treatment. 2 and subsequent doses of about 80 mg / m 2 An additional cycle may be administered, for example on day 1. The cycle may be about 2 weeks.

[0433] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 150 mg / m2 on day 1 of the first cycle of treatment. 2 and subsequent doses of about 100 mg / m 2 An additional cycle may be administered, for example on day 1. The cycle may be about 2 weeks.

[0434] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 170 mg / m2 on day 1 of the first cycle of treatment. 2 and subsequent doses of about 80 mg / m 2 An additional cycle may be administered, for example on day 1. The cycle may be about 2 weeks.

[0435] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 170 mg / m2 on day 1 of the first cycle of treatment. 2 and subsequent doses of about 100 mg / m 2 An additional cycle may be administered, for example on day 1. The cycle may be about 2 weeks.

[0436] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a loading dose of 170 mg / m in cycle 1. 2 and 100 mg / m2 as subsequent doses in additional cycles. 2 The cycle may be about 2 or 3 weeks.

[0437] On day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of about 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or about 170 mg / m 2 and the treatment cycle may be three weeks.

[0438] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of about 80 mg / m on day 1 of the first cycle of treatment. 2 and the cycle may be about 3 weeks.

[0439] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of about 100 mg / m on day 1 of the first cycle of treatment. 2 and the cycle may be about 3 weeks.

[0440] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of about 120 mg / m on day 1 of the first cycle of treatment. 2 and the cycle may be about 3 weeks.

[0441] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 135 mg / m on day 1 of the first cycle of treatment. 2 and the cycle may be about 3 weeks.

[0442] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of about 150 mg / m on day 1 of the first cycle of treatment. 2 and the cycle may be about 3 weeks.

[0443] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of about 170 mg / m on day 1 of the first cycle of treatment. 2 and the cycle may be about 3 weeks.

[0444] According to one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of about 100 mg / m for all cycles, i.e., the first and additional cycles. 2 The cycle may be about 2 or 3 weeks.

[0445] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 80 mg / m2 on day 1 of the first cycle of treatment. 2 and subsequent doses of about 80 mg / m 2 An additional cycle may be administered, for example on day 1. The cycle may be about 3 weeks.

[0446] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 100 mg / m2 on day 1 of the first cycle of treatment. 2 and subsequent doses of about 100 mg / m 2 An additional cycle may be administered, for example on day 1. The cycle may be about 3 weeks.

[0447] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 120 mg / m2 on day 1 of the first cycle of treatment. 2 and subsequent doses of about 120 mg / m 2 An additional cycle may be administered, for example on day 1. The cycle may be about 3 weeks.

[0448] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 135 mg / m2 on day 1 of the first cycle of treatment. 2 and subsequent doses of about 135 mg / m 2 An additional cycle may be administered, for example on day 1. The cycle may be about 3 weeks.

[0449] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 150 mg / m2 on day 1 of the first cycle of treatment. 2 and subsequent doses of about 150 mg / m 2 An additional cycle may be administered, for example on day 1. The cycle may be about 3 weeks.

[0450] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 170 mg / m2 on day 1 of the first cycle of treatment. 2 and subsequent doses of about 170 mg / m 2 An additional cycle may be administered, for example on day 1. The cycle may be about 3 weeks.

[0451] The antibody-drug conjugate can be tusamitamaravtansine (huMAb2-3-SPDB-DM4).

[0452] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of about 2 to about 20 mg / kg, or about 4 to about 15 mg / kg, or about 6 to about 10 mg / kg, or about 8 mg / kg. The anti-VEGFR-2 antibody may be administered at a dose of about 2, 4, 6, 8, 10, 12, 14, 16, 18, or about 20 mg / kg.

[0453] In one embodiment, the anti-VEGFR-2 antibody may be administered at 8 mg / kg.

[0454] In one embodiment, the anti-VEGFR-2 antibody may be administered at 10 mg / kg.

[0455] In one embodiment, the anti-VEGFR-2 antibody may be administered at 8 mg / kg and the cycle may be about 2 weeks.

[0456] In one embodiment, the anti-VEGFR-2 antibody may be administered at 10 mg / kg and the cycle may be about 3 weeks.

[0457] The administered dose of the anti-VEGFR-2 antibody can be the same for the first and additional cycles of treatment.

[0458] On day 1 of the first cycle, the anti-VEGFR-2 antibody can be administered at a dose of about 8 mg / kg.

[0459] On day 1 of an additional cycle (at least one cycle following the first cycle), the anti-VEGFR-2 antibody can be administered at a dose of about 8 mg / kg.

[0460] According to one embodiment, the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg on day 1 of the first cycle of treatment, and the cycle may be about 2 or 3 weeks. In some embodiments, the cycle may be about 2 weeks.

[0461] According to one embodiment, the anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg on day 1 of the first cycle of treatment, and the cycle may be about 2 or 3 weeks. In some embodiments, the cycle may be about 3 weeks.

[0462] According to one embodiment, the anti-VEGFR-2 antibody may be administered as a loading dose on day 1 of the first cycle of treatment at a dose of about 8 mg / kg, and as a subsequent dose at a dose of about 8 mg / kg in additional cycles, e.g., on day 1. A cycle may be about 2 weeks.

[0463] According to one embodiment, the anti-VEGFR-2 antibody may be administered as a loading dose on day 1 of a first cycle of treatment at a dose of about 10 mg / kg, and as a subsequent dose at a dose of about 10 mg / kg in additional cycles, e.g., on day 1. A cycle may be about 3 weeks.

[0464] According to one embodiment, the anti-VEGFR-2 antibody may be administered as a loading dose on day 1 of a first cycle of treatment at a dose of about 10 mg / kg, and as a subsequent dose at a dose of about 8 mg / kg in additional cycles, e.g., on day 1. A cycle may be about 2 or 3 weeks. A cycle may be about 2 weeks.

[0465] The anti-VEGFR-2 antibody can be ramucirumab.

[0466] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 80 mg / m 2 on day 1 of the first cycle of treatment and about 80 mg / m 2 and the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg as a loading dose on day 1 of the first cycle of treatment and at a dose of about 8 mg / kg as a subsequent dose on additional cycles, e.g., on day 1. The cycle may be about 2 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0467] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 100 mg / m 2 on day 1 of the first cycle of treatment and about 100 mg / m 2and an anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg as a loading dose on day 1 of the first cycle of treatment and at a dose of about 8 mg / kg as a subsequent dose on additional cycles, e.g., on day 1. The cycle may be about 2 weeks. An antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0468] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 150 mg / m 2 on day 1 of the first cycle of treatment and about 80 mg / m 2 and the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg as a loading dose on day 1 of the first cycle of treatment and at a dose of about 8 mg / kg as a subsequent dose on additional cycles, e.g., on day 1. The cycle may be about 2 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0469] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 150 mg / m 2 on day 1 of the first cycle of treatment and about 100 mg / m 2 and an anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg as a loading dose on day 1 of the first cycle of treatment and at a dose of about 8 mg / kg as a subsequent dose on additional cycles, e.g., on day 1. The cycle may be about 2 weeks. An antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0470] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody has a loading dose of about 170 mg / m 2 on day 1 of the first cycle of treatment and about 80 mg / m 2and an anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg as a loading dose on day 1 of the first cycle of treatment and at a dose of about 8 mg / kg as a subsequent dose on additional cycles, e.g., on day 1. The cycle may be about 2 weeks. An antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0471] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody has a loading dose of about 170 mg / m 2 on day 1 of the first cycle of treatment and about 100 mg / m 2 and an anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg as a loading dose on day 1 of the first cycle of treatment and at a dose of about 8 mg / kg as a subsequent dose on additional cycles, e.g., on day 1. The cycle may be about 2 weeks. An antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0472] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 80 mg / m 2 on day 1 of the first cycle of treatment and about 80 mg / m 2 and an anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg as a loading dose on day 1 of the first cycle of treatment and at a dose of about 10 mg / kg as a subsequent dose on additional cycles, e.g., on day 1. The cycle may be about 3 weeks. An antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0473] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 100 mg / m 2 on day 1 of the first cycle of treatment and about 100 mg / m2 and an anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg as a loading dose on day 1 of the first cycle of treatment and at a dose of about 10 mg / kg as a subsequent dose on additional cycles, e.g., on day 1. The cycle may be about 3 weeks. An antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0474] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody has a loading dose of about 120 mg / m 2 on day 1 of the first cycle of treatment and about 120 mg / m 2 and an anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg as a loading dose on day 1 of the first cycle of treatment and at a dose of about 10 mg / kg as a subsequent dose on additional cycles, e.g., on day 1. The cycle may be about 3 weeks. An antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0475] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody has a loading dose of about 135 mg / m 2 on day 1 of the first cycle of treatment and about 135 mg / m 2 and an anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg as a loading dose on day 1 of the first cycle of treatment and at a dose of about 10 mg / kg as a subsequent dose on additional cycles, e.g., on day 1. The cycle may be about 3 weeks. An antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0476] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 150 mg / m 2on day 1 of the first cycle of treatment and about 150 mg / m 2 and an anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg as a loading dose on day 1 of the first cycle of treatment and at a dose of about 10 mg / kg as a subsequent dose on additional cycles, e.g., on day 1. The cycle may be about 3 weeks. An antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0477] According to one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody has a loading dose of about 170 mg / m 2 on day 1 of the first cycle of treatment and at a dose of about 170 mg / m 2 and an anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg as a loading dose on day 1 of the first cycle of treatment and at a dose of about 10 mg / kg as a subsequent dose on additional cycles, e.g., on day 1. The cycle may be about 3 weeks. An antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0478] lung cancer In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of about 80 to about 170 mg / m 2 , for example about 80 mg / m 2 , or about 100 mg / m 2 , or about 120 mg / m 2 , or about 135 mg / m 2 , or about 150 mg / m 2 or about 170 mg / m 2 and for example about 100 mg / m 2The pharmaceutical composition or combination of the present disclosure may be such that the anti-VEGFR-2 antibody can be administered at a dose of about 8 mg / kg to about 10 mg / kg.

[0479] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, e.g., non-squamous non-small cell lung cancer (NSQ NSCLC), the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a concentration of about 80 mg / m 2 ~about 170mg / m 2 The anti-VEGFR-2 antibody may be administered at a dose ranging from about 8 mg / kg to about 10 mg / kg.

[0480] In various embodiments, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at about 80, 90, 100, 110, 120, 130, 135, 140, 145, 150, 155, 160, 165, or about 170 mg / m 2 may be administered in a dose of

[0481] In various embodiments, the anti-VEGFR-2 antibody may be administered at a dose of about 8, 8.5, 9, 9.5, or about 10 mg / kg.

[0482] In the use for treating lung cancer, in the first cycle of treatment, for example as described above, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at about 80 mg / m 2 or about 100 mg / m 2 or about 170 mg / m 2 Such a dose may be a loading dose or a first dose.

[0483] For use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 80 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody in the first cycle of treatment, for example as set forth above. 2 or about 100 mg / m 2 , or about 120 mg / m 2, or about 135 mg / m 2 , or about 150 mg / m 2 , or about 170 mg / m 2 The dosage may be such that it can be administered in a dose of 100 mg / kg or more.

[0484] For use in treating lung cancer, the antibody-drug conjugate is administered at a dose of 80 mg / m on day 1 of the first cycle of treatment. 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 or 150 mg / m 2 Such a dose may be a loading dose.

[0485] For use in treating lung cancer, the antibody-drug conjugate is administered at a dose of 80 mg / m on day 1 of the first cycle of treatment. 2 or 100 mg / m 2 and the treatment cycle may be two weeks.

[0486] For use in treating lung cancer, the antibody-drug conjugate is administered at a dose of 120 mg / m on day 1 of the first cycle of treatment. 2 , 135 mg / m 2 or 150 mg / m 2 and the treatment cycle may be three weeks.

[0487] For use in treating lung cancer, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg on day 1 of the first cycle of treatment, and the cycle may be two weeks.

[0488] For use in treating lung cancer, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg on day 1 of the first cycle of treatment, and the cycle may be three weeks.

[0489] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 80 mg / m 2The administration may be performed on the first day (day 1) of the first cycle of treatment. The cycle may last for about two weeks.

[0490] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 100 mg / m 2 The administration may be performed on the first day (day 1) of the first cycle of treatment. The cycle may last for about two weeks.

[0491] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 120 mg / m 2 The administration may be performed on the first day (day 1) of the first cycle of treatment. The cycle may last for about three weeks.

[0492] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 135 mg / m 2 The administration may be performed on the first day (day 1) of the first cycle of treatment. The cycle may last for about three weeks.

[0493] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 150 mg / m 2 The administration may be performed on the first day (day 1) of the first cycle of treatment. The cycle may last for about three weeks.

[0494] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 170 mg / m 2 The administration may be performed on the first day (day 1) of the first cycle of treatment. The cycle may be about 3 weeks.

[0495] As described above, the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), may further include at least one additional cycle of treatment in addition to the first cycle of treatment. The pharmaceutical composition or combination of the present disclosure may comprise an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of about 80 mg / m 2 or about 100 mg / m 2 , about 120mg / m 2 or about 135 mg / m 2 or about 150 mg / m 2 or 170 mg / m 2 The administration may be performed on the first day (day 1) of an additional cycle of treatment. Such a dose may be a subsequent dose.

[0496] On day 1 of at least one additional cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 or 150 mg / m 2 may be administered in a dose of

[0497] The antibody-drug conjugate is administered at a dose of 80 mg / m on day 1 of at least one additional cycle of treatment. 2 or 100 mg / m 2 and the cycle may be two weeks.

[0498] Antibody-drug conjugate at 120 mg / m on day 1 of at least one additional cycle of treatment. 2 , 135 mg / m 2 or 150 mg / m 2 and the cycle may last for three weeks.

