ANTIBODY-DRUG CONJUGATE AND ITS USES

Abstract

ANTIBODY-DRUG CONJUGATE AND USES THEREOF The present invention relates generally to the field of medicine. More particularly, it relates to novel antibody-drug conjugates and their uses. (No figure)

Description

Title of the invention: ANTIBODY-DRUG CONJUGATE AND ITS USES FIELD OF THE INVENTION

[0001] The present invention relates generally to the field of medicine. More particularly, it relates to novel antibody-drug conjugates and their uses. PRIOR ART

[0002] The receptors for the different endothelins (designated ET1, ET2 and ET3 in humans) belong to the family of receptors with 7 transmembrane domains, also known as GPCRs for "G Protein Coupled Receptors". In humans, endothelin receptors have two main subtypes: subtype A (ETA-R) and subtype B (ETB-R). The fact that these receptors are classified in the GPCR family gives them a complex three-dimensional structure.

[0003] The endothelin axis and its receptors are involved in several pathophysiological functions and dysfunctions. Non-limiting examples include high blood pressure, atherosclerosis, coronary artery disease, renal dysfunction, cerebrovascular disease, Crohn's disease, pulmonary fibrosis, asthma, etc. In addition, endothelin receptors have also been shown to be associated with the development of many cancers, by promoting the proliferation, survival and dissemination of cancer cells as well as angiogenesis.Regarding the endothelin receptor subtype B (ETB-R), the latter presents a modification of its expression level particularly in melanomas, colon cancer - pancreatic cancer - triple negative breast cancer (TNBC; triple negative breast cancer) - lung cancer - thyroid cancer, renal tumors and adrenal tumors such as pheochromocytoma and paragangliomas, Kaposi's sarcoma, glioblastomas (brain tumors), and cases of bladder cancer. It is also established that the endothelin receptor subtype B is involved in the failure of recognition of certain cancer cells, in particular ovarian cancer cells by the immune system, by inducing a strong reduction in lymphocytic infiltration. It is important to highlight the expression of ETB-R in pediatric tumors.In particular, the most common brain tumors in children can be cited, including embryonal tumors (e.g. medulloblastomas, rhabdoid and teratoid tumors) and glial tumors such as gliomas or ependydomas. More rarely, they can be . cited are malignant pituitary or pineal germ cell tumors, plexus tumors such as choroid plexus carcinomas. Finally, retinoblastomas, Ewing's sarcoma, osteosarcoma, neuroblastomas, rhabdomyosarcomas and nephroblastomas can also be cited.

[0004] ETB-R is also overexpressed in certain patient populations with monoclonal gammopathies associated with malignant hematological diseases, such as multiple myeloma, Waldenstrom's disease and B-cell lymphomas. It can also exist in various lymphomas, particularly salivary gland lymphomas and lymphatic gland lymphomas. It is also possible to find it in certain myelodysplasias.

[0005] Thus, targeting an ETB-R conformer expressed on the surface of cancer cells, particularly glioblastoma cells and adenocarcinomas, using an antibody-drug conjugate (ADC) appears particularly relevant in human clinical biology in terms of therapeutic tools by targeting these tumor cells. However, in the arsenal of passive immunotherapy for cancers using monoclonal antibodies, no ADC has been proven to date.

[0006] Furthermore, and while ADCs appear to be a promising therapeutic tool, some are very toxic, others have poor pharmacokinetics, still others have a limited therapeutic index reducing their clinical efficacy and a large proportion of them use conventional microtubule agents which are confronted with resistance mechanisms, especially in indications with little or no response to chemotherapy.

[0007] To fill this therapeutic gap and meet the needs of patients, the inventors therefore set themselves the goal of obtaining an optimized antibody-drug conjugate (antibody drug conjugate or ADC) capable of targeting conformers of the B subtype of the endothelin receptor expressed on the surface of cancer cells and causing their cell death. BRIEF OVERVIEW OF THE INVENTION

[0008] Faced with this major challenge of having safe and effective tools for fighting cancer, the inventors have developed new optimized antibody-drug conjugates (antibody drug conjugate or ADC). Also, a first aim of the invention is to provide a new ADC. A second aim of the invention is to propose this ADC for its use as a medicament, in particular in the prevention and / or treatment of a tumor. Another aim of the invention is to provide a pharmaceutical composition comprising the ADC of the invention as well as its use in the diagnosis, prevention and / or treatment of a tumor. DETAILED DESCRIPTION

[0009] In its most general aspect, the invention relates to an antibody-drug conjugate (ADC) comprising the formula (I):

[0010] Ac-[TC-B-(LM)-AS] (I),

[0011] in which: • Ac is an anti-ETB-R antibody, one of its fragments or one of its derivatives; • TC is a conjugation head chosen from: maleimide coupled to a glutamic acid (Mal-Glu), polyether, amino acids, benzyl group, amines, ketones and thioester linkers stabilized upon hydrolysis with haloacetamides, keto-sulfones, methylsulfonylphenyl-loxadiazole, carbonylacrylic; • B represents “PEG2-Glu-(Glu-Met)” and is absent or present; • L is a linker cleavable by lysosomal cathepsins, said cleavable linker being optionally coupled to p-aminobenzyl alcohol (PAB) or one of its derivatives; • M is a drug selected from: topoisomerase inhibitors, alkylating agents, antimicrotubule agents and their prodrug forms; and • AS is a solubilizing agent chosen from: polysarcosine (PSAR) and polyethylene glycol (PEG),

[0012] and wherein the drug-antibody ratio (DAR) is from 2 to 16 and said anti-ETB-R comprises: • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of QXi IVHSNGX2TY (SEQ ID NO: 1) where Xi represents S or N and X2 represents N or Y, • CDR2 whose amino acid sequence includes or consists of KVX3 where X3 represents S or F, and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPX4X5 (SEQ ID NO: 2) where X4 represents W or L, and X5 represents T or no amino acid, and

[0013] a heavy chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of IDPNSGGTKYNEKFKS (SEQ ID NO: 4) or DPNSGGT (SEQ ID NO: 5), and • CDR3 whose amino acid sequence comprises or consists of ARE-GEFAWFAY (SEQ ID NO: 6) or VREGWDAWFVY (SEQ ID NO: 7); or • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of KSSQSLLDSDGKTYLN (SEQ ID NO: 8), • CDR2 whose amino acid sequence comprises or consists of LVSKLDS (SEQ ID NO: 9), and • CDR3 whose amino acid sequence comprises or consists of WQGTHFPYT (SEQ ID NO: 10), and

[0014] a heavy chain comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYWMQ (SEQ ID NO: 11), • CDR2 whose amino acid sequence comprises or consists of TIYPGDGDTSYAQKFKG (SEQ ID NO: 12), and • CDR3 whose amino acid sequence comprises or consists of WGYAYDIDN (SEQ ID NO: 13).

[0015] Unexpectedly, the inventors determined that a synergy occurs between the different constituents of the antibody-drug conjugate of the invention, which promotes better bioavailability of the latter and increased stability thereof. This is reflected in particular by a significant reduction in the unwanted release of the drug in a healthy (i.e. non-tumor) environment, thus avoiding undesirable effects. Surprisingly, the inventors also demonstrated that the concentration of the antibody-drug conjugate of the invention in tumors was well above that which was predictable. The inventors, by developing the antibody-drug conjugate as described above, have therefore provided the medical profession with a new, innovative therapeutic tool for fighting cancer that is safe and effective.

