Antibody combinations including anti-CEACAM5 antibody-drug conjugate, anti-VEGFR-2 antibody, and anti-PD1 / PD-L1 antibody.

Abstract

This disclosure relates to a combination of (i) an antibody-drug conjugate (ADC) containing an anti-CEACAM5 antibody, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or an anti-PD-L1 antibody for use in the treatment of cancer.

Description

[Technical Field]

[0001] References to sequence listings This application includes a sequence listing submitted electronically in .xml format, which is incorporated herein by reference in its entirety. The above .xml copy, created on January 23, 2023, is named PI022904.WO SANOFI(S323)LISTING SEQUENCE.xml.

[0002] This disclosure relates to the field of therapeutic treatment for cancers expressing CEACAM5. A particular aspect of this disclosure relates to combination therapies for treating cancers including lung cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, and pancreatic cancer, with an immunoconjugate including a VEGFR-2 inhibitor, an anti-PD-1 or anti-PD-L1 agent, and an anti-CEACAM5 antibody. [Background technology]

[0003] According to the World Health Organization, cancer is the second leading cause of death globally, accounting for approximately 9.6 million deaths in 2018. Therefore, there remains a continued need to provide improved drug combinations and regimens for the treatment of cancer.

[0004] Carcinoembryonic antigens (CEAs) are glycoproteins involved in cell adhesion. CEAs were first identified in 1965 as proteins normally expressed by the fetal intestine during the first six months of pregnancy (Gold and Freedman, J Exp Med, 121, 439, 1965), and have been found in pancreatic, liver, and colon cancers. The CEA family belongs to the immunoglobulin superfamily. The CEA family, consisting of 18 genes, is subdivided into two protein subgroups: the carcinoembryonic antigen-associated cell adhesion molecule (CEACAM) subgroup and the pregnancy-specific glycoprotein subgroup (Kammerer & Zimmermann, BMC Biology 2010, 8:12).

[0005] 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 small number of normal epithelial tissues, such as columnar and goblet cells of the colon, mucocele cells of the stomach, and squamous epithelial 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). Therefore, CEACAM5 may constitute a suitable treatment target for tumor-specific targeted approaches such as antibody-drug conjugates (ADCs).

[0006] Antibody-drug conjugates (ADCs) contain antibodies conjugated to chemotherapeutic agents such as cytotoxic agents, growth inhibitors, or cell proliferation suppressants. The chemotherapeutic agent is typically conjugated to the antibody via a chemical linker. These antibody-drug conjugates (ADCs) hold great potential in cancer chemotherapy, enabling the selective delivery of potent chemotherapeutic agents targeting cancer cells, resulting in improved efficacy, reduced systemic toxicity, and improved pharmacokinetics, pharmacodynamics, and distribution compared to conventional chemotherapy. To date, hundreds of diverse antibody-drug conjugates (ADCs) have been developed for various cancers, some of which are approved for human use.

[0007] The mechanism of action of antibody-drug conjugates (ADCs) begins with their binding to specific antigens that are well expressed on tumor cells, in order to achieve selective and efficient internal distribution of the drug. Selectively targeting tumor cells with potent cytotoxic agents using ADCs is now demonstrated to be an effective strategy for treating cancer, as evidenced by the recent approvals of brentuximab vedotin for the treatment of Hodgkin's lymphoma and trastuzumab emtansine (T-DM1) for the treatment of relapsed metastatic HER2-positive breast cancer (Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012;30(18):2183-9; Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J (Med. 2012;19:1783-91). Many other malignant diseases with unmet medical needs, such as solid tumors and cancers, may benefit from such treatment options.

[0008] An international patent application, published as International Publication No. 2014 / 079886, discloses an antibody that binds to the A3-B3 domains of human and cynomolgus monkey (Macaca fascicularis) CEACAM5 protein and does not significantly cross-react with human CEACAM1, human CEACAM6, human CEACAM7, human CEACAM8, cynomolgus monkey (Macaca fascicularis) CEACAM1, cynomolgus monkey (Macaca fascicularis) CEACAM6, and cynomolgus monkey (Macaca fascicularis) CEACAM8. This antibody is conjugated to a meitansinoid, thereby enabling IC50 We provided an antibody-drug conjugate with a value of 1 nM or less that exhibits significant cytotoxic activity against MKN45 human gastric cancer cells.

[0009] Disclosed in International Publication No. 2014 / 079886, huMAb2-3-SPDB-DM4 is an immunoconjugate (antibody-drug conjugate, ADC) containing a humanized anti-CEACAM5 antibody conjugated to a meitansinoid derivative 4 (DM4), a potent mitotic inhibitor that inhibits microtubule assembly. DM4 is stable in plasma and covalently binds to the antibody via an optimized linker SPDB [N-succinimidyl 4-(2-pyridyldithio)-butanoic acid] that is cleavable intracellularly. After binding and internalization in target cancer cells, huMAb2-3-SPDB-DM4 is degraded, releasing cytotoxic DM4 metabolites. huMAb2-3-SPDB-DM4 is also known as tusamitamabrabutansin.

[0010] International Publication No. 2020 / 161214, whose entire contents are incorporated herein by reference, discloses the use of anti-CEACAM5 immunoconjugates (ADCs) for the treatment of lung cancer.

[0011] Vascular endothelial growth factor (VEGF) is considered a key pro-angiogenic 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 numerous cell types, including cancer cells, tumor stroma, and invasive myeloid cells, leading to excessive endothelial cell proliferation and loss of mechanisms for inducing angiogenesis.

[0012] 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 cancer. Autophosphorylation of VEGFR-2 kinase is one of the earliest events upon VEGF binding and is crucial for kinase activation 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 inhibits its activation. Ramucirumab is approved for use as monotherapy in hepatocellular carcinoma; as monotherapy in metastatic gastric cancer, gastroesophageal junction adenocarcinoma (GEJ), or metastatic colorectal cancer, and in combination with chemotherapy; and in combination with chemotherapy for metastatic non-small cell lung cancer.

[0013] Immune checkpoint inhibitors (ICIs), administered alone or in combination with other anticancer therapies, have demonstrated activity to treat a variety of tumor types, including non-small cell lung cancer (NSCLC), and possess a manageable safety profile when combined with cytotoxic agents. Pembrolizumab (KEYTRUDA®), a humanized IgG4 monoclonal antibody against programmed cell death protein 1 (PD-1), is indicated as a monotherapy for first-line treatment in NSCLC patients expressing programmed cell death ligand 1 protein (PD-L1).

[0014] Lung cancer is one of the most commonly diagnosed cancers and is a leading cause of cancer-related mortality worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and includes several histopathological subtypes, of which adenocarcinoma (60%) and squamous cell carcinoma (15%) are the most common.

[0015] The majority of NSCLC patients are in an advanced stage at diagnosis. The median overall survival (OS) for these patients is 8 to 12 months, and the 5-year survival rate was approximately 25% in 2015. Approximately 15% to 20% of NSCLC patients have tumors with important genomic alterations suitable for targeted therapy, including epidermal growth factor receptor (EGFR) mutations and ROS receptor tyrosine kinase 1 (ROS1) and anaplastic lymphoma kinase (ALK) rearrangements.

[0016] Until recently, chemotherapy was the only treatment option available for advanced or metastatic NSQ NSCLC lacking targetable mutations. Systemic therapy with platinum-based doublet regimens, with or without maintenance therapy, was the current first-line treatment for patients with advanced NSCLC. The standard second-line treatment for NSCLC is docetaxel, and its activity has been found to be enhanced by the addition of ramucirumab.

[0017] More recently, immunotherapy has ushered in a new paradigm for the treatment of NSCLC. In particular, monoclonal antibodies targeting the programmed death-1 receptor (PD-1) / PD ligand-1 (PD-L1) pathway have emerged as a potent new treatment tool in several clinical trials.

[0018] Three drugs targeting the PD-1 pathway (nivolumab, pembrolizumab, and cemiprimab) are approved for the treatment of both chemotherapy-naive and / or previously treated advanced-stage NSCLC, but only a small fraction of patients (20%–30%) respond to these treatments. Despite improved outcomes with new treatment lines including anti-PD-1 / PD-L1 antibodies, the disease often progresses. Therefore, additional treatment approaches are needed to improve clinical efficacy and health-related quality of life (HRQOL) in patients with advanced / metastatic NSCLC.

[0019] Criscitiello et al. (J Hematol Oncol, 2021) have disclosed a combination of tusamitamaburabutansine and pembrolizumab or a combination of tusamitamaburabutansine and ramucirumab for the treatment of NSQ NSCLC.

[0020] Gazzah et al. (Annals of Oncology, 2022) disclose the combination of tusamitamaburabutansine and pembrolizumab or tusamitamaburabutansine and ramucirumab for the treatment of NSQ NSCLC. 5-150 mg / m² 2 The dosage was tested, and the maximum tolerable dose was 100 mg / m² every two weeks. 2 I confirmed that this was the case.

[0021] In trial NCT04524689-CARMEN-LC05, dated December 12, 2022, the combination of tusamitamaburabtansine and pembrolizumab for the treatment of NSQ NSCLC was disclosed. Administration of an ADC in combination with pembrolizumab every three weeks was disclosed. Data were not disclosed.

[0022] The study NCT04394624-SAR408701-CARMEN-LC04 (January 9, 2023) in pre-conditioned patients with non-squamous non-small cell lung cancer (NSQ NSCLC) discloses the combination of tusamitamab tansine and ramucirumab for the treatment of NSQ NSCLC. Administration of an ADC in combination with ramucirumab every two weeks is disclosed. Data are not disclosed.

[0023] Paz-Ares et al., Poster, 2022 (Oncologypro.esmo.org) discloses a combination of tusamitamaburabutansine and pembrolizumab for the treatment of NSQ NSCLC. Administration of an ADC in combination with pembrolizumab every three weeks is disclosed. Treatment with tusamitamaburabutansine and pembrolizumab in NSQ NSCLC patients with CEACAM5 expression ≥2 in ≥50% of tumor cells (measured by IHC) is disclosed. Data are not disclosed.

[0024] VEGFR-2 and PD-L1 as combination therapies enhance the immune activation signature (Li Y, Amaladas N, O'Mahony M, et al. Treatment with a VEGFR-2 antibody results in intra-tumor immune modulation and enhances anti-tumor efficacy of PD-L1 blockade in syngeneic murine tumor models. PLoS ONE. 2022;17(7):e0268244. Published July 18, 2022, Doi:10.1371 / journal.pone.0268244).

[0025] Positive results from Phase III trials in non-small cell lung cancer (adenocarcinoma), renal cell carcinoma, and hepatocellular carcinoma demonstrate that the combination of PD-1 / PD-L1 antibodies and anti-VEGF agents significantly improved clinical outcomes compared to standard treatments (Hack SP, Zhu AX, Wang Y. Augmenting Anticancer Immunity Through Combined Targeting of Angiogenic and PD-1 / PD-L1 Pathways: Challenges and Opportunities. Front Immunol..2020;11:598877. Published November 5, 2020. doi:10.3389 / fimmu.2020.598877). [Overview of the project] [Problems that the invention aims to solve]

[0026] While treatment for advanced non-small cell lung cancer (NSCLC) has improved in recent years, there is still a need for new treatment methods that are effective as the disease progresses.

[0027] The anticancer efficacy of the combination of PD-1 / PD-L1 antibodies and anti-VEGF antibodies needs to be improved.

[0028] There is a need to improve the anti-cancer response of the combination of PD-1 / PD-L1 antibodies and anti-VEGF antibodies against lung cancer.

[0029] There is a need to improve the anti-cancer response of the combination of PD-1 / PD-L1 antibodies and anti-VEGF antibodies against non-squamous non-small cell lung cancer.

[0030] There is a need to improve the anti-cancer response of the combination of PD-1 / PD-L1 antibodies and anti-VEGF antibodies against gastric cancer.

[0031] The present invention aims to satisfy all or some of those needs. [Means for solving the problem]

[0032] According to one of its purposes, this disclosure relates to a combination of (i) an antibody-drug conjugate (ADC) containing an anti-CEACAM5 antibody, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or an anti-PD-L1 antibody for use in the treatment of cancer.

[0033] VEGFR-2 inhibitors may be selected from among VEGFR-2 inhibitors and receptor tyrosine kinase inhibitors.

[0034] As shown in the Examples section, in a mouse model of CEACAM5 gastric cancer, an anticancer synergistic effect was observed with (i) an antibody-drug conjugate (ADC) containing an anti-CEACAM5 antibody, e.g., huMAb2-3-SPDB-DM4, (ii) an anti-VEGFR-2 antibody, and (iii) a triplet combination containing an anti-PD-1 antibody or PD-L1 antibody. Compared to ADChuMAb2-3-SPDB-DM4 alone and the standard treatment regimen (consisting of co-administration of anti-muVEGFR-2 mAb, DC101 + anti-muPD-1 mAb), the triplet combination resulted in permanent and complete regression. Furthermore, the triplet combination yielded a longer-lasting and more robust response with durable complete regression compared to both duplex combinations (huMAb2-3-SPDB-DM4 with anti-muVEGFR-2 mAb or huMAb2-3-SPDB-DM4 with anti-muPD1 mAb).

[0035] This disclosure relates to an anti-CEACAM5 antibody, a chemotherapeutic agent for treating cancer, and an anti-VEGFR-2 antibody for use in combination with an antibody-drug conjugate (ADC) containing an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0036] This disclosure relates to an anti-CEACAM5 antibody and an anti-PD-L1 antibody or anti-PD-L1 antibody for use in combination with an antibody-drug conjugate (ADC) comprising a chemotherapeutic agent for treating cancer and a VEGFR-2 inhibitor.

[0037] In some embodiments, the present disclosure relates to antibody-drug conjugates (ADCs) comprising a VEGFR-2 inhibitor and an anti-CEACAM5 antibody for use in combination with an anti-PD-1 antibody or an anti-PD-L1 antibody to treat cancer.

[0038] In this disclosure, the terms "antibody-drug conjugate containing an anti-CEACAM5 antibody" and "ADC" are used interchangeably.

[0039] In some embodiments, the ADC, VEGFR-2 inhibitor, and anti-PD-1 antibody or anti-PD-L1 antibody may each be present in an effective amount.

[0040] In some embodiments, the use may be for subjects that require it.

[0041] In some embodiments, cancer can be CEACAM5-positive cancer, meaning that cancer (or tumor) cells express CEACAM5.

[0042] In a particular embodiment, the anti-CEACAM5 antibody includes CDR-H1 having the amino acid sequence of SEQ ID NO: 1, CDR-H2 having the amino acid sequence of SEQ ID NO: 2, CDR-H3 having the amino acid sequence of SEQ ID NO: 3, CDR-L1 having the amino acid sequence of SEQ ID NO: 4, CDR-L2 having the amino acid sequence NTR, and CDR-L3 having the amino acid sequence of SEQ ID NO: 5.

[0043] In some embodiments, the anti-CEACAM5 antibody may include a variable heavy chain domain (VH) consisting of SEQ ID NO: 6 and a variable light chain domain (VL) consisting of SEQ ID NO: 7.

[0044] In some embodiments, the anti-CEACAM5 antibody may be tusamitamab.

[0045] In some embodiments, the antibody-drug conjugate may comprise at least one chemotherapeutic agent.

[0046] In some embodiments, the chemotherapeutic agent may be selected from the group consisting of radioisotopes, protein toxins, low molecular weight toxins, and combinations thereof.

[0047] In some embodiments, the low molecular weight toxin may be selected from antimetabolites, DNA alkylating agents, DNA crosslinking agents, DNA intercalating agents, antimicrotubule agents, topoisomerase inhibitors, and combinations thereof.

[0048] In certain embodiments, the antimicrotubule agent is selected from taxanes, vinca alkaloids, maytansinoids, colchicine, podophyllotoxin, griseofulvin, and any combination thereof.

[0049] In some embodiments, the cytotoxic agent may be a meitansinoid.

[0050] In some embodiments, the maytansinoid may be selected from N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine (DM1) or N2'-deacetyl-N2'(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4) and combinations thereof.

[0051] In some embodiments, an anti-CEACAM5 antibody may be covalently bound to at least one chemotherapeutic agent via a cleavable or non-cleavable linker.

[0052] In some embodiments, the linker may be selected from N-succinimidylpyridyl dithiobutyrate (SPDB), 4-(-iridin-2-yldisulfanyl)-2-sulfobutyrate (sulfo-SPDB), and succinimidyl (N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).

[0053] In some embodiments, an anti-CEACAM5 antibody may be covalently bound to at least one chemotherapeutic agent via a cleavable linker, the linker being selected from N-succinimidylpyridyl dithiobutyrate (SPDB), 4-(pyridine-2-yldisulfanyl)-2-sulfobutyrate (sulfo-SPDB), and succinimidyl (N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).

[0054] 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 are covalently bound to N2'-deacetyl-N-2'(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4) via N-succinimidylpyridyl dithiobutyrate (SPDB).

[0055] In certain embodiments, the antibody-drug conjugate is characterized by a drug-antibody ratio (DAR) in the range of 1 to 10.

[0056] In some embodiments, the antibody-drug conjugate may be tusamitamabrabutansine.

[0057] In some embodiments, the cancer may be a CEACAM5-expressing cancer.

[0058] In certain embodiments, cancer expresses CEACAM5 at a moderate or high intensity, as defined by immunohistochemistry.

[0059] In some embodiments, the cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% to less than 50% of cancer cells as measured by immunohistochemistry. Such cancers express CEACAM5 at a moderate intensity.

[0060] In some embodiments, the cancer may be a CEACAM5-positive cancer, where more than 50% of the cancer cells have a CEACAM5 immunohistochemical intensity of 2+ or higher as measured by immunohistochemistry. Such cancers express CEACAM5 at high intensity.

[0061] In some embodiments, the cancer is selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, gastroesophageal junction adenocarcinoma (GEJ) cancer, esophageal cancer, lung cancer, cervical cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., bile duct cancer), prostate cancer, neuroendocrine cancer, and skin cancer.

[0062] In some embodiments, the cancer may be selected from gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, esophageal cancer, pancreatic cancer, and lung cancer.

[0063] In some embodiments, the cancer is gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, or esophageal cancer.

[0064] In some embodiments, the cancer may be pancreatic cancer.

[0065] In some embodiments, the cancer may be lung cancer.

[0066] In some embodiments, the lung cancer may be non-squamous non-small cell lung cancer (NSQ NSCLC).

[0067] In some embodiments, non-squamous non-small cell lung cancer may be advanced or metastatic NSQ NSCLC.

[0068] In certain embodiments, non-squamous non-small cell lung cancer has NSQ NSCLC without epidermal growth factor receptor (EGFR) sensitization mutations, v-raf mouse sarcoma virus oncogene homolog B1 (BRAF) mutations, or anaplastic lymphoma kinase / c-ros oncogene 1 (ALK / ROS) modifications.

[0069] In some embodiments, the combination may be administered to subjects who have not received prior systemic chemotherapy for cancer treatment.

[0070] In some embodiments, (i) an antibody-drug conjugate, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be formulated in the form of three distinct pharmaceutical compositions, where (a) the first pharmaceutical composition may comprise an antibody-drug conjugate, (b) the second pharmaceutical composition may comprise a VEGFR-2 inhibitor, and (c) the third pharmaceutical composition may comprise an anti-PD-1 antibody or anti-PD-L1 antibody.

[0071] In some embodiments, (i) an antibody-drug conjugate, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered simultaneously, separately, or sequentially to a subject requiring it.

[0072] In some embodiments, (i) an antibody-drug conjugate, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered sequentially to a subject requiring it.

[0073] In some embodiments, the VEGFR-2 inhibitor may be administered before the antibody-drug conjugate.

[0074] In some embodiments, the antibody-drug conjugate may be administered before the anti-PD-1 antibody or after the anti-PD-L1 antibody.

[0075] In some embodiments, (i) an antibody-drug conjugate, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered for at least one cycle of treatment.

[0076] In some embodiments, (i) an antibody-drug conjugate, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered on day 1 of the first cycle of treatment.

[0077] In some embodiments, (i) an antibody-drug conjugate, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered on day 1 of at least one additional cycle of treatment.

[0078] In some embodiments, (i) an antibody-drug conjugate, (ii) an anti-VEGFR-2 antibody, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered on day 1 of the first and at least one additional cycle of treatment.

[0079] In some embodiments, the treatment cycle can be about two, three, or four weeks.

[0080] In some embodiments, the treatment cycle can be about two or three weeks.

[0081] In some embodiments, the treatment cycle can be about two weeks.

[0082] In some embodiments, the treatment cycle can be about three weeks.

[0083] In some embodiments, the antibody-drug conjugate can be administered at a dose of 80 mg / m 2 ~170 mg / m 2 or at a dose of 80 mg / m 2 ~150 mg / m 2 or at a dose of 100 mg / m 2 ~120 mg / m 2

[0084] In some embodiments, the antibody-drug conjugate can be administered at a dose of 150 mg / m 2 or 120 mg / m 2

[0085] In some embodiments, the VEGFR-2 inhibitor can be administered at a dose of 2 mg / kg to 20 mg / kg, 4 mg / kg to 18 mg / kg, 5 mg / kg to 16 mg / kg, 6 mg / kg to 15 mg / kg, 7 mg / kg to 14 mg / kg, 7.5 mg / kg to 13 mg / kg, 8 mg / kg to 12 mg / kg, 8.5 mg / kg to 10 mg / kg.

[0086] In some embodiments, a VEGFR-2 inhibitor such as an anti-VEGFR-2 antibody can be administered at a dose of 6 mg / kg to 10 mg / kg, or at a dose of 8 mg / kg to 10 mg / kg, or at a dose of 6 mg / kg, or at a dose of 8 mg / kg, or at a dose of 10 mg / kg.

[0087] ​In some embodiments, the VEGFR-2 inhibitor may be administered at a dose of 2 mg / kg or 4 mg / kg.

[0088] In some embodiments, the VEGFR-2 inhibitor may be administered in doses of 5 mg / kg to 10 mg / kg.

[0089] In some embodiments, VEGFR-2 inhibitors may be administered in doses of 7.5 mg / kg to 15 mg / kg.

[0090] In some embodiments, the VEGFR-2 inhibitor may be administered in doses of 2, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg.

[0091] In some embodiments, the VEGFR-2 inhibitor may be administered in doses of 2, 4, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, or 15 mg / kg.

[0092] In some embodiments, the VEGFR-2 inhibitor may be administered every two weeks.

[0093] In some embodiments, the VEGFR-2 inhibitor may be administered every three weeks.

[0094] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody may be administered in doses of 100 mg to 1000 mg, 150 mg to 800 mg, 200 mg to 600 mg, 240 mg to 500 mg, or 300 mg to 400 mg.

[0095] In various embodiments, anti-PD-1 antibody or anti-PD-L1 antibody may be administered in doses of approximately 100, 150, 200, 220, 240, 260, 280, 300, 350, 400, 500, 600, 700, 800, 900, or approximately 1000 mg.

[0096] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody may be administered in doses of 150 mg to 400 mg, 150 mg to 300 mg, or 200 mg.

[0097] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody may be administered in doses of 1-10 mg / kg, 2-8 mg / kg, or 3-6 mg / kg.

[0098] In various embodiments, anti-PD-L1 antibodies or anti-PD-L1 antibodies may be administered in doses of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg.

[0099] In some embodiments, an anti-PD-1 antibody or anti-PD-L1 antibody may be administered at a dose of approximately 3 mg / kg.

[0100] In some embodiments, an anti-PD-1 antibody or an anti-PD-L1 antibody may be administered every two weeks.

[0101] In some embodiments, an anti-PD-1 antibody or an anti-PD-L1 antibody may be administered every three weeks.

[0102] In some embodiments, an anti-PD-1 antibody or an anti-PD-L1 antibody may be administered every four weeks.

[0103] In some embodiments, the antibody-drug conjugate is 120 mg / m². 2 ~150mg / m 2 VEGFR-2 inhibitors may be administered in doses of 6 mg / kg to 10 mg / kg, and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of 200 mg.

[0104] In some embodiments, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 120 mg / m². 2 or 150 mg / m² 2 It may be administered in doses of [specify dose], and the treatment cycle may be 3 weeks.

[0105] In some embodiments, on day 1 of the first cycle of treatment, the antibody-drug conjugate is administered at a dose of 150 mg / m². 2 It may be administered in doses of [specify dose], and the treatment cycle may be 3 weeks.

[0106] In some embodiments, the antibody-drug conjugate is administered at 150 mg / m² on day 1 of the first cycle of treatment. 2 The antibody-drug conjugate may be administered at a dose of 120 mg / m² on day 1 of at least one additional cycle of treatment. 2 It may be administered in doses of [specify dose], and the treatment cycle may be 3 weeks.

[0107] In some embodiments, on day 1 of the first cycle of treatment, the VEGFR-2 inhibitor may be administered at a dose of 6 mg / kg to 10 mg / kg, and the cycle may be 3 weeks long.

[0108] In some embodiments, the VEGFR-2 inhibitor 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 long.

[0109] In some embodiments, on day 1 of a subsequent (or additional) cycle of treatment, the VEGFR-2 inhibitor may be administered at a dose of 6 mg / kg to 10 mg / kg, and the cycle may be 3 weeks long.

[0110] In some embodiments, on day 1 of the subsequent cycle following treatment, the VEGFR-2 inhibitor may be administered at doses of 6 mg / kg, 8 mg / kg, or 10 mg / kg, and the cycle may be 3 weeks long.

[0111] In some embodiments, the VEGFR-2 inhibitor may be administered at a dose of 10 mg / kg on day 1 of the first cycle of treatment, and at least one additional cycle of treatment may be administered at a dose of 10 mg / kg, 8 mg / kg, or 6 mg / kg, with the treatment cycle being 3 weeks.

[0112] In some embodiments, an anti-PD-1 antibody or anti-PD-L1 antibody may be administered at a dose of 200 mg on day 1 of the first treatment cycle and at least one subsequent cycle, and the treatment cycle may be 3 weeks.

[0113] In some embodiments, on the first day of the first cycle of treatment and on the first day of at least one additional cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg. The treatment cycle may be 3 weeks.

[0114] In some embodiments, on day 1 of the first cycle of treatment, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, on day 1 of at least one subsequent cycle of treatment, (i) antibody-drug conjugates may be administered at a dose of 120 mg / m². 2 or 150 mg / m² 2 (ii) VEGFR-2 inhibitors may be administered in doses of 6 mg / kg, 8 mg / kg or 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of 200 mg. The treatment cycle may be 3 weeks.

[0115] In some embodiments, on day 1 of the first cycle of treatment, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, on day 1 of at least one subsequent cycle of treatment, (i) antibody-drug conjugates may be administered at a dose of 120 mg / m². 2(ii) VEGFR-2 inhibitors may be administered at doses of 6 mg / kg or 8 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at doses of 200 mg, with treatment cycles of 3 weeks.

[0116] In some embodiments, on day 1 of the first cycle of treatment, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) a VEGFR-2 inhibitor may be administered at a dose of 10 mg / kg, (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered at a dose of 200 mg, on day 1 of at least one subsequent cycle of treatment, (i) an antibody-drug conjugate at 120 mg / m² 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 6 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0117] In some embodiments, the cancer may be lung cancer, and the cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity of 2+ or higher in more than 50% of cancer cells or a CEACAM5 immunohistochemical intensity of 2+ or higher in 1% to less than 50% of cancer cells, and on day 1 of the first cycle (i) the antibody-drug conjugate is 150 mg / m² 2 (ii) an anti-VEGFR-2 inhibitor may be administered at a dose of 10 mg / kg, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered at a dose of 200 mg, with a cycle of 3 weeks.

[0118] In some embodiments, on day 1 of the subsequent cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a subsequent dose of 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a subsequent dose of 200 mg, with a cycle of 3 weeks.