[0499] The anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg on day 1 of at least one additional cycle of treatment, and the cycle may be two weeks.

[0500] The anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg on day 1 of at least one additional cycle of treatment, and the cycle may be three weeks.

[0501] In some embodiments, in use for treating lung cancer, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 80 mg / m 2 The administration may be performed on the first day (day 1) of an additional cycle of treatment. The cycle may last for about two weeks.

[0502] In some embodiments, in use for treating lung cancer, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 100 mg / m 2 The administration may be performed on the first day (day 1) of an additional cycle of treatment. The cycle may last for about two weeks.

[0503] In some embodiments, in use for treating lung cancer, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 120 mg / m 2 The administration may be performed on the first day (day 1) of an additional cycle of treatment. The cycle may last for about three weeks.

[0504] In some embodiments, in use for treating lung cancer, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 135 mg / m 2 The administration may be performed on the first day (day 1) of an additional cycle of treatment. The cycle may last for about three weeks.

[0505] In some embodiments, in use for treating lung cancer, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 150 mg / m 2 The administration may be performed on the first day (day 1) of an additional cycle of treatment. The cycle may last for about three weeks.

[0506] In some embodiments, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is at about 170 mg / m 2 The administration may be performed on the first day (day 1) of an additional cycle of treatment. The cycle may last for about three weeks.

[0507] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate at about 80 mg / m 2 on day 1 (day 1) of the first cycle of treatment at a dose of about 80 mg / m 2 may be administered on day 1 of an additional cycle at a dose of 0.1 mg / kg / day. The cycle may last for 2 weeks.

[0508] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate at about 100 mg / m 2 on day 1 (day 1) of the first cycle of treatment at a dose of about 100 mg / m 2 The cycle may be such that it may be administered on day 1 of an additional cycle at a dose of 0.1 mg / kg / day. The cycle may last for 2 weeks.

[0509] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate at about 120 mg / m 2 on day 1 (day 1) of the first cycle of treatment at a dose of about 120 mg / m 2 on day 1 of an additional cycle. The cycle may last for 3 weeks.

[0510] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate having a concentration of about 135 mg / m 2 on day 1 (day 1) of the first cycle of treatment at a dose of about 135 mg / m 2 on day 1 of an additional cycle. The cycle may last for 3 weeks.

[0511] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate at about 150 mg / m 2on day 1 (day 1) of the first cycle of treatment at a dose of about 150 mg / m 2 on day 1 of an additional cycle. The cycle may last for 3 weeks.

[0512] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 170 mg / m 2 on day 1 (day 1) of the first cycle of treatment at a dose of about 100 or 170 mg / m 2 on day 1 of an additional cycle. The cycle may last for 3 weeks.

[0513] In use for treating lung cancer, in the first cycle of treatment and / or in additional cycles of treatment, for example as described above, the pharmaceutical composition or combination of the present disclosure may be such that the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg or about 10 mg / kg. In some embodiments, the pharmaceutical composition or combination of the present disclosure may be such that the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg. In some embodiments, the pharmaceutical composition or combination of the present disclosure may be such that the anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg. Administration may be performed on day 1 (day 1) of the (first and additional) cycle of treatment.

[0514] In some embodiments, the cycle may be about 2 or 3 weeks.

[0515] In some embodiments, the pharmaceutical compositions or combinations of the present disclosure may be such that the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg and the cycle may be two weeks.

[0516] In some embodiments, the pharmaceutical compositions or combinations of the present disclosure may be such that the anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg and the cycle may be 3 weeks.

[0517] The administered dose of the anti-VEGFR-2 antibody can be the same for the first and additional cycles of treatment.

[0518] On day 1 of the first cycle, the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg.

[0519] On day 1 of an additional cycle (at least one cycle following the first cycle), the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg.

[0520] According to one embodiment, the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg on day 1 of the first cycle of treatment, and the cycle may be about 2 or 3 weeks. In some embodiments, the cycle may be about 2 weeks.

[0521] According to one embodiment, the anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg on day 1 of the first cycle of treatment, and the cycle may be about 2 or 3 weeks. In some embodiments, the cycle may be about 3 weeks.

[0522] According to one embodiment, the anti-VEGFR-2 antibody may be administered as a loading dose on day 1 of the first cycle of treatment at a dose of about 8 mg / kg, and as a subsequent dose at a dose of about 8 mg / kg in additional cycles, e.g., on day 1. A cycle may be about 2 weeks.

[0523] According to one embodiment, the anti-VEGFR-2 antibody may be administered as a loading dose on day 1 of the first cycle of treatment at a dose of about 10 mg / kg, and as a subsequent dose at a dose of about 10 mg / kg in additional cycles, e.g., on day 1. The cycle may be about 3 weeks.

[0524] According to one embodiment, the anti-VEGFR-2 antibody may be administered as a loading dose on day 1 of a first cycle of treatment at a dose of about 10 mg / kg, and as a subsequent dose at a dose of about 8 mg / kg in additional cycles, e.g., on day 1. A cycle may be about 2 or 3 weeks. A cycle may be about 2 weeks.

[0525] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the present disclosure provides a dose of about 80 to about 170 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody in the first and additional cycles of treatment. 2 , for example about 100 mg / m 2 and the anti-VEGFR-2 antibody may be administered at a dose of about 8 or about 10 mg / kg. In some embodiments, the cycle may be about 2 weeks.

[0526] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the disclosure comprises administering an antibody-drug conjugate at a dose of 80 mg / m on day 1 of the first cycle and on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the treatment cycle may be two weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0527] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the disclosure comprises administering an antibody-drug conjugate at a dose of 100 mg / m on day 1 of the first cycle and on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the treatment cycle may be two weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0528] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the present disclosure provides a dose of about 80 to about 170 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody in the first and additional cycles of treatment. 2 , for example about 170 mg / m 2 and the anti-VEGFR-2 antibody may be administered at a dose of about 8 or about 10 mg / kg. In some embodiments, the cycle may be about 3 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0529] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the disclosure comprises administering an antibody-drug conjugate at a dose of 120 mg / m on day 1 of the first cycle and on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the cycle of treatment may be 3 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0530] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the disclosure comprises administering an antibody-drug conjugate at a dose of 135 mg / m on day 1 of the first cycle and on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the cycle of treatment may be 3 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0531] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the disclosure comprises administering an antibody-drug conjugate at a dose of 150 mg / m on day 1 of the first cycle and on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the cycle of treatment may be 3 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0532] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the present disclosure is administered in a dose of about 80 mg / m2 as a loading dose on day 1 of the first cycle of treatment. 2 and a subsequent dose of about 80 mg / m on day 1 of an additional cycle 2 and the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg on day 1 of the first cycle of treatment as a loading dose, and about 8 mg / kg as a subsequent dose on day 1 of additional cycles. The cycle may be about 2 weeks.

[0533] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the present disclosure is administered in a dose of about 100 mg / m2 as a loading dose on day 1 of the first cycle of treatment. 2 and a subsequent dose of about 100 mg / m on day 1 of an additional cycle. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg on day 1 of the first cycle of treatment as a loading dose, and about 8 mg / kg as a subsequent dose on day 1 of additional cycles. The cycle may be about 2 weeks.

[0534] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the present disclosure is administered in a dose of about 120 mg / m2 as a loading dose on day 1 of the first cycle of treatment. 2 and a subsequent dose of about 120 mg / m on day 1 of an additional cycle. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg on day 1 of the first cycle of treatment as a loading dose, and about 10 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 3 weeks.

[0535] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the present disclosure is administered in a dose of about 135 mg / m2 as a loading dose on day 1 of the first cycle of treatment. 2 and a subsequent dose of about 135 mg / m on day 1 of an additional cycle. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg on day 1 of the first cycle of treatment as a loading dose, and about 10 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 3 weeks.

[0536] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the present disclosure is administered in a dose of about 150 mg / m2 as a loading dose on day 1 of the first cycle of treatment. 2 and a subsequent dose of about 150 mg / m on day 1 of an additional cycle. 2and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg on day 1 of the first cycle of treatment as a loading dose, and about 10 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 3 weeks.

[0537] In some embodiments, for use in treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the pharmaceutical composition or combination of the present disclosure is administered in a dose of about 170 mg / m2 as a loading dose on day 1 of the first cycle of treatment. 2 and a subsequent dose of about 170 mg / m on day 1 of an additional cycle 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg on day 1 of the first cycle of treatment as a loading dose, and about 10 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 3 weeks.

[0538] In some embodiments, the antibody-drug conjugate combination comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating lung cancer, such as non-small cell lung cancer, e.g., non-squamous non-small cell lung cancer (NSQ NSCLC), in a patient with CEACAM5-positive cancer (defined as cancer with CEACAM5 immunohistochemical [IHC] intensity of 2+ or greater in 50% or more of the cancer cells, or with intensity of 2+ or greater in 1% and less than 50% of the cancer cells).

[0539] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating lung cancer, such as non-small cell lung cancer, e.g., non-squamous non-small cell lung cancer (NSQ NSCLC), in a patient, where the patient has CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, and where on day 1 of the first cycle, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of 80 mg / m 2 and the cycle is 2 weeks.

[0540] In some embodiments, on day 1 of the additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg for the subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 80 mg / m 2 and the cycle is 2 weeks.

[0541] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0542] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating lung cancer, such as non-small cell lung cancer, e.g., non-squamous non-small cell lung cancer (NSQ NSCLC), in a patient, where the patient has CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, and where on day 1 of the first cycle, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of 100 mg / m 2 and the cycle is 2 weeks.

[0543] In some embodiments, on day 1 of an additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg for subsequent doses, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 100 mg / m 2 and the cycle is 2 weeks.

[0544] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0545] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating lung cancer, such as non-small cell lung cancer, e.g., non-squamous non-small cell lung cancer (NSQ NSCLC), in a patient, wherein the patient has CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, and on day 1 of the first cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of 120 mg / m 2 and the cycle is three weeks.

[0546] In some embodiments, on day 1 of the additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg as a subsequent dose, and consecutively, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of 120 mg / m 2 and the cycle is three weeks.

[0547] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0548] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating lung cancer, such as non-small cell lung cancer, e.g., non-squamous non-small cell lung cancer (NSQ NSCLC), in a patient, where the patient has CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, and where on day 1 of the first cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of 135 mg / m 2 and the cycle is three weeks.

[0549] In some embodiments, on day 1 of the additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg as a subsequent dose, and consecutively, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of 135 mg / m as a subsequent dose. 2 and the cycle is three weeks.

[0550] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0551] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating lung cancer, such as non-small cell lung cancer, e.g., non-squamous non-small cell lung cancer (NSQ NSCLC), in a patient, where the patient has CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater but less than 50% of the cancer cells, and where on day 1 of the first cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of 150 mg / m 2 and the cycle is three weeks.

[0552] In some embodiments, on day 1 of the additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg as a subsequent dose, and consecutively, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of 150 mg / m as a subsequent dose. 2 and the cycle is three weeks.

[0553] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0554] In certain embodiments, the patient has a cancer with high CEACAM5 expression on tumor cells.High CEACAM5 expression on tumor cells can be defined as 2+ or higher intensity in 50% or more of cancer cells as measured by immunohistochemistry (IHC).

[0555] The lung cancer can be non-squamous non-small cell lung cancer (NSQ NSCLC).

[0556] In a particular embodiment, a body surface area (BSA) of 2.2 m 2 For patients with > 2.2 mg / kg / day, the dose of the antibody-drug conjugate containing the anti-CEACAM5 antibody is 2.2 mg / kg / day. 2 The calculation can be based on the BSA of

[0557] The lung cancer can be non-squamous non-small cell lung cancer (NSQ NSCLC).

[0558] In some embodiments, the dosing regimen comprises administering a dose over a period of about 10 minutes to about 48 hours, or about 1 hour to about 48 hours, e.g., a period of 1 hour to 4 hours. In one aspect of this embodiment, the dose frequency varies from twice a week to once every three weeks, e.g., every two weeks or every three weeks.

[0559] In one embodiment, the treatment period is at least 4 or 6 months.

[0560] Gastric and gastroesophageal jugular (GEJ) cancer In some embodiments, for example, for use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a concentration of about 80 mg / m 2 ~about 170mg / m 2 or about 100 mg / m 2 ~about 170mg / m 2 For example, about 150 mg / m 2 ~about 170mg / m 2 The anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg to about 10 mg / kg.

[0561] In various embodiments, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a concentration of about 80, 100, 110, 120, 130, 135, 140, 145, 150, 155, 160, 165, or about 170 mg / m 2 may be administered in a dose of

[0562] In various embodiments, the anti-VEGFR-2 antibody may be administered at a dose of about 8, 8.5, 9, 9.5, or about 10 mg / kg.

[0563] For use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg on day 1 of the first cycle of treatment, and the cycle may be 2 weeks.

[0564] For use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg on day 1 of the first cycle of treatment, and the cycle may be 3 weeks.

[0565] For use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer, in the first cycle of treatment, for example as described above, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m2 , 150 mg / m 2 or about 170 mg / m 2 may be administered at a dose of

[0566] For use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer, in the first cycle of treatment, for example as described above, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of about 120 mg / m 2 , 135 mg / m 2 , about 150mg / m 2 or about 170 mg / m 2 may be administered at a dose of

[0567] For use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer, the antibody-drug conjugate is administered at a dose of 80 mg / m on day 1 of the first cycle of treatment. 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 Such a dose may be a loading dose. The treatment cycle may be 2 weeks or 3 weeks.

[0568] In some embodiments, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is at a concentration of about 100 mg / m 2 The administration may be performed on day 1 (day 1) of the first cycle of treatment. Such a dose may be a loading dose. The cycle of treatment may be 2 weeks or 3 weeks.