[0016] According to another embodiment, the subject of the invention is the antibody-drug conjugate (ADC) as described above comprising the formula (II):

[0017] Ac-[TC-(LM)-AS] (II),

[0018] in which: • Ac is an anti-ETB-R antibody, one of its fragments or one of its derivatives; • TC is a conjugation head chosen from: maleimide coupled to a glutamic acid (Mal-Glu), polyether, amino acids, benzyl group, amines, ketones and thioester linkers stabilized upon hydrolysis with haloacetamides, keto-sulfones, methylsulfonylphenyl-loxadiazole, carbonylacrylic; • L is a linker cleavable by lysosomal cathepsins, said cleavable linker being optionally coupled to p-aminobenzyl alcohol (PAB) or one of its derivatives; • M is a drug selected from: topoisomerase inhibitors, alkylating agents, antimicrotubule agents and their prodrug forms; and • AS is a solubilizing agent chosen from: polysarcosine (PSAR) and polyethylene glycol (PEG),

[0019] and wherein the drug-antibody ratio (DAR) is from 2 to 16 and said anti-ETB-R comprises: • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of QXi IVHSNGX2TY (SEQ ID NO: 1) where Xi represents S or N and X2 represents N or Y, • CDR2 whose amino acid sequence includes or consists of KVX3 where X3 represents S or F, and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPX4X5 (SEQ ID NO: 2) where X4 represents W or L, and X5 represents T or no amino acid, and

[0020] a heavy chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of IDPNSGGTKYNEKFKS (SEQ ID NO: 4) or DPNSGGT (SEQ ID NO: 5), and • CDR3 whose amino acid sequence comprises or consists of ARE-GEFAWFAY (SEQ ID NO: 6) or VREGWDAWFVY (SEQ ID NO: 7); or • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of KSSQSLLDSDGKTYLN (SEQ ID NO: 8), • CDR2 whose amino acid sequence comprises or consists of LVSKLDS (SEQ ID NO: 9), and • CDR3 whose amino acid sequence comprises or consists of WQGTHFPYT (SEQ ID NO: 10), and

[0021] a heavy chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYWMQ (SEQ ID NO: 11), • CDR2 whose amino acid sequence comprises or consists of TIYPGDGDTSYAQKFKG (SEQ ID NO: 12), and • CDR3 whose amino acid sequence comprises or consists of WGYAYDIDN (SEQ ID NO: 13).

[0022] By "medicine (M)" is meant any substance or composition presented as having curative or preventive properties with regard to human or animal diseases. In the invention, this is chosen from: topoisomerase inhibitors, alkylating agents, antimicrotubule agents and their prodrug forms. In the family of topoisomerase I inhibitors, mention may be made of irinotecan, topotecan, camptothecin, SN38, exatecan, silatecan, cositycan, lurtotecan, gimatecan, bleotecan and rubitecan. In the family of alkylating agents, mention may be made of dacarbazine. In the family of antimicrotubule agents, mention may be made of the family of taxanes including in particular paclitaxel. As mentioned above, this drug may be in a prodrug form, i.e. an inactive form which, after administration, is converted by the body into a pharmacologically active drug.In the invention, the drug is in particular exatecan and its prodrug forms, among which may be cited salts, esters, ethers, glucuronides, galactamines, cyclodextrins and amides of exatecan. Among its prodrug forms of Exatecan, Dxd (Exatecan derivative) is one of the best known.

[0023] According to another embodiment, the invention therefore relates to the antibody-drug conjugate as described above, in which M is a drug chosen from: exatecan and its prodrug forms (eg Dxd). In particular, the invention relates to the antibody-drug conjugate as described above in which M is exatecan.

[0024] By "antibody (Ab)" is meant an immunoglobulin, which is a glycoprotein comprising at least two heavy (H) chains and at least two light (L) chains linked together by one or more disulfide bridges. Each heavy chain comprises a variable (VH) region (or domain) and a constant region comprising 3 domains, usually designated CH1, CH2 and CH3. Each light chain comprises a variable (VL) region (or domain) and a constant region comprising a single domain, usually designated CL. The variable regions of the heavy and light chains involved in antigen recognition can be further subdivided into 3 hypervariable regions, also called "complementarity determining regions" (CDR), flanked by 4 more conserved regions, also called framework regions (FR).The organization of each heavy chain (or light chain) variable region is, from the N-terminus to the C-terminus, as follows: FRI, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The three-dimensional folding of these variable regions is such that all 6 CDRs are exposed on the same side of the protein and allow the formation of a structure. specific recognizing a specific antigen. Furthermore, the term "antibody" includes, within the scope of the present invention, not only complete antibody molecules but also fragments and derivatives thereof. By "antibody fragment" is meant, within the scope of the present invention, both a monovalent fragment which has a single antigen-binding site and a divalent fragment which has two antigen-combining sites. Thus, a fragment according to the invention has at least one antigen-binding site. Among these fragments, mention may be made of the Fab, F(ab')2, Fv fragments, and other fragments which retain the antigen-binding site (scFv and diabody). A Fab fragment is a monovalent fragment consisting of the entire light chain and a portion of the heavy chain (Fd) comprising the VH and CH1 domains as previously defined.An F(ab')2 fragment is a divalent fragment corresponding to the association of two Fab fragments linked by the disulfide bridges present at the hinge region of immunoglobulins ("Hinge") located between the constant domains CH1 and CH2. An Fv fragment is a monovalent fragment consisting only of the variable regions VL and VH of the light and heavy chains of an antibody. An scFv fragment is a monovalent polypeptide fragment, obtained only by genetic engineering, corresponding to the variable domains linked by a peptide bond. A diabody is a recombinant and divalent antibody molecule consisting of two scFv molecules head to tail due to a peptide bond too short to allow the formation of an scFv.The fragments according to the invention also cover the fragments as previously mentioned whose half-life has been increased by chemical modification, in particular by incorporation into a liposome or by introduction of a poly(alkylene) glycol such as a poly(ethylene) glycol (PEG), this technique being called "PEGylation" and giving fragments such as Fab-PEG, F(ab')2-PEG or Fv-PEG. By recombinant route, it is also possible to generate single or fused fragments of the antibody according to the present invention, having more effective and better controlled solid tumor penetrability and pharmacokinetic properties. The antibody fragments useful in the context of the present invention may be natural or recombinant. By "antibody derivative", is meant, in the context of the present invention, antibody fragments obtained by genetic engineering such as single-chain Fv molecules (scFv) and single-domain antibodies (dAb).The term also includes antibody-like molecules that can be produced using phage display or other random selection techniques and humanized mice such as Harbour Mice® technology. Thus, "antibody fragments" and "antibody derivatives" cover all molecules that contain a structure, preferably a peptide, that is part of the recognition site (i.e., the part of the antibody that binds to or combines with the epitope or . the antigen) of an antibody according to the present invention. In particular and according to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R fragment is chosen from the group of fragments consisting of: Fv, Fab, F(ab')2, Fab', dsFv, scFv, sc(Fv)2, "diabodies".

[0025] As mentioned above, the invention implements an antibody, a fragment thereof or a derivative thereof, capable of recognizing the endothelin receptor of subtype B (ETB-R; SEQ ID NO: 59). Among them, the following antibodies may be cited: SKM101, SKM103, SKM104, SKM106 and SKM107 (or optimized versions thereof); the sequences of which are summarized in Table 1 below.

[0026] [Tables 1] Anti-ETB-R (SEQ ID NOs) SKM 101 SKM 103 SKM 104 SKM 106 SKM 107 Light chain CDR1 (aa) 14 8 8 14 17 CDR2 (aa) KVS 9 9 KVF KVS CDR3 (aa) 15 10 10 16 18 Variable region (aa) 19 27 35 43 51 Complete (aa) 20 28 36 44 52 Complete (nt) 21 29 37 45 53 Heavy chain CDR1 (aa) 3 11 11 3 3 CDR2 (aa) 4 12 12 5 5 CDR3 (aa) 6 13 13 7 6 Variable region (aa) 22 30 38 46 54 Complete (aa) 23 31 39 47 55 Complete (nt) 24 32 40 48 56 Complete LALA (aa) 25 33 41 49 57 Complete LALA (nt) 26 34 42 50 58

[0027] Table 1. Anti-ETB-R & corresponding sequences.

[0028] aa: amino acid; nt: nucleotide.

[0029] By "antibody drug conjugate (ADC)" is meant complex molecules composed of an antibody linked to a biologically active payload or cytotoxic (anticancer) drug. Antibody drug conjugates are examples of bioconjugates and immunoconjugates, and are a class of biopharmaceutical drugs designed in particular for targeted therapy for the prevention and / or treatment of cancers. Unlike chemotherapy, ADCs are designed to target and kill tumor cells while sparing healthy cells. Indeed, ADCs combine the targeting capabilities of monoclonal antibodies and the cancer-killing capacity of cytotoxic drugs, and thus be designed to distinguish between healthy and diseased tissues.