[0119] In some embodiments, on day 1 of the subsequent cycle, (i) the antibody-drug conjugate is administered at 120 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered in a subsequent dose of 6 or 8 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in a subsequent dose of 200 mg, with a cycle of 3 weeks.

[0120] In some embodiments, the VEGFR-2 inhibitor may be administered before the antibody-drug conjugate, and the antibody-drug conjugate may be administered before the anti-PD-1 antibody or the anti-PD-L1 antibody.

[0121] In some embodiments, the VEGFR-2 inhibitor is selected from among anti-VEGFR-2 antibodies and receptor tyrosine kinase inhibitors.

[0122] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0123] In some embodiments, the anti-VEGFR-2 antibody may be ramucirumab.

[0124] In some embodiments, the receptor tyrosine kinase inhibitor is aflibercept or nintedanib.

[0125] In some embodiments, the anti-PD-1 antibody may be selected from the group consisting of pembrolizumab, nivolumab, semiprimab, cintilimab, dostarimab, tislerizumab, retifanlimab, and tripalimab.

[0126] In some embodiments, the anti-PD-1 antibody may be pembrolizumab or cintilimab.

[0127] In some embodiments, the anti-PD-L1 antibody may be selected from the group consisting of atezolizumab, avelumab, and durvalumab.

[0128] In some embodiments, (i) the antibody-drug conjugate may be tusamitamabrabutansine, (ii) the anti-VEGFR-2 antibody may be ramucirumab, and (iii) the anti-PD-1 antibody may be pembrolizumab.

[0129] In one of its purposes, this disclosure relates to a pharmaceutical composition comprising (i) an antibody-drug conjugate disclosed herein, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody, and a pharmaceutically acceptable excipient.

[0130] In some embodiments, the VEGFR-2 inhibitor in the pharmaceutical compositions disclosed herein may be an anti-VEGFR-2 antibody.

[0131] In some embodiments, the anti-VEGFR-2 antibody in the pharmaceutical compositions disclosed herein may be ramucirumab.

[0132] In some embodiments, the anti-PD-1 antibody in the pharmaceutical compositions disclosed herein may be pembrolizumab.

[0133] In accordance with one of its purposes, this disclosure relates to (i) pharmaceutical compositions comprising an antibody-drug conjugate and a pharmaceutically acceptable excipient as disclosed herein, (ii) pharmaceutical compositions comprising a VEGFR-2 inhibitor and a pharmaceutically acceptable excipient, and (iii) kits comprising a pharmaceutical composition comprising an anti-PD-1 antibody or an anti-PD-L1 antibody and a pharmaceutically acceptable excipient.

[0134] In some embodiments, the kits disclosed herein may contain a VEGFR-2 inhibitor that is an anti-VEGFR-2 antibody.

[0135] In some embodiments, the anti-VEGFR-2 antibody in the kits disclosed herein may be ramucirumab.

[0136] According to one of its purposes, this disclosure relates to a pharmaceutical composition or a kit disclosed herein for use in treating cancer.

[0137] According to one of its purposes, this disclosure relates to the use of (i) antibody-drug conjugates disclosed herein, (ii) VEGFR-2 inhibitors, and (iii) combinations of anti-PD-1 antibodies or anti-PD-L1 antibodies for the manufacture of pharmaceutical compositions or kits for the treatment of cancer.

[0138] According to one of its purposes, the present disclosure relates to a method for treating cancer in a subject in need thereof, the method comprising at least the step of sequentially administering (i) an antibody-drug conjugate disclosed herein, (ii) a VEGFR-2 inhibitor, and (iii) a combination of an anti-PD-1 antibody or an anti-PD-L1 antibody. [Brief explanation of the drawing]

[0139] [Figure 1] The decision tree for the triplet cohort of tsusamitamabrabutansine is shown. [Figure 2] This represents a graphical explanation of the test design. [Figure 3]Figures 3A-3C show the activity of the immunoconjugate huMAb2-3-SPDB-DM4 (Figures 3A-C - dashed lines), the anti-muPD-1 antibody (Figure 3B - dashed / dotted lines), and the anti-muVEGFR-2 antibody, DC-101 (Figure 3A - dashed / dotted lines), used as a single agent, a double combination (Figures 3A-B - diamond shapes), or a triple combination (Figure 3C - diamond shapes) in a subcutaneous colon MC38 syngeneic tumor model in 57BL / 6 mice. huMAb2-3-SPDB-DM4 was administered as a single IV dose on day 10, followed by a 25 mg / kg dose (indicated by a black inverted triangle - TT ADC). Anti-muPD-1 antibody was administered at 10 mg / kg after an IV dose on days 10, 14, and 17, and anti-muVEGFR-2 antibody was administered at 20 mg / kg after an IV dose on days 10, 14, and 17 (indicated by a gray inverted triangle - TT DC101 mAb or TT antibody-mPD1 mAb). The control group consisted of untreated mice (gray line). The curves showing the change in tumor volume by treatment group represent the median ± median absolute deviation (MAD) for each day in each group. [Modes for carrying out the invention]

[0140] A brief explanation of arrays Sequence IDs 1-5 show the sequences CDR-H1, CDR-H2, CDR-H3, CDR-L1, and CDR-L3 of the anti-CEACAM5 antibody (huMAb2-3).

[0141] Sequence ID 6 shows the sequence of the variable domain (VH) of the heavy chain of the anti-CEACAM5 antibody (huMAb2-3).

[0142] Sequence ID 7 shows the sequence of the variable domain (VL) of the light chain of the anti-CEACAM5 antibody (huMAb2-3).

[0143] Sequence ID 8 shows the heavy chain sequence of the anti-CEACAM5 antibody (huMAb2-3).

[0144] Sequence ID 9 shows the light chain sequence of the anti-CEACAM5 antibody (huMAb2-3).

[0145] Sequence ID 10 shows the heavy chain sequence of the anti-VEGFR-2 antibody ramucirumab.

[0146] Sequence ID 11 shows the light chain sequence of the anti-VEGFR-2 antibody ramucirumab.

[0147] Sequence IDs 12-17 show the sequences CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 of the anti-VEGFR-2 antibody ramucirumab.

[0148] definition Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have meanings generally understood by those skilled in the art. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press may provide those skilled in the art with a general dictionary of many of the terms used in this disclosure. Exemplary methods and materials are described below, but similar or equivalent methods and materials may also be used in the practice or testing of this disclosure. In the event of any conflict, this specification, including definitions, shall prevail. In general, the terminology used in relation to and for the cell and tissue culture, molecular biology, virology, immunology, microbiology, genetics, analytical chemistry, synthetic organic chemistry, medical chemistry and medicinal chemistry, and protein and nucleic acid chemistry and hybridization described herein is well known and commonly used in the art. Enzyme reactions and purification techniques are performed as commonly practiced in the art or as described herein, in accordance with the manufacturer's specifications. Furthermore, unless otherwise required by context, singular terms shall include plurals, and plural terms shall include singulars.

[0149] Units, prefixes, and symbols are given in their International System of Units (SI) approved forms. Numerical ranges include the number defining the range. Unless otherwise indicated, amino acid sequences are written from left to right in the amino-carboxyl direction. The headings provided herein are not limitations on the various aspects of this disclosure. Thus, terms defined immediately thereafter are defined in more detail by referring to this specification as a whole.

[0150] All publications and other references mentioned herein are invoked by reference as a whole. While many sources are cited herein, such citations do not constitute an acknowledgment that any of those sources constitute common technical knowledge in the art.

[0151] Throughout this specification and its embodiments, variations of the words “have” and “comprise,” or “has,” “having,” “comprises,” or “comprising,” will be understood to mean that they encompass the specified integer or group of integers, but do not exclude any other integer or group of integers. Whenever a situation is described herein in the language of “comprise,” it will be understood that other similar situations are also provided, described in the terms “consist of” and / or “essentially become from.”

[0152] It should be noted that the terms “one (a)” or “one (an)” entity refer to one or more of those entities; for example, “nucleotide sequence” is understood to represent one or more nucleotide sequences. Thus, the terms “one (a)” (or “one (an)”), “one or more” and “at least one” can be used interchangeably herein.

[0153] Furthermore, when used herein, “and / or” should be interpreted as the specific disclosure of each of two particular features or components that have or do not have the other. Thus, the term “and / or” as used in phrases such as “A and / or B” is intended herein to include “A and B,” “A or B,” “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B, and / or C” is intended to include each of the following situations: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0154] The terms “approximately” or “about” are used herein to mean roughly, roughly, around, within or within a range. When the term “about” is used with a numerical range, it modifies that range by extending the boundary above and below the indicated number. Generally, the term “about” can modify a number above and below a stated value by, for example, a difference of 10 percent above or below (higher or lower). In some embodiments, the term indicates a deviation of ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%, ±0.4%, ±0.3%, ±0.2%, ±0.1%, ±0.05%, or ±0.01% from the indicated number. In some embodiments, “about” indicates a deviation of ±10% from the indicated number. In some embodiments, “about” indicates a deviation of ±5% from the indicated number. In some embodiments, “about” indicates a deviation of ±4% from the indicated number. In some embodiments, "approximately" indicates a deviation of ±3% from the indicated value. In some embodiments, "approximately" indicates a deviation of ±2% from the indicated value. In some embodiments, "approximately" indicates a deviation of ±1% from the indicated value. In some embodiments, "approximately" indicates a deviation of ±0.9% from the indicated value. In some embodiments, "approximately" indicates a deviation of ±0.8% from the indicated value. In some embodiments, "approximately" indicates a deviation of ±0.7% from the indicated value. In some embodiments, "approximately" indicates a deviation of ±0.6% from the indicated value. In some embodiments, "approximately" indicates a deviation of ±0.5% from the indicated value. In some embodiments, "approximately" indicates a deviation of ±0.4% from the indicated value. In some embodiments, "approximately" indicates a deviation of ±0.3% from the indicated value. In some embodiments, "approximately" indicates a deviation of ±0.1% from the indicated value. In some embodiments, "approximately" indicates a deviation of ±0.05% from the indicated value. In some embodiments, "approximately" indicates a deviation of ±0.01% from the indicated value.

[0155] An antibody can be a natural or conventional antibody in which two heavy chains are linked to each other by disulfide bonds, and each heavy chain is linked to a light chain by disulfide bonds. 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 antibody molecules: IgM, IgD, IgG, IgA, and IgE. Each chain contains different sequence domains. The light chain contains two domains or regions: a variable domain (VL) and a constant domain (CL). The heavy chain contains four domains: a variable domain (VH) and three constant domains (CH1, CH2, and CH3, collectively called CH). The variable regions of both the light (VL) and heavy (VH) chains determine the binding recognition and specificity to the antigen. The constant domains of the light chain (CL) and heavy chain (CH) confer important biological properties such as antibody chain association, secretion, transplacental migration, complement binding, and binding to the Fc receptor (FcR). The Fv fragment is the N-terminal portion of the Fab fragment of immunoglobulins and consists of a variable region of one light chain and one heavy chain. Antibody specificity lies in the structural complementarity between the antibody binding site and the antigenic determinant. The antibody binding site is mainly composed of residues derived from the hypervariable or complementarity-determining region (CDR). Occasionally, residues derived from the non-hypervariable region or framework region (FR) affect the entire domain structure and therefore the binding site. Thus, the complementarity-determining region or CDR refers to the amino acid sequence that together defines the binding affinity and specificity of the native Fv region of the native immunoglobulin binding site. The light and heavy chains of immunoglobulins each contain three CDRs, called CDR1-L, CDR2-L, CDR3-L, and CDR1-H, CDR2-H, and CDR3-H, respectively. Therefore, a conventional antibody-antigen binding site contains six CDRs, including sets of CDRs from the heavy chain V region and the light chain V region, respectively.

[0156] The "framework region" (FR) refers to the amino acid sequence interposed between CDRs, i.e., the relatively conserved portions of the immunoglobulin light chain variable region and immunoglobulin heavy chain variable region across different immunoglobulins of the same species. The light and heavy chains of immunoglobulins each have four FRs, called FR1-L, FR2-L, FR3-L, FR4-L, and FR1-H, FR2-H, FR3-H, and FR4-H, respectively. Human framework regions are substantially identical (approximately 85% or more, particularly 90%, 95%, 97%, 99%, or 100%) to the framework regions of naturally occurring human antibodies.

[0157] In the context of this disclosure, the definition of CDR / FR in immunoglobulin light chains or heavy chains should be determined based on the definition by IMGT (Lefranc et al. Dev.Comp.Immunol., 2003, 27(1):55-77; www.imgt.org).

[0158] As used herein, the term “antibody” refers to conventional antibodies and their fragments, as well as single-domain antibodies and their fragments, in particular variable heavy chains of single-domain antibodies, and chimeric, humanized, bispecific, or multispecific antibodies.

[0159] As used herein, antibody or immunoglobulin also includes “single-domain antibodies,” which are antibodies whose complementarity-determining region is part of a single-domain polypeptide, as described more recently. Examples of single-domain antibodies include heavy-chain antibodies, antibodies that naturally lack a light chain, single-domain antibodies derived from conventional four-chain antibodies, and engineered single-domain antibodies. Single-domain antibodies may be derived from any species, including but not limited to mice, humans, camels, llamas, goats, rabbits, and cattle. Single-domain antibodies may be naturally occurring single-domain antibodies known as light-chain-lacking heavy-chain antibodies. In particular, camelid species, such as camels, dromedaries, llamas, alpacas, and guanacos, produce light-chain-lacking heavy-chain antibodies. Camel heavy-chain antibodies also lack the CH1 domain.

[0160] The variable heavy chains of these single-domain antibodies lacking light chains are known in the art as "VHH" or "Nanobody®". Similar to conventional VH domains, VHH contains four FRs and three CDRs. VHH has advantages over conventional antibodies. They are about 10 times smaller than IgG molecules, and as a result, well-folded functional VHH can be produced by in vitro expression with high yield. Furthermore, VHH is very stable and resistant to protease action. The properties and production of VHH are outlined in Harmsen and De Haard HJ (Appl. Microbiol. Biotechnol. 2007 Nov;77(1):13-22).

[0161] As used herein, the terms “monoclonal antibody” or “mAb” refer to an antibody molecule with a single amino acid sequence against a specific antigen and should not be interpreted as requiring antibody production by any particular method. Monoclonal antibodies can be produced by a single clone of a B cell or hybridoma, but they can also be produced by recombinants, i.e., protein engineering.

[0162] The term "humanized antibody" refers to an antibody that is entirely or partially of non-human origin and has been modified to evade or minimize the immune response in humans, particularly by substituting specific amino acids in the framework regions of the VH and VL domains. The constant domains of humanized antibodies are, in most cases, the human CH and CL domains.

[0163] A (conventional) antibody "fragment" is a part of an intact antibody, particularly the antigen-binding region 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. Conventional antibody fragments can also be heavy chain antibodies or single-domain antibodies such as VHH.

[0164] The term "Fab" refers to an antibody fragment with a molecular weight of approximately 50,000 and antigen-binding activity, in which approximately half of the N-terminal side of the heavy chain and the entire light chain are linked by disulfide bonds. It is typically obtained by treating IgG with a protease such as papain.

[0165] The term "F(ab')2" refers to an antibody fragment with a molecular weight of approximately 100,000 and slightly greater antigen-binding activity than two identical Fab fragments linked via a disulfide bond in the hinge region. This is typically obtained by treating IgG with a protease such as pepsin.

[0166] The term "Fab'" refers to an antibody fragment with a molecular weight of approximately 50,000 and antigen-binding activity, obtained by cleaving the disulfide bond in the hinge region of F(ab')2.

[0167] A single-stranded Fv ("scFv") polypeptide is a VH::VL heterodimer typically expressed from a gene fusion containing VH and VL encoding genes linked by a covalently bonded peptide-encoding linker. The human scFv fragments of this disclosure contain a CDR maintained in an appropriate conformation, particularly by using recombination techniques. Divalent and multivalent antibody fragments can be spontaneously formed by the association of monovalent scFv or produced by coupling monovalent scFv with a peptide linker such as divalent sc(Fv)2. "dsFv" is a VH::VL heterodimer stabilized by a disulfide bond. "(dsFv)2" indicates two dsFv coupled by a peptide linker.

[0168] The term "bispecific antibody" or "BsAb" refers to an antibody that combines the antigen-binding sites of two antibodies within a single molecule. Therefore, a BsAb can bind to two different antigens simultaneously. Genetic engineering is increasingly used to design, modify, and produce antibodies or antibody derivatives with a desired set of binding properties and effector functions, as described, for example, in European Patent Application Publication No. 2050 764A1.

[0169] The term "multispecific antibody" refers to an antibody that combines two or more antibody antigen-binding sites within a single molecule.

[0170] The term "diabody" refers to a small antibody fragment having two antigen-binding sites, which contains 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 on the same chain, the domains are forced to pair with a complementary domain on another chain, creating two antigen-binding sites.

[0171] An amino acid sequence that is "at least 85% identical to the reference sequence" is a sequence that, in its entire length, has sequence identity of 85% or more, particularly 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% with the full-length reference amino acid sequence.

[0172] The percentage of "sequence identity" between amino acid sequences can be determined by comparing two sequences that are optimally aligned across a comparison window. The portion of the polynucleotide or polypeptide sequence within the comparison window may contain additions or deletions (i.e., gaps) compared to a reference sequence (which does not contain additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions where identical nucleic acid bases or amino acid residues exist in both sequences, obtaining the number of matched positions, dividing the number of matched positions by the total number of positions within 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 in 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.

[0173] A "conservative amino acid substitution" is a substitution in which an amino acid residue is replaced by another amino acid residue having a side chain R group with similar chemical properties (e.g., charge, size, or hydrophobicity). Generally, conservative amino acid substitutions do not substantially alter the functional properties of a protein. Examples of amino acids with side chains having 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, and 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.

[0174] "Purified" and "isolated," when referring to polypeptides (i.e., the antibodies of this disclosure) or nucleotide sequences, mean that the indicated molecule exists in the substantial absence of other biological macromolecules of the same type. As used herein, the term "purified" specifically means the presence of at least 75%, 85%, 95%, or 98% (by weight) of the same type of biological macromolecule. An "isolated" nucleic acid molecule encoding a particular polypeptide refers to a nucleic acid molecule that substantially contains no other nucleic acid molecules that do not encode the polypeptide of interest. However, the molecule may contain several additional bases or parts that do not adversely affect the fundamental characteristics of the composition.

[0175] As used herein, the terms “subject” or “patient” mean mammals such as rodents, cats, dogs, and primates. In particular, the subject as disclosed herein is human.

[0176] As used herein, “administer” or “to administer” means to deliver the compositions described herein, for example, lipid nanoparticles, to a target. The compositions may be administered to a target using methods known in the art. In particular, the compositions may be administered intravenously, subcutaneously, intramuscularly, intradermally, or via any mucosal surface, for example, orally, sublingually, phalanxally, transnasally, rectally, transvaginally, or via the pulmonary route. In some embodiments, the administration is intravenous. In some embodiments, the administration is subcutaneous.

[0177] In this specification, the terms “to treat” or “treatment” or “therapy” refer to the administration or consumption of any composition disclosed herein for the purpose of curing, healing, alleviating, reducing, altering, correcting, improving, enhancing, or influencing the symptoms of a disorder or condition, or for the purpose of preventing or delaying the onset of symptoms or complications, or otherwise stopping or inhibiting the further onset of the disorder in a statistically significant manner. More specifically, “to treat” or “treatment” includes any approach to obtain a beneficial or desired outcome in the cancerous condition of interest. Beneficial or desired clinical outcomes may include, but are not limited to, the reduction or improvement of one or more cancerous symptoms or conditions, the reduction or decrease in the severity of the cancerous disease or cancerous symptoms, the stabilization of the cancerous disease or cancerous symptoms, i.e., the prevention of worsening, the prevention of the spread of the cancerous disease or cancerous symptoms, or the delay or slowing of the progression of the cancerous disease or cancerous symptoms. This includes improvement or alleviation of the cancerous disease condition, reduction of cancerous disease recurrence, and remission, whether partial or whole, and whether detectable or not. In other words, as used herein, “treatment” includes any cure, improvement, or alleviation of the cancerous disease or symptoms. "Reduction" of symptoms or disease means a decrease in the severity or frequency of the disease or symptoms, or the elimination of the disease or symptoms.

[0178] As used herein, the term “effective dose” refers to the amount that provides a therapeutic benefit in the treatment, prevention, or management of the pathological process under consideration. The specific therapeutically effective dose can be readily determined by a typical healthcare professional and may vary depending on factors such as the type and stage of the pathological process under consideration, the patient’s medical history and age, and the administration of other therapeutic agents.

[0179] Unit: mg / m 2 "This refers to the amount of the patient's body surface covered per dose (1 m²). 2 This indicates the amount of compound in milligrams per unit. Those skilled in the art are aware of methods for determining the required amount of compound to be administered based on the patient's body surface, which can be calculated based on height and weight.

[0180] The unit "mg / kg" indicates the amount of compound in milligrams per kilogram of body weight administered per dose to a patient. Those skilled in the art are familiar with methods for determining the required amount of compound to be treated based on the patient's body weight.

[0181] For clarity, it should be understood that certain features of the Disclosure, described in relation to separate embodiments, may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the Disclosure, described in relation to a single embodiment, may also be provided separately or in any preferred secondary combination.

[0182] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. However, any methods and materials similar to or equivalent to those described herein may also be used in the implementation or testing of this disclosure. All publications referenced herein are incorporated herein by reference to disclose and explain such methods and / or materials in the context in which those publications are cited.

[0183] The following list of suppliers, raw materials, and ingredients, including their combinations and mixtures, is enumerated as is within the scope of this specification.

[0184] It should be understood that any upper limit of any numerical limitation provided throughout this specification encompasses all lower numerical limitations, as those expressly stated herein. Any lower limit of any numerical limitation provided throughout this specification encompasses all higher numerical limitations, as those expressly stated herein. Any numerical range provided throughout this specification encompasses all narrower numerical ranges within such wider ranges, as those expressly stated herein.

[0185] For example, all lists of items, such as a list of raw materials, are intended to be and must be interpreted as Markush groups. Therefore, all lists can be read and interpreted as items "selected from a group consisting of lists of items and combinations and mixtures thereof."

[0186] In this specification, trademark names may be used to refer to components, including various raw materials, used in this disclosure. The inventors do not intend to limit themselves in this specification to any particular trademarked material. In the description herein, materials equivalent to those referenced by trademark names (e.g., those available from different suppliers under different names or reference numbers) may be substituted and used.

[0187] Antibody-drug conjugate containing anti-CEACAM5 antibody This disclosure relates to antibody-drug conjugates (ADCs) comprising a VEGFR-2 inhibitor or a fragment thereof, and an anti-CEACAM5 antibody or a fragment thereof, used in combination with an anti-PD-1 antibody or an anti-PD-L1 antibody or a fragment thereof, for the treatment of cancer.

[0188] Antibody-drug conjugates typically comprise 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. Specifically, in an antibody-drug conjugate, the anti-CEACAM5 antibody is covalently bound to at least one chemotherapeutic agent via a cleavable or non-cleavable linker.

[0189] Anti-CEACAM5 antibody According to one embodiment, the antibody-drug conjugate comprises a humanized anti-CEACAM5 antibody or a fragment thereof.

[0190] According to one embodiment, the antibody-drug conjugate comprises a humanized anti-CEACAM5 antibody or a fragment thereof.

[0191] In some embodiments, the anti-CEACAM5 antibody may include CDR-H1, corresponding to SEQ ID NO: 1; CDR-H2, corresponding to SEQ ID NO: 2; CDR-H3, corresponding to SEQ ID NO: 3; CDR-L1, corresponding to SEQ ID NO: 4; CDR-L2, corresponding to the amino acid sequence NTR; and CDR-L3, corresponding to SEQ ID NO: 5.

[0192] In further embodiments, the anti-CEACAM5 antibody or fragment thereof comprises a heavy chain variable domain (VH) having at least 90% identity with SEQ ID NO: 6, and a light chain variable domain (VL) having at least 90% identity with SEQ ID NO: 7, wherein CDR1-H consists of SEQ ID NO: 1, CDR2-H consists of SEQ ID NO: 2, CDR3-H consists of SEQ ID NO: 3, CDR1-L consists of SEQ ID NO: 4, CDR2-L consists of the amino acid sequence NTR, and CDR3-L consists of SEQ ID NO: 5.

[0193] In further embodiments, the anti-CEACAM5 antibody or fragment thereof comprises a heavy chain variable domain (VH) having at least 92%, at least 95%, and at least 98% identity with SEQ ID NO: 6, and a light chain variable domain (VL) having at least 92%, at least 95%, and at least 98% identity with SEQ ID NO: 7, wherein CDR1-H consists of SEQ ID NO: 1, CDR2-H consists of SEQ ID NO: 2, CDR3-H consists of SEQ ID NO: 3, CDR1-L consists of SEQ ID NO: 4, CDR2-L consists of the amino acid sequence NTR, and CDR3-L consists of SEQ ID NO: 5.

[0194] In some embodiments, the anti-CEACAM5 antibody or its fragment comprises a variable heavy chain domain (VH) consisting of SEQ ID NO: 6 and a variable light chain domain (VL) consisting of SEQ ID NO: 7.

[0195] In further embodiments, the anti-CEACAM5 antibody or its fragment is, -FR1-H extends to amino acid positions 1-25, CDR1-H extends to amino acid positions 26-33 (SEQ ID NO: 1), FR2-H extends to amino acid positions 34-50, CDR2-H extends to amino acid positions 51-58 (SEQ ID NO: 2), FR3-H extends to amino acid positions 59-96, CDR3-H extends to amino acid positions 97-109 (SEQ ID NO: 3), and FR4-H extends to amino acid positions 110-120, sequence [ka] A variable domain of the heavy chain consisting of, -FR1-L extends to amino acid positions 1-26, CDR1-L extends to amino acid positions 27-32 (SEQ ID NO: 4), FR2-L extends to amino acid positions 33-49, CDR2-L extends to amino acid positions 50-52, FR3-L extends to amino acid positions 53-88, CDR3-L extends to amino acid positions 89-97 (SEQ ID NO: 5), and FR4-L extends to amino acid positions 98-107. [ka] It includes a variable domain of light chain consisting of [the specified components].

[0196] In further embodiments, the anti-CEACAM5 antibody or its fragment comprises a heavy chain (HC) having at least 90% sequence identity with SEQ ID NO: 8 and a light chain (LC) having at least 90% sequence identity with SEQ ID NO: 9, where CDR1-H is derived from SEQ ID NO: 1, CDR2-H from SEQ ID NO: 2, CDR3-H from SEQ ID NO: 3, CDR1-L from SEQ ID NO: 4, CDR2-L from the amino acid sequence NTR, and CDR3-L from SEQ ID NO: 5.

[0197] In further embodiments, the anti-CEACAM5 antibody or its fragment comprises a heavy chain (HC) having at least 92%, at least 95%, and at least 98% identity with SEQ ID NO: 8 and a light chain (LC) having at least 92%, at least 95%, and at least 98% identity with SEQ ID NO: 9, wherein CDR1-H consists of SEQ ID NO: 1, CDR2-H consists of SEQ ID NO: 2, CDR3-H consists of SEQ ID NO: 3, CDR1-L consists of SEQ ID NO: 4, CDR2-L consists of the amino acid sequence NTR, and CDR3-L consists of SEQ ID NO: 5.

[0198] In certain embodiments, 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.

[0199] Anti-CEACAM5 antibodies may also be single-domain antibodies or fragments thereof. In particular, single-domain antibody fragments may consist of a variable heavy chain (VHH) containing CDR1-H, CDR2-H, and CDR3-H of the antibody described above. The antibody may also be a heavy-chain antibody, i.e., an antibody lacking a light chain, which may or may not contain the CH1 domain.