[0569] In some embodiments, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is at about 120 mg / m 2 The administration may be performed on day 1 (day 1) of the first cycle of treatment. Such a dose may be a loading dose. The cycle of treatment may be 2 weeks or 3 weeks.

[0570] In some embodiments, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is at about 135 mg / m 2 The administration may be performed on day 1 (day 1) of the first cycle of treatment. Such a dose may be a loading dose. The cycle of treatment may be 2 weeks or 3 weeks.

[0571] In some embodiments, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is at about 150 mg / m 2 The administration may be performed on day 1 (day 1) of the first cycle of treatment. Such a dose may be a loading dose. The cycle of treatment may be 2 weeks or 3 weeks.

[0572] In some embodiments, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is at about 170 mg / m 2 The administration may be performed on day 1 (day 1) of the first cycle of treatment. Such a dose may be a loading dose. The cycle of treatment may be 2 weeks or 3 weeks.

[0573] As described above, the use for treating gastric cancer (GC) or GEJ cancer may include at least one additional cycle of treatment in addition to the first cycle of treatment. The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 80 mg / m2 of an antibody-drug conjugate comprising an anti-CEACAM5 antibody in the additional cycle of treatment. 2 or about 100 mg / m 2 , about 120mg / m 2 or about 135 mg / m 2 or about 150 mg / m 2 or 170 mg / m 2 The administration may be performed on the first day (day 1) of an additional cycle of treatment. Such a dose may be a subsequent dose.

[0574] On day 1 of at least one additional cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 , 100 mg / m 2, 120 mg / m 2 , 135 mg / m 2 or 150 mg / m 2 may be administered in a dose of

[0575] In some embodiments, the antibody-drug conjugate is administered at 80 mg / m on day 1 of at least one additional cycle of treatment. 2 or 100 mg / m 2 and the cycle may be two weeks.

[0576] Antibody-drug conjugate at 120 mg / m on day 1 of at least one additional cycle of treatment. 2 , 135 mg / m 2 or 150 mg / m 2 and the cycle may last for three weeks.

[0577] The anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg on day 1 of at least one additional cycle of treatment, and the cycle may be two weeks.

[0578] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg on day 1 of at least one additional cycle of treatment, and the cycle may be 3 weeks.

[0579] The antibody-drug conjugate containing the anti-CEACAM5 antibody is administered at about 80 mg / m for additional cycles of treatment. 2 Administration can be performed on the first day (day 1) of an additional cycle of treatment. The cycle of treatment can be 2 weeks or 3 weeks.

[0580] The antibody-drug conjugate containing the anti-CEACAM5 antibody is administered at about 100 mg / m for additional cycles of treatment. 2 Administration can be performed on the first day (day 1) of an additional cycle of treatment. The cycle of treatment can be 2 weeks or 3 weeks.

[0581] The antibody-drug conjugate containing the anti-CEACAM5 antibody is administered at about 120 mg / m for additional cycles of treatment. 2 Administration can be performed on the first day (day 1) of an additional cycle of treatment. The cycle of treatment can be 2 weeks or 3 weeks.

[0582] The antibody-drug conjugate containing the anti-CEACAM5 antibody is administered at about 135 mg / m 2 Administration can be performed on the first day (day 1) of an additional cycle of treatment. The cycle of treatment can be 2 weeks or 3 weeks.

[0583] The antibody-drug conjugate containing the anti-CEACAM5 antibody is administered at about 150 mg / m for additional cycles of treatment. 2 Administration can be performed on the first day (day 1) of an additional cycle of treatment. The cycle of treatment can be 2 weeks or 3 weeks.

[0584] The antibody-drug conjugate containing the anti-CEACAM5 antibody is administered at about 170 mg / m 2 Administration can be performed on the first day (day 1) of an additional cycle of treatment. The cycle of treatment can be 2 weeks or 3 weeks.

[0585] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 80 mg / m to treat gastric cancer (GC) or GEJ cancer. 2 on day 1 (day 1) of the first cycle of treatment and about 80 mg / m on day 1 of additional cycles 2 A cycle may be 3 weeks.

[0586] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 100 mg / m to treat gastric cancer (GC) or GEJ cancer. 2 on day 1 (day 1) of the first cycle of treatment and about 100 mg / m on day 1 of additional cycles 2 A cycle may be 3 weeks.

[0587] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 120 mg / m to treat gastric cancer (GC) or GEJ cancer. 2 on day 1 (day 1) of the first cycle of treatment and about 120 mg / m on day 1 of additional cycles 2 A cycle may be 3 weeks.

[0588] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 135 mg / m to treat gastric cancer (GC) or GEJ cancer. 2 on day 1 (day 1) of the first cycle of treatment and about 135 mg / m on day 1 of additional cycles 2 A cycle may be 3 weeks.

[0589] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 150 mg / m to treat gastric cancer (GC) or GEJ cancer. 2 on day 1 (day 1) of the first cycle of treatment and about 80 mg / m on day 1 of additional cycles 2 A cycle may be 2 weeks.

[0590] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 150 mg / m to treat gastric cancer (GC) or GEJ cancer. 2 on day 1 (day 1) of the first cycle of treatment and about 100 mg / m on day 1 of additional cycles 2A cycle may be 2 weeks.

[0591] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 150 mg / m to treat gastric cancer (GC) or GEJ cancer. 2 on day 1 (day 1) of the first cycle of treatment and about 150 mg / m on day 1 of additional cycles 2 A cycle may be 3 weeks.

[0592] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 170 mg / m to treat gastric cancer (GC) or GEJ cancer. 2 on day 1 (day 1) of the first cycle of treatment and about 80 mg / m on day 1 of additional cycles 2 A cycle may be 2 weeks.

[0593] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 170 mg / m to treat gastric cancer (GC) or GEJ cancer. 2 on day 1 (day 1) of the first cycle of treatment and about 100 mg / m on day 1 of additional cycles 2 A cycle may be administered in a dose of 100 mg / kg / day. A cycle may be 2 or 3 weeks. A cycle may be 2 weeks.

[0594] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 170 mg / m to treat gastric cancer (GC) or GEJ cancer. 2 on day 1 (day 1) of the first cycle of treatment and about 170 mg / m on day 1 of additional cycles 2 A cycle may be 3 weeks.

[0595] In use for treating gastric cancer (GC) or GEJ cancer, in the first cycle of treatment and / or additional cycles of treatment, e.g., as described above, the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg or about 10 mg / kg. In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg. Administration may occur on the first day (day 1) of the cycle of treatment. In some embodiments, the pharmaceutical composition or combination of the present disclosure may be such that the anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg. Administration may occur on the first day (day 1) of the (first and additional) cycle of treatment.

[0596] In some embodiments, the cycle is 2 or 3 weeks.

[0597] In some embodiments, the pharmaceutical compositions or combinations of the present disclosure may be such that the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg and the cycle may be two weeks.

[0598] In some embodiments, the pharmaceutical compositions or combinations of the present disclosure may be such that the anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg and the cycle may be 3 weeks.

[0599] The administered dose of the anti-VEGFR-2 antibody can be the same for the first and additional cycles of treatment.

[0600] On day 1 of the first cycle, the anti-VEGFR-2 antibody can be administered at a dose of about 8 mg / kg.

[0601] On day 1 of an additional cycle (at least one cycle following the first cycle), the anti-VEGFR-2 antibody can be administered at a dose of about 8 mg / kg.

[0602] According to one embodiment, the anti-VEGFR-2 antibody may be administered at a dose of about 8 mg / kg on day 1 of the first cycle of treatment, and the cycle may be about 2 or 3 weeks. In some embodiments, the cycle may be about 2 weeks.

[0603] According to one embodiment, the anti-VEGFR-2 antibody may be administered at a dose of about 10 mg / kg on day 1 of the first cycle of treatment, and the cycle may be about 2 or 3 weeks. In some embodiments, the cycle may be about 3 weeks.

[0604] According to one embodiment, the anti-VEGFR-2 antibody may be administered as a loading dose on day 1 of a first cycle of treatment at a dose of about 8 mg / kg, and as a subsequent dose at a dose of about 8 mg / kg in additional cycles, e.g., on day 1. A cycle may be about 2 weeks.

[0605] According to one embodiment, the anti-VEGFR-2 antibody may be administered as a loading dose on day 1 of a first cycle of treatment at a dose of about 10 mg / kg, and as a subsequent dose at a dose of about 10 mg / kg in additional cycles, e.g., on day 1. A cycle may be about 3 weeks.

[0606] According to one embodiment, the anti-VEGFR-2 antibody may be administered as a loading dose on day 1 of a first cycle of treatment at a dose of about 10 mg / kg, and as a subsequent dose at a dose of about 8 mg / kg in additional cycles, e.g., on day 1. A cycle may be about 2 or 3 weeks. A cycle may be about 2 weeks.

[0607] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical compositions or combinations disclosed herein provide a dose of about 80 to about 170 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody in the first and additional cycles of treatment. 2 , for example about 100 mg / m 2and the anti-VEGFR-2 antibody may be administered at a dose of about 8 or about 10 mg / kg. In some embodiments, the cycle may be about 2 or about 3 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0608] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical composition or combination of the disclosure is administered at a dose of 80 mg / m of antibody-drug conjugate on day 1 of the first cycle and on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the cycle of treatment may be 3 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0609] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical composition or combination of the disclosure is administered at a dose of 100 mg / m of antibody-drug conjugate on day 1 of the first cycle and on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the cycle of treatment may be 3 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0610] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical composition or combination of the disclosure provides an antibody-drug conjugate at a dose of 120 mg / m on day 1 of the first cycle and on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the cycle of treatment may be 3 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0611] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical composition or combination of the disclosure provides an antibody-drug conjugate at a dose of 135 mg / m on day 1 of the first cycle and day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the cycle of treatment may be 3 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0612] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical composition or combination of the disclosure is administered at a dose of 150 mg / m of antibody-drug conjugate on day 1 of the first cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the antibody-drug conjugate may be administered at a dose of 80 mg / m on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg and the treatment cycle may be two weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0613] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical composition or combination of the disclosure is administered at a dose of 150 mg / m of antibody-drug conjugate on day 1 of the first cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the antibody-drug conjugate may be administered at a dose of 100 mg / m on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg and the treatment cycle may be two weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0614] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical composition or combination of the disclosure is administered at a dose of 150 mg / m of antibody-drug conjugate on day 1 of the first cycle and on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the cycle of treatment may be 3 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0615] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical composition or combination of the disclosure comprises a 170 mg / m antibody-drug conjugate on day 1 of the first cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the antibody-drug conjugate may be administered at a dose of 80 mg / m on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg and the treatment cycle may be two weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0616] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical composition or combination of the disclosure comprises a 170 mg / m antibody-drug conjugate on day 1 of the first cycle. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, and the antibody-drug conjugate may be administered at a dose of 100 mg / m on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg and the treatment cycle may be two weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0617] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical composition or combination of the disclosure provides a 170 mg / m2 antibody-drug conjugate on day 1 of the first cycle and on day 1 of at least one additional cycle of treatment. 2 and the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, and the cycle of treatment may be 3 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody-drug conjugate.

[0618] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical compositions or combinations of the present disclosure comprise a method for treating gastric cancer (GC) or GEJ cancer, in which the administered dose of an antibody-drug conjugate comprising an anti-CEACAM5 antibody is about 80 mg / m as a loading dose on day 1 of the first cycle of treatment. 2 and approximately 80 mg / m on day 1 of an additional cycle as a subsequent dose. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg on day 1 of the first cycle of treatment as a loading dose and about 8 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 3 weeks.

[0619] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical compositions or combinations of the present disclosure comprise a method for treating gastric cancer (GC) or GEJ cancer, in which the administered dose of an antibody-drug conjugate comprising an anti-CEACAM5 antibody is about 100 mg / m as a loading dose on day 1 of the first cycle of treatment. 2 and approximately 100 mg / m on day 1 of an additional cycle as a subsequent dose. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg on day 1 of the first cycle of treatment as a loading dose, and about 8 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 3 weeks.

[0620] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical compositions or combinations of the present disclosure comprise a method for treating gastric cancer (GC) or GEJ cancer, in which the administered dose of an antibody-drug conjugate comprising an anti-CEACAM5 antibody is about 120 mg / m as a loading dose on day 1 of the first cycle of treatment. 2 and approximately 120 mg / m on day 1 of an additional cycle as a subsequent dose. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg on day 1 of the first cycle of treatment as a loading dose and about 10 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 3 weeks.

[0621] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical compositions or combinations of the present disclosure comprise a method for treating gastric cancer (GC) or GEJ cancer, in which the administered dose of an antibody-drug conjugate comprising an anti-CEACAM5 antibody is about 135 mg / m as a loading dose on day 1 of the first cycle of treatment. 2 and approximately 135 mg / m on day 1 of an additional cycle as a subsequent dose. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg on day 1 of the first cycle of treatment as a loading dose and about 10 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 3 weeks.

[0622] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical compositions or combinations of the present disclosure comprise a method for treating gastric cancer (GC) or GEJ cancer, in which the administered dose of an antibody-drug conjugate comprising an anti-CEACAM5 antibody is about 150 mg / m as a loading dose on day 1 of the first cycle of treatment. 2 and approximately 80 mg / m on day 1 of an additional cycle as a subsequent dose. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg on day 1 of the first cycle of treatment as a loading dose and about 8 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 2 weeks.

[0623] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical compositions or combinations of the present disclosure comprise a method for treating gastric cancer (GC) or GEJ cancer, in which the administered dose of an antibody-drug conjugate comprising an anti-CEACAM5 antibody is about 150 mg / m as a loading dose on day 1 of the first cycle of treatment. 2 and approximately 100 mg / m on day 1 of an additional cycle as a subsequent dose. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg on day 1 of the first cycle of treatment as a loading dose and about 8 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 2 weeks.