[0030] To achieve the antibody-drug conjugate, different molecules are used to make the covalent link between the antibody on the one hand and the drug on the other hand. Among these molecules we find: the bioconjugation head (also called spacer or connectors), a linker (which can be coupled to the leaving group p-aminobenzyl alcohol (PAB) or one of its derivatives) and a solubilizing agent.

[0031] By "bioconjugation head", reference is made to maleimide coupled to a glutamic acid (Mal-Glu), to the polyether, to the amino acids, to the benzyl group, to the amines, to the ketones and to the thioester linkers stabilized to hydrolysis with haloacetamides, ketosulfones, methylsulfonylphenyloxadiazole, carbonylacrylic. In particular, reference is made to maleimide coupled to a glutamic acid (Mal-Glu), to the polyether, to the amino acids, to the benzyl group, to the amines and to the ketones. Advantageously, it is maleimide coupled to a glutamic acid (Mal-Glu). According to another embodiment, the invention therefore relates to the antibody-drug conjugate as described above, in which TC is a conjugation head chosen from: maleimide coupled to a glutamic acid (Mal-Glu), polyether, amino acids, the benzyl group, amines and ketones.In particular, the invention relates to the antibody-drug conjugate as described above, in which TC is a maleimide conjugation head coupled to a glutamic acid.

[0032] By "linker (L)" is meant in the invention a short assembly of amino acids cleavable by lysosomal cathepsins chosen from: the dipeptide Val-Cit, the dipeptide Phe-Lys, the dipeptide Val-Ala, the tripeptide Ala-Ala-Asn and the quadripeptide Gly-Gly-Phe-Gly, each of these linkers being optionally coupled to p-aminobenzyl alcohol (PAB) or one of its derivatives. In particular, these are the dipeptides Phe-Lys and Val-Ala, which are advantageously coupled to PAB to form the linkers Phe-Lys-PAB and Val-Ala-PAB. According to another embodiment, the invention therefore has the following characteristics: object the antibody-drug conjugate as described above, in which L is a linker, in particular coupled to p-aminobenzyl alcohol (PAB), chosen from: the dipeptide Phe-Lys and the dipeptide Val-Ala. In particular, the subject of the invention is the antibody-drug conjugate as described above, in which L is a linker coupled to p-aminobenzyl alcohol (PAB) chosen from: Phe-Lys-PAB and Val-Ala-PAB.

[0033] Note that between the bioconjugation head and the linker, an element B representing “PEG2-Glu-(Glu-Met)” can be added. Element B can therefore be absent or present in the ADC of the invention.

[0034] By “solubilizing agent (SA)” is meant in the invention either polysarcosine (PSAR) or polyethylene glycol (PEG).

[0035] Concerning the PSAR, this can be a monomer or a polymer whose number of PSARs varies from 2 to 40, in particular from 8 to 24 and advantageously be 10 or 16. The polymer can nevertheless comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 PSARs. According to another embodiment, the subject of the invention is therefore the antibody-drug conjugate as described above, in which AS is polysarcosine (PSAR) either in the form of a monomer or in the form of a polymer whose PSAR number varies from 2 to 40. In particular, the subject of the invention is the antibody-drug conjugate as described above, in which AS is polysarcosine (PSAR) in the form of a polymer whose PSAR number is 10.

[0036] Concerning the PEG, this can be a monomer or a bi-branched, tri-branched, cyclic or linear polymer whose number of PEGs varies from 2 to 40, in particular from 8 to 24 and advantageously be 10 or 16. The polymer can nevertheless comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39 or 40 PEGs. According to another embodiment, the subject of the invention is therefore the antibody-drug conjugate as described above, in which AS is polyethylene glycol (PEG) either in the form of a monomer or in the form of a bi-branched, tri-branched, cyclic or linear polymer whose number of PEGs varies from 2 to 40. In particular, the subject of the invention is the antibody-drug conjugate as described above, in which AS is polyethylene glycol (PEG) in the form of a bi-branched polymer whose number of PEGs is 10 or 16.

[0037] “Drug-antibody ratio (DAR)” refers to the average number of drugs conjugated to antibodies. In the invention, this is from 2 to 16 and is in particular from 2, 4 or 8 to 16, and is advantageously 8. In other words, the drug-antibody ratio (DAR) may be in the invention 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.

[0038] In view of the above, it is therefore understood that according to another embodiment, the subject of the invention is therefore the antibody-drug conjugate as described above, said antibody-drug conjugate comprising the formula (III):

[0039] Ac-[Mal-Glu-B-(LM)-AS] (III),

[0040] in which: • Ac is an anti-ETB-R antibody, one of its fragments or one of its derivatives; • Mal-Glu is a maleimide conjugation head coupled to a glutamic acid; • B represents “PEG2-Glu-(Glu-Met)” and is absent or present; • L is a linker cleavable by lysosomal cathepsins, said cleavable linker being chosen from: the dipeptide Val-Cit, the dipeptide Phe-Lys, the dipeptide Val-Ala, the tripeptide Ala-Ala-Asn and the quadripeptide Gly-Gly-Phe-Gly, each of these linkers being optionally coupled to p-aminobenzyl alcohol (PAB) or one of its derivatives; • M is a drug selected from: irinotecan, topotecan, camptothecin, SN38, exatecan, silatecan, cositycan, lurtotecan, gimatecan, bleotecan, rubitecan, dacarbazine, paclitaxel and their prodrug forms; and • AS is a solubilizing agent chosen from: polysarcosine (PSAR) and polyethylene glycol (PEG),

[0041] and in which the drug-antibody ratio (DAR) is comprised from 2 to 16 and said anti-ETB-R comprises: • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of QXi IVHSNGX2TY (SEQ ID NO: 1) where Xi represents S or N and X2 represents N or Y, • CDR2 whose amino acid sequence includes or consists of KVX3 where X3 represents S or F, and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPX4X5 (SEQ ID NO: 2) where X4 represents W or L, and X5 represents T or no amino acid, and

[0042] a heavy chain comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of IDPNSGGTKYNEKFKS (SEQ ID NO: 4) or DPNSGGT (SEQ ID NO: 5), And • CDR3 whose amino acid sequence comprises or consists of ARE-GEFAWFAY (SEQ ID NO: 6) or VREGWDAWFVY (SEQ ID NO: 7); or • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of KSSQSLLDSDGKTYLN (SEQ ID NO: 8), • CDR2 whose amino acid sequence comprises or consists of LVSKLDS (SEQ ID NO: 9), and • CDR3 whose amino acid sequence comprises or consists of WQGTHFPYT (SEQ ID NO: 10), and

[0043] a heavy chain comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYWMQ (SEQ ID NO: 11), • CDR2 whose amino acid sequence comprises or consists of TIYPGDGDTSYAQKFKG (SEQ ID NO: 12), and • CDR3 whose amino acid sequence comprises or consists of WGYAYDIDN (SEQ ID NO: 13).

[0044] It is also understood that according to another embodiment, the subject of the invention is therefore the antibody-drug conjugate as described above, said antibody-drug conjugate comprising the formula (IV):

[0045] Ac-[Mal-Glu-(LM)-AS] (IV),

[0046] in which: • Ac is an anti-ETB-R antibody, one of its fragments or one of its derivatives; • Mal-Glu is a maleimide conjugation head coupled to a glutamic acid; • L is a linker cleavable by lysosomal cathepsins, said cleavable linker being chosen from: the dipeptide Val-Cit, the dipeptide Phe-Lys, the dipeptide Val-Ala, the tripeptide Ala-Ala-Asn and the quadripeptide Gly-Gly-Phe-Gly, each of these linkers being optionally coupled to p-aminobenzyl alcohol (PAB) or one of its derivatives; • M is a drug selected from: irinotecan, topotecan, camptothecin, SN38, exatecan, silatecan, cositycan, lurtotecan, gimatecan, bleotecan, rubitecan, dacarbazine, paclitaxel and their prodrug forms; and • AS is a solubilizing agent chosen from: polysarcosine (PSAR) and polyethylene glycol (PEG),

[0047] and in which the drug-antibody ratio (DAR) is comprised from 2 to 16 and said anti-ETB-R comprises: • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of QXi IVHSNGX2TY (SEQ ID NO: 1) where Xi represents S or N and X2 represents N or Y, • CDR2 whose amino acid sequence includes or consists of KVX3 where X3 represents S or F, and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPX4X5 (SEQ ID NO: 2) where X4 represents W or L, and X5 represents T or no amino acid, and

[0048] a heavy chain comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of IDPNSGGTKYNEKFKS (SEQ ID NO: 4) or DPNSGGT (SEQ ID NO: 5), and • CDR3 whose amino acid sequence comprises or consists of ARE-GEFAWFAY (SEQ ID NO: 6) or VREGWDAWFVY (SEQ ID NO: 7); or • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of KSSQSLLDSDGKTYLN (SEQ ID NO: 8), • CDR2 whose amino acid sequence comprises or consists of LVSKLDS (SEQ ID NO: 9), and • CDR3 whose amino acid sequence comprises or consists of WQGTHFPYT (SEQ ID NO: 10), and

[0049] a heavy chain comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYWMQ (SEQ ID NO: 11), • CDR2 whose amino acid sequence comprises or consists of TIYPGDGDTSYAQKFKG (SEQ ID NO: 12), and • CDR3 whose amino acid sequence comprises or consists of WGYAYDIDN (SEQ ID NO: 13).

