Ceacam5 antibody-drug conjugate for use in cancer therapy

Abstract

Provided are compositions and methods to treat cancers that express CEACAM5 Certain aspects of the disclosure relate to monotherapy with immunoconjugates comprising an anti- CEACAM5 antibody. Other aspects of the disclosure relate to combination therapies with immunoconjugates comprising an anti-CEACAM5 antibody and a nucleoside metabolic inhibitor. The disclosed compositions are used to treat pancreatic cancer.

Description

CEACAM5 ANTIBODY-DRUG CONJUGATE FOR USE IN CANCER THERAPYREFERENCE TO SEQUENCE LISTING

[0001] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on October 15, 2025, is named PI025617_WO_SANOFI.xml, and is 12 917 bytes in size.FIELD

[0002] The present disclosure relates to cancer treatments in which the cancers express carcinoembryonic antigen-related cell adhesion molecules 5 (CEACAM5). Certain aspects of the disclosure relate to monotherapy with immunoconjugates comprising an anti-CEACAM5 antibody. Other aspects of the disclosure relate to the immunoconjugates comprising an anti- CEACAM5 antibody in combination with a nucleoside metabolic inhibitor.BACKGROUND

[0003] Antibody-drug conjugates (ADCs) have been shown to be an effective strategy for cancer treatment by selectively targeting potent cytotoxic agents to tumor cells. For example, ADCs have been approved for brentuximab vedotin for the treatment of Hodgkin lymphoma, and trastuzumab emtansine (T-DM1) for the treatment of relapsed metastatic HER2+ breast cancer.

[0004] Pancreatic cancer is an aggressive gastrointestinal cancer that accounts for tens of thousands of deaths per year in the United States. Unfortunately, it is characterized by extensive local growth and early metastasis, making surgical control of disease uncommon. As a result, chemotherapeutic agents are often employed to control growth and spread of the cancer, as well as to prolong life.

[0005] While multiple treatments have been used for individuals with pancreatic cancer, more effective treatments are needed.SUMMARY

[0006] In one aspect, the present application relates to methods of treating cancer in a subject in need thereof, the method comprising administrating to the subject an effective amount of (i) an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antigen binding fragment thereof and (ii) a nucleoside metabolic inhibitor, wherein the cancer expresses CEAC M5.

[0007] In some embodiments, the present application relates to an antibody-drug conjugate (ADC) comprising an anti-CEACAM5-antibody, or antigen binding fragment thereof, for use in combination with a nucleoside metabolic inhibitor for treating a cancer in a subject in need thereof, wherein the cancer expresses CEACAM5.

[0008] In some embodiments, the present application relates to a combination comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5-antibody, or antigen binding fragment thereof, and a nucleoside metabolic inhibitor, the combination being for use for treating a cancer in a subject in need thereof, wherein the cancer expresses CEAC M5.

[0009] The uses comprise administrating to the subject an effective amount of (i) an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antigen binding fragment thereof and (ii) a nucleoside metabolic inhibitor.

[0010] In the combination, the antibody-drug conjugate (ADC) and the nucleoside metabolic inhibitor may be administered simultaneously, separately (or concurrently), or sequentially (one being after or before the other).

[0011] In another aspect, the present application relates to methods of treating cancer in a subject in need thereof, the method comprising administrating to the subject an effective amount of (i) an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antigen binding fragment thereof and (ii) gemcitabine, wherein the cancer expresses CEAC M5.

[0012] In some embodiments, the present application relates to an antibody-drug conjugate (ADC) comprising an anti-CEACAM5-antibody, or antigen binding fragment thereof, for use in combination with gemcitabine for treating a cancer in a subject in need thereof, wherein the cancer expresses CEACAM5.

[0013] In some embodiments, the present application relates to a combination comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5-antibody, or antigen binding fragment thereof, and gemcitabine, the combination being for use for treating a cancer in a subject in need thereof, wherein the cancer expresses CEACAM5.

[0014] The uses comprise administrating to the subject an effective amount of (i) an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antigen binding fragment thereof and (ii) gemcitabine.

[0015] In the combination, the antibody-drug conjugate (ADC) and gemcitabine may be administered simultaneously, separately (or concurrently), or sequentially (one being after or before the other).

[0016] In some embodiments, the anti-CEACAM5 antibody comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acid sequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5.

[0017] In some embodiments, the anti-CEACAM5 antibody comprises a variable domain of a heavy chain (VH) consisting of the sequence of SEQ ID NO: 6 and a variable domain of a light chain (VL) consisting of the sequence of SEQ ID NO: 7.

[0018] In some embodiments, the anti-CEACAM5 antibody comprises a heavy chain (HC) consisting of the sequence of SEQ ID NO: 8 and a light chain (LC) consisting of the sequence of SEQ ID NO: 9.

[0019] In some embodiments, the anti-CEACAM5 antibody is a humanized monoclonal anti-CEACAM5 antibody.

[0020] In some embodiments, the anti-CEACAM5 antibody is tusamitamab (SAR408377).

[0021] In some embodiments, the ADC comprises at least one cytotoxic agent.

[0022] In some embodiments, the ADC comprises a cleavable or non-cleavable linker.

[0023] In some embodiments, the ADC comprises at least one cytotoxic agent and / or a cleavable linker.

[0024] In some embodiments, the ADC comprising the anti-CEACAM5 antibody is covalently attached via a cleavable or non-cleavable linker to the at least one cytotoxic agent.

[0025] In some embodiments, the ADC comprising the anti-CEACAM5 antibody comprises a cleavable linker.

[0026] In some embodiments, the linker is selected from N-succinimidyl pyridyldithiobutyrate (SPDB), 4-(Pyridin-2-yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB), and succinimidyl (N-maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC).

[0027] In some embodiments, the cleavable linker is selected from N-succinimidyl pyridyldithiobutyrate (SPDB) and 4-(Pyridin-2-yldisulfanyl)-2-sulfo-butyric acid (sulfo- SPDB).

[0028] In some embodiments, the cytotoxic agent is selected from the group consisting of antimetabolite, DNA-alkylating agent, DNA-cross-linking agent, DNA-intercalating agent, anti-microtubule agent, topoisomerase inhibitor, and any combination thereof.

[0029] In some embodiments, the cytotoxic agent is an anti-microtubule agent.

[0030] In some embodiments, the anti-microtubule agent is a maytansinoid.

[0031] In some embodiments, the maytansinoid is selected from the group consisting of N2’-deacetyl-N2’-(3-mercapto-l-oxopropyl)-maytansine (DM1), N2’-deacetyl-N2’(4-methyl- 4-mercapto-l-oxopentyl)-maytansine (DM4), and any combination thereof.

[0032] In some embodiments, the maytansinoid is DM4.

[0033] In some embodiments, the ADC is tusamitamab ravtansine (SAR408701).

[0034] In some embodiments, the cancer expresses CEACAM5 with moderate or high intensity defined by immunohistochemistry.

[0035] In some embodiments, the CEACAM5 expression is defined as a CEACAM5 immunohistochemistry (IHC) intensity of at least about 2+ in at least about 50% of tumor cells.

[0036] In certain embodiments, the subject has a cancer having a moderate CEACAM5 expression on tumor cells. A moderate CEACAM5 expression on tumor cells may be defined as being >2+ intensity in >1% and <50% of tumor cells, as measured by immunohistochemistry (IHC).

[0037] In certain embodiments, the subject has a cancer having a high CEACAM5 expression on tumor cells. A high CEACAM5 expression on tumor cells may be defined as being >2+ intensity in >50% of cells, as measured by immunohistochemistry.

[0038] In some embodiments, the subject has a cancer having a CEACAM5 expression defined as a CEACAM5 immunohistochemistry (IHC) intensity of at least about 2+ in at least about 50% of tumor cells.

[0039] In some embodiments, the cancer is pancreatic cancer.

[0040] In some embodiments, the cancer is a metastatic cancer.

[0041] In some embodiments, the cancer is pancreatic ductal adenocarcinoma.

[0042] In some embodiments, the cancer is a metastatic pancreatic ductal adenocarcinoma.

[0043] In some embodiments, the ADC is administered at a dose from about 60 mg / m2to about 210 mg / m2.

[0044] In some embodiments, the ADC is administered at a dose from 60 mg / m2to 210 mg / m2.

[0045] In some embodiments, the ADC is administered at an initial dose followed by one or more secondary doses.

[0046] In some embodiments, the ADC is administered at an initial dose from about 100 mg / m2to about 170 mg / m2.

[0047] In some embodiments, the ADC is administered at an initial dose from about 135 mg / m2to about 170 mg / m2.

[0048] In some embodiments, the ADC is administered at an initial dose of about 135 mg / m2or aboutl50 mg / m2or about 170 mg / m2.

[0049] In some embodiments, the ADC is administered at a secondary dose from about 80 mg / m2to about 100 mg / m2.

[0050] In some embodiments, the ADC is administered at a secondary dose of about 80 mg / m2or about 100 mg / m2.

[0051] In some embodiments, the ADC is administered at an initial dose from 100 mg / m2to 170 mg / m2and at a secondary dose from 80 mg / m2to 100 mg / m2.

[0052] In some embodiments, the dose is calculated based on a body surface area (BSA) of 2.20 m2if the subject’s BSA is greater than about 2.20 m2.

[0053] In some embodiments, the ADC is administered at a dose level of 5, 10, 20, 30, 40, 60, 80, 100, 120, 135, 150, 170, 180, or 210 mg / m2based on the body surface area of the subject.

[0054] In some embodiments, the ADC is administered to the subject at an initial dose of about 135 mg / m2or about 170 mg / m2on day 1 of a first cycle and at a secondary dose of about 80 mg / m2or about 100 mg / m2thereafter.

[0055] In some embodiments, the ADC is administered to the subject at an initial dose of about 135 mg / m2, or about 135 mg / m2, or about 170 mg / m2on day 1 of a first cycle and at a secondary dose of about 80 mg / m2or about 100 mg / m2thereafter.

[0056] In some embodiments, the ADC is administered at an initial dose of 135 mg / m2, 150 mg / m2, or 170 mg / m2on day 1 of a first cycle and at a secondary dose of 80 mg / m2or 100 mg / m2thereafter.

[0057] In some embodiments, a cycle is 14 days.

[0058] In some embodiments, the ADC is administered to the subject at secondary dose every two weeks.

[0059] In some embodiments, the ADC is administered intravenously.

[0060] In some embodiments, the nucleoside metabolic inhibitor is administered after the ADC.

[0061] In some embodiments, the nucleoside metabolic inhibitor is gemcitabine.

[0062] In some embodiments, the nucleoside metabolic inhibitor is administered at a dose from about 600 mg / m2to about 1000 mg / m2.

[0063] In some embodiments, the nucleoside metabolic inhibitor is administered at a dose from about 600 mg / m2to about 1000 mg / m2for at least one cycle.

[0064] In some embodiments, the nucleoside metabolic inhibitor is administered at an initial dose of about 600 mg / m2, 800 mg / m2, or about 1000 mg / m2.

[0065] In some embodiments, the nucleoside metabolic inhibitor is administered on about day 1, about day 8, and about day 15 of each cycle.

[0066] In some embodiments, the nucleoside metabolic inhibitor is administered on about day 1, about day 8, and about day 15 of a cycle of 4 weeks.

[0067] In some embodiments, gemcitabine is administered at a dose from about 600 mg / m2to about 1000 mg / m2.

[0068] In some embodiments, gemcitabine is administered at a dose from 600 mg / m2to 1000 mg / m2for at least one cycle.

[0069] In some embodiments, gemcitabine is administered at an initial dose of about 600 mg / m2, 800 mg / m2, or about 1000 mg / m2.

[0070] In some embodiments, gemcitabine is administered on about day 1, about day 8, and about day 15 of each cycle.

[0071] In some embodiments, gemcitabine is administered on about day 1, about day 8, and about day 15 of a cycle of 4 weeks.

[0072] In some embodiments, gemcitabine is administered on day 1, day 8, and day 15 of each cycle.

[0073] In some embodiments, a cycle is 28 days.

[0074] In some embodiments, the nucleoside metabolic inhibitor is administered every 4 weeks after day 1.

[0075] In some embodiments, the nucleoside metabolic inhibitor is administered intravenously.

[0076] In some embodiments, gemcitabine is administered every 4 weeks after day 1.

[0077] In some embodiments, gemcitabine is administered intravenously.

[0078] In some embodiments, the subject is at least about 18 years old.

[0079] In some embodiments, the subject has at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) vl .1 criteria that has not been irradiated.

[0080] In some embodiments, the lesion is at least about 10 mm in the longest diameter.

[0081] In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of about 0 to about 1.

[0082] In some embodiments, the subject has metastatic cancer.

[0083] In some embodiments, the subject has pancreatic ductal adenocarcinoma.

[0084] In some embodiments, the subject is administered the ADC and gemcitabine after pancreatic surgery, radiation, and chemotherapies, and combinations thereof.

[0085] In some embodiments, the subject was previously treated with chemotherapies comprising fluoropyrimidine-based therapy before administering the ADC comprising an anti- CEACAM5 antibody and nucleoside metabolic inhibitor.

[0086] In some embodiments, the subject was previously treated with 5 -fluorouracil, leucovorin, liposomal irinotecan, oxaliplatin, nab-paclitaxel, and combinations thereof.

[0087] In some embodiments, the method further comprises administering a premedication to the subject.

[0088] In some embodiments, the administering the premedication is administered to the subject before each administration of ADC.

[0089] In some embodiments, the premedication is dexamethasone and / or a histamine Hl antagonist.

[0090] In some embodiments, the dexamethasone is administered at a dose of about 10 mg.

[0091] In some embodiments, the dexamethasone is administered to the subject intravenously

[0092] In some embodiments, the histamine Hl antagonist is diphenhydramine or dexchlorpheniramine.

[0093] In some embodiments, the diphenhydramine is administered intravenously to the subject in a dose of about 50 mg.

[0094] In some embodiments, the administering the premedication to the subject is before each administration of gemcitabine.

[0095] In some embodiments, the premedication is an antiemetic preventive premedication.

[0096] In some embodiments, the antiemetic preventive premedication is a 5-HT3 receptor antagonist or dexamethasone.

[0097] In another aspect, the present application relates to compositions comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antibody fragment thereof and nucleoside metabolic inhibitor.

[0098] In another aspect, the present application relates to a pharmaceutical composition comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antibody fragment thereof and a nucleoside metabolic inhibitor.

[0099] In another aspect, the present application relates to a pharmaceutical composition comprising a combination comprising an antibody-drug conjugate (ADC) comprising an anti- CEACAM5 antibody or antibody fragment thereof and a nucleoside metabolic inhibitor.

[0100] In another aspect, the present application relates to compositions comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antibody fragment thereof and gemcitabine.

[0101] In another aspect, the present application relates to a pharmaceutical composition comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antibody fragment thereof and gemcitabine.

[0102] In another aspect, the present application relates to a pharmaceutical composition comprising a combination comprising an antibody-drug conjugate (ADC) comprising an anti- CEACAM5 antibody or antibody fragment thereof and gemcitabine.

[0103] A pharmaceutical composition may comprise at least one pharmaceutically acceptable excipient.

[0104] In another aspect, the present application relates to a kit comprising (i) an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antibody fragment thereof and (ii) a nucleoside metabolic inhibitor, in separate formulations. The separate formulations may be packaged in separate containers.

[0105] In another aspect, the present application relates to a kit comprising (i) an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antibody fragment thereof and (ii) gemcitabine, in separate formulations. The separate formulations may be packaged in separate containers.

[0106] In some embodiments, the pharmaceutical composition or the kit may be for the use for treating a cancer, wherein the cancer expresses CEACAM5.

[0107] In some embodiments, the present application relates to a pharmaceutical composition comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody, or antibody fragment thereof, and gemcitabine, said pharmaceutical composition being for use for treating a cancer, wherein the cancer expresses CEACAM5.

[0108] In some embodiments, the present application relates to a kit comprising (i) an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody, or antibody fragment thereof, and (ii) gemcitabine, in separate formulations, said kit being for use for treating a cancer, wherein the cancer expresses CEACAM5.

[0109] In another aspect, the present application relates to an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 -antibody, or antigen binding fragment thereof, for usefor treating a pancreatic cancer in a subject in need thereof, wherein the pancreatic cancer expresses CEACAM5, the use comprising administrating to said subject at a dose of 60 mg / m2to 210 mg / m2based on the body surface area of said subject. The cancer may be metastatic.

[0110] In some embodiments, the antibody-drug conjugate comprising an anti- CEACAM5 -antibody, or antigen binding fragment thereof, is for use in combination with a nucleoside metabolic inhibitor for treating a pancreatic cancer in a subject in need thereof, wherein the pancreatic cancer expresses CEACAM5, the use comprising administrating to said subject said antibody-drug conjugate at a dose of 60 mg / m2to 210 mg / m2based on the body surface area of said subject.

[0111] In some embodiments, the antibody-drug conjugate comprising an anti- CEACAM5 -antibody, or antigen binding fragment thereof, is for use in combination with gemcitabine for treating a pancreatic cancer in a subject in need thereof, wherein the pancreatic cancer expresses CEACAM5, the use comprising administrating to said subject said antibodydrug conjugate at a dose of 60 mg / m2to 210 mg / m2based on the body surface area of said subject.

[0112] The cancer may be a pancreatic ductal adenocarcinoma.

[0113] In some embodiments, the anti-CEACAM5 antibody comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acid sequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5.

[0114] In some embodiments, the anti-CEACAM5 antibody comprises a variable domain of a heavy chain (VH) consisting of the sequence of SEQ ID NO: 6 and a variable domain of a light chain (VL) consisting of the sequence of SEQ ID NO: 7.

[0115] In some embodiments, the anti-CEACAM5 antibody comprises a heavy chain (HC) consisting of the sequence of SEQ ID NO: 8 and a light chain (LC) consisting of the sequence of SEQ ID NO: 9.

[0116] In some embodiments, the anti-CEACAM5 antibody is a humanized monoclonal anti-CEACAM5 antibody.

[0117] In some embodiments, the anti-CEACAM5 antibody is tusamitamab (SAR408377).

[0118] In some embodiments, the ADC comprises at least one cytotoxic agent.

[0119] In some embodiments, the ADC anti-CEACAM5 antibody is covalently attached via a cleavable or non-cleavable linker to the at least one cytotoxic agent.

[0120] In some embodiments, the ADC comprising the anti-CEACAM5 antibody comprises a cleavable linker.

[0121] In some embodiments, the linker is selected from N-succinimidyl pyridyldithiobutyrate (SPDB), 4-(Pyridin-2-yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB), and succinimidyl (N-maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC).

[0122] In some embodiments, the cytotoxic agent is selected from the group consisting of antimetabolite, DNA-alkylating agent, DNA-cross-linking agent, DNA-intercalating agent, anti-microtubule agent, topoisomerase inhibitor, and any combination thereof.

[0123] In some embodiments, the anti-microtubule agent is a maytansinoid.

[0124] In some embodiments, the maytansinoid is selected from the group consisting of N2’-deacetyl-N2’-(3-mercapto-l-oxopropyl)-maytansine (DM1), N2’-deacetyl-N2’(4-methyl- 4-mercapto-l-oxopentyl)-maytansine (DM4), and any combination thereof.

[0125] In some embodiments, the maytansinoid is DM4.

[0126] In some embodiments, the ADC is tusamitamab ravtansine (SAR408701).

[0127] In some embodiments, the nucleoside metabolic inhibitor is gemcitabine.

[0128] In another aspect, the present application relates to an antibody-drug conjugate comprising an anti-CEACAM5-antibody, or antigen binding fragment thereof, for use in combination with gemcitabine for treating a pancreatic ductal adenocarcinoma in a subject in need thereof, wherein the adenocarcinoma expresses CEACAM5.

[0129] In some embodiments, the antibody-drug conjugate is administered at an initial dose of 135 mg / m2or 170 mg / m2on day one of a first cycle and at a secondary dose of 80 mg / m2or 100 mg / m2thereafter, and gemcitabine is administered at a dose from 600 mg / m2to 1000 mg / m2.

[0130] In some embodiments, the antibody-drug conjugate is administered for 1 to 12 cycles, on day 1 of each cycle, wherein a cycle is 2 weeks.

[0131] In some embodiments, gemcitabine is administered for 1 to 12 cycles, on day 1, day 8, and day 15 of each cycle, wherein a cycle is 4 weeks.

[0132] In another aspect, the present application relates to an antibody-drug conjugate comprising an anti-CEACAM5-antibody, or antigen binding fragment thereof, for use in combination with gemcitabine for treating a cancer in a subject in need thereof, wherein the cancer expresses CEACAM5, and wherein the antibody-drug conjugate is tusamitamab ravtansine.

[0133] In some embodiments, the antibody-drug conjugate is administered at an initial dose of 135 mg / m2or 170 mg / m2on day one of a first cycle and at a secondary dose of 80 mg / m2or 100 mg / m2thereafter, and gemcitabine is administered at a dose from 600 mg / m2to 1000 mg / m2.

[0134] In some embodiments, the antibody-drug conjugate is administered for 1 to 12 cycles, on day 1 of each cycle, wherein a cycle is 2 weeks.

[0135] In some embodiments, gemcitabine is administered for 1 to 12 cycles, on day 1, day 8, and day 15 of each cycle, wherein a cycle is 4 weeks.

[0136] In another aspect, the present application relates to an antibody-drug conjugate comprising an anti-CEACAM5-antibody, or antigen binding fragment thereof, for use in combination with gemcitabine for treating a pancreatic ductal adenocarcinoma in a subject in need thereof, wherein the adenocarcinoma expresses CEACAM5, and wherein the antibodydrug conjugate is tusamitamab ravtansine.

[0137] In some embodiments, the antibody-drug conjugate is administered at an initial dose of 135 mg / m2or 170 mg / m2on day one of a first cycle and at a secondary dose of 80 mg / m2or 100 mg / m2thereafter, and gemcitabine is administered at a dose from 600 mg / m2to 1000 mg / m2.

[0138] In some embodiments, the antibody-drug conjugate is administered for 1 to 12 cycles, on day 1 of each cycle, wherein a cycle is 2 weeks.

[0139] In some embodiments, gemcitabine is administered for 1 to 12 cycles, on day 1, day 8, and day 15 of each cycle, wherein a cycle is 4 weeks.

[0140] In another aspect, the present application relates to a method of treating a pancreatic cancer in a subject in need thereof, the method comprising administrating to the subject an effective amount of an antibody-drug conjugate (ADC) comprising an anti- CEACAM5 antibody or antigen binding fragment thereof, wherein the metastatic pancreaticcancer expresses CEACAM5 and wherein the antibody-drug conjugate is administered at a dose of 60 mg / m2to 210 mg / m2based on the body surface area of the subject.

[0141] In some embodiments, the pancreatic cancer is a metastatic pancreatic cancer.

[0142] In some embodiments, the anti-CEACAM5 antibody comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acid sequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5.

[0143] In some embodiments, the anti-CEACAM5 antibody comprises a variable domain of a heavy chain (VH) consisting of the sequence of SEQ ID NO: 6 and a variable domain of a light chain (VL) consisting of the sequence of SEQ ID NO: 7.

[0144] In some embodiments, the anti-CEACAM5 antibody comprises a heavy chain (HC) consisting of the sequence of SEQ ID NO: 8 and a light chain (LC) consisting of the sequence of SEQ ID NO: 9.

[0145] In some embodiments, the anti-CEACAM5 antibody is a humanized monoclonal anti-CEACAM5 antibody.

[0146] In some embodiments, the anti-CEACAM5 antibody is tusamitamab (SAR408377).

[0147] In some embodiments, the ADC comprises at least one cytotoxic agent.

[0148] In some embodiments, the anti-CEACAM5 antibody is covalently attached via a cleavable or non-cleavable linker to the at least one cytotoxic agent.

[0149] In some embodiments, the linker is selected from N-succinimidyl pyridyldithiobutyrate (SPDB), 4-(Pyridin-2-yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB), and succinimidyl (N-maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC).

[0150] In some embodiments, the cytotoxic agent is selected from the group consisting of antimetabolite, DNA-alkylating agent, DNA-cross-linking agent, DNA-intercalating agent, anti-microtubule agent, topoisomerase inhibitor, and any combination thereof.

[0151] In some embodiments, the anti-microtubule is a maytansinoid.

[0152] In some embodiments, the maytansinoid is selected from the group consisting of N2’ -deacetyl- -(3-mercapto-l -oxopropylj-maytansine (DM1 ), N2’ -deacetyl- (4-methyl-4- mercapto-l-oxopentyl)-maytansine (DM4), and any combination thereof.

[0153] In some embodiments, the maytansinoid is DM4.

[0154] In some embodiments, the ADC is tusamitamab ravtansine (SAR408701).

[0155] In some embodiments, the cancer expresses CEACAM5 with moderate or high intensity defined by immunohistochemistry.

[0156] In some embodiments, the CEACAM5 expression is defined as a CEACAM5 immunohistochemistry (IHC) intensity of at least about 2+ in at least about 50% of tumor cell.

[0157] In some embodiments, the ADC is administered at a dose from about 100 mg / m2to about 210 mg / m2.

[0158] In some embodiments, the ADC is administered at a dose from about 100 mg / m2to about 170 mg / m2.

[0159] In some embodiments, the ADC is administered as an initial dose followed by one or more secondary doses.

[0160] In some embodiments, the ADC is administered at a dose from about 60 mg / m2to about 210 mg / m2.

[0161] In some embodiments, the ADC is administered at a dose from about 80 mg / m2to about 170 mg / m2.

[0162] In some embodiments, the ADC is administered at a dose from about 100 mg / m2to about 170 mg / m2.

[0163] In some embodiments, the ADC is administered at an initial dose of about 170 mg / m2.

[0164] In some embodiments, the ADC is administered at a secondary dose of about 80 mg / m2or about 100 mg / m2.

[0165] In some embodiments, the dose is calculated based on a body surface area (BSA) of 2.20 m2if the subject’s BSA is greater than about 2.20 m2'

[0166] In some embodiments, the ADC is administered at a dose level of 5, 10, 20, 30, 40, 60, 80, 100, 120, 135, 150, 170, 180, or 210 mg / m2based on the body surface area of the subject.

[0167] In some embodiments, the ADC is administered at an initial dose of about 135 mg / m2, about 150 mg / m2or about 170 mg / m2on day 1 of a first cycle and at a dose of about 80 mg / m2or about 100 mg / m2thereafter.

[0168] In some embodiments, the ADC is administered to the subject on day 1 of the first cycle over 1 hour 30 minutes.

[0169] In some embodiments, a cycle is 14 days.

[0170] In some embodiments, the ADC is administered intravenously.

[0171] In some embodiments, the subject is retreated if the subject has a neutrophils count of at least about 1.5 x 109 / L, platelets count of at least about 100 x 109 / L, an hemoglobin count of at least about 9 mg / dL, a total bilirubin count of at most about 1.5 x ULN, AST-ALT count of at most about 2.5 x ULN or about < 5 x ULN in case of documented liver metastasis, and / or no IMP-related toxicity of Grade > 1 except for alopecia or of baseline severity.

[0172] In some embodiments, the subject is at least about 18 years old.

[0173] In some embodiments, the subject has at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) vl .1 criteria that has not been irradiated.

[0174] In some embodiments, the lesion is at least about 10 mm in the longest diameter.

[0175] In some embodiments, the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of about 0 to about 1.

[0176] In some embodiments, the subject has pancreatic ductal adenocarcinoma.

[0177] In some embodiments, the CEACAM5 expression is demonstrated by centrally assessed IHC assay.

[0178] In some embodiments, the subject is administered the ADC after pancreatic surgery, radiation, and chemotherapies, and combinations thereof.

[0179] In some embodiments, the subject was previously treated with chemotherapies comprising fluoropyrimidine-based therapy before administering the ADC comprising an anti- CEACAM5 antibody.

[0180] In some embodiments, the subject was previously treated with 5 -fluorouracil, leucovorin, liposomal irinotecan, oxaliplatin, nab-paclitaxel, and combinations thereof.

[0181] In some embodiments, the subject was previously treated with gemcitabine and / or is intolerant to gemcitabine.

[0182] In some embodiments, the method further comprises administering premedication to the subject.

[0183] In some embodiments, the administering the premedication to the subject is before each administration of tusamitamab ravtansine.

[0184] In some embodiments, the premedication is dexamethasone and / or an histamine Hl antagonist.

[0185] In some embodiments, the dexamethasone is administered intravenously to the subject in a dose of about 10 mg.

[0186] In some embodiments, the histamine Hl antagonist is diphenhydramine or dexchlorpheniramine.

[0187] In some embodiments, the diphenhydramine is administered intravenously to the subject in a dose of about 50 mg.

[0188] In another aspect, the present application relates to methods of treating pancreatic cancer in a subject comprising: administering to a subject in need thereof a pharmaceutical composition comprising an initial dose of 135 mg / m2, 150 mg / m2or about 170 mg / m2of an antibody drug conjugate on day 1 of a first cycle and a dose of about 80 mg / m2or about 100 mg / m2thereafter; wherein the antibody drug conjugate comprise an antibody or antigen binding fragment thereof that binds CEACAM5 and is covalently attached to DM4, wherein the antibody or antigen-binding fragment thereof comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acid sequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5 and wherein the subject has pancreatic cancer.

[0189] In another aspect, the present application relates to methods of treating pancreatic cancer in a subject, the method comprising administering to the subject an effective amount an antibody-drug conjugate (ADC) comprising an antibody or antigen binding fragment thereof that binds CEACAM5 and is covalently attached to DM4, wherein the subject has at least one inclusion criteria selected from the group consisting of: i. the subject is at least 18 years old; ii. has the pancreatic ductal adenocarcinoma; iii. has at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria that has not been irradiated; iv has an Eastern Cooperative Oncology Group (ECOG) performance status of about 0 to about 1; v. was previously treated with 5 -fluorouracil-based therapy, leucovorin, liposomal irinotecan, oxaliplatin, nab-paclitaxel, capecitabine, and combinations thereof; vi. the cancerexpresses CEACAM5 of at least about 2+ in at least about 50% of tumor cells as determined by immunohistochemistry; and vii. has documented radiographic progression or documented intolerance after at least 1 prior systemic chemotherapy line which included either gemcitabine or relapsed within 6 months of completion of gemcitabine adjuvant therapy.