[0624] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical compositions or combinations of the present disclosure comprise a method for treating gastric cancer (GC) or GEJ cancer, in which the administered dose of an antibody-drug conjugate comprising an anti-CEACAM5 antibody is about 150 mg / m as a loading dose on day 1 of the first cycle of treatment. 2 and approximately 150 mg / m on day 1 of an additional cycle as a subsequent dose. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg on day 1 of the first cycle of treatment as a loading dose and about 10 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 3 weeks.

[0625] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical compositions or combinations of the present disclosure comprise a method for treating gastric cancer (GC) or GEJ cancer, in which the administered dose of an antibody-drug conjugate comprising an anti-CEACAM5 antibody is about 170 mg / m as a loading dose on day 1 of the first cycle of treatment. 2 and approximately 80 mg / m on day 1 of an additional cycle as a subsequent dose. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg on day 1 of the first cycle of treatment as a loading dose and about 8 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 2 weeks.

[0626] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical compositions or combinations of the present disclosure comprise a method for treating gastric cancer (GC) or GEJ cancer, in which the administered dose of an antibody-drug conjugate comprising an anti-CEACAM5 antibody is about 170 mg / m as a loading dose on day 1 of the first cycle of treatment. 2 and approximately 100 mg / m on day 1 of an additional cycle as a subsequent dose. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg on day 1 of the first cycle of treatment as a loading dose and about 8 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 2 weeks.

[0627] In some embodiments, for use in treating gastric cancer (GC) or GEJ cancer, the pharmaceutical compositions or combinations of the present disclosure comprise a method for treating gastric cancer (GC) or GEJ cancer, in which the administered dose of an antibody-drug conjugate comprising an anti-CEACAM5 antibody is about 170 mg / m as a loading dose on day 1 of the first cycle of treatment. 2 and approximately 170 mg / m on day 1 of an additional cycle as a subsequent dose. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg on day 1 of the first cycle of treatment as a loading dose and about 10 mg / kg on day 1 of additional cycles as subsequent doses. The cycle may be about 3 weeks.

[0628] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient having CEACAM5-positive cancer (defined as cancer with CEACAM5 immunohistochemical [IHC] intensity of 2+ or greater in 50% or more of the cancer cells or CEACAM5 intensity of 2+ or greater in 1% and less than 50% of the cancer cells).

[0629] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, wherein the patient has a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater and less than 50% cancer cells, and on day 1 of the first cycle, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody may be administered at a dose of 150 mg / m 2 and the cycle may be two weeks.

[0630] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 80 mg / m as a subsequent dose on day 1 of an additional cycle. 2 and the cycle may be two weeks.

[0631] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0632] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, wherein the patient has a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater and less than 50% cancer cells, and on day 1 of the first cycle, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody may be administered at a dose of 170 mg / m 2 and the cycle may be two weeks.

[0633] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 8 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 100 mg / m as a subsequent dose on day 1 of an additional cycle. 2 and the cycle may be two weeks.

[0634] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0635] In some embodiments, a combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, wherein the patient has a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater and less than 50% cancer cells, and on day 1 of the first cycle, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody may be administered at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the cycle may be three weeks.

[0636] In some embodiments, on day 1 of an additional cycle, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the cycle may be three weeks.

[0637] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0638] In some embodiments, a combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, wherein the patient has a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater and less than 50% cancer cells, and on day 1 of the first cycle, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody may be administered at a dose of 80 mg / m 2 and the cycle may be three weeks.

[0639] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 80 mg / m as a subsequent dose on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0640] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0641] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, wherein the patient has a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater and less than 50% cancer cells, and on day 1 of the first cycle, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody may be administered at a dose of 100 mg / m 2 and the cycle may be three weeks.

[0642] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by administration of an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a subsequent dose of 100 mg / m on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0643] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0644] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, wherein the patient has a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater and less than 50% cancer cells, and on day 1 of the first cycle, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody may be administered at a dose of 120 mg / m 2 and the cycle may be three weeks.

[0645] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at 120 mg / m as a subsequent dose on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0646] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0647] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, wherein the patient has a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater and less than 50% cancer cells, and on day 1 of the first cycle, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody may be administered at a dose of 135 mg / m 2 and the cycle may be three weeks.

[0648] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by administration of an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a subsequent dose of 135 mg / m on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0649] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0650] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, wherein the patient has a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater and less than 50% cancer cells, and on day 1 of the first cycle, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody may be administered at a dose of 150 mg / m 2 and the cycle may be three weeks.

[0651] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a subsequent dose of 150 mg / m on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0652] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0653] In some embodiments, the combination of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be for use in treating gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, wherein the patient has a CEACAM5 positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or greater cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or greater in 1% or greater and less than 50% cancer cells, and on day 1 of the first cycle, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg, thereafter the antibody-drug conjugate comprising the anti-CEACAM5 antibody may be administered at a dose of 170 mg / m 2 and the cycle may be three weeks.

[0654] In some embodiments, the anti-VEGFR-2 antibody may be administered at a dose of 10 mg / kg as a subsequent dose, followed by an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a subsequent dose of 170 mg / m on day 1 of an additional cycle. 2 and the cycle may be three weeks.

[0655] In some embodiments, the patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells.

[0656] In certain embodiments, the patient has a cancer with high CEACAM5 expression on tumor cells.High CEACAM5 expression on tumor cells can be defined as 2+ or higher intensity in 50% or more of cancer cells as measured by immunohistochemistry (IHC).

[0657] In certain embodiments, for patients with a body surface area (BSA) greater than 2.2 m2, the dose of an antibody-drug conjugate comprising an anti-CEACAM5 antibody can be calculated based on 2.2 m2 of BSA.

[0658] Pharmaceutical Compositions or Combinations In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 60 to about 210 mg / m 2 , or about 80 to about 170 mg / m 2 , or about 100 to about 170 mg / m 2 , or about 100 to about 150 mg / m 2 The anti-VEGFR-2 antibody is administered at a dose of about 2 to about 20 mg / kg, or about 4 to about 15 mg / kg, or about 6 to about 10 mg / kg, or about 8 mg / kg, or about 10 mg / kg.

[0659] The pharmaceutical composition or combination of the present disclosure may be such that the antibody-drug conjugate comprising the anti-CEACAM5 antibody may be administered in the dosages described above.

[0660] In some embodiments, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 60 to about 210 mg / m 2 , or about 80 to about 170 mg / m 2 , or about 100 to about 150 mg / m 2 The dosage may be such that it is administered in a dose of

[0661] In various embodiments, the pharmaceutical compositions or combinations of the disclosure comprise an antibody-drug conjugate comprising an anti-CEACAM5 antibody at about 60, 80, 70, 90, 100, 110, 120, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205 or about 210 mg / m 2 The dosage may be such that it is administered in a dose of

[0662] In various embodiments, the pharmaceutical compositions or combinations of the present disclosure comprise an antibody-drug conjugate comprising an anti-CEACAM5 antibody at about 60, 80, 100, 120, 135, 150, 170, 180, 190, or about 210 mg / m 2 The dosage may be such that it is administered in a dose of

[0663] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 80 mg / m 2 The dosage may be such that it is administered in a dose of

[0664] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 100 mg / m 2 The dosage may be such that it is administered in a dose of

[0665] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 120 mg / m 2 The dosage may be such that it is administered in a dose of

[0666] According to one embodiment, the pharmaceutical composition or combination of the present disclosure has an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 135 mg / m 2 The dosage may be such that it is administered in a dose of

[0667] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 150 mg / m 2 The dosage may be such that it is administered in a dose of

[0668] According to one embodiment, the pharmaceutical composition or combination of the present disclosure has an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a concentration of about 170 mg / m 2 The dosage may be such that it is administered in a dose of

[0669] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises a loading dose of about 80, 100, 120, 135, 150 or 170 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 The dosage may be such that it is administered in a dose of

[0670] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises a loading dose of about 120, 135, 150 or 170 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 The dosage may be such that it is administered in a dose of

[0671] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of about 80 mg / m 2 The dosage may be such that it is administered in a dose of

[0672] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of about 100 mg / m 2 The dosage may be such that it is administered in a dose of

[0673] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of about 120 mg / m 2 The dosage may be such that it is administered in a dose of

[0674] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of about 135 mg / m 2 The dosage may be such that it is administered in a dose of

[0675] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of about 150 mg / m 2 The dosage may be such that it is administered in a dose of

[0676] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of about 170 mg / m 2 The dosage may be such that it is administered in a dose of

[0677] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of about 80, 100, 120, 135, 150 or 170 mg / m2 in the first cycle of treatment. 2 and then in additional cycles at subsequent doses of about 80, 100, 120, 135, 150 or 170 mg / m 2 The dosage may be such that it is administered in a dose of

[0678] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises a subsequent dose of about 80 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 The dosage may be such that it is administered in a dose of

[0679] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises a subsequent dose of about 100 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody.2 The dosage may be such that it is administered in a dose of

[0680] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises a subsequent dose of about 120 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 The dosage may be such that it is administered in a dose of

[0681] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises a subsequent dose of about 135 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 The dosage may be such that it is administered in a dose of

[0682] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises a subsequent dose of about 150 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 The dosage may be such that it is administered in a dose of

[0683] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises a subsequent dose of about 170 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 The dosage may be such that it is administered in a dose of

[0684] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 80 mg / m 2 and the cycle may be about two weeks.

[0685] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of 80 mg / m2 in the first cycle of treatment. 2 and 80 mg / m for additional cycles 2 The cycle may be about two weeks.

[0686] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 100 mg / m 2 and the cycle may be about two weeks.

[0687] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of 100 mg / m2 in the first cycle of treatment. 2 and 100 mg / m2 for additional cycles 2 The cycle may be about two weeks.

[0688] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 150 mg / m 2 and the cycle may be about two weeks.

[0689] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody, the antibody-drug conjugate being administered at a loading dose of 150 mg / m2 in the first cycle of treatment. 2 and 80 mg / m for additional cycles 2 The cycle may be about two weeks.

[0690] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody, the antibody-drug conjugate being administered at a loading dose of 150 mg / m2 in the first cycle of treatment. 2 and 100 mg / m2 for additional cycles 2 The cycle may be about two weeks.

[0691] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 170 mg / m 2 and the cycle may be about 2 or 3 weeks.

[0692] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of 170 mg / m2 in the first cycle of treatment. 2 and 80 mg / m for additional cycles 2 The cycle may be about 2 or 3 weeks. The cycle may be about 2 weeks.

[0693] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of 170 mg / m2 in the first cycle of treatment. 2 and 100 mg / m2 for additional cycles 2 The cycle may be about 2 or 3 weeks. The cycle may be about 2 weeks.

[0694] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 80 mg / m 2 and the cycle may be such that it is 3 weeks.

[0695] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of 80 mg / m2 in the first cycle of treatment. 2 and 80 mg / m for additional cycles 2 The cycle may be about 3 weeks.

[0696] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 100 mg / m 2 and the cycle may be about 3 weeks.

[0697] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody, the antibody-drug conjugate being administered at a loading dose of 100 mg / m2 in the first cycle of treatment. 2 and 80 mg / m for additional cycles 2 The cycle may be about 3 weeks.

[0698] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 120 mg / m 2 and the cycle may be about 3 weeks.

[0699] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of 120 mg / m2 in the first cycle of treatment. 2 and 120 mg / m2 for additional cycles 2 The cycle may be about 3 weeks.

[0700] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 135 mg / m 2 and the cycle may be about 3 weeks.

[0701] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody, the antibody-drug conjugate being administered at a loading dose of 135 mg / m2 in the first cycle of treatment. 2and 135 mg / m2 for additional cycles 2 The cycle may be about 3 weeks.

[0702] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 150 mg / m 2 and the cycle may be about 3 weeks.

[0703] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody, the antibody-drug conjugate being administered at a loading dose of 150 mg / m2 in the first cycle of treatment. 2 and 150 mg / m2 for additional cycles 2 The cycle may be about 3 weeks.

[0704] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 170 mg / m 2 and the cycle may be about 3 weeks.

[0705] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a loading dose of 170 mg / m2 in the first cycle of treatment. 2 and 170 mg / m2 for additional cycles 2 The cycle may be about 3 weeks.

[0706] According to one embodiment, the pharmaceutical composition or combination of the present disclosure comprises an antibody-drug conjugate comprising an anti-CEACAM5 antibody at a dose of 100 mg / m 2 The cycle may be about 2 or 3 weeks.

[0707] In some embodiments, a pharmaceutical composition or combination of the present disclosure may be such that the anti-VEGFR-2 antibody is administered at a dose of about 2 to about 20 mg / kg, or about 4 to about 15 mg / kg, or about 6 to about 10 mg / kg, or about 8 mg / kg. The anti-VEGFR-2 antibody may be administered at a dose of about 2, 4, 6, 8, 10, 12, 14, 16, 18, or about 20 mg / kg.

[0708] In one embodiment, the pharmaceutical composition or combination of the present disclosure may be such that the anti-VEGFR-2 antibody is administered at 8 mg / kg.

[0709] In one embodiment, the pharmaceutical composition or combination of the present disclosure may be such that the anti-VEGFR-2 antibody is administered at 10 mg / kg.

[0710] In one embodiment, the anti-VEGFR-2 antibody is administered at 8 mg / kg and the cycle is about 2 weeks.

[0711] In one embodiment, the pharmaceutical composition or combination of the present disclosure may be such that the anti-VEGFR-2 antibody is administered at 10 mg / kg and the cycle is about 3 weeks.