[0200] A single-domain antibody or its fragment may include the framework region of a camelid single-domain antibody and, optionally, the constant domain of a camelid single-domain antibody.

[0201] Anti-CEACAM5 antibodies may also be antibody fragments selected from the group consisting of Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, and diabodies, particularly humanized antibody fragments.

[0202] The antibody may also be a bispecific or multispecific antibody formed from antibody fragments, where at least one antibody fragment is an antibody fragment according to the present disclosure. A multispecific antibody is a multivalent protein complex, such as those described, for example, in European Patent Application Publication No. 2050764A1 or U.S. Patent Application Publication No. 2005 / 0003403A1.

[0203] Anti-CEACAM5 antibodies and their fragments can be produced by any technique known in the art. In particular, the antibodies can be produced by techniques such as those described below.

[0204] Anti-CEACAM5 antibodies and their fragments can be isolated (e.g., purified) from a vector such as a membrane or lipid vesicle (e.g., liposome), or can be used contained within a vector.

[0205] Anti-CEACAM5 antibodies and their fragments can be produced alone or in combination by any technique known in the art, for example, any chemical, biological, genetic, or enzymatic technique, though not limited to these.

[0206] By knowing the amino acid sequence of a desired sequence, those skilled in the art can readily produce anti-CEACAM5 antibodies and their fragments using standard techniques for polypeptide production. For example, they can be synthesized using well-known solid-phase methods, particularly using commercially available peptide synthesizers (e.g., those manufactured by Applied Biosystems, Foster City, California), according to the manufacturer's instructions. Alternatively, anti-CEACAM5 antibodies and their fragments 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 the DNA sequence encoding the desired (poly)peptide into an expression vector and introducing such a vector into a suitable eukaryotic or prokaryotic host expressing the desired polypeptide, from which they can later be isolated using well-known techniques.

[0207] Anti-CEACAM5 antibodies and their fragments can be appropriately isolated from the culture medium by conventional immunoglobulin purification procedures such as protein A-Sepharose chromatography, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography.

[0208] Methods for producing humanized antibodies based on conventional recombinant DNA and gene transfection techniques are well known in the art (see, for example, Riechmann L. et al. 1988; Neuberger MS. et al. 1985). Antibodies can be humanized using various techniques known in the art, such as those disclosed in WO 2009 / 032661 pamphlet, CDR grafting (EP 239,400; WO 91 / 09967 pamphlet; US 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 (US Pat. No. 5,565,332). General recombinant DNA techniques for preparing such antibodies are also known (see EP 125023 and WO 96 / 02576 pamphlet).

[0209] The Fab of an anti-CEACAM5 antibody can be obtained by treating an antibody that specifically reacts with CEACAM5 with a protease such as papain. Also, the Fab of an 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, and introducing the vector into prokaryotic or eukaryotic cells (if necessary) to express the Fab of the anti-CEACAM5 antibody.

[0210] The F(ab’)2 of an anti-CEACAM5 antibody can be obtained by treating an antibody that specifically reacts with CEACAM5 with a protease, pepsin. Also, the F(ab’)2 of an anti-CEACAM5 antibody can be manufactured by binding it to the following Fab’ via a thioether bond or a disulfide bond.

[0211] The Fab’ of an anti-CEACAM5 antibody can be obtained by treating F(ab’)2 that specifically reacts with CEACAM5 with a reducing agent such as dithiothreitol. Further, the Fab’ of an anti-CEACAM5 antibody can be prepared 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 cell or a eukaryotic cell (if necessary) for expression.

[0212] The scFv of an anti-CEACAM5 antibody can be produced by obtaining the sequences of CDRs 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 into a prokaryotic or eukaryotic cell (if necessary) to express the scFv. To produce 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 the framework of a human scFv fragment of a known three-dimensional structure (for example, WO 98 / 45322 pamphlet; WO 87 / 02671 pamphlet; US Patent No. 5,859,205; US Patent No. 5,585,089; US Patent No. 4,816,567; European Patent No. 0173494).

[0213] In one embodiment, the anti-CEACAM5 antibody is tusamitamab (CAS [2349294-95-5]).

[0214] Chemotherapeutic agent The antibody-drug conjugates for use as disclosed herein typically comprise at least one chemotherapeutic agent (also referred to herein as a cytotoxic agent). As used herein, chemotherapeutic agents refer to agents that kill cells, including cancer cells. Such agents preferably halt the division and growth of cancer cells and reduce the size of tumors. The term “chemotherapeutic agent” is used herein interchangeably with the terms “cytotoxic agent,” “growth inhibitor,” or “cell growth suppressant.”

[0215] As used herein, the term “chemotherapeutic agent” refers to a substance that inhibits or prevents the function of a cell and / or causes cell destruction. The term “chemotherapeutic agent” is intended to include radioisotopes, enzymes, antibiotics, and toxins such as low-molecular-weight toxins or enzymatically active toxins (including their fragments and / or variants) of bacterial, fungal, plant or animal origin, as well as various antitumor or anticancer agents disclosed below. In some embodiments, the chemotherapeutic agent is an antimetabolite.

[0216] In further embodiments, the chemotherapeutic agent may be selected from the group consisting of radioisotopes, protein toxins, low molecular weight toxins, and combinations thereof.

[0217] Radioactive isotopes include those suitable for treating cancer. Such radioactive isotopes generally emit primarily beta rays. In further embodiments, the radioactive isotope 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 The radioactive isotope is selected from the group consisting of radioactive isotopes of Lu and combinations thereof. In one embodiment, the radioactive isotope is an α radioactive isotope, more specifically Th 227 This emits alpha radiation.

[0218] In further embodiments, the low molecular weight toxin is selected from antimetabolites, DNA alkylating agents, DNA crosslinking agents, DNA intercalating agents, antimicrotubule agents, topoisomerase inhibitors, and combinations thereof.

[0219] In further embodiments, the antimicrotubule agent is selected from the group consisting of taxanes, vinca alkaloids, maytansinoids, colchicine, podophyllotoxin, gluceofulvin, and combinations thereof.

[0220] In some embodiments, the cytotoxic agent may be a meitansinoid.

[0221] According to one embodiment, the maytansinoid is selected from maytansinol, maytansinol analogs, and combinations thereof.

[0222] Suitable meitansinol analogs include those having modified aromatic rings and those having modifications at other positions. Such suitable meitansinoids are listed in U.S. Patents No. 4,424,219; No. 4,256,746; No. 4,294,757; No. 4,307,016; No. 4,313,946; No. 4,315,929; No. 4,331,598; No. 4,361,650; and This information is disclosed in Specification No. 4,362,663; Specification No. 4,364,866; Specification No. 4,450,254; Specification No. 4,322,348; Specification No. 4,371,533; Specification No. 6,333,410; Specification No. 5,475,092; Specification No. 5,585,499; and Specification No. 5,846,545.

[0223] In further embodiments, the cytotoxic conjugates of the present disclosure utilize a thiol-containing maytansinoid (DM1), formally known as N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine, as the cytotoxic agent. DM1 has the following structural formula (I): [ka] It is represented by [this].

[0224] In further embodiments, the cytotoxic conjugates of the present disclosure utilize DM4, a thiol-containing maytansinoid formally known as N2'-deacetyl-N-2'(4-methyl-4-mercapto-1-oxopentyl)-maytansine, as the cytotoxic agent. DM4 has the following structural formula (II): [ka] It is represented by [this].

[0225] In further embodiments of the present disclosure, other maytansins can be used, including thiol and disulfide-containing maytansinoids having mono- or dialkyl substitutions on carbon atoms having sulfur atoms. These include maytansinoids having acylated amino acid side chains having acyl groups having hindered sulfhydryl groups at C-3, C-14 hydroxymethyl, C-15 hydroxy, or C-20 desmethyl, wherein the carbon atoms of the acyl groups having thiol functional groups have one or two substituents, and the substituents are linear or branched alkyl or alkenyl groups having CH3, C2H5, 1 to 10 reagents, and any aggregates that may be present in solution.

[0226] Examples of these cytotoxic agents and conjugation methods are further shown in International Publication No. 2008 / 010101, which is incorporated by reference.

[0227] The immunoconjugates described herein can be prepared as described in International Publication No. 2004 / 091668, the entirety of which is incorporated herein by reference.

[0228] 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.

[0229] In a further embodiment, in the antibody-drug conjugate, the anti-CEACAM5 antibody covalently binds to at least one cytotoxic agent via a cleavable or non-cleavable linker.

[0230] In a further embodiment, the linker is selected from the group consisting of N-succinimidyl pyridyldithio butyrate (SPDB), 4-(pyridin-2-yl disulfanyl)-2-sulfobutanoic acid (sulfO-SPDB), and succinimidyl (N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC).

[0231] In a further embodiment, the linker binds to a lysine or cysteine residue in the Fc region of the anti-CEACAM5 antibody. In a further embodiment, the linker forms a disulfide bond or a thioether bond with maytansine.

[0232] In particular, the anti-CEACAM5 antibody-drug conjugate is as follows: Formula (III):

Chemical formula

Chemical formula

Chemical formula

[0233] In equations (III), (IV), and (V) above, "n" corresponds to the number of conjugated chemotherapeutic agent molecules per antibody molecule. This corresponds to the "drug-to-antibody ratio" (or "DAR") as defined below, and can range from 1 to 10.

[0234] In further embodiments, the antibody-drug conjugate of the present disclosure comprises an anti-CEACAM5 antibody comprising the heavy chain (VH) of SEQ ID NO: 8 and the light chain (VL) of SEQ ID NO: 9 (tusamitamab), where tusamitamab is covalently bound to N2'-deacetyl-N-2'(4-methyl-4-mercapto-1-oxopentyl)-maytansine (DM4) via N-succinimidylpyridyl dithiobutyrate (SPDB). This yields the antibody-drug conjugate tusamitamaburabutansine (huMAb2-3-SPDB-DM4).

[0235] In one embodiment, the antibody-drug conjugate of the present disclosure is tusamitamablubutansine (CAS[2254086-60-5]).

[0236] As used herein, "linker" means a chemical moiety containing a covalent bond or chain of atoms that covalently binds an antibody to a chemotherapeutic agent moiety (e.g., a cell proliferation inhibitor, a cytotoxic agent, or a growth inhibitor). Suitable linkers are well known in the art and include disulfide groups, thioether groups, acid-unstable groups, photosensitive groups, peptidase-unstable groups, and esterase-unstable groups.

[0237] Conjugates can be prepared by in vitro methods. Conjugate groups are used to link a drug or prodrug to an antibody, such as a chemotherapeutic agent. Suitable conjugate groups are well known in the art and include disulfide groups, thioether groups, acid-unstable groups, photo-unstable groups, peptidase-unstable groups, and esterase-unstable groups. Conjugations of antibodies with chemotherapeutic agents of this disclosure, such as cytotoxic agents, are not limited to, but include, N-succinimidylpyridyl dithiobutyrate (SPDB), 4-[(5-nitro-2-pyridinyl)dithio]-2,5-dioxo-1-pyrrolidinyl ester (nitro-SPDB), 4-(pyridine-2-yldisulfanyl)-2-sulfobutyrate (sulfo-SPDB), N-succinimidyl (2-pyridyldithio)propionate (SPDP), succinimidyl (N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC), and iminothiolane (IT These can be prepared using various bifunctional protein coupling agents, including difunctional derivatives of imide esters (such as dimethyladipimidate HCl), active esters (such as diserate subtinimidyl), aldehydes (such as glutaraldehyde), bis-azide 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, lysine immunotoxins can be prepared as described in Vitetta et al (1987). Carbon-labeled 1-isothiocyanatobenzylmethyldiethylenetriaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for the conjugation of radioactive nucleotides to antibodies (International Publication No. 94 / 11026).

[0238] The linker may be a "cleavage linker" that facilitates the release of chemotherapeutic agents in cells. For example, acid-unstable linkers, peptidase-sensitive linkers, esterase-unstable linkers, photosensitive linkers, or disulfide-containing linkers (see, for example, U.S. Patent No. 5,208,020) can be used. The linker may also be a "non-cleavage linker" (e.g., an SMCC linker) which may provide better resistance in some cases.

[0239] Generally, conjugates are (i) A step of contacting an aqueous solution of a buffered cell binding agent (e.g., an antibody according to the Disclosure) with a linker and a solution of a chemotherapeutic agent, such as a cytotoxic compound (or drug); (ii) The conjugate formed in (i) may then be obtained by a method that includes the step of separating the unreacted cell binding agent (e.g., the antibody of the Disclosure) and the unreacted chemotherapeutic agent, e.g., the unreacted cytotoxic compound (or drug).

[0240] Aqueous solutions of cell-binding agents can be buffered with a buffer such as potassium phosphate, acetate, citrate, or N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (Hepes buffer). The buffer depends on the properties of the cell-binding agent (e.g., the antibody of this disclosure). Chemotherapy agents, such as cytotoxic compounds (or drugs), are dissolved in organic polar solvents, such as dimethyl sulfoxide (DMSO) or dimethylacetamide (DMA).

[0241] The reaction temperature is typically between 20°C and 40°C. The reaction time can vary from 1 to 24 hours. The reaction between the cell conjugate and the chemotherapeutic agent, such as a cytotoxic agent, can be monitored by size exclusion chromatography (SEC) using refractive index measurements and / or a UV detector. If the conjugate yield is too low, the reaction time can be extended.

[0242] To carry out the separation in step (ii), several different chromatographic methods can be used by those skilled in the art. The conjugate can be purified, for example, from the aggregate by mixed support chromatography such as SEC, adsorption chromatography (ion exchange chromatography, IEC, etc.), hydrophobic interaction chromatography (HIC), affinity chromatography, hydroxyapatite chromatography, or high-performance liquid chromatography (HPLC). Purification by dialysis or diafiltration can also be used.

[0243] As used herein, the term “aggregate” means an association that may be formed between two or more cell-binding agents, which may or may not be modified by conjugation. Aggregates can be formed under the influence of numerous parameters, including high concentrations of cell-binding agents in solution (e.g., antibodies of this disclosure), pH of the solution, high shear force, the number of bound dimers and their hydrophobicity, and temperature (see Wang & Gosh, 2008, J. Membrane Sci., 318:311-316 and the references cited therein). It should be noted that the relative effects of some of these parameters have not been clearly established. For proteins and antibodies, those skilled in the art refer 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 (see Walter et al., 1993, Anal. Biochem., 212(2):469-480).

[0244] After step (i) or (ii), the conjugate-containing solution may be subjected to a further step (iii) of chromatography, ultrafiltration and / or diafiltration.

[0245] The conjugate is recovered in an aqueous solution at the end of these steps.

[0246] In further embodiments, the antibody-drug conjugate according to this disclosure is characterized by a “drug-to-antibody ratio” (or “DAR”) in the range of 1 to 10, or 2 to 5, or 3 to 4. This is generally the case for conjugates containing a meitansinoid molecule.

[0247] This DAR number can vary depending on the properties of the antibody and drug used (i.e., chemotherapeutic agents, e.g., cytotoxic agents or growth inhibitors) along with the experimental conditions used for conjugation (reaction time, solvent, and properties of any co-solvent, such as the ratio of chemotherapeutic agent (e.g., growth inhibitor) to antibody). Therefore, contact between an antibody and a chemotherapeutic agent, e.g., a cytotoxic agent or growth inhibitor, results in a mixture containing several conjugates with different drug-to-antibody ratios, optionally a naked antibody, or optionally, aggregate ratios that differ from each other. Thus, the determined DAR is an average value.

[0248] A method that can be used to determine the DAR consists of measuring the ratio of the absorbances of a substantially purified conjugate solution at λD and 280 nm using a spectrophotometer. 280 nm is a wavelength commonly used to measure protein concentrations, such as antibody concentrations. The wavelength λD is selected so that the drug can be distinguished from the antibody; that is, as is readily known to those skilled in the art, λD is a wavelength at which the drug (i.e., chemotherapeutic agent) has a high absorbance, and λD is a wavelength sufficiently far from 280 nm to avoid substantial overlap of the absorbance peaks of the drug and the antibody. In the case of meitansinoid molecules, λD may be selected as 252 nm. The method for calculating the DAR can be obtained from Antony S. Dimitrov (ed), LLC, 2009, Therapeutic Antibodies and Protocols, vol 525, 445, Springer Science.

[0249] The absorbance of the conjugate at λD (AλD) and 280 nm (A280) is measured using either a monomer peak from size exclusion chromatography (SEC) analysis (enabling the calculation of the "DAR(SEC)" parameter) or a classical spectrophotometer (enabling the calculation of the "DAR(UV)" parameter). The absorbance can be expressed as follows: AλD=(cD x εDλD)+(cA x εAλD) A280=(cD x εD280)+(cA x εA280) (In the formula, 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.

[0250] The resolution of these two equations, which have two unknowns, yields the following equation: cD=[(εA280 x AλD)-(εAλD x A280)] / [(εDλD x εA280)-(εAλD x εD280)] cA=[A280-(cD x εD280)] / εA280

[0251] Next, the average DAR is calculated from the ratio of the antibody concentration to the drug concentration: DAR = cD / cA.

[0252] VEGFR-2 inhibitors The combinations described herein include VEGFR-2 inhibitors for the treatment of cancer.

[0253] VEGFR-2 inhibitors are selected from among anti-VEGFR-2 antibodies and receptor tyrosine kinase inhibitors.

[0254] In some embodiments, the receptor tyrosine kinase inhibitor is selected from aflibercept, nintedanib, pegaptanib, convercept, axitinib, cabozantinib, pazopanib, sorafenib, and sunitinib.

[0255] In some embodiments, the receptor tyrosine kinase inhibitor is selected from among and aflibercept.

[0256] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0257] In some embodiments, the combinations of the present disclosure include an anti-VEGFR-2 antibody or a fragment thereof for the treatment of cancer.

[0258] In one embodiment, the anti-VEGFR-2 antibody is a monoclonal antibody or a fragment thereof having antagonist activity against VEGFR-2. In one embodiment, the anti-VEGFR-2 antibody is IgG.

[0259] The anti-VEGFR-2 antibody is preferably adapted to the patient. For example, it is preferable to use an anti-mouse VEGFR-2 antibody such as DC-101 in mice and an anti-human VEGFR-2 antibody in humans.

[0260] 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.

[0261] In one embodiment, the anti-VEGFR-2 antibody comprises the light chain and heavy chain CDR of ramucirumab.

[0262] In one embodiment, the anti-VEGFR-2 antibody comprises the heavy chain variable domain (VH) and the light chain variable domain (VL) of ramucirumab.

[0263] In a further embodiment, the anti-VEGFR-2 antibody comprises a heavy chain (HC) having at least 92%, at least 95%, and at least 98% identity with SEQ ID NO: 10, and a light chain (LC) having at least 92%, at least 95%, and at least 98% identity with SEQ ID NO: 11.

[0264] The anti-VEGFR-2 antibody or its fragment may be a single-domain antibody or its fragment. In particular, a single-domain antibody fragment may consist of a variable heavy chain (VHH) containing CDR1-H, CDR2-H, and CDR3-H of the antibody described above. The antibody may also be a heavy-chain antibody, i.e., an antibody lacking a light chain, which may or may not contain the CH1 domain.

[0265] A single-domain antibody or its fragment may include the framework region of a camelid single-domain antibody and, optionally, the constant domain of a camelid single-domain antibody.

[0266] Anti-VEGFR-2 antibodies may be antibody fragments selected from the group consisting of Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, and diabodies, and may particularly be humanized antibody fragments.

[0267] The antibody may also be a bispecific or multispecific antibody formed from antibody fragments, wherein at least one antibody fragment is the antibody fragment according to this disclosure. Anti-VEGFR-2 antibodies and their fragments can be produced by any technique well known in the art. In particular, the antibody can be produced by techniques already described.

[0268] Anti-VEGFR-2 antibodies and their fragments can be isolated (e.g., purified) from or contained within a vector, such as a membrane or lipid vesicle (e.g., liposome).

[0269] Anti-VEGFR-2 antibodies and their fragments can be produced alone or in combination by any technique known in the art, for example, any chemical, biological, genetic, or enzymatic technique, though not limited to these.

[0270] Anti-PD-1 antibody; anti-PD-L1 antibody The combinations described herein include anti-PD-1 antibodies or anti-PD-L1 antibodies or fragments thereof for the treatment of cancer.

[0271] In one embodiment, the anti-PD-1 antibody or anti-PD-L1 antibody, or a fragment thereof, is a monoclonal antibody having activity that interferes with the interaction between PD-1 and PD-L1. In one embodiment, the anti-PD-1 antibody or anti-PD-L1 antibody is IgG.

[0272] Anti-PD-1 and anti-PD-L1 antibodies, which can interfere with the interaction between PD-1 expressed on the surface of immune cells and PD-L1 expressed on the surface of cancer cells, are useful as immune checkpoint inhibitors. This is because they block pathways that shield tumor cells from immune system components that are capable of fighting cancer and are ready to do so. When PD-1 and PD-L1 interact, they form a biochemical "shield" that protects tumor cells from being destroyed by the immune system. Therefore, blocking either PD-1 or PD-L1, resulting in the disruption of the interaction between PD-1 and PD-L1, interferes with or unmasks the biochemical "shield" that protects tumor cells from being destroyed by the immune system.

[0273] Several anti-PD-1 antibodies have been approved for clinical use in the treatment of cancer. These include pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), semiprimab (LIBTAYO®), cintilimab (TYVYT®), dostarimab (JEMPERLI®), and tislerizumab.

[0274] Similarly, several anti-PD-L1 antibodies have been approved for clinical use in the treatment of cancer. These include atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), and durvalumab (IMFINZI®).

[0275] In one embodiment, the anti-PD-1 antibody is pembrolizumab or cintilimab.

[0276] In one embodiment, the anti-PD-1 antibody is pembrolizumab, which is a fully human monoclonal IgG1 antibody against human PD-1.

[0277] In one embodiment, an anti-PD-1 antibody or its fragment comprises the light chain and heavy chain CDR of pembrolizumab.

[0278] In one embodiment, the anti-PD-1 antibody or its fragment comprises the heavy chain variable domain (VH) and the light chain variable domain (VL) of pembrolizumab.

[0279] In one embodiment, the anti-PD-1 antibody is cintirimab. In one embodiment, the anti-PD-1 antibody or its fragment comprises the light chain and heavy chain CDR of cintirimab. In one embodiment, the anti-PD-1 antibody or its fragment comprises the heavy chain variable domain (VH) and light chain variable domain (VL) of cintirimab.

[0280] The anti-PD-1 antibody or anti-PD-L1 antibody or its fragment may be a single-domain antibody or its fragment. In particular, a single-domain antibody fragment may consist of a variable heavy chain (VHH) containing CDR1-H, CDR2-H, and CDR3-H of the above antibody. The antibody may also be a heavy-chain antibody, i.e., an antibody lacking a light chain, which may or may not contain the CH1 domain.

[0281] A single-domain antibody or its fragment may include the framework region of a camelid single-domain antibody and, optionally, the constant domain of a camelid single-domain antibody.

[0282] The anti-PD-1 antibody or anti-PD-L1 antibody may be an antibody fragment selected from the group consisting of Fv, Fab, F(ab')2, Fab', dsFv, (dsFv)2, scFv, sc(Fv)2, and diabody, and may also be a humanized antibody fragment.

[0283] The antibody may also be a bispecific or multispecific antibody formed from antibody fragments, wherein at least one antibody fragment is the antibody fragment according to this disclosure. Anti-PD-1 antibodies or anti-PD-L1 antibodies and their fragments can be produced by any technique well known in the art. In particular, the antibodies are produced by techniques already described.

[0284] Anti-PD-1 antibodies or anti-PD-L1 antibodies and their fragments can be isolated (e.g., purified) from a vector such as a membrane or lipid vesicle (e.g., liposome), or used in conjunction with a vector.

[0285] Anti-PD-1 antibodies or anti-PD-L1 antibodies and their fragments can be produced alone or in combination by any technique known in the art, for example, any chemical, biological, genetic, or enzymatic technique, though not limited to these.

[0286] cancer In one embodiment, cancer is a carcinoma, sarcoma, or blastoma. In a further embodiment, cancer is a carcinoma.

[0287] According to one embodiment, the cancer is a cancer that expresses CEACAM5. A cancer that expresses CEACAM5 may also be called a CEACAM5-positive cancer.

[0288] In some embodiments, the cancer is a CEACAM5-positive cancer.

[0289] CEACAM5-positive cancer is defined as cancer in which the immunohistochemical [IHC] intensity of CEACAM5 is 2+ or higher in 50% or more of cancer cells, or 2+ or higher in 1% or more but less than 50% of cellular tumors (or cancer cells).

[0290] In certain embodiments, cancer has negative or low CEACAM5 expression on tumor cells. Negative or low CEACAM5 expression on tumor cells is defined as a CEACAM5 immunohistochemical [IHC] intensity ≥ 2+ in less than 1% of cells, as measured by immunohistochemistry (IHC).

[0291] In certain embodiments, cancer has moderate CEACAM5 expression on tumor cells. Moderate CEACAM5 expression on tumor cells can be defined as an intensity of 2+ or higher in 1% to less than 50% of cancer cells, as measured by CEACAM5 immunohistochemistry [IHC].

[0292] In certain embodiments, cancer has high CEACAM5 expression on tumor cells. High CEACAM5 expression on tumor cells can be defined as an intensity of 2+ or higher in more than 50% of cancer cells, as measured by CEACAM5 immunohistochemistry [IHC].

[0293] Immunohistochemical techniques for detecting antigens on cells or tissue sections by immunological and chemical reactions are well known in this field. These techniques are highly sensitive and specific and can detect a wide variety of antigens. The method may include the following steps: a step of binding an antibody to a specific antigen; a step of forming an antibody-antigen complex by incubation with a secondary enzyme-conjugated antibody; and a step of generating a colored deposit at the antibody-antigen binding site in the presence of an enzyme-catalyzed substrate and chromogen.

[0294] CEACAM5 tumor expression can be determined by using immunohistochemistry (IHC) assays. The assays may be performed using anti-CEACAM5 antibodies, such as SANOFI antibody clone 769. Anti-CEACAM5 clone 769 is a mouse monoclonal antibody with the same specificity as tusamitamabrabutansin for the CEACAM5 target. The assays may be performed using the Techmate platform former or the Dako / Agilent Autostainer Link 48 IHC. CEACAM5 reactivity was interpreted by a certified pathologist using semi-quantitative percentage scores (calculated by summing the percentages of intensities of 2+ or higher) or H-scores for CEACAM5 plasma membrane staining (whole or polarized) in tumor cells.

[0295] According to one embodiment, the cancer is selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, esophageal cancer, 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, biliary tract cancer (e.g., bile duct cancer), prostate cancer, neuroendocrine cancer, and skin cancer.

[0296] In some embodiments, the cancer may be selected from gastric cancer, gastroesophageal junction (GEJ) adenocarcinoma, esophageal cancer, and lung cancer.

[0297] According to one embodiment, the cancer is gastric cancer or gastroesophageal junction adenocarcinoma (GEJ).

[0298] According to one embodiment, the cancer is gastric cancer.

[0299] In some embodiments, the cancer may be pancreatic cancer.

[0300] According to one embodiment, the cancer is lung cancer. The lung cancer may be non-squamous non-small cell lung cancer (NSQ NSCLC).