[0190] In another aspect, the present application relates to methods of treating pancreatic cancer in a subject, the method comprising administering to the subject an effective amount an antibody-drug conjugate (ADC) comprising an antibody or antigen binding fragment thereof that binds CEACAM5 and is covalently attached to DM4, wherein the subject has at least one inclusion criteria selected from the group consisting of: i. the subject is at least 18 years old; ii. has the pancreatic ductal adenocarcinoma; iii. has at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) vl.l criteria that has not been irradiated; iv has an Eastern Cooperative Oncology Group (ECOG) performance status of about 0 to about 1; v. was previously treated with 5 -fluorouracil-based therapy, leucovorin, liposomal irinotecan, oxaliplatin, nab-paclitaxel, capecitabine, and combinations thereof; vi. the cancer expresses CEACAM5 of at least about 2+ in at least about 50% of tumor cells as determined by immunohistochemistry; and vii. has documented radiographic progression or documented intolerance after at least 1 prior systemic chemotherapy line which included either gemcitabine or relapsed within 6 months of completion of gemcitabine adjuvant therapy; and wherein the subject does not have at least one criterion selected from the group consisting of: i. medical condition requiring administration of a medication that is metabolized by cytochrome P450; ii. untreated brain metastases or history of leptomeningeal disease; iii. history of acquired immunodeficiency syndrome disease requiring antiretroviral treatment, or active hepatitis A; and iv. unresolved corneal disorder or any previous corneal disorder.

[0191] In some embodiments, the antibody-drug conjugate (ADC) comprising an antibody or antigen binding fragment thereof that binds CEACAM5 and is covalently attached to DM4 is tusamitamab ravtansine (SAR408701).

[0192] In some embodiments, the antibody-drug conjugate (ADC) comprising an antibody or antigen binding fragment thereof that binds CEACAM5 and is covalently attached to DM4 is administered at a dose from about 135 mg / m2, 150 mg / m2, or about 170 mg / m2.

[0193] In some embodiments, the antibody-drug conjugate (ADC) comprising an antibody or antigen binding fragment thereof that binds CEACAM5 and is covalently attachedto DM4 is administered at an initial dose from about 135 mg / m2, about 150 mg / m2, or about 170 mg / m2.

[0194] In some embodiments, the ADC is administered at a secondary dose of about 80 mg / m2or about 100 mg / m2.

[0195] In another aspect, the present application relates to the use of an antibody-drug conjugate (ADC) comprising an anti-CEACAM5-antibody, or antigen binding fragment thereof, in combination with a nucleoside metabolic inhibitor, for the manufacture of a medicament for treating a cancer that expresses CEACAM5.

[0196] In another aspect, the present application relates to the use of an antibody-drug conjugate (ADC) comprising an anti-CEACAM5-antibody, or antigen binding fragment thereof, in combination with gemcitabine, for the manufacture of a medicament for treating a cancer that expresses CEACAM5.BRIEF DESCRIPTION OF THE DRAWINGS

[0197] FIG. 1 is a schematic diagram depicting the decision process for ADC loading dose in Cohort C of a Phase 2 clinical trial according to embodiments of the present disclosure.

[0198] FIG. 2 is a schematic diagram depicting the study design of a Phase 2 clinical trial according to embodiments of the present disclosure.

[0199] FIG. 3 illustrates the best relative change in tumor size observed in the participants of Cohort B, treated with tusamitamab ravtansine monotherapy. SD means Stable Disease. PD means Progressive Disease. PR means Partial Response.

[0200] FIG. 4 illustrates the best relative change in tumor size observed in the participants of Cohort C, treated with tusamitamab ravtansine + gemcitabine combination therapy. SD means Stable Disease. PD means Progressive Disease. PR means Partial Response.

[0201] FIG. 5 illustrates the duration of treatment observed in the participants of CohortB, treated with tusamitamab ravtansine monotherapy. The best overall response and the overall response at different times during treatment are indicated for each participant.

[0202] Fig. 6 illustrates the duration of treatment observed in the participants of CohortC, treated with tusamitamab ravtansine and gemcitabine in combination therapy. The best overall response and the overall response at different times during treatment are indicated for each participant.DETAILED DESCRIPTION

[0203] Before the disclosure is described, it is to be understood that disclosure is not limited to methods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing embodiments only, and is not intended to be limiting, because the scope of the disclosure will be limited only by the appended claims.

[0204] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0205] The disclosure provides compositions and methods of using antibody-drug conjugates (ADC), a.k.a. immunoconjugates, for cancer treatment such as pancreatic cancers and for improvement of at least one symptom of the disease. These compositions include at least one antibody that specifically binds carcinoembryonic antigen 5 (CEACAM5).

[0206] The antibody in the ADC is a humanized anti-CEACAM5 antibody conjugated to a maytansinoid derivative 4 (DM4) [N2’-deacetyl-N2’-(4-methyl-4-mercapto-l-oxopentyl)- maytansine], a potent antimitotic agent that inhibits microtubule assembly. DM4 is covalently bound to the antibody through an optimized linker SPDB [N-succinimidyl 4-(2-pyridyldithio)- butyrate] that is stable in plasma and cleavable inside cells. After binding and internalization in targeted cancer cells, the ADC is degraded, releasing cytotoxic DM4 metabolites.

[0207] The ADC specifically binds to the A3B3 domain of human CEACAM5 and does not recognize other CEACAMs presenting A or / and B domains in their structure (CEACAM1, CEACAM6, CEACAM7 and CEACAM8). The naked antibody and the ADC bind to recombinant human CEACAM5 with an affinity of about 0.02 nM (ELISA) and display high affinity for CEACAM5 expressing tumor cells (I<DAI>I>0.24 - 0.68 nM).

[0208] After binding to the CEACAM5 antigen, the ADC is internalized by the cancer cells via antigen-mediated endocytosis, delivered to lysosomes and degraded into the lysine- linked derivative lysine-SPDB-DM4. The lysine-SPDB-DM4 gets further degraded to DM4 that is subsequently S-methylated to form methyl-DM4 [Me-DM4]; all three metabolites have potent cytotoxic activity through binding to tubulin and inhibition of microtubule polymerization. In some embodiments, the immunoconjugate is tusamitamab ravtansine.

[0209] The ADC (e.g., tusamitamab ravtansine) can be combined with a nucleoside metabolic inhibitor such as gemcitabine (Gemzar, 2', 2' -difluorodeoxy cytidine) in a combination therapy. Gemcitabine is a chemotherapeutic agent that becomes active after intracellular phosphorylation by deoxycytidine kinase as only its di- and tri-phosphate forms possess cytotoxic activity. The diphosphate form inhibits ribonucleotide reductase, an enzyme that is essential for normal DNA synthesis, and the triphosphate form competes with deoxycytidine triphosphate for incorporation into DNA as an inactive base.

[0210] As used herein, CEACAM5 expressing cancer refers to several types of cancer, including breast cancer, pancreatic cancer, colorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiment the cancer is pancreatic ductal adenocarcinoma (PDAC).Pancreatic Cancers

[0211] Pancreatic cancer occurs when a cell in the pancreas is damaged, causing the malignant (cancer) cell to start growing out of control. Pancreatic cancer types can be divided into two larger categories: exocrine pancreatic cancer, which includes adenocarcinoma (the most common type of pancreatic cancer), and neuroendocrine pancreatic cancer. Each category has several cancer types that may vary in their symptoms and prognosis.

[0212] Exocrine pancreatic cancer develops from exocrine cells, which make up the exocrine gland and ducts of the pancreas. The exocrine gland secretes enzymes that help break down carbohydrates, fats, proteins, and acids in the duodenum. The various types of exocrine pancreatic cancers make up many of all cancers of the pancreas. They include adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, and colloid carcinoma.

[0213] Pancreatic neuroendocrine tumors (NETs) develop from cells in the endocrine gland of the pancreas, which secretes the hormones insulin and glucagon into the bloodstream to regulate blood sugar. This type of pancreatic cancer is rare.

[0214] Various treatments have been used for pancreatic cancer. First line therapy can include the combination therapy of 5-fluorouracil / leucovorin plus oxaliplatin and irinotecan(FOLFIRINOX) and nab-paclitaxel plus gemcitabine, or single-agent gemcitabine. For those patients previously treated with fluoropyrimidine-based therapy, second-line therapies can include gemcitabine monotherapy, the combination of 5-fluorouracil, leucovorin, and liposomal irinotecan (if no prior irinotecan).

[0215] Treatments for cancers, including pancreatic cancers, can include additional therapies such as angiogenesis inhibitors, epidermal growth factor receptor (EGFR) inhibitors, and immune checkpoint inhibitors.

[0216] Angiogenesis inhibitors may include, but are not limited to, Axitinib (Inlyta), Bevacizumab (Avastin), Cabozantinib (Cometriq), Everolimus (Afinitor, Zortress), Lenalidomide (Revlimid), Pazopanib (Votrient), Ramucirumab (Cyramza), Regorafenib (Stivarga), Sorafenib (Nexavar), Sunitinib (Sutent), Thalidomide (Synovir, Thalomid), Vandetanib (Caprelsa), and Ziv-aflibercept (Zaltrap).

[0217] EGFR inhibitors may include, but are not limited to, gefitinib (Iressa), erlotinib (Tarceva), lapatinib (Tykerb), cetuximab (Erbitux), neratinib (Nerlynx), osimertinib (Tagrisso), panitumumab (Vectibix), vandetanib (Caprelsa), necitumumab (Protrazza), and dacomitinib (Vizimpro).

[0218] Immune checkpoint inhibitors may include, but are not limited to, Programmed Death 1 receptor (PD-1) binding agents (e.g., pembrolizumab, nivolumab, cemiplimab, sintilimab, dostarlimab, and tislelizumab), Programmed Death-ligand 1 (PD-L1) binding agents (e.g., atezolizumab, avelumab, durvalumab), CTLA-4 binding agents (e.g., ipilimumab), 0X40 or OX40L binding agents, Adenosine A2A receptor binding agents, B7-H3 binding agents, B7- H4 binding agents, BTLA binding agents, Indoleamine 2,3-dioxygenase binding agents, Killercell Immunoglobulin-like Receptor (KIR) binding agents, Lymphocyte Activation Gene-3 (LAG-3) binding agents, nicotinamide adenine dinucleotide phosphate NADPH oxidase isoform (N0X2) binding agents, T-cell Immunoglobulin domain and Mucin domain 3 (TIM-3) binding agents, V-domain Ig suppressor of T cell activation (VISTA) binding agents, Glucocorticoid-Induced TNFR family Related gene (GITR) binding agents, and Sialic acidbinding immunoglobulin-type lectin 7 (SIGLEC7) binding agents.CEACAM5 and Indications

[0219] Carcinoembryonic antigen (CEA) is a glycoprotein involved in cell adhesion. CEA was first identified in 1965 (Gold and Freedman, J Exp Med, 121, 439, 1965) as a protein normally expressed by fetal gut during the first six months of gestation, and found in cancers of the pancreas, liver and colon. The CEA family belongs to the immunoglobulin superfamily. The CEA family, which consists of 18 genes, is sub-divided in two sub-groups of proteins: the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) sub-group and the pregnancy-specific glycoprotein subgroup (Kammerer & Zimmermann, BMC Biology 2010, 8: 12).

[0220] In humans, the CEACAM sub-group consists of 7 members: CEACAM1, CEACAM3, CEACAM4, CEACAM5, CEACAM6, CEACAM7, CEACAM8. Numerous studies have shown that CEACAM5, identical to the originally identified CEA, is highly expressed on the surface of colorectal, gastric, gastroesophageal junction, esophageal, lung, breast, prostate, ovary, cervix and bladder tumor cells and weakly expressed in few normal epithelial tissues such as columnar epithelial and goblet cells in colon, mucous neck cells in the stomach, and squamous epithelial cells in esophagus and cervix (Hammarstrom et al, 2002, in "Tumor Markers, Physiology, Pathobiology, Technology and Clinical Applications" Eds. Diamandis E. P. et al., AACC Press, Washington pp 375). Thus, CEACAM5 may constitute a therapeutic target suitable for tumor-specific targeting approaches, such as immunoconjugates.

[0221] The extracellular domains of CEACAM family members are composed of repeated immunoglobulin-like (Ig-like) domains which have been categorized in 3 types, A, B and N, according to sequence homologies. CEACAM5 contains seven such domains, namely N, Al, Bl, A2, B2, A3, and B3.

[0222] CEACAM5 Al, A2, and A3 domains, on one hand, and Bl, B2, and B3 domains, on the other hand, show high sequence homologies, the A domains of human CEACAM5 presenting from 84 to 87% pairwise sequence similarity, and the B domains from 69 to 80%. Furthermore, other human CEACAM members presenting A and / or B domains in their structure, namely CEACAM1 , CEAC AM6, CEACAM7, and CEACAM8, show homology with human CEACAM5. In particular, the A and B domains of human CEACAM6 protein display sequence homologies with Al and A3 domains, and any of Bl to B3 domains of human CEACAM5, respectively, which are even higher than observed among the A domains and the B domains of human CEACAM5.

[0223] Embodiments of the disclosure are methods of treating cancer, wherein the cancer expresses CEACAM5.

[0224] In an embodiment the cancer is breast cancer, pancreatic cancer, colorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0225] In another embodiment, the cancer is pancreatic cancer.

[0226] In another embodiment, the cancer is pancreatic ductal adenocarcinoma.

[0227] In another embodiment, the cancer is metastatic.Anti-CEACAM5 Antibody

[0228] Numerous anti-CEA antibodies were generated in view of CEA-targeted diagnostic or therapeutic purposes. Specificity towards related antigens has always been mentioned as a concern in this field, as an example by Sharkey et al (1990, Cancer Research 50, 2823). Due to the above-mentioned homologies, some of previously described antibodies may demonstrate binding to repetitive epitopes of CEACAM5 present in the different immunoglobulin domains show cross-reactivity to other CEACAM members such as CEACAM1, CEACAM6, CEACAM7, or CEACAM8, lacking specificity to CEACAM5. The specificity of the anti-CEACAM5 antibody is desired in view of CEA-targeted therapies such that it binds to human CEACAM5 -expressing tumor cells but does not bind to some normal tissues expressing other CEACAM members. It is noteworthy that CEACAM1, CEACAM6, and CEACAM8 have been described as expressed by neutrophils of human and non-human primates (Ebrahimmnejad et al, 2000, Exp Cell Res, 260, 365; Zhao et al, 2004, J Immunol Methods 293, 207; Strickland et al, 2009 J Pathol, 218, 380) where they have been shown to regulate granulopoiesis and to play a role in immune response.

[0229] The ADC has been shown to be capable of being internalized into cells expressing CEACAM5 after binding, and to induce cytotoxic activity on tumor cells in vitro. ADC is also able to markedly inhibit tumor growth in vivo in mice bearing human primary colon and stomach tumors. See WO 2014 / 079886, which is incorporated herein by reference in its entirety.

[0230] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of the value it modifies (rounded up to the nearest whole number if the value is not subdividable, such as a number of molecules or nucleotides). For example, the phrase “about 100 mg” would encompass 90 mg to 110 mg, inclusive; the phrase “about 2500 mg” would encompass 2250 mg to 2750 mg. When applied to a percentage, the term “about” refers to plus or minus 10% relative to that percentage. For example, the phrase “about 20%” would encompass 18-22% and “about 80%” would encompass 72-88%, inclusive. Moreover, where “about” is used herein in conjunction with a quantitative term it is understood that in addition to the value plus or minus 10%, the exact value of the quantitative term is also contemplated and described. For example, the term “about 23%” expressly contemplates, describes, and includes exactly 23%.

[0231] It is to be noted that the term "a" or "an" entity refers to one or more of that entity; for example, "a symptom," is understood to represent one or more symptoms. As such, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0232] Furthermore, "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: 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).

[0233] It is understood that wherever aspects are described herein with the language "comprising," otherwise analogous aspects described in terms of "consisting of’ and / or "consisting essentially of’ are also provided.

[0234] As used herein “CEACAM5” designates the “carcinoembryonic antigen-related cell adhesion molecule 5”, also known as “CD66e” (Cluster of Differentiation 66e) or CEA. CEACAM5 is a glycoprotein involved in cell adhesion. CEACAM5 is highly expressed in particular on the surface of colorectal, gastric, gastroesophageal junction, esophageal, lung, and uterine tumor cells.

[0235] A reference sequence of full length human CEACAM5, including signal peptide (positions 1-34) and propeptide (positions 686-702), is available from the GenBank database under accession number AAA51967.1. Five nonsynonymous SNPs have been identified with afrequency higher than 2% in Caucasian population, four of them being localised in the N domain (at positions 80, 83, 112, 113), the last one in the A2 domain (at position 398) of human CEACAM5.

[0236] The term "antibody," as used herein, also includes antigen-binding fragments of full antibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulated chemically or by using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add, or delete amino acids, etc.

[0237] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide, or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules, such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies, chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, VHH or NANOBODY® (e.g., monovalent VHH, and bivalent VHH), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment," as used herein.

[0238] An antigen-binding fragment of an antibody will typically comprise at least one variable domain. The variable domain may be of any size or amino acid composition and will generally comprise at least one CDR which is adjacent to or in frame with one or more framework sequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains may be situated relative to one another in any suitablearrangement. For example, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers. Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.

[0239] In certain embodiments, an antigen-binding fragment of an antibody may contain at least one variable domain covalently linked to at least one constant domain. Non-limiting, exemplary configurations of variable and constant domains that may be found within an antigenbinding fragment of an antibody include: (i) VH-CH1; (ii) VH-CH2; (iii) VH-CH3; (iv) VH- CH1-CH2; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3; (vn) VH-CL; (vm) VL-CH1; (ix) VL- CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xn) VL-CH1-CH2-CH3; (xm) VL-CH2-CH3; and (xiv) VL-CL. In any configuration of variable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may in various embodiments consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody may in various embodiments comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurations listed above in non-covalent association with one another and / or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).

[0240] In specific embodiments, the antibody or antibody fragment for use in the method of the disclosure may be a multispecific antibody, which may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for epitopes of more than one target polypeptide. An exemplary bi-specific antibody format that can be used in the context of the present disclosure involves the use of a first immunoglobulin (Ig) CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bispecific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second CH3 may further comprise an Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second CH3 include: D16E, L18M, N44S, K52N, V57M, andV82I (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of IgGl antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of IgG4 antibodies.

[0241] Variations on the bi-specific antibody format described above are contemplated within the scope of the present disclosure. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may in various embodiments be adapted for use in the context of an antigen-binding fragment of an anti-CEACAM5 antibody using routine techniques available in the art.

[0242] The CEACAM5 antibodies disclosed herein may comprise one or more amino acid substitutions, insertions and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present disclosure includes antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and / or CDR regions are back-mutated to the corresponding germline residue(s) or to a conservative amino acid substitution (natural or non-natural) of the corresponding germline residue(s) (such sequence changes are referred to herein as "germline back-mutations"). A person of ordinary skill in the art, starting with the heavy and light chain variable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline back-mutations or combinations thereof. In certain embodiments, all of the framework residues and / or CDR residues within the VH and / or VL domains are mutated back to the germline sequence. In other embodiments, only certain residues are mutated back to the germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. Furthermore, the antibodies of the present disclosure may contain any combination of two or more germline back- mutations within the framework and / or CDR regions, i.e., wherein certain individual residues are mutated back to the germline sequence while certain other residues that differ from thegermline sequence are maintained. Once obtained, antibodies and antigen-binding fragments that contain one or more germline back-mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present disclosure.

[0243] The constant region of an antibody is important in the ability of an antibody to fix complement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody may be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0244] The term "human antibody", as used herein, is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies featured in the disclosure may in various embodiments nonetheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in some embodiments CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0245] The term "recombinant human antibody", as used herein, is intended to include all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as antibodies expressed using a recombinant expression vector transfected into a host cell (described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al., (1992) Nucl. Acids Res. 20:6287-6295, incorporated herein by reference in its entirety,) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinantantibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0246] Human antibodies can exist in two forms that are associated with hinge heterogeneity. In an embodiment, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In another embodiment, the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody). These embodiments / forms have been extremely difficult to separate, even after affinity purification.

[0247] The term "humanized antibody" or “humanized antibody” refers to an antibody which is wholly or partially of non-human origin, and which has been modified to replace certain amino acids, for instance in the framework regions of the VH and VL domains, in order to avoid or minimize an immune response in humans. The constant domains of a humanized antibody are most of the time human CH and CL domains.

[0248] Numerous methods for humanisation / humanization of an antibody sequence are known in the art; see e.g., the review by Almagro & Fransson (2008) Front Biosci. 13: 1619- 1633. One commonly used method is CDR grafting, or antibody reshaping, which involves grafting of the CDR sequences of a donor antibody, generally a mouse antibody, into the framework scaffold of a human antibody of different specificity. Since CDR grafting may reduce the binding specificity and affinity, and thus the biological activity, of a CDR grafted non-human antibody, back mutations may be introduced at selected positions of the CDR grafted antibody to retain the binding specificity and affinity of the parent antibody. Identification of positions for possible back mutations can be performed using information available in the literature and in antibody databases. Amino acid residues that are candidates for back mutations are typically those that are located at the surface of an antibody molecule, while residues that are buried or that have a low degree of surface exposure will not normally be altered. An alternative humanization technique to CDR grafting and back mutation is resurfacing, in which non-surface exposed residues of non-human origin are retained, while surface residues are altered to human residues. Another alternative technique is known as “guided selection” (Jespers et al. (1994) Biotechnology 12, 899) and can be used to derive froma murine antibody a fully human antibody conserving the epitope and binding characteristics of the parental antibody.

[0249] The frequency of appearance of the second form in various intact IgG isotypes is due to, but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al., (1993) Molecular Immunology 30: 105, incorporated by reference in its entirety) to levels typically observed using a human IgGl hinge. The instant disclosure encompasses in various embodiments antibodies having one or more mutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.

[0250] An "isolated antibody," as used herein, means an antibody that has been identified and separated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an "isolated antibody." In various embodiments, the isolated antibody also includes an antibody in situ within a recombinant cell. In other embodiments, isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. In various embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0251] The term "specifically binds," or the like, means that an antibody or antigenbinding fragment thereof forms a complex with an antigen that is relatively stable under physiologic conditions. Methods for determining whether an antibody specifically binds to an antigen are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. For example, an antibody that "specifically binds" CEACAM5, as used herein, includes antibodies that bind CEACAM5 or portion thereof with a KD of less than about 1000 nM, less than about 500 nM, less than about 300 nM, less than about 200 nM, less than about 100 nM, less than about 90 nM, less than about 80 nM, less than about 70 nM, less than about 60 nM, less than about 50 nM, less than about 40 nM, less than about 30 nM, less than about 20 nM, less than about 10 nM, less than about 5 nM, less than about 4 nM, less than about 3 nM, less than about 2 nM, less than about 1 nM or about 0.5 nM, as measured in a surface plasmon resonance assay. Specific binding can also be characterized by a dissociation constantof at least about 1x1 O'6M or smaller. In other embodiments, the dissociation constant is at least about 1x1 O'7M, 1x1 O'8M, or 1x1 O'9M. An isolated antibody that specifically binds human CEACAM5 may, however, have cross-reactivity to other antigens, such as CEACAM5 molecules from other (non-human) species.

[0252] The term "surface plasmon resonance", as used herein, refers to an optical phenomenon that allows for the analysis of real-time interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORE™ system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0253] The term "KD", as used herein, is intended to refer to the equilibrium dissociation constant of an antibody-antigen interaction.

[0254] “Affinity” is defined, in theory, by the equilibrium association between the whole antibody and the antigen. It can be experimentally assessed by a variety of known methods, such as measuring association and dissociation rates with surface plasmon resonance or measuring the EC50 (or apparent KD) in an immunochemical assay (ELISA, FACS). In these assays, the EC50 is the concentration of the antibody which induces a response halfway between the baseline and maximum after some specified exposure time on a defined concentration of antigen by ELISA (enzyme-linked immuno-sorbent assay) or cell expressing the antigen by FACS (Fluorescence Activated Cell Sorting).

[0255] A monoclonal antibody binding to antigen 1 (Agl) is “cross-reactive” to antigen 2 (Ag2) when the EC50s are in a similar range for both antigens. In the present application, a monoclonal antibody binding to Agl is cross-reactive to Ag2 when the ratio of affinity of Ag2 to affinity of Agl is equal or less than 10 (for instance 5, 2, 1 or 0.5), affinities being measured with the same method for both antigens.

[0256] Affinity for human CEAC AM5 or for Macaca fascicularis CEAC AM5 may be determined as the EC50 value in an ELISA using soluble recombinant CEACAM5 as capture antigen.

[0257] The antibody of the disclosure may also have an apparent dissociation constant (apparent KD), as may be determined by FACS analysis on tumor cell line MKN45 (DSMZ, ACC 409) or on xenograft tumor cells deriving from patient (CR-IGR-034P available from Oncodesign Biotechnology, tumor collection CReMEC), which is <25 nM, for instance <20nM, <10 nM, <5 nM, <3 nM or <1 nM. The apparent KD may be within the range 0.01-20 nM, or may be within the range 0.1-20 nM, 0.1-10 nM, or 0.1-5 nM.

[0258] Additionally, antibodies according to the disclosure have been shown to be able to detect CEACAM5 expression by immunoassays or immunohistochemistry in frozen and formalin-fixed and paraffin embedded (FFPE) tissue sections.

[0259] The term "epitope" refers to an antigenic determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstance, an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.

[0260] The anti-CEACAM5 antibodies useful for the methods described herein may in various embodiments include one or more amino acid substitutions, insertions and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences from which the antibodies were derived. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present disclosure includes in various embodiments methods involving the use of antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and / or CDR regions are mutated to the corresponding residue(s) of the germline sequence from which the antibody was derived, or to the corresponding residue(s) of another human germline sequence, or to a conservative amino acid substitution of the corresponding germline residue(s) (such sequence changes are referred to herein collectively as "germline mutations"). Numerous antibodies and antigen-binding fragments may be constructed which comprise one or more individual germline mutations or combinations thereof. In certain embodiments, all of the framework and / or CDR residues within the VH and / or VL domains are mutated back to the residues found in the original germline sequence from which the antibody was derived. In other embodiments, only certain residues are mutated back to the originalgermline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. In other embodiments, one or more of the framework and / or CDR residue(s) are mutated to the corresponding residue(s) of a different germline sequence (i.e., a germline sequence that is different from the germline sequence from which the antibody was originally derived). Furthermore, the antibodies may contain any combination of two or more germline mutations within the framework and / or CDR regions, e.g., wherein certain individual residues are mutated to the corresponding residue of a certain germline sequence while certain other residues that differ from the original germline sequence are maintained or are mutated to the corresponding residue of a different germline sequence. Once obtained, antibodies and antigenbinding fragments that contain one or more germline mutations can be easily tested for one or more desired property such as, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. The use of antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present disclosure.

[0261] The present disclosure also includes methods involving the use of anti- CEACAM5 antibodies comprising variants of any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein having one or more conservative substitutions. For example, the present disclosure includes the use of anti- CEACAM5 antibodies having HCVR, LCVR, and / or CDR amino acid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 or fewer, etc. conservative amino acid substitutions relative to any of the HCVR, LCVR, and / or CDR amino acid sequences disclosed herein.

[0262] According to the present disclosure, the anti-CEACAM5 antibody, or antigenbinding fragment thereof, in various embodiments comprises a heavy chain variable region (HCVR), light chain variable region (LCVR), and / or complementarity determining regions (CDRs) comprising any of the amino acid sequences of the anti-CEACAM5 antibodies described in Inti. Patent Pub. No. WO 2014 / 079886 Al, incorporated herein by reference in its entirety.

[0263] Amino acid sequence modification(s) of the antibodies described herein are contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. It is known that when a humanised antibody is producedby simply grafting only CDRs in VH and VL of an antibody derived from a non-human animal in FRs of the VH and VL of a human antibody, the antigen binding activity may be reduced in comparison with that of the original antibody derived from a non-human animal. It is considered that several amino acid residues of the VH and VL of the non-human antibody, not only in CDRs but also in FRs, may be directly or indirectly associated with the antigen binding activity. Hence, substitution of these amino acid residues with different amino acid residues derived from FRs of the VH and VL of the human antibody would reduce the binding activity. In order to solve the problem, in human antibodies grafted with non-human CDRs, attempts have to be made to identify, among amino acid sequences of the FR of the VH and VL of human antibodies, an amino acid residue which is directly associated with binding of the antibody, or which interacts with an amino acid residue of a CDR, or which maintains the three-dimensional structure of the antibody and which is directly associated with binding to the antigen. The reduced antigen binding activity could be increased by replacing the identified amino acids with amino acid residues of the original antibody derived from a non-human animal.

[0264] Modifications and changes may be made in the structure of the antibodies of the present disclosure, and in the DNA sequences encoding them, and still result in a functional antibody or polypeptide with desirable characteristics.

[0265] A further object of the present disclosure also encompasses functionconservative variants of the polypeptides of the present disclosure. For example, certain amino acids may be substituted by other amino acids in a protein structure without appreciable loss of activity. Since the interactive capacity and nature of a protein define its biological functional activity, certain amino acid substitutions can be made in a protein sequence, and of course in its DNA encoding sequence, while nevertheless obtaining a protein with like properties. It is thus contemplated that various changes may be made in the antibody sequences of the disclosure, or corresponding DNA sequences which encode said polypeptides, without appreciable loss of their biological activity. It is known in the art that certain amino acids may be substituted by other amino acids having a similar hydropathic index or score and still result in a protein with similar biological activity, i.e. still obtain a biological functionally equivalent protein. It is also possible to use well-established technologies, such as alanine-scanning approaches, to identify, in an antibody or polypeptide of the disclosure, all the amino acids that can be substituted without significant loss of binding to the antigen. Such residues can be qualified as neutral, sincethey are not involved in antigen binding or in maintaining the structure of the antibody. One or more of these neutral positions can be substituted by alanine or by another amino acid can without changing the main characteristics of the antibody or polypeptide of the disclosure.