[0712] The pharmaceutical compositions or combinations of the present disclosure may be such that the administered dose of the anti-VEGFR-2 antibody may be the same for the first and additional cycles of treatment.

[0713] The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 80 mg / m2 as a loading dose on day 1 of the first cycle of treatment for an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 and a subsequent dose of about 80 mg / m on day 1 of an additional cycle. 2The dose of the anti-VEGFR-2 antibody may be about 8 mg / kg, such that on day 1 of the first cycle of treatment, the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg as a loading dose and on day 1 of an additional cycle, the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg as a subsequent dose. The cycle may be about 2 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0714] The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 80 mg / m2 as a loading dose on day 1 of the first cycle of treatment for an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 and about 80 mg / m on day 1 of an additional cycle. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg as a loading dose on day 1 of the first cycle of treatment and about 10 mg / kg as a subsequent dose on day 1 of additional cycles. The cycle may be about 3 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0715] The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 100 mg / m2 as a loading dose on day 1 of the first cycle of treatment for an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 and a subsequent dose of about 100 mg / m on day 1 of an additional cycle. 2 and the administered dose of the anti-VEGFR-2 antibody may be at a dose of about 8 mg / kg as a loading dose on day 1 of a first cycle of treatment and at a dose of about 8 mg / kg as a subsequent dose on day 1 of an additional cycle. The cycle may be about 2 weeks. The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody antibody-drug conjugate.

[0716] The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 100 mg / m2 as a loading dose on day 1 of the first cycle of treatment for an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2and about 100 mg / m on day 1 of an additional cycle. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg as a loading dose on day 1 of a first cycle of treatment and about 10 mg / kg as a subsequent dose on day 1 of additional cycles. A cycle may be about 3 weeks.

[0717] The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 120 mg / m2 as a loading dose on day 1 of the first cycle of treatment for an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 and about 120 mg / m on day 1 of an additional cycle. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg as a loading dose on day 1 of a first cycle of treatment and about 10 mg / kg as a subsequent dose on day 1 of additional cycles. A cycle may be about 3 weeks.

[0718] The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 135 mg / m2 as a loading dose on day 1 of the first cycle of treatment for an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 and about 135 mg / m on day 1 of an additional cycle as a subsequent dose. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg as a loading dose on day 1 of a first cycle of treatment and about 10 mg / kg as a subsequent dose on day 1 of additional cycles. A cycle may be about 3 weeks.

[0719] The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 150 mg / m2 as a loading dose on day 1 of the first cycle of treatment for an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 and about 80 mg / m on day 1 of an additional cycle. 2and the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg as a loading dose on day 1 of a first cycle of treatment and about 8 mg / kg as a subsequent dose on day 1 of additional cycles. A cycle may be about 2 weeks.

[0720] The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 150 mg / m2 as a loading dose on day 1 of the first cycle of treatment for an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 and about 100 mg / m on day 1 of an additional cycle. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg as a loading dose on day 1 of a first cycle of treatment and about 8 mg / kg as a subsequent dose on day 1 of additional cycles. A cycle may be about 2 weeks.

[0721] The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 150 mg / m2 as a loading dose on day 1 of the first cycle of treatment for an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 and about 150 mg / m on day 1 of an additional cycle. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg as a loading dose on day 1 of a first cycle of treatment and about 10 mg / kg as a subsequent dose on day 1 of additional cycles. A cycle may be about 3 weeks.

[0722] The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 170 mg / m2 as a loading dose on day 1 of the first cycle of treatment for an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 and about 80 mg / m on day 1 of an additional cycle. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg as a loading dose on day 1 of a first cycle of treatment and about 8 mg / kg as a subsequent dose on day 1 of additional cycles. A cycle may be about 2 weeks.

[0723] The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 170 mg / m2 as a loading dose on day 1 of the first cycle of treatment for an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 and about 100 mg / m on day 1 of an additional cycle. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 8 mg / kg as a loading dose on day 1 of a first cycle of treatment and about 8 mg / kg as a subsequent dose on day 1 of additional cycles. A cycle may be about 2 weeks.

[0724] The pharmaceutical composition or combination of the present disclosure may be administered at a dose of about 170 mg / m2 as a loading dose on day 1 of the first cycle of treatment for an antibody-drug conjugate comprising an anti-CEACAM5 antibody. 2 and about 170 mg / m on day 1 of an additional cycle. 2 and the administered dose of the anti-VEGFR-2 antibody may be about 10 mg / kg as a loading dose on day 1 of a first cycle of treatment and about 10 mg / kg as a subsequent dose on day 1 of additional cycles. A cycle may be about 3 weeks.

[0725] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody may be administered for a period ranging from about 30 minutes to about 3 hours, or from about 45 minutes to about 2.5 hours, or from about 1 hour to about 2 hours, or about 1.5 hours. In some embodiments, the period may be about 1.5 hours.

[0726] In some embodiments, the anti-VEGFR-2 antibody may be administered for a period ranging from about 20 minutes to about 2.5 hours, or from about 30 minutes to about 2 hours, or from about 45 minutes to about 1.5 hours, or about 1 hour. In some embodiments, the period may be about 1 hour.

[0727] The period between administration of the anti-VEGFR-2 antibody and administration of the antibody-drug conjugate comprising an anti-CEACAM5 antibody may range from about 20 minutes to about 5 hours, from about 30 minutes to about 3 hours, from about 40 minutes to about 2 hours, from about 50 minutes to about 1.5 hours, or may last about 1 hour.

[0728] In some embodiments, the period between administration of the anti-VEGFR-2 antibody and administration of the antibody-drug conjugate comprising an anti-CEACAM5 antibody can be about 1 hour.

[0729] In some embodiments, the anti-VEGFR-2 antibody is administered prior to the antibody-drug conjugate comprising the anti-CEACAM5 antibody.

[0730] In a further embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be administered for a treatment comprising about 8 to about 16 cycles. According to one embodiment, the cycles may be selected from one-week cycles, two-week cycles, three-week cycles, four-week cycles, five-week cycles, six-week cycles or more weekly cycles.

[0731] In a further embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be administered in a first cycle and at least one additional cycle. The use disclosed herein may include 2 to 16 cycles.

[0732] In some embodiments, the (first or additional) cycle may be about 2 weeks.

[0733] In some embodiments, the (first or additional) cycle may be about 3 weeks.

[0734] According to one embodiment, one cycle comprises: - administering an anti-VEGFR-2 antibody at a dose of 2-20 mg / kg at least once per cycle; and - Antibody-drug conjugate at 60-210mg / m 2should be administered at least once per cycle at a dose of Includes.

[0735] In one embodiment, the antibody-drug conjugate comprising the anti-CEACAM5 antibody is administered at a dose of 60 to 210 mg / m on day 1 of the cycle. 2 The dose is administered.

[0736] In one embodiment, the anti-VEGFR-2 antibody is administered at a dose of 2-20 mg / kg on day 1 of the cycle.

[0737] In one embodiment, the anti-VEGFR-2 antibody is administered at a dose of 2-20 mg / kg on days 2 and 5 of the cycle.

[0738] In one embodiment, the anti-VEGFR-2 antibody is administered at a dose of 2-20 mg / kg on day 2 of the cycle.

[0739] In one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at about 60, 80, 70, 90, 100, 110, 120, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205 or about 210 mg / m 2 The dose is administered.

[0740] In one embodiment, the anti-VEGFR-2 antibody is administered at a dose of about 2, 4, 6, 8, 10, 12, 14, 16, 18, or about 20 mg / kg on day 1 of the cycle.

[0741] In one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of 80, 100, 120, 135, 150 or 170 mg / m 2 on day 1 of the first cycle of treatment, with subsequent doses of 100 or 170 mg / m 2 on day 1 of each additional cycle. The anti-VEGFR-2 antibody is administered at a dose of about 8 or 10 mg / kg on the first cycle and on day 1 of each additional cycle of treatment.

[0742] In one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of 150 or 170 mg / m 2 on day 1 of the first cycle of treatment, with subsequent doses of 80 or 100 mg / m 2 and on day 1 of additional cycles at a dose of about 8 mg / kg. The anti-VEGFR-2 antibody is administered at a dose of about 8 mg / kg on the first cycle of treatment and on day 1 of additional cycles. The cycles may last for 2 weeks.

[0743] In one embodiment, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a loading dose of 100 or 170 mg / m 2 on day 1 of the first cycle of treatment, with subsequent doses of 100 or 170 mg / m 2 The anti-VEGFR-2 antibody is administered at a dose of about 8 or 10 mg / kg on day 1 of the first and additional cycles of treatment. A cycle may last for 2 or 3 weeks.

[0744] In one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at 80 or 100 mg / m on day 1 of the first cycle of treatment. 2 and 80 or 100 mg / m on day 1 of an additional cycle. 2 The anti-VEGFR-2 antibody is administered at a dose of about 8 mg / kg on day 1 of the first cycle of treatment and of additional cycles. A cycle may last for 2 weeks.

[0745] In one embodiment, the antibody-drug conjugate is administered at a dose of 170 mg / m on day 1 of the first cycle of treatment. 2 and 100 or 170 mg / m on day 1 of an additional cycle. 2 The anti-VEGFR-2 antibody is administered at a dose of about 8 or 10 mg / kg on day 1 of the first cycle and additional cycles of treatment. A cycle may last for 2 or 3 weeks.

[0746] In some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be administered once per cycle. Administration may occur on day 1 of each cycle.

[0747] According to some embodiments, in the use for treating gastric or GEJ cancer, one cycle (the first cycle and any additional cycles) comprises: i) About 100 to about 170 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 at a dose of, for example, about 150 mg / m 2 ~about 170mg / m 2 at a dose of, for example, about 135 mg / m 2 , about 150mg / m 2 or about 170 mg / m 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg to about 10 mg / kg once per cycle, for example on day 1 of the cycle; Includes.

[0748] Administration can occur on day 1 of a cycle.

[0749] The cycle may be about two weeks.

[0750] The antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody.

[0751] According to some embodiments, in the use for treating gastric or GEJ cancer, the first cycle comprises: i) about 150 to about 170 mg / m of the antibody-drug conjugate 2 , e.g. 170 mg / m 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0752] In such an embodiment, such a cycle may be the first cycle.

[0753] According to some embodiments, in the use for treating gastric or GEJ cancer, the first cycle comprises: i) About 150 to about 170 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 at a dose of, for example, 150 mg / m 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0754] In such an embodiment, such a cycle may be the first cycle.

[0755] According to some embodiments, in the use for treating gastric or GEJ cancer, the additional cycle comprises: i) about 100 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0756] In such embodiments, such cycles may be additional cycles.

[0757] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody.

[0758] The cycle may last for two weeks.

[0759] According to some embodiments, in the use for treating gastric or GEJ cancer, the first cycle comprises: i) about 150 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0760] In such an embodiment, such a cycle may be the first cycle.

[0761] According to some embodiments, in the use for treating gastric or GEJ cancer, the additional cycle comprises: i) About 80 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0762] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for two weeks.

[0763] According to some embodiments, in the use for treating gastric or GEJ cancer, the first cycle comprises: i) about 150 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0764] In such an embodiment, such a cycle may be the first cycle.

[0765] According to some embodiments, in the use for treating gastric or GEJ cancer, the additional cycle comprises: i) about 100 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0766] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for two weeks.

[0767] According to some embodiments, in the use for treating gastric or GEJ cancer, the first cycle comprises: i) about 170 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0768] In such an embodiment, such a cycle may be the first cycle.

[0769] According to some embodiments, in the use for treating gastric or GEJ cancer, the additional cycle comprises: i) About 80 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0770] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for two weeks.

[0771] According to some embodiments, in the use for treating gastric or GEJ cancer, the first cycle comprises: i) about 170 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0772] In such an embodiment, such a cycle may be the first cycle.

[0773] According to some embodiments, in the use for treating gastric or GEJ cancer, the additional cycle comprises: i) about 100 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0774] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for two weeks.

[0775] According to some embodiments, in the use for treating gastric or GEJ cancer, the first cycle comprises: i) about 100 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0776] In such an embodiment, such a cycle may be the first cycle.

[0777] According to some embodiments, in the use for treating gastric or GEJ cancer, the additional cycle comprises: i) about 100 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0778] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for three weeks.

[0779] According to some embodiments, in the use for treating gastric or GEJ cancer, the first cycle comprises: i) about 120 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0780] In such an embodiment, such a cycle may be the first cycle.

[0781] According to some embodiments, in the use for treating gastric or GEJ cancer, the additional cycle comprises: i) about 120 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0782] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for three weeks.

[0783] According to some embodiments, in the use for treating gastric or GEJ cancer, the first cycle comprises: i) about 135 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0784] In such an embodiment, such a cycle may be the first cycle.

[0785] According to some embodiments, in the use for treating gastric or GEJ cancer, the additional cycle comprises: i) about 135 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0786] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for three weeks.

[0787] According to some embodiments, in the use for treating gastric or GEJ cancer, the first cycle comprises: i) about 150 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0788] In such an embodiment, such a cycle may be the first cycle.

[0789] According to some embodiments, in the use for treating gastric or GEJ cancer, the additional cycle comprises: i) about 150 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0790] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for three weeks.

[0791] According to some embodiments, in the use for treating gastric or GEJ cancer, the first cycle comprises: i) about 170 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0792] In such an embodiment, such a cycle may be the first cycle.

[0793] According to some embodiments, in the use for treating gastric or GEJ cancer, the additional cycle comprises: i) about 170 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0794] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for three weeks.

[0795] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), one cycle (the first cycle and any additional cycles) comprises: i) About 80 to about 170 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 , for example about 80 mg / m 2 or about 100 mg / m 2 or about 170 mg / m 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 to about 10 mg / kg once per cycle, for example on day 1 of the cycle; Includes.