[0050] According to another embodiment, the subject of the invention is therefore the antibody-drug conjugate as described above, in which L is a linker, in particular coupled to p-aminobenzyl alcohol (PAB) or one of its derivatives, chosen from: the dipeptide Phe-Lys and the dipeptide Val-Ala. In particular, the subject of the invention is the antibody-drug conjugate as described above, wherein L is a linker coupled to p-aminobenzyl alcohol (PAB) selected from: Phe-Lys-PAB and Val-Ala-PAB.

[0051] According to another embodiment, the invention therefore relates to the antibody-drug conjugate as described above, in which M is a drug chosen from: exatecan, dacarbazine, paclitaxel and their prodrug forms. In particular, the invention relates to the antibody-drug conjugate as described above, in which M is exatecan and its prodrug forms.

[0052] According to another embodiment, the subject of the invention is therefore the antibody-drug conjugate as described above, in which AS is polysarcosine (PSAR), said PSAR being in particular a monomer or a polymer whose number of PSARs varies from 2 to 40 (advantageously is 10). According to another embodiment, the subject of the invention is therefore the antibody-drug conjugate as described above, in which AS is polyethylene glycol (PEG), said PEG being in particular a bi-branched, tri-branched, cyclic or linear monomer or polymer whose number of PEGs varies from 2 to 40 (advantageously is 10 or 16).

[0053] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which the anti-ETB-R, one of its fragments or one of its derivatives, is linked to Mal-Glu-(Phe-Lys-PAB-M)-PEGio of formula (V):

[0054] [Chem.l] (V)

[0055] or Mal-Glu-(Val-Ala-PAB-M)-PEG10 of formula (VI):

[0056] [Chem.2] o-O' "OH (VI).

[0057] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which the anti-ETB-R, one of its fragments or one of its derivatives, is linked to Mal-Glu-(Phe-Lys-PAB-M)-PEGi6 of formula (VII):

[0058] [Chem.3] (VII)

[0059] or Mal-Glu-(Val-Ala-PAB-M)-PEG16 of formula (VIII):

[0060] [Chem.4] (VIII).

[0061] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which the anti-ETB-R, one of its fragments or one of its derivatives, is linked to Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-M)-PSARi0 of formula (IX):

[0062] [Chem.5] (IX).

[0063] According to another embodiment, the invention relates to the antibody-drug conjugate as described above, in which the anti-ETB-R, one of its fragments or one of its derivatives, is linked to Mal-Glu-(Phe-Lys-PAB-M)-PSARn or to Mal-Glu-(Val-Ala-PAB-M)-PSARn where n varies from 1 to 40.

[0064] In view of the above, it is understood that according to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which the anti-ETB-R, one of its fragments or one of its derivatives, is linked to: • Mal-Glu-(Phe-Lys-PAB-M)-PEGio of formula (V); • Mal-Glu-(Val-Ala-PAB-M)-PEG10 of formula (VI); • Mal-Glu-(Phe-Lys-PAB-M)-PEG16 of formula (VII); • Mal-Glu-(Val-Ala-PAB-M)-PEG16 of formula (VIII); • Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-M)-PSAR10 of formula (IX); • Mal-Glu-(Phe-Lys-PAB-M)-PSARn where n varies from 1 to 40; or • Mal-Glu-(Val-Ala-PAB-M)-PSARn where n varies from 1 to 40.

[0065] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which M is a drug chosen from: exatecan and its prodrug forms (eg salts, esters, ethers, glucuronides, galactamines, cyclodextrins and amides of exatecan). In particular, the subject of the invention is the antibody-drug conjugate as described above, in which M is a drug chosen from: exatecan and Dxd (Exatecan derivative). Advantageously, the subject of the invention is the antibody-drug conjugate as described above, in which M is exatecan.

[0066] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R, one of its fragments or one of its derivatives, is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi0 of formula (X):

[0067] [Chem. 6] Û'" XÔH

[0068]

[0069] (X) or Mal-Glu-(Val-Ala-PAB-exatecan)-PEGio of formula (XI): [Chem. 7] ^o. ,-XO --- --- OH ^0-4^ 'O

[0070]

[0071]

[0072] (XI), exatecan may be in a prodrug form. According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R, one of its fragments or one of its derivatives, is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XII): [Chem. 8] (XII)

[0073]

[0074] or Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XIII): [Chem.9]

[0075]

[0076]

[0077] (XIII), exatecan may be in a prodrug form. According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which the anti-ETB-R, one of its fragments or one of its derivatives, is linked to Mal-Glu-PEG2 -Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSARio of formula (XIV): [Chem. 10]

[0078]

[0079]

[0080] (XIV), exatecan may be in a prodrug form. According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which the anti-ETB-R, one of its fragments or one of its derivatives, is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PSARn or to Mal-Glu-(Val-Ala-PAB-exatecan)-PSARn where n varies from 1 to 40, the exatecan possibly being in a prodrug form. In view of the above, it is understood that according to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which the anti-ETB-R, one of its fragments or one of its derivatives, is linked to: • Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGio of formula (X); • Mal-Glu-(Val-Ala-PAB-exatecan)-PEGio of formula (XI); • Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XII); • Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XIII); • Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSARio formula (XIV); • Mal-Glu-(Phe-Lys-PAB-exatecan)-PSARn where n varies from 1 to 40; or • Mal-Glu-(Val-Ala-PAB-exatecan)-PSARn where n varies from 1 to 40,

[0081] exatecan may be in a prodrug form. In particular, the subject of the invention is the antibody-drug conjugate as described above, in which the anti-ETB-R, one of its fragments or one of its derivatives, is linked to: • Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGio of formula (X); • Mal-Glu-(Val-Ala-PAB-exatecan)-PEGio of formula (XI); • Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XII); • Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XIII); • Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSARio formula (XIV); • Mal-Glu-(Phe-Lys-PAB-exatecan)-PSARn where n varies from 1 to 40; or • Mal-Glu-(Val-Ala-PAB-exatecan)-PSARn where n varies from 1 to 40.

[0082] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R, one of its fragments or one of its derivatives, is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XII):

[0083] [Chem. 11] C £ (XII).

[0084] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R, one of its fragments or one of its derivatives, is linked to Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XIII):

[0085] [Chem. 12] (XIII).