[0266] Neutral positions can be seen as positions where any amino acid substitution could be incorporated to the antibodies. Indeed, in the principle of alanine-scanning, alanine is chosen since it this residue does not carry specific structural or chemical features. It is generally admitted that if an alanine can be substituted for a specific amino acid without changing the properties of a protein, many other, if not all amino acid substitutions are likely to be also neutral. In the opposite case where alanine is the wild-type amino acid, if a specific substitution can be shown as neutral, it is likely that other substitutions would also be neutral. As outlined above, amino acid substitutions are generally therefore based on the relative similarity of the amino acid side-chain substituents, for example, their hydrophobicity, hydrophilicity, charge, size, and the like. Exemplary substitutions which take any of the foregoing characteristics into consideration are well known to those of skill in the art and include arginine and lysine; glutamate and aspartate; serine and threonine; glutamine and asparagine; and valine, leucine, and isoleucine.

[0267] It may be also desirable to modify the antibody of the disclosure with respect to effector function, e.g., to enhance antigen-dependent cell-mediated cytotoxicity (ADCC) and / or complement dependent cytotoxicity (CDC) of the antibody. This may be achieved by introducing one or more amino acid substitutions in an Fc region of the antibody. Alternatively, or additionally, cysteine residue(s) may be introduced in the Fc region, thereby allowing interchain disulfide bond formation in this region. The homodimeric antibody thus generated may have improved internalization capability and / or increased complement-mediated cell killing and / or antibody-dependent cellular cytotoxicity (ADCC) (Caron PC. et al. 1992; and Shopes B. 1992).

[0268] Another type of amino acid modification of the antibody of the disclosure may be useful for altering the original glycosylation pattern of the antibody, i.e., by deleting one or more carbohydrate moieties found in the antibody, and / or adding one or more glycosylation sites that are not present in the antibody. The presence of either of the tripeptide sequences asparagine-X-serine, and asparagine-X-threonine, where X is any amino acid except proline, creates a potential glycosylation site. Addition or deletion of glycosylation sites to the antibodyis conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tripeptide sequences (for N-linked glycosylation sites).

[0269] Another type of modification involves the removal of sequences identified, either in silico or experimentally, as potentially resulting in degradation products or heterogeneity of antibody preparations. As examples, deamidation of asparagine and glutamine residues can occur depending on factors such as pH and surface exposure. Asparagine residues are particularly susceptible to deamidation, primarily when present in the sequence Asn-Gly, and to a lesser extent in other dipeptide sequences such as Asn-Ala. When such a deamidation site, in particular Asn-Gly, is present in an antibody or polypeptide of the disclosure, it may therefore be desirable to remove the site, typically by conservative substitution to remove one of the implicated residues. Such substitutions in a sequence to remove one or more of the implicated residues are also intended to be encompassed by the present disclosure.

[0270] Another type of covalent modification involves chemically or enzymatically coupling glycosides to the antibody. These procedures are advantageous in that they do not require production of the antibody in a host cell that has glycosylation capabilities for N-or O- linked glycosylation. Depending on the coupling mode used, the sugar(s) may be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups such as those of cysteine, (d) free hydroxyl groups such as those of serine, threonine, or hydroxyproline, (e) aromatic residues such as those of phenylalanine, tyrosine, or tryptophan, or (f) the amide group of glutamine. For example, such methods are described in Inti. Patent Pub. No. W087 / 05330.

[0271] Removal of any carbohydrate moieties present on the antibody may be accomplished chemically or enzymatically. Chemical deglycosylation requires exposure of the antibody to the compound trifluoromethanesulfonic acid, or an equivalent compound. This treatment results in the cleavage of most or all sugars except the linking sugar (N- acetylglucosamine or N-acetylgalactosamine), while leaving the antibody intact. Chemical deglycosylation is described by SojahrH. etal. (1987) and by Edge, AS. etal. (1981). Enzymatic cleavage of carbohydrate moieties on antibodies can be achieved using a variety of endo-and exo-glycosidases as described by Thotakura, NR. et al. (1987).

[0272] Another type of covalent modification of the antibody comprises linking the antibody to one of a variety of nonproteinaceous polymers, e.g., polyethylene glycol,polypropylene glycol, or poly oxyalkylenes, in the manner set forth in US Patent Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192; or 4,179,337.

[0273] In an embodiment, the anti-CEACAM5 antibody is Tusamitamab (CAS Registry No. 2349294-95-5).

[0274] Tusamitamab comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acid sequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5.HCDR1: GFVFSSYD (SEQ ID NO: 1)HCDR2: ISSGGGIT (SEQ ID NO: 2)HCDR3: AAHYFGSSGPFAY (SEQ ID NO: 3)LCDR1: ENIFSY (SEQ ID NO: 4)LCDR2: NTRLCDR3: QHHYGTPFT (SEQ ID NO: 5)

[0275] Tusamitamab comprises a variable domain of a heavy chain (VH) consisting of SEQ ID NO: 6 and a variable domain of a light chain (VL) consisting of SEQ ID NO: 7.EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGI TYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQ GTLVTVSS(SEQ ID NO: 6)DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGV PSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIK (SEQ ID NO: 7)EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGI TYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT C PPC PAPELLGGPSVFLFPPI<PI<DTLMISRTPEVTCVVVDVSHEDPEVI<FNWYVDGVEVHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CT<VSNI<ALPAPIEI<TISI<AI< GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(SEQ ID NO: 8)DIQMTQSPASLSASVGDRVTTTCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGV PSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL S STLTLSKAD YEKHKVYACEVTHQGLS SPVTKSFNRGEC(SEQ ID NO: 9)Cytotoxic Payload and Immunoconjugate

[0276] The present disclosure also includes “cytotoxic conjugates”, or “immunoconjugates”, or “antibody-drug conjugates”, or “conjugates”. As used herein, all these terms have the same meaning and are interchangeable.

[0277] Accordingly, provided is an “immunoconjugate” comprising an antibody of the disclosure (e.g., anti-CEACAM5 antibody) linked or conjugated to at least one growth inhibitory agent, such as a cytotoxic agent or a radioactive isotope.

[0278] A "growth inhibitory agent", or “anti-proliferative agent”, which can be used indifferently, refers to a compound or composition which inhibits growth of a cell, especially tumour cell, either in vitro or in vivo.

[0279] The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents the function of cells and / or causes destruction of cells. The term "cytotoxic agent" is intended to include chemotherapeutic agents, enzymes, antibiotics, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and / or variants thereof, and the various antitumor or anti cancer agentsdisclosed below. In some embodiments, the cytotoxic agent is an antimetabolite. In some embodiments, the cytotoxic agent is a taxoid, vincas, a maytansinoid or maytansinoid analog such as DM1 or DM4, a small drug, a tomaymycin or pyrrolobenzodiazepine derivative, a cryptophycin derivative, a leptomycin derivative, an auristatin or dolastatin analog, a prodrug, topoisomerase inhibitors such as a topoisomerase II inhibitors, a DNA alkylating agent, DNA- cross-linking agent, DNA-intercalating agent, an anti-tubulin agent, a CC-1065 or CC-1065 analog, or any combination thereof.

[0280] As used herein “maytansinoids” denotes maytansinoids and maytansinoid analogs. Maytansinoids are drugs that inhibit microtubule formation and that are highly toxic to mammalian cells.

[0281] Examples of suitable maytansinoids include maytansinol and maytansinol analogs.

[0282] Examples of suitable maytansinol analogues include those having a modified aromatic ring and those having modifications at other positions. Such suitable maytansinoids are disclosed in U.S. Patent Nos. 4,424,219; 4,256,746; 4,294,757; 4,307,016; 4,313,946; 4,315,929; 4,331,598; 4,361,650; 4,362,663; 4,364,866; 4,450,254; 4,322,348; 4,371,533; 6,333,410; 5,475,092; 5,585,499; and 5,846,545.

[0283] Specific examples of suitable analogues of maytansinol having a modified aromatic ring include:

[0284] (1) C -19-dechloro (U.S. Pat. No. 4,256,746) (prepared by LAH reduction of ansamytocin P2);

[0285] (2) C-20-hydroxy (or C-20-demethyl) + / -C- 19-dechloro (U.S. Pat. Nos. 4,361,650 and 4,307,016) (prepared by demethylation using Streptomyces or Actinomyces or dechlorination using LAH); and

[0286] (3) C-20-demethoxy, C-20-acyloxy (-OCOR), + / -dechloro (U.S. Pat. No 4,294,757) (prepared by acylation using acyl chlorides).

[0287] Specific examples of suitable analogues of maytansinol having modifications of other positions include:

[0288] (1) C-9-SH (U.S. Pat. No. 4,424,219) (prepared by the reaction of maytansinol with H2S or P2S5);

[0289] (2) C-14-alkoxy methyl (demethoxy / OUOR) (U.S. Pat. No. 4,331,598);

[0290] (3) C-14-hydroxymethyl or acyloxymethyl (CH2OH or CH2OAC) (U.S. Pat. No. 4,450,254) (prepared from Nocardia)

[0291] (4) C-15-hydroxy / acyloxy (U.S. Pat. No. 4,364,866) (prepared by the conversion of maytansinol by Streptomyces)

[0292] (5) C-15-methoxy (U.S. Pat. Nos. 4,313,946 and 4,315,929) (isolated from Trewia nudiflora)

[0293] (6) C-l 8-N-demethy I (U.S. Pat. Nos. 4,362,663 and 4,322,348) (prepared by the demethylation of maytansinol by Streptomyces) and

[0294] (7) 4,5-deoxy (U.S. Pat. No 4,371,533) (prepared by the titanium trichloride / LAH reduction of maytansinol).

[0295] In an embodiment of the disclosure, the cytotoxic conjugates of the present disclosure utilize the thiol-containing maytansinoid (DM1), formally termed V2’-deacetyl- V2’ - (3-mercapto-l-oxopropyl)-maytansine, as the cytotoxic agent. DM1 is represented by the following structural formula (I):

[0296] In another embodiment, the cytotoxic conjugates of the present disclosure utilize the thiol-containing maytansinoid DM4, formally termed / V2’-deacetyl- / V-2’(4-methyl-4- mercapto-l-oxopentyl)-maytansine, as the cytotoxic agent. DM4 is represented by the following structural formula (II):

[0297] In further embodiments of the disclosure, other maytansines, including thiol and disulfide-containing maytansinoids bearing a mono or di-alkyl substitution on the carbon atom bearing the sulfur atom, may be used. These include a maytansinoid having, at C-3, C-14 hydroxymethyl, C-15 hydroxy, or C-20 desmethyl, an acylated amino acid side chain with an acyl group bearing a hindered sulfhydryl group, wherein the carbon atom of the acyl group bearing the thiol functionality has one or two substituents, said substituents being CH3, C2H5, linear or branched alkyl or alkenyl having from 1 to 10 reagents and any aggregate which may be present in the solution.

[0298] Examples of these cytotoxic agents and of methods of conjugation are further given in the application WO 2008 / 010101 which is incorporated by reference.

[0299] The term “radioactive isotope” is intended to include radioactive isotopes suitable for treating cancer, such as At211, Bi212, Er169, I131, I125, Y90, In111, P32, Re186, Re188, Sm153, Sr89, and radioactive isotopes of Lu. Such radioisotopes generally emit mainly betaradiation. In an embodiment the radioactive isotope is alpha-emitter isotope, more precisely Thorium 227 which emits alpha-radiation.

[0300] The immunoconjugates according to the present disclosure can be prepared as described in the application WO 2004 / 091668, the entire content of which is incorporated herein by reference.

[0301] In some embodiments, the antibodies of the present disclosure are covalently attached, directly or via a cleavable or non-cleavable linker, to at least one cytotoxic agent or growth inhibitory agent.

[0302] ‘ ‘Linker”, as used herein, means a chemical moiety comprising a covalent bond or a chain of atoms that covalently attaches a polypeptide (e.g., an antibody) to a drug (or prodrug) moiety. Suitable linkers are well known in the art and include disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groups and esterase labile groups. Exemplary linkers include, but are not limited to, heterobifunctional crosslinking reagents such as N-succinimidyl pyridyldithiobutyrate (SPDB), butanoic acid 4-[(5-nitro-2- pyridinyl)dithio]-2,5-dioxo-l-pyrrolidinyl ester (nitro-SPDB), 4-(Pyridin-2-yldisulfanyl)-2- sulfo-butyric acid (sulfo-SPDB), N-succinimidyl (2-pyridyldithio) propionate (SPDP), succinimidyl (N-maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p-azidobenzoyl)-hexanediamine), bis-diazonium derivatives (such as bis-(p- diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bisactive fluorine compounds (such as l,5-difluoro-2,4- dinitrobenzene). For example, a ricin immunotoxin can be prepared as described in Vitetta et al (1987). Carbon labeled 1- isothiocyanatobenzyl methyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody (WO 94 / 11026).

[0303] The linker may be a "cleavable linker" facilitating release of the cytotoxic agent or growth inhibitory agent in the cell. For example, an acid-labile linker, a peptidase-sensitive linker, an esterase labile linker, a photolabile linker or a disulfide-containing linker (See e.g., U.S. Patent No. 5,208,020) may be used. The linker may be also a "non-cleavable linker" (for example SMCC linker) that might lead to better tolerance in some cases.

[0304] In some embodiments, a fusion protein comprising the antibody of the disclosure and a cytotoxic or growth inhibitory polypeptide may be made, by recombinant techniques or peptide synthesis. The length of DNA may comprise respective regions encoding the two portions of the conjugate either adjacent one another or separated by a region encoding a linker peptide which does not destroy the desired properties of the conjugate.

[0305] The antibodies of the present disclosure may also be used in Dependent Enzyme Mediated Prodrug Therapy by conjugating the polypeptide to a prodrug-activating enzyme which converts a prodrug (e.g., a peptidyl chemotherapeutic agent, see WO81 / 01145) to an active anti-cancer drug (See, for example, WO 88 / 07378 and U.S. Patent No. 4,975,278). Theenzyme component of the immunoconjugate useful for ADEPT includes any enzyme capable of acting on a prodrug in such a way to convert it into its more active, cytotoxic form. Enzymes that are useful in the method of this disclosure include, but are not limited to, alkaline phosphatase useful for converting phosphate-containing prodrugs into free drugs; arylsulfatase useful for converting sulfate-containing prodrugs into free drugs; cytosine deaminase useful for converting non-toxic fluorocytosine into the anticancer drug, 5-fluorouracil; proteases, such as serratia protease, thermolysin, subtilisin, carboxypeptidases and cathepsins (such as cathepsins B and L), that are useful for converting peptide-containing prodrugs into free drugs; D- alanylcarboxypeptidases, useful for converting prodrugs that contain D-amino acid substituents; carbohydrate-cleaving enzymes such as O-galactosidase and neuraminidase useful for converting glycosylated prodrugs into free drugs; P-lactamase useful for converting drugs derivatized with P-lactams into free drugs; and penicillin amidases, such as penicillin V amidase or penicillin G amidase, useful for converting drugs derivatized at their amine nitrogens with phenoxyacetyl or phenylacetyl groups, respectively, into free drugs. The enzymes can be covalently bound to the polypeptides of the disclosure by techniques well known in the art such as the use of the heterobifunctional crosslinking reagents discussed above.

[0306] According to an embodiment, in the conjugate of the disclosure, the growth inhibitory agent is a maytansinoid, in an embodiment DM1 or DM4.

[0307] In said conjugate, the antibody is conjugated to said at least one growth inhibitory agent by a linking group. In an embodiment said linking group is a cleavable or a non-cleavable linker, such as SPDB, sulfo-SPDB, or SMCC.

[0308] The conjugate may be selected from the group consisting of:

[0309] an antibody-SPDB-DM4 conjugate of formula (III)

[0310] an antibody-sulfo-SPDB-DM4 conjugate of formula (IV)Ab-SulfoSPDB-DM4

[0311] and

[0312] an antibody-SMCC-DMl conjugate of formula (V)Ab-SMCC-DM1

[0313] In an embodiment the conjugate is a conjugate of formula (III), (IV) or (V) as defined above, in which the antibody is an antibody described herein.

[0314] In formulas (III), (IV) and (V) above, “n” corresponds to the number of molecules of chemotherapeutic agent conjugated per molecule of antibody. It corresponds to the “drug-to-antibody ratio” (or “DAR”) defined herein and may range from 1 to 10.

[0315] In an embodiment, the conjugate is ADC (CAS Registry No. 2254086-60-5).

[0316] The conjugates of the disclosure may be prepared by in vitro methods. In general, the conjugate can be obtained by a process comprising the steps of:

[0317] (i) bringing into contact an optionally-buffered aqueous solution of an antibody according to the disclosure) with solutions of a linker and a cytotoxic compound; and

[0318] (ii) then optionally separating the conjugate which was formed in (i) from the unreacted antibody, linker and cytotoxic compounds.

[0319] The aqueous solution of cell-binding agent can be buffered with buffers such as, e.g., potassium phosphate, acetate, citrate or N-2 -Hydroxy ethylpiperazine-N’-2-ethanesulfonic acid (HEPES buffer). The buffer depends upon the nature of the cell-binding agent. The cytotoxic compound is in solution in an organic polar solvent, e.g., dimethyl sulfoxide (DMSO) or dimethylacetamide (DMA).

[0320] The reaction temperature is usually comprised between 20 and 40°C. The reaction time can vary from 1 to 24 hours. The reaction between the cell-binding agent and thecytotoxic agent can be monitored by size exclusion chromatography (SEC) with a refractometric and / or UV detector. If the conjugate yield is too low, the reaction time can be extended.

[0321] A number of different chromatography methods can be used by the person skilled in the art in order to perform the separation of step (ii): the conjugate can be purified e.g., by SEC, adsorption chromatography (such as ion exchange chromatography, IEC), hydrophobic interaction chromatography (HIC), affinity chromatography, mixed-support chromatography such as hydroxyapatite chromatography, or high-performance liquid chromatography (HPLC). Purification by dialysis or diafiltration can also be used.

[0322] As used herein, the term “aggregates” means the associations which can be formed between two or more cell-binding agents, said agents being modified or not by conjugation. The aggregates can be formed under the influence of a great number of parameters, such as a high concentration of cell-binding agent in the solution, the pH of the solution, high shearing forces, the number of bonded dimers and their hydrophobic character, the temperature (see Wang & Gosh, 2008, J. Membrane Set., 318: 311-316, and references cited therein); note that the relative influence of some of these parameters is not clearly established. In the case of proteins and antibodies, the person skilled in the art will refer to Cromwell et al. (2006, AAPS Journal, 8(3): E572-E579). The content in aggregates can be determined with techniques well known to the skilled person, such as SEC (see Walter et al., 1993, Anal. Biochem., 212(2): 469- 480).

[0323] After step (i) or (ii), the conjugate-containing solution can be submitted to an additional step (iii) of chromatography, ultrafiltration and / or diafiltration.

[0324] The conjugate is recovered at the end of these steps in an aqueous solution.

[0325] According to an embodiment, the conjugate according to the disclosure is characterised by a “drug-to-antibody ratio” (or “DAR”) ranging from 1 to 10, for instance from 2 to 5, or for example from 3 to 4. This is generally the case of conjugates including maytansinoid molecules.

[0326] This DAR number can vary with the nature of the antibody and of the drug (e.g,. the growth-inhibitory agent) used along with the experimental conditions used for the conjugation (like the ratio growth-inhibitory agent / antibody, the reaction time, the nature of the solvent and of the cosolvent if any). Thus, the contact between the antibody and the growth- inhibitory agent leads to a mixture comprising several conjugates differing from one another bydifferent drug-to-antibody ratios; optionally the naked antibody; optionally aggregates. The DAR that is determined is thus a mean value.

[0327] A method which can be used to determine the DAR consists in measuring spectrophotometrically the ratio of the absorbance at of a solution of substantially purified conjugate atand 280 nm. 280 nm is a wavelength generally used for measuring protein concentration, such as antibody concentration. The wavelength AD is selected to allow discriminating the drug from the antibody, i.e., as readily known to the skilled person, AD is a wavelength at which the drug has a high absorbance and AD is sufficiently remote from 280 nm to avoid substantial overlap in the absorbance peaks of the drug and antibody. AD may be selected as being 252 nm in the case of maytansinoid molecules. A method of DAR calculation may be derived from Antony S. Dimitrov (ed), LLC, 2009, Therapeutic Antibodies and Protocols, vol 525, 445, Springer Science:

[0328] The absorbances for the conjugate at AD (AAD) and at 280 nm (A280) are measured either on the monomeric peak of the size exclusion chromatography (SEC) analysis (allowing to calculate the “DAR(SEC)” parameter) or using a classic spectrophotometer apparatus (allowing to calculate the “DAR(UV)” parameter). The absorbances can be expressed as follows:

[0329] Aw = (CD x eow) + (CA X CAW)

[0330] A280 = (CD x eo28o) + (CA X eA28o)

[0331] wherein:

[0332] CD and CA are respectively the concentrations in the solution of the drug and of the antibody,

[0333] 0DZD and eD28o are respectively the molar extinction coefficients of the drug at AD and 280 nm, and

[0334] CAW and eA28o are respectively the molar extinction coefficients of the antibody at AD and 280 nm.

[0335] Resolution of these two equations with two unknowns leads to the following equations:

[0336] CD = [(CA28O x Aw) - (CAW X A280)] / [(eow x eA28o) - (CAW X eo28o)]

[0337] CA = [A280 - (CD X eo28o)] / CA28O

[0338] The average DAR is then calculated from the ratio of the drug concentration to that of the antibody: DAR = CD / CA.Antimetabolic Nucleoside Inhibitor

[0339] Antimetabolic nucleoside inhibitors typically structurally resemble natural metabolites, which are involved in normal metabolic processes of cancer cells such as the synthesis of nucleic acids and proteins. The antimetabolites, however, differ enough from the natural metabolites such that they interfere with the metabolic processes of cancer cells. In the cell, antimetabolites are mistaken for the metabolites they resemble, and are processed by the cell in a manner analogous to the normal compounds. The presence of the “decoy” metabolites prevents the cells from carrying out vital functions and the cells are unable to grow and survive. For example, antimetabolites may exert cytotoxic activity by substituting these fraudulent nucleotides into cellular DNA, thereby disrupting cellular division, or by inhibition of critical cellular enzymes, which prevents replication of DNA. In some embodiments, the antimetabolic nucleoside inhibitor is gemcitabine.

[0340] Gemcitabine (2',2'-difluorodeoxycytidine) is an antimetabolite nucleoside analog or nucleoside metabolic inhibitor that has a wide spectrum of antitumor activity and is used as a cytotoxic agent for the treatment of cancers including lung and pancreatic cancers. Gemcitabine is represented by the following structural formula (I):

[0341] Gemcitabine becomes active after intracellular phosphorylation by deoxycytidine kinase as only its di- and tri-phosphate forms possess cytotoxic activity. Specifically, the triphosphate form competes with deoxycytidine triphosphate for incorporation into DNA as an inactive base, and the diphosphate form inhibits ribonucleotide reductase, an enzyme that is essential for normal DNA synthesis. The preparation and activity of gemcitabineare described in US 4,526,988; US 4,808,614; US 5,464,826; US 5,428,176; US 5,756,775; and US 6,001 ,994, the entire contents of which are hereby incorporated by reference in their entirety. In some embodiments, the gemcitabine used is sold under the tradename of GEMZAR™ OR INFUGEM™. In some embodiments, gemcitabine and salts thereof are used for treating cancer such as pancreatic cancer. In some embodiments, gemcitabine and salts thereof are used in combination with an ADC (e.g., tusamitamab ravtansine) used for treating cancer (e.g., pancreatic).Combination Therapies

[0342] Some embodiments of the methods described herein comprise administering to the subject one or more additional therapeutic agents in combination with the antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody. As used herein, the expression “in combination with” means that the additional therapeutic agents are administered before, after, or concurrent with the pharmaceutical composition comprising an anti-CEACAM5 antibody. In some embodiments, the term “in combination with” includes sequential or concomitant administration of the ADC comprising an anti-CEACAM5 antibody and a second therapeutic agent. Methods to treat cancer (e.g., pancreatic) includes administering an ADC (e.g., tusamitamab ravtansine) in combination with a second therapeutic agent (e.g., gemcitabine) for additive or synergistic activity.

[0343] For example, when administered “before” the pharmaceutical composition comprising the ADC, the additional therapeutic agent may be administered about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes, or about 10 minutes prior to the administration of the pharmaceutical composition comprising the ADC. When administered “after” the pharmaceutical composition comprising the ADC, the additional therapeutic agent may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, or about 72 hours after the administration of the pharmaceutical composition comprising the IL-4R antagonist. “Concurrent” administration comprising the ADC means that the additional therapeutic agent is administered to the subject in a separate dosage form withinless than 5 minutes (before, after, or at the same time) of administration of the ADC, or administered to the subject as a single combined dosage formulation comprising both the additional therapeutic agent and the ADC or as separate formulations, one comprising the ADC and the other comprising the additional therapeutic agent. In some embodiments, the additional therapeutic agent is nucleoside metabolic inhibitor. In some embodiments, the nucleoside metabolic inhibitor is gemcitabine.

[0344] In some embodiments, the method of treating cancer is administering to a subject in need thereof an effective amount of an antibody-drug conjugate (ADC) comprising an anti- CEACAM5 antibody before administering the nucleoside metabolic inhibitor, (e.g., gemcitabine). In some embodiments, the method of treating cancer is administering to a subject in need thereof an effective amount of tusamitamab ravtansine before administering gemcitabine.

[0345] In some embodiments, an additional therapeutic agent is a premedication. The term “premedication” means administration of a medication before a treatment or procedure. In some embodiments, the premedication is administered to the subject before each administration of the ADC. Exemplary premedications include histamine Hl antagonist an antiemetic preventive premedication such dexamethasone and / or a histamine Hl antagonist. In some embodiments, the dexamethasone is administered at a dose of about 10 mg. In some embodiments, the dexamethasone is administered to the subject intravenously. In some embodiments, the histamine Hl antagonist is diphenhydramine or dexchlorpheniramine. In some embodiments, the histamine Hl antagonist is diphenhydramine or dexchlorpheniramine can be administered intravenously. In some embodiments, the histamine Hl antagonist is diphenhydramine or dexchlorpheniramine can be administered intravenously to the subject in a dose of about 50 mg. In some embodiments, the premedications include dexamethasone and / or a histamine Hl that can be administered to a subject before administering an ADC.

[0346] In some embodiments, the premedication is administered to a subject before each administration of gemcitabine. In some embodiments, the premedication is an antiemetic preventive premedication. Exemplary antiemetic preventive premedications are a 5-HT3 receptor antagonist or dexamethasone. In some embodiments, the 5-HT3 receptor antagonist or dexamethasone is administered to a subject before each administration of gemcitabine.Pharmaceutical Compositions

[0347] The antibodies, immunoconjugates, and compounds of the disclosure may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.

[0348] Thus, another object of the disclosure relates to a pharmaceutical composition comprising an antibody, an immunoconjugate or a compound of the disclosure and a pharmaceutically acceptable carrier or excipient.

[0349] Another object of the disclosure relates to a pharmaceutical composition comprising (i) an antibody, an immunoconjugate or a compound of the disclosure, (ii) a nucleoside metabolic inhibitor, and (iii) a pharmaceutically acceptable carrier or excipient.

[0350] Another object of the disclosure relates to a pharmaceutical composition comprising (i) an antibody, an immunoconjugate or a compound of the disclosure, (ii) gemcitabine, and (iii) a pharmaceutically acceptable carrier or excipient.

[0351] The disclosure also relates to an antibody, an immunoconjugate or a compound according to the disclosure, for use as a medicament.

[0352] The disclosure also relates to an antibody, an immunoconjugate or a compound according to the disclosure, in combination with a nucleoside metabolic inhibitor, for use as a medicament.

[0353] The disclosure also relates to an antibody, an immunoconjugate or a compound according to the disclosure, in combination with gemcitabine, for use as a medicament.

[0354] The disclosure also relates to an antibody, an immunoconjugate or a compound according to the disclosure, for use for treating cancer.

[0355] The disclosure also relates to an antibody, an immunoconjugate or a compound according to the disclosure, in combination with a nucleoside metabolic inhibitor, for use for treating cancer.

[0356] The disclosure also relates to an antibody, an immunoconjugate or a compound according to the disclosure, in combination with gemcitabine, for use for treating cancer.

[0357] "Pharmaceutically" or "pharmaceutically acceptable" refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate. A pharmaceutically acceptablecarrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material, or formulation auxiliary of any type.

[0358] As used herein, “pharmaceutically-acceptable carriers” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, and the like that are physiologically compatible. Examples of suitable carriers, diluents and / or excipients include one or more of water, amino acids, saline, phosphate buffered saline, buffer phosphate, acetate, citrate, succinate; amino acids and derivates such as histidine, arginine, glycine, proline, glycylglycine; inorganic salts NaCl, calcium chloride; sugars or polyalcohols such as dextrose, glycerol, ethanol, sucrose, trehalose, mannitol; surfactants such as Polysorbate 80, polysorbate 20, poloxamer 188; and the like, as well as combination thereof. In many cases, it is preferable to include isotonic agents, such as sugars, polyalcohols, or sodium chloride in the composition, and formulation may also contain an antioxidant such as tryptamine and a stabilizing agent such as Tween 20.

[0359] The form of the pharmaceutical compositions, the route of administration, the dosage and the regimen naturally depend upon the condition to be treated, the severity of the illness, the age, weight, and gender of the patient, and the like.

[0360] The pharmaceutical compositions of the disclosure can be formulated for a topical, oral, parenteral, intranasal, intravenous, intramuscular, subcutaneous, or intraocular administration and the like. In some embodiments, the pharmaceutical composition comprises tusamitamab ravtansine or gemcitabine. In some embodiments the pharmaceutical compositions comprising tusamitamab ravtansine is administered intravenously. In some embodiments the pharmaceutical compositions comprising gemcitabine is administered intravenously.

[0361] In an embodiment, the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected. These may be isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.

[0362] The pharmaceutical composition can be administrated through drug combination devices.

[0363] The doses used for the administration can be adapted as a function of various parameters, and for instance as a function of the mode of administration used, of the relevant pathology, or alternatively of the desired duration of treatment.

[0364] To prepare pharmaceutical compositions, an effective amount of the antibody or immunoconjugate of the disclosure may be dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium.