[0301] Non-small cell lung cancer (NLC) is a disease in which malignant (cancer) cells form in the lung tissue. Smoking is the main cause of this disease. It is a type of epithelial lung cancer other than small cell lung cancer. There are several types of NLC. Each type of NLC has different types of cancer cells. Each type of cancer cell proliferates and spreads in different ways. The types of NLC are determined by the types of cells found in the cancer and how the cells appear under a microscope. (1) Squamous cell carcinoma: Cancer that begins with squamous epithelial cells (thin, flat cells that look like fish scales). This is also called epidermal carcinoma. (2) Large cell carcinoma: Cancer that can begin with several types of large cells. (3) Adenocarcinoma: Cancer that begins with cells that line the alveoli and produce substances such as mucus.

[0302] In some embodiments, non-squamous non-small cell lung cancer may be advanced or metastatic NSQ NSCLC.

[0303] According to one embodiment, the patient is a patient having a malignant tumor, particularly a malignant solid tumor, more specifically a locally advanced or metastatic solid malignant tumor. A metastatic solid malignant tumor may be a metastatic carcinoma, for example. The carcinoma or cyst may be as described above.

[0304] In some embodiments, non-squamous non-small cell lung cancer does not have epidermal growth factor receptor (EGFR) sensitive mutations, v-raf mouse sarcoma virus oncogene homolog B1 (BRAF) mutations, or anaplastic lymphoma kinase / c-ros oncogene 1 (ALK / ROS) changes.

[0305] Combination treatment Administration sequence This disclosure relates to an antibody-drug conjugate comprising an anti-CEACAM5 antibody for use in treating cancer in subjects requiring simultaneous, separate, or sequential administration of a VEGFR-2 inhibitor and an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0306] According to this disclosure, ADCs are intended for use in combination with VEGFR-2 inhibitors and anti-PD-1 antibodies or anti-PD-L1 antibodies to treat cancer. This disclosure also relates to VEGFR-2 inhibitors for use in combination with ADCs and anti-PD-1 antibodies or anti-PD-8L1 antibodies to treat cancer. This disclosure also relates to anti-PD-1 antibodies or anti-PD-L1 antibodies for use in combination with ADCs and VEGFR-2 inhibitors to treat cancer.

[0307] In some embodiments, (i) an antibody-drug conjugate, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered simultaneously (or concurrently), separately, or sequentially to a subject requiring it.

[0308] As used herein, the expression “in combination with” means that a VEGFR-2 inhibitor or an anti-PD-1 antibody or anti-PD-L1 antibody is administered before, after, or concurrently with the ADC. In some embodiments, the term “in combination with” includes the sequential or concurrent administration of the ADC and the VEGFR-2 inhibitor or anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, “combination” as used with respect to an antibody-drug conjugate comprising a VEGFR-2 inhibitor, an anti-CEACAM5 antibody, and an anti-PD-1 antibody or anti-PD-L1 antibody is intended to refer to antibodies that are individually formulated and administered sequentially to subjects requiring them for cancer indications.

[0309] A method for treating cancer (e.g., GC, GEJ cancer, NSQ NSCLC) involves administering an antibody-drug conjugate containing an anti-CEACAM5 antibody (e.g., tusamitamabrabutansine) in combination with a VEGFR-2 inhibitor and an anti-PD-1 antibody or anti-PD-L1 antibody for additive or synergistic activity.

[0310] In some embodiments, (i) an antibody-drug conjugate, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody are administered sequentially to the target in need.

[0311] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0312] According to some embodiments, ADCs and VEGFR-2 inhibitors are administered simultaneously, separately, or sequentially to subjects requiring them.

[0313] According to one embodiment, ADCs and VEGFR-2 inhibitors are administered simultaneously to subjects requiring them. For example, ADCs and VEGFR-2 inhibitors are administered almost simultaneously on day 1 of the treatment cycle. The simultaneous administration of ADCs and VEGFR-2 inhibitors may be via the same route.

[0314] According to one embodiment, the ADC and the VEGFR-2 inhibitor are administered separately to the subject requiring them. For example, the ADC and the VEGFR-2 inhibitor are administered on day 1 of the cycle, by separate routes or at separate locations on the subject's body. The separate administrations of the ADC and the VEGFR-2 inhibitor may be simultaneous or close together, for example, within 5 minutes or less.

[0315] According to one embodiment, ADCs and VEGFR-2 inhibitors are administered sequentially to subjects requiring them. For example, ADCs and VEGFR-2 inhibitors are administered at different times on day 1 of the cycle, for instance, ADCs are administered 1 to 3 hours after VEGFR-2 inhibitors. The sequential administration of ADCs and VEGFR-2 inhibitors may be via separate or the same route. The sequential administration of ADCs and VEGFR-2 inhibitors may include the administration of ADCs after VEGFR-2 inhibitors. ADCs may be administered approximately 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours after VEGFR-2 inhibitors. ADCs may be administered approximately 1 hour after VEGFR-2 inhibitors.

[0316] In sequential administration, the interval between the administration of the VEGFR-2 inhibitor and the antibody-drug conjugate containing the anti-CEACAM5 antibody may last from about a few minutes to about a few hours, several days, or several weeks. In some embodiments, the interval may range from about 5 minutes to about 3 hours, for example, 10 minutes to about 2.5 hours, about 30 minutes to about 2 hours, or about 1 hour to about 1.5 hours. The interval 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.

[0317] In some embodiments, the VEGFR-2 inhibitor is administered over a period of one hour.

[0318] In some embodiments, the antibody-drug conjugate containing an anti-CEACAM5 antibody is administered over a period of 1.5 hours.

[0319] In some embodiments, in sequential administration, the interval between the administration of the VEGFR-2 inhibitor and the antibody-drug conjugate containing the anti-CEACAM5 antibody may range from about 5 minutes to about 3 hours, for example, 10 minutes to about 2.5 hours, about 30 minutes to about 2 hours, or about 1 hour to about 1.5 hours. In sequential administration on the same day of the cycle, the interval 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.

[0320] The interval between the administration of a VEGFR-2 inhibitor and the administration of an antibody-drug conjugate containing an anti-CEACAM5 antibody may range from approximately 20 minutes to 5 hours, 30 minutes to 3 hours, 40 minutes to 2 hours, 50 minutes to 1.5 hours, or may last for approximately 1 hour.

[0321] In one embodiment, in sequential administration on the same day of the cycle, the time between the administration of the VEGFR-2 inhibitor and the antibody-drug conjugate containing an anti-CEACAM5 antibody may be at least 1 hour.

[0322] In sequential administration, antibody-drug conjugates (ADCs) containing anti-CEACAM5 antibodies may be administered after or before VEGFR-2 inhibitors.

[0323] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered prior to the VEGFR-2 inhibitor.

[0324] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered after a VEGFR-2 inhibitor.

[0325] In some embodiments, the order of administration of the antibody-drug conjugate containing an anti-CEACAM5 antibody and the VEGFR-2 inhibitor may be the same throughout all treatment cycles.

[0326] When administered "before" ADC, VEGFR-2 inhibitors may be administered approximately 72 hours, 60 hours, 48 ​​hours, 36 hours, 24 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 10 minutes before ADC administration.

[0327] When administered "after" ADC, VEGFR-2 inhibitors may be administered approximately 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, or 72 hours after administration of the antibody-drug conjugate containing the anti-CEACAM5 antibody.

[0328] In some embodiments, the VEGFR-2 inhibitor may be administered before the antibody-drug conjugate.

[0329] In some embodiments, a method of treating cancer involves administering an effective amount of an antibody-drug conjugate containing an anti-CEACAM5 antibody to a patient in need of it, prior to administering a VEGFR-2 inhibitor.

[0330] In some embodiments, a method of treating cancer involves administering to a patient in need an effective amount of an antibody-drug conjugate containing an anti-CEACAM5 antibody, after administering a VEGFR-2 inhibitor.

[0331] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0332] According to some embodiments, the ADC and the anti-PD-1 antibody or anti-PD-L1 antibody are administered simultaneously, separately, or sequentially to the target requiring them.

[0333] According to one embodiment, the ADC and the anti-PD-1 antibody or anti-PD-L1 antibody are administered simultaneously to the subject requiring them. For example, the ADC and the anti-PD-1 antibody or anti-PD-L1 antibody are administered almost simultaneously on day 1 of the treatment cycle. The simultaneous administration of the ADC and the anti-PD-1 antibody or anti-PD-L1 antibody may be via the same route.

[0334] According to one embodiment, the ADC and the anti-PD-1 antibody or anti-PD-L1 antibody are administered separately to the subject requiring them. For example, the ADC and the anti-PD-1 antibody or anti-PD-L1 antibody are administered on day 1 of the cycle, by separate routes, or at separate locations on the subject's body. The separate administrations of the ADC and the anti-PD-1 antibody or anti-PD-L1 antibody may occur simultaneously or at close intervals, for example, within 5 minutes.

[0335] According to one embodiment, the ADC and the anti-PD-1 antibody or anti-PD-L1 antibody are administered sequentially to the subject requiring them. For example, the ADC and the anti-PD-1 antibody or anti-PD-L1 antibody are administered at different times on day 1 of the cycle, for example, the ADC is administered 1 to 3 hours after the anti-PD-1 antibody or anti-PD-L1 antibody. The sequential administration of the ADC and the anti-PD-1 antibody or anti-PD-L1 antibody may be via separate routes or the same route. The sequential administration of the ADC and the anti-PD-1 antibody or anti-PD-L1 antibody may include the administration of the ADC after the anti-PD-1 antibody or anti-PD-L1 antibody. The ADC may be administered about 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or about 6 hours after the anti-PD-1 antibody or anti-PD-L1 antibody. The ADC may be administered about 1 hour after the anti-PD-1 antibody or anti-PD-L1 antibody.

[0336] In sequential administration, the interval between the administration of an anti-PD-1 antibody or anti-PD-L1 antibody and the antibody-drug conjugate containing an anti-CEACAM5 antibody may last for several minutes to several hours, several days, or several weeks. In some embodiments, the interval may range from about 5 minutes to about 3 hours, for example, 10 minutes to about 2.5 hours, about 30 minutes to about 2 hours, or about 1 hour to about 1.5 hours. The interval 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.

[0337] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody is administered over a period of one hour.

[0338] In some embodiments, the antibody-drug conjugate containing an anti-CEACAM5 antibody is administered over a period of 1.5 hours.

[0339] In some embodiments, in sequential administration, the interval between the administration of an anti-PD-1 antibody or anti-PD-L1 antibody and the antibody-drug conjugate containing an anti-CEACAM5 antibody may range from about 5 minutes to about 3 hours, for example, 10 minutes to about 2.5 hours, about 30 minutes to about 2 hours, or about 1 hour to about 1.5 hours. In sequential administration on the same day of the cycle, the interval 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.

[0340] In one embodiment, in sequential administration, the time between the administration of an anti-PD-1 antibody or anti-PD-L1 antibody and the antibody-drug conjugate containing an anti-CEACAM5 antibody may be at least 1 hour.

[0341] In sequential administration, antibody-drug conjugates (ADCs) containing anti-CEACAM5 antibodies may be administered after or before anti-PD-1 antibodies or anti-PD-L1 antibodies.

[0342] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered before an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0343] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered after an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0344] In some embodiments, the order of administration of the antibody-drug conjugate containing an anti-CEACAM5 antibody and an anti-PD-1 antibody or anti-PD-L1 antibody may be the same throughout all treatment cycles.

[0345] When administered "before" ADC, anti-PD-1 antibody or anti-PD-L1 antibody may be administered approximately 72 hours, 60 hours, 48 ​​hours, 36 hours, 24 hours, 12 hours, 10 hours, 8 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, or 10 minutes before ADC administration.

[0346] When administered "after" an ADC, the anti-PD-1 antibody or anti-PD-L1 antibody may be administered approximately 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours, 36 hours, 48 ​​hours, 60 hours, or 72 hours after administration of the antibody-drug conjugate containing the anti-CEACAM5 antibody.

[0347] In some embodiments, an anti-PD-1 antibody or an anti-PD-L1 antibody may be administered before the antibody-drug conjugate.

[0348] In some embodiments, a method for treating cancer involves administering an effective amount of antibody-drug conjugate containing an anti-CEACAM5 antibody to a subject in need of treatment before administering an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0349] In some embodiments, a method for treating cancer involves administering an effective amount of an antibody-drug conjugate containing an anti-CEACAM5 antibody to a subject in need, after administering an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0350] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the ADC may be administered sequentially.

[0351] In some embodiments, the ADC may be administered before the anti-PD-1 antibody or the anti-PD-L1 antibody.

[0352] The disclosure also relates to a method for treating cancer in a subject requiring such treatment, comprising administering a VEGFR-2 inhibitor to the subject requiring such treatment, administering an antibody-drug conjugate comprising an anti-CEACAM5 antibody, and administering an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0353] The disclosure also relates to a method for treating cancer in subjects requiring cancer treatment, comprising sequentially administering the following in order to the subject: (a) a VEGFR-2 inhibitor, (b) an antibody-drug conjugate including an anti-CEACAM5 antibody, and (c) an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0354] This disclosure also relates to a combination of a VEGFR-2 inhibitor, an antibody-drug conjugate including an anti-CEACAM5 antibody, and an anti-PD-1 antibody or an anti-PD-L1 antibody for use in treating cancer.

[0355] This combination is intended for sequential administration of a VEGFR-2 inhibitor, an antibody-drug conjugate including an anti-CEACAM5 antibody, and an anti-PD-1 antibody or anti-PD-L1 antibody.

[0356] The treatment methods or uses disclosed herein may achieve synergistic effects in reducing tumor size.

[0357] The treatment methods or uses disclosed herein may achieve synergistic effects in inhibiting tumor growth.

[0358] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0359] This disclosure also relates to a combination for the manufacture of a pharmaceutical product for the treatment of cancer, comprising an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or an anti-PD-L1 antibody. The pharmaceutical product may contain antibodies formulated individually in separate containers.

[0360] In one embodiment, the present disclosure relates to the use of a combination of (i) an antibody-drug conjugate disclosed herein, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody for the manufacture of a pharmaceutical composition or kit for the treatment of cancer. The pharmaceutical composition or kit may contain antibodies formulated individually in separate containers.

[0361] In one embodiment, the combination allows for the simultaneous, separate, or sequential administration of an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0362] In one embodiment, the combination allows for the simultaneous administration of an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0363] In one embodiment, the combination allows for the separate administration of an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0364] In one embodiment, the combination allows for the sequential administration of an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0365] In further embodiments, the combinations described herein are pharmaceutical combinations.

[0366] In further embodiments, the combination according to this disclosure is a pharmaceutical parts kit.

[0367] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0368] According to some embodiments, ADCs, VEGFR-2 inhibitors, and anti-PD-1 antibodies or anti-PD-L1 antibodies are administered simultaneously, separately, or sequentially to subjects requiring them.

[0369] According to one embodiment, ADC, VEGFR-2 inhibitor, and anti-PD-1 antibody or anti-PD-L1 antibody are administered simultaneously to the target in need. For example, ADC, VEGFR-2 inhibitor, and anti-PD-1 antibody or anti-PD-L1 antibody are administered almost simultaneously on day 1 of the treatment cycle. The simultaneous administration of ADC, VEGFR-2 inhibitor, and anti-PD-1 antibody or anti-PD-L1 antibody may be via the same route.

[0370] According to one embodiment, the ADC, VEGFR-2 inhibitor, and anti-PD-1 antibody or anti-PD-L1 antibody are administered separately to the subject in need. For example, the ADC, VEGFR-2 inhibitor, and anti-PD-1 antibody or anti-PD-L1 antibody are administered on day 1 of the cycle, by separate routes, or at separate locations on the subject's body. The separate administrations of the ADC, VEGFR-2 inhibitor, and anti-PD-1 antibody or anti-PD-L1 antibody may occur simultaneously or at close intervals, for example, within 5 minutes or less.

[0371] According to one embodiment, an ADC, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or anti-PD-L1 antibody are administered sequentially to the subject requiring them. For example, the ADC, VEGFR-2 inhibitor, and anti-PD-1 antibody or anti-PD-L1 antibody are administered at different times on day 1 of the cycle, for example, the ADC is administered 1 to 3 hours after the VEGFR-2 inhibitor, and the anti-PD-1 antibody or anti-PD-L1 antibody is administered 1 to 3 hours after the ADC. The sequential administration of the ADC, VEGFR-2 inhibitor, and anti-PD-1 antibody or anti-PD-L1 antibody may be via separate routes or the same route. The sequential administration of the ADC, VEGFR-2 inhibitor, and anti-PD-1 antibody or anti-PD-L1 antibody may include the administration of the ADC after the VEGFR-2 inhibitor and the administration of the anti-PD-1 antibody or anti-PD-L1 antibody after the ADC. ADC may be administered approximately 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours after the VEGFR-2 inhibitor and the anti-PD-1 antibody or anti-PD-L1 antibody, and the anti-PD-1 antibody or anti-PD-L1 antibody may be administered approximately 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or 6 hours after the ADC. The anti-CEACAM5 antibody may be administered approximately 1 hour after the anti-PD-1 antibody or anti-PD-L1 antibody.

[0372] In sequential administration, the interval between the administration of an antibody-drug conjugate containing an anti-PD-1 antibody or anti-PD-L1 antibody and an anti-CEACAM5 antibody, and the administration of a VEGFR-2 inhibitor and an ADC, may last from several minutes to several hours, several days, or several weeks. In some embodiments, the interval may range from about 5 minutes to about 3 hours, for example, 10 minutes to about 2.5 hours, about 30 minutes to about 2 hours, or about 1 hour to about 1.5 hours. The interval between administrations 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.

[0373] In some embodiments, the VEGFR-2 inhibitor 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.

[0374] In some embodiments, the VEGFR-2 inhibitor is administered over a period of one hour.

[0375] In some embodiments, the antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered for a period ranging from about 30 minutes to about 3 hours, or about 45 minutes to about 2.5 hours, or about 1 hour to about 2 hours, or about 1.5 hours. In some embodiments, the period may be about 1.5 hours.

[0376] In some embodiments, the antibody-drug conjugate containing an anti-CEACAM5 antibody is administered over a period of 1.5 hours.

[0377] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 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.

[0378] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody is administered over a period of one hour.

[0379] In some embodiments, (i) an antibody-drug conjugate, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody are administered sequentially to the target in need.

[0380] In some embodiments, in sequential administration, the interval between the administration of an antibody-drug conjugate containing an anti-PD-1 antibody or anti-PD-L1 antibody and an anti-CEACAM5 antibody and the administration of a VEGFR-2 inhibitor and an ADC may range from about 5 minutes to about 3 hours, for example, 10 minutes to about 2.5 hours, about 30 minutes to about 2 hours, or about 1 hour to about 1.5 hours. In sequential administration on the same day of the cycle, the interval 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.

[0381] In one embodiment, in sequential administration, the time between the administration of an antibody-drug conjugate containing an anti-PD-1 antibody or an anti-PD-L1 antibody and an anti-CEACAM5 antibody and the administration of a VEGFR-2 inhibitor and an ADC may be at least 1 hour.

[0382] In sequential administration, antibody-drug conjugates (ADCs) containing anti-CEACAM5 antibodies may be administered after or before anti-VEGFR-2 antibodies.

[0383] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered after an anti-VEGFR-2 antibody.

[0384] In sequential administration, antibody-drug conjugates (ADCs) containing anti-CEACAM5 antibodies may be administered after or before anti-PD-1 antibodies or anti-PD-L1 antibodies.

[0385] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered before an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0386] In some embodiments, the order of administration of the antibody-drug conjugate containing an anti-CEACAM5 antibody and an anti-PD-1 antibody or anti-PD-L1 antibody may be the same throughout all treatment cycles.

[0387] In some embodiments, the VEGFR-2 inhibitor may be administered before the antibody-drug conjugate, and the antibody-drug conjugate may be administered before the anti-PD-1 antibody or the anti-PD-L1 antibody.

[0388] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0389] In some embodiments, the administration order of an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or anti-PD-L1 antibody may vary along the treatment cycle. In some embodiments, one or more treatment cycles may include a first administration order, and one or more treatment cycles may include a second administration order, where the first and second orders are different.

[0390] In some embodiments, for example in use for treating cancer, in the first cycle of treatment, the antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered after the VEGFR-2 inhibitor and before the anti-PD-1 antibody or anti-PD-L1 antibody, and in subsequent cycles of treatment, the ADC may be administered after the VEGFR-2 inhibitor and before the anti-PD-1 antibody or anti-PD-L1 antibody.

[0391] In some embodiments, for example in use for treating cancer, in the first cycle of treatment, the antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered after the VEGFR-2 inhibitor and before the anti-PD-1 antibody or anti-PD-L1 antibody, and in subsequent cycles of treatment, the ADC may be administered before the VEGFR-2 inhibitor and before the anti-PD-1 antibody or anti-PD-L1 antibody.

[0392] In some embodiments, for example in use for treating cancer, in the first cycle of treatment, the antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered before the VEGFR-2 inhibitor and before the anti-PD-1 antibody or anti-PD-L1 antibody, and in subsequent cycles of treatment, the ADC may be administered before the VEGFR-2 inhibitor and before the anti-PD-1 antibody or anti-PD-L1 antibody.

[0393] In some embodiments, the administration order of the antibody-drug conjugate containing an anti-CEACAM5 antibody, the VEGFR-2 inhibitor, and the anti-PD-1 antibody or anti-PD-L1 antibody remains constant throughout the treatment cycle. In some embodiments, the VEGFR-2 inhibitor is administered before the antibody-drug conjugate, and the antibody-drug conjugate is administered before the anti-PD-1 antibody or anti-PD-L1 antibody.

[0394] In some embodiments, for example, in use to treat cancers such as gastric cancer, GEJ adenocarcinoma, pancreatic cancer, or lung cancer, an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered after a VEGFR-2 inhibitor and before an anti-PD-1 antibody or anti-PD-L1 antibody for the first and all subsequent treatment cycles.

[0395] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0396] In some embodiments, the administration regimen may include doses administered over a period of about 10 minutes to about 48 hours, or about 1 hour to about 48 hours, for example, 1 hour to 4 hours. In some embodiments, the administration regimen may include doses administered over a period of about 1 hour.

[0397] In one aspect of this embodiment, the administration frequency changes from twice a week to once every three weeks, for example, every two weeks or every three weeks.

[0398] In one aspect of this embodiment, the administration frequency may be once every three weeks.

[0399] In one embodiment, the treatment period is at least 4 or 6 months.

[0400] Treatment cycle The treatment or course of treatment may include at least one treatment cycle.

[0401] 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.

[0402] In further embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or anti-PD-L1 antibody may be administered for treatment comprising approximately 8 to approximately 16 cycles. According to one embodiment, the cycles may be selected from 1-week cycles, 2-week cycles, 3-week cycles, 4-week cycles, 5-week cycles, 6-week cycles, or longer cycles.

[0403] The first cycle and the additional cycles may be the same or different.

[0404] For example, the first cycle may include the administration of a loading dose (or first dose), and additional cycles may include the administration of subsequent doses (or second doses), i.e., different doses for the loading and subsequent doses.

[0405] In this disclosure, the terms “additional cycle” and “subsequent cycle” are used interchangeably.

[0406] Alternatively, the first cycle and additional cycles may involve the administration of the same dose, i.e., the same dose for the loading and subsequent doses. In such embodiments, the “loading” and “subsequent” doses are referred to as “doses.”

[0407] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered in different doses for the loading dose in the first cycle and the subsequent dose in additional cycles, i.e., loading and subsequent doses.

[0408] In some embodiments, the antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered in the same dose in the first cycle and subsequent cycles, i.e., the same dose for loading and subsequent doses.

[0409] In some embodiments, the VEGFR-2 inhibitor may be administered in a loading dose in the first cycle and in subsequent doses in additional cycles, i.e., different doses may be administered for the loading and subsequent doses.

[0410] In some embodiments, the VEGFR-2 inhibitor may be administered in the same dose in the first cycle and subsequent cycles, i.e., the same dose for loading and subsequent doses.

[0411] In some embodiments, an anti-PD-1 antibody or anti-PD-L1 antibody may be administered in a loading dose in the first cycle and in subsequent doses in additional cycles, i.e., different doses may be administered for the loading and subsequent doses.

[0412] In some embodiments, an anti-PD-1 antibody or an anti-PD-L1 antibody may be administered in the same dose in the first cycle and subsequent cycles, i.e., the same dose for loading and subsequent doses.

[0413] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered in the same dose in the first cycle and subsequent cycles, and a VEGFR-2 inhibitor and an anti-PD-1 antibody or anti-PD-L1 antibody may be administered in the same dose in the first cycle and subsequent cycles, i.e., the loading and subsequent doses.

[0414] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered in different doses for the loading dose in the first cycle and the subsequent dose in the additional cycle, i.e., for the loading and subsequent doses; a VEGFR-2 inhibitor may be administered in the same dose for the first cycle and the additional cycle, i.e., for the loading and subsequent doses; and an anti-PD-1 antibody or anti-PD-L1 antibody may be administered in the same dose for the first cycle and the additional cycle, i.e., for the loading and subsequent doses.

[0415] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered in different doses for the loading dose in the first cycle and the subsequent dose in the additional cycle, i.e., for the loading and subsequent doses; a VEGFR-2 inhibitor may be administered in different doses for the loading dose in the first cycle and the subsequent dose in the additional cycle, i.e., for the loading and subsequent doses; and an anti-PD-1 antibody or an anti-PD-L1 antibody may be administered in the same dose for the first cycle and the additional cycle, i.e., for the loading and subsequent doses.

[0416] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0417] The treatment cycle can last approximately 1 to 6 weeks, 1 to 4 weeks, or 1 to 3 weeks.

[0418] In some embodiments, the treatment cycle may last for at least about two weeks.

[0419] In some embodiments, the treatment cycle may last for at least about three weeks.

[0420] In some embodiments, a treatment cycle may include a treatment period of at least one day of the cycle, for example, day 1, day 2, day 3, day 4, day 5, or day 6, 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.

[0421] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or anti-PD-L1 antibody may be administered once per day and two on other days, either on the same day or on different days in the treatment cycle.

[0422] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and one of either an anti-PD-1 antibody or an anti-PD-L1 antibody may be administered on day 1 of the treatment cycle, while the others may be administered on day 1 or 2 of the treatment cycle.

[0423] In some embodiments, the treatment cycle, i.e., the first cycle and additional cycles, may include a treatment period on the first day of the cycle and a rest period that continues until the completion of the cycle.

[0424] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or anti-PD-L1 antibody may be administered on day 1 of the first treatment cycle and on day 1 of at least one additional treatment cycle.

[0425] Antibody-drug conjugates containing anti-CEACAM5 antibodies, VEGFR-2 inhibitors, and anti-PD-1 or anti-PD-L1 antibodies may be administered on day 1 of each treatment cycle.

[0426] A treatment (or course of treatment) may include at least one first cycle of treatment (cycle 1) and at least one additional (subsequent) cycle. A treatment may include 2–16, 3–15, 4–14, 5–13, 6–12, 7–11, 8–10, or about 9 cycles. A treatment may include 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or more cycles.

[0427] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or anti-PD-L1 antibody may be administered once per cycle. Administration may be performed on day 1 of each cycle.

[0428] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0429] ADC dosage In some embodiments, an antibody-drug conjugate comprising a VEGFR-2 inhibitor and an anti-CEACAM5 antibody and a chemotherapeutic agent for use in combination with an anti-PD-1 antibody or anti-PD-L1 antibody to treat cancer, wherein the concentration is 60 mg / m². 2 ~210 mg / m² 2 , or approximately 80 to 170 mg / m² 2 , or approximately 100 to 170 mg / m² 2 , or approximately 120 to 170 mg / m² 2 , or approximately 135 to 170 mg / m² 2 , or approximately 150-170 mg / m² 2 An antibody-drug conjugate administered at a dose is disclosed.

[0430] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0431] In some embodiments, the antibody-drug conjugate is approximately 60 to 210 mg / m². 2 , or approximately 80 to 170 mg / m² 2 , or approximately 100 to 150 mg / m² 2 It is administered in the following dosage.