[0796] Administration can occur on day 1 of a cycle.

[0797] In such embodiments, the cycle is about two weeks or three weeks.

[0798] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody.

[0799] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), one cycle (the first cycle and any additional cycles) comprises: i) about 80 or about 100 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0800] Administration can occur on day 1 of a cycle.

[0801] In such an embodiment, the cycle is about two weeks.

[0802] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody.

[0803] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), one cycle (the first cycle and any additional cycles) comprises: i) About 100 to about 170 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 at a dose of, for example, about 170 mg / m 2 once per cycle, e.g., on the day of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 or about 10 mg / kg once per cycle, e.g., on day 1 of the cycle. Includes.

[0804] Administration can occur on day 1 of a cycle.

[0805] In such embodiments, the cycle is about two weeks or three weeks.

[0806] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody.

[0807] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the first cycle comprises: i) About 80 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0808] In such an embodiment, such a cycle may be the first cycle.

[0809] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the additional cycle comprises: i) About 80 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0810] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for two weeks.

[0811] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the first cycle comprises: i) about 100 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0812] In such an embodiment, such a cycle may be the first cycle.

[0813] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the additional cycle comprises: i) about 100 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 8 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0814] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for two weeks.

[0815] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the first cycle comprises: i) about 120 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0816] In such an embodiment, such a cycle may be the first cycle.

[0817] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the additional cycle comprises: i) about 120 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody 2once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0818] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for three weeks.

[0819] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the first cycle comprises: i) about 135 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0820] In such an embodiment, such a cycle may be the first cycle.

[0821] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the additional cycle comprises: i) about 135 mg / m of an antibody-drug conjugate comprising an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0822] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for three weeks.

[0823] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the first cycle comprises: i) about 150 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0824] In such an embodiment, such a cycle may be the first cycle.

[0825] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the additional cycle comprises: i) about 150 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0826] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for three weeks.

[0827] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the first cycle comprises: i) about 170 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0828] In such an embodiment, such a cycle may be the first cycle.

[0829] According to some embodiments, in the use for treating lung cancer, such as non-small cell lung cancer, such as non-squamous non-small cell lung cancer (NSQ NSCLC), the additional cycle comprises: i) about 170 mg / m of an antibody-drug conjugate containing an anti-CEACAM5 antibody 2 once per cycle, e.g., on day 1 of the cycle; ii) administering an anti-VEGFR-2 antibody at a dose of about 10 mg / kg once per cycle, e.g., on day 1 of the cycle; Includes.

[0830] In those embodiments, the antibody-drug conjugate may be administered after the anti-VEGFR-2 antibody. The cycle may last for three weeks.

[0831] Unit: mg / m 2 " is the area of ​​1 m of the patient's body surface that is administered per dose. 2 The amount of compound in mg per unit area is shown. Those skilled in the art will know how to determine the amount of compound required to be administered based on the patient's body surface, which can be calculated based on height and weight.

[0832] The unit "mg / kg" indicates the amount of compound in mg per kg of patient's body administered per dose. Those skilled in the art know how to determine the required amount of compound to be treated based on the patient's body weight.

[0833] In some embodiments, in the uses disclosed herein, the administration of the antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody may be performed by a parenteral route. A suitable parenteral route may be intravenous infusion.

[0834] The present disclosure further relates to a pharmaceutical composition comprising an antibody-drug conjugate comprising an anti-CEACAM5 antibody and further comprising an anti-VEGFR-2 antibody.

[0835] The present disclosure further relates to a pharmaceutical composition comprising an antibody-drug conjugate comprising an anti-CEACAM5 antibody, an anti-VEGFR-2 antibody, and at least one pharma- ceutically acceptable excipient.

[0836] The pharmaceutical composition can include an antibody-drug conjugate comprising an anti-CEACAM5 antibody, ramucirumab, and a pharma- ceutically acceptable excipient.

[0837] The pharmaceutical composition can include tusamitamaravtansine, ramucirumab, and a pharmaceutically acceptable excipient.

[0838] According to some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody can be formulated in the form of two separate pharmaceutical compositions, (i) one pharmaceutical composition comprising an antibody-drug conjugate comprising an anti-CEACAM5 antibody, and (ii) the other pharmaceutical composition comprising an anti-VEGFR-2 antibody.

[0839] According to some embodiments, an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody can be formulated in the form of two separate pharmaceutical compositions: (i) one pharmaceutical composition comprising an antibody-drug conjugate comprising an anti-CEACAM5 antibody and at least one pharma- ceutically acceptable excipient, and (ii) another pharmaceutical composition comprising an anti-VEGFR-2 antibody and at least one pharma- ceutically acceptable excipient.

[0840] The present disclosure further relates to a kit comprising (i) a pharmaceutical composition comprising an antibody-drug conjugate comprising an anti-CEACAM5 antibody and (ii) a pharmaceutical composition comprising an anti-VEGFR-2 antibody, in separate or combined formulations.

[0841] The present disclosure further relates to (i) a pharmaceutical composition comprising an antibody-drug conjugate comprising an anti-CEACAM5 antibody and at least one pharma- ceutically acceptable excipient, and (ii) a kit comprising a pharmaceutical composition comprising an anti-VEGFR-2 antibody and at least one pharma- ceutically acceptable excipient, in separate or combined formulations.

[0842] The present disclosure further relates to pharmaceutical compositions comprising antibody-drug conjugates comprising an anti-CEACAM5 antibody and further comprising an anti-VEGFR-2 antibody for use in the treatment of cancer.

[0843] The present disclosure further relates to a pharmaceutical composition comprising an antibody-drug conjugate comprising an anti-CEACAM5 antibody, an anti-VEGFR-2 antibody, and at least one pharma- ceutically acceptable excipient, for use in treating cancer.

[0844] The present disclosure further relates to a kit comprising (i) a pharmaceutical composition comprising an antibody-drug conjugate comprising an anti-CEACAM5 antibody and (ii) a pharmaceutical composition comprising an anti-VEGFR-2 antibody, in separate or combined formulations, for use in treating cancer.

[0845] The present disclosure further relates to (i) a pharmaceutical composition comprising an antibody-drug conjugate comprising an anti-CEACAM5 antibody and at least one pharma- ceutically acceptable excipient, and (ii) a kit comprising a pharmaceutical composition comprising an anti-VEGFR-2 antibody and at least one pharma- ceutically acceptable excipient, in separate or combined formulations, for use in the treatment of cancer.

[0846] "Pharmaceutical excipient" or "pharmaceutical acceptable excipient" refers to molecular entities and compositions that do not produce adverse allergic reactions or other untoward reactions when administered to a mammal, particularly a human, as appropriate. A pharmaceutical acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.

[0847] As used herein, "a pharma- ceutically acceptable carrier or excipient" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, etc. Examples of suitable carriers, diluents and / or excipients include water, amino acids, saline, phosphate buffered saline, phosphate buffer, acetate, citrate, succinate; amino acids and derivatives such as histidine, arginine, glycine, proline, glycylglycine; inorganic salts NaCl, calcium chloride; sugars or polyalcohols such as dextrose, glycerol, ethanol, sucrose, trehalose, mannitol; surfactants such as polysorbate 80, polysorbate 20, poloxamer 188, etc., and combinations thereof. In many cases, it is preferred to include an isotonic agent, such as a sugar, polyalcohol or sodium chloride, in the composition, and the formulation may also contain an antioxidant, such as tryptamine, and a stabilizer, such as Tween 20.

[0848] The form of the pharmaceutical composition, the route of administration, the dosage and the regimen will naturally depend on the condition to be treated, the severity of the disease, the age, weight and sex of the patient, etc.

[0849] The pharmaceutical compositions of the present disclosure can be formulated for topical, oral, parenteral, intranasal, intravenous, intramuscular, subcutaneous or intraocular administration, etc. In one embodiment, the pharmaceutical compositions and combinations of the present disclosure are formulated for intravenous administration.

[0850] In particular, the pharmaceutical compositions contain pharma- ceutically acceptable vehicles or excipients for injectable preparations, which may in particular be isotonic sterile saline (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride, etc., or mixtures of such salts) or dry compositions, in particular lyophilized compositions, which, on addition of sterile water or saline, as the case may be, allow the constitution of an injectable solution.

[0851] The pharmaceutical composition may be administered via a drug combination device.

[0852] The dose used for administration can be adapted as a function of various parameters, in particular as a function of the mode of use, the pathology involved or the desired duration of treatment.

[0853] To prepare a pharmaceutical composition, an effective amount of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and an anti-VEGFR-2 antibody can be dissolved or dispersed in a pharma- ceutically acceptable carrier or aqueous medium.

[0854] Pharmaceutical forms suitable for injection use include sterile aqueous solutions or dispersions; formulations containing sesame oil, peanut oil or aqueous propylene glycol; sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and injectable in a suitable device or system for delivery without degradation. It must be stable under the conditions of manufacture and storage and must be protected against the contaminating action of microorganisms such as bacteria and fungi.

[0855] The solution of the active compound as a free base or a pharmacologically acceptable salt can be prepared in water mixed appropriately with a surfactant.Dispersions can also be prepared in glycerol, liquid polyethylene glycols and their mixtures and in oils.Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0856] Antibody-drug conjugates containing anti-CEACAM5 antibodies can be formulated into compositions in neutral or salt form. Pharmaceutically acceptable salts include acid addition salts (formed with free amino groups of the protein) and are formed with inorganic acids, such as hydrochloric or phosphoric acid, or organic acids such as acetic, oxalic, tartaric, mandelic, etc. Salts formed with free carboxyl groups can also be derived from inorganic bases, such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, or ferric hydroxide, and organic bases, such as isopropylamine, trimethylamine, glycine, histidine, procaine, etc.

[0857] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0858] Sterile injection solution is prepared by incorporating the required amount of active compound into suitable solvent together with various other ingredients as listed above as necessary, followed by filtration sterilization.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle that contains basic dispersion medium and other necessary ingredients from those listed above.In the case of sterile powder for preparing sterile injection solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains powder of active ingredient + any additional desired ingredient from its previously sterile filtered solution.

[0859] The preparation of more or more concentrated solutions for direct injection is also contemplated, and the use of DMSO as a solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of active agent to small tumor areas.

[0860] Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the types of injectable solutions described above, although drug release capsules and the like can also be used.

[0861] For parenteral administration in aqueous solution, for example, the solution should be appropriately buffered if necessary, and the liquid diluent should first be rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this regard, the sterile aqueous media that can be used will be known to those skilled in the art in light of this disclosure. For example, one dose can be dissolved in 1 ml of isotonic NaCl solution and added to 1000 ml of subcutaneous infusion fluid or injected at the proposed injection site (see, for example, "Remington's Pharmaceutical Sciences", 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the patient being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual patient.

[0862] Antibody-drug conjugates, including anti-CEACAM5 antibodies, formulated for parenteral administration, e.g., intravenous or intramuscular injection; other pharma- ceutically acceptable forms include, for example, tablets or other solids for oral administration; time-release capsules; and any other forms currently in use.

[0863] In certain embodiments, the use of liposomes and / or nanoparticles is contemplated for the introduction of the polypeptide into the host cell. The formation and use of liposomes and / or nanoparticles are known to those of skill in the art.

[0864] Nanocapsules can generally entrap compounds in a stable and reproducible manner. To avoid side effects due to intracellular polymer overload, such ultrafine particles (size of about 0.1 μm) are generally designed using polymers that can be degraded in vivo. Biodegradable polyalkyl-cyanoacrylate nanoparticles or biodegradable polylactide or polylactide-co-glycolide nanoparticles that meet these requirements are contemplated for use in the present disclosure, and such particles can be easily made.

[0865] Liposomes are formed from phospholipids that disperse in aqueous media and spontaneously form multilamellar concentric bilayer vesicles, also called multilamellar vesicles (MLVs). MLVs generally have diameters between 25 nm and 4 μm. Sonication of MLVs results in the formation of small unilamellar vesicles (SUVs) with diameters ranging from 200 to 500 Å, which contain aqueous solution in their core. The physical properties of liposomes depend on pH, ionic strength and the presence of divalent cations.

[0866] A brief description of the sequence SEQ ID NOs: 1 to 5 show the sequences CDR-H1, CDR-H2, CDR-H3, CDR-L1 and CDR-L3 of the anti-CEACAM5 antibody (huMAb2-3).

[0867] SEQ ID NO: 6 shows the sequence of the variable domain (VH) of the heavy chain of the anti-CEACAM5 antibody (huMAb2-3).

[0868] SEQ ID NO: 7 shows the sequence of the variable domain (VL) of the light chain of the anti-CEACAM5 antibody (huMAb2-3).

[0869] SEQ ID NO: 8 shows the heavy chain sequence of anti-CEACAM5 antibody (huMAb2-3).

[0870] SEQ ID NO: 9 shows the light chain sequence of the anti-CEACAM5 antibody (huMAb2-3).

[0871] SEQ ID NO: 10 shows the heavy chain sequence of the anti-VEGFR-2 antibody ramucirumab.

[0872] SEQ ID NO: 11 shows the light chain sequence of the anti-VEGFR-2 antibody ramucirumab.