[0086]

[0087]

[0088] According to another embodiment, the invention relates to the antibody-drug conjugate as described above, in which the drug-antibody ratio (DAR) is from 4 to 16 or from 8 to 16, and is in particular 2, 4 or 8 or 16. According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R comprises: • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of QSIVHSNGNTY (SEQ ID NO: 14), • CDR2 whose amino acid sequence comprises or consists of KVS (corresponding to amino acids 55 to 57 of the sequence SEQ ID NO: 19), and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPWT (SEQ ID NO: 15), and a heavy chain comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of IDPNSGGTKYNEKFKS (SEQ ID NO: 4), and • CDR3 whose amino acid sequence comprises or consists of ARE-GEFAWFAY (SEQ ID NO: 6); or • a light chain comprising from the N-terminus to the C-terminus • CDR1 whose amino acid sequence comprises or consists of QSIVHSNGNTY (SEQ ID NO: 14), • CDR2 whose amino acid sequence includes or consists of KVF (corresponding to amino acids 54 to 56 of the sequence SEQ ID NO: 43), and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPLT (SEQ ID NO: 16), and

[0089] a heavy chain comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of DPDSGGT (SEQ ID NO: 5), and • CDR3 whose amino acid sequence comprises or consists of VREGWDAWFVY (SEQ ID NO: 7); or • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of QNIVHSNGYTY (SEQ ID NO: 17), • CDR2 whose amino acid sequence comprises or consists of KVS (corresponding to amino acids 55 to 57 of the sequence SEQ ID NO: 51), and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPL (SEQ ID NO: 18), and

[0090] a heavy chain comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of DPDSGGT (SEQ ID NO: 5), and • CDR3 whose amino acid sequence comprises or consists of ARE-GEFAWFAY (SEQ ID NO: 6).

[0091] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R comprises a light chain comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of KSS-QSLLDSDGKTYLN (SEQ ID NO: 8), • CDR2 whose amino acid sequence comprises or consists of LVSKLDS (SEQ ID NO: 9), and • CDR3 whose amino acid sequence comprises or consists of WQGTHFPYT (SEQ ID NO: 10), and

[0092] a heavy chain comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYWMQ (SEQ ID NO: 11), • CDR2 whose amino acid sequence comprises or consists of TIYPGDGDTSYAQKFKG (SEQ ID NO: 12), and • CDR3 whose amino acid sequence comprises or consists of WGYAYDIDN (SEQ ID NO: 13).

[0093] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R comprises: • a light chain comprising a variable region having at least 80% identity with the sequence SEQ ID NO: 19, said variable region comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of QSIVHSNGNTY (SEQ ID NO: 14), • CDR2 whose amino acid sequence comprises or consists of KVS (corresponding to amino acids 55 to 57 of the sequence SEQ ID NO: 19), and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPWT (SEQ ID NO: 15), and

[0094] a heavy chain comprising a variable region having at least 80% identity with the sequence SEQ ID NO: 22, said variable region comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of IDPNSGGTKYNEKFKS (SEQ ID NO: 4), and • CDR3 whose amino acid sequence comprises or consists of ARE-GEFAWFAY (SEQ ID NO: 6); or • a light chain comprising a variable region having at least 80% identity with the sequence SEQ ID NO: 43, said variable region comprising from the N-terminal end to the C-terminal end • CDR1 whose amino acid sequence comprises or consists of QSIVHSNGNTY (SEQ ID NO: 14), • CDR2 whose amino acid sequence comprises or consists of KVF (corresponding to amino acids 54 to 56 of the sequence SEQ ID NO: 43), and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPLT (SEQ ID NO: 16), and

[0095] a heavy chain comprising a variable region having at least 80% identity with the sequence SEQ ID NO: 46, said variable region comprising from the N- end terminal to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of DPDSGGT (SEQ ID NO: 5), and • CDR3 whose amino acid sequence comprises or consists of VREGWDAWFVY (SEQ ID NO: 7); or • a light chain comprising a variable region having at least 80% identity with the sequence SEQ ID NO: 51, said variable region comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of QNIVHSNGYTY (SEQ ID NO: 17), • CDR2 whose amino acid sequence comprises or consists of KVS (corresponding to amino acids 55 to 57 of the sequence SEQ ID NO: 51), and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPL (SEQ ID NO: 18), and

[0096] a heavy chain comprising a variable region having at least 80% identity with the sequence SEQ ID NO: 54, said variable region comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of DPDSGGT (SEQ ID NO: 5), and • CDR3 whose amino acid sequence comprises or consists of ARE-GEFAWFAY (SEQ ID NO: 6); or • a light chain comprising a variable region having at least 80% identity with the sequence SEQ ID NO: 27, said variable region comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of KSSQSLLDSDGKTYLN (SEQ ID NO: 8), • CDR2 whose amino acid sequence comprises or consists of LVSKLDS (SEQ ID NO: 9), and • CDR3 whose amino acid sequence comprises or consists of WQGTHFPYT (SEQ ID NO: 10), and

[0097] a heavy chain comprising a variable region having at least 80% identity with the sequence SEQ ID NO: 30, said variable region comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYWMQ (SEQ ID NO: 11), • CDR2 whose amino acid sequence comprises or consists of TIYPGDGDTSYAQKFKG (SEQ ID NO: 12), and • CDR3 whose amino acid sequence comprises or consists of WGYAYDIDN (SEQ ID NO: 13); or • a light chain comprising a variable region having at least 80% identity with the sequence SEQ ID NO: 35, said variable region comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of KSSQSLLDSDGKTYLN (SEQ ID NO: 8), • CDR2 whose amino acid sequence comprises or consists of LVSKLDS (SEQ ID NO: 9), and • CDR3 whose amino acid sequence comprises or consists of WQGTHFPYT (SEQ ID NO: 10), and

[0098] a heavy chain comprising a variable region having at least 80% identity with the sequence SEQ ID NO: 38, said variable region comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYWMQ (SEQ ID NO: 11), • CDR2 whose amino acid sequence comprises or consists of TIYPGDGDTSYAQKFKG (SEQ ID NO: 12), and • CDR3 whose amino acid sequence comprises or consists of WGYAYDIDN (SEQ ID NO: 13).

[0099] By "% identity" is meant the percentage determined by direct comparison of two oligonucleotide sequences (nucleic acid sequence), determining the number of identical nucleotides between the two sequences, then dividing it by the number of nucleotides in the longer sequence of the two, and multiplying the result by 100. By "having at least 80% identity" is therefore meant that the aforementioned percentage identity is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or is 100%.In this regard, it should be noted that this definition applies to all embodiments of the invention including when it is a direct comparison of two polypeptide sequences (amino acid sequence). Furthermore, it is understood that sequences having at least 80% identity with a reference sequence. retain the same properties and functions, or even improve them.

[0100] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R comprises: • a light chain comprising a variable region of sequence SEQ ID NO: 19 and a heavy chain comprising a variable region of sequence SEQ ID NO: 22; or • a light chain comprising a variable region of sequence SEQ ID NO: 43 and a heavy chain comprising a variable region of sequence SEQ ID NO: 46; or • a light chain comprising a variable region of sequence SEQ ID NO: 51 and a heavy chain comprising a variable region of sequence SEQ ID NO: 54; or • a light chain comprising a variable region of sequence SEQ ID NO: 27 and a heavy chain comprising a variable region of sequence SEQ ID NO: 30; or • a light chain comprising a variable region of sequence SEQ ID NO: 35 and a heavy chain comprising a variable region of sequence SEQ ID NO: 38.

[0101] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R comprises a heavy chain comprising the mutations chosen from: • L234A / L235A (LALA); • L234F / L235E / P331S (FES); • L234F / L235Q / K322Q (FQQ); • A330S / P331S; • L234A / L235A / P329G (LALAPG); • L234A / G237A; • L234A / L235A / G237A; • L234A / L235A / G237A / P238S / H268A / A330S / P330S; • L234A / L235E; • G236R / L328R; and • L234A / L235A / K322A.

[0102] Advantageously, it should be noted that the introduction of these mutations renders the antibody-drug conjugate as described above silent and reduces non-specific binding to immune cells. The ADCC effector functions of the antibody are thus inhibited, which prevents non-specific degradation and release of the payloads after, for example, phagocytosis by macrophages.

[0103] According to another embodiment, the invention advantageously relates to the antibody-drug conjugate as described above, in which said anti-ETB-R comprises a heavy chain comprising an LALA mutation. By "LALA mutation", reference is made to the Leucine (L), Alanine (A) substitutions in the following positions: L234A / L235A (LALA). These substitutions reduce binding to the Fc receptors FcyRI, FcyRII and FcyRIII as well as to the complement Clq. This mutation is used in order to avoid activation of the Fc receptors. Moreover, many therapeutic antibodies using LALA mutations have been the subject of clinical trials (e.g. bimagrumab NCT01925209, cemiplimab NCT02383212, galcanezumab NCT03559257, progolimab NCT03912389, risankizumab NCT02684370, spesolimab NCT03482635, teplizumab NCT00385697).