[0432] In various embodiments, the antibody-drug conjugate containing an anti-CEACAM5 antibody is present in an amount of approximately 60, 70, 80, 90, 100, 110, 120, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, or approximately 210 mg / m². 2 It is administered in the following dosage.

[0433] In various embodiments, the antibody-drug conjugate containing an anti-CEACAM5 antibody is administered at approximately 60, 80, 100, 120, 135, 150, 170, 180, 190, or approximately 210 mg / m². 2 It is administered in the following dosage.

[0434] In some embodiments, the ADC is approximately 80 mg / m² 2 ~about 170mg / m 2 In this dosage, or approximately 80 mg / m² 2 ~about 150mg / m 2 At a dose of approximately 100 mg / m², or about 100 mg / m². 2 ~about 120mg / m 2 It may be administered in the following dose.

[0435] In some embodiments, the ADC is approximately 80 mg / m² 2 Or approximately 100 mg / m² 2 Or approximately 120 mg / m² 2 Or approximately 150 mg / m² 2 Or approximately 170 mg / m² 2 It may be administered in the following dose.

[0436] In some embodiments, the ADC is approximately 150 mg / m² 2 Or approximately 120 mg / m² 2 It may be administered in the following dose.

[0437] According to one embodiment, the antibody-drug conjugate containing an anti-CEACAM5 antibody is approximately 80 mg / m². 2 It is administered in the following dosage.

[0438] In some embodiments, the ADC is approximately 100 mg / m² 2 It may be administered in the following dose.

[0439] In some embodiments, the ADC is approximately 120 mg / m² 2 It may be administered in the following dose.

[0440] In some embodiments, the ADC is approximately 150 mg / m² 2 It may be administered in the following dose.

[0441] In some embodiments, the ADC is approximately 170 mg / m² 2 It may be administered in the following dose.

[0442] According to one embodiment, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose (or first dose) of approximately 80, 100, 120, 150, or approximately 170 mg / m². 2 It is administered in the following dosage.

[0443] According to one embodiment, the antibody-drug conjugate containing an anti-CEACAM5 antibody is used as a loading dose of approximately 120 or approximately 150 mg / m². 2 It is administered in the following dosage.

[0444] According to one embodiment, an antibody-drug conjugate containing an anti-CEACAM5 antibody is used as a loading dose of approximately 80 mg / m². 2 It is administered in the following dosage.

[0445] According to one embodiment, the antibody-drug conjugate containing an anti-CEACAM5 antibody is used as a loading dose of approximately 100 mg / m². 2 It is administered in the following dosage.

[0446] According to one embodiment, the antibody-drug conjugate containing an anti-CEACAM5 antibody is used as a loading dose of approximately 120 mg / m². 2 It is administered in the following dosage.

[0447] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 150 mg / m 2 as a loading dose.

[0448] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody is administered at a dose of about 170 mg / m 2 as a loading dose.

[0449] According to one embodiment, the loading dose is for a 2-week treatment cycle.

[0450] According to one embodiment, the loading dose is for a 3-week treatment cycle.

[0451] The loading dose can be administered on the first day of the first cycle.

[0452] On the first day of the first cycle, the antibody-drug conjugate comprising an anti-CEACAM5 antibody can be administered at a dose of about 80 mg / m 2 , 100 mg / m 2 , 120 mg / m 2 , 150 mg / m 2 or about 170 mg / m 2 as a dose.

[0453] On the first day of the first cycle, the antibody-drug conjugate comprising an anti-CEACAM5 antibody can be administered at a dose of about 120 mg / m 2 or about 150 mg / m 2 as a dose.

[0454] On the first day of the first cycle, the antibody-drug conjugate comprising an anti-CEACAM5 antibody can be administered at a dose of about 120 mg / m 2 as a dose.

[0455] On the first day of the first cycle, the antibody-drug conjugate comprising an anti-CEACAM5 antibody can be administered at a dose of about 150 mg / m 2 as a dose.

[0456] The first cycle of treatment can be 3 weeks.

[0457] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody can be administered as a subsequent dose (or second dose) at a dose of about 80, 100, 120, 150 or about 170 mg / m 2 .

[0458] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody can be administered as a subsequent dose (or second dose) at a dose of about 120 or about 150 mg / m 2 .

[0459] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody can be administered as a subsequent dose at a dose of about 80 mg / m 2 .

[0460] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody can be administered as a subsequent dose at a dose of about 100 mg / m 2 .

[0461] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody can be administered as a subsequent dose at a dose of about 120 mg / m 2 .

[0462] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody can be administered as a subsequent dose at a dose of about 150 mg / m 2 .

[0463] According to one embodiment, an antibody-drug conjugate comprising an anti-CEACAM5 antibody can be administered as a subsequent dose at a dose of about 170 mg / m 2 .

[0464] The subsequent dose can be administered on day 1 of the cycle following the first cycle (subsequent or additional cycles).

[0465] On day 1 of the additional cycle (at least one cycle following the first cycle), the antibody-drug conjugate containing the anti-CEACAM5 antibody is administered at approximately 80 mg / m². 2 It may be administered in the following dose.

[0466] On day 1 of the additional cycle (at least one cycle following the first cycle), the antibody-drug conjugate containing the anti-CEACAM5 antibody is administered at approximately 100 mg / m². 2 It may be administered in the following dose.

[0467] On day 1 of the additional cycle (at least one cycle following the first cycle), the antibody-drug conjugate containing the anti-CEACAM5 antibody was administered at approximately 120 mg / m². 2 It may be administered in the following dose.

[0468] On day 1 of the additional cycle (at least one cycle following the first cycle), the antibody-drug conjugate containing the anti-CEACAM5 antibody is administered at approximately 150 mg / m². 2 It may be administered in the following dose.

[0469] On day 1 of the additional cycle (at least one cycle following the first cycle), the antibody-drug conjugate containing the anti-CEACAM5 antibody was administered at approximately 170 mg / m². 2 It may be administered in the following dose.

[0470] The subsequent (or additional) cycle of treatment may be 3 weeks.

[0471] According to one embodiment, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered in the first cycle of treatment, for example on day 1, as a loading dose of about 80, 100, 120, 150, or about 170 mg / m². 2 The dose is given first, and then in an additional cycle, for example on day 1, the subsequent dose is approximately 80, 100, 120, 150, or approximately 170 mg / m². 2 It is administered in the following dosage.

[0472] According to one embodiment, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered in the first cycle of treatment, for example, on day 1, as a loading dose of about 120 or about 150 mg / m². 2 The initial dose is followed by a subsequent dose of approximately 120 or 150 mg / m² on, for example, day 1 of the additional cycle. 2 It is administered in the following dosage.

[0473] According to one embodiment, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1, for example, during the first cycle of treatment. 2 The initial dose is followed by a subsequent dose of approximately 120 or 150 mg / m² on, for example, day 1 of the additional cycle. 2 It is administered in the following dosage.

[0474] According to one embodiment, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first cycle of treatment. 2 The dose is given as follows, and then on day 1 of the additional cycle, a subsequent dose of approximately 120 or approximately 150 mg / m² is given. 2 It is administered in this dose. The cycle may be approximately 3 weeks.

[0475] According to one embodiment, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first cycle of treatment. 2 At this dose, then on day 1 of the additional cycle, a subsequent dose of approximately 150 mg / m² is administered. 2 It is administered in this dose. The cycle may be approximately 3 weeks.

[0476] According to one embodiment, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first cycle of treatment. 2 At this dose, then on day 1 of the additional cycle, a subsequent dose of approximately 120 mg / m² is administered. 2 It is administered in this dose. The cycle may be approximately 3 weeks.

[0477] In certain embodiments, the body surface area (BSA) is 2.2 m².2 For patients with the above condition, the dose of antibody-drug conjugate containing anti-CEACAM5 antibody is 2.2m 2 It can be calculated based on the BSA.

[0478] The antibody-drug conjugate may be tusamitamabrabutansine (huMAb2-3-SPDB-DM4).

[0479] VEGFR-2 inhibitor dosage In some embodiments, VEGFR-2 inhibitors may be administered in doses of 2 mg / kg to 20 mg / kg, 4 mg / kg to 18 mg / kg, 5 mg / kg to 16 mg / kg, 6 mg / kg to 15 mg / kg, 7 mg / kg to 14 mg / kg, 7.5 mg / kg to 13 mg / kg, 8 mg / kg to 12 mg / kg, and 8.5 mg / kg to 10 mg / kg.

[0480] In some embodiments, the VEGFR-2 inhibitor may be administered at a dose of 2 mg / kg or 4 mg / kg.

[0481] In some embodiments, the VEGFR-2 inhibitor may be administered in doses of 5 mg / kg to 10 mg / kg.

[0482] In some embodiments, VEGFR-2 inhibitors may be administered in doses of 7.5 mg / kg to 15 mg / kg.

[0483] In some embodiments, the VEGFR-2 inhibitor may be administered in doses of 2, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 mg / kg.

[0484] In some embodiments, the VEGFR-2 inhibitor may be administered in doses of 2, 4, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 11, 12, 13, 14, or 15 mg / kg.

[0485] In some embodiments, the VEGFR-2 inhibitor may be administered every two weeks.

[0486] In some embodiments, the VEGFR-2 inhibitor may be administered every three weeks.

[0487] VEGFR-2 inhibitors are administered in doses of 2 mg / kg to 20 mg / kg, or approximately 4 to 15 mg / kg, or approximately 6 to 10 mg / kg, or approximately 8 mg / kg, or approximately 10 mg / kg. VEGFR-2 inhibitors may be administered in doses of approximately 2, 4, 6, 8, 10, 12, 14, 16, 18, or approximately 20 mg / kg.

[0488] In some embodiments, the VEGFR-2 inhibitor may be administered in doses of 6 mg / kg, 8 mg / kg, or 10 mg / kg.

[0489] In some embodiments, the VEGFR-2 inhibitor may be administered at a dose of approximately 6 mg / kg.

[0490] In some embodiments, the VEGFR-2 inhibitor may be administered at a dose of approximately 8 mg / kg.

[0491] In some embodiments, the VEGFR-2 inhibitor may be administered at a dose of approximately 10 mg / kg.

[0492] According to one embodiment, the VEGFR-2 inhibitor is administered as a loading dose (or first dose) of approximately 6 mg / kg, 8 mg / kg, or 10 mg / kg.

[0493] According to one embodiment, the VEGFR-2 inhibitor is administered as a loading dose of approximately 8 mg / kg or 10 mg / kg.

[0494] According to one embodiment, the VEGFR-2 inhibitor is administered at a loading dose of approximately 6 mg / kg.

[0495] According to one embodiment, the VEGFR-2 inhibitor is administered at a loading dose of approximately 8 mg / kg.

[0496] According to one embodiment, the VEGFR-2 inhibitor is administered at a loading dose of approximately 10 mg / kg.

[0497] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0498] According to one embodiment, the load dose is for a two-week treatment cycle.

[0499] According to one embodiment, the loading dose is for a 3-week treatment cycle.

[0500] The loading dose may be administered on day 1 of the first cycle.

[0501] On day 1 of the first cycle, the antibody-drug conjugate containing the anti-CEACAM5 antibody may be administered at a dose of approximately 6 mg / kg, 8 mg / kg, or 10 mg / kg.

[0502] On day 1 of the first cycle, the antibody-drug conjugate containing the anti-CEACAM5 antibody may be administered at a dose of approximately 8 mg / kg or approximately 10 mg / kg.

[0503] On day 1 of the first cycle, the antibody-drug conjugate containing the anti-CEACAM5 antibody may be administered at a dose of approximately 8 mg / kg.

[0504] On day 1 of the first cycle, the antibody-drug conjugate containing the anti-CEACAM5 antibody may be administered at a dose of approximately 10 mg / kg.

[0505] The first treatment cycle may be 3 weeks.

[0506] According to one embodiment, the VEGFR-2 inhibitor may be administered as a subsequent dose (or second dose) of approximately 6 mg / kg, 8 mg / kg, or approximately 10 mg / kg.

[0507] According to one embodiment, a VEGFR-2 inhibitor may be administered as a subsequent dose (or second dose) at approximately 8 or approximately 10 mg / kg.

[0508] According to one embodiment, a VEGFR-2 inhibitor may be administered as a subsequent dose of approximately 6 mg / kg.

[0509] According to one embodiment, a VEGFR-2 inhibitor may be administered as a subsequent dose of approximately 8 mg / kg.

[0510] According to one embodiment, a VEGFR-2 inhibitor may be administered as a subsequent dose of approximately 10 mg / kg.

[0511] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0512] Subsequent doses may be administered on day 1 of the cycle (subsequent or additional cycle) following the first cycle.

[0513] On day 1 of an additional cycle (at least one cycle following the first cycle), an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered at a dose of approximately 6 mg / kg.

[0514] On day 1 of an additional cycle (at least one cycle following the first cycle), an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered at a dose of approximately 8 mg / kg.

[0515] On day 1 of an additional cycle (at least one cycle following the first cycle), an antibody-drug conjugate containing an anti-CEACAM5 antibody may be administered at a dose of approximately 10 mg / kg.

[0516] The subsequent treatment cycle may be three weeks.

[0517] According to one embodiment, the VEGFR-2 inhibitor is administered in a first treatment cycle, for example on day 1, as a loading dose of about 8 or about 10 mg / kg, and then in an additional cycle, for example on day 1, as a subsequent dose of about 6, 8, or about 10 mg / kg.

[0518] According to one embodiment, the VEGFR-2 inhibitor is administered in a first treatment cycle, for example on day 1, as a loading dose of about 8 or about 10 mg / kg, and then in an additional cycle, for example on day 1, as a subsequent dose of about 8 or about 10 mg / kg.

[0519] According to one embodiment, the VEGFR-2 inhibitor is administered in a first treatment cycle, for example on day 1, as a loading dose of about 10 mg / kg, and then in an additional cycle, for example on day 1, as a subsequent dose of about 6, about 8, or about 10 mg / kg.

[0520] According to one embodiment, the VEGFR-2 inhibitor is administered in a first treatment cycle, for example on day 1, as a loading dose of about 10 mg / kg, and then in an additional cycle, for example on day 1, as a subsequent dose of about 8 or about 10 mg / kg.

[0521] According to one embodiment, the VEGFR-2 inhibitor is administered in a first treatment cycle, for example on day 1, as a loading dose of approximately 10 mg / kg, and then in an additional cycle, for example on day 1, as a subsequent dose of approximately 10 mg / kg.

[0522] According to one embodiment, the VEGFR-2 inhibitor is administered in a first treatment cycle, for example on day 1, as a loading dose of approximately 10 mg / kg, and then in an additional cycle, for example on day 1, as a subsequent dose of approximately 8 mg / kg.

[0523] According to one embodiment, the VEGFR-2 inhibitor is administered in the first treatment cycle, for example on day 1, as a loading dose of approximately 10 mg / kg; then in the second treatment cycle, for example on day 1, as a subsequent dose of approximately 8 mg / kg; and then in an additional cycle, for example on day 1, as a subsequent dose of approximately 6 mg / kg.

[0524] According to one embodiment, the VEGFR-2 inhibitor is administered as a loading dose of approximately 8 or 10 mg / kg on day 1 of the first cycle of treatment, and then as a subsequent dose of approximately 6, 8, or 10 mg / kg on day 1 of the additional cycle. The cycle may be approximately 3 weeks long.

[0525] According to one embodiment, the VEGFR-2 inhibitor is administered as a loading dose of approximately 8 or 10 mg / kg on day 1 of the first cycle of treatment, and then as a subsequent dose of approximately 8 or 10 mg / kg on day 1 of the additional cycle. The cycle may be approximately 3 weeks long.

[0526] According to one embodiment, the VEGFR-2 inhibitor is administered as a loading dose of approximately 10 mg / kg on day 1 of the first cycle of treatment, and then as a subsequent dose of approximately 6, 8, or 10 mg / kg on day 1 of the additional cycle. The cycle may be approximately 3 weeks long.

[0527] According to one embodiment, the VEGFR-2 inhibitor is administered as a loading dose of approximately 10 mg / kg on day 1 of the first cycle of treatment, and then as a subsequent dose of approximately 8 or 10 mg / kg on day 1 of the additional cycle. The cycle may be approximately 3 weeks long.

[0528] In one embodiment, the VEGFR-2 inhibitor is administered as a loading dose of approximately 10 mg / kg on day 1 of the first cycle of treatment, and then as a subsequent dose of approximately 10 mg / kg on day 1 of the additional cycle. The cycle may last approximately 3 weeks.

[0529] In one embodiment, the VEGFR-2 inhibitor is administered as a loading dose of approximately 10 mg / kg on day 1 of the first cycle of treatment, and then as a subsequent dose of approximately 8 mg / kg on day 1 of the additional cycle. The cycle may last approximately 3 weeks.

[0530] According to one embodiment, the VEGFR-2 inhibitor is administered as a loading dose of approximately 10 mg / kg on day 1 of the first treatment cycle, then as a subsequent dose of approximately 8 mg / kg on day 1 of the second treatment cycle, and then as a subsequent dose of approximately 6 mg / kg on day 1 of the additional cycle. The cycle may last approximately 3 weeks.

[0531] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0532] The anti-VEGFR-2 antibody may be ramucirumab.

[0533] Dosage of anti-PD-1 antibody or anti-PD-L1 antibody In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody may be administered in doses of 100 mg to 1000 mg, 150 mg to 800 mg, 200 mg to 600 mg, 240 mg to 500 mg, or 300 mg to 400 mg.

[0534] In various embodiments, anti-PD-1 antibody or anti-PD-L1 antibody may be administered in doses of 100, 150, 200, 220, 240, 260, 280, 300, 350, 400, 500, 600, 700, 800, 900, or about 1000 mg.

[0535] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody may be administered in doses of approximately 150 mg to approximately 400 mg, or approximately 150 mg to approximately 300 mg, or approximately 200 mg. The anti-PD-1 antibody or anti-PD-L1 antibody may be administered in doses of approximately 150, 155, 160, 165, 170, 175, 185, 190, 195, 200, 205, 210, 215, 22, 225, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, or approximately 300 mg.

[0536] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody may be administered in doses of 1-10 mg / kg, 2-8 mg / kg, or 3-6 mg / kg.

[0537] In some embodiments, anti-PD-1 antibody or anti-PD-L1 antibody may be administered in doses of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg / kg.

[0538] In some embodiments, an anti-PD-1 antibody or anti-PD-L1 antibody may be administered at a dose of approximately 3 mg / kg.

[0539] In some embodiments, an anti-PD-1 antibody or an anti-PD-L1 antibody may be administered every two weeks.

[0540] In some embodiments, an anti-PD-1 antibody or an anti-PD-L1 antibody may be administered every three weeks.

[0541] In some embodiments, an anti-PD-1 antibody or an anti-PD-L1 antibody may be administered every four weeks.

[0542] In some embodiments, an anti-PD-1 antibody or anti-PD-L1 antibody may be administered in a dose of approximately 200 mg.

[0543] According to one embodiment, an anti-PD-1 antibody or anti-PD-L1 antibody is administered as a loading dose (or first dose) of approximately 150 mg to approximately 400 mg, or approximately 150 mg to approximately 300 mg, or approximately 200 mg.

[0544] According to one embodiment, an anti-PD-1 antibody or anti-PD-L1 antibody is administered at a dose of approximately 200 mg as a loading dose (or first dose).

[0545] According to one embodiment, the load dose is for a two-week treatment cycle.

[0546] According to one embodiment, the loading dose is for a 3-week treatment cycle.

[0547] The loading dose may be administered on day 1 of the first cycle.

[0548] On day 1 of the first cycle, an anti-PD-1 antibody or anti-PD-L1 antibody is administered in a dose of approximately 150 mg to 400 mg, or approximately 150 mg to 300 mg, or approximately 200 mg.

[0549] On day 1 of the first cycle, an anti-PD-1 antibody or anti-PD-L1 antibody is administered at a dose of approximately 200 mg.

[0550] The first treatment cycle may be 3 weeks.

[0551] According to one embodiment, an anti-PD-1 antibody or anti-PD-L1 antibody is administered as a subsequent dose (or second dose) in a dose of approximately 150 mg to approximately 400 mg, or approximately 150 mg to approximately 300 mg, or approximately 200 mg.

[0552] According to one embodiment, an anti-PD-1 antibody or anti-PD-L1 antibody is administered as a subsequent dose (or second dose) of approximately 200 mg.

[0553] Subsequent doses may be administered on day 1 of the cycle (subsequent or additional cycle) following the first cycle.

[0554] On day 1 of an additional cycle (at least one cycle following the first cycle), an anti-PD-1 antibody or anti-PD-L1 antibody may be administered at a dose of approximately 200 mg.

[0555] The subsequent treatment cycle may be three weeks.

[0556] According to one embodiment, an anti-PD-1 antibody or anti-PD-L1 antibody is administered in the first cycle of treatment, for example on day 1, as a loading dose of approximately 150 mg to approximately 400 mg, or approximately 150 mg to approximately 300 mg, or approximately 200 mg, and then in an additional cycle, for example on day 1, as a subsequent dose of approximately 150 mg to approximately 400 mg, or approximately 150 mg to approximately 300 mg, or approximately 200 mg.

[0557] According to one embodiment, a PD-1 antibody or anti-PD-L1 antibody is administered in the first cycle of treatment, for example on day 1, as a loading dose of approximately 200 mg, and then in an additional cycle, for example on day 1, as a subsequent dose of approximately 200 mg.

[0558] According to one embodiment, an anti-PD-1 antibody or anti-PD-L1 antibody is administered on day 1 of the first cycle of treatment as a loading dose of approximately 150 mg to approximately 400 mg, or approximately 150 mg to approximately 300 mg, or approximately 200 mg, and then on day 1 of the additional cycle as a subsequent dose of approximately 150 mg to approximately 400 mg, or approximately 150 mg to approximately 300 mg, or approximately 200 mg. The cycle may last approximately 3 weeks.

[0559] According to one embodiment, an anti-PD1 or anti-PD-L1 antibody is administered as a loading dose of approximately 200 mg on day 1 of the first treatment cycle, and then as a subsequent dose of approximately 200 mg on day 1 of the additional cycle. The cycle may last approximately 3 weeks.

[0560] In some embodiments, the anti-PD-1 antibody may be pembrolizumab.

[0561] Combination dosage According to one embodiment, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 80, 100, 120, 150, or approximately 170 mg / m² on day 1 of the first treatment cycle. 2 VEGFR-2 inhibitors may be administered in doses of approximately 8 or 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of approximately 150 mg to approximately 400 mg, or approximately 150 mg to approximately 300 mg, or approximately 200 mg as a loading dose on day 1 of the first treatment cycle.

[0562] According to one embodiment, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered in an additional cycle, for example on day 1, as a subsequent dose of about 80, 100, 120, or about 150 mg / m². 2 VEGFR-2 inhibitors may be administered in additional cycles, for example on day 1, as a subsequent dose of about 6, 8, or 10 mg / kg, and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in additional cycles, for example on day 1, as a subsequent dose of about 150 mg to about 400 mg, or about 150 mg to about 300 mg, or about 200 mg.

[0563] According to one embodiment, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 80, 100, 120, 150, or approximately 170 mg / m² on day 1 of the first cycle of treatment. 2 For additional cycles, for example on day 1, the subsequent dose may be approximately 80, 100, 120, or 150 mg / m². 2VEGFR-2 inhibitors may be administered in doses of approximately 8 or 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and in additional cycles, for example on day 1, as a subsequent dose of approximately 6, 8, or 10 mg / kg. Anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of approximately 150 mg to approximately 400 mg, or approximately 150 mg to approximately 300 mg, or approximately 200 mg as a loading dose on day 1 of the first treatment cycle, and in additional cycles, for example on day 1, as a subsequent dose of approximately 150 mg to approximately 400 mg, or approximately 150 mg to approximately 300 mg, or approximately 200 mg. A cycle may last approximately 2 or 3 weeks. A cycle may last approximately 3 weeks.

[0564] Antibody-drug conjugates may be administered after a VEGFR-2 inhibitor and before an anti-PD-1 antibody or anti-PD-L1 antibody.

[0565] In some embodiments, on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) The VEGFR-2 inhibitor is administered at a dose of 10 mg / kg, and (iii) the anti-PD-1 antibody or anti-PD-L1 antibody is administered at a dose of 200 mg.

[0566] In some embodiments, on day 1 of at least one additional treatment cycle, the antibody-drug conjugate is administered at a dose of 120 or 150 mg / m². 2 It is administered in the following dosage.

[0567] In some embodiments, the VEGFR-2 inhibitor is administered at a dose of 6, 8, or 10 mg / kg on day 1 of at least one additional treatment cycle.

[0568] In some embodiments, an anti-PD-1 antibody or anti-PD-L1 antibody is administered at a dose of 200 mg on day 1 of at least one additional treatment cycle.

[0569] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 120 or 150 mg / m² on day 1 of the first treatment cycle. 2 The dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 120 or 150 mg / m². 2 VEGFR-2 inhibitors may be administered in doses such as a loading dose of approximately 10 mg / kg on day 1 of the first treatment cycle, and a subsequent dose of approximately 6, 8, or 10 mg / kg on, for example, day 1 of an additional cycle; and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in a loading dose of approximately 200 mg on day 1 of the first treatment cycle, and a subsequent dose of approximately 200 mg on, for example, day 1 of an additional cycle.

[0570] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 The dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 120 or 150 mg / m². 2 VEGFR-2 inhibitors may be administered in doses such as a loading dose of approximately 10 mg / kg on day 1 of the first treatment cycle, and a subsequent dose of approximately 6, 8, or 10 mg / kg on, for example, day 1 of an additional cycle; and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in a loading dose of approximately 200 mg on day 1 of the first treatment cycle, and a subsequent dose of approximately 200 mg on, for example, day 1 of an additional cycle.

[0571] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 In the initial dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 120 or 150 mg / m². 2VEGFR-2 inhibitors may be administered in doses of approximately 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and approximately 8 or 10 mg / kg as a subsequent dose on, for example, day 1 of the additional cycle. Anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of approximately 200 mg as a loading dose on day 1 of the first treatment cycle, and approximately 200 mg as a subsequent dose on, for example, day 1 of the additional cycle.

[0572] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 In the initial dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 120 or 150 mg / m². 2 VEGFR-2 inhibitors may be administered in doses such as a loading dose of approximately 10 mg / kg on day 1 of the first treatment cycle, and a subsequent dose of approximately 8 mg / kg on, for example, day 1 of the additional cycle; and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in a loading dose of approximately 200 mg on day 1 of the first treatment cycle, and a subsequent dose of approximately 200 mg on, for example, day 1 of the additional cycle.

[0573] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 In the initial dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 120 or 150 mg / m². 2 VEGFR-2 inhibitors may be administered in doses of approximately 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and approximately 10 mg / kg as a subsequent dose on, for example, day 1 of the additional cycle. Anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of approximately 200 mg as a loading dose on day 1 of the first treatment cycle, and approximately 200 mg as a subsequent dose on, for example, day 1 of the additional cycle.

[0574] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 In the initial dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 120 or 150 mg / m². 2 VEGFR-2 inhibitors may be administered in doses such as a loading dose of approximately 10 mg / kg on day 1 of the first treatment cycle, and a subsequent dose of approximately 6 mg / kg on, for example, day 1 of the additional cycle; and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in a loading dose of approximately 200 mg on day 1 of the first treatment cycle, and a subsequent dose of approximately 200 mg on, for example, day 1 of the additional cycle.