[0873] SEQ ID NOs: 12 to 17 show the sequences CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 of the anti-VEGFR-2 antibody ramucirumab. [Brief description of the drawings]

[0874] [Figure 1]Activity of antibody-drug conjugate huMAb2-3-SPDB-DM4 and anti-muVEGFR-2 antibody DC-101 as single agents or in combination against subcutaneous gastric patient-derived xenografts STO-IND-0006 in SCID mice. Change in tumor volume by treatment group. Curves represent median + or - MAD for each day in each group. [Diagram 2] Activity of antibody-drug conjugate huMAb2-3-SPDB-DM4 and anti-muVEGFR-2 antibody DC-101 as single agents or in combination against subcutaneous gastric patient-derived xenografts SA-STO-0014 in SCID mice. Change in tumor volume by treatment group. Curves represent median + or - MAD for each day in each group. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0875] Example 1: Activity of antibody-drug conjugate huMAb2-3-SPDB-DM4 in combination with anti-muVEGFR-2 antibody DC-101 against subcutaneous gastric patient-derived xenografts STO-IND-0006 in SCID mice. DC-101 is a rat anti-mouse VEGFR-2 mAb that is frequently used as a surrogate mAb to ramucirumab for in vivo studies because ramucirumab does not cross-react with mouse VEGFR-2.

[0876] Experimental procedure The activity of huMAb2-3-SPDB-DM4 or the anti-muVEGFR-2, DC-101, was evaluated as single agents or in combination in subcutaneous gastric patient-derived xenografts (PDX), STO-IND-0006, implanted subcutaneously in female SCID mice. The control group was left untreated. The doses of compounds used are given in mg / kg.

[0877] For STO-IND-0006 PDXs, the median tumor burden was 172.5mm 3Mice were randomized into 4 groups (n=10-12) 26 days after tumor implantation, when 100% CI, 0.01 to 0.18. huMAb2-3-SPDB-DM4 was administered at 5 mg / kg on days 24, 31, and 38 after a 3-week IV dosing cycle, and DC-101 antibody was administered at 20 mg / kg on days 25, 28, 32, 35, 39, and 42 after a 3-week IV dosing cycle.

[0878] For the evaluation of antitumor activity, animals were weighed daily and tumors were measured twice weekly by calipers. A dose that caused a 20% weight loss in the nadir (mean of the group) or more than 10% drug deaths was considered an overly toxic dose. Animal body weights included tumor weight. Tumor volume was calculated using the formula mass (mm 3 ) = [length (mm) x width (mm) x width (mm)] / 2. Primary efficacy endpoints were ΔT / ΔC, percent median regression, partial regression, and complete regression (PR and CR).

[0879] The change in tumor volume for each treatment (T) and control (C) is calculated for each tumor by subtracting the tumor volume on the first treatment day (staging day) from the tumor volume on the designated observation day. The median ΔT is calculated for the treatment group and the median ΔC is calculated for the control group. The ratio ΔT / ΔC is then calculated and expressed as a percentage: ΔT / ΔC=(ΔT / ΔC)×100.

[0880] A dose is considered therapeutically active if ΔT / ΔC is less than 40% and highly active if ΔT / ΔC is less than 10%. If ΔT / ΔC is less than 0, the dose is considered highly active and the percentage of regression is dated (Plowman J, Dykes DJ, Hollingshead M, Simpson-Herren L and Alley MC. Human tumor xenograft models in NCI drug development. In:Feibig HH BA, editor.Basel:Karger.;1999 p 101-125).

[0881] Percent tumor regression is defined as the percentage reduction in tumor volume in a treatment group on a particular observation day compared to the volume on day 1 of the first treatment.

[0882] The % regression is calculated for each animal and at a particular time point. The median % regression is then calculated for the group.

number

[0883] Partial Regression (PR): Regression is defined as partial if the tumor volume is reduced to 50% of the tumor volume at the start of treatment.

[0884] Complete regression (CR): Tumor volume = 0 mm 3 Complete regression is achieved with CR (CR is considered when tumor volume cannot be recorded).

[0885] result The results of the experiment on STO-IND-0006 PDX are shown in Figure 1 and Table 1.

[0886] STO-IND-0006 PDXs are aggressive tumors and can be cachectic, inducing weight loss and necessitating premature ethical euthanasia of one mouse in both the control and huMAb2-3-SPDB-DM4 groups prior to study termination. huMAb2-3-SPDB-DM4 and DC-101 were administered at doses below the maximum tolerated dose (MTD) and treatment was well tolerated and did not induce further toxicity.

[0887] huMAb2-3-SPDB-DM4 as a single agent was inactive with a ΔT / ΔC at D46 equal to 60%. DC-101 as a single agent was active with a ΔT / ΔC equal to 33% (p=0.0050 vs. control).

[0888] The combination of huMAb2-3-SPDB-DM4 and DC-101 was highly active with ΔT / ΔC lower than 0% (p<0.0001 vs. control) and 100% tumor regression, 9 / 9 PR and 6 / 9 CR. The effect of the combination of huMAb2-3-SPDB-DM4 and DC-101 was significantly different from the effect of huMAb2-3-SPDB-DM4 alone from days 31 to 46 (end of study for huMAb2-3-SPDB-DM4 group) and from days 31 to 56 to the effect of DC-101 alone.

[0889] In conclusion of the studies in STO-IND-0006 PDX, the combination of huMAb2-3-SPDB-DM4 and DC-101 after three cycles of treatment was highly active in inducing complete regression, despite the lack of activity of huMAb2-3-SPDB-DM4 as a single agent and the modest activity of DC-101 as a single agent.

[0890] [Table 1]

[0891] Example 2: Activity of antibody-drug conjugate huMAb2-3-SPDB-DM4 in combination with anti-muVEGFR-2 antibody DC-101 against subcutaneous gastric patient-derived xenografts SA-STO-0014 in SCID mice. Experimental procedure The activity of huMAb2-3-SPDB-DM4 and DC-101 was evaluated as single agents or in combination in subcutaneously implanted gastric PDX, SA-STO-0014, implanted subcutaneously in female SCID mice. The control group was left untreated. The doses of compounds used are given in mg / kg.

[0892] SA-STO-0014 PDXs had a median tumor burden of 161.5mm 3Mice were randomized into 4 groups (n=10-12) on day 26 after tumor implantation, which reached 100%. huMAb2-3-SPDB-DM4 was administered at 5 mg / kg after 2-week cycles of IV dosing on days 21 and 28. DC-101 antibody was administered at 20 mg / kg after 2-week cycles of IV dosing on days 22, 25, 29, and 32.

[0893] For the conditions for evaluating antitumor activity and toxicity, see above (Example 1).

[0894] result The results of SA-STO-0014 PDX are shown in Figure 2 and Table 2.

[0895] huMAb2-3-SPDB-DM4 and DC-101 treatment was well tolerated and did not induce toxicity.

[0896] huMAb2-3-SPDB-DM4 as a single agent was highly active with a ΔT / ΔC at D42 lower than 0% (p<0.0001 vs. control) and tumor regression of 75%, 7 / 10 PR and 3 / 10 CR. DC-101 as a single agent was active with a ΔT / ΔC equal to 36% (p<0.0001 vs. control).

[0897] The combination of huMAb2-3-SPDB-DM4 and DC-101 was highly active with ΔT / ΔC lower than 0% (p<0.0001 vs. control) and 83% tumor regression, 9 / 10 PR and 6 / 10 CR. The effect of the combination of huMAb2-3-SPDB-DM4 and DC-101 was significantly different from the effect of huMAb2-3-SPDB-DM4 alone at day 53 and significantly different from the effect of DC-101 alone from days 29 to 53.

[0898] In conclusion of the studies in SA-STO-0014 PDX, huMAb2-3-SPDB-DM4 was highly active and the combination of huMAb2-3-SPDB-DM4 with DC-101 after two cycles of treatment allowed for longer sustained high activity compared to huMAb2-3-SPDB-DM4 as a single agent.

[0899] [Table 2]

[0900] Example 3: Efficacy in combination with anti-vascular endothelial growth factor receptor-2 (VEGFR-2) antibodies in gastric patient-derived xenografts (PDX). Cyramza® (ramucirumab) is an anti-VEGFR-2 antibody approved in combination with paclitaxel in secondary gastric cancer. In vivo evaluation of tusamitamab ravtansine (an ADC of the present disclosure) in combination with ramucirumab was performed on gastric PDX, providing compelling data supporting the replacement of paclitaxel with tusamitamab ravtansine in combination with ramucirumab in the clinic. Because ramucirumab cannot bind to mouse VEGFR-2, in vivo studies were performed in patient-derived xenograft (PDX)-implanted mice using a surrogate antibody that recognizes the mouse receptor (anti-muVEGFR-2). Administration of the anti-muVEGFR-2 antibody to these animals was able to inhibit the growth of a range of tumor types, including primary human gastric tumor fragments.

[0901] Experimental procedure Carcinoembryonic antigen-related cell adhesion molecule 5 expression is polarized (i.e., restricted to the apical side of well-differentiated cells) in the epithelial gastric patient-derived xenograft PDX STO-IND-0006. The antitumor activity of tusamitamaravtansine alone and in combination with an anti-muVEGFR-2 antibody was evaluated in SCID mice bearing this PDX after 2-week weekly cycles compared with the paclitaxel / anti-muVEGFR-2 antibody combination.

[0902] Treatment began on day 27 after tumor implantation. Tusamitama ravtansine was administered IV at 5 mg / kg on days 27 and 34. Paclitaxel was administered IV at 20 mg / kg.

[0903] On days 27 and 34, anti-muVEGFR-2 antibody was administered IV at 20 mg / kg on days 28, 31, 35, and 38 (Table 10).

[0904] The primary efficacy endpoint was the percentage change in tumor volume from baseline summarized by the median ratio between treatment and control groups (ΔT / ΔC), where percent median regression was defined as the % reduction in tumor volume in the treatment group on a given observation day compared to the volume on day 1 of treatment, partial regression (PR) where the tumor volume was reduced to at least 50% of the tumor volume at the start of treatment, and tumor volume not recordable (i.e., 14 mm 3 A complete regression (CR) was defined as a response if the progression-free survival (PFS) was less than 100%.

[0905] Interpretation of ΔT / ΔC expressed as a percentage was based on the following criteria: >40%: inactive; <40%: active; <10%: very active; <0%: highly active. Tumor-free survivors (TFS) are defined as the number of animals with undetectable tumors at the end of the study (i.e., 120 days after tumor implantation).

[0906] result STO-IND-0006 PDXs were observed to be cachectic and induce body weight loss (BWL) even in control untreated tumor-bearing mice. Paclitaxel was administered at the maximum tolerated dose (MTD) determined in non-tumor-bearing mice. In STO-IND-0006 tumor-bearing mice, additive BWL was observed for paclitaxel alone or in combinations that individually caused dramatic BWL (>20%) or death. Weight loss was observed from day 48 for all groups treated with paclitaxel or groups in which no activity was observed (control and tusamitamab ravtansine-treated groups). No BWL was observed in groups treated with anti-muVEGFR-2 antibody and the combination of tusamitamab ravtansine with anti-muVEGFR-2 antibody.

[0907] As shown in Table 10, tusamitamab ravtansine alone was inactive with a ΔT / ΔC equal to 91%. Paclitaxel alone was significantly active with a ΔT / ΔC equal to 28% (p=0.0011). Anti-muVEGFR-2 antibody alone was significantly active with a ΔT / ΔC equal to 29% (p=0.0011).

[0908] The combination of tusamitamaravtansine and anti-muVEGFR-2 antibody was significantly more active than both single agents with ΔT / ΔC<0% (p<0.0001) and tumor regressions in 17% of 9 mice and 3 PRs, demonstrating therapeutic synergy in this tusamitamaravtansine-insensitive PDX.

[0909] [Table 3]

[0910] Example 4: Gastric patient-derived xenograft STO-IND-0006 after 3 weekly cycles. Experimental procedure A separate study was performed on the same patient-derived xenografts (PDXs) combining tusamitamab ravtansine with an anti-muVEGFR-2 antibody over a 3-week treatment period. Combination with paclitaxel was not evaluated due to the toxicity of paclitaxel observed in the 2-week treatment study.

[0911] Treatment began 24 days after tumor implantation. Tusamitama ravtansine was administered IV at 5 mg / kg on days 24, 31, and 38. Anti-muVEGFR-2 antibody was administered IV at 20 mg / kg on days 25, 28, 32, 35, 39, and 42 (Table 11).

[0912] result STO-IND-0006 PDXs were cachectic and induced rapid weight loss (BWL) (>20%) or death in individuals for groups where no activity was observed (control and tusamitamab ravtansine-treated groups). No BWL was observed in groups treated with anti-muVEGFR-2 antibody and the combination of tusamitamab ravtansine with anti-muVEGFR-2 antibody.

[0913] As shown in Table 11, tusamitamab ravtansine alone was inactive, with a ΔT / ΔC equal to 60%. Only the anti-muVEGFR-2 antibody was significantly active, with a ΔT / ΔC equal to 33% (p=0.0166).

[0914] The combination of tusamitamab ravtansine and anti-muVEGFR-2 antibody was significantly more active than both single agents with ΔT / ΔC <0% (p<0.0001), 100% tumor regression, 9 PR in 9 mice and 6 CR in 9 mice, demonstrating therapeutic synergy in this tusamitamab ...

Claims

1. An antibody-drug conjugate comprising an anti-CEACAM5 antibody for use in combination with an anti-VEGFR2 antibody to treat cancer.

2. the anti-CEACAM5 antibody comprises a CDR-H1 consisting of SEQ ID NO: 1, a CDR-H2 consisting of SEQ ID NO: 2, a CDR-H3 consisting of SEQ ID NO: 3, a CDR-L1 consisting of SEQ ID NO: 4, a CDR-L2 consisting of the amino acid sequence NTR, and a CDR-L3 consisting of SEQ ID NO: 5; and / or the anti-CEACAM5 antibody comprises a heavy chain variable domain (VH) consisting of SEQ ID NO: 6 and a light chain variable domain (VL) consisting of SEQ ID NO: 7; and / or The antibody-drug conjugate for use according to claim 1 , wherein the anti-CEACAM5 antibody comprises a heavy chain (HC) consisting of SEQ ID NO:8 and a light chain (LC) consisting of SEQ ID NO:

9.