[0365] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and injectable with the appropriate device or system for delivery without degradation. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

[0366] Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0367] A polypeptide, antibody or immunoconjugate of the disclosure can be formulated into a composition in a neutral or salt form. Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, glycine, histidine, procaine and the like.

[0368] The carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils. The proper fluidity can be maintained, for example, using a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and using surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it is preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0369] Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with any of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0370] The preparation of more concentrated, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area.

[0371] Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. The formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.

[0372] For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In this connection, sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, "Remington's Pharmaceutical Sciences" 15th Edition, pages 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of thesubject being treated. The person responsible for administration will determine the appropriate dose for the individual subject.

[0373] The antibody or immunoconjugate of the disclosure may be formulated within a therapeutic mixture to comprise about 0.01 to 100 milligrams, per dose or so. In some embodiments, tusamitamab ravtansine is packaged in 30 ml glass vials containing 125 mg / ml ADC.

[0374] In addition to the antibody or immunoconjugate formulated for parenteral administration, such as intravenous or intramuscular injection, other pharmaceutically acceptable forms include, e.g., tablets or other solids for oral administration; time release capsules; and any other form currently used.

[0375] In certain embodiments, the use of liposomes and / or nanoparticles is contemplated for the introduction of polypeptides into host cells. The formation and use of liposomes and / or nanoparticles are known to those of skill in the art.

[0376] Nanocapsules can generally entrap compounds in a stable and reproducible way. To avoid side effects due to intracellular polymeric overloading, such ultrafine particles (sized around 0.1 pm) are generally designed using polymers able to be degraded in vivo. Biodegradable polyalkyl-cyanoacrylate nanoparticles, or biodegradable polylactide or polylactide co glycolide nanoparticules that meet these requirements are contemplated for use in the present disclosure, and such particles may be easily made.

[0377] Liposomes are formed from phospholipids that are dispersed in an aqueous medium and spontaneously form multilamellar concentric bilayer vesicles (also termed multilamellar vesicles (MLVs)). MLVs generally have diameters of from 25 nm to 4 pm. Sonication of MLVs results in the formation of small unilamellar vesicles (SUVs) with diameters in the range of 200 to 500 A, containing an aqueous solution in the core. The physical characteristics of liposomes depend on pH, ionic strength, and the presence of divalent cations.Methods of TreatmentAnti-CEACAM5 ADC and combination of anti-CEACAM5 ADC and gemcitabine

[0378] An aspect of the disclosure is a method of treating a cancer, wherein the method comprises administering to a subject in need thereof an effective amount of an anti-CEACAM5 ADC. Another aspect of the disclosure is a method of treating a cancer, wherein the methodcomprises administering to a subject in need thereof an effective amount of (i) an anti- CEACAM5 ADC and (ii) nucleoside metabolic inhibitor. In some embodiments, the method of treating a cancer comprises administering to a subject in need thereof an effective amount of an anti-CEAC AM5 ADC. Another aspect of the disclosure is a method of treating a cancer, wherein the method comprises administering to a subject in need thereof an effective amount of (i) an anti-CEACAM5 ADC and (ii) gemcitabine.

[0379] As used herein, an “effective amount” or "therapeutically effective amount" is a dose of the therapeutic that results in treatment of CEACAM5 expressing cancer (e.g., pancreatic cancer).

[0380] As used herein, “treating” “treat,” “treatment” or the like refers to causing a detectable improvement in one or more symptoms associated with a CEACAM5 expressing cancer or causing a biological effect (e.g., a decrease in the level of a particular biomarker) that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s). Also encompassed by the term is diminishing the extent of the disease, stabilizing the disease (e.g., preventing or delaying the worsening of the disease), preventing or delaying the spread (e.g., metastasis) of the disease, preventing or delaying the recurrence of the disease, delay or slowing the progression of the disease, ameliorating the disease state, providing a remission (partial or total) of the disease, increasing the quality of life, and / or prolonging survival.

[0381] For example, a dose of therapeutic which causes an improvement in any of the following symptoms or conditions associated with a CEACAM5 expressing cancer is deemed a "therapeutically effective amount.”

[0382] In another example, a treatment has not been effective when a dose of therapeutic does not result in a detectable improvement in one or more parameters or symptoms associated with a CEACAM5 expressing cancer (e.g., pancreatic cancer) or which does not cause a biological effect that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s) of cancer.

[0383] According to some of these embodiments, the anti-CEACAM5 ADC is administered intravenously.

[0384] In accordance with the methods of the present disclosure, a therapeutically effective amount of therapeutic that is administered to the subject will vary depending upon theage and the size (e.g., body weight or body surface area) of the subject as well as the route of administration and other factors well known to those of ordinary skill in the art. In some embodiments, the subject is at least 18 years old.

[0385] An aspect of the disclosure is a method of treating a cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of (i) an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody and (ii) nucleoside metabolic inhibitor, wherein the cancer expresses CEACAM5. In some embodiments, the method of treating a cancer in a subject in need thereof comprises administering to the subject an effective amount of (i) an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody and (ii) gemcitabine. In some embodiments, the method of treating a cancer in a subject in need thereof comprises administering to the subject an effective amount of tusamitamab ravtansine and gemcitabine.

[0386] In an embodiment, the anti-CEACAM5 antibody comprises a HCDR1 having the amino acid sequence of SEQ ID NO: la HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acid sequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5.HCDR1: GFVFSSYD (SEQ ID NO: 1)HCDR2: ISSGGGIT (SEQ ID NO: 2)HCDR3: AAHYFGSSGPFAY (SEQ ID NO: 3)LCDR1: ENIFSY (SEQ ID NO: 4)LCDR2: NTRLCDR3: QHHYGTPFT (SEQ ID NO: 5)

[0387] In certain embodiments, the anti-CEACAM5 antibody comprises a variable domain of a heavy chain (VH) consisting of SEQ ID NO: 6.

[0388] In certain embodiments, the anti-CEACAM5 antibody comprises a variable domain of a light chain (VL) consisting of SEQ ID NO: 7.

[0389] In certain embodiments, the anti-CEACAM5 antibody comprises a variable domain of a heavy chain (VH) consisting of SEQ ID NO: 6 and a variable domain of a light chain (VL) consisting of SEQ ID NO: 7.EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGI TYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQ GTLVTVSS (SEQ ID NO: 6)DIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGV PSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIK (SEQ ID NO: 7)

[0390] In certain embodiments, the anti-CEACAM5 antibody comprises a heavy chain (HC) consisting of SEQ ID NO: 8.

[0391] In certain embodiments, the anti-CEACAM5 antibody comprises a light chain (LC) consisting of SEQ ID NO: 9.

[0392] 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.EVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGI TYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPI<PI<DTLMISRTPEVTCVVVDVSHEDPEVI<FNWYVDGVE VHNAI<TI<PREEQYNSTYRVVSVLTVLHQDWLNGI<EYI<CT<VSNI<ALPAPIEI<TISI<AI< GQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 8)DIQMTQSPASLSASVGDRVTTTCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGV PSRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIKRTVAAPSVFIF PPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL S STLTLSKAD YEKHKVYACEVTHQGLS SPVTKSFNRGEC (SEQ ID NO: 9)

[0393] In certain embodiments, the antibody-drug conjugate comprises a cytotoxic agent.

[0394] In certain embodiments, the antibody-drug conjugate comprises a cytotoxic agent selected from the group consisting of antimetabolite, DNA-alkylating agent, DNA-cross- linking agent, DNA-intercalating agent, anti-microtubule agent, topoisomerase inhibitor, and any combination thereof.

[0395] In certain embodiments, the antibody-drug conjugate comprises an antimicrotubule agent.

[0396] In certain embodiments, the antibody-drug conjugate comprises a maytansinoid.

[0397] In certain embodiments, the antibody-drug conjugate comprises a maytansinoid selected from the group consisting of N2’-deacetyl-N2’-(3-mercapto-l-oxopropyl)-maytansine (DM1), N2’-deacetyl-N2’(4-methyl-4-mercapto-l-oxopentyl)-maytansine (DM4), and any combination thereof.

[0398] In certain embodiments, the antibody-drug conjugate comprises N2’-deacetyl- N2’(4-methyl-4-mercapto-l-oxopentyl)-maytansine (DM4).

[0399] In certain embodiments, the antibody-drug conjugate comprises a cleavable or non-cleavable linker.

[0400] In certain embodiments, the antibody-drug conjugate comprises a cleavable linker.

[0401] In certain embodiments, the antibody-drug conjugate comprises a cleavable linker selected from N-succinimidyl pyridyldithiobutyrate (SPDB) and 4-(Pyridin-2- yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB).

[0402] In certain embodiments, the antibody-drug conjugate comprises at least one cytotoxic agent and / or a cleavable linker.

[0403] In certain embodiments, the antibody-drug conjugate comprises a cytotoxic agent and a cleavable linker.

[0404] In certain embodiments, the antibody-drug conjugate comprises an anti- CEACAM5 antibody which is linked to N2’-deacetyl-N2’(4-methyl-4-mercapto-l-oxopentyl)- maytansine (DM4) via N-succinimidyl pyridyldithiobutyrate (SPDB).

[0405] In certain embodiments, the antibody-drug conjugate is tusamitamab ravtansine.Anti-CEACAM5 ADC Dosing

[0406] The therapeutically effective amount of the ADC comprising the antibody that is administered to the subject varies depending upon the age and the size (e.g., body weight or body surface area) of the subject as well as the route of administration and other factors well known to those of ordinary skill in the art.

[0407] In some embodiments, the dose of the ADC varies depending on the body surface area of the subject. In certain embodiments, the dose of the ADC administered to the subject is from about 1 mg / m2to about 500 mg / m2. In some embodiments, the dose of the ADC administered to the subject is from about 5 mg to about 300 mg / m2. In various embodiments, the dose of the ADC administered to the subject is from about 5 to about 250 mg / m2. In various embodiments, the dose of the ADC administered to the subject is from about 60 to about 210 mg / m2. In various embodiments, the dose is about 5, 10, 20, 30, 40, 60, 80, 100, 120, 135, 150, 170, 180, or 210 mg / m2based on the body surface area of the subject.

[0408] In some embodiments, the dose of the immunoconjugate is about 1 mg / m2, about 5 mg / m2, 10 mg / m2, about 15 mg / m2, about 20 mg / m2, about 25 mg / m2, about 30 mg / m2, about 35 mg / m2, about 40 mg / m2, about 45 mg / m2, about 50 mg / m2, about 55 mg / m2, about 60 mg / m2, about 65 mg / m2, about 70 mg / m2, about 75 mg / m2, about 80 mg / m2, about 85 mg / m2, about 90 mg / m2, about 95 mg / m2, about 100 mg / m2, about 105 mg / m2, about 110 mg / m2, about 115 mg / m2, about 120 mg / m2, about 125 mg / m2, about 130 mg / m2, about 135 mg / m2, about 140 mg / m2, about 145 mg / m2, about 150 mg / m2, about 155 mg / m2, about 160 mg / m2, about 165 mg / m2, about 170 mg / m2, about 175 mg / m2, about 180 mg / m2, about 185 mg / m2, about 190 mg / m2, about 195 mg / m2, about 200 mg / m2, about 205 mg / m2, about 210 mg / m2, about 215 mg / m2, about 220 mg / m2, about 225 mg / m2, about 230 mg / m2, about 235 mg / m2, about 240 mg / m2, about 245 mg / m2, about 250 mg / m2, about 255 mg / m2, about 260 mg / m2, about 265mg / m2, about 270 mg / m2, about 275 mg / m2, about 280 mg / m2, about 285 mg / m2, about 290 mg / m2, about 295 mg / m2, about 300 mg / m2, about 325 mg / m2, about 350 mg / m2, about 375 mg / m2, about 400 mg / m2, about 425 mg / m2, about 450 mg / m2, about 475 mg / m2, or about 500 mg / m2.

[0409] In some embodiments, the ADC is administered intravenously at about 5, 10, 20, 30, 40, 60, 80, 100, 120, 135, 150, 170, 180, or 210 mg / m2based on the body surface area of the subject.

[0410] As used herein, “administered from about 1 to about 500 mg / kg” means that the referred to substance is administered at any value within the stated range including the endpoints of the range. For example, “the dose of the ADC administered to the patient is from 1 mg / m2to 500 mg / m2,” includes administration of 1 mg / m2of the ADC, 500 mg / m2of the ADC, and all doses in between. In various embodiments of the method, the ADC comprising the antibody, is used at a dose listed in Example 1.

[0411] In certain embodiments, the dose of ADC administered to the subject is from about 1 mg / m2to about 500 mg / m2.

[0412] In some embodiments, the dose of the ADC administered to the subject is from about 5 mg / m2to about 300 mg / m2.

[0413] In various embodiments, the dose of the ADC administered to the subject is from about 5 mg / m2to about 250 mg / m2.

[0414] In further embodiments, the dose of the ADC administered to the subject is from about 60 mg / m2to about 210 mg / m2.

[0415] In some embodiments, the dose of the ADC administered to the subject is from about 80 mg / m2to about 170 mg / m2.

[0416] In some embodiments, the dose of the ADC administered to the subject is from about 100 mg / m2to about 170 mg / m2.

[0417] In some embodiments, the dose of the ADC administered to the subject is from about 135 mg / m2to about 170 mg / m2.

[0418] In various embodiments, the dose of the ADC is about 5, 10, 20, 30, 40, 60, 80, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, or 210 mg / m2based on the body surface area of the subject.

[0419] In various embodiments, the dose of the ADC is about 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, or 170 mg / m2based on the body surface area of the subject.

[0420] In various embodiments the ADC is administered at a dose level of 5, 10, 20, 30, 40, 60, 80, 100, 120, 135, 150, 170, 180, or 210 mg / m2based on the body surface area of the subject.

[0421] In an embodiment, the dose of the ADC is about 80 mg / m2.

[0422] In an embodiment, the dose of the ADC is 80 mg / m2.

[0423] In an embodiment, the dose of the ADC is about 100 mg / m2.

[0424] In an embodiment, the dose of the ADC is 100 mg / m2.

[0425] In an embodiment, the dose of the ADC is about 135 mg / m2.

[0426] In an embodiment, the dose of the ADC is 135 mg / m2.

[0427] In an embodiment, the dose of the ADC is about 150 mg / m2.

[0428] In an embodiment, the dose of the ADC is 150 mg / m2.

[0429] In an embodiment, the dose of the ADC is about 170 mg / m2.

[0430] In an embodiment, the dose of the ADC is 170 mg / m2.Gemcitabine Dosing

[0431] In certain embodiments, the dose of the gemcitabine varies depending on the body surface area of the subject.

[0432] In certain embodiments, the dose of the gemcitabine administered to the subject is from about 500 mg / m2to about 1500 mg / m2.

[0433] In certain embodiments, the dose of the gemcitabine administered to the subject is from about 500 mg / m2to about 1250 mg / m2.

[0434] In certain embodiments, the dose of the gemcitabine administered to the subject is from about 600 mg / m2to about 1000 mg / m2.

[0435] In various embodiments, the dose of the gemcitabine is about 600, 650, 700, 750, 800, 850, 900, 950, and 1000 mg / m2based on the body surface area of the subject.

[0436] In an embodiment, the dose of the gemcitabine is about 600 mg / m2.

[0437] In an embodiment, the dose of the gemcitabine is 600 mg / m2.

[0438] In an embodiment, the dose of the gemcitabine is about 800 mg / m2.

[0439] In an embodiment, the dose of the gemcitabine is 800 mg / m2.

[0440] In an embodiment, the dose of the gemcitabine is about 1000 mg / m2.

[0441] In an embodiment, the dose of the gemcitabine is 1000 mg / m2.Dosing Schedules for CEACAM5 ADC and Gemcitabine in Mono and Combination Therapies

[0442] In certain embodiments, the CEACAM5 ADC (e.g., tusamitamab ravtansine) is administered to the subject for about 1 to about 12 cycles. In certain embodiments, the CEACAM5 ADC is administered to the subject for at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 cycles. In certain embodiments, the CEACAM5 ADC is administered to the subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cycles. In certain embodiments, the CEACAM5 ADC is administered to the subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cycles.

[0443] In certain embodiments, the gemcitabine is administered to the subject for about 1 to about 12 cycles. In certain embodiments, the gemcitabine is administered to the subject for at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 cycles. In certain embodiments, the gemcitabine is administered to the subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cycles. In certain embodiments, the gemcitabine is administered to the subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cycles.

[0444] In certain embodiments, the CEACAM5 ADC is administered to the subject for about 1 to about 12 cycles, and gemcitabine is administered to the subject for about 1 to about 12 cycles. In certain embodiments, the CEACAM5 ADC is administered to the subject for at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 cycles, and the gemcitabine is administered to the subject for at least about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 cycles. In certain embodiments, the CEACAM5 ADC is administered to the subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cycles, and the gemcitabine is administered to the subject for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cycles. In certain embodiments, the CEACAM5 ADC is administered to the subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cycles, and the gemcitabine is administered to the subject for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 cycles.

[0445] In certain embodiments, each cycle is between about 1 to about 8 weeks. In certain embodiments, each cycle is about 1, about 2, about 3, about 4, about 5, about 6, about 7, or about 8 weeks. In certain embodiments, each cycle is 1, 2, 3, 4, 5, 6, 7, or 8 weeks.

[0446] In certain embodiments, each cycle is about 1 week. In certain embodiments, each cycle is 1 week. In certain embodiments, each cycle is about 4 to about 10 days. In certain embodiments, each cycle is 4 days. In certain embodiments, each cycle is 5 days. In certain embodiments, each cycle is 6 days. In certain embodiments, each cycle is 7 days. In certain embodiments, each cycle is 8 days. In certain embodiments, each cycle is 9 days. In certain embodiments, each cycle is 10 days. In certain embodiments, at least one cycle is 1, 2, 3, 4, or5 days shorter or longer than at least one other cycle.

[0447] In certain embodiments, each cycle is about 2 weeks. In certain embodiments, each cycle is 2 weeks. In certain embodiments, each cycle is about 11 to about 17 days. In certain embodiments, each cycle is 11 days. In certain embodiments, each cycle is 12 days. In certain embodiments, each cycle is 13 days. In certain embodiments, each cycle is 14 days. In certain embodiments, each cycle is 15 days. In certain embodiments, each cycle is 16 days. In certain embodiments, each cycle is 17 days. In certain embodiments, at least one cycle is 1, 2, 3, 4, or5 days shorter or longer than at least one other cycle.

[0448] In certain embodiments, each cycle is about 3 weeks. In certain embodiments, each cycle is 3 weeks. In certain embodiments, each cycle is about 18 to about 24 days. In certain embodiments, each cycle is 18 days. In certain embodiments, each cycle is 19 days. In certain embodiments, each cycle is 20 days. In certain embodiments, each cycle is 21 days. In certain embodiments, each cycle is 22 days. In certain embodiments, each cycle is 23 days. In certain embodiments, each cycle is 24 days. In certain embodiments, at least one cycle is 1, 2, 3, 4, or5 days shorter or longer than at least one other cycle.

[0449] In certain embodiments, each cycle is about 4 weeks. In certain embodiments, each cycle is 4 weeks. In certain embodiments, each cycle is about 25 to about 31 days. In certain embodiments, each cycle is 25 days. In certain embodiments, each cycle is 26 days. In certain embodiments, each cycle is 27 days. In certain embodiments, each cycle is 8 days. In certain embodiments, each cycle is 29 days. In certain embodiments, each cycle is 30 days. In certain embodiments, each cycle is 31 days. In certain embodiments, at least one cycle is 1, 2, 3, 4, or5 days shorter or longer than at least one other cycle.

[0450] In certain embodiments, each cycle is about 5 weeks. In certain embodiments, each cycle is 5 weeks. In certain embodiments, each cycle is about 32 to about 38 days. In certain embodiments, each cycle is 32 days. In certain embodiments, each cycle is 33 days. In certain embodiments, each cycle is 34 days. In certain embodiments, each cycle is 35 days. In certain embodiments, each cycle is 36 days. In certain embodiments, each cycle is 37 days. In certain embodiments, each cycle is 38 days. In certain embodiments, at least one cycle is 1, 2, 3, 4, or5 days shorter or longer than at least one other cycle.

[0451] In certain embodiments, each cycle is about 6 weeks. In certain embodiments, each cycle is 6 weeks. In certain embodiments, each cycle is about 39 to about 45 days. In certain embodiments, each cycle is 39 days. In certain embodiments, each cycle is 40 days. In certain embodiments, each cycle is 41 days. In certain embodiments, each cycle is 42 days. In certain embodiments, each cycle is 43 days. In certain embodiments, each cycle is 44 days. In certain embodiments, each cycle is 45 days. In certain embodiments, at least one cycle is 1, 2, 3, 4, or5 days shorter or longer than at least one other cycle.

[0452] In certain embodiments, each cycle is about 7 weeks. In certain embodiments, each cycle is 7 weeks. In certain embodiments, each cycle is about 46 to about 52 days. In certain embodiments, each cycle is 46 days. In certain embodiments, each cycle is 47 days. In certain embodiments, each cycle is 48 days. In certain embodiments, each cycle is 49 days. In certain embodiments, each cycle is 50 days. In certain embodiments, each cycle is 51 days. In certain embodiments, each cycle is 52 days. In certain embodiments, at least one cycle is 1, 2, 3, 4, or5 days shorter or longer than at least one other cycle.

[0453] In certain embodiments, each cycle is about 8 weeks. In certain embodiments, each cycle is 8 weeks. In certain embodiments, each cycle is about 53 to about 59 days. In certain embodiments, each cycle is 53 days. In certain embodiments, each cycle is 54 days. In certain embodiments, each cycle is 55 days. In certain embodiments, each cycle is 56 days. In certain embodiments, each cycle is 57 days. In certain embodiments, each cycle is 58 days. In certain embodiments, each cycle is 59 days. In certain embodiments, at least one cycle is 1, 2, 3, 4, or5 days shorter or longer than at least one other cycle.

[0454] In certain embodiments, each ADC cycle is selected from the group consisting of about two weeks, about three weeks, about four weeks, about five weeks, or about six weeks. In certain embodiments, each ADC cycle is about two weeks. In certain embodiments, eachADC cycle is about three weeks. In certain embodiments, each ADC cycle is about four weeks. In certain embodiments, each ADC cycle is about five weeks. In certain embodiments, each ADC cycle is about six weeks.

[0455] In certain embodiments, each ADC cycle is selected from the group consisting of two weeks, three weeks, four weeks, five, or six weeks. In certain embodiments, each ADC cycle is two weeks. In certain embodiments, each ADC cycle is three weeks. In certain embodiments, each ADC cycle is four weeks. In certain embodiments, each ADC cycle is five weeks. In certain embodiments, each ADC cycle is about six weeks.

[0456] In certain embodiments, the ADC is administered to the subject on about day 1, about day 2, about day 3 about day 4, about day 5, or about day 6 of the cycle. In certain embodiments, the ADC is administered to the subject on day 1, 2, 3, 4, 5, or 6 of the cycle. In certain embodiments, the ADC is administered to the subject on day 1 of the cycle.

[0457] In some embodiments, the ADC is administered to the subject in a day from over 30 minutes to 2 hours. In some embodiments the ADC is administered to the subject on day 1 of the first cycle over 1 hour, or over 1 hour 30 minutes.

[0458] In certain embodiments, each gemcitabine cycle is selected from the group consisting of about two weeks, about three weeks, about four weeks, about five weeks, or about six weeks. In certain embodiments, each gemcitabine cycle is about two weeks. In certain embodiments, each gemcitabine cycle is about three weeks. In certain embodiments, each gemcitabine cycle is about four weeks. In certain embodiments, each gemcitabine cycle is about five weeks. In certain embodiments, each gemcitabine cycle is about six weeks.

[0459] In certain embodiments, each gemcitabine cycle is selected from the group consisting of two weeks, three weeks, four weeks, five, or six weeks. In certain embodiments, each gemcitabine cycle is two weeks. In certain embodiments, each gemcitabine cycle is three weeks. In certain embodiments, each gemcitabine cycle is four weeks. In certain embodiments, each gemcitabine cycle is five weeks. In certain embodiments, each gemcitabine cycle is about six weeks.

[0460] In certain embodiments, the gemcitabine is administered to the subject on about day 1, about day 2, about day 3 about day 4, about day 5, about day 6, about day 7, about day 8, about day 9, about day 10, about day 11, about day 12, about day 13, about day 14, about day 15, about day 16, about day 17, about day 18, about day 19, and / or about day 20 of the cycle.In certain embodiments, the gemcitabine is administered to the subject on day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and / or 20 of the cycle. In certain embodiments, the gemcitabine is administered to the subject on day 1, 8, and / or 15 of the cycle. In certain embodiments, the gemcitabine is administered to the subject on day 1, 8, and 15 of the cycle.

[0461] In certain embodiments, the gemcitabine is administered to the subject on day 1, 8, and 15 of a cycle of 4 weeks.

[0462] In some embodiments, the gemcitabine is administered to the subject in a day from 15 minutes to 2 hours. In some embodiments the gemcitabine is administered to the subject in a day within in 15 minutes, 45 minutes, 60 minutes, or 90 minutes. In some embodiments the gemcitabine is administered to the subject on day 1 of the first cycle over 15 minutes or over 30 minutes or over 45 minutes.

[0463] In some embodiments, the gemcitabine is administered to the subject on day 1 of the first cycle over 30 minutes to 2 hours. In some embodiments the ADC is administered to the subject on day 1 of the first cycle over 1 hour, or over 1 hour 30 minutes.

[0464] In certain embodiments, the ADC is administered to the subject in a dose of about 60 mg / m2to about 210 mg / m2. In certain embodiments, the ADC is administered to the subject intravenously in a dose of 60 mg / m2to 210 mg / m2. In certain embodiments, the ADC is administered to the subject intravenously.

[0465] In certain embodiments, the ADC is administered to the subject in a dose of about 100 mg / m2to about 170 mg / m2. In certain embodiments, the ADC is administered to the subject intravenously in a dose of 100 mg / m2to 170 mg / m2. In certain embodiments, the ADC is administered to the subject intravenously.

[0466] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 80 mg / m2.

[0467] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 85 mg / m2.

[0468] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 90 mg / m2.

[0469] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 95 mg / m2.

[0470] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 100 mg / m2.

[0471] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 105 mg / m2.

[0472] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 110 mg / m2.

[0473] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 115 mg / m2.

[0474] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 120 mg / m2.

[0475] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 125 mg / m2.

[0476] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 130 mg / m2.

[0477] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 135 mg / m2.

[0478] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 140 mg / m2.

[0479] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 145 mg / m2.

[0480] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 150 mg / m2.

[0481] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 155 mg / m2.

[0482] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 160 mg / m2.

[0483] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 165 mg / m2.

[0484] In certain embodiments, the ADC is administered to the subject intravenously in a dose of about 170 mg / m2.

[0485] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 80 mg / m2.

[0486] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 85 mg / m2.

[0487] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 90 mg / m2.

[0488] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 95 mg / m2.

[0489] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 100 mg / m2.

[0490] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 105 mg / m2.

[0491] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 110 mg / m2.

[0492] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 115 mg / m2.

[0493] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 120 mg / m2.

[0494] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 125 mg / m2.

[0495] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 130 mg / m2.

[0496] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 135 mg / m2.

[0497] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 140 mg / m2.

[0498] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 145 mg / m2.

[0499] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 150 mg / m2.

[0500] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 155 mg / m2.

[0501] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 160 mg / m2.

[0502] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 165 mg / m2.

[0503] In certain embodiments, the ADC is administered to the subject intravenously in a dose of 170 mg / m2.

[0504] In certain embodiments, the gemcitabine is administered to the subject in a dose of about 400 mg / m2to about 1200 mg / m2. In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of 400 mg / m2to 1200 mg / m2. In certain embodiments, the gemcitabine is administered to the subject intravenously.

[0505] In certain embodiments, the gemcitabine is administered to the subject in a dose of about 600 mg / m2to about 1000 mg / m2. In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of 600 mg / m2to 1000 mg / m2. In certain embodiments, the gemcitabine is administered to the subject intravenously.

[0506] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of about 600 mg / m2.

[0507] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of about 650 mg / m2.

[0508] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of about 700 mg / m2.

[0509] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of about 750 mg / m2.

[0510] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of about 800 mg / m2.

[0511] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of about 850 mg / m2.

[0512] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of about 900 mg / m2.

[0513] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of about 950 mg / m2.

[0514] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of about 1000 mg / m2.

[0515] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of 600 mg / m2.

[0516] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of 650 mg / m2.

[0517] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of 700 mg / m2.

[0518] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of 750 mg / m2.

[0519] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of 800 mg / m2.

[0520] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of 850 mg / m2.

[0521] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of 900 mg / m2.

[0522] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of 950 mg / m2.

[0523] In certain embodiments, the gemcitabine is administered to the subject intravenously in a dose of 1000 mg / m2.

[0524] In general, the combination of CEACAM5 ADC (e.g., tusamitamab ravtansine) and gemcitabine may be administered simultaneously or contemporaneously in any order. In certain embodiments, the CEACAM5 ADC and gemcitabine are administered sequentially. In certain embodiments, the CEACAM5 ADC is administered before the gemcitabine. In certain embodiments, the CEACAM5 ADC is administered after the gemcitabine.

[0525] In certain embodiments, there is a delay of at least about 30 minutes between the end of administration of the first agent and the start of administration of the second agent, provided the administration of both agents is completed within a single day or 24-hour period.

[0526] In certain embodiments, two or more (e.g., 2, 3, 4, or 5 or more) doses are administered at the beginning of the treatment regimen as an “initial dose,” a “secondary dose” and a “tertiary dose.” The terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the ADC or metabolic nucleoside inhibitor. Thus, the “initial dose” is the dose that is administered at the beginning of the treatment regimen (also referred to as the “baseline dose” or “loading dose”); the “secondary doses” are the doses that are administered after the initial dose; and the “tertiary doses” are the doses that are administered after the secondary doses.

[0527] The initial, secondary, and tertiary doses may all contain the same amount of the ADC or metabolic nucleoside inhibitor or may differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of the ADC or metabolic nucleoside inhibitor contained in the initial, secondary and / or tertiary doses varies from one another (e.g., adjusted up or down as appropriate) during treatment.