[0575] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 In the initial dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 150 mg / m² 2 VEGFR-2 inhibitors may be administered in doses such as a loading dose of approximately 10 mg / kg on day 1 of the first treatment cycle, and a subsequent dose of approximately 6, 8, or 10 mg / kg on, for example, day 1 of the additional cycle; and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in a loading dose of approximately 200 mg on day 1 of the first treatment cycle, and a subsequent dose of approximately 200 mg on, for example, day 1 of the additional cycle.

[0576] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 The dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 150 mg / m² 2VEGFR-2 inhibitors may be administered in doses such as approximately 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and approximately 10 mg / kg as a subsequent dose on, for example, day 1 of the additional cycle; and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses such as approximately 200 mg as a loading dose on day 1 of the first treatment cycle, and approximately 200 mg as a subsequent dose on, for example, day 1 of the additional cycle.

[0577] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 The dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 150 mg / m² 2 VEGFR-2 inhibitors may be administered in doses such as approximately 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and approximately 8 mg / kg as a subsequent dose on, for example, day 1 of the additional cycle; and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses such as approximately 200 mg as a loading dose on day 1 of the first treatment cycle, and approximately 200 mg as a subsequent dose on, for example, day 1 of the additional cycle.

[0578] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 The dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 150 mg / m² 2 VEGFR-2 inhibitors may be administered in doses such as approximately 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and approximately 6 mg / kg as a subsequent dose on, for example, day 1 of the additional cycle; and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses such as approximately 200 mg as a loading dose on day 1 of the first treatment cycle, and approximately 200 mg as a subsequent dose on, for example, day 1 of the additional cycle.

[0579] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 In this dose, and as a subsequent dose, for example on day 1 of an additional cycle, approximately 150 mg / m² 2 VEGFR-2 inhibitors may be administered in doses of approximately 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and approximately 8 mg / kg as a subsequent dose on day 1 of the second cycle, and then approximately 6 mg / kg as a subsequent dose on day 1 of the additional cycle. Anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of approximately 200 mg as a loading dose on day 1 of the first treatment cycle, and approximately 200 mg as a subsequent dose on, for example, day 1 of the additional cycle.

[0580] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 The dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 120 mg / m² 2 VEGFR-2 inhibitors may be administered in doses of approximately 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and in additional cycles, for example on day 1, as a subsequent dose of approximately 6, 8, or 10 mg / kg; anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of approximately 200 mg as a loading dose on day 1 of the first treatment cycle, and in additional cycles, for example on day 1, as a subsequent dose of approximately 200 mg.

[0581] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 The dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 120 mg / m² 2VEGFR-2 inhibitors may be administered in doses such as approximately 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and approximately 10 mg / kg as a subsequent dose on, for example, day 1 of the additional cycle; and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses such as approximately 200 mg as a loading dose on day 1 of the first treatment cycle, and approximately 200 mg as a subsequent dose on, for example, day 1 of the additional cycle.

[0582] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 The dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 120 mg / m² 2 VEGFR-2 inhibitors may be administered in doses such as approximately 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and approximately 8 mg / kg as a subsequent dose on, for example, day 1 of the additional cycle; and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses such as approximately 200 mg as a loading dose on day 1 of the first treatment cycle, and approximately 200 mg as a subsequent dose on, for example, day 1 of the additional cycle.

[0583] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 The dose, and in additional cycles, for example on day 1, as a subsequent dose, approximately 120 mg / m² 2 VEGFR-2 inhibitors may be administered in doses such as approximately 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and approximately 6 mg / kg as a subsequent dose on, for example, day 1 of the additional cycle; and anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses such as approximately 200 mg as a loading dose on day 1 of the first treatment cycle, and approximately 200 mg as a subsequent dose on, for example, day 1 of the additional cycle.

[0584] In some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 In this dose, and as a subsequent dose, for example on day 1 of an additional cycle, approximately 120 mg / m² 2 VEGFR-2 inhibitors may be administered in doses of approximately 10 mg / kg as a loading dose on day 1 of the first treatment cycle, and approximately 8 mg / kg as a subsequent dose on day 1 of the second cycle, and then approximately 6 mg / kg as a subsequent dose on day 1 of the additional cycle. Anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of approximately 200 mg as a loading dose on day 1 of the first treatment cycle, and approximately 200 mg as a subsequent dose on, for example, day 1 of the additional cycle.

[0585] The cycle can be approximately 3 weeks.

[0586] Antibody-drug conjugates may be administered after a VEGFR-2 inhibitor and before an anti-PD-1 antibody or anti-PD-L1 antibody.

[0587] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0588] In some embodiments, on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) The VEGFR-2 inhibitor is administered at a dose of 10 mg / kg, and (iii) the anti-PD-1 antibody or anti-PD-L1 antibody is administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0589] In some embodiments, the antibody-drug conjugate is administered at a dose of 120 or 150 mg / m² on day 1 of at least one additional treatment cycle. 2 It may be administered in doses of [specify dose], and the treatment cycle may be 3 weeks.

[0590] In some embodiments, the anti-VEGFR-2 antibody is administered at a dose of 6, 8, or 10 mg / kg on day 1 of at least one additional treatment cycle, and the treatment cycle may be 3 weeks long.

[0591] In some embodiments, an anti-PD-1 antibody or anti-PD-L1 antibody is administered at a dose of 200 mg on day 1 of at least one additional treatment cycle, and the treatment cycle may be 3 weeks long.

[0592] In some embodiments, on day 1 of the first cycle of treatment, (i) the antibody-drug conjugate is administered at 120 or 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered in doses of 8 or 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered in doses of 120 or 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered in doses of 6 mg / kg, 8 mg / kg, or 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of 200 mg, with treatment cycles of 3 weeks.

[0593] In some embodiments, on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at a dose of 120 mg / m². 2 or 150 mg / m² 2 (ii) VEGFR-2 inhibitors may be administered in doses of 6 mg / kg, 8 mg / kg, or 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of 200 mg. The treatment cycle may be 3 weeks.

[0594] In some embodiments, on day 1 of the first treatment cycle and on day 1 of at least one additional treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg. The treatment cycle may be 3 weeks.

[0595] In some embodiments, on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at a dose of 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at doses of 6 mg / kg or 8 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at doses of 200 mg, with treatment cycles of 3 weeks.

[0596] In some embodiments, on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) a dose of (ii) a VEGFR-2 inhibitor may be administered at a dose of 10 mg / kg, (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered at a dose of 200 mg, on day 1 of at least one subsequent treatment cycle, (i) an antibody-drug conjugate at 150 mg / m² 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0597] In some embodiments, on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2(ii) a dose of (ii) a VEGFR-2 inhibitor may be administered at a dose of 10 mg / kg, (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered at a dose of 200 mg, on day 1 of at least one subsequent treatment cycle, (i) an antibody-drug conjugate at 150 mg / m² 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 8 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0598] In some embodiments, on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at a dose of 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 6 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0599] In some embodiments, on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at a dose of 150 mg / m². 2 (ii) a VEGFR-2 inhibitor may be administered as a subsequent dose of approximately 8 mg / kg on day 1 of the second cycle, and then as a subsequent dose of approximately 6 mg / kg on day 1 of the additional cycle, (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered as a dose of 200 mg, and the treatment cycle may be 3 weeks.

[0600] In some embodiments, on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at 120 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0601] In some embodiments, on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at 120 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 8 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0602] In some embodiments, on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at 120 mg / m². 2(ii) VEGFR-2 inhibitors may be administered at a dose of 6 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0603] In some embodiments, on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at a dose of 120 mg / m². 2 (ii) a VEGFR-2 inhibitor may be administered as a subsequent dose of approximately 8 mg / kg on day 1 of the second cycle, and then as a subsequent dose of approximately 6 mg / kg on day 1 of the additional cycle, (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered as a dose of 200 mg, and the treatment cycle may be 3 weeks.

[0604] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0605] In some embodiments, the VEGFR-2 inhibitor may be administered before the antibody-drug conjugate, and the antibody-drug conjugate may be administered before the anti-PD-1 antibody or the anti-PD-L1 antibody.

[0606] The antibody-drug conjugate may be tusamitamabrabutansine (huMAb2-3-SPDB-DM4).

[0607] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0608] In some embodiments, the anti-VEGFR-2 antibody may be ramucirumab.

[0609] In some embodiments, the anti-PD-1 antibody may be pembrolizumab.

[0610] Combination treatments for lung cancer In some embodiments, the cancer may be lung cancer.

[0611] In some embodiments, the lung cancer may be non-squamous non-small cell lung cancer (NSQ NSCLC).

[0612] In some embodiments, non-squamous non-small cell lung cancer may be advanced or metastatic NSQ NSCLC.

[0613] In certain embodiments, the subject has an NSQ NSCLC without epidermal growth factor receptor (EGFR) sensitization mutation, a v-raf mouse sarcoma virus oncogene homolog B1 (BRAF) mutation, or an anaplastic lymphoma kinase / c-ros oncogene 1 (ALK / ROS) modification.

[0614] In some embodiments, lung cancer may be a CEACAM5-positive cancer in which, as measured by immunohistochemistry, more than 50% of cancer cells have a CEACAM5 immunohistochemical intensity of ≥2+, or 1% to less than 50% of cancer cells have a CEACAM5 immunohistochemical intensity of ≥2+.

[0615] In some embodiments, the cancer may be a CEACAM5-positive cancer, where more than 50% of the cancer cells have a CEACAM5 immunohistochemical intensity of 2+ or higher as measured by immunohistochemistry.

[0616] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity of ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, or a CEACAM5 immunohistochemical intensity of ≥2+ in 1% to less than 50% of cancer cells, and (i) the antibody-drug conjugate is approximately 120 or 150 mg / m² 2(ii) VEGFR-2 inhibitors may be administered at a dose of approximately 8 or 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg.

[0617] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity of ≥2+ in ≥50% of cancer cells as measured by immunohistochemistry, or a CEACAM5 immunohistochemical intensity of ≥2+ in ≥1% to ≥50% of cancer cells, and on day 1 of the first cycle (i) the antibody-drug conjugate is 120 or 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 8 or 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a cycle of 3 weeks.

[0618] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity of ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, or a CEACAM5 immunohistochemical intensity of ≥2+ in 1% to less than 50% of cancer cells, and on day 1 of the first cycle, (i) the antibody-drug conjugate is 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a cycle of 3 weeks.

[0619] In some embodiments, the antibody-drug conjugate is administered at 120 mg / m² on day 1 of at least one additional cycle of treatment. 2 or 150 mg / m² 2 It may be administered in doses of [specify dose], and the treatment cycle may be 3 weeks.

[0620] In some embodiments, the anti-VEGFR-2 antibody is administered at a dose of 6, 8, or 10 mg / kg on day 1 of at least one additional treatment cycle, and the treatment cycle may be 3 weeks long.

[0621] In some embodiments, an anti-PD-1 antibody or anti-PD-L1 antibody is administered at a dose of 200 mg on day 1 of at least one additional treatment cycle, and the cycle may be 3 weeks long.

[0622] In some embodiments, on day 1 of the subsequent cycle, (i) the antibody-drug conjugate is administered at 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a subsequent dose of 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a subsequent dose of 200 mg, with a cycle of 3 weeks.

[0623] In some embodiments, on day 1 of the subsequent cycle, (i) the antibody-drug conjugate is administered at 120 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered in a subsequent dose of 6 or 8 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in a subsequent dose of 200 mg, with a cycle of 3 weeks.

[0624] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, and an antibody-drug conjugate containing an anti-CEACAM5 antibody is administered as a loading dose of approximately 150 mg / m² on day 1 of the first treatment cycle. 2 The dose is as follows, and on day 1 of the additional cycle, a subsequent dose of approximately 120 or 150 mg / m² is administered. 2 VEGFR-2 inhibitors may be administered in doses of approximately 10 mg / kg as a loading dose on day 1 of the first treatment cycle and approximately 6, 8, or 10 mg / kg as a subsequent dose on day 1 of the additional cycle. Anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of approximately 200 mg as a loading dose on day 1 of the first treatment cycle and approximately 200 mg as a subsequent dose on day 1 of the additional cycle. The treatment cycle is 3 weeks.

[0625] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, and on day 1 of the first treatment cycle and on day 1 of at least one additional treatment cycle, (i) the antibody-drug conjugate is 150 mg / m² 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0626] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, and on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is 150 mg / m² 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at a dose of 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered in doses of 6 mg / kg or 8 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered in doses of 200 mg, and the treatment cycle may be 3 weeks.

[0627] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, and on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is 150 mg / m² 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at a dose of 150 mg / m². 2(ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0628] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, and on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is 150 mg / m² 2 (ii) a VEGFR-2 inhibitor may be administered at a dose of 10 mg / kg, (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered at a dose of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) an antibody-drug conjugate may be administered at a dose of 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 8 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0629] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, and on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is 150 mg / m² 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at a dose of 150 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 6 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0630] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, and on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is 150 mg / m² 2 (ii) a VEGFR-2 inhibitor may be administered at a dose of 10 mg / kg, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered at a dose of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) an antibody-drug conjugate may be administered at a dose of 150 mg / m². 2 (ii) a VEGFR-2 inhibitor may be administered in a dose of approximately 8 mg / kg as a subsequent dose on day 1 of the second cycle, and then in a dose of approximately 6 mg / kg as a subsequent dose on day 1 of the additional cycle, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered in a dose of 200 mg, and the treatment cycle may be 3 weeks.

[0631] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, and on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is 150 mg / m² 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at a dose of 120 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0632] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, and on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is 150 mg / m² 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at a dose of 120 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 8 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0633] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, and on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is 150 mg / m² 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 10 mg / kg, (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) antibody-drug conjugates may be administered at a dose of 120 mg / m². 2 (ii) VEGFR-2 inhibitors may be administered at a dose of 6 mg / kg, and (iii) anti-PD-1 antibodies or anti-PD-L1 antibodies may be administered at a dose of 200 mg, with a treatment cycle of 3 weeks.

[0634] In some embodiments, lung cancer may be a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥2+ in more than 50% of cancer cells as measured by immunohistochemistry, and on day 1 of the first treatment cycle, (i) the antibody-drug conjugate is 150 mg / m² 2(ii) a VEGFR-2 inhibitor may be administered at a dose of 10 mg / kg, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered at a dose of 200 mg, and on day 1 of at least one subsequent treatment cycle, (i) an antibody-drug conjugate may be administered at 120 mg / m². 2 (ii) a VEGFR-2 inhibitor may be administered in a dose of approximately 8 mg / kg as a subsequent dose on day 1 of the second cycle, and then in a dose of approximately 6 mg / kg as a subsequent dose on day 1 of the additional cycle, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be administered in a dose of 200 mg, and the treatment cycle may be 3 weeks.

[0635] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0636] According to some embodiments, in a use or method for treating lung cancer such as non-small cell lung cancer, including non-squamous non-small cell lung cancer (NSQ NSCLC), one cycle (first cycle and additional cycles) is: i) The process of administering a VEGFR-2 inhibitor at a dose of approximately 6 to 10 mg / kg once per cycle, for example on day 1 of the cycle; ii) Approximately 120 or 150 mg / m² of antibody-drug conjugate containing anti-CEACAM5 antibody 2 For example, approximately 150 mg / m² 2 The process involves administering the dose once per cycle, for example, on day 1 of the cycle; and iii) The administration of an anti-PD-1 antibody or anti-PD-L1 antibody may include a step in which a dose of 200 mg is administered, for example, on day 1 of the cycle.

[0637] The drug can be administered on day 1 of the cycle.

[0638] The cycle is approximately 3 weeks.

[0639] Antibody-drug conjugates can be administered after anti-VEGFR-2 antibody therapy.

[0640] Antibody-drug conjugates may be administered before anti-PD-1 antibody or anti-PD-L1 antibody.

[0641] According to some embodiments, in a use or method for treating lung cancer such as non-small cell lung cancer, including non-squamous non-small cell lung cancer (NSQ NSCLC), one cycle (first cycle and additional cycles) is: i) The process of administering a VEGFR-2 inhibitor at a dose of approximately 10 mg / kg once per cycle, for example on day 1 of the cycle: ii) Approximately 150 mg / m² of antibody-drug conjugate containing anti-CEACAM5 antibody 2 The procedure involves administering the drug once per cycle, for example, on day 1 of the cycle; iii) The administration of an anti-PD-1 antibody or anti-PD-L1 antibody may include a step in which a dose of 200 mg is administered, for example, on day 1 of the cycle.

[0642] According to some embodiments, in a use or method for treating lung cancer such as non-small cell lung cancer, including non-squamous non-small cell lung cancer (NSQ NSCLC), one cycle (first cycle and additional cycles) is: i) The process of administering a VEGFR-2 inhibitor at a dose of approximately 8 mg / kg once per cycle, for example on day 1 of the cycle; ii) Approximately 150 mg / m² of antibody-drug conjugate containing anti-CEACAM5 antibody 2 The procedure involves administering the drug once per cycle, for example, on day 1 of the cycle; iii) The administration of an anti-PD-1 antibody or anti-PD-L1 antibody may include a step in which a dose of 200 mg is administered, for example, on day 1 of the cycle.

[0643] According to some embodiments, in a use or method for treating lung cancer such as non-small cell lung cancer, including non-squamous non-small cell lung cancer (NSQ NSCLC), one cycle (first cycle and additional cycles) is: i) The process of administering a VEGFR-2 inhibitor at a dose of approximately 8 mg / kg once per cycle, for example on day 1 of the cycle; ii) Approximately 120 mg / m² of antibody-drug conjugate containing anti-CEACAM5 antibody 2 The procedure involves administering the drug once per cycle, for example, on day 1 of the cycle; iii) The administration of an anti-PD-1 antibody or anti-PD-L1 antibody may include a step in which a dose of 200 mg is administered, for example, on day 1 of the cycle.

[0644] According to some embodiments, in a use or method 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 is: i) The process of administering a VEGFR-2 inhibitor at a dose of approximately 10 mg / kg once per cycle, for example on day 1 of the cycle: ii) Approximately 150 mg / m² of antibody-drug conjugate containing anti-CEACAM5 antibody 2 The procedure involves administering the drug once per cycle, for example, on day 1 of the cycle; iii) The administration of an anti-PD-1 antibody or anti-PD-L1 antibody may include a step in which a dose of 200 mg is administered once per cycle, for example on day 1 of the cycle.

[0645] In such embodiments, such a cycle may be a first cycle.

[0646] According to some embodiments, in a use or method for treating lung cancer such as non-small cell lung cancer (NSQ NSCLC), an additional cycle is provided. i) Administering a VEGFR-2 inhibitor at a dose of approximately 6, 8, or 10 mg / kg once per cycle, for example on day 1 of the cycle: ii) Approximately 120 or 150 mg / m² of antibody-drug conjugate containing anti-CEACAM5 antibody 2 The procedure involves administering the drug once per cycle, for example, on day 1 of the cycle; iii) The administration of an anti-PD-1 antibody or anti-PD-L1 antibody may include a step in which a dose of 200 mg is administered once per cycle, for example on day 1 of the cycle.

[0647] According to some embodiments, in a use or method for treating lung cancer such as non-small cell lung cancer (NSQ NSCLC), an additional cycle is provided. i) The process of administering a VEGFR-2 inhibitor at a dose of approximately 10 mg / kg once per cycle, for example on day 1 of the cycle: ii) Approximately 150 mg / m² of antibody-drug conjugate containing anti-CEACAM5 antibody 2 The process involves administering the drug once per cycle, for example, on day 1 of the cycle, and iii) The administration of an anti-PD-1 antibody or anti-PD-L1 antibody may include a step in which a dose of 200 mg is administered once per cycle, for example on day 1 of the cycle.

[0648] According to some embodiments, in a use or method for treating lung cancer such as non-small cell lung cancer (NSQ NSCLC), an additional cycle is provided. i) The procedure involves administering a VEGFR-2 inhibitor at a dose of approximately 10 mg / kg once per cycle, for example, on day 1 of the cycle: ii) Approximately 120 mg / m² of antibody-drug conjugate containing anti-CEACAM5 antibody 2 The process involves administering the dose once per cycle, for example, on day 1 of the cycle; and iii) The administration of an anti-PD-1 antibody or anti-PD-L1 antibody may include a step in which a dose of 200 mg is administered once per cycle, for example on day 1 of the cycle.

[0649] According to some embodiments, in a use or method for treating lung cancer such as non-small cell lung cancer (NSQ NSCLC), an additional cycle is provided. i) The process of administering a VEGFR-2 inhibitor at a dose of approximately 8 mg / kg once per cycle, for example on day 1 of the cycle; ii) Approximately 120 mg / m² of antibody-drug conjugate containing anti-CEACAM5 antibody 2 The process involves administering the dose once per cycle, for example, on day 1 of the cycle; and iii) The administration of an anti-PD-1 antibody or anti-PD-L1 antibody may include a step in which a dose of 200 mg is administered once per cycle, for example on day 1 of the cycle.

[0650] According to some embodiments, in a use or method for treating lung cancer such as non-small cell lung cancer (NSQ NSCLC), an additional cycle is provided. ia) The process of administering a VEGFR-2 inhibitor at a dose of approximately 8 mg / kg once during the second cycle, for example on day 1 of the second cycle, and ib) A procedure in which a VEGFR-2 inhibitor is administered at a dose of approximately 6 mg / kg once per subsequent cycle, for example on day 1 of the subsequent cycle; ii) Approximately 150 mg / m² of antibody-drug conjugate containing anti-CEACAM5 antibody 2 The procedure involves administering the drug once per cycle, for example, on day 1 of the cycle; iii) The administration of an anti-PD-1 antibody or anti-PD-L1 antibody may include a step in which a dose of 200 mg is administered, for example, on day 1 of the cycle.

[0651] According to some embodiments, in a use or method for treating lung cancer such as non-small cell lung cancer (NSQ NSCLC), an additional cycle is provided. ia) The process of administering a VEGFR-2 inhibitor at a dose of approximately 8 mg / kg once during the second cycle, for example on day 1 of the second cycle, and ib) A process in which a VEGFR-2 inhibitor is administered at a dose of approximately 6 mg / kg once per subsequent cycle, for example on day 1 of the subsequent cycle. ii) Approximately 120 mg / m² of antibody-drug conjugate containing anti-CEACAM5 antibody 2 The procedure involves administering the drug once per cycle, for example, on day 1 of the cycle; and iii) The administration of an anti-PD-1 antibody or anti-PD-L1 antibody may include a step in which a dose of 200 mg is administered, for example, on day 1 of the cycle.

[0652] One cycle can last three weeks.

[0653] In some embodiments, the VEGFR-2 inhibitor may be administered before the antibody-drug conjugate, and the antibody-drug conjugate may be administered before the anti-PD-1 antibody or the anti-PD-L1 antibody.

[0654] The antibody-drug conjugate may be tusamitamabrabutansine (huMAb2-3-SPDB-DM4).

[0655] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0656] In some embodiments, the anti-VEGFR-2 antibody may be ramucirumab.

[0657] In one embodiment, the anti-PD-1 antibody is pembrolizumab or cintilimab.

[0658] In one embodiment, the anti-PD-1 antibody is cintilimab.

[0659] In some embodiments, the anti-PD-1 antibody may be pembrolizumab.

[0660] Pharmaceutical composition or combination In some embodiments, the present disclosure relates to a pharmaceutical composition comprising (i) an antibody-drug conjugate disclosed herein, (ii) a VEGFR-2 inhibitor, (iii) an anti-PD-1 antibody or anti-PD-L1 antibody, and a pharmaceutically acceptable excipient.

[0661] In some embodiments, (i) an antibody-drug conjugate, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be formulated in a single pharmaceutical composition.

[0662] In some embodiments, (i) an antibody-drug conjugate, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be formulated in the form of two separate pharmaceutical compositions, where (a) one pharmaceutical composition may comprise an antibody-drug conjugate and a VEGFR-2 inhibitor, and the other pharmaceutical composition may comprise an anti-PD-1 antibody or anti-PD-L1 antibody; or (b) one pharmaceutical composition may comprise an antibody-drug conjugate, and the other pharmaceutical composition may comprise a VEGFR-2 inhibitor and an anti-PD-1 antibody or anti-PD-L1 antibody; or (c) one pharmaceutical composition may comprise an antibody-drug conjugate and an anti-PD-1 antibody or anti-PD-L1 antibody, and the other pharmaceutical composition may comprise a VEGFR-2 inhibitor.

[0663] In some embodiments, (i) an antibody-drug conjugate, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody may be formulated in the form of three distinct pharmaceutical compositions, where (a) the first pharmaceutical composition may comprise an antibody-drug conjugate, (b) the second pharmaceutical composition may comprise a VEGFR-2 inhibitor, and (c) the third pharmaceutical composition may comprise an anti-PD-1 antibody or anti-PD-L1 antibody.

[0664] In some embodiments, the Disclosure relates to (i) pharmaceutical compositions comprising an antibody-drug conjugate disclosed herein and a pharmaceutically acceptable excipient, (ii) pharmaceutical compositions comprising a VEGFR-2 inhibitor and a pharmaceutically acceptable excipient, and (iii) kits comprising a pharmaceutical composition comprising an anti-PD-1 antibody or an anti-PD-L1 antibody and a pharmaceutically acceptable excipient.

[0665] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0666] In some embodiments, the present disclosure relates to a pharmaceutical composition or kit disclosed herein for use in treating cancer.

[0667] When an antibody-drug conjugate, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or anti-PD-L1 antibody are formulated as three separate pharmaceutical compositions, the three separate pharmaceutical compositions may be administered simultaneously, separately, or sequentially to the target requiring them. In some embodiments, the three separate pharmaceutical compositions may be administered sequentially to the target requiring them.

[0668] In some embodiments, the pharmaceutical compositions or combinations of the present disclosure are such that an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or anti-PD-L1 antibody are administered according to the above-mentioned doses.

[0669] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0670] In some embodiments, in the uses disclosed herein, the administration of an antibody-drug conjugate comprising an anti-CEACAM5 antibody and / or a VEGFR-2 inhibitor and / or an anti-PD-1 antibody or anti-PD-L1 antibody may be carried out via parenteral routes. A suitable parenteral route may be intravenous infusion.

[0671] This disclosure further relates to a pharmaceutical composition comprising an antibody-drug conjugate containing an anti-CEACAM5 antibody, and further comprising a VEGFR-2 inhibitor and / or an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0672] This disclosure further relates to a pharmaceutical composition comprising an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor and / or an anti-PD-1 antibody or anti-PD-L1 antibody, and at least one pharmaceutically acceptable excipient.

[0673] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0674] The pharmaceutical composition may comprise an antibody-drug conjugate containing an anti-CEACAM5 antibody, ramucirumab and / or pembrolizumab, and pharmaceutically acceptable excipients.

[0675] The pharmaceutical composition may comprise an antibody-drug conjugate containing an anti-CEACAM5 antibody, ramucirumab and / or cintilimab, and pharmaceutically acceptable excipients.

[0676] The pharmaceutical composition may comprise tusamitamaburabutansine, ramucirumab and / or pembrolizumab, and pharmaceutically acceptable excipients.

[0677] According to some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or anti-PD-L1 antibody can be formulated in the form of three distinct pharmaceutical compositions: (i) one pharmaceutical composition comprising an antibody-drug conjugate containing an anti-CEACAM5 antibody; (ii) one pharmaceutical composition comprising a VEGFR-2 inhibitor; and (iii) one pharmaceutical composition comprising an anti-PD-1 antibody or anti-PD-L1 antibody.

[0678] According to some embodiments, an antibody-drug conjugate containing an anti-CEACAM5 antibody, a VEGFR-2 inhibitor, and an anti-PD-1 antibody or anti-PD-L1 antibody can be formulated in the form of three distinct pharmaceutical compositions: (i) one pharmaceutical composition comprising an antibody-drug conjugate containing an anti-CEACAM5 antibody and at least one pharmaceutically acceptable excipient; (ii) one pharmaceutical composition comprising a VEGFR-2 inhibitor and at least one pharmaceutically acceptable excipient; and (iii) one pharmaceutical composition comprising an anti-PD-1 antibody or anti-PD-L1 antibody and at least one pharmaceutically acceptable excipient.