[0104] According to another embodiment, the invention therefore relates to the antibody-drug conjugate as described above, in which said anti-ETB-R comprises: • a light chain comprising a variable region of sequence SEQ ID NO: 19 and a heavy chain comprising a variable region of sequence SEQ ID NO: 22, said heavy chain comprising in particular an LALA mutation; or • a light chain comprising a variable region of sequence SEQ ID NO: 43 and a heavy chain comprising a variable region of sequence SEQ ID NO: 46, said heavy chain comprising in particular an LALA mutation; or • a light chain comprising a variable region of sequence SEQ ID NO: 51 and a heavy chain comprising a variable region of sequence SEQ ID NO: 54, said heavy chain comprising in particular an LALA mutation; or • a light chain comprising a variable region of sequence SEQ ID NO: 27 and a heavy chain comprising a variable region of sequence SEQ ID NO: 30, said heavy chain comprising in particular an LALA mutation; or • a light chain comprising a variable region of sequence SEQ ID NO: 35 and a heavy chain comprising a variable region of sequence SEQ ID NO: 38, said heavy chain comprising in particular an LALA mutation.

[0105] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R comprises: • a light chain having at least 80% identity with the sequence SEQ ID NO: 20, said light chain comprising a variable region of sequence SEQ ID NO: 19, and

[0106] a heavy chain having at least 80% identity with the sequence SEQ ID NO: 23, said heavy chain comprising a variable region of sequence SEQ ID NO: 22 and in particular comprising an LALA mutation; or • a light chain having at least 80% identity with the sequence SEQ ID NO: 44, said light chain comprising a variable region of sequence SEQ ID NO: 43, and

[0107] a heavy chain having at least 80% identity with the sequence SEQ ID NO: 47, said heavy chain comprising a variable region of sequence SEQ ID NO: 46 and in particular comprising an LALA mutation; or • a light chain having at least 80% identity with the sequence SEQ ID NO: 52, said light chain comprising a variable region of sequence SEQ ID NO: 51, and

[0108] a heavy chain having at least 80% identity with the sequence SEQ ID NO: 55, said heavy chain comprising a variable region of sequence SEQ ID NO: 54 and in particular comprising an LALA mutation; or • a light chain having at least 80% identity with the sequence SEQ ID NO: 28, said light chain comprising a variable region of sequence SEQ ID NO: 27, and

[0109] a heavy chain having at least 80% identity with the sequence SEQ ID NO: 31, said heavy chain comprising a variable region of sequence SEQ ID NO: 30 and comprising in particular an LALA mutation; or • a light chain having at least 80% identity with the sequence SEQ ID NO: 36, said light chain comprising a variable region of sequence SEQ ID NO: 35, and

[0110] a heavy chain having at least 80% identity with the sequence SEQ ID NO: 39, said heavy chain comprising a variable region of sequence SEQ ID NO: 38 and comprising in particular an LALA mutation.

[0111] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R comprises: • / SKM 101 / a light chain of sequence SEQ ID NO: 20 and a heavy chain of sequence SEQ ID NO: 23 or 25; or • / SKM 106 / a light chain of sequence SEQ ID NO: 44 and a heavy chain of sequence SEQ ID NO: 47 or 49; or • / SKM 107 / a light chain of sequence SEQ ID NO: 52 and a heavy chain of sequence SEQ ID NO: 55 or 57; or • / SKM 103 / a light chain of sequence SEQ ID NO: 28 and a heavy chain of sequence SEQ ID NO: 31 or 33; or • / SKM 104 / a light chain of sequence SEQ ID NO: 36 and a chain heavy with sequence SEQ ID NO: 39 or 41.

[0112] In particular, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R comprises: • a light chain of sequence SEQ ID NO: 20 and a heavy chain of sequence SEQ ID NO: 23; or • a light chain of sequence SEQ ID NO: 44 and a heavy chain of sequence SEQ ID NO: 47; or • a light chain of sequence SEQ ID NO: 52 and a heavy chain of sequence SEQ ID NO: 55; or • a light chain of sequence SEQ ID NO: 28 and a heavy chain of sequence SEQ ID NO: 31; or • a light chain of sequence SEQ ID NO: 36 and a heavy chain of sequence SEQ ID NO: 39.

[0113] In particular, the invention also relates to the antibody-drug conjugate as described above, in which said anti-ETB-R comprises: • a light chain of sequence SEQ ID NO: 20 and a heavy chain of sequence SEQ ID NO: 25; or • a light chain of sequence SEQ ID NO: 44 and a heavy chain of sequence SEQ ID NO: 49; or • a light chain of sequence SEQ ID NO: 52 and a heavy chain of sequence SEQ ID NO: 57; or • a light chain of sequence SEQ ID NO: 28 and a heavy chain of sequence SEQ ID NO: 33; or • a light chain of sequence SEQ ID NO: 36 and a heavy chain of sequence SEQ ID NO: 41.

[0114] Advantageously, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is SKM 101 comprising a light chain of sequence SEQ ID NO: 20 (which can be encoded by the nucleic acid of sequence SEQ ID NO: 21) and a heavy chain of sequence SEQ ID NO: 23 or 25 (which can be respectively encoded by the nucleic acid of sequence SEQ ID NO: 24 or 26). Advantageously, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is SKM 106 comprising a light chain of sequence SEQ ID NO: 44 (which can be encoded by the nucleic acid of sequence SEQ ID NO: 45) and a heavy chain of sequence SEQ ID NO: 47 or 49 (which can be respectively encoded by the nucleic acid of sequence SEQ ID NO: 48 or 50).Advantageously, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is SKM 107 comprising a light chain of sequence SEQ ID NO: 52 (which . can be encoded by the nucleic acid of sequence SEQ ID NO: 53) and a heavy chain of sequence SEQ ID NO: 55 or 57 (which can be respectively encoded by the nucleic acid of sequence SEQ ID NO: 56 or 58). Advantageously, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is SKM 103 comprising a light chain of sequence SEQ ID NO: 28 (which can be encoded by the nucleic acid of sequence SEQ ID NO: 29) and a heavy chain of sequence SEQ ID NO: 31 or 33 (which can be respectively encoded by the nucleic acid of sequence SEQ ID NO: 32 or 34).Advantageously, the invention also relates to the antibody-drug conjugate as described above, in which said anti-ETB-R is SKM 104 comprising a light chain of sequence SEQ ID NO: 36 (which can be encoded by the nucleic acid of sequence SEQ ID NO: 37) and a heavy chain of sequence SEQ ID NO: 39 or 41 (which can be respectively encoded by the nucleic acid of sequence SEQ ID NO: 40 or 42).

[0115] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGio of formula (X),

[0116] and wherein said anti-ETB-R is SKM 101 comprising a light chain of sequence SEQ ID NO: 20 and a heavy chain of sequence SEQ ID NO: 23 or 25.

[0117] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGio of formula (X),

[0118] and wherein said anti-ETB-R is SKM 106 comprising a light chain of sequence SEQ ID NO: 44 and a heavy chain of sequence SEQ ID NO: 47 or 49.

[0119] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGio of formula (X),

[0120] and wherein said anti-ETB-R is SKM 107 comprising a light chain of sequence SEQ ID NO: 52 and a heavy chain of sequence SEQ ID NO: 55 or 57.

[0121] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGio of formula (X),

[0122] and wherein said anti-ETB-R is SKM 103 comprising a light chain of sequence SEQ ID NO: 28 and a heavy chain of sequence SEQ ID NO: 31 or 33.

[0123] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGio of formula (X),

[0124] and wherein said anti-ETB-R is SKM 104 comprising a light chain of sequence SEQ ID NO: 36 and a heavy chain of sequence SEQ ID NO: 39 or 41.

[0125] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Val-Ala-PAB-exatecan)-PEGio of formula (XI),

[0126] and wherein said anti-ETB-R is SKM 101 comprising a light chain of sequence SEQ ID NO: 20 and a heavy chain of sequence SEQ ID NO: 23 or 25.

[0127] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Val-Ala-PAB-exatecan)-PEGio of formula (XI),

[0128] and wherein said anti-ETB-R is SKM 106 comprising a light chain of sequence SEQ ID NO: 44 and a heavy chain of sequence SEQ ID NO: 47 or 49.