[0528] In some embodiments, the secondary dose may be lower than the initial dose. For example, one or more initial doses of 170 mg / m2of CEACAM5 ADC may be administered followed by secondary doses of about 80 mg / m2or about 100 mg / m2. In some embodiments, the methods comprise an initial dose of about 135 mg / m2to about 170 mg / m2of CEACAM5 ADC. In certain embodiments, the methods comprise one or more secondary doses or of about 80 mg / m2to about 100 mg / m2of CEACAM5 ADC. In some embodiments, the nucleoside metabolic inhibitor is administered at an initial dose from about 600 mg / m2to about 1000 mg / m2. In some embodiments, gemcitabine is administered at an initial dose from about 600 mg / m2to about 1000 mg / m2.

[0529] In some embodiments, the antibody-drug conjugate is administered at an initial dose from 100 mg / m2to 170 mg / m2.

[0530] In some embodiments, the antibody-drug conjugate is administered at a secondary dose from 80 mg / m2to 100 mg / m2.

[0531] In some embodiments, the antibody-drug conjugate is administered at an initial dose from 100 mg / m2to 170 mg / m2and at a secondary dose from 80 mg / m2to 100 mg / m2.

[0532] In some embodiments, the antibody-drug conjugate is administered at an initial dose of 135 mg / m2, 150 mg / m2, or 170 mg / m2.

[0533] In some embodiments, the antibody-drug conjugate is administered at a secondary dose of 80 mg / m2or 100 mg / m2.

[0534] In some embodiments, the antibody-drug conjugate is administered at an initial dose of 135 mg / m2, 150 mg / m2, or 170 mg / m2on day 1 of a first cycle and at a secondary dose of 80 mg / m2or 100 mg / m2thereafter.

[0535] In some embodiments, the antibody-drug conjugate is administered at secondary dose every 2 weeks.

[0536] In some embodiments, the antibody-drug conjugate is administered at an initial dose of 135 mg / m2or 170 mg / m2on day one of a first cycle and at a secondary dose of 80 mg / m2or 100 mg / m2thereafter, and gemcitabine is administered at a dose from 600 mg / m2to 1000 mg / m2.

[0537] In some embodiments, the antibody-drug conjugate is administered for 1 to 12 cycles, on day 1 of each cycle, wherein a cycle is 2 weeks.

[0538] In some embodiments, gemcitabine is administered for 1 to 12 cycles, on day 1, day 8, and day 15 of each cycle, wherein a cycle is 4 weeks.

[0539] In some embodiments, a kit comprising a dosage form of an antibody, that specifically binds a cancer cell that expresses CEACAM5, wherein the antibody comprises three heavy chain CDR sequences comprising SEQ ID NOs: 1, 2, and 3, respectively, and three light chain CDR sequences comprising SEQ ID NO: 4, NTR, and SEQ ID NO: 5, respectively, for the treatment of pancreatic cancer is provided. In some embodiments, the antibody comprises a heavy chain variable region (HCVR) sequence of SEQ ID NO: 6 and a light chain variable region (LCVR) sequence of SEQ ID NO: 7. In some embodiments, the antibody comprises the heavy chain comprising SEQ ID NO: 8 and the light chain comprising SEQ ID NO: 9. In some embodiments the antibody is tusamitamab (SAR408377). In some embodiments, the antibody is immunoconjugate. In some embodiments, the immunoconjugate is tusamitamab ravtansine (SAR408701). In some embodiments, a kit includes a nucleoside metabolic inhibitor such as gemcitabine. In some embodiments the kit can include each of an antibody, that specifically binds a cancer cell that expresses CEACAM5 and a nucleoside metabolic inhibitor. In some embodiments the kit can include each of tusamitamab ravtansine, and gemcitabine. The kit can comprise a label or package insert, wherein the label or package insert comprises instructionsfor administering the dosage form for the cancer treatment. The instructions can recite a dosing regimen described further herein for cancer treatment.Treatment Populations

[0540] The methods provided herein include administering to a subject in need thereof a therapeutic composition comprising an ADC and / or nucleoside metabolic inhibitor. The expression “a subject in need thereof’ means a human that exhibits one or more symptoms or indicia of cancer, or who has been diagnosed with cancer such as pancreatic cancer.

[0541] In some embodiments, the subject in need thereof is at least 18 years old, has at least one measurable lesion according to the RECIST vl.l criteria that has not been irradiated, has lesions that are at least about 10 mm in the longest diameter, has an ECOG performance status of about 0 to about 1, has cancer in which the CEACAM5 expression is defined as a CEACAM5 immunohistochemistry (IHC) intensity of at least about 2+ in at least about 50% of tumor cell.

[0542] In some embodiments, the subject in need therefor has pancreatic cancer, metastatic pancreatic cancer, or pancreatic ductal adenocarcinoma. In some embodiments, the subject in need thereof has received surgery, radiation, or other chemotherapies. In some embodiments, the subject was unsuccessfully treated by gemcitabine and / or is intolerant to gemcitabine. In some embodiments, the subject was unsuccessfully treated by a 5 -fluorouracil based regimen and / or is intolerant to a 5 -fluorouracil based regimen. For example, the subject may have been previously treated with 5-fluorouracil, leucovorin, liposomal irinotecan, oxaliplatin, nab-paclitaxel, and combinations thereof before administration of the ADC and / or gemcitabine. In some embodiments, the subject may have been previously treated with anthracycline- or taxane-based regimens, hormonal therapy, and human epidermal growth factor receptor 2 (HER2) targeted therapy in combination with chemotherapy before administration of the ADC and / or gemcitabine. In some embodiments, the subject may have been previously treated with Sacituzumab govitecan before the ADC and / or gemcitabine. In some embodiments, the subject is sensitive, or the cancer is refectory to anti -tubulin agents. In some embodiments, the subject is sensitive, or the cancer is refectory to monotherapy of gemcitabine. In some embodiments, the subject prior to receiving an ADC and / or gemcitabine, has been prescribed or is currently taking dexamethasone and / or a histamine Hl antagonist.Methods for Assessing Pharmacodynamic Parameters

[0543] Also provided are methods for assessing one or more pharmacodynamic parameters in a subject in need thereof, caused by administration of a pharmaceutical composition comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antigen binding fragment thereof and / or nucleoside metabolic inhibitor, wherein the cancer expresses CEACAM5. In some embodiments a reduction or improvement of some symptoms may correlate with an improvement in one or more pharmacodynamic parameters. Examples of pharmacodynamic parameters include, for example, biomarker expression levels, maximum concentration observed after infusion (Cmax), area under the plasma concentration versus time curve calculated using the trapezoidal method (AUC) example from -114 days, total body clearance of a drug from plasma calculated using the following equation from AUC: CL=dose / AUC.

[0544] To assess a pharmacodynamic parameter, the parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition. In some embodiments, the pharmacokinetic parameters of SAR408701, gemcitabine, and dFdU will be calculated using noncompartmental methods from concentrations obtained after administration of the ADC and / or nucleoside metabolic inhibitor.

[0545] In some embodiments, circulating tumor DNA (ctDNA), which is single- or double-stranded DNA released by the tumor cells into the blood is used to diagnose and monitor cancer. In some embodiments, the ctDNA is used to determine the tumor progression, prognosis and assist in targeted therapies. In some embodiments, the circulating DNA measured is CEA that is determined at prescreening, baseline and during the treatment period. In some embodiments, the levels of ctDNA are reduced after treatment with ADC or ADC in combination with gemcitabine.

[0546] Fragmented circulating tumor DNA or cfDNA is released from the tumor in the plasma and can readily be extracted and analyzed for mutation of common cancer genes. Subtractive mutation analysis will be performed with germline DNA data to identify tumor specific somatic genetic aberrations. Mutation profiling analysis will be performed and thepotential correlation of specific mutation(s) with clinical outcomes will be assessed. The list (not exhaustive) of the genes that could be mutated is: AKT1, ALK, BRAF, CDKN1B, CDKN2A, CDKN2D, EGFR, ESRI, FGFR4, HER2, HRAS, KRAS, MDM2, MED1, MET, NRAS, PIK3CA, PTEN, RBI, RET, ROS1, and TP53.

[0547] In some embodiments, blood samples are assessed for the presence of anti- therapeutic antibodies against tusamitamab ravtansine.

[0548] In some embodiments, one or more symptoms associated with a CEACAM5 expressing cancer are improved with administering to the subject an effective amount of an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody and / or a nucleoside metabolic inhibitor, wherein the cancer expresses CEACAM5.

[0549] As used herein, the term “baseline,” means parameters measured for a subject prior to or at the time of administration of a composition comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody and / or the nucleoside metabolic inhibitor. To determine whether the requisite parameter has “improved,” the parameter is quantified at baseline and at a time point after administration of the pharmaceutical composition described herein. The difference between the value of the parameter at a particular time point following initiation of treatment and the value of the parameter at baseline is used to establish whether there has been an “improvement” in the related parameters (e.g., an increase or decrease depending on the specific parameter being measured). In some embodiments, subjects administered with the ADC comprising an anti-CEACAM5 antibody and / or the gemcitabine showed less than one treatment-related adverse event. In some embodiments, lesions from baseline were improved. In some embodiments, the CEACAM5 expression is reduced. In some embodiments, the CEACAM5 expression is reduced as defined as a CEACAM5 immunohistochemistry (IHC) intensity from at least about 2+ in at least about 50% of tumor cells.

[0550] In some embodiments, the lesions are reduced after treatment. In some embodiments, the size of the lesions is reduced at least 5%, at least 10%, at least 15%, at least 20%, at least 30% at least 40% at least 50% at least 60% at least 70% at least 80%. In some embodiments, the size of the lesions is reduced from 55 to 80%. In some embodiments the administration of the ADC or ADC in combination with gemcitabine does not result in development of a dose-limiting toxicity. In some embodiments, the administration of ADC orADC in combination with gemcitabine reduces or eliminates the risk of corneal toxicity (e.g., presenting as keratitis / microcystic keratopathy, peripheral neuropathy, colitis (including hemorrhagic, mainly in participants with a known history of colitis or gastrointestinal tract conditions), cardiotoxicity (myocardial or conduction abnormalities), hematologic cytopenias (e.g. anemia, neutropenia, or thrombocytopenia), and hepatotoxicity (e.g. increased ALT, AST, or alkaline phosphatase, as well as systemic acute hypersensitivity reactions (including anaphylaxis and local infusion site reactions. In some embodiments, the administration of ADC or ADC in combination with gemcitabine reduces or eliminates AEs of Grade3 or higher severity such as neutropenia, fatigue, neuropathy, febrile neutropenia. In some embodiments, the administration reduces in size or eliminates the metastases.

[0551] In some embodiments, the cancers (e.g., pancreatic) that are refractory to other therapies responds to the ADC and / or gemcitabine.Embodiments of the disclosure

[0552] The present disclosure relates to the following embodiments.

[0553] One embodiment relates to a method of treating cancer in a subject in need thereof, the method comprising administrating to the subject an effective amount of (i) an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antigen binding fragment thereof and (ii) a nucleoside metabolic inhibitor, wherein the cancer expresses CEAC M5.

[0554] Embodiment 2: the method according to embodiment 1, wherein the anti- CEACAM5 antibody comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acid sequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5.

[0555] Embodiment 3: the method according to embodiment 1, wherein the anti- CEACAM5 antibody comprises a variable domain of a heavy chain (VH) consisting of the sequence of SEQ ID NO: 6 and a variable domain of a light chain (VL) consisting of the sequence of SEQ ID NO: 7.

[0556] Embodiment 4: the method according to any one of the previous embodiments, wherein the anti-CEACAM5 antibody is a humanized monoclonal anti-CEACAM5 antibody.

[0557] Embodiment 5: the method according to any one of the previous embodiments, wherein the anti-CEACAM5 antibody is tusamitamab (SAR408377).

[0558] Embodiment 6: the method according to any one of the previous embodiments, wherein the ADC comprises at least one cytotoxic agent.

[0559] Embodiment 7: the method according to embodiment 6, wherein the ADC comprising the anti-CEACAM5 antibody is covalently attached via a cleavable linker to the at least one cytotoxic agent.

[0560] Embodiment 8: the method according to embodiment 7, wherein the linker is selected from the group consisting of N-succinimidyl pyridyldithiobutyrate (SPDB), 4-(Pyridin- 2-yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB), and succinimidyl (N-maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC).

[0561] Embodiment 9: the method according to any one of embodiments 6-8, wherein the cytotoxic agent is selected from the group consisting of antimetabolite, DNA-alkylating agent, DNA-cross-linking agent, DNA-intercalating agent, anti-microtubule agent, topoisomerase inhibitor, and any combination thereof.

[0562] Embodiment 10: the method according to embodiment 9, wherein the antimicrotubule agent is a maytansinoid.

[0563] Embodiment 11 : the method according to embodiment 10, wherein the maytansinoid is selected from the group consisting of N2’-deacetyl-N2’ -(3 -mercapto- 1- oxopropyl)-maytansine (DM1), N2’-deacetyl-N2’(4-methyl-4-mercapto-l -oxopentyl)- maytansine (DM4), and any combination thereof

[0564] Embodiment 12: the method according to embodiment 11, wherein the maytansinoid is DM4.

[0565] Embodiment 13: the method according to any one of the previous embodiments, wherein the ADC is tusamitamab ravtansine (SAR408701).

[0566] Embodiment 14: the method according to any one of the previous embodiments, wherein the cancer expresses CEACAM5 with moderate or high intensity defined by immunohistochemistry.

[0567] Embodiment 15: the method according to any one of the previous embodiments, wherein the CEACAM5 expression is defined as a CEACAM5 immunohistochemistry (IHC) intensity of at least about 2+ in at least about 50% of tumor cells.

[0568] Embodiment 16: the method according to any one of the previous embodiments, wherein the cancer is pancreatic cancer.

[0569] Embodiment 17: the method according to any one of the previous embodiments, wherein the ADC is administered at a dose from about 60 mg / m2to about 210 mg / m2

[0570] Embodiment 18: the method according to any one of the previous embodiments, wherein the ADC is administered as an initial dose followed by one or more secondary doses.

[0571] Embodiment 19: the method according to any one of the previous embodiments, wherein the ADC is administered at an initial dose from about 100 mg / m2to about 170 mg / m2.

[0572] Embodiment 20: the method according to any one of the previous embodiments, wherein the ADC is administered at an initial dose of about 135 mg / m2, 150 mg / m2, or about 170 mg / m2

[0573] Embodiment 21 : the method according to any one of the previous embodiments, wherein the ADC is administered at a secondary dose from about 80 mg / m2to about 100 mg / m2.

[0574] Embodiment 22: the method according to any one of the previous embodiments, wherein the ADC is administered at a secondary dose of about 80 mg / m2or about 100 mg / m2.

[0575] Embodiment 23: the method according to any one of the previous embodiments, wherein the ADC is administered to the subject at an initial dose of about 135 mg / m2, 150 mg / m2, or about 170 mg / m2on day 1 of a first cycle and at a secondary dose of about 80 mg / m2or about 100 mg / m2thereafter.

[0576] Embodiment 24: the method according to embodiment 23, wherein a cycle is 14 days.

[0577] Embodiment 25: the method according to any one of one of the previous embodiments, wherein the ADC is administered to the subject at secondary dose every two weeks.

[0578] Embodiment 26: the method according to any one of the previous embodiments, wherein the nucleoside metabolic inhibitor is administered after the ADC.

[0579] Embodiment 27: the method according to any one of the previous embodiments, wherein the nucleoside metabolic inhibitor is gemcitabine.

[0580] Embodiment 28: the method according to any one of the previous embodiments, wherein the nucleoside metabolic inhibitor is administered at a dose from about 600 mg / m2to about 1000 mg / m2.

[0581] Embodiment 29: the method according to any one of the previous embodiments, wherein the nucleoside metabolic inhibitor is administered at an initial dose of about 600 mg / m2, 800 mg / m2, or about 1000 mg / m2.

[0582] Embodiment 30: the method according to any one of the previous embodiments, wherein the nucleoside metabolic inhibitor is administered on about day 1, about day 8, and about day 15 of each cycle.

[0583] Embodiment 31 : the method according to embodiment 30, wherein a cycle is 28 days.

[0584] Embodiment 32: the method according to embodiment 30 or 31, wherein the nucleoside metabolic inhibitor is administered every 4 weeks after day 1.

[0585] Embodiment 33: the method according to any one of the previous embodiments, wherein the subject has at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) vl .1 criteria that has not been irradiated.

[0586] Embodiment 34: the method according to embodiment 33, wherein the lesion is at least about 10 mm in the longest diameter.

[0587] Embodiment 35: the method according to any one of the previous embodiments, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of about 0 to about 1.

[0588] Embodiment 36: the method according to any one of the previous embodiments, wherein the subject has metastatic cancer.

[0589] Embodiment 37: the method according to any one of the previous embodiments, wherein the subject has pancreatic ductal adenocarcinoma.

[0590] Embodiment 38: the method according to any one of the previous embodiments, wherein the subject is administered the ADC and gemcitabine after pancreatic surgery, radiation, and chemotherapies, and combinations thereof.

[0591] Embodiment 39: the method according to any one of the previous embodiments, wherein the subject was previously treated with chemotherapies comprising fluoropyrimidine-based therapy before administering the ADC comprising an anti-CEACAM5 antibody and nucleoside metabolic inhibitor.

[0592] Embodiment 40: the method according to any one of the previous embodiments, wherein the subject was previously treated with 5 -fluorouracil, leucovorin, liposomal irinotecan, oxaliplatin, nab-paclitaxel, and combinations thereof.

[0593] Embodiment 41 : the method according to any one of the previous embodiments, further comprising administering a premedication to the subject.

[0594] Embodiment 42: the method according to embodiment 41, wherein administering the premedication is administered to the subject before each administration of ADC.

[0595] Embodiment 43: the method according to embodiment 41 or 42, wherein the premedication is dexamethasone and / or a histamine Hl antagonist.

[0596] Embodiment 44: the method according to embodiment 43, wherein the dexamethasone is administered at a dose of about 10 mg.

[0597] Embodiment 45: the method according to embodiment 43, wherein the histamine Hl antagonist is diphenhydramine or dexchlorpheniramine.

[0598] Embodiment 46: the method according to embodiment 45, wherein the diphenhydramine is administered intravenously to the subject in a dose of about 50 mg.

[0599] Embodiment 47: the method according to any one of embodiments 41-46, wherein administering the premedication to the subject is before each administration of gemcitabine.

[0600] Embodiment 48: the method according to embodiment 47, wherein the premedication is an antiemetic preventive premedication.

[0601] Embodiment 49: the method according to embodiment 48, wherein the antiemetic preventive premedication is a 5-HT3 receptor antagonist or dexamethasone.

[0602] Embodiment 50: the composition comprising an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody or antibody fragment thereof and a nucleoside metabolic inhibitor.

[0603] Embodiment 51 : the composition according to embodiment 50, wherein the anti- CEACAM5 antibody comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acidsequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5.

[0604] Embodiment 52: the composition according to embodiment 50, wherein the anti- CEACAM5 antibody comprises a variable domain of a heavy chain (VH) consisting of the sequence of SEQ ID NO: 6 and a variable domain of a light chain (VL) consisting of the sequence of SEQ ID NO: 7.

[0605] Embodiment 53: the composition according to any one of embodiments 50-52, wherein the anti-CEACAM5 antibody is a humanized monoclonal anti-CEACAM5 antibody.

[0606] Embodiment 54: the composition according to any one of embodiments 50-53, wherein the anti-CEACAM5 antibody is tusamitamab (SAR408377).

[0607] Embodiment 55: the composition according to any one of embodiments 50-54, wherein the ADC comprises at least one cytotoxic agent.

[0608] Embodiment 56: the composition according to embodiment 55, wherein the ADC anti-CEACAM5 antibody is covalently attached via a cleavable linker to the at least one cytotoxic agent.

[0609] Embodiment 57: the composition according to embodiment 56, wherein the linker is selected from the group consisting of N-succinimidyl pyridyldithiobutyrate (SPDB), 4- (Pyridin-2-yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB), and succinimidyl (N- maleimidomethyl) cy cl ohexane-1 -carboxylate (SMCC).

[0610] Embodiment 58: the composition according to any one of embodiments 55-57, wherein the cytotoxic agent is selected from the group consisting in antimetabolite, DNA- alkylating agent, DNA-cross-linking agent, DNA-intercalating agent, anti-microtubule agent, topoisomerase inhibitor, and any combination thereof

[0611] Embodiment 59: the composition according to embodiment 58, wherein the antimicrotubule agent is a maytansinoid.

[0612] Embodiment 60: the composition according to embodiment 59, wherein the maytansinoid is selected from the group consisting of N2’-deacetyl-N2’ -(3 -mercapto- 1- oxopropyl)-maytansine (DM1), N2’-deacetyl-N2’(4-methyl-4-mercapto-l -oxopentyl)- maytansine (DM4), and any combination thereof.

[0613] Embodiment 61: the composition according to embodiment 60, wherein the maytansinoid is DM4.

[0614] Embodiment 62: the composition according to any one of embodiments 50-61, wherein the ADC is tusamitamab ravtansine (SAR408701).

[0615] Embodiment 63: the composition according to any one of embodiments 50-62, wherein the nucleoside metabolic inhibitor is gemcitabine.

[0616] Embodiment 64: the method of treating a pancreatic cancer in a subject in need thereof, the method comprising administrating to the subject an effective amount of an antibodydrug conjugate (ADC) comprising an anti-CEACAM5 antibody or antigen binding fragment thereof, wherein the metastatic pancreatic cancer expresses CEACAM5 and wherein the ADC is administered at a dose of 60 mg / m2to 210 mg / m2based on the body surface area of the subject.

[0617] Embodiment 65: the method of embodiment 64, wherein the pancreatic cancer is a metastatic pancreatic cancer.

[0618] Embodiment 66: the method according to embodiment 64 or 65, wherein the anti-CEACAM5 antibody comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acid sequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5.

[0619] Embodiment 67: the method according to embodiment 64 or 65, wherein the anti-CEACAM5 antibody comprises a variable domain of a heavy chain (VH) consisting of the sequence of SEQ ID NO: 6 and a variable domain of a light chain (VL) consisting of the sequence of SEQ ID NO: 7.

[0620] Embodiment 68: the method according to any one of embodiments 64-67, wherein the anti-CEACAM5 antibody is a humanized monoclonal anti-CEACAM5 antibody.

[0621] Embodiment 69: the method according to any one of embodiments 64-68, wherein the anti-CEACAM5 antibody is tusamitamab (SAR408377).

[0622] Embodiment 70: the method according to any one of embodiments 64-69, wherein the ADC comprises at least one cytotoxic agent.

[0623] Embodiment 71: the method according to embodiment 70, wherein the anti- CEACAM5 antibody is covalently attached via a cleavable linker to the at least one cytotoxic agent.

[0624] Embodiment 72: the method according to embodiment 71, wherein the linker is selected from the group consisting of N-succinimidyl pyridyldithiobutyrate (SPDB), 4-(Pyridin- 2-yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB), and succinimidyl (N-maleimidomethyl) cyclohexane- 1 -carboxylate (SMCC).

[0625] Embodiment 73: the method according to any one of embodiments 70-72, wherein the cytotoxic agent is selected from the group consisting antimetabolite, DNA- alkylating agent, DNA-cross-linking agent, DNA-intercalating agent, anti-microtubule agent, topoisomerase inhibitor, and any combination thereof.

[0626] Embodiment 74: the method according to embodiment 73, wherein the antimicrotubule agent is a maytansinoid.

[0627] Embodiment 75: the method according to embodiment 74, wherein the maytansinoid is selected from the group consisting of N2’-deacetyl-N2’ -(3 -mercapto- 1- oxopropyl)-maytansine (DM1), N2’-deacetyl-N2’(4-methyl-4-mercapto-l -oxopentyl)- maytansine (DM4), and any combination thereof.

[0628] Embodiment 76: the method according to embodiment 75, wherein the maytansinoid is DM4.

[0629] Embodiment 77: the method according to any one of embodiments 64-76, wherein the ADC is tusamitamab ravtansine (SAR408701).

[0630] Embodiment 78: the method according to any one of embodiments 64-77, wherein the cancer expresses CEACAM5 with moderate or high intensity defined by immunohistochemistry.

[0631] Embodiment 79: the method according to any one of embodiments 64-78, wherein the CEACAM5 expression is defined as a CEACAM5 immunohistochemistry (IHC) intensity of at least about 2+ in at least about 50% of tumor cell.

[0632] Embodiment 80: the method according to any one of embodiments 64-79, wherein the ADC is administered at a dose from about 100 mg / m2to about 170 mg / m2.

[0633] Embodiment 81: the method according to any one of embodiments 64-80, wherein the ADC is administered as an initial dose followed by one or more secondary doses.

[0634] Embodiment 82: the method according to any one of embodiments 64-81, wherein the ADC is administered at an initial dose from about 100 mg / m2to about 170 mg / m2.

[0635] Embodiment 83: the method according to any one of embodiments 64-82, wherein the ADC is administered at an initial dose of about 135 mg / m2, 150 mg / m2, or about 170 mg / m2

[0636] Embodiment 84: the method according to embodiment 83, wherein the ADC is administered at a secondary dose of about 80 mg / m2or about 100 mg / m2.

[0637] Embodiment 85: the method according to any one of embodiments 64-84, wherein the ADC is administered to the subject at an initial dose of about 135 mg / m2, about 150 mg / m2or about 170 mg / m2on day 1 of a first cycle and at a dose of about 80 mg / m2or about 100 mg / m2thereafter.

[0638] Embodiment 86: the method according to any one of embodiments 64-85, wherein a cycle is 14 days.

[0639] Embodiment 87: the method according to any one of embodiments 64-86, wherein the subject is retreated if the subject has a neutrophils count of at least about 1.5 x 109 / L, platelets count of at least about 100 x 109 / L, an hemoglobin count of at least about 9 mg / dL, a total bilirubin count of at most about 1.5 x ULN, AST-ALT count of at most about 2.5 x ULN or about < 5 x ULN in case of documented liver metastasis, and / or no IMP-related toxicity of Grade > 1 except for alopecia or of baseline severity.

[0640] Embodiment 88: the method according to any one of embodiments 64-87, wherein the subject has at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) vl .1 criteria that has not been irradiated.

[0641] Embodiment 89: the method according to embodiment 88, wherein the lesion is at least about 10 mm in the longest diameter.

[0642] Embodiment 90: the method according to any one of embodiments 64-89, wherein the subject has an Eastern Cooperative Oncology Group (ECOG) performance status of about 0 to about 1.

[0643] Embodiment 91: the method according to any one of embodiments 64-90, wherein the subject has pancreatic ductal adenocarcinoma.

[0644] Embodiment 92: the method according to any one of embodiments 64-91, wherein the subject is administered the ADC after pancreatic surgery, radiation, and chemotherapies, and combinations thereof.

[0645] Embodiment 93: the method according to any one of embodiments 64-92, wherein the subject was previously treated with chemotherapies comprising fluoropyrimidine- based therapy before administering the ADC comprising an anti-CEACAM5 antibody.

[0646] Embodiment 94: the method according to any one of embodiments 64-93, wherein the subject was previously treated with 5 -fluorouracil, leucovorin, liposomal irinotecan, oxaliplatin, nab-paclitaxel, and combinations thereof.

[0647] Embodiment 95: the method according to any one of embodiments 64-94, wherein the subject was previously treated with gemcitabine and / or is intolerant to gemcitabine.

[0648] Embodiment 96: the method according to any one of embodiments 64-95, further comprising administering premedication to the subject.

[0649] Embodiment 97: the method according to embodiment 96, wherein administering the premedication to the subject is before each administration of the antibody drug conjugate.

[0650] Embodiment 98: the method according to embodiment 96 or 97, wherein the premedication is dexamethasone and / or a histamine Hl antagonist.

[0651] Embodiment 99: the method according to embodiment 98, wherein the dexamethasone is administered intravenously to the subject in a dose of about 10 mg.

[0652] Embodiment 100: the method according to embodiment 99, wherein the histamine Hl antagonist is diphenhydramine or dexchlorpheniramine.

[0653] Embodiment 101 : the method according to embodiment 100, wherein the diphenhydramine is administered intravenously to the subject in a dose of about 50 mg.

[0654] Embodiment 102: the method of treating pancreatic cancer in a subject comprising:

[0655] administering to a subject in need thereof a pharmaceutical composition comprising an antibody drug conjugate at an initial dose of about 135 mg / m2, 150 mg / m2, or about 170 mg / m2on day 1 of a first cycle and a dose of about 80 mg / m2or about 100 mg / m2thereafter,

[0656] wherein the antibody drug conjugate comprise an antibody or antigen binding fragment thereof that binds CEACAM5 and is covalently attached to DM4, wherein the antibody or antigen-binding fragment thereof comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acid sequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5 and wherein the subject has pancreatic cancer.

[0657] Embodiment 103: a method of treating pancreatic cancer in a subject, the method comprising administering to the subject an effective amount an antibody-drug conjugate (ADC) comprising an antibody or antigen binding fragment thereof that binds CEACAM5 and is covalently attached to DM4, wherein the subject has at least one inclusion criteria selected from the group consisting of:

[0658] i. the subject is at least 18 years old;

[0659] ii. has the pancreatic ductal adenocarcinoma;

[0660] iii. has at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) vl .1 criteria that has not been irradiated;

[0661] iv has an Eastern Cooperative Oncology Group (ECOG) performance status of about 0 to about 1 ;

[0662] v. was previously treated with 5 -fluorouracil-based therapy, leucovorin, liposomal irinotecan, oxaliplatin, nab-paclitaxel, capecitabine, and combinations thereof;

[0663] vi. the cancer expresses CEACAM5 of at least about 2+ in at least about 50% of tumor cells as determined by immunohistochemistry; and

[0664] vii. has documented radiographic progression or documented intolerance after at least 1 prior systemic chemotherapy line which included either gemcitabine or relapsed within 6 months of completion of gemcitabine adjuvant therapy.