3. at least one chemotherapeutic agent; Optionally, the chemotherapeutic agent is selected from the group consisting of a radioisotope, a protein toxin, a small molecule toxin, and combinations thereof; Optionally, the small molecule toxin is selected from antimetabolites, DNA alkylating agents, DNA cross-linking agents, DNA intercalating agents, anti-microtubule agents, topoisomerase inhibitors, and combinations thereof; Optionally, the chemotherapeutic agent is selected from the group consisting of taxanes, vinca alkaloids, maytansinoids, colchicine, podophyllotoxin, gluseofulvin, and combinations thereof; 3. The antibody-drug conjugate for use according to claim 1 or 2, optionally wherein the maytansinoid is selected from the group consisting of N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N2'-deacetyl-N-2'(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4), and combinations thereof.

4. the anti-CEACAM5 antibody is covalently attached to the at least one chemotherapeutic agent via a cleavable or non-cleavable linker; 4. The antibody-drug conjugate for use according to claim 3, wherein optionally the linker is selected from the group consisting of N-succinimidyl pyridyldithiobutyrate (SPDB), 4-(pyridin-2-yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB), and succinimidyl (N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).

5. 5. The antibody-drug conjugate for use according to any one of claims 1 to 4, comprising a CEACAM5 antibody comprising a heavy chain (HC) consisting of SEQ ID NO: 8 and a light chain (LC) consisting of SEQ ID NO: 9 (huMAb2-3), and covalently linked to N2'-deacetyl-N-2'(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4) via N-succinimidylpyridyldithiobutyrate (SPDB).

6. the antibody-drug conjugate and the anti-VEGFR2 antibody are formulated into a single pharmaceutical composition comprising the antibody-drug conjugate and the anti-VEGFR2 antibody; or The antibody-drug conjugate for use according to any one of claims 1 to 5, wherein the antibody-drug conjugate and the anti-VEGFR2 antibody are formulated in the form of two separate pharmaceutical compositions, (i) one pharmaceutical composition comprising the antibody-drug conjugate, and (ii) the other pharmaceutical composition comprising the anti-VEGFR2 antibody.

7. the antibody-drug conjugate and the anti-VEGFR2 antibody are administered separately or sequentially to a patient in need thereof; 7. The antibody-drug conjugate for use according to claim 6, optionally wherein the antibody-drug conjugate is administered after the anti-VEGFR-2 antibody.

8. the antibody-drug conjugate and the anti-VEGFR-2 antibody are administered for at least one cycle of treatment; Optionally, the antibody-drug conjugate and the anti-VEGFR-2 antibody are administered on day 1 of a first cycle of treatment; Optionally, the antibody-drug conjugate and the anti-VEGFR-2 antibody are administered on day 1 of at least one additional cycle of treatment; 8. The antibody-drug conjugate for use according to any one of claims 1 to 7, optionally wherein the treatment cycle is 2 weeks or 3 weeks.

9. the cancer is a CEACAM5-expressing cancer, and / or the cancer is a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in 50% or more of the cancer cells; or the cancer is a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in more than 1% but less than 50% of cancer cells; 9. The antibody-drug conjugate for use according to any one of claims 1 to 8, wherein optionally the cancer is selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, lung cancer, cervical cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer; optionally, the cancer is selected from gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, and lung cancer.

10. 60 mg / m 2 ~210 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 2 mg / kg to 20 mg / kg; and / or 80 mg / m 2 ~170 mg / m 2 10. The method according to claim 1, wherein the Antibody-drug conjugates for the described uses.

11. The antibody-drug conjugate for use according to any one of claims 1 to 10, wherein the lung cancer is non-squamous non-small cell lung cancer.

12. On day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and / or the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg to 10 mg / kg, and / or On day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 , 100 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the treatment cycle is 2 weeks; and / or On day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the treatment cycle is 3 weeks; and / or On day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the treatment cycle is 3 weeks; and / or the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg and the treatment cycle is 2 weeks; and / or The antibody-drug conjugate for use according to any one of claims 8 to 11, wherein the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg and the treatment cycle is 3 weeks.

13. The cancer is lung cancer, and the antibody-drug conjugate is administered at a concentration of 80 mg / m 2 ~170 mg / m 2 is administered at a dose of Optionally, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 or 150 mg / m 2 is administered at a dose of Optionally, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 or 100 mg / m 2 and the treatment cycle is 2 weeks; Optionally, on day 1 of a first cycle of treatment, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, and the cycle is 2 weeks; Optionally, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 120 mg / m 2 or 150 mg / m 2 and the treatment cycle is 3 weeks; Optionally, on day 1 of a first cycle of treatment, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and the cycle is 3 weeks; Optionally, on day 1 of at least one additional cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 or 150 mg / m 2 is administered at a dose of Optionally, on day 1 of at least one additional cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 or 100 mg / m 2 and the cycle is 2 weeks; Optionally, on day 1 of at least one additional cycle of treatment, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, and the cycle is 2 weeks; Optionally, on day 1 of at least one additional cycle of treatment, the antibody-drug conjugate is administered at a dose of 120 mg / m 2 or 150 mg / m 2 and the cycle lasts for 3 weeks, Optionally, on day 1 of at least one additional cycle of treatment, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and the cycle is 3 weeks; Optionally, day 1 of the first cycle of treatment and day 1 of at least one additional cycle On day 1, the antibody-drug conjugate was administered at a dose of 80 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, and the treatment cycle is 2 weeks; Optionally, on day 1 of the first cycle of treatment and day 1 of at least one additional cycle, the antibody-drug conjugate is administered at a dose of 100 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, and the treatment cycle is 2 weeks; Optionally, on day 1 of the first cycle and day 1 of at least one additional cycle of treatment, the antibody-drug conjugate is administered at a dose of 120 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and the treatment cycle is 3 weeks; Optionally, on day 1 of the first cycle and day 1 of at least one additional cycle of treatment, the antibody-drug conjugate is administered at a dose of 150 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and the treatment cycle is 3 weeks.

14. The cancer is lung cancer in a patient, and the patient has CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more but less than 50% of the cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 80 mg / m 2 and the cycle is 2 weeks; Optionally, on day 1 of an additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg as a subsequent dose, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 80 mg / m as a subsequent dose. 2 and said cycle is 2 weeks.

15. the cancer is lung cancer in a patient, and the patient has CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more but less than 50% of the cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 100 mg / m 2 and the cycle is 2 weeks; Optionally, on day 1 of an additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg as a subsequent dose, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 100 mg / kg as a subsequent dose. 2 and said cycle is 2 weeks.

16. the cancer is lung cancer in a patient, and the patient has CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more but less than 50% of the cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 120 mg / m 2 and the cycle is 3 weeks; Optionally, on day 1 of an additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg as a subsequent dose, and consecutively, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 120 mg / kg as a subsequent dose. 2 and said cycle is 3 weeks.

17. The cancer is lung cancer in a patient, and the patient has CEAC of 2+ or higher in 50% or more of the cancer cells. and (c) a patient has a CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or greater in greater than 1% and less than 50% of cancer cells, or a CEACAM5 immunohistochemical intensity of 2+ or greater in greater than 1% and less than 50% of cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 150 mg / m 2 and the cycle is 3 weeks; Optionally, on day 1 of an additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg as a subsequent dose, and consecutively, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 150 mg / kg as a subsequent dose. 2 and said cycle is 3 weeks.

18. the cancer is gastric cancer or gastroesophageal adenocarcinoma (GEJ) cancer, and the antibody-drug conjugate is administered at a concentration of 80 mg / m 2 ~170 mg / m 2 is administered at a dose of Optionally, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 is administered at a dose of Optionally, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the cycle is 2 weeks; Optionally, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 150 mg / m 2 or 170 mg / m 2 and the cycle is 2 weeks; Optionally, on day 1 of at least one additional cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 or 100 mg / m 2 and the cycle is 2 weeks.

19. 19. The antibody-drug conjugate for use according to claim 18, wherein the anti-VEGFR2 antibody is administered at a dose of 8 mg / kg and the cycle is 2 weeks.

20. On day 1 of the first cycle, the antibody-drug conjugate is administered at a dose of 150 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, and on day 1 of at least one additional cycle of treatment, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, and the treatment cycle is 2 weeks; or On day 1 of the first cycle, the antibody-drug conjugate was administered at a dose of 170 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, and on day 1 of at least one additional cycle of treatment, the antibody-drug conjugate is administered at a dose of 100 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, and the treatment cycle is 2 weeks; and / or The cancer is gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, and the patient has CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more but less than 50% of the cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 150 mg / m 2 and the cycle is 2 weeks; Optionally, on day 1 of an additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg as a subsequent dose, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 80 mg / m as a subsequent dose. 2 and said cycle is 2 weeks.

21. The cancer is gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, and the patient has CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more but less than 50% of the cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 170 mg / m 2 and the cycle is 2 weeks; Optionally, on day 1 of an additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 8 mg / kg as a subsequent dose, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 100 mg / kg as a subsequent dose. 2 and said cycle is 2 weeks.

22. The antibody-drug conjugate was at a concentration of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 135 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and said cycle is 3 weeks; and / or The antibody-drug conjugate was administered at a concentration of 120 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and the cycle is 3 weeks.

23. the anti-VEGFR2 antibody is administered at a dose of 10 mg / kg and the cycle is 3 weeks; and / or On day 1 of the first cycle of treatment and day 1 of at least one additional cycle, the antibody-drug conjugate is administered at a dose of 80 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and the treatment cycle is 3 weeks; or On day 1 of the first cycle of treatment and day 1 of at least one additional cycle, the antibody-drug conjugate is administered at a dose of 100 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and the treatment cycle is 3 weeks; or On day 1 of the first cycle of treatment and day 1 of at least one additional cycle, the antibody-drug conjugate is administered at a dose of 120 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and the treatment cycle is 3 weeks; or On day 1 of the first cycle of treatment and day 1 of at least one additional cycle, the antibody-drug conjugate is administered at a dose of 135 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and the treatment cycle is 3 weeks; or On day 1 of the first cycle of treatment and day 1 of at least one additional cycle, the antibody-drug conjugate is administered at a dose of 150 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg and the treatment cycle is 3 weeks; or On day 1 of the first cycle of treatment and day 1 of at least one additional cycle, the antibody-drug conjugate is administered at a dose of 170 mg / m 2 and the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and the treatment cycle is 3 weeks.

24. The cancer is gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, and the patient has CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more but less than 50% of the cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and said cycle is 3 weeks; and / or On day 1 of the additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg as a subsequent dose, followed by the antibody-drug combination comprising an anti-CEACAM5 antibody. The conjugate was administered at a subsequent dose of 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 150 mg / m 2 or 170 mg / m 2 and said cycle is 3 weeks.

25. The cancer is gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, and the patient has CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more but less than 50% of the cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 80 mg / m 2 and the cycle is 3 weeks; and / or On day 1 of the additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg as a subsequent dose, and subsequently the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 80 mg / kg as a subsequent dose. 2 and said cycle is 3 weeks.

26. The cancer is gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, and the patient has CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more but less than 50% of the cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 100 mg / m 2 and said cycle is 3 weeks; and / or On day 1 of the additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg as a subsequent dose, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 100 mg / kg as a subsequent dose. 2 and said cycle is 3 weeks.

27. The cancer is gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, and the patient has CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more but less than 50% of the cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 120 mg / m 2 and said cycle is 3 weeks; and / or On day 1 of the additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg as a subsequent dose, and subsequently the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 120 mg / kg as a subsequent dose. 2 and said cycle is 3 weeks.

28. The cancer is gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, and the patient has CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more but less than 50% of the cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 135 mg / m 2 and the cycle is 3 weeks.

25. The antibody-drug conjugate for use according to any one of claims 18 and 22 to 24.

29. On day 1 of the additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg as a subsequent dose, and subsequently the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 135 mg / m as a subsequent dose. 2 and said cycle is 3 weeks.

30. The cancer is gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, and the patient has CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more but less than 50% of the cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 150 mg / m 2 and said cycle is 3 weeks; and / or On day 1 of the additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg as a subsequent dose, and subsequently the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 150 mg / kg as a subsequent dose. 2 and said cycle is 3 weeks.

31. The cancer is gastric cancer (GC) or gastroesophageal adenocarcinoma (GEJ) cancer in a patient, and the patient has CEACAM5-positive cancer with a CEACAM5 immunohistochemical intensity of 2+ or higher in 50% or more of the cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% or more but less than 50% of the cancer cells, and on day 1 of a first cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 170 mg / m 2 and said cycle is 3 weeks; and / or On day 1 of the additional cycle, the anti-VEGFR-2 antibody is administered at a dose of 10 mg / kg as a subsequent dose, and subsequently, the antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of 170 mg / kg as a subsequent dose. 2 and said cycle is 3 weeks.

32. tusamitamavutansine; and / or The antibody-drug conjugate for use according to any one of claims 1 to 31, wherein the anti-VEGFR-2 antibody is ramucirumab.

33. A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 1 to 5, an anti-VEGFR2 antibody, and a pharmaceutically acceptable excipient.

34. A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 1 to 5, ramucirumab, and a pharmaceutically acceptable excipient.

35. A pharmaceutical composition comprising tusamitamaravtansine, ramucirumab, and a pharmaceutically acceptable excipient.

36. A kit comprising: (i) a pharmaceutical composition of the antibody-drug conjugate of any one of claims 1 to 5 and a pharmaceutically acceptable excipient; and (ii) a pharmaceutical composition comprising an anti-VEGFR2 antibody and a pharmaceutically acceptable excipient.

37. A pharmaceutical composition according to any one of claims 33 to 35 or a kit according to claim 36 for use in treating cancer.

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