[0679] The disclosure further relates to (i) a pharmaceutical composition comprising an antibody-drug conjugate comprising an anti-CEACAM5 antibody, (ii) a pharmaceutical composition comprising a VEGFR-2 inhibitor in separate formulations or in combination formulations, and (iii) a kit comprising a pharmaceutical composition comprising an anti-PD-1 antibody or an anti-PD-L1 antibody.

[0680] The disclosure further relates to a kit comprising (i) one pharmaceutical composition comprising an antibody-drug conjugate comprising an anti-CEACAM5 antibody and at least one pharmaceutically acceptable excipient, (ii) one pharmaceutical composition comprising a VEGFR-2 inhibitor and at least one pharmaceutically acceptable excipient, and (iii) one pharmaceutical composition comprising an anti-PD-1 antibody or an anti-PD-L1 antibody and at least one pharmaceutically acceptable excipient in separate formulations or in combination formulations.

[0681] In some embodiments, the VEGFR-2 inhibitor is an anti-VEGFR-2 antibody.

[0682] "Pharmaceutical excipients" or "pharmaceutically acceptable excipients" refer to molecular entities and compositions that, as necessary, do not cause adverse allergic reactions or other undesirable reactions when administered to mammals, particularly humans. Pharmaceutically acceptable carriers or excipients refer to any kind of non-toxic solid, semi-solid, or liquid fillers, diluents, encapsulating materials, or formulation aids.

[0683] As used herein, “pharmaceutically acceptable carrier or excipient” includes any physiologically compatible solvent, dispersion medium, coating, antimicrobial agent, and antifungal agent. Examples of suitable carriers, diluents, and / or excipients include water, amino acids, physiological saline, phosphate-buffered saline, phosphate buffer, acetate, citrate, succinate; amino acids and derivatives such as histidine, arginine, glycine, proline, and glycylglycine; inorganic salts such as NaCl and calcium chloride; sugars or polyalcohols such as dextrose, glycerol, ethanol, sucrose, trehalose, and mannitol; surfactants such as polysorbate 80, polysorbate 20, and poloxamer 188, and one or more combinations thereof. Often, it is preferable to include isotonic agents, such as sugars, polyalcohols, or sodium chloride in the composition, and the formulation may also contain antioxidants, such as tryptamine, and stabilizers, such as Tween 20.

[0684] The form, route of administration, dosage, and regimen of a pharmaceutical composition naturally depend on the condition being treated, the severity of the disease, the patient's age, weight, and sex, etc.

[0685] The pharmaceutical compositions of this disclosure can be formulated for topical, oral, parenteral, intranasal, intravenous, intramuscular, subcutaneous, or intraocular administration. In one embodiment, the pharmaceutical compositions and combinations of this disclosure are formulated for intravenous administration.

[0686] In particular, pharmaceutical compositions contain pharmaceutically acceptable vehicles or excipients for injectable formulations. These may be dry compositions, especially lyophilized compositions, that enable the formation of an injectable solution when isotonic sterile saline (such as monosodium or disodium phosphate, sodium chloride, potassium, calcium or magnesium, or mixtures of such salts), or optionally sterile water or saline.

[0687] The pharmaceutical composition may be administered through a drug combination device.

[0688] The dosage used for administration can be adapted as a function of various parameters, particularly the mode of use, the associated pathological condition, or the desired duration of treatment.

[0689] To prepare a pharmaceutical composition, an effective amount of an antibody-drug conjugate containing an anti-CEACAM5 antibody and a VEGFR-2 inhibitor can be dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium.

[0690] Pharmaceutical forms suitable for injection include sterile aqueous solutions or dispersions; preparations containing sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the immediate preparation of sterile injection solutions or dispersions. In all cases, the form must be sterile and injectable using an appropriate apparatus or system for delivery without decomposition. It must be stable under manufacturing and storage conditions and protected from contamination by microorganisms such as bacteria and fungi.

[0691] Solutions of the active compound as a free base or a pharmacokinetically acceptable salt can be prepared in water appropriately mixed with a surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, mixtures thereof, and oils. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth.

[0692] Antibody-drug conjugates containing anti-CEACAM5 antibodies can be formulated into neutral or salt compositions. Pharmaceutically acceptable salts include acid addition salts (formed with free amino groups of the protein), which are formed with inorganic acids such as hydrochloric acid or phosphoric acid, or organic acids such as acetic acid, oxalic acid, tartaric acid, or mandelic acid. 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, or procaine.

[0693] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. Appropriate fluidity can be maintained, for example, by the use of a coating such as lecithin, by subsequent particle size adjustments in the case of dispersions, and by the use of surfactants. Prevention of microbial action can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it is preferable to include an isotonic agent, such as sugar or sodium chloride. Sustained absorption of the injectable composition can be achieved by the use of absorption-delaying agents, such as aluminum monostearate and gelatin in the composition.

[0694] Sterile injectable solutions are prepared by incorporating the required amount of active compound, along with various other components listed above as needed, into a suitable solvent, followed by sterilization by filtration. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile vehicle containing a basic dispersion medium and other necessary components from those listed above. For sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient + any additional desired components from its previously sterilized filtered solution.

[0695] The preparation of larger or higher-concentration solutions for direct injection is also being considered, and the use of DMSO as a solvent is expected to result in extremely rapid penetration, allowing for the delivery of high concentrations of the active agent to small tumor areas.

[0696] Once formulated, the solution is administered in a manner compatible with the administered preparation, in a treatment-effective amount. The preparation can be easily administered in various dosage forms, such as the types of injection solutions mentioned above, but drug-releasing capsules and the like can also be used.

[0697] For parenteral administration in aqueous solutions, for example, the solution should be appropriately buffered as needed, and the liquid diluent should first be isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In this regard, sterile aqueous media that can be used are 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 injection solution, or injected into the proposed injection site (see, for example, “Remington's Pharmaceutical Sciences” 15th Edition, pages 1035-1038 and 1570-1580). Some variation in the dose will inevitably occur depending on the condition of the subject being treated. In any case, the person responsible for administration will determine the appropriate dose for each individual subject.

[0698] Other pharmaceutically acceptable forms include antibody-drug conjugates containing anti-CEACAM5 antibodies formulated for parenteral administration, such as intravenous or intramuscular injection; tablets or other solids for oral administration; time-release capsules; and any other forms currently in use.

[0699] In certain embodiments, the use of liposomes and / or nanoparticles is intended for the introduction of polypeptides into host cells. The formation and use of liposomes and / or nanoparticles are known to those skilled in the art.

[0700] Nanocapsules can generally capture compounds in a stable and reproducible manner. To avoid side effects due to intracellular polymer overload, such ultrafine particles (approximately 0.1 μm in size) are generally designed using polymers that can be degraded in vivo. Biodegradable polyalkyl-cyanoacrylate nanoparticles, or biodegradable polylactide or polylactide coglycolide nanoparticles that meet these requirements, are intended for use in this disclosure, and such particles can be readily fabricated.

[0701] Liposomes are formed from phospholipids that disperse in an aqueous medium and spontaneously form multilayer concentric bilayer vesicles (also called multilayer vesicles (MLVs)). MLVs generally have a diameter of 25 nm to 4 μm. Sonic treatment of MLVs results in the formation of smaller monolayer vesicles (SUVs) with a diameter ranging from 200 to 500 Å, containing an aqueous solution in the core. The physical properties of liposomes depend on pH, ionic strength, and the presence of divalent cations. [Examples]

[0702] The following examples illustrate the most well-known embodiments of the Disclosure. However, it should be understood that these are merely illustrative or descriptive of the application of the principles of the Disclosure. Numerous variations and alternative compositions, methods, and systems can be envisioned by those skilled in the art without departing from the spirit and scope of the Disclosure. Thus, although the Disclosure has been specifically described above, the following examples provide further details in relation to what is currently considered to be the most practical and preferred embodiments of the Disclosure.

[0703] Example 1: An open-label, single-arm trial to evaluate tusamitamablubutansine (SAR408701) used in combination with ramucirumab and pembrolizumab in patients with metastatic non-squamous non-small cell lung cancer (NSQ NSCLC) with CEACAM5-positive tumors. rational The objective of this study was to evaluate the safety, tolerability, and antitumor activity (efficacy) of tusamitamaburabutansine in combination with ramucirumab and pembrolizumab in patients with CEACAM5-positive (CEACAM5 ≥ 50%) NSQ NSCLC tumors.

[0704] The combination of tusamitamabrabutansine and ramucirumab may represent a treatment regimen with an improved safety profile compared to the docetaxel and ramucirumab combination approved for the treatment of advanced NSCLC. The addition of pembrolizumab may be a new option for the treatment of advanced NSQ NSCLC after platinum and immune checkpoint inhibitor (ICI) therapy.

[0705] Purpose and endpoint

[0706] [Table 1]

[0707] Abbreviations: ATA = Anti-treatment antibody; BOR = Best overall response; CR = Complete response; DLT = Dose-limiting toxicity; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events; NSQ NSCLC = Non-squamous non-small cell lung cancer; PK = Pharmacokinetics; PR = Partial response; RECIST = Response evaluation criteria in solid tumors.

[0708] Test design This is a phase 2, open-label, single-arm, single-cohort, multicenter study evaluating the safety, efficacy (antitumor activity), and pharmacokinetics (PK) of tusamitamabrabansin, ramucirumab, and pembrolizumab (triplet cohort) in patients with metastatic CEACAM5-positive (defined as CEACAM5 immunohistochemical [IHC] intensity ≥2+ in ≥50% of cells) NSQ NSCLC tumors previously treated with platinum-based chemotherapy and immune checkpoint inhibitors (ICIs).

[0709] The pre-screening phase corresponds to the period of tumor sample collection from participants to enable the central IHC to determine the CEACAM5 status. Only participants with NSQ NSCLC determined to be CEACAM5 positive by the central IHC underwent the protocol screening procedure during the screening period. Once the CEACAM5 results became available, only participants with a positive result (defined as CEACAM5 expression with an intensity of ≥2+ including at least 50% of the tumor cell population) in a stored tumor sample (or a fresh biopsy sample if a stored sample is unavailable) entered the screening phase.

[0710] During the screening phase, all inclusion / exclusion criteria are checked to confirm the eligibility of participants for the treatment portion.

[0711] Once participants are screened, they may be determined to be eligible for the treatment phase.

[0712] The triplet cohort has only one portion. Participants will receive ramucirumab 10 mg / kg, tusamitamaburabutansine, followed by pembrolizumab 200 mg every three weeks to assess the tolerability of the combination to be used in future clinical trials. The first three participants will receive ramucirumab 10 mg / kg, tusamitamaburabutansine 150 mg / m². 2 Next, pembrolizumab 200 mg is administered every three weeks (Q3W). Tusamitamab tansine is started at least one hour after the completion of ramucirumab infusion.

[0713] The starting dose of tusamitamabrabutansine is 150 mg / m². 2 This was defined based on findings from the first-in-human trial TED13751. In this trial, the RP2D of tusamitamabrabutancin given Q3W was 170 mg / m². 2 It was 170 mg / m². 2 Considering that the pharmacokinetic parameter of tusamitamabrabutansine exposure during cycle 1 of monotherapy in Q2W is significantly associated with the occurrence of grade 2 or higher corneal events, 150 mg / m² 2 This may reduce ocular toxicity, and the overall dose is 170 mg / m². 2 It is expected to be better tolerated than the recommended dose of 100 mg / m². 2 This corresponds to the same dose intensity as the Q2W dose.

[0714] A minimum one-week delay is required between the initial dose administered to the first participant treated in the DL cohort and the administration to the next two participants treated in the same DL cohort. If one-third or fewer of the participants treated with the initial dose experience a DLT, treat three additional participants to confirm the tolerability of the combination. - If less than 1 / 6 of participants treated with the starting dose experienced DLT, the starting dose should be RP2D. - If two out of six participants treated with the starting dose experience a DLT, the dose is gradually reduced to DL-1. If more than two-thirds of participants treated with the starting dose experience a DLT, the dose will be gradually reduced to DL-1. If one or fewer of the first three participants treated with DL-1 experience DLT, three additional participants will be treated with this DL. - If less than 1 / 6 of the participants treated with DL-1 experience DLT, DL-1 becomes RP2D. If more than 2 / 6 of participants treated with DL-1 experience DLT, an alternative dosage may be considered, or the triplet cohort may be terminated. If more than two-thirds of participants treated with DL-1 experience DLT, an alternative dosage may be considered, or the triplet cohort may be terminated. Note: If more than 2 / 6 or 2 / 3 of participants treated with DL-1 experience DLT, an alternative dosage may be considered by the sponsor from a safety perspective after consultation with the study committee (SC).

[0715] Table 4 shows the dose reduction in cases of DLT occurring in two or more of the first three participants or in six participants in the DL triplet cohort. Figure 2 shows the dose determination tree.

[0716] [Table 2]

[0717] DL = Dose level; Q3W = Every 3 weeks

[0718] Tusamitamab tansine was administered at least one hour after the completion of ramucirumab infusion. BSA 2.20m 2 For patients with the above condition, the dose of tusamitamaburabutansine is 2.20 mg. 2 Calculated based on the BSA.

[0719] The trial cutoff for the secondary objective response rate (ORR) endpoint analysis in the triplet cohort corresponds to the date on which all evaluable treated patients have undergone at least two tumor assessments after baseline, experienced a confirmed objective response, or discontinued the trial for any reason. This trial cutoff is approximately 4.5 months after the last participant's first investigational drug (IMP) administration date: 3 months for two tumor assessments and 1.5 months if confirmation of response is required.

[0720] Dose adjustment / dose delay Dose adjustments and / or cycle delays are acceptable in cases of adverse reactions. In cases of toxicity, cycle delays and dose changes should be implemented. The full dose regimen is administered, and every effort is made to maximize dose intensity.

[0721] If dose reduction is necessary, the trial intervention will be administered as shown in Table 3:

[0722] [Table 3]

[0723] Patients requiring dose reduction of tusamitamaburabutansine or ramucirumab will continue to receive dose reduction until discontinuation of tusamitamaburabutansine / ramucirumab / pembrolizumab or termination of the study.

[0724] Number of participants In the triplet cohort, approximately 74 participants were pre-screened to obtain a maximum of approximately 12 participants eligible for DLT evaluation.

[0725] Intervention group and duration The participants' study period includes the following: • Screening period: up to 28 days Treatment duration: After successful screening, enrolled participants received the study intervention until disease progression, unacceptable adverse events (AEs), or until the participant or researcher decided to discontinue treatment. Each treatment cycle would last three weeks in the triplet cohort. After discontinuation of the study intervention, participants returned to the study site approximately 30 days after the last administration of the investigational drug (IMP) or before the participant received another anticancer therapy for treatment completion evaluation, whichever came first. • Safety follow-up visits: Safety follow-up visits were conducted approximately 90 days after the last dose of iMP. Further follow-up visits were not required if ongoing related AEs / SAEs had resolved or stabilized. The expected duration of the study intervention for participants varied based on the date of disease progression; the median expected duration of the trial per participant was estimated at 11 months (up to 1 month for screening, 6 months for treatment, and 4 months for treatment completion evaluation and safety follow-up visits).

[0726] Trial intervention The trial interventions include tusamitamaburabutansine, ramucirumab, and pembrolizumab. Premedication will be administered before each dose to prevent hypersensitivity reactions. Each treatment cycle will last for three weeks in the triplet cohort.

[0727] The test drugs administered to the triplet cohort are detailed in Table 4.

[0728] [Table 4]

[0729] Investigational drug On day 1 of each treatment cycle, the patient's BSA is determined using their current weight and baseline height, and the dose may not be adjusted if the weight change is ≤5%.

[0730] Ramucirumab Ramucirumab is administered before the administration of tusamitamabrabutansine.

[0731] • Formulation: CYRAMZA® (ramucirumab) is a concentrated injectable solution supplied in 10 mL or 50 mL single-use vials. Each vial contains either 100 mg of ramucirumab per 10 mL (10 mg / mL) or 500 mg of ramucirumab per 50 mL (10 mg / mL). • Route of administration: Intravenous (IV) infusion. • Dosage regimen: - In the triplet cohort, ramucirumab was administered as an IV infusion of 10 mg / kg over 1 hour on day 1 of every 3-week cycle. Prior to each infusion, premedication was administered (as per the approved product label) to prevent hypersensitivity reactions.

[0732] Tsusamitamabrabutanshin The tusamitamab ravtansine injection should be started at least one hour after the completion of the ramucirumab injection. • Formulation: Tusamitamaburabutansine is supplied as a 25 mL extractable volume concentrate for a 125 mg solution contained in a 30 mL Type I glass vial. • Route of administration: IV infusion. • Dosage regimen: - In the triplet cohort, tusamitamabrabutancin 150 mg / m² 2 (If SC deems it to be an appropriate dose, then 120 mg / m²) 2 The drug is administered via IV infusion over a period of 1 hour, for 30 minutes on the first day, and then every 3 weeks thereafter. ·Body surface area (BSA) 2.20m 2 For patients with the above condition, the dose of tusamitamaburabutansine is 2.2 mg. 2 It will be calculated based on the BSA.

[0733] pembrolizumab In the triplet cohort, pembrolizumab is administered after ramucirumab and tusamitamabrab tansine. • Formulation: Keytruda® (pembrolizumab) is a concentrated infusion solution supplied in a single-dose vial containing 100 mg / 4 mL (25 mg / mL) of solution. • Route of administration: Intravenous (IV) infusion. • Dosage regimen: Pembrolizumab is administered as a 200 mg intravenous infusion over 30 minutes on day 1, followed by another dose on Q3W.

[0734] Non-investigational drugs Premedication: Both tusami tamaburabu tansine and ramucirumab carry a potential risk of infusion-related allergic reactions. Therefore, an IV histamine H1 antagonist (diphenhydramine 50 mg IV or equivalent, e.g., cetirizine, promethazine, dexchlorpheniramine, subject to local approval and availability) was administered to all participants approximately 15 minutes before ramucirumab administration was required. If a participant had previously experienced an infusion-related reaction (IRR) after a dose of ramucirumab or tusami tamaburabu tansine, premedication for subsequent infusions would also include dexamethasone 10 mg IV and acetaminophen (paracetamol). All medications used as premedication are listed on the concomitant premedication page.

[0735] Statistical considerations: Calculating sample size: Triple-item cohort: The cohort will have only one component: safety run-in. To confirm RP2D, 6 to 12 DLT-evaluable participants will be enrolled.

[0736] Part 1 (safety run-in) aims to establish the recommended dose (RD) of tusamitamabrabutansine in combination with ramucirumab based on observed DLTs.

[0737] The triplet cohort (safety run-in only) is designed to evaluate the tolerability of tusamitamablubutansine in combination with ramucirumab and pembrolizumab in the NSQ NSCLC population and to confirm the recommended dose.

[0738] Main analysis group All treatment population: All registered participants were exposed to the test treatment, regardless of the amount of treatment administered. This population is the primary population for the analysis of all efficacy parameters.

[0739] DLT evaluable population: For the triplet cohort: Participants who received one cycle at at least 80% of the intended dose for each IMP in the combination. Participants must have completed cycle 1 unless they experienced DLT before the end of cycle 1.

[0740] ATA population: All treatment participants with at least one post-baseline ATA result (negative, positive, or inconclusive).

[0741] [Table 5]

[0742] statistical analysis Efficacy analysis All efficacy analyses will be performed on the entire treatment population (the primary population for the analysis of all efficacy parameters). All efficacy analyses will be summarized only for the subgroup of participants treated with the recommended dose (i.e., participants treated with the starting dose will be excluded if this differs from the RP2D).

[0743] A summary of the effectiveness analysis is shown in Table 6.

[0744] [Table 6]

[0745] ORR = Objective Performance Ratio

[0746] Analysis of secondary efficacy endpoints in the triplet cohort ORR is estimated by dividing the number of participants with confirmed objective responses (CR or PR as BOR), derived according to RECIST v1.1, by the number of participants in the analysis population.

[0747] BOR is the best tumor response observed from the first administration of IMP to disease progression, death, or initiation of post-treatment anticancer therapy, whichever comes first.

[0748] ORR is summarized for the entire treatment population using descriptive statistics. In addition, a two-tailed 95% confidence interval is calculated using the Clopper-Pearson method.

[0749] DLTs observed during the DLT observation period (Cycle 1 and Cycle 2) will be summarized for each dose level within the DLT-evaluable population. Furthermore, AEs meeting the DLT criteria in subsequent cycles will be summarized for the entire treatment population. Further details will be provided by the participants.

[0750] Analysis of the primary endpoint of the triplet cohort DLTs observed during the DLT observation period (Cycle 1) will be summarized by dose level for the DLT-evaluable population. Furthermore, AEs meeting the DLT criteria in subsequent cycles will be summarized for the entire treatment population. Details will be provided by the participants.

[0751] Analysis of safety endpoints All safety analyses are performed for the triplet cohort, for the entire treatment population in Part 1 (Safety Introduction), at both dose levels and overall.

[0752] Safety data summaries are performed by the participants. For each safety parameter, the baseline value is defined as the most recent value or measurement obtained up to the first dose of IMP.

[0753] Table 7 shows an overview of the safety analysis.

[0754] [Table 7]

[0755] ATA = Anti-treatment antibody; TEAE = Adverse event occurring under treatment; SAE = Serious adverse event; SAP = Statistical analysis plan.

[0756] The observation period is divided into four segments. The pre-screening period is defined as the time until the participant gives informed consent for pre-screening or provides supplemental informed consent (for participants with already available CEACAM5 expression results), up to the day before informed consent for screening. The screening period is defined as the time until a participant gives screening-informed consent for the first dose of IMP. The treatment period is defined as the time from the first dose of IMP to 30 days after the last dose of IMP. The post-treatment period is defined as the time from 31 days after the last dose of IMP to the closure of the study or death, whichever comes first.

[0757] The number and percentage of participants experiencing adverse events (TEAEs) occurring under treatment by primary organ class (SOC) and preferred terminology (PT) are summarized by NCI-CTCAE V5.0 grade (all grades, and grade ≥ 3) for all treated populations. Similar summaries are prepared for treatment-related TEAEs, TEAEs resulting in final discontinuation, TEAEs resulting in dose changes, serious TEAEs, TEAEs with fatal outcomes, adverse events of special interest (AESIs), and AEs / SAEs occurring during the post-treatment period. In addition, the number (%) of participants with any of the grade 5 AEs (TEAEs and post-treatment) is summarized.

[0758] Hematological and clinical chemical results, where applicable, are evaluated according to NCI-CTCAE V5.0. The number and percentage of participants with laboratory abnormalities (all grades and per grade) using the worst grade during the treatment period are provided for all treated populations.

[0759] Analysis of primary outcome measures Dose-limiting toxicities observed during the DLT observation period (cycle 1 of the triplet cohort) are summarized by dose level for the DLT-evaluable population. Furthermore, AEs meeting the DLT criteria in subsequent cycles are summarized for the entire treatment population. Further details are provided by the patients.

[0760] Analysis of all adverse events Adverse events will be collected from the time of signing the pre-screening informed consent until at least 30 days after the last infusion of the study procedure. All AEs will be classified according to NCI-CTCAE V5.0 and categorized by system organ class (SOC) / preferred term (PT) according to the latest available version of the MedDRA dictionary. • Pre-screening AEs are defined as AEs that occur during the pre-screening period. A screening AE is defined as any AE that occurs during the screening period. • An adverse event (AE) occurring under treatment is defined as an AE that develops, worsens (at the discretion of the principal investigator), or becomes serious during the treatment period. Post-treatment AEs are defined as AEs reported during the post-treatment period.

[0761] The NCI-CTCAE grade will be considered in the summary. For participants who have experienced the same PT multiple times, the highest grade will be used.

[0762] The primary focus of AE reporting is TEAEs (Thoroughly Epidemic-Related Effect). Pre-screening, screening, and post-treatment AEs will be described separately.

[0763] Adverse events that occurred under treatment: An overall overview of TEAE is provided. The number and percentage of participants who have experienced any of the following are provided: ·TEAE: • Grade 3 or higher TEAE • Grade 5 TEAE (Any TEAE with a fatal outcome during the treatment period) • Severe TEAE • TEAE that leads to final discontinuation of treatment • Treatment-related TEAE • Treatment-related TEAE grade 3 or higher • TEAE related to serious medical procedures ·AESI

[0764] The number and percentage of participants who have experienced TEAE by primary SOC and PT are summarized by the NCI-CTCAE V5.0 grade (all grades and grades 3 or higher) for all treatment populations.

[0765] Similar summaries will be prepared for treatment-related TEAEs, TEAEs resulting in final discontinuation, TEAEs resulting in dose changes, serious TEAEs, TEAEs with fatal outcomes, AESIs, and AEs / SAEs occurring during the post-treatment period. In addition, the number (%) of participants with any of the grade 5 AEs (TEAEs and post-treatment) will be summarized.

[0766] Analysis of clinical laboratory evaluation Clinical laboratory values ​​are analyzed after conversion to standard international units (IFRS). IFRS is used in all lists and tables.

[0767] Hematological and clinical chemical results, where applicable, are evaluated according to NCI-CTCAE V5.0. The number and percentage of participants with laboratory abnormalities (all grades and per grade) using the worst grade during the treatment period are provided for all treated populations.

[0768] If the NCI-CTCAE V5.0 grading scale is not applied, the number of participants with laboratory abnormalities that are outside the normal laboratory range will be displayed.

[0769] Analysis of immunogenicity Immunogenicity analysis and potential impacts on PK, safety, and efficacy should be documented in the SAP and performed on the ATA population.

[0770] Other analyses The analysis of PK, pharmacodynamics, and exploratory biomarkers is described in the statistical analysis plan and finalized before database locking.

[0771] The population PK methodology is described in a separate report provided by the Pharmacokinetics, Dynamics, and Metabolism (PKDM) Modeling and Simulation Group.

[0772] Test group Inclusion Criteria Participants are eligible to be included in the examination only if they meet all of the following criteria.

[0773] age Participants must be 18 years of age or older (or the legal age of participation in their country if they are over 18) at the time they sign the informed consent form.

[0774] Participant types and disease characteristics NSQ: Histologically or cytologically validated diagnosis of NSCLC Progression of metastatic disease that meets both of the following two criteria: a) Having progressive disease during or after platinum-based chemotherapy (at least two cycles). Subsequent treatment after platinum-based chemotherapy is not considered a separate regimen. Adjuvant / neoadjuvant treatment for patients who relapse with metastatic disease within six months of or within six months of treatment completion is considered the first-line treatment. and b) Having progressive disease during or after treatment with one immune checkpoint inhibitor (anti-PD1 / PD-L1); this can be done as monotherapy or in combination with platinum-based chemotherapy (in any order).

[0775] For tumor genotypes with sensitized EGFR mutations, BRAF mutations, or ALK / ROS alterations, disease progression was demonstrated during treatment with platinum-based chemotherapy and immune checkpoint inhibitors, in addition to treatments approved for that genotype.

[0776] CEACAM5 expression prospectively demonstrated by a 2+ or stronger intensive assessment immunohistochemistry (IHC) assay containing at least 50% of the tumor cell population in a stored tumor sample (or a fresh biopsy sample if a stored tumor sample is unavailable). At least five slides of formalin-fixed, paraffin-embedded (FFPE) tumor tissue sectioned to a thickness of 4 μm are required. If limited material is available, the patient may still be considered eligible after discussion with the donor, and they may assess and confirm that the available material is sufficient for the important assessment.