[0665] Embodiment 104: a method of treating pancreatic cancer in a subject, the method comprising administering to the subject an effective amount an antibody-drug conjugate (ADC) comprising an antibody or antigen binding fragment thereof that binds CEACAM5 and is covalently attached to DM4, wherein the subject has at least one inclusion criteria selected from the group consisting of:

[0666] i. the subject is at least 18 years old;

[0667] ii. has the pancreatic ductal adenocarcinoma;

[0668] iii. has at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) vl .1 criteria that has not been irradiated;

[0669] iv has an Eastern Cooperative Oncology Group (ECOG) performance status of about 0 to about 1 ;

[0670] v. was previously treated with 5 -fluorouracil-based therapy, leucovorin, liposomal irinotecan, oxaliplatin, nab-paclitaxel, capecitabine, and combinations thereof;

[0671] vi. the cancer expresses CEACAM5 of at least about 2+ in at least about 50% of tumor cells as determined by immunohistochemistry; and

[0672] vii. has documented radiographic progression or documented intolerance after at least 1 prior systemic chemotherapy line which included either gemcitabine or relapsed within 6 months of completion of gemcitabine adjuvant therapy; and

[0673] wherein the subject does not have at least one criterion selected from the group consisting of:

[0674] i. medical condition requiring administration of a medication that is metabolized by cytochrome P450;

[0675] ii. untreated brain metastases or history of leptomeningeal disease;

[0676] iii. history of acquired immunodeficiency syndrome disease requiring antiretroviral treatment, or active hepatitis A; and

[0677] iv. unresolved corneal disorder or any previous corneal disorder.

[0678] Embodiment 105 : the method according to embodiment 103 or 104, wherein the antibody-drug conjugate (ADC) comprising an antibody or antigen binding fragment thereof that binds CEACAM5 and is covalently attached to DM4 is tusamitamab ravtansine (SAR408701).

[0679] Embodiment 106: the method according to any one of embodiments 103-105, wherein the antibody-drug conjugate (ADC) comprising an antibody or antigen binding fragment thereof that binds CEACAM5 and is covalently attached to DM4 is administered at a dose from about 135 mg / m2, 150 mg / m2, or about 170 mg / m2.

[0680] Embodiment 107: the method according any one of embodiments 103-106, wherein the antibody-drug conjugate (ADC) comprising an antibody or antigen bindingfragment thereof that binds CEACAM5 and is covalently attached to DM4 is administered at an initial dose from about 135 mg / m2, 150 mg / m2, or about 170 mg / m2.

[0681] Embodiment 108: the method according to any one of embodiments 103-107, wherein the ADC is administered at a secondary dose of about 80 mg / m2or about 100 mg / m2.

[0682] Embodiment 109: an antibody-drug conjugate comprising an anti-CEACAM5- antibody, or antigen binding fragment thereof, for use in combination with a nucleoside metabolic inhibitor for treating a cancer in a subject in need thereof, wherein the cancer expresses CEACAM5.

[0683] Embodiment 110: the antibody-drug conjugate for the use of embodiment 109, wherein the anti-CEACAM5-antibody comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acid sequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5.

[0684] Embodiment 111 : the antibody-drug conjugate for the use of embodiment 109 or 110, wherein the anti-CEACAM5 -antibody comprises a variable domain of a heavy chain (VH) consisting of the sequence of SEQ ID NO: 6 and a variable domain of a light chain (VL) consisting of the sequence of SEQ ID NO: 7.

[0685] Embodiment 112: the antibody-drug conjugate for the use of any one of embodiments 109 to 111, wherein the anti-CEACAM5-antibody is tusamitamab.

[0686] Embodiment 113: the antibody-drug conjugate for the use of any of embodiments 109 to 112, wherein the antibody-drug conjugate comprises at least one cytotoxic agent.

[0687] Embodiment 114: the antibody-drug conjugate for the use of any of embodiments 109 to 113, wherein the antibody-drug conjugate comprises a cleavable linker.

[0688] Embodiment 115: the antibody-drug conjugate for the use of any of embodiments 109 to 114, wherein the antibody-drug conjugate is tusamitamab ravtansine.

[0689] Embodiment 116: the antibody-drug conjugate for the use of any of embodiments 109 to 115, wherein the cancer expresses CEACAM5 with moderate or high intensity defined by immunohistochemistry.

[0690] Embodiment 117: the antibody-drug conjugate for the use of any of embodiments 109 to 116, wherein the CEACAM5 expression is defined as a CEACAM5 immunohistochemistry (IHC) intensity of at least 2+ in at least 50% of tumor cells.

[0691] Embodiment 118: the antibody-drug conjugate for the use of any of embodiments 109 to 117, wherein the cancer is pancreatic cancer.

[0692] Embodiment 119: the antibody-drug conjugate for the use of any of embodiments 109 to 118, wherein the antibody-drug conjugate is administered at a dose from 60 mg / m2to 210 mg / m2

[0693] Embodiment 120: the antibody-drug conjugate for the use of any of embodiments 109 to 119, wherein the antibody-drug conjugate is administered at an initial dose from 100 mg / m2to 170 mg / m2.

[0694] Embodiment 121 : the antibody-drug conjugate for the use of any of embodiments 109 to 120, wherein the antibody-drug conjugate is administered at a secondary dose from 80 mg / m2to 100 mg / m2.

[0695] Embodiment 122: the antibody-drug conjugate for the use of any of embodiments 109 to 121, wherein the antibody-drug conjugate is administered to the subject at an initial dose of 135 mg / m2, 150 mg / m2, or 170 mg / m2on day 1 of a first cycle and at a secondary dose of 80 mg / m2or 100 mg / m2thereafter.

[0696] Embodiment 123 : the antibody-drug conjugate for the use of any of embodiments 109 to 122, wherein the antibody-drug conjugate is administered at secondary dose every 2 weeks.

[0697] Embodiment 124: the antibody-drug conjugate for the use of any of embodiments 109 to 123, wherein the nucleoside metabolic inhibitor is gemcitabine.

[0698] Embodiment 125: the antibody-drug conjugate for the use of any of embodiments 109 to 124, wherein the nucleoside metabolic inhibitor is administered at a dose from 600 mg / m2to 1000 mg / m2.

[0699] Embodiment 126: the antibody-drug conjugate for the use of any of embodiments 109 to 125, wherein the nucleoside metabolic inhibitor is administered on day 1, day 8, and day 15 of each cycle.

[0700] Embodiment 127: the antibody-drug conjugate for the use of any of embodiments 109 to 126, wherein the subject has a metastatic cancer.

[0701] Embodiment 128: the antibody-drug conjugate for the use of any of embodiments 109 to 127, wherein the subject has pancreatic ductal adenocarcinoma.

[0702] Embodiment 129: a pharmaceutical composition comprising the antibody-drug conjugate of any of embodiments 109 to 128 and a nucleoside metabolic inhibitor.

[0703] Embodiment 130: a kit comprising (i) the antibody-drug conjugate of any of embodiments 109 to 128 and (ii) a nucleoside metabolic inhibitor, in separate formulations.

[0704] Embodiment 131: the pharmaceutical composition according to embodiment 129 or the kit according to embodiment 130 for the use for treating a cancer wherein the cancer expresses CEACAM5.

[0705] Embodiment 132: an antibody-drug conjugate comprising an anti-CEACAM5- antibody, or antigen binding fragment thereof, for use for treating a pancreatic cancer in a subject in need thereof, wherein the pancreatic cancer expresses CEACAM5, the use comprising administrating to said subject said antibody-drug conjugate at a dose of 60 mg / m2to 210 mg / m2based on the body surface area of said subject.

[0706] Embodiment 133: the antibody-drug conjugate for the use of embodiment 132, wherein the anti-CEACAM5-antibody comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acid sequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5

[0707] Embodiment 134: the antibody-drug conjugate for the use of embodiment 132 or 133, wherein the anti-CEACAM5 -antibody comprises a variable domain of a heavy chain (VH) consisting of the sequence of SEQ ID NO: 6 and a variable domain of a light chain (VL) consisting of the sequence of SEQ ID NO: 7.

[0708] Embodiment 135: the antibody-drug conjugate for the use of any one of embodiments 132 to 134, wherein the anti-CEACAM5-antibody is tusamitamab.

[0709] Embodiment 136: the antibody-drug conjugate for the use of any of embodiments 132 to 135, wherein the antibody-drug conjugate comprises at least one cytotoxic agent.

[0710] Embodiment 137: the antibody-drug conjugate for the use of any of embodiments 132 to 136, wherein the antibody-drug conjugate comprises a cleavable linker.

[0711] Embodiment 138: the antibody-drug conjugate for the use of any of embodiments 132 to 137, wherein the antibody-drug conjugate is tusamitamab ravtansine.

[0712] Embodiment 139: the antibody-drug conjugate for the use of any of embodiments 132 to 138, wherein the cancer expresses CEACAM5 with moderate or high intensity defined by immunohistochemistry.

[0713] Embodiment 140: the antibody-drug conjugate for the use of embodiment 139, wherein the CEACAM5 expression is defined as a CEACAM5 immunohistochemistry (IHC) intensity of at least 2+ in at least 50% of tumor cells.

[0714] Embodiment 141 : the antibody-drug conjugate for the use of any of embodiments 132 to 140, wherein the cancer is metastatic.

[0715] Embodiment 142: the antibody-drug conjugate for the use of any of embodiments 132 to 139, wherein the cancer is pancreatic ductal adenocarcinoma.

[0716] Embodiment 143 : the antibody-drug conjugate for the use of any of embodiments 132 to 142, wherein the antibody-drug conjugate is administered at an initial dose from 100 mg / m2to 170 mg / m2

[0717] Embodiment 144: the antibody-drug conjugate for the use of any of embodiments 132 to 143, wherein the antibody-drug conjugate is administered at a secondary dose from 80 mg / m2to 100 mg / m2.

[0718] The antibody-drug conjugate for the use of any of embodiments 132 to 144, wherein the ADC is administered to the subject at an initial dose of 135 mg / m2, 150 mg / m2, or 170 mg / m2on day 1 of a first cycle and at a secondary dose of 80 mg / m2or 100 mg / m2thereafter.

[0719] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made, and equivalents may be substituted without departing from the true spirit and scope of the invention. It will be readily apparent to those skilled in the art that other suitable modifications and adaptations of the methods described herein may be made using suitable equivalents without departing from the scope of the embodiments disclosed herein. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit, and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.Having now described certain embodiments in detail, the same will be more clearly understood by reference to the following examples, which are included for purposes of illustration only and are not intended to be limiting.LIST OF REFERENCESAll publications and references cited herein are expressly incorporated herein by reference in their entirety.1. Hammarstrom S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol. 1999;9(2):67-81.2. Gold P, Freedman SO. Specific carcinoembryonic antigens of the human digestive system. J Exp Med. 1965; 122(3): 467-81.3. Thompson JA. Molecular cloning and expression of carcinoembryonic antigen family members. Tumor Biol. 1995; 16(1): 10-6.4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology Pancreatic adenocarcinoma. Version 3. [Online], 2019 [cited 2022 Jul 21]; Available from: URL:https: / / www. nccn.org / professionals / physician_gls / pdf / pancreatic. pdf.5. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, et al. Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine. N Engl J Med. 2013;369(18): 1691-703.6. Hesketh PJ, Kris MG, Basch E, Bohlke K, Barbour SY, Clark-Snow RA, et al. Antiemetics: ASCO Guideline Update. J Clin Oncol. 2020;38(24):2782-97.7. American Cancer Society. Cancer facts and figures 2011. [cited 2022 Jul 21]; Available from: URL:https: / / www. cancer.org / research / cancer-facts-statistics / all-cancer-facts- figures / cancer-facts-figures-2011.html.8. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics Review (CSR) 1975-2016. [Online], [cited 2022 Jul 21], National Cancer Institute. Bethesda, MD. Available from: URL:https: / / seer.cancer.gov / csr / 1975_2016 / .9. American Cancer Society. Cancer facts and figures 2013. [Online], [cited 2022 Jul 21]; Available from: URL:https: / / www. cancer.org / content / dam / cancer-org / research / cancer-facts-and-statistics / annual-cancer-facts-and-figures / 2013 / cancer-facts-and-figures-special-section- 2013.pdf.10. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-25.11. Mita N, Iwashita T, Uemura S, Yoshida K, Iwasa Y, Ando N, et al. Second-Line Gemcitabine Plus Nab-Paclitaxel for Patients with Unresectable Advanced Pancreatic Cancer after First-Line FOLFIRINOX Failure. J Clin Med. 2019 May 29;8(6):761.12. Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015;33(28):3199-212.13. Oken MM, Creech RH, Tormey DC, Horton J, Davis IE, McFadden ET, et al. Toxicity and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 1982;5(6):649-55. 14. Eisenhauer EA, Therasse P, Bogaerts J Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47.EXAMPLESExample 1. Phase 2, Open-Label, Multicenter, Multicohort Trial of Treatment of Patients with CEACAM5-Positive Advanced Solid Tumors

[0720] The efficacy (anti-tumor activity), safety, tolerability, pharmacokinetic (PK), and immunogenicity of tusamitamab ravtansine, an ADC with anti-carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5) conjugated to the cytotoxic agent DM4 is assessed as a monotherapy in participants with pancreatic adenocarcinoma cancer (mPAC) (Cohort B) with CEACAM5 -positive tumors, and also as combination therapy with gemcitabine in participants with mPAC (Cohort C) with CEACAM5 -positive tumors.1. ObjectivesPrimary objective(1) Cohort B, and Cohort C Part 2

[0721] The primary objective of this trial for Cohort B, and Cohort C Part 2 is to assess the antitumor activity of tusamitamab ravtansine monotherapy and in combination with gemcitabine in mPAC.(2) Cohort C Part 1

[0722] The primary objective of this trial for Cohort C Part 1 is to confirm the recommended tusamitamab ravtansine dose when administered in combination with gemcitabine.Secondary objective

[0723] The secondary objectives of this trial are the following:

[0724] (i) To assess the safety and tolerability of tusamitamab ravtansine administered as monotherapy and in combination with gemcitabine.

[0725] (ii) To assess other efficacy parameters of tusamitamab ravtansine administered as monotherapy and in combination with gemcitabine.

[0726] (iii) To assess the immunogenicity of tusamitamab ravtansine. The endpoint consists of incidence of participants with antitherapeutic antibodies (ATAs) against tusamitamab ravtansine.

[0727] (iv) To assess the pharmacokinetics (PK) of tusamitamab ravtansine and gemcitabine when given in combination. The endpoint consists of the pharmacokinetic parameters of tusamitamab ravtansine and gemcitabine.Tertiary Objective

[0728] The tertiary objectives of this trial are the following:

[0729] (i) To explore CEACAM5 expression on circulating tumoral cells (CTCs).

[0730] (ii) To explore modulations of circulating CEA as a potential pharmacodynamics biomarker of response to ADC treatment and to evaluate circulating CEA levels at prescreening. The endpoint consists in the circulating CEA at prescreening, baseline and during the treatment period.

[0731] (iii) To assess the relationship between the tumor mutation profiles detected in the circulating free DNA (cfDNA) at baseline with efficacy outcome.

[0732] (iv) To explore potential sets of biomarkers from tumor DNA and RNA analyses, beside target expression, as potential biomarkers of response to tusamitamab ravtansine treatment.2. End PointsPrimary Endpoints

[0733] The endpoint consists of the Objective Response Rate (ORR) of tusamitamab ravtansine, defined as the proportion of participants who have a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST).

[0734] The endpoint consists of the incidence of dose-limiting toxicites (DLTs) in the 28 Day DLT observation period (Cycle 1).Secondary Endpoints

[0735] The endpoint consists of:

[0736] the incidence of participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs) and laboratory abnormalities according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

[0737] - the progression-free survival (PFS), defined as the time from the date of first ADC administration to the date of the first documented disease progression or death due to any cause, whichever comes first;

[0738] - the disease control rate (DCR), defined as the percentage of participants who have achieved confirmed CR, confirmed PR or stable disease as per RECIST vl.l; and

[0739] - the duration of response (DOR), defined as the time from first documented evidence of confirmed CR or confirmed PR until progressive disease determined per RECIST vl.l or death from any cause, whichever occurs first.

[0740] The endpoint consists of incidence of participants with antitherapeutic antibodies (ATAs) against tusamitamab ravtansine.

[0741] The endpoint consists of the pharmacokinetic parameters of tusamitamab ravtansine and gemcitabine.Tertiary Endpoints

[0742] The endpoint consists of CEACAM5 expression assessment on CTCs from participants with positive CEACAM5 expression on tumor tissue.

[0743] The endpoint consists in the circulating CEA at prescreening, baseline and during the treatment period.

[0744] The end point consists of the Mutation analysis for tumor cfDNA at baseline.

[0745] The end point consists of the biomarker annotation for tumor DNA and RNA at baseline.3. Study design

[0746] This is a Phase 2, open-label, multi-cohort, multi-center study assessing the efficacy (antitumor activity), safety, and immunogenicity of ADC in the treatment of participants with mPAC (Cohort B [monotherapy] and Cohort C [in combination with gemcitabine]) with CEACAM5 -positive tumors (defined as CEACAM5 IHC intensity >2+ in >50% of tumor cells).

[0747] Treatment allocation is performed using an interactive response technology (IRT). After being screened, the eligible participants receive ADC as single agent treatment (Cohort B) or in combination with gemcitabine (Cohort C) until documented disease progression, unacceptable toxicity, new anticancer therapy initiation, or the participant’s or Investigator’s decision to stop the treatment.

[0748] In B, participants receive a tusamitamab ravtansine loading dose at 170 mg / m2on Day 1 of Cycle 1, followed by 100 mg / m2Q2W from Cycle 2 and in all other cycles.

[0749] In Cohort C, each treatment cycle is 28 days (4 weeks). Cohort C comprises 2 parts:

[0750] Part 1 (Safety Run-In): In Part 1 of Cohort C, participants receive tusamitamab ravtansine initial or loading dose at 170 mg / m2on Day 1, followed by 100 mg / m2every 2 weeks (Q2W); participants also receive gemcitabine 1000 mg / m2on Day 1, Day 8, and Day 15 every 4 weeks (Q4W). In the case that it is decided to reduce the initial loading dose of tusamitamab ravtansine to DL 1 (Table 1), a tusamitamab ravtansine loading dose of 135 mg / m2is administered to participants on Day 1 of Cycle 1.

[0751] Table 1 shows dose levels for Part 1 (safety run-in).Table 1.Dose level (DL) Tusamitamab ravtansine GemcitabineStarting dose 170 mg / m2on DI; 1000 mg / m2on DI, D8, and100 mg / m2Q2W thereafter DI 5 Q4WMinus -1 (DL -1) 135 mg / m2on DI; 1000 mg / m2on DI, D8, and100 mg / m2Q2W thereafter DI 5 Q4WBSA = body surface area; DL -l=dose level -1; Q2W = every 2 weeks; Q4W = every 4 weeks.For participants with a BSA >2.2 m2, the ADC dose is calculated based on a BSA of 2.2 m2

[0752] For participants with a BSA > 2.2 m2, the ADC dose is calculated based on a BSA of 2.2 m2.

[0753] The starting dose for tusamitamab ravtansine is selected as the maximum tolerated dose (MTD) used in studies evaluating ADC as loading-dose monotherapy. Enough participants are enrolled in Part 1 to achieve 3 to 12 participants evaluable for DLTs to confirmthe recommended dose. The tolerability of the combination is assessed in Part 1 according to the algorithm illustrated in Figure 1. The DLT observation period is the first cycle (approximately 28 days). A DLT-evaluable participant must have completed 1 cycle of treatment or have been discontinued from study treatment because of a DLT; DLT-nonevaluable participants are replaced. A minimum delay of 1 week is required between the initial dose in the first participant treated in a DL cohort and dosing of the next 2 participants treated at the same DL.

[0754] Part 2 (Additional Participant): In Part 2 of Cohort C, the recommended dose confirmed in Part 1 is evaluated for activity in 24 to 27 additional participants. A total of 30 participants, including participants treated at the recommended dose in Part 1 , are evaluated for activity.

[0755] The expected duration of study treatment for participants may vary, based on the progression date and cohort; the median expected duration of the study per participant is estimated to be 8 months for Cohort C and 6 months for Cohort B (up to 1 month for screening, a median of 4 or 2 months for treatment in Cohort C and Cohort B, respectively, a median of 1 month for EOT, and a follow-up visit 90 days after the last IMP administration).

[0756] Serious adverse events / adverse event of special interest (AESIs) (regardless of relationship with study treatment) and IMP-related AEs ongoing at the end of study treatment, and any new IMP-related AEs / SAEs / AESIs are followed until resolution or stabilization (defined as an event ongoing without any change for at least 3 months). A safety follow-up visit is performed 90 days after the last IMP administration. If ongoing IMP related AEs / serious adverse events (SAEs) / AESIs are resolved or stabilized, no further safety follow-up visit is needed, otherwise an on-site follow-up visit are performed every 12 weeks.4. Schedule of activitiesBelow is Flowchart 1 showing the procedures for Cohort B.Flowchart 1.AE = adverse event; AESI = adverse event of special interest; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AP = alkaline phosphatase; AST = aspartate aminotransferase; ATA = anti- therapeutic antibody; BSA = body surface area; BUN = blood urea nitrogen; CEA = carcinoembryonic antigen; CEACAM5 = carcinoembryonic antigen-related cell adhesion molecule 5; cfDNA = circulating free deoxyribonucleic acid; CT = computed tomography; CTC = circulating tumoral cells; CR = complete response; D = Day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EOT = end-of-treatment; FFPE = formalin-fixed paraffin embedded; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent form; IHC = immunohistochemistry; IMP = investigational medicinal product; IRT = interactive response technology; LDH = lactate dehydrogenase; mPAC = metastatic pancreatic adenocarcinoma; MRI = magnetic resonance imaging; PR = partial response; RECIST = response evaluation criteria in solid tumors; RNA = ribonucleic acid; SAE = serious adverse event; WBC = white blood cell; WOCBP = woman of childbearing potential. a Prescreening Informed Consent is signed by the participant before CEACAM5 assay on archival or fresh tumor tissue. b Informed consent should be signed before any study specific procedures. It can be signed more than 28 days prior to initiation of therapy. Screening time indicates in which timeframe exams used to support eligibility have to be done prior to initiation of therapy. Routine baseline tests performed prior to ICF signature do not need to be repeated as long as they are within the screening-defined timeframe. Assessments must be performed prior to first IMP administration: participants must have confirmed CEACAM5 expression as assessed centrally. Baseline evaluation should be completed within 1 week prior to initiation of therapy, except for tumor assessment, circulating CEA, and ocular tests that may be performed within 4 weeks prior to the first IMP administration. Results of these tests should be reviewed by the Investigator prior to initiation of therapy. c At the follow-up visit, SAEs / AESIs (regardless of relationship with study treatment) and IMP- related AEs ongoing at the end of study treatment, and any new IMP -related AEs / SAEs / AESIs are followed until resolution or stabilization (stabilization is defined as an event ongoing without any change for at least 3 months). Further anti -cancer treatment is collected at the follow-up visit, including date of progression if any. Participants who stopped treatment before documented progressive disease (achieving stable disease, or CR or PR) should undergo a tumor assessment and an on-site follow-up visit every 12 weeks until radiological disease progression, the start of new anti -cancer therapy, withdrawal of participant’s consent, or cut-off date for secondary efficacy endpoints, whichever comes first. After documented progressive disease or the start of a new anti-cancer therapy, participants are followed until any ongoing IMP -related AEs / SAEs / AESIs are resolved or stabilized. Participants with documented disease progression should attend an on-site follow-up visit 90 days after the last IMP administration. If ongoing IMP -related AEs / SAEs / AESIs are resolved or stabilized, no further safety follow-up visit is needed. If IMP -related AEs / SAEs / AESIs ongoing, an on-site follow-up visit is performed every 12 weeks. d DI of Cycle 2 and of each subsequent cycle corresponds to D15 of the previous cycle (±2 days). As of Cycle 2, procedures can be done on the day of infusion (before infusion) or the day before. e mPAC: Preferably at the metastatic site; Cell collections (eg, from pleural effusion) processed as FFPE blocks are acceptable. f At least 3 x 10 pm slides (best) or 6 x 5 pm slides (or equivalent to the same total amount of material) from FFPE tissue (from same sample as the one used for CEACAM5 expression status if possible) from treatment start for mPAC (only screened participants). g Women of childbearing potential (WOCBP) must have a negative serum pregnancy test result within 7 days prior to the initial dose of IMP. A pregnancy test (urine or serum as required by local regulations) is repeated every 4 weeks before each IMP administration and at the EOT evaluation (30 ±5 days after the last IMP administration).h Hematology: hemoglobin, hematocrit, RBC, WBC with differential, platelet counts (If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC >0.5 x 109 / L). Liver function tests: AST, ALT, total bilirubin, conjugated bilirubin, AP. Renal function tests: urea (or BUN) and creatinine. Electrolytes: sodium, potassium, calcium, phosphate, chloride. Others: glucose, LDH, albumin and total proteins. In case of Grade >3 liver function abnormal tests, additional tests are repeated every 2-3 days until recovery to baseline value. Additional tests are performed when clinically appropriate. Tests can be performed on the same day or within the 2 days before initiating study intervention. / Day 1 hematology, blood chemistry and coagulation tests may be omitted if baseline test performed within 7 days are normal. If baseline tests are abnormal, they should be repeated within 2 days of first study intervention. j Only AEs related to the fresh biopsy procedure (if applicable) and occurring within 1 month after the fresh biopsy is recorded in the eCRF. k Chest, abdomen, pelvic CT-scan or MRI and any other examinations as clinically indicated are performed to assess disease status at baseline and then every 8 weeks (±7 days) until EOT, and then every 12 weeks until progressive disease, new anticancer therapy, death, withdrawal of participant’s consent, or study cut-off date for secondary efficacy endpoints, whichever comes first. Bone CT-scan or MRI and other examinations should be performed if clinically indicated. Brain CT scan or MRI should be performed at baseline and followed during treatment only for participants with brain lesions at baseline. / ADC ATA samples are collected before start of infusion of each cycle until C3, at C7, and thereafter every 6 cycles (ie, C13, C19, etc). The remaining plasma volume may also be used for further investigations including pharmacokinetics if deemed relevant in case of ATA positive results.Below is Flowchart 2 showing the procedures for Cohort C.Flowchart 2.IllAE = adverse event; AESI = adverse event of special interest; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AP = alkaline phosphatase; AST = aspartate aminotransferase; ATA = antitherapeutic antibody; BSA = body surface area; BUN = blood urea nitrogen; CEA = carcinoembryonic antigen; CEACAM5 = carcinoembryonic antigen-related cell adhesion molecule 5; cfDNA = circulating free deoxyribonucleic acid; CT = computed tomography; CTC = circulating tumoral cells; CR = complete response; D = Day; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EOT = end-of-treatment; FFPE = formalin-fixed paraffin embedded; HCV = hepatitis C virus; HIV = human immunodeficiency virus; ICF = informed consent form; IHC = immunohistochemistry; IMP = investigational medicinal product; IRT = interactive response technology; LDH = lactate dehydrogenase; mPAC = metastatic pancreatic adenocarcinoma; MRI = magnetic resonance imaging; PK = pharmacokinetics; PR = partial response; RECIST = response evaluation criteria in solid tumors; RNA = ribonucleic acid; SAE = serious adverse event; WBC = white blood cell; WOCBP = woman of childbearing potential. a Prescreening Informed Consent is signed by the participant before CEACAM5 assay on archival or fresh tumor tissue.b Informed consent should be signed before any study specific procedures. It can be signed more than 28 days prior to initiation of therapy. Screening time indicates in which timeframe exams used to support eligibility have to be done prior to initiation of therapy. Routine baseline tests performed prior to ICF signature do not need to be repeated as long as they are within the screening-defined timeframe. Assessments must be performed prior to first IMP administration: participants must have confirmed CEACAM5 expression as assessed centrally. Baseline evaluation should be completed within 1 week prior to initiation of therapy, except for tumor assessment, circulating CEA, and ocular tests that may be performed within 4 weeks prior to the first IMP administration. Results of these tests should be reviewed by the Investigator prior to initiation of therapy. c At the follow-up visit, SAEs / AESIs (regardless of relationship with study treatment) and IMP- related AEs ongoing at the end of study treatment, and any new IMP -related AEs / SAEs / AESIs are followed until resolution or stabilization (stabilization is defined as an event ongoing without any change for at least 3 months). Further anticancer treatment is collected at the follow-up visit, including date of progression, if any. Participants who stopped treatment before documented progressive disease (achieving stable disease, or CR or PR) should undergo a tumor assessment and an on-site follow-up visit every 12 weeks until radiological disease progression, the start of new anticancer therapy, withdrawal of participant’s consent, or cut-off date for secondary efficacy endpoints, whichever comes first. After documented progressive disease or the start of a new anticancer therapy, participants are followed until any ongoing IMP -related AEs / SAEs / AESIs are resolved or stabilized. Participants with documented disease progression should attend an on-site follow-up visit 90 days after the last IMP administration. If ongoing IMP -related AEs / SAEs / AESIs are resolved or stabilized, no further safety follow-up visit is needed. If IMP -related AEs / SAEs / AESIs ongoing, an on-site follow-up visit are performed every 12 weeks. d DI of Cycle 2 and of each subsequent cycle corresponds to D29 of the previous cycle (±3 days). As of Cycle 2, procedures can be done on the day of infusion (before infusion) or the day before. e mPAC: Preferably at the metastatic site; cell collections (eg, from pleural effusion) processed as FFPE blocks are acceptable. f At least 3 x 10 pm slides (best) or 6 x 5 m slides (or equivalent to the same total amount of material) from FFPE tissue (from same sample as that used for CEACAM5 expression status, if possible) from treatment start for mPAC (only screened participants). g Women of childbearing potential (WOCBP) must have a negative serum pregnancy test result within 7 days prior to the initial dose of IMP. A pregnancy test (urine or serum as required by local regulations) is repeated every 4 weeks before each IMP administration and at the EOT evaluation (30±5 days after the last IMP administration). h Hematology: hemoglobin, hematocrit, RBC, WBC with differential, platelet counts (If Grade 4 neutropenia, assess ANC every 2 to 3 days until ANC >0.5 x 109 / L). Liver function tests: AST, ALT, total bilirubin, conjugated bilirubin, AP. Renal function tests: urea (or BUN) and creatinine. Electrolytes: sodium, potassium, calcium, phosphate, chloride. Others: glucose, LDH, albumin and total proteins. In case of Grade >3 liver function abnormal tests, additional tests are repeated every 2-3 days until recovery to baseline value. Additional tests are performed when clinically appropriate. Tests can be performed on the same day or within the 2 days before initiating study intervention. / Day 1 hematology, blood chemistry and coagulation tests may be omitted if baseline test performed within 7 days are normal. If baseline tests are abnormal, they should be repeated within 2 days of first study intervention. j Only AEs related to the fresh biopsy procedure (if applicable) and occurring within 1 month after the fresh biopsy is recorded in the eCRF.k Chest, abdomen, pelvic CT scan or MRI and any other examinations as clinically indicated are performed to assess disease status at baseline and then every 8 weeks (±7 days) until EOT, and then every 12 weeks until progressive disease, new anticancer therapy, death, withdrawal of participant’s consent, or study cut-off date for secondary efficacy endpoints, whichever comes first. Bone CT scan or MRI and other examinations should be performed if clinically indicated. Brain CT scan or MRI should be performed at baseline and followed during treatment only for participants with brain lesions at baseline.116Below are Flowchart 3 (cycle 1) and Flowchart 4 (cycle 2) showing PK / ATA for ADC and gemcitabine samples for Cohort C (First 10 participants)Flowchart 3.Abbreviations: ATA = antitherapeutic antibody; C = cycle; D = day; dFdU=metabolite of gemcitabine; EOI = End of infusion time (ie, for tusamitamab ravtansine: when the pump beeps before flush = 1.5 hour, for gemcitabine = 30 min); EOT = End-of-treatment; h = hour ; IMP = investigational medicinal product; IV = intravenous; min = minutes ; PK = pharmacokinetics; RNT = relative nominal time; SOI = start of infusion. a Samples collected strictly before start of infusion (SOI), when applicable, ADC and gemcitabine predose samples can be collected at the same time before ADC administration. b Sample must be collected even if the infusion planned is not done or delayed on CID 15 and on C2D29 (corresponding to C3D1).Note: Sampling for PK and ATA may be reduced or stopped during the course of the study upon notification from the Sponsor.118Flowchart 4.Abbreviations: ATA = antitherapeutic antibody; C = cycle; D = day; EOI = End of infusion time (ie, for tusamitamab ravtansine: when the pump beeps before flush = 1.5 hour, for gemcitabine = 30 min); EOT = End-of-treatment; h = hour ; IMP = investigational medicinal product; IV = intravenous; min = minutes ; PK = pharmacokinetics; RNT = relative nominal time;SOI = start of infusion. a Samples collected strictly before start of infusion (SOI), when applicable, tusamitamab ravtansine and gemcitabine predose samples can be collected at the same time before tusamitamab ravtansine administration. b Sample must be collected even if the infusion planned is not done or delayed on C1D15 and on C2D29 (corresponding to C3D1). c ADC ATA samples are collected at SOI at Cycle 7 and thereafter every 3 cycles (ie, CIO, Cl 3, 16...)Note: Sampling for PK and ATA may be reduced or stopped during the course of the study upon notification from the Sponsor.119Below is Flowchart 5 showing PK / ATA for ADC and gemcitabine samples for Cohort C (after first 10 participants)Flowchart 5.Abbreviations: ATA = antitherapeutic anti bo J\ , C cj cle, D Ja\ , LO1 = end of infusion time(ie, for tusamitamab: when the pump beeps before flush = 1.5 hour); EOT = End-of-treatment visit; IMP = investigational medicinal product; IV = intravenous; PK = pharmacokinetics; RNT = relative nominal; SOI= start of infusion. a Samples collected strictly before start of infusion (SOI) b ADC ATA samples are collected at SOI at Cycle 7 and thereafter every 3 cycles (ie, CIO, Cl 3, 16...)Note: Sampling for PK and ATA may be reduced or stopped during the course of the study upon notification from the Sponsor.5. PatientsInclusion Criteria

[0757] Participants are eligible to be included in the study if they satisfy the following criteria:(1) Age

[0758] Participant must be at least 18 years of age (or country’s legal age of majority if >18 years), at the time of signing the informed consent.(2) Type of participant and disease characteristics

[0759] Participants with at least one measurable lesion according to the RECIST vl .1 criteria that has not been irradiated (ie, newly arising lesions in previously irradiated areas) are accepted. The lesion must be >10 mm in the longest diameter (except lymph nodes, which must have short axis >15 mm) with computed tomography (CT) (preferred) or magnetic resonance imaging (MRI) scans.