[0129] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Val-Ala-PAB-exatecan)-PEGio of formula (XI),

[0130] and wherein said anti-ETB-R is SKM 107 comprising a light chain of sequence SEQ ID NO: 52 and a heavy chain of sequence SEQ ID NO: 55 or 57.

[0131] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Val-Ala-PAB-exatecan)-PEGio of formula (XI),

[0132] and wherein said anti-ETB-R is SKM 103 comprising a light chain of sequence SEQ ID NO: 28 and a heavy chain of sequence SEQ ID NO: 31 or 33.

[0133] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Val-Ala-PAB-exatecan)-PEGio of formula (XI),

[0134] and wherein said anti-ETB-R is SKM 104 comprising a light chain of sequence SEQ ID NO: 36 and a heavy chain of sequence SEQ ID NO: 39 or 41.

[0135] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XII),

[0136] and wherein said anti-ETB-R is SKM 101 comprising a light chain of sequence SEQ ID NO: 20 and a heavy chain of sequence SEQ ID NO: 23 or 25.

[0137] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XII),

[0138] and wherein said anti-ETB-R is SKM 106 comprising a light chain of sequence SEQ ID NO: 44 and a heavy chain of sequence SEQ ID NO: 47 or 49.

[0139] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal- Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XII),

[0140] and wherein said anti-ETB-R is SKM 107 comprising a light chain of sequence SEQ ID NO: 52 and a heavy chain of sequence SEQ ID NO: 55 or 57.

[0141] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XII),

[0142] and wherein said anti-ETB-R is SKM 103 comprising a light chain of sequence SEQ ID NO: 28 and a heavy chain of sequence SEQ ID NO: 31 or 33.

[0143] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XII),

[0144] and wherein said anti-ETB-R is SKM 104 comprising a light chain of sequence SEQ ID NO: 36 and a heavy chain of sequence SEQ ID NO: 39 or 41.

[0145] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XIII),

[0146] and wherein said anti-ETB-R is SKM 101 comprising a light chain of sequence SEQ ID NO: 20 and a heavy chain of sequence SEQ ID NO: 23 or 25.

[0147] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XIII),

[0148] and wherein said anti-ETB-R is SKM 106 comprising a light chain of sequence SEQ ID NO: 44 and a heavy chain of sequence SEQ ID NO: 47 or 49.

[0149] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XIII),

[0150] and wherein said anti-ETB-R is SKM 107 comprising a light chain of sequence SEQ ID NO: 52 and a heavy chain of sequence SEQ ID NO: 55 or 57.

[0151] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XIII),

[0152] and wherein said anti-ETB-R is SKM 103 comprising a light chain of sequence SEQ ID NO: 28 and a heavy chain of sequence SEQ ID NO: 31 or 33.

[0153] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XIII),

[0154] and wherein said anti-ETB-R is SKM 104 comprising a light chain of sequence SEQ ID NO: 36 and a heavy chain of sequence SEQ ID NO: 39 or 41.

[0155] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSARio of formula (XIV),

[0156] and in which said anti-ETB-R is SKM 101 comprising a light chain of sequence SEQ ID NO: 20 and a heavy chain of sequence SEQ ID NO: 23 or 25.

[0157] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSARio of formula (XIV),

[0158] and in which said anti-ETB-R is SKM 106 comprising a light chain of sequence SEQ ID NO: 44 and a heavy chain of sequence SEQ ID NO: 47 or 49.

[0159] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSARio of formula (XIV),

[0160] and in which said anti-ETB-R is SKM 107 comprising a light chain of sequence SEQ ID NO: 52 and a heavy chain of sequence SEQ ID NO: 55 or 57.

[0161] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSARio of formula (XIV),

[0162] and in which said anti-ETB-R is SKM 103 comprising a light chain of sequence SEQ ID NO: 28 and a heavy chain of sequence SEQ ID NO: 31 or 33.

[0163] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSARio of formula (XIV),

[0164] and in which said anti-ETB-R is SKM 104 comprising a light chain of sequence SEQ ID NO: 36 and a heavy chain of sequence SEQ ID NO: 39 or 41.

[0165] According to another embodiment, the invention relates to the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PSARn or to Mal-Glu-(Val-Ala-PAB-exatecan)-PSARn where n varies from 1 to 40,

[0166] and wherein said anti-ETB-R is SKM 101 comprising a light chain of sequence SEQ ID NO: 20 and a heavy chain of sequence SEQ ID NO: 23 or 25.

[0167] According to another embodiment, the invention relates to the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PSARn or to Mal-Glu-(Val-Ala-PAB-exatecan)-PSARn where n varies from 1 to 40,

[0168] and wherein said anti-ETB-R is SKM 106 comprising a light chain of sequence SEQ ID NO: 44 and a heavy chain of sequence SEQ ID NO: 47 or 49.

[0169] According to another embodiment, the subject of the invention is the antibody- medicament as described above, wherein said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PSARn or Mal-Glu-(Val-Ala-PAB-exatecan)-PSARn where n varies from 1 to 40,

[0170] and wherein said anti-ETB-R is SKM 107 comprising a light chain of sequence SEQ ID NO: 52 and a heavy chain of sequence SEQ ID NO: 55 or 57.

[0171] According to another embodiment, the invention relates to the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PSARn or to Mal-Glu-(Val-Ala-PAB-exatecan)-PSARn where n varies from 1 to 40,

[0172] and wherein said anti-ETB-R is SKM 103 comprising a light chain of sequence SEQ ID NO: 28 and a heavy chain of sequence SEQ ID NO: 31 or 33.

[0173] According to another embodiment, the invention relates to the antibody-drug conjugate as described above, in which said anti-ETB-R is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PSARn or to Mal-Glu-(Val-Ala-PAB-exatecan)-PSARn where n varies from 1 to 40,

[0174] and wherein said anti-ETB-R is SKM 104 comprising a light chain of sequence SEQ ID NO: 36 and a heavy chain of sequence SEQ ID NO: 39 or 41.

[0175] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, said antibody-drug conjugate being obtained using site-specific technologies known to those skilled in the art. Among these technologies, mention may be made of that of Synnafix, Mablink, Araris, Catalant, ThioBridge® and BTG ([3-transglutaminase). In particular, the subject of the invention is the antibody-drug conjugate as described above, said antibody-drug conjugate being obtained using the site-specific ThioBridge® technology, which makes it possible to conjugate antibodies and drugs at the cysteine ​​residues of the antibody.

[0176] According to a second aspect of the invention, the subject of the invention is the antibody-drug conjugate as described above for its use as a medicament.

[0177] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above for its use in the prevention and / or treatment of a tumor. It should be noted that the ADC of the invention can be used either as monotherapy or in combination with other treatment protocols (chemotherapy, radiotherapy, immunotherapy, etc.). Also and according to another embodiment, the subject of the invention is the antibody-drug conjugate (ADC) as described above for its use as described above, said ADC being used as monotherapy or in combination. The invention may therefore relate to a kit-of-parts comprising at least the antibody-drug conjugate as described above and another product (e.g. another ADC, an anti-tumor agent, etc.), and the use of this kit- o / -parts for the simultaneous, separate or sequential combined administration of said ADC and said other product.

[0178] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above for its use as described above in the prevention and / or treatment of a tumor in an adult (adult) or in a child (minor; pediatrics).

[0179] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above for its use as described above in the prevention and / or treatment of a primary and / or metastatic solid tumor and / or a relapse. In particular, the subject of the invention is the antibody-drug conjugate as described above for its use in the prevention and / or treatment of a primary solid tumor. In particular, the subject of the invention is the antibody-drug conjugate as described above for its use in the prevention and / or treatment of a metastatic solid tumor. In particular, the subject of the invention is also the antibody-drug conjugate as described above for its use in the prevention and / or treatment of a primary and metastatic solid tumor.In particular, the invention also relates to the antibody-drug conjugate as described above for its use in the prevention and / or treatment of a relapse (e.g. reappearance of the primary tumor after a period of remission).