[0777] At least one measurable lesion according to RECIST v1.1, as determined by the local principal investigator's radiological assessment. A radioactive lesion can be considered measurable only if progression is demonstrated in the radioactive lesion.

[0778] Eastern Cooperative Oncology Group (ECOG) Performance Status: 0-1.

[0779] Exclusion criteria Participants will be excluded from the exam if any of the following criteria apply:

[0780] Health condition A history of uncontrolled brain metastases and leptomeningeal disease. Patients with previously treated brain metastases are stable (i.e., no evidence of progression on imaging for at least 4 weeks prior to the first dose of the study intervention, and any neurological symptoms have returned to baseline); there is no evidence of new or expanding brain metastases; and patients do not require systemic corticosteroids to manage brain metastases within 3 weeks prior to the first dose of the study intervention.

[0781] A serious concurrent illness, including any severe medical condition, that the principal investigator or sponsor believes may interfere with the patient's participation in the trial or the interpretation of the results.

[0782] A history of invasive malignant tumors other than those treated in this study within the past three years, with the exception of basal cell carcinoma or squamous cell carcinoma of excised / resected skin, in-vivo carcinoma of the cervix, or other local tumors that are considered to have been cured by local treatment.

[0783] A known acquired immunodeficiency syndrome (AIDS)-related disorder or a known HIV disease requiring antiretroviral treatment, or a history of active hepatitis A, hepatitis B (defined as either a positive HB antigen test or a positive hepatitis B virus DNA test exceeding the detection limit of the assay), or hepatitis C (defined as a known positive hepatitis C antibody result and a known quantitative hepatitis C virus (HCV) RNA result exceeding the detection limit of the assay).

[0784] Non-recovery of any prior treatment-related toxicity < Grade 2 according to NCI CTCAE V5.0, excluding alopecia, vitiligo, or active thyroiditis controlled by hormone replacement therapy.

[0785] Unresolved corneal damage or any previous corneal damage considered by an ophthalmologist to predict a higher risk of drug-induced keratopathy. Contact lens use is not permitted. Patients who use contact lenses and are unwilling to discontinue their use during the trial intervention period will be excluded.

[0786] Radiographic evidence of airway or vascular invasion or intratumoral cavity, regardless of histological findings.

[0787] A history of uncontrolled hereditary or acquired arterial thromboembolic disorder, or a history of aneurysms.

[0788] Major surgery within 28 days prior to day 1 / first IMP injection, or placement of a subcutaneous venous access device within 7 days prior to day 1. Postoperative bleeding or wound complications from surgical procedures performed in the past two months.

[0789] A history of total bleeding (defined as more than 1 / 2 teaspoon or 2.5 mL) within two months prior to the first dose of the study intervention.

[0790] Clinically relevant congestive heart failure (CHF; NYHA II-IV, or LVEF <50%), or symptomatic or poorly controlled cardiac arrhythmias.

[0791] Any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular disorder, or transient ischemic attack, within 6 months prior to the first dose of the study intervention.

[0792] Uncontrolled arterial hypertension (systolic ≥ 150 mM Hg or diastolic ≥ 90 mM Hg) despite standard medical management. Participants with a systolic pressure greater than 150 mm Hg or a diastolic pressure greater than 90 mm Hg are not eligible to participate in the study.

[0793] A severe or non-healing wound, skin ulcer, or fracture within 28 days prior to the first dose of the study intervention.

[0794] Gastrointestinal (Gi) perforation and / or fistula within 6 months prior to the first dose of the study intervention.

[0795] Significant bleeding disorder, vasculitis, or grade 3–4 gastrointestinal (Gi) bleeding within 3 months prior to the first dose of the study intervention.

[0796] History or presence of intestinal obstruction, inflammatory bowel disease, or extensive bowel resection; Crohn's disease, ulcerative colitis, or chronic diarrhea.

[0797] A medical condition with a narrow treatment area requiring co-administration of drugs metabolized by CYP450 (see Appendix 9, Section 10.9); where dose reduction cannot be considered.

[0798] Medical conditions requiring concomitant administration of a potent CYP3A inhibitor (see Appendix 10; Section 10.10), unless it can be discontinued at least two weeks before the first dose of the trial intervention.

[0799] Previous therapy / combination therapy Concurrent treatment with any other anti-cancer therapy. Prior chemotherapy in two or more lines in a metastatic setting. Pre-treatment with ramucirumab or docetaxel. Any prior therapy targeting CEACAM5. Previous treatment with meitansinoids (DM1 or DM4 antibody drug conjugate). For previous antitumor therapies (chemotherapy, targeted drugs, immunotherapy, and radiotherapy, or any treatment in clinical trials), a washout period prior to the first dose of the study intervention, whichever is shorter: less than 3 weeks or less than 5 times the half-life. Contraindications to the use of corticosteroid premedication.

[0800] Current procedural anticoagulation therapy with warfarin, low molecular weight heparin, or similar agents. Patients receiving prophylactic low-dose anticoagulation therapy are eligible if they meet the coagulation parameters defined by the inclusion criteria (INR ≤ 1.5 or PT ≤ 1.5 × ULN, and PTT / aPTT ≤ 1.5 × ULN).

[0801] Diagnostic evaluation A decline in organ function as defined by one of the following: a) Estimated glomerular filtration rate (eGFR) < 60 mL / min / 1.73 m² as estimated using serum creatinine > 1.5 × upper limit of normal range (ULN) or dietary modification in renal disease (MDRD) method. 2 1.0~1.5×ULN accompanied by [unclear]. b) Total bilirubin > 1.0 × ULN. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) > 2.5 × ULN, or AST, ALT > 5 × ULN in cases of documented liver metastases or AST, ALT > 1.5 × ULN in combination with alkaline phosphatase (ALP) > 2.5 × ULN. In patients with bone metastases, ALP > 5 × ULN with normal ALT / AST. c) Neutrophil count <1.5 × 10⁹ / L or platelet count <100 × 10⁹ / L or hemoglobin <9 g / dL (no blood transfusions within 2 weeks prior to screening)

[0802] A urine dipstick showing 2+ or higher proteinuria, or routine analysis (unless less than 1000 mg of protein is shown in a 24-hour urine collection).

[0803] Triple-term cohort exclusion A history of active autoimmune disease requiring systemic treatment within the past two years. History of allogeneic tissue / solid organ transplantation. Active infection requiring IV systemic therapy within two weeks prior to the first experimental intervention or the onset of active tuberculosis. A history of interstitial lung disease or pneumonitis requiring oral or intravenous steroids. Symptomatic herpes zoster within 3 months prior to screening. Severe allergy to humanized monoclonal antibodies. Any form of radiation therapy to the lungs >30 Gy within 6 months of the initial experimental intervention dose. Participants have received or are scheduled to receive a live vaccine within 30 days prior to the first trial intervention dose. Thyroid-stimulating hormone (TSH) outside the normal range. If TSH is outside the normal range at baseline, the subject may still be eligible if T3 and free T4 are within the normal range.

[0804] Effectiveness evaluation Regarding the triplet cohort: Tumor evaluations were performed every six weeks (with a ±7-day window), and the scheduled evaluation time was not changed in the event of cycle delay.

[0805] The disease status will be assessed at baseline by performing a chest-abdomen-pelvis CT scan or MRI and any other clinically indicated tests, and then every six weeks during the study treatment period until discontinuation of IMP; the disease status will be assessed at the end of the study treatment unless it has already been done in the last cycle.

[0806] Confirmation radiation assessments were performed at least four weeks after the initial documentation of the response.

[0807] For patients who have not received imaging within the past four weeks after discontinuation of IMP, tumor assessment should be performed using EOT.

[0808] Brain CT scans or MRIs were performed at baseline, and only patients with baseline brain lesions were followed. Imaging evaluations during the treatment period were scheduled using the date of Cycle 1, Day 1 as the reference date for all time points, and not based on the date of the previous imaging time point. Delays in imaging evaluations to accommodate treatment delays were not permitted. The same tumor evaluation technique was used throughout the study for a given lesion / participant.

[0809] Safety evaluation Physical examination A complete physical examination includes, at a minimum, an assessment of major bodily systems, including temperature, blood pressure, heart rate, and cardiovascular and central nervous systems. Weight is also measured and recorded before premedication and IMP administration at all treatment visits, and at the end of treatment and follow-up visits. Height is recorded only at screening.

[0810] ECOG performance status should be assessed before each IMP administration and at follow-up visits.

[0811] The principal investigator must pay particular attention to clinical signs associated with a history of serious illness.

[0812] Any new findings or worsening of previous findings should be reported as new adverse events (AEs).

[0813] Specific eye examination A specific, complete ophthalmic examination at baseline includes: assessment of ocular / visual symptoms and ophthalmic tests, including visual acuity, dilated slit-lamp, and Schirmer test.

[0814] Standard specific eye examinations include the following: • Evaluate ocular / visual symptoms (i.e., blurred vision, photophobia, dry eyes, etc.) at each visit before each trial intervention. Record the onset and end dates of symptoms. Visual acuity is always required during screening and when clinically instructed. • Always use a slit lamp under dilation during screening and whenever clinically instructed. • Always use the Schirmer test during screening and when clinically instructed.

[0815] In participants with ocular / visual symptoms (e.g., blurred vision, photophobia), a complete ophthalmological examination is repeated at the time of ocular toxicity, regardless of grade. Subsequently, visual acuity, dilated slit-lamp examination, and Schirmer test are repeated weekly until the condition resolves to Grade 1 (unless less frequent evaluation by an ophthalmologist based on lesion characteristics is not recommended). If recurrent ocular toxicity is observed in subsequent cycles, dilated visual acuity, slit-lamp examination, and Schirmer test are performed at the time of event onset, and then weekly until the condition resolves to Grade 1.

[0816] Vital signs Body temperature, blood pressure, and heart rate are assessed during each physical examination. Manual means are used only when automated equipment is unavailable. • Before measuring blood pressure and pulse, participants should be given at least 5 minutes of rest in a quiet environment without distractions (e.g., television, mobile phone).

[0817] Cardiac evaluation electro-cardiogram A single 12-lead ECG is required at baseline screening, before and after the initial IMP administration (within 30 minutes of infusion completion), before IMP administration in each cycle, and at the end of treatment evaluation (days 22-30 after the last IMP administration). This study can be performed on the same day as or the day before the study intervention administration. ECGs should be repeated as clinically indicated. A single 12-lead ECG was obtained using an ECG device that automatically calculates heart rate and measures PR, QRS, QT, and QTcF intervals. • ECGs are interpreted by a qualified physician at our facility as soon as possible after ECG collection, ideally while the patient is still present, for the purpose of performing additional ECGs or for immediate patient management if clinically relevant findings are identified.

[0818] Echocardiography or MUGA scan Echocardiography or multi-acquisition (MUGA) scans to assess the left ventricular ejection fraction (LVEF) are evaluated during the screening period and whenever clinically indicated.

[0819] Clinical Safety Laboratory Evaluation Generally, these tests are performed in each cycle, and during the first two cycles, blood tests and liver function tests are evaluated weekly.

[0820] If grade 4 neutropenia occurs, assess the ANc every 2-3 days until AN C ≥ 0.5 × 10⁹ / L.

[0821] In cases of abnormal liver function tests of grade 3 or higher, additional tests should be performed every 2-3 days until baseline values ​​are restored. Additional trials should be conducted where clinically appropriate. These trials can be performed on the same day or the day before administration of the trial intervention.

[0822] The principal investigator must review the laboratory test report and document this review in the source document.

[0823] Pharmacokinetics Blood samples are collected to measure the concentrations of tusamitamabrabutansine and ramucirumab.

[0824] Non-compartmental analysis The pharmacokinetic parameters of tusamitamablubutansine are calculated using a non-compartmental method from the concentrations assayed in Part 1 (Safety Introduction). Parameters include, but are not limited to, those listed in Table 8:

[0825] [Table 8]

[0826] Group approach Data from plasma concentrations of tusamitamaburabutansine are used for population PK analysis using nonlinear mixed-effects modeling. Empirical Bayesian estimates of individual exposure parameters, such as maximum concentration (Cmax), trough concentration (Ctrough), and area under the curve (AUC), are derived. The population PK analysis is reported in a separate report.

[0827] Pharmacodynamics Approximately 3 mL of venous blood samples for measuring circulating CEA should be collected during pre-screening, at baseline, and as close as possible to the treatment period as possible to the tumor evaluation.

[0828] If CEA sample collection is scheduled on the day of the procedure visit, the sample must be collected before the start of ramucirumab injection and tusamitamabrab tansine injection.

[0829] biomarkers The collection of samples for other biomarker studies is also part of this trial. The following samples are required for biomarker studies and will be collected from all participants in this trial: • Tumor tissue samples will be collected and assayed for CEACAM5 expression to determine eligibility for this test. • Collect blood samples for IgG measurement and investigate the effect of IgG levels on the PK of tusamitamablubutansine.

[0830] The level of IgG in blood collected before the infusion on day 1 of cycle 1 will be determined by the central laboratory. For this study, 2 mL of blood will be collected, corresponding to 1 mL of serum. Instructions for the collection and handling of biological samples will be provided by the sponsor in a separate laboratory manual. Samples may be stored for up to 15 years (or according to local regulations) after the last visit of the last participant for the study at a site selected by the principal investigator, to allow for further analysis of the biomarker response to trebrutinib.

[0831] Immunogenicity evaluation Blood samples will be collected from all participants to assess the presence of ATA against tusamitamabrabutansine in plasma.

[0832] Plasma samples are screened for antibodies that bind to tusamitamablubutansine, and the titers of confirmed positive samples are reported.

[0833] Example 2: Activity of the immunoconjugate huMAb2-3-SPDB-DM4, anti-muPD-1 antibody, anti-muVEGFR-2 antibody, and DC-101 as monotherapy, in dual or triplet combinations, against a subcutaneous colon MC38 syngeneic tumor model in C57Bl / 6 mice. rational Preclinical studies of PD-1 and PD-L1 blockers heavily rely on syngeneic mouse tumor models with intact immune systems, which facilitate the dismantling of immunosuppressive mechanisms in the tumor microenvironment. Commercially developed monoclonal antibodies (mAbs) targeting human PD-L1 and PD-1 do not exhibit cross-reactivity with their mouse orthologues, and surrogate anti-mouse antibodies are often used instead to inhibit these immune checkpoints (Schofield et al, Activity of murine surrogate antibodies for durvalumab and tremelimumab lacking effector function and the ability to deplete regulatory T cells in mouse models of cancer, mAbs, 2021;13:1). While functionally equivalent to treatment human antibodies, they are not strictly equivalent (IgG isotype, affinity level, biological activity, effector function, etc.). Clone RMP1-14 (rat IgG1 anti-muPD-1) was used for preclinical investigations of anti-muPD-1 surrogate mAbs, which are PD-1 blockers.

[0834] DC-101 is an antagonist rat anti-mouse VEGFR-2 mAb developed as a surrogate mAb for ramucirumab in in vivo studies because it does not cross-react with ramucirumab, as it closely resembles mouse VEGFR-2 and its biochemical and pharmacodynamic properties (Witte et al. Cancer and Metastasis Reviews. 1998;17:155-161).

[0835] In addition, the CEACAM5 protein is not expressed in rodents, and mouse tumors engineered with human CEACAM5 do not proliferate in immunocompetent mice, because these experiments are performed with huMAb2-3-SPDB-DM4 ADC at doses high enough to deliver the payload in a nonspecific manner. Administering it at high doses leverages the enhanced permeability and retention effects observed in solid tumors subcutaneously implanted in mice, thereby resulting in selective delivery of the high molecular weight drug to the tumor site.

[0836] Experimental Procedure In female C57Bl / 6 mice, the activity of huMAb2-3-SPDB-DM4, anti-muPD-1 antibody, and anti-muVEGFR-2 antibody was evaluated as monotherapy or in dual or triplet combinations in subcutaneously transplanted subcutaneous colon MC38 syngeneic tumors. The control group remained untreated. The dosage of the compounds used is given in mg / kg.

[0837] In mice, the median tumor burden was approximately 142 mm². 3 When the mice reached a certain stage, they were randomized to eight groups (six mice per group) on day 10 after tumor transplantation. huMAb2-3-SPDB-DM4 was administered at 25 mg / kg after a single intravenous (IV) dose on day 10, anti-muPD-1 antibody was administered at 10 mg / kg after intraperitoneal (IP) administration on days 10, 14, and 17, and anti-muVEGFR-2 antibody was administered at 20 mg / kg after IP administration on days 10, 14, and 17.

[0838] To evaluate antitumor activity, animal body weight was measured, and tumors were measured twice weekly using calipers. A dose that resulted in a 20% weight loss or more than 10% drug-induced death (nadir, mean of the group) was considered an excessively toxic dose. Animal body weight included tumor weight. Tumor volume was expressed using the formula mass(mm²). 3 The calculation was performed using the formula: ΔT / ΔC = [length (mm) × width (mm) × width (mm)] / 2. The primary efficacy endpoints were ΔT / ΔC, median percentage regression, partial regression, and complete regression (PR and CR).

[0839] The change in tumor volume for each treatment (T) and control (C) group is calculated for each tumor by subtracting the tumor volume on the first treatment day (stage diagnosis day) from the tumor volume on the specified observation day. The median ΔT is calculated for the treatment group and the median ΔC is calculated for the control group. Next, the ratio ΔT / ΔC is calculated and expressed as a percentage: ΔT / ΔC = (Delta T / Delta C) x 100.

[0840] The dose is considered therapeutically active when dT / dC is less than 40%, and highly active when dT / dC is less than 10%. If ΔT / ΔC is less than 0, the dose is considered highly active, and the regression percentage 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 p101-125):

[0841] % tumor regression is defined as the percentage reduction in tumor volume in the treatment group on a given observation day compared to the volume on day 1 of the initial treatment.

[0842] For a specific time point and for each animal, the percentage of regression is calculated. Next, for that group, the median percentage of regression is calculated:

number

[0843] Partial regression (PR): Regression is defined as partial if the tumor volume decreases to 50% of its initial volume at the start of treatment.

[0844] Complete regression (CR): Tumor volume = 0 mm 3 Complete regression is achieved (CR is considered when tumor volume cannot be recorded).

[0845] result The results of efficacy evaluations of the immunoconjugates huMAb2-3-SPDB-DM4, anti-muPD-1 antibody, anti-muVEGFR-2 antibody, and DC-101, used as monotherapy, in dual or triplet combinations, against a subcutaneous colon MC38 syngeneic tumor model in C57Bl / 6 mice are presented in Figures 3A-3C and Table 9.

[0846] As a monotherapy, huMAb2-3-SPDB-DM4 was active after a single IV dose at 25 mg / kg, with a ΔT / ΔC of 32% (no significant difference between control and CR) and 1 / 6 complete response at day 24.

[0847] The anti-muVEGFR-2 mAb, DC101, as a monotherapy, was inactive after three iP administrations at 20 mg / kg, with a ΔT / ΔC of 70% at D24 (not significant compared to the control).

[0848] Anti-muPD-1 mAb as monotherapy was inactive after three iP administrations at 10 mg / kg, and the ΔT / ΔC at D24 was superior to 100% (not significant compared to the control) and 1 / 6 CR.

[0849] Co-administration of anti-muVEGFR-2 mAb, DC101+, and anti-muPD-1 mAb as monotherapy was inactive after co-administration of three iPs, exhibiting a ΔT / ΔC at D24 that was superior to 100% (no significant difference between control and CR) and 1 / 6 CR.

[0850] The dual combination of huMAb2-3-SPDB-DM4 and anti-muVEGFR-2, DC101mAb, was highly active, with a ΔT / ΔC at D24 lower than 0% (p<0.0001 compared to control), and a median tumor regression of 77% and 3 / 6 complete response (CR). This dual combination was significantly more active than both mono-agent arms (huMAb2-3-SPDB-DM4 alone and anti-muVEGFR-2 alone), demonstrating a synergistic therapeutic effect.

[0851] The dual combination of huMAb2-3-SPDB-DM4 and an anti-muPD-1 mAb was active, with a ΔT / ΔC of 28% (p=0.0085 compared to control) and equivalent 3 / 6 complete response (CR) at D24.

[0852] The triplet combination of huMAb2-3-SPDB-DM4, anti-muVEGFR-2, DC101, and anti-muPD-1 mAb was highly active, with a ΔT / ΔC at D24 lower than 0% (p=0.0085 compared to control), and median tumor regression of 100% and 5 / 6 CR. The triplet combination was significantly more active than both monotherapy arms (huMAb2-3-SPDB-DM4 alone and anti-muVEGFR-2 mAb, DC101 + anti-muPD-1 mAb concurrently), demonstrating a synergistic therapeutic effect.

[0853] In conclusion, a synergistic effect was observed with the triplet combination, resulting in permanent complete regression, compared to huMAb2-3-SPDB-DM4 alone and the standard treatment regimen (consisting of co-administration of anti-muVEGFR-2 mAb, DC101 + anti-muPD-1 mAb). Furthermore, the triplet combination resulted in a longer-lasting and more robust response with durable complete regression compared to both dual combinations (huMAb2-3-SPDB-DM4 with anti-muVEGFR-2 mAb or huMAb2-3-SPDB-DM4 with anti-muPD1 mAb).

[0854] [Table 9]

Claims

1. A combination of (i) an antibody-drug conjugate (ADC) containing an anti-CEACAM5 antibody, (ii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody for use in the treatment of cancer.

2. The combination for use according to claim 1, wherein the anti-CEACAM5 antibody comprises CDR-H1 having the amino acid sequence of SEQ ID NO: 1, CDR-H2 having the amino acid sequence of SEQ ID NO: 2, CDR-H3 having the amino acid sequence of SEQ ID NO: 3, CDR-L1 having the amino acid sequence of SEQ ID NO: 4, CDR-L2 having the amino acid sequence NTR, and CDR-L3 having the amino acid sequence of SEQ ID NO:

5.

3. The combination for use according to claim 1 or 2, wherein the anti-CEACAM5 antibody is tusamitamab.

4. The antibody-drug conjugate for use according to any one of claims 1 to 3, wherein the antibody-drug conjugate comprises at least one chemotherapeutic agent.

5. The combination for use according to claim 4, wherein the cytotoxic agent is a meitansinoid selected from the group consisting of N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-meitansin (DM1), N2'-deacetyl-N2'(4-methyl-4-mercapto-1-oxopentyl)-meitansin (DM4), and any combination thereof.

6. The combination for use according to claim 4 or 5, wherein the anti-CEACAM5 antibody is covalently bonded to the at least one chemotherapeutic agent via an inclementable linker, the linker being selected from N-succinimidylpyridyl dithiobutyrate (SPDB), 4-(pyridine-2-yldisulfanyl)-2-sulfobutyrate (sulfo-SPDB), and succinimidyl (N-maleimidomethyl)cyclohexane-1-carboxylate (SMCC).

7. The combination for use according to any one of claims 1 to 6, wherein the antibody-drug conjugate is tusamitamabrabutansine.

8. The combination for use according to any one of claims 1 to 7, wherein the cancer is a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥ 2+ in 1% to less than 50% of cancer cells, or a CEACAM5-positive cancer having a CEACAM5 immunohistochemical intensity ≥ 2+ in 50% or more of cancer cells.

9. A combination for use according to any one of claims 1 to 8, wherein the cancer is selected from hepatocellular carcinoma, colorectal cancer, gastric cancer, gastroesophageal junction adenocarcinoma (GEJ), esophageal cancer, lung cancer, cervical cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer, prostate cancer, neuroendocrine cancer, and skin cancer.

10. The combination for use according to claim 9, wherein the lung cancer is non-squamous non-small cell lung cancer (NSQ NSCLC).

11. The combination for use according to any one of claims 1 to 11, wherein the anti-VEGFR-2 antibody is administered before the antibody-drug conjugate.

12. The combination for use according to any one of claims 1 to 12, wherein the antibody-drug conjugate is administered before the anti-PD-1 antibody or anti-PD-L1 antibody.

13. The combination for use according to any one of claims 1 to 13, wherein (i) the antibody-drug conjugate, (ii) the VEGFR-2 inhibitor, and (iii) the anti-PD-1 antibody or anti-PD-L1 antibody are administered on day 1 of a first and at least one additional treatment cycle.

14. The combination for use according to claim 14, wherein the treatment cycle is two weeks or three weeks.

15. The antibody-drug conjugate is 80 mg / m². ２ ~170 mg / m² ２ The dosage, or 80 mg / m² ２ ~150 mg / m² ２ The dosage, or 100 mg / m² ２ ~120 mg / m² ２ The dosage, or 150 mg / m² ２ The dosage, or 120 mg / m² ２ A combination for use according to any one of claims 1 to 15, administered in the dose of [specify dose].

16. The combination for use according to any one of claims 1 to 16, wherein the VEGFR-2 inhibitor is administered in doses of 2 mg / kg to 20 mg / kg, 4 mg / kg to 18 mg / kg, 5 mg / kg to 16 mg / kg, 6 mg / kg to 15 mg / kg, 7 mg / kg to 14 mg / kg, 7.5 mg / kg to 13 mg / kg, 8 mg / kg to 12 mg / kg, and 8.5 mg / kg to 10 mg / kg.

17. The combination for use according to any one of claims 1 to 17, wherein the anti-PD-1 antibody or the anti-PD-L1 antibody is administered in a dose of 100 mg to 1000 mg, or 150 mg to 800 mg, or 200 mg to 600 mg, or 240 mg to 500 mg, or 300 mg to 400 mg.

18. On the first day of the first treatment cycle and on the first day of at least one additional treatment cycle, (i) the body-drug conjugate is administered at a dose of 150 mg / m ２ of, (ii) the VEGFR-2 inhibitor is administered at a dose of 10 mg / kg, (iii) the anti-PD-1 antibody or anti-PD-L1 antibody is administered at a dose of 200 mg, and the treatment cycle is 3 weeks, the combination for use according to any one of claims 1 to 18.

19. The combination for use according to any one of claims 1 to 19, wherein the VEGFR-2 inhibitor is selected from an anti-VEGFR-2 antibody and a receptor tyrosine kinase inhibitor.

20. The combination for use according to claim 19, wherein the anti-VEGFR-2 antibody is ramucirumab.

21. The combination for use according to claim 19, wherein the receptor tyrosine kinase inhibitor is selected from aflibercept, nintedanib, pegaptanib, convercept, axitinib, cabozantinib, pazopanib, sorafenib, and sunitinib.

22. The combination for use according to any one of claims 1 to 20, wherein the anti-PD-1 antibody is selected from the group consisting of pembrolizumab, nivolumab, semiprimab, cintilimab, dostarimab, tislerizumab, retifanlimab, and tripalimab.

23. The combination for use according to claim 21, wherein the anti-PD-1 antibody is pembrolizumab or cintilimab.

24. (i) an antibody-drug conjugate according to any one of claims 1 to 7, (ii) a VEGFR-2 inhibitor, (iii) an anti-PD-1 antibody or anti-PD-L1 antibody, and a pharmaceutically acceptable excipient.

25. (i) a pharmaceutical composition comprising an antibody-drug conjugate according to any one of claims 1 to 7 and a pharmaceutically acceptable excipient; (ii) a pharmaceutical composition comprising a VEGFR-2 inhibitor and a pharmaceutically acceptable excipient; and (iii) a kit comprising a pharmaceutical composition comprising an anti-PD-1 antibody or anti-PD-L1 antibody and a pharmaceutically acceptable excipient.

26. A pharmaceutical composition according to any one of claims 23 to 24 or a kit according to claim 24 for use in treating cancer.

27. (i) For the manufacture of pharmaceutical compositions or kits for the treatment of cancer Use of an antibody-drug conjugate according to any one of claims 1 to 7, (iii) a VEGFR-2 inhibitor, and (iii) an anti-PD-1 antibody or anti-PD-L1 antibody in combination.

Images