[0760] Participants with ECOG performance status 0 to 1.

[0761] Evidence of metastatic disease.

[0762] Cohorts B and C - mPAC:

[0763] Have confirmed diagnosis of pancreatic ductal adenocarcinoma.

[0764] Expression of CEACAM5 as demonstrated prospectively by a centrally-assessed IHC assay of >2+ in intensity involving at least 50% of the tumor cell population in archival tumor sample (or, if not available, a fresh biopsy sample). At least 5 fresh cut slides of FFPE tumor tissue sectioned at a thickness of 4 to 5 pm are required. Cell collections (e.g., from pleural effusion) processed as FFPE blocks are acceptable. If less material is available, the participant could still be considered eligible after discussion with the Sponsor, who may assess and confirm that the available material is sufficient for key evaluations.

[0765] Cohort B - mPAC:

[0766] Cohort B: Have documented radiographic progression or documented intolerance after at least 1 prior systemic chemotherapy line which included either gemcitabine(or relapsed within 6 months of completion of gemcitabine adjuvant therapy) or a 5-fluorouracil based regimen (including capecitabine) but no more than 2 prior chemotherapy lines for locally advanced / metastatic disease.(3) Sex

[0767] Male participants are eligible to participate if they agree to the following during the intervention period and for at least 4 months after the last dose of tusamitamab ravtansine, and at least 6 months after the last dose of gemcitabine:

[0768] Refrain from donating sperm; and

[0769] Be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or

[0770] Must agree to use contraception / barrier (agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person).

[0771] Female participants are eligible to participate if they are not pregnant or breastfeeding, and at least one of the following conditions applies:

[0772] Is not a woman of childbearing potential (WOCBP);

[0773] Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, for at least 7 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period; and

[0774] A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) before the first dose of study intervention.(4) Informed Consent

[0775] Capable of giving signed informed consent.(5) Criterion added in amended protocol (only for participants in Cohort C)

[0776] Have documented radiographic progression or documented intolerance after 1stline fluoropyrimidine-containing chemotherapy (or relapsed within 6 months of completion of chemotherapy as adjuvant therapy) for locally advanced / metastatic disease.Exclusion Criteria

[0777] Participants are excluded from the study if any of the following criteria applied:(1) Medical conditions

[0778] Medical condition requiring concomitant administration of a medication with a narrow therapeutic window, that is metabolized by cytochrome P450 (CYP450), and for which a dose reduction cannot be considered.

[0779] Medical conditions requiring concomitant administration of strong CYP3A inhibitor, unless it can be discontinued at least 2 weeks before the first administration of study intervention.

[0780] Life expectancy less than 3 months.

[0781] Untreated brain metastases or history of leptomeningeal disease. Participants with previously treated brain metastases may participate provided that:

[0782] - they are stable (ie, without evidence of progression by imaging for at least 4 weeks prior to the first administration of study treatment, and any neurologic symptoms have returned to baseline);

[0783] - there is no evidence of new or enlarging brain metastases; and

[0784] - the participant does not require any systemic corticosteroids to manage brain metastases within 3 weeks prior to the first dose of study intervention.

[0785] Significant concomitant illness, including any severe medical condition that, in the opinion of the Investigator or Sponsor, would impair the participant’s participation in the study or interpretation of the results.

[0786] History within the last 3 years of an invasive malignancy other than the one treated in this study, with the exception of resected / ablated basal or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix, or other local tumors considered cured by local treatment.

[0787] History of known acquired immunodeficiency syndrome (AIDS) related illnesses or known human immunodeficiency virus (HIV) disease requiring antiretroviral treatment, or active hepatitis A, B (defined as either positive HBsAg or positive hepatitis B viraldeoxyribonucleic acid [DNA] test above the lower limit of detection of the assay), or C (defined as a known positive hepatitis C antibody result and known quantitative hepatitis C virus [HCV] RNA results greater than the lower limits of detection of the assay) infection. HIV serology is tested at screening only for participants enrolled in any country where mandatory per local requirements.

[0788] Non-resolution of any prior treatment-related toxicity to < Grade 2 according to NCI-CTCAE v5.0, except for alopecia, vitiligo, or active thyroiditis controlled with hormone replacement therapy (HRT).

[0789] Unresolved corneal disorder or any previous corneal disorder considered by an ophthalmologist to predict higher risk of drug-induced keratopathy.

[0790] Use of contact lenses. Participants using contact lenses who are not willing to stop wearing them for the duration of the study intervention are excluded.(2) Prior / concomitant therapy

[0791] Concurrent treatment with any other anti-cancer therapy.

[0792] Washout period before the first administration of study intervention of less than 3 weeks or less than 5 times the half-life, whichever is shorter, for prior anti-tumor therapy (chemotherapy, targeted agents, immunotherapy and radiotherapy, or any investigational treatment).

[0793] Any prior therapy targeting CEACAM5.

[0794] Prior maytansinoid DM4 treatment (ADC).

[0795] Any major surgery within the preceding 3 weeks of the first study intervention administration.(3) Prior / concurrent clinical study experience

[0796] Previous enrollment in this study or current participation in any other clinical study involving an investigational study treatment or any other type of medical research.(4) Diagnostic assessments

[0797] Poor renal function as defined by serum creatinine >1.5 * upper limit of normal (ULN) or 1.0 to 1.5 x ULN with estimated glomerular filtration rate (eGFR) <60 mL / min / 1.73 m2as estimated using a modification of diet in renal disease (MDRD) formula.

[0798] Poor hepatic function as defined by total bilirubin >1.5 x ULN (except participants with Gilbert's syndrome, for whom total bilirubin <3.0 x ULN with direct bilirubin <1.5 x ULN is allowed).

[0799] Poor hepatic function as defined by AST, ALT, or alkaline phosphatase (AP) >2.5 x ULN, except participants with liver metastases for whom AST, ALT, or AP <5 x ULN is allowed or participants with bone metastases for whom AP <5 x ULN is allowed.

[0800] Poor bone marrow function as defined by neutrophils <1.5 x 109 / L or platelet count <100 x 109 / L or hemoglobin <9 g / dL (no blood and blood product transfusion within 2 weeks before screening).(5) Other exclusions

[0801] Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized.

[0802] Any country -related specific regulation that would prevent the participant from entering the study.

[0803] Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures.

[0804] Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals (in conjunction with Section 1.61 of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)-Good Clinical Practice (GCP) Ordinance E6).

[0805] Any specific situation during study implementation / course that may rise ethics considerations.

[0806] Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study.(6) Criterion only for participants in Cohort C

[0807] Any previous systemic therapy with taxane or gemcitabine (for Cohort C only). 6. Study interventions and concomitant therapy

[0808] Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol. Intervention Administered

[0809] Table 2 shows the overview of the interventions administered.Table 2.Intervention tusamitamab ravtansine (SAR408701) gemcitabine labelIntervention tusamitamab ravtansine (SAR408701) gemcitabine nameType Drug DrugDose Concentrated solution for IV lyophilized powder for formulation reconstitution for IVnUnit dose 5 mg / mL not applicable strength(s)Dosage level(s) Loading dose 170 mg / m2(or 135 mg / m21000 mg / m2over 30 minutes on only for Cohort C) over 1 hour 30 minutes Day 1, Day 8, and Day 15, Q4W on Day 1 of Cycle 1 Other doses 100 mg / m2Q2WFor participants with a BSA >2.20 m2, the dose is calculated based on a BSA of 2.20 m2Route of IV infusion / ? IV infusion / ? administrationUse experimental experimentalIMP or NIMP IMP IMPPackaging and Supplied in a 30 mL glass vial containing Per specifications for locally labeling 125 mg / 25 mL tusamitamab ravtansine available / marketed source, where(SAR408701). Packaging is in accordance local sourcing is possible with the administration schedule. The content of the labeling at vial and box level is in accordance with the local regulatory specifications and requirements.Current / Former Not applicable As per locally marketed name(s) or formulation alias(es) _ a. For locally sourced IMP, if the recommended formulation is not available. Local approved formation can be used after confirmed with the Sponsor. b. Infusion via a central line is preferred (line is flushed before infusion), if available. Prior to dosing, each participant's dose is individually prepared by the study pharmacist and labeled with protocol number, participant number, and treatment description.

[0810] Table 3 below shows the arms and associated interventions.Table 3.Arm name Cohort B (mPAC) Cohort C (mPAC)Associated interventions tusamitamab tusamitamab(intervention label [s]) ravtansine ravtansine(SAR408701) (SAR408701) + gemcitabine

[0811] After the study cut-off date for the secondary efficacy endpoints, participants with observed clinical benefit who are still receiving study treatment can continue on study treatment.

[0812] Study intervention is administered until documented disease progression, unacceptable toxicity, new anti-cancer therapy initiation, or the participant’s or Investigator’s decision to stop the treatment.Premedication for tusamitamab ravtansine

[0813] Premedication with a histamine Hl antagonist (oral diphenhydramine 50 mg or equivalent [eg, dexchlorpheniramine] given approximately 15 minutes to 1 hour before tusamitamab ravtansine (SAR408701) administration depending on the administration form - IV or oral [15 minutes prior for IV and 1 hour prior for oral]) is required for all participants before the administration of tusamitamab ravtansine (SAR408701). If a participant has experienced an infusion reaction following previous tusamitamab ravtansine (SAR408701) administration, premedication also include dexamethasone 10 mg IV for future infusions. If theparticipant does not experience any hypersensitivity reactions after 4 cycles, the premedication can be discontinued at the discretion of the Investigator.Premedication for gemcitabine

[0814] Antiemetic preventive therapy must be given according to ASCO guidelines and the local practice. Gemcitabine is known as a low-emetic-risk antineoplastic agent. According to ASCO anti-emetics guidelines updated on May 6th, 2020, adults treated with low-emetic-risk antineoplastic agents should be offered a single dose of a 5-HT3 receptor antagonist or a single 8°mg dose of dexamethasone before antineoplastic treatment.Preparation, Handling, Storage, and Accountability

[0815] The Investigator or designee must confirm appropriate temperature conditions have been maintained during transit for all study intervention received and any discrepancies are reported and resolved before use of the study intervention.

[0816] Only participants enrolled in the study may receive study intervention and only authorized site staff may supply or administer study intervention. All study intervention must be stored in a secure, environmentally controlled, and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the Investigator and authorized site staff.

[0817] The Investigator, institution, or the head of the medical institution (where applicable) is responsible for study intervention accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition records).Dose Modification(1) Determination of recommended dose for Cohort C

[0818] During Part 1 of Cohort C, recommended dose of tusamitamab ravtansine in combination with gemcitabine is determined according to the DLTs observed in participants according to the algorithm shown in Figure 1 :• If 0 / 3 participants experience a DLT at the starting loading dose, the starting loading dose is RP2D.• If 1 / 3 participants experience a DLT at the starting dose, the next 3 participants of the combination arm are treated at the same DL to confirm the tolerability of the combination at the starting dose. o If <1 / 6 participants treated at the starting dose experiences a DLT, the starting dose is the RP2D. o If >2 / 6 participants treated at the starting dose experience a DLT, the dose is de-escalated to DL-1 for the next 3 participants of the combination arm.• If >2 / 3 participants experience a DLT at the starting dose, the dose is de-escalated to DL-1 for the next 3 participants of the combination arm. o If <1 / 3 participants treated at the DL-1 experiences a DLT, the next 3 participants of the combination arm are treated at the same DL to confirm the tolerability of the combination at DL-1.■ If <1 / 6 participant treated at the DL-1 experiences a DLT, the DL- 1 is the RP2D.■ If >2 / 6 participants treated at the DL-1 experience a DLT, an alternative dosage might be considered or the study part may be stopped. o If >2 / 3 participants treated at DL-1 experience a DLT, an alternative dosage might be considered or the study part may be stopped.

[0819] The tolerability of the combinations is assessed in 3 to 12 participants depending on DLTs observed. Dose modification and dose schedules are shown in Table 1. Definitions of DLTs are provided in Table 4.

[0820] Table 4 below shows the dose-limiting toxicities.Table 4.Hematological abnormalitiesGrade 4 neutropenia for 7 or more consecutive days.Grade 3 to 4 neutropenia complicated by fever (temperature >38.5°C on more than 1 occasion) or microbiologically or radiographically documented infectionGrade >3 thrombocytopenia associated with clinically significant bleeding requiring clinical interventionNonhematological abnormalitiesGrade 4 nonhematologic AEGrade >3 keratopathyIn addition, any other AE that the recruiting Investigators and Sponsor deem to be dose limiting, regardless of its grade, may also be considered as DLT.Abbreviations: AE = adverse event; DLT = dose-limiting toxicity.

[0821] All AEs specified in Table 4 occurring during the first cycle of treatment, unless due to disease progression or to a cause obviously unrelated to IMP, is considered DLTs. During the DLT evaluation period in the safety run-in part, IMPs can be delayed but not omitted; the DLT evaluation period is prolonged in such cases. The duration of the DLT observation period is longer for a participant who delays initiation of Cycle 2 due to a treatment-related AE for which the event’s duration would determine whether the AE meets the definition of a DLT. The severity of AEs is assessed according to NCI CTCAE Version 5.0.(2) Individual dose adjustment / dose delay: Cohort B and Cohort C Part 2

[0822] Dose adjustment and / or cycle delays are permitted in case of adverse reactions.

[0823] Dose adjustments are made according to the worst grade of adverse reaction observed within a cycle. If a participant experiences several adverse reactions and there are conflicting recommendations, the most conservative dose adjustment recommended is followed.

[0824] Administration of the study treatment is discontinued in the event of a TEAE that persists despite appropriate dose modifications or any other AE that, in the opinion of the Investigator, warrants discontinuation.

[0825] All changes to study treatment administration must be recorded in the eCRF.

[0826] In the event of neutropenia, therapeutic granulocyte colony-stimulating factor (G-CSF) should be administered according to the current American Society of ClinicalOncology (ASCO) guidelines. In the event of neutropenia or febrile neutropenia, prophylactic G-CSF should be started, and in the event of a second episode beside prophylactic G-CSF, the dose should be reduced. The acceptable treatment window is ±2 days for Cohort B and ±3 days for Cohort C.

[0827] One dose reduction of tusamitamab ravtansine and 2 dose reductions of gemcitabine are allowed during the conduct of the study for safety reasons. If a second dose reduction of tusamitamab ravtansine is considered necessary, this is decided on a case-by-case basis following discussion with the Sponsor. In the event of a dose reduction, the study intervention is administered as shown in Table 5. Dose delays are allowed for safety management. Retreatment of participants that requires more than a 1 month dose delay must be justified following a case-by-case risk benefit assessment See Table 6 for guidance on dose modification or discontinuation.

[0828] Table 5 below shows dose modification for toxicity.Table 5Drug name Dose 1stdose reduction 2nddose reduction tusamitamab 100 mg / m2Q2W 80 mg / m2Q2W (not permitted)gemcitabine 1000 mg / m2800 mg / m2600 mg / m2a Dose modification is applicable from Cycle 2. The loading dose remains 170 mg / m2(or 135 mg / m2in Cohort C).

[0829] If appropriate, and if in the opinion of the Investigator, the toxicity is related to 1 of the 2 drugs (tusamitamab ravtansine or gemcitabine) instead of the combination, and more than 1 cycle delay is needed, the unrelated drug can be continued, and the related drug may be omitted if the delay exceeds 7 days, upon discussion with the Sponsor, and administration resumed at following recovery from the toxicity to Grade <1. If the toxicity is related to the combination, both agents should be reduced (if applicable), omitted, or definitively discontinued according to the recommended dose modifications. If 1 of the 2 drugs (tusamitamab ravtansineor gemcitabine) is prematurely permanently discontinued, the other drug can be continued until disease progression.

[0830] Table 6 below shows the recommended dose modification or discontinuation for tusamitamab ravtansine.Table 6.Event Symptoms Dose modification Dose modification Supportive severity (tusamitamab (gemcitabine) care(NCI-CTCAE ravtansine) guidelines v5.0)Infusion-related Grade 1-2 Interrupt Interrupt Give reactioneg Qra(je<2 tusamitamab gemcitabine diphenhydra nausea headache ravtansine infusion, infusion and start mine tachycardia, tusamitamab appropriate 50 mg IV hypotension, ravtansine may be treatment. and / or rash, shortness of resumed only after dexamethason breath. participant Reduce infusione 10 mg IV' recovery, at half thera(Cby 50% Dexamethaso previous infusion ne can be ra(C« added as premedication for upcoming cycles for tusamitamab ravtansineGrade 3-4 Interrupt Interrupt Give eg symptomatic tusamitamab gemcitabine diphenhydra bronchospasm ravtansine infusion infusion and mine urticaria lesionsan<^ definitively definitively 50 mg IV covering >30% discontinue discontinue and / orBSA tusamitamab gemcitabine dexamethason hypotension, ravtansine. e 10 mg IV angioedema. and / or epinephrine and any required treatment per Investigator judgment.Event Symptoms Dose modification Dose modification Supportive severity (tusamitamab (gemcitabine) care (NCI-CTCAE ravtansine) guidelines v5.0)Ocular toxicity: Grade 1 Next infusion of Administer Standard Keratopathy / kerat Asymptomatic, tusamitamab gemcitabine as ocular itis^ associated Corneal lesions ravtansine at the planned examination with tusamitamab only observed on same dose, with or is planned as ravtansine routine ocular without cycle delay, recommended examination and depending on the by the not requiring recommendation ophthalmolog topical treatment. from the ist. ophthalmologist (nature and extent of the lesion).Grade 2 1stepisode: Administer StandardSymptomatic, tusamitamab gemcitabine the ocular moderate ravtansine cycle same day as examination decrease in visual delay until tusamitamab weekly until acuity (best resolution to ravtansine resolutionccorrected visual Grade 1 Start curative acuity 20 / 40 and (asymptomatic) and treatment per better or 3 lines restart tusamitamab ophthalmolog or less decreased ravtansine at the ist vision from same dose. recommendati known baseline) 2ndepisode: delay on. cycle until After resolution to Grade resuming 1 (asymptomatic) study and tusamitamab treatment, ravtansine dose participant reduction.Event Symptoms Dose modification Dose modification Supportive severity (tusamitamab (gemcitabine) care (NCI-CTCAE ravtansine) guidelines v5.0)Grade 3 1stepisode: Administer should beSymptomatic tusamitamab gemcitabine as followed with with marked ravtansine cycle planned if standard dec delay until definitive ocular rease in visual acuity ( resolution discontinuation of examination best corrected visual (asymptomatic) and tusamitamab by every two acuity worse than restart tusamitamab ravtansine cycles, even 20 / 40 or more ravtansine with asymptomatic th dose reduction. during next an 3 lines of four cycles. If decreased vision 2ndepisode: from known definitive no recurrence, baseline, up to discontinuation of standard 20 / 200); corneal tusamitamab process with ulcer; limiting follow-up ravtansine. with ocular self-care ADL. symptom is resumed.Management of study drug and follow-up process upon recurrence to be discussed according to Grade of the event at recurrence, clinical benefit from study drug and recommendati on from the ophthalmolog ist.Event Symptoms Dose modification Dose modification Supportive severity (tusamitamab (gemcitabine) care(NCI-CTCAE ravtansine) guidelines v5.0)Grade 4 Definitive Administer Complete thePerforation best discontinuation of gemcitabine as corneal corrected visual tusamitamab planned. examination acuity of 20 / 200 ravtansine. as or worse in the recommended affected eye by ophthalmolog ist. Repeat the standard ocular examination weeklycuntil resolution^.Start curative treatment per ophthalmolog ist recommendati on.Conduction Grade 1 tusamitamab No action ECG disorder Mild symptoms ravtansine performed associated with administration to be once weekly tusamitamab continued upon until event ravtansine decision by the resolution.Investigator and AdditionalSponsor, depending evaluations on the nature of the such as LVEF conduction and Holter disorder. monitoring should be performed when relevant.Grade >2 Definitive No action ECG to be discontinuation of repeated tusamitamab twice weekly ravtansine. until eventGrade>3 Definitive Decrease resolution, discontinuation of gemcitabine to next Prompt tusamitamab lower dose level cardiology ravtansine. per Table 5. consultationEvent Symptoms Dose modification Dose modification Supportive severity (tusamitamab (gemcitabine) care(NCI-CTCAE ravtansine) guidelines v5.0)Grade>4 Definitive Definitive Additional discontinuation of discontinuation of evaluations tusamitamab gemcitabine suchasLVEF ravtansine.and Holter monitoring should be performed when relevant.Neutrophil count Grade 1 No change in No change in No decreased <LLN- tusamitamab gemcitabine intervention.1500 / mm3; ravtansine administration<LLN-1.5 x 109 / administration. LGrade 2 Delay the cycle No change in No<1500- until recovery of gemcitabine intervention.1000 / mm3; ANC > 1500 / mm3. administration<1.5-1.0 x 109 / L Restart at the same dose.Grade 3 Delay the cycle. Delay the cycle and Follow ASCO<1000-500 / mm3; Restart the administer on the guidelines on<1.0-0.5 x 109 / L treatment when same day as usage G-CSFOr ANC >1500 / mm3at tusamitamab andGrade 4 1<7 dav<0 the same dose on ravtansine when antibiotherap the same day as ANC >1500 / mm3y. Repeat the gemcitabine (only on Day 1 and Day test everyfor Cohort C). 15, until 3 days.Prophylactic G-CSF ANC >1000 / mm3can be consideredonDay 8, at dose in all subsequent reduced per Table cycles 5.Administer prophylactic G- CSF and in all subsequent cycles.Event Symptoms Dose modification Dose modification Supportive severity (tusamitamab (gemcitabine) care(NCI-CTCAE ravtansine) guidelines v5.0)Grade 4 >7 days Delay the cycle 1stepisode: Delay Follow ASCO<500 / mm3; until the cycle and guidelines on<0.5 x 109 / L ANC >1500 / mm3. administer on the usage of G-1st episode: same day as CSF and administer next tusamitamab antibiotherap cycle at the same ravtansine when y. Repeat the dose and administer ANC >1500 / mm3test every growth factorsonDay 1 and Day 3 days.2nd episode:Linl’' , administer ANC >1000 / mm tusamitamabonDay at dose ravtansine reduced per Table tusamitamab ravtansine at Administer reduced dose prophylactic G-3rd episode: SF and in all definitive subsequent cycles, discontinuation 2ndepisode: Delay the cycle and administer on the same day as tusamitamab ravtansine when ANC >1500 / mm3on Day 1 and Day 15, until ANC >1000 / mm3on Day 8, and decrease 2 dose levels per Table 5.Administer prophylactic G- CSF and in all subsequent cycles. 3rd episode: definitive discontinuationEvent Symptoms Dose modification Dose modification Supportive severity (tusamitamab (gemcitabine) care (NCI-CTCAE ravtansine) guidelines v5.0)Febrile Grade 3 Delay cycle until 1stepisode: To ensure neutropenia Absolute ANC >1500 / mm3. Delay the cycle and relative dose neutrophil count 1st episode: administer when intensity, G- <1000 / mm3with administer next ANC >1500 / mm3CSF is a single cycle at the same on Day 1 and Day recommended temperature of dose and administer 15, until as secondary >38.3°C (101°F) G-CSF ANC >1000 / mm3prophylaxis in or a sustained 2nd episode: on Day 8, and all temperature of administer decrease to next participants >38°C (100.4°F) tusamitamab lower dose level with Grade >3 for more than ravtansine at per Table 5. febrile 1 hour reduced dose Administer neutropenia3rd episode: prophylactic G- ASCO definitive CSF and in all guideline is discontinuation subsequent cycles. recommended 2ndepisode: Delay for supportive the cycle and treatment if administer when there are no ANC >1500 / mm3defined on Day 1 and Day clinical 15, until standards. ANC >1000 / mm3on Day 8, and decrease 2 dose levels per Table 5 (to 600 mg / m2) Administer prophylactic G- CSF and in all subsequent cycles. 3rdepisode: definitive discontinuationEvent Symptoms Dose modification Dose modification Supportive severity (tusamitamab (gemcitabine) care(NCI-CTCAE ravtansine) guidelines v5.0)Grade 4 Administration 1stepisode: Delay To ensureT i fe-threatening changes to be the administration relative dose consequences decided at the until intensity, G-Investigator’s ANC >1500 / mm3CSF is discretion. on Day 1 and Day recommended1st episode: 15, until as secondary administer next ANC >1000 / mm3prophylaxis in cycle at reducedonDay 8, and all dose and administer decrease to next participantsG-CSF or lower dose level with Grade >3 definitively per Table 5. febrile discontinue Administer neutropenia2nd episode: prophylactic G- ASCO definitive CSF and in all guideline is discontinuation subsequent cycles. recommended2ndepisode: for supportiveDefinitive treatment if discontinuation. there are no defined clinical standards.Thrombocytopeni Grade 1 Delay until Delay the No a Platelets <LLN- platelets >100.0 x 1 administration until intervention.75 000 / mm3; 09 / L. platelets >100.0 x 1<LLN-75.0 x 109 / Restart at the same 09 / L on Day 1 andL dose. Day 15, administer gemcitabine as planned on Day 8.Restart at the same dose.Grade 2 Delay until Delay the NoPlatelets recovery of administration until intervention.<75 000-50 000 / platelets >100.0 x 1 platelets >100.0 x 1 mm309 / L. 09 / L on Day 1 and<75.0-50.0 x 109 / Restart at the same Day 15, untilL dose. platelets >75.0 x 109 / L on Day 8, and decrease to next lower dose level per Table 5.Event Symptoms Dose modification Dose modification Supportive severity (tusamitamab (gemcitabine) care(NCI-CTCAE ravtansine) guidelines v5.0)Grade>3 Administration 1stepisode: Delay AdditionalPlatelets changes to be the administration hematology<50 000 / min3- decided at the until tests are done<50.0 x 109 / L Investigator’s platelets >100.0 x 1 every 2-3 discretion. 09 / L on Day 1 and days until1 st episode : Day 15, until recovery to administer next platelets >75.0 x 10 baseline cycle at reduced9 / Lon Day 8, and value, dose or definitively decrease to next Platelet discontinue lower dose level transfusions2nd episode: PerTable 5. 2canbe definitive episode: definitive considered discontinuation discontinuation. pgr clinical practice.Hepatic enzyme Grade 1-2 Administer Administer No increase tusamitamab gemcitabine as intervention. ravtansine as planned planned.Grade 3 Delay the cycle. Withhold AdditionalRestart the gemcitabine until liver function treatment until recovery to tests are done recovery to Grade Grade 1 and every 2-31. decrease to next days until lower dose level recovery to per Table 5. baseline value.Grade 4 tusamitamab Gemcitabine Additional ravtansine should should be liver function be permanently permanently tests are done discontinued. discontinued. every 2-3 days until recovery to baseline value.Peripheral Grade 1 No action No action Participant neuropathy Asymptomaticw'10'iasEvent Symptoms Dose modification Dose modification Supportive severity (tusamitamab (gemcitabine) care (NCI-CTCAE ravtansine) guidelines v5.0)Grade 2 Delay cycle, dose No action ongoing gradeModerate reduction if no 1 neuropathy symptoms; improvement with has high risk limiting dose delay of worsening of his / her instrumental Activities of symptoms and should be Daily Living closelyGrade 3 Definitive No action followed.Severe discontinuation symptoms; limiting self-careActivities ofDaily LivingGrade 4 Definitive No actionLife-threatening discontinuation consequences; urgentHemorrhage Grade 3 Definitive Decrease discontinuation gemcitabine to next lower dose level per Table 5.Grade 4 Definitive Definitive discontinuation discontinuation of gemcitabineASCO = American Society of Clinical Oncology, ASOCT = Anterior segment optical coherence, BSA = Body surface area, ECG = Electrocardiogram, G-CSF = Granulocyte colony-stimulating factor, Hb = Hemoglobin, IMP = Investigational medicinal product, IV = Intravenous; LLN = Lower limit of normal, LVEF = Left ventricular ejection fraction, NCI-CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events, RBC = Red blood cell. a tusamitamab ravtansine is stable at least 7.5 hours in the infusion bag at room temperature. If necessary, a new infusion should be prepared with the remaining dose to be administered. b The NCI-CTCAE v5.0 grading is to be applied to keratopathy. c Standard ocular examination per protocol includes visual acuity, slit-lamp examination, Schirmer’s test, and enquiring for ocular / visual symptoms. d When possible at the site, photographs should be done when findings are first documented and to follow progression when relevant. Any additional relevant ocular examination can be done if indicated.(3) Retreatment Criteria

[0831] All participants entered into the study is treated at Day 1 of each cycle, and participants in Cohort C, also at Day 8 and Day 15 of each cycle. A participant may receive additional study interventions if he / she meets the retreatment criteria as determined by the Investigator and agrees to be retreated.

[0832] For the retreatment of all participants on Day 1 (or, for Cohort C, on Day 15) of each subsequent cycle, the participant must meet all of the following criteria to be eligible for retreatment:• Neutrophils count >1.5 x 109 / L• Platelets >100 x 109 / L• Hemoglobin >9 mg / dL• Total bilirubin <1.5 x ULN (except participants with Gilbert's syndrome, for whom total bilirubin <3.0 x ULN with direct bilirubin <1.5 x ULN is allowed)• AST, ALT <2.5 x ULN or <5 x ULN in case of documented liver metastasis• No IMP-related toxicity Grade >1 (except for alopecia) or baseline severity.For the treatment of participants on Day 8 of each cycle in Cohort C, the participant must meet all of the following criteria to be eligible for retreatment:• Neutrophil count >1 x 109 / L• Platelets >75 x 1O9 / LConcomitant Therapy

[0833] Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, and / or herbal supplements) that the participant is receiving at the time of enrollment or receives during the study must be recorded along with:• Reason for use; andDates of administration including start and end dates

[0834] Concomitant medications should be kept to a minimum during the study.

[0835] Concomitant medication may be considered on a case-by-case basis by the Investigator, in accordance with the following guidelines:• Palliative radiotherapy may be given for control of pain for palliative intents. Approval should be obtained from the Sponsor prior to initiating treatment if palliative radiotherapy is being considered, and prior to resuming therapy on the study. The irradiated area should be as small as possible and should never involve more than 20% of the bone marrow in any given 3 -week period. In all such cases, the possibility of tumor progression should be ruled out by physical and radiological assessments of the tumor. If the only evaluable lesions are to be irradiated, the participant stops the study intervention. The irradiated area cannot be used as a parameter for response assessment.• Any background therapy taken by the participant for concomitant illnesses other than cancer (e.g., HRT, statin, antihypertensive medication) is allowed.• Supportive treatment as medically indicated for the participant's well-being may be prescribed at the Investigator's discretion. Every medication or treatment taken by the participant during the trial and the reason for its administration must be recorded on the eCRF.The following concomitant treatments are not permitted during the study:• Concurrent treatment with other investigational drugs.• Concurrent treatment with any other anti-cancer therapy not specified in the protocol, including immunotherapy, hormonal therapy, targeted therapy or biological therapies.• The primary prophylactic use of Granulocyte-Colony Stimulating Factor is not allowed during the first cycle, but secondary prophylaxis or therapeutic administration is allowed.The use of prophylactic erythropoietin during the first cycle.Participants treated or intended to be treated with drugs presented as CYP substrates with a narrow therapeutic range should be carefully monitored.• Concomitant use of strong CYP3A inhibitors should be avoided from 2 weeks before tusamitamab ravtansine administration up to the last tusamitamab ravtansine administration.• The use of contact lenses is not permitted during the study treatment period.7. Clinical MonitoringPharmacokinetics

[0836] Blood samples are collected for the measurement of tusamitamab ravtansine (SAR408701), gemcitabine and its metabolite (dFdU).

[0837] Pharmacokinetic samples could be used for testing analytical method performance such as comparability and incurred sample reproducibility and for possible exploratory analysis of drug metabolites.Noncompartmental analysis

[0838] Pharmacokinetic parameters of SAR408701, gemcitabine, and dFdU are calculated using noncompartmental methods from concentrations obtained after administration assayed in the first 10 participants. The parameters include, but may not be limited to, those listed in Table 7.

[0839] Table 7 below shows the list of pharmacokinetic parameters and definitions.Table 7.Analyte Cycle / Day Parameter Definition tusamitamab 1 / 1 CmaxMaximum concentration observed after infusion ravtansineAUCo-i4d Area under the plasma concentration versus time curve calculated using the trapezoidal method from time 0 to 14 days. gemcitabine 1 / 1 CL Total body clearance of a drug from plasma calculated using the following equation from AUC: CL=dose / AUC dFdU 1 / 1 Cmax Maximum concentration observed after infusionPopular Approach

[0840] Data from plasma concentrations of tusamitamab ravtansine may be used for population PK analysis by nonlinear, mixed-effects modeling. Empirical Bayesian estimation of individual exposure parameters such as maximum concentration (Cmax), trough concentration (Ctrough), and area under the curve (AUC) are derived.8. GeneticsCirculating tumor DNA analysis

[0841] A 20 mL blood sample corresponding to about 10 mL of plasma for tumor circulating free deoxyribonucleic acid (cfDNA) isolation and an additional 2 mL blood sample for germline DNA are collected at pre-infusion of Cycle 1 Day 1.

[0842] Samples are planned to be transferred to a central laboratory for cfDNA / DNA extraction and mutational profiling of key cancer genes to understand the significance of existing mutation during tusamitamab ravtansine treatment.

[0843] Fragmented circulating tumor DNA or cfDNA is released from the tumor in the plasma and can readily be extracted and analyzed for mutation of common cancer genes. Subtractive mutation analysis is performed with germline DNA data to identify tumor specific somatic genetic aberrations. Mutation profiling analysis is performed and the potential correlation of specific mutation(s) with clinical outcomes are assessed.

[0844] For example, and without limitation, the list of the genes that can be mutated is: AKT1, ALK, BRAF, CDKN1B, CDKN2A, CDKN2D, EGFR, ESRI, FGFR4, HER2, HRAS, KRAS, MDM2, MED1, MET, NRAS, PIK3CA, PTEN, RBI, RET, ROS1, and TP53.Tumor DNA and RNA analyses

[0845] Although tumor CEACAM5 expression is a major parameter driving the activity of an anti-CEACAM5 ADC such as tusamitamab ravtansine, other factors may significantly contribute. Tumor tissue is therefore also be requested to explore the potential relationship between clinical endpoints following tusamitamab ravtansine therapy and potential sets of biomarkers besides target expression that could be predictive of response.

[0846] Forthat purpose, 3 x 10 pm slides (or equivalent such as 6 x 5 pm or other) from the same sample as the one sent for CEACAM5 assessment at prescreening are requested atscreening or Cycle 1 Day 1. The samples may serve to investigate other potential biomarkers of response. In tumor tissue, biomarker annotation could include, but may not be restricted to, genomic annotation by sequencing, gene copy number variation, gene expression (mRNA and miRNA), and proteomic profiling.Biomarkers

[0847] Circulating carcinoembryonic antigen (CEA) levels are collected at prescreening, baseline, during the treatment (every 8 weeks), EOT, and follow-up period (every 12 weeks) at the time of laboratory assessment as close as possible to tumor assessment (and no more than 2 weeks from the tumor assessment) until confirmed disease progression.

[0848] Venous blood samples of approximately 3 mL (volume may change depending on local laboratory assay) are collected for measurement at the local laboratory.9. Statistical considerationsSample Size Determination

[0849] Assuming a prescreening failure rate of 85% for mPAC Cohort B, and 58% for mPAC Cohort C, and a screening failure rate of 20% for the 2 cohorts, approximately 242 participants for the mPAC Cohort B, and 90 participants for mPAC Cohort C are prescreened to achieve up to approximately 29 treated participants evaluable for activity for mPAC Cohort B, and 30 participants evaluable for activity in mPAC Cohort C.

[0850] For Cohort C safety run-in (Part 1), the actual sample size is expected to vary depending on DLTs observed. It is anticipated that around 3 to 12 DLT-evaluable participants are enrolled. Table 8 lists the estimated ORRs and 95% exact Cis by the numbers of responders from a sample size of 29 treated participants evaluable for activity for mPAC cohort, and Table 9 lists the estimated ORRs and Cis 30 treated participants evaluable for activity for combination cohort.

[0851] The Table 8 below shows the estimated ORR depending on the numbers of responders for mPAC Cohort B.Table 8.Number of responders Objective response rate in %(N=29) (95% Clopper-Pearson CI)3 10.34 (2.19-27.35)4 13.79 (3.89-31.66)5 17.24 (5.85-35.77)6 20.69 (7.99-39.72)7 24.14 (10.30-43.54)8 27.59 (12.73-47.24)9 31.03 (15.28-50.83)CI = confidence interval; mPAC = metastatic pancreatic adenocarcinoma; ORR = objective response rate.

[0852] Table 9 below shows the estimated ORR depending on the numbers of responders for Cohort C.

[0853] Table 9.Number of responders Objective response rate in %(N=30) (95% Clopper-Pearson CI)4 13.33 (3.76-30.72)5 16.67 (5.64-34.72)6 20.00 (7.71-38.57)7 23.33 (9.93-42.28)8 26.67 (12.28-45.89)9 30.00 (14.73-49.40)CI = confidence interval; ORR = objective response rate.Population for analysis

[0854] Table 10 shows the populations for analysis.Table 10.Population DescriptionPrescreened All participants who signed the prescreening informed consent forCEACAM5 assay assessment of their biopsy.Screened All participants who signed screening informed consent for study participation.DLT-Evaluable (Cohort C Participants who received 1 cycle with at least 80% of the intendedPart 1) dose for tusamitamab ravtansine at each of the first 2 infusions and gemcitabine at each of the first 3 infusions unless they discontinued the study intervention before the end of Cycle 1 due to a DLT.All-treated All registered participants exposed to the study treatment, regardless of the amount of treatment administered. This population is the primary population for all efficacy parameters.Activity All treated participants who have measurable disease at study entry and at least one post-baseline evaluable tumor assessment. Participants with no post-baseline evaluable tumor assessment but with an early clinical progression or who died from disease progression are also included in this set. This population is the secondary population for analysis of efficacy parameters.PK All treated participants with at least 1 postbaseline PK result with adequate documentation of dosing and sampling dates and times.ATA All treated participants with at least one post-baseline ATA result(negative, positive, or inconclusive).CEACAM5 = carcinoembryonic antigen-related cell adhesion molecule 5; ATA = antittherapeutic antibodies.Statistical analysis(1) General Considerations

[0855] This study is designed to obtain preliminary efficacy and safety data on the use of tusamitamab ravtansine administered to participants with CEACAM5 -positive tumors known to be sensitive to anti-tubulin agents at a loading dose of 170 mg / m2on Day 1 of Cycle 1, followed by 100 mg / m2Q2W for Cohort B, and at a loading dose of 170 mg / m2(or 135 mg / m2) on Day 1 of Cycle 1 , followed by 100 mg / m2Q2W, combined with gemcitabine 1000 mg / m2on Day 1 , Day 8, and Day 15 every 4 weeks (Q4W), for Cohort C.

[0856] 95% Cis is provided for the primary and secondary efficacy endpoints.

[0857] Each cohort is analyzed separately.

[0858] All efficacy analyses are performed on the All-treated population (primary population for all efficacy parameters). In addition, the primary endpoint (ORR as per RECIST vl.l) and DCR are analyzed on the activity population (secondary population). Objective response rate, as well as PFS, DCR and DOR, are derived using the local radiologist’ s / Investigator ’ s assessment.

[0859] The study cut-off for the primary analysis (ORR) for each cohort corresponds to the date on which all treated evaluable participants of the cohort have had at least 2 postbaseline tumor assessments, experienced confirmed objective response, or have discontinued the study for any reason. For participants with 2 postbaseline tumor assessments and occurrence of response at the second post baseline tumor assessment, it also includes the confirmatory assessment. An interim analysis is performed when the first 15 treated evaluable participants in Cohort C have had at least 2 postbaseline tumor assessments, experienced confirmed objective response, or have discontinued the study for any reason. Once 15 participants have been treated, enrollment may be paused until a decision regarding the interim analysis can be made.

[0860] The analysis cut-off date for secondary efficacy endpoints including DOR and PFS (final cutoff date) is 6 months after the cut-off date of the primary analysis. The primary analysis of ORR and DCR is updated at that time.

[0861] All safety analyses are performed on the All-treated population. For each safety parameter, the baseline value is defined as the latest value or measurement taken before the first administration of the IMP.

[0862] The observation period is divided into 4 segments:• The prescreening period is defined as the time from when the participants give prescreening informed consent to the day before the screening informed consent.• The screening period is defined as the time from when the participants give screening informed consent to the first administration of the IMP.• The treatment period is defined as the time from the first administration of IMP up to 30 days after the last administration of IMP.• The post-treatment period is defined as the time from the 31st day after the last administration of IMP to study closure or death, whichever occurs first.(2) Primary end point

[0863] The primary efficacy endpoint is the ORR. The ORR is estimated by dividing the number of participants with confirmed objective response (CR or PR as best overall response [BOR]), determined according to RECIST vl.l, by the number of participants from the analysis population.

[0864] The BOR is the best tumor response observed from the date of first IMP administration until disease progression, death, cut-off date or initiation of post-treatment anticancer therapy, whichever occurs first.

[0865] ORR is summarized for the All-treated population with descriptive statistics. In addition, 2 sided 95% Cis are computed using the Clopper-Pearson method.

[0866] ORR is also summarized on the activity population as a supplementary analysis.

[0867] A primary endpoint for Part 1 of Cohort C is DLTs observed during the 28-day DLT observation period (Cycle 1); incidences of DLTs are summarized on the DLT-evaluable population, by dose level. In addition, AEs that meet the DLT criteria in subsequent cycles are summarized on the all-treated population.(3) Secondary end point

[0868] The safety and efficacy secondary endpoints include safety, PFS, DCR, DOR per RECIST vl.l, PK and immunogenicity.(4) Adverse events

[0869] Adverse events recollected from the time prescreening informed consent is signed until at least 30 days after the last infusion of the study treatment. All AEs are categorized according to NCI-CTCAE v5.0 and classified by SOC and PT according to the latest available version of the medical dictionary for regulatory activities (MedDRA).• Prescreening AEs are defined as AEs occurring during the prescreening period.• Screening AEs are defined as any AEs occurring during the screening period.• Treatment-emergent AEs are defined as AEs that develop, worsen (according to the Investigator’s opinion), or become serious during the treatment period.• Post-treatment AEs are defined as AEs that are reported during the posttreatment period.

[0870] The NCI-CTCAE grade are taken into account in the summary of AEs. For participants with multiple occurrences of the same PT, the maximum grade is used.

[0871] The primary focus of AE reporting is on TEAEs.

[0872] The number and percentage of participants experiencing TEAEs by primary SOC and PT are summarized by NCI-CTCAE v5.0 grade (all grades and Grade >3) for the All-treated population. Similar summaries are prepared for treatment-related TEAEs, TEAEs leading to definitive discontinuation, TEAEs leading to dose modification, serious TEAEs, TEAEs with fatal outcome, AESIs, and AEs / SAEs occurring during the post-treatment period. In addition, the number and percentage of participants with any Grade 5 AE (TEAE and post-treatment) is summarized.(5) Clinical laboratory evaluations

[0873] Clinical laboratory values are analyzed after conversion into standard international units.

[0874] Hematology and clinical chemistry results are graded according to the NCI- CTCAE v5.0, when applicable.

[0875] When the NCI-CTCAE v5.0 grading scale is not applicable, the number of participants with a laboratory abnormality out-of-normal range value are displayed.(6) Progression free analysis

[0876] Progression-free survival is defined as the time from the date of first IMP administration to the date of the first radiological documentation of progressive disease according to RECIST vl.l or death due to any cause before the analysis cut-off date, whichever occurs first.(7) Disease control rate

[0877] The DCR is estimated by dividing the number of participants with confirmed objective response or stable disease (CR or PR or stable disease as BOR), determined according to RECIST vl.l, by the number of participants from the analysis population.(8) Duration of response

[0878] The DOR is defined as the time from the date of first initial occurrence of the confirmed CR or PR to the date of first radiological documentation of progressive disease according to RECIST vl.l before the initiation of any post-treatment anti-cancer therapy or death due to any cause, whichever occurs first.(9) Immunogenicity

[0879] Immunogenicity analyses are performed on the ATA population.Example 2: Efficacy results2. A. Best Overall Response, Objective Response Rate (ORR), Disease Control Rate (DCR) and Tumor shrinkage

[0880] Table 11 below shows the summary of Best Overall Response, Objective Response Rate (ORR) and Disease Control Rate (DCR) for participants of Cohort B and Cohort C as per RECIST 1.1 - Activity population.Table 11. mPAC Cohort B mPAC Cohort CObjective Response Rate (confirmed CR and PR) [n 1 (3.8) 5 (31.3) (%)]95% CI' 0.10 to 19.64 11.02 to 58.66Disease control rate [n (%)] 8 (30.8) 12 (75.0) 95% CI' 14.33 to 51.79 47.62 to 92.73CI = Confidence Interval; CR = Complete Response; PR = Partial Response;aIncluding participants with unconfirmed CR or PR;bIncluding participants with no post -baseline evaluable tumor assessment but with early clinical progression;cEstimated by Clopper Pearson interval.

[0881] As shown in Table 11, an Objective Response Rate (ORR) of 31.3% was observed in Cohort C, whereas the ORR was of 3.8% in Cohort B.

[0882] A Disease Control Rate (DCR) of 75.0% was observed in Cohort C, whereas the DCRin Cohort B was 30.8%. The disease remained stable in 43.8% of the participants of Cohort C, whereas it remained stable in only 26.9% of the participants of Cohort B.

[0883] Additionally, as shown in FIG. 4, a significant tumor shrinkage of approximatively 60% was observed in three patients of Cohort C. As a comparative, the best tumor shrinkage observed in Cohort B was approximately 30% (FIG. 3). 2.B. Duration of response

[0884] Table 12 below shows a summary of duration of response for responder participants of Cohort B and Cohort C as per RECIST 1.1 - Responders in activity population.Table 12. mPAC Cohort B mPAC Cohort C(N=28) (N=16)Number of responders’ 1 5Participants with an event [n(%)] 1 (100) 2 (40.0)Participants censored [n(%)] 0 3 (60.0)Kaplan-Meier estimates of DOR (months)Median (95% CI)» 4.11 (NC ; NC) 7.26 (3.713 ; NC)CI = Confidence Interval; DOR = Duration of Response; NC = Not Calculated;aIncluding participants with unconfirmed CR or PR;bComputed using the logdog transformation of the survival function and the methods of Brookmeyer and Crowley. Note: Percentages are calculated based on number of responders.

[0885] As shown in Table 12, a median Duration of Response (DOR) of 7.26 months was observed in Cohort C, whereas the median DOR was of 4.11 months in Cohort B.

[0886] Additionally, as shown in FIG. 6, 4 of the 16 evaluable treated participants of Cohort C (25%) had at least 8 months of treatment and their treatment was ongoing at the time of data extraction. 6 of the 16 evaluable participants of Cohort C (37,5%) had at least 6 months of treatment. As a comparative, only 3 of the 26 evaluable participants of Cohort B (11,5%) had at least 6 months of treatment (FIG. 5).2.C. Progression-Free Survival

[0887] Table 13 below shows the summary of Progression-Free Survival (PFS) for Cohort B and Cohort C as per RECIST 1.1 - All-treated population.Table 13.Kaplan-Meier estimates of PFS(months)a25% quantile (95% CI) (months) 1.48 (0.854 ; 1.708) 2.32 (0.099 ; 3.745)Median survival (95% CI) (months) 1.87 (1.643 ; 2.267) 4.73 (1.873 ; NC)75% quantile (95% CI) (months) 3.58 (1.906 ; 7.195) 9.13 (4.731 ; NC)PFS Probability (95%CI)b3 months 0.286 (0.135 ; 0.456) 0.682 (0.395 ; 0.854)6 months 0 107 (0.027 ; 0.251 ) 0 307 (0.098 ; 0.548)9 months 0.071 (0.013 ; 0.204) 0.307 (0.098 ; 0.548)12 months 0.036 (0.003 ; 0.154) 0.000 (0.098 ; 0.548)Number of participants at riskb3 months 8 106 months 3 49 months 2 112 months 1 0CI = Confidence Interval; PFS = Progression-Free Survival; NC = Not Calculated;aEstimated using a log-log transformation of the survival function and the method of Brookmeyer and Crowley;bComputed using the log-log transformation of the survival function and the methods of Brookmeyer and Crowley. Note: Percentages are calculated based on number of responders.

[0888] As shown in Table 13, a median Progression-Free Survival (PFS) of 4,73 months was observed in Cohort C, whereas the median PFS was of 1,87 in Cohort B. As a comparative, the median PFS is 3.8 months for the Standard of Care (nab-paclitaxel+gemcitabine).Example 3: Safety results

[0889] Table 14 below shows the safety profile relating to the monotherapy (Tusamitamab Ravtansine) and the combination therapy (Tusamitamab Ravtansine + Gemcitabine).Table 14.Anj? Grade 5 TEAE, n (%) 3 (11) 3 (19)Any TEAE leading to 7 (25) 1 (6.3) permanent full intervention discontinuation, n (%)Corneal CMQ TEAEs all 28.6 12.5 grades (%)Grade a 3, n (%) 1 (3.6) 1 (6.3)Peripherical neuropathy 11 37.5SMQ all grades (%)Grade a 3 (%) 0 0TEAE = Treatment Emergent Adverse Event

[0890] As shown in Table 14, the safety profile of the combination therapy is similar to the one of the Tusamitamab Ravtansine monotherapy.

[0891] Table 15 below shows the most frequent TEAEs observed in participants of Cohort C, which were treated with the combination therapy (Tusamitamab Ravtansine + Gemcitabine).Table 15.Tusa rav + gem(N=16)Krererrea lerm tr'i) ... . _ . _All grades Grade 23Peripheral neuropathy 3 (19) 0Vision blurred 3 (19) 0TEAE = Treatment Emergent Adverse Event; AE = Adverse Effect

Claims

CLAIMS1. An antibody-drug conjugate comprising an anti-CEACAM5 -antibody, or antigen binding fragment thereof, for use in combination with gemcitabine for treating a cancer in a subject in need thereof, wherein the cancer expresses CEACAM5.

2. The antibody-drug conjugate for the use of claim 1, wherein the anti-CEACAM5- antibody comprises a HCDR1 having the amino acid sequence of SEQ ID NO: 1, a HCDR2 having the amino acid sequence of SEQ ID NO: 2, a HCDR3 having the amino acid sequence of SEQ ID NO: 3, a LCDR1 having the amino acid sequence of SEQ ID NO: 4, a LCDR2 having the amino acid sequence NTR, and a LCDR3 having the amino acid sequence of SEQ ID NO: 5, optionally wherein the anti-CEACAM5 -antibody comprises a variable domain of a heavy chain (VH) consisting of the sequence of SEQ ID NO: 6 and a variable domain of a light chain (VL) consisting of the sequence of SEQ ID NO: 7.

3. The antibody-drug conjugate for the use of claim 1 or 2, wherein the anti-CEACAM5- antibody is tusamitamab.

4. The antibody-drug conjugate for the use of any of claims 1 to 3, wherein the antibodydrug conjugate comprises at least one cytotoxic agent and / or a cleavable linker.

5. The antibody-drug conjugate for the use of claim 4, wherein the at least one cytotoxic agent is selected from the group consisting of antimetabolite, DNA-alkylating agent, DNA- cross-linking agent, DNA-intercalating agent, anti-microtubule agent, topoisomerase inhibitor, and any combination thereof.

6. The antibody-drug conjugate for the use of claim 4 or 5, wherein the at least one cytotoxic agent is an anti-microtubule agent, optionally wherein said anti-microtubule agent is a maytansinoid,optionally wherein said maytansinoid is selected from the group consisting of -deacetyl- N2’-(3-mercapto-l-oxopropyl)-maytansine (DM1), N2’-deacetyl-N2’(4-methyl-4-mercapto- l-oxopentyl)-maytansine (DM4), and any combination thereof.

7. The antibody-drug conjugate for the use of any of claims 4 to 6, wherein the cleavable linker is selected from N-succinimidyl pyridyldithiobutyrate (SPDB) and 4-(Pyridin-2- yldisulfanyl)-2-sulfo-butyric acid (sulfo-SPDB).

8. The antibody-drug conjugate for the use of any of claims 1 to 7, wherein the antibodydrug conjugate is tusamitamab ravtansine.

9. The antibody-drug conjugate for the use of any of claims 1 to 8, wherein the cancer expresses CEACAM5 with moderate or high intensity defined by immunohistochemistry, optionally wherein the CEACAM5 expression is defined as a CEACAM5 immunohistochemistry (IHC) intensity of at least 2+ in at least 50% of tumor cells.

10. The antibody-drug conjugate for the use of any of claims 1 to 9, wherein the cancer is pancreatic cancer.

11. The antibody-drug conjugate for the use of any of claims 1 to 10, wherein the cancer is a metastatic cancer and / or wherein the cancer is pancreatic ductal adenocarcinoma.

12. The antibody-drug conjugate for the use of any of claims 1 to 11, wherein the antibodydrug conjugate is administered at a dose from 60 mg / m2to 210 mg / m2, optionally wherein the antibody-drug conjugate is administered at an initial dose from 100 mg / m2to 170 mg / m2and / or at a secondary dose from 80 mg / m2to 100 mg / m2.

13. The antibody-drug conjugate for the use of any of claims 1 to 12, wherein the antibodydrug conjugate is administered at an initial dose of 135 mg / m2, 150 mg / m2, or 170 mg / m2on day 1 of a first cycle and at a secondary dose of 80 mg / m2or 100 mg / m2thereafter,optionally wherein the antibody-drug conjugate is administered at secondary dose every 2 weeks.

14. The antibody-drug conjugate for the use of any of claims 1 to 13, wherein gemcitabine is administered at a dose from 600 mg / m2to 1000 mg / m2for at least one cycle, optionally wherein gemcitabine is administered on day 1, day 8, and day 15 of each cycle.

15. A pharmaceutical composition comprising the antibody-drug conjugate of any of claims 1 to 8 and gemcitabine, said pharmaceutical composition being optionally for use for treating a cancer, wherein the cancer expresses CEACAM5.

16. A kit comprising (i) the antibody-drug conjugate of any of claims 1 to 8 and (ii) gemcitabine, in separate formulations, said kit being optionally for use for treating a cancer, wherein the cancer expresses CEACAM5.

17. An antibody-drug conjugate comprising an anti-CEACAM5-antibody, or antigen binding fragment thereof, for use in combination with gemcitabine for treating a pancreatic ductal adenocarcinoma in a subject in need thereof, wherein the adenocarcinoma expresses CEACAM5.

18. An antibody-drug conjugate comprising an anti-CEACAM5-antibody, or antigen binding fragment thereof, for use in combination with gemcitabine for treating a cancer in a subject in need thereof, wherein the cancer expresses CEACAM5, and wherein the antibodydrug conjugate is tusamitamab ravtansine.

19. An antibody-drug conjugate comprising an anti-CEACAM5-antibody, or antigen binding fragment thereof, for use in combination with gemcitabine for treating a pancreatic ductal adenocarcinoma in a subject in need thereof, wherein the adenocarcinoma expresses CEACAM5, and wherein the antibody-drug conjugate is tusamitamab ravtansine.

20. The antibody-drug conjugate for the use of any of claims 17 to 19, wherein the antibodydrug conjugate is administered at an initial dose of 135 mg / m2or 170 mg / m2on day one of a first cycle and at a secondary dose of 80 mg / m2or 100 mg / m2thereafter, and wherein gemcitabine is administered at a dose from 600 mg / m2to 1000 mg / m2.

21. The antibody-drug conjugate for the use of any of claims 17 to 20, wherein the antibodydrug conjugate is administered for 1 to 12 cycles, on day 1 of each cycle, wherein a cycle is 2 weeks.

22. The antibody-drug conjugate for the use of any of claims 17 to 21, wherein gemcitabine is administered for 1 to 12 cycles, on day 1, day 8, and day 15 of each cycle, wherein a cycle is 4 weeks.

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