[0180] Solid cancerous tumors, identifiable by a localized cluster of cells, are distinguished from blood cell cancers, such as leukemias, whose cancer cells circulating in the blood or lymph are dispersed throughout the body. Solid tumors can develop in any tissue: skin, mucous membranes, bones, organs, etc. They are the most common since, alone, they represent 90% of human cancers. There are 2 types of tumors: • carcinomas arising from epithelial cells (skin, mucous membranes, glands). Examples: breast, lung, prostate, intestinal, liver cancers, etc. • sarcomas, less common, originating from connective tissue cells (known as “support” tissues). Examples: bone cancers, cartilage cancers, etc.

[0181] According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above for its use as described above in the prevention and / or treatment of a tumor chosen from: • melanoma; • colon cancer - liver cancer - bladder cancer - pancreatic cancer - ovarian cancer - triple negative breast cancer (TNBC; triple negative breast cancer) - lung cancer - thyroid cancer; • liver tumors; • renal tumors and adrenal tumors such as pheochromocytoma and paraganglioma; • Kaposi's Sarcoma; • glioblastomas (brain tumors); • childhood brain tumors including embryonic tumors (e.g. medulloblastomas, rhabdoid and teratoid tumors) and glial tumors such as gliomas or ependydomas; • malignant pituitary or pineal germ cell tumors; • plexus tumors such as choroid plexus carcinomas; • retinoblastomas; • Ewing's sarcoma; • osteosarcoma; • neuroblastomas; • rhabdomyosarcomas; • nephroblastomas; • monoclonal gammopathies associated with malignant hematological diseases, such as than multiple myeloma, Waldenstrom's disease and B-cell lymphomas; • lymphoma such as salivary gland lymphomas and lymph gland lymphomas; • myelodysplasias; • adenocarcinomas; and • malignant blood diseases (primary or metastatic).

[0182] According to another aspect of the invention, the subject of the invention is a pharmaceutical composition comprising the antibody-drug conjugate as described above (as active principle or as active substance) and a pharmaceutically acceptable vehicle.

[0183] By "pharmaceutically acceptable vehicle" is meant according to the present invention any substance which is added to an ADC according to the present invention to promote its transport, avoid its substantial degradation in said composition and / or increase its half-life. Advantageously, such a pharmaceutically acceptable vehicle is sterile and pyrogen-free. It may be water, propylene glycol, vegetable oils or other suitable organic solvents. It is chosen according to the type of application of the pharmaceutical composition of the invention and in particular according to its mode of administration. Thus, the pharmaceutical composition according to the invention consists of at least one ADC according to the present invention in free form or in the form of an addition salt with a pharmaceutically acceptable acid, in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product.

[0184] According to another embodiment, the subject of the invention is the pharmaceutical composition as described above in which said antibody-drug conjugate is at a (unit) dose of 1 to 1,000 mg or at a (unit) dose of 0.015 to 15 mg / kg (based on a man weighing 66.6 kg).

[0185] “From 1 to 1000 mg” also means that the (unit) dose can be from 1 100 mg, 1 to 200 mg, 1 to 300 mg, 1 to 400 mg, 1 to 500 mg, 1 to 600 mg, 1 to 700 mg, 1 to 800 mg, 1 to 900 mg, 100 to 1,000 mg, 200 to 1,000 mg, 300 to 1,000 mg, 400 to 1,000 mg, 500 to 1,000 mg, 600 to 1,000 mg, 700 to 1,000 mg, 800 to 1,000 mg, 900 to 1,000 mg, 100 to 900 mg, 200 to 800 mg, 300 to 700 mg or 400 to 600 mg. This also means that this (unit) dose can be 1 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg or 1000 mg.

[0186] “From 0.015 to 15 mg / kg” also means that the (unit) dose may be understood from 0.015 to 1.5 mg / kg, from 0.015 to 3 mg / kg, from 0.015 to 4.5 mg / kg, from 0.015 to 6 mg / kg, from 0.015 to 7.5 mg / kg, from 0.015 to 9 mg / kg, from 0.015 to 10.5 mg / kg, from 0.015 to 12 mg / kg, from 0.015 to 13.5 mg / kg, from 1.5 to 15 mg / kg, from 3 to 15 mg / kg, from 4.5 to 15 mg / kg, from 6 to 15 mg / kg, from 7.5 to 15 mg / kg, from 9 to 15 mg / kg, from 10.5 to 15 mg / kg, from 12 to 15 mg / kg, from 13.5 at 15 mg / kg, 1.5 to 13.5 mg / kg, 3 to 12 mg / kg, 4.5 to 10.5 mg / kg or 6 to 9 mg / kg. This also means that this (unit) dose can be 0.015 mg / kg, 1.5 mg / kg, 3 mg / kg, 4.5 mg / kg, 6 mg / kg, 7.5 mg / kg, 9 mg / kg, 10.5 mg / kg, 12 mg / kg, 13.5 mg / kg or 15 mg / kg.

[0187] According to another aspect of the invention, the subject of the invention is the pharmaceutical composition as described above for its use in the prevention and / or treatment of a tumor. It should be noted that the pharmaceutical composition of the invention can be used either as monotherapy or in combination with other pharmaceutical compositions from other treatment protocols (chemotherapy, radiotherapy, immunotherapy, etc.). Also and according to another embodiment, the subject of the invention is the pharmaceutical composition as described above for its use as described above, said pharmaceutical composition being used as monotherapy or in combination. The invention may therefore relate to a kit-of-parts comprising at least the pharmaceutical composition as described above and another pharmaceutical composition (eg comprising another ADC [i.e. different from that of the invention], an anti-tumor agent, etc.), and the use of this kit-of-parts for the simultaneous, separate or sequential combined administration of said pharmaceutical composition as described above and said other pharmaceutical composition.

[0188] According to another embodiment, the invention has as its object the invention has as its object the pharmaceutical composition as described above for its use as described above in the prevention and / or treatment of a tumor in an adult (major) or in a child (minor; pediatrics).

[0189] According to another embodiment, the invention relates to the pharmaceutical composition as described above for its use as described above in the prevention and / or treatment of a primary and / or metastatic solid tumor and / or a relapse. In particular, the invention relates to the pharmaceutical composition as described above for its use as described above in the prevention and / or treatment of a primary solid tumor. In particular, the invention relates to the pharmaceutical composition as described above for its use as described above in the prevention and / or treatment of a metastatic solid tumor.In particular, the invention also relates to the pharmaceutical composition as described above for its use as described above in the prevention and / or treatment of a primary and metastatic solid tumor. In particular, the invention also relates to the pharmaceutical composition as described above for its use as described above in the prevention and / or treatment of a relapse (eg reappearance of the primary tumor after a period of remission).

[0190] According to another embodiment, the subject of the invention is the pharmaceutical composition as described above for its use as described above in the prevention and / or treatment of a tumor chosen from: • melanoma; • colon cancer - liver cancer - bladder cancer - pancreatic cancer - ovarian cancer - triple negative breast cancer (TNBC; triple negative breast cancer) - lung cancer - thyroid cancer; • liver tumors; • renal tumors and adrenal tumors such as pheochromocytoma and paraganglioma; • Kaposi's Sarcoma; • glioblastomas (brain tumors); • childhood brain tumors including embryonic tumors (e.g. medulloblastomas, rhabdoid and teratoid tumors) and glial tumors such as gliomas or ependydomas; • malignant pituitary or pineal germ cell tumors; • plexus tumors such as choroid plexus carcinomas; • retinoblastomas; • Ewing's sarcoma; • osteosarcoma; • neuroblastomas; • rhabdomyosarcomas; • nephroblastomas; • monoclonal gammopathies associated with malignant hematological diseases, such as than multiple myeloma, Waldenstrom's disease and B-cell lymphomas; • lymphoma such as salivary gland lymphomas and lymph gland lymphomas; • myelodysplasias; • adenocarcinomas; and • malignant blood diseases (primary or metastatic).

[0191] According to another embodiment, the invention relates to the pharmaceutical composition as described above for its use as described above, said pharmaceutical composition being used: by systemic route; by local route; by parenteral route (for example intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intrasternal, intracranial, intramuscular or subcutaneous); by intratumoral route; by topical route; by rectal route; by intranasal route or by inhalation.

[0192] Sterile compositions for parenteral administration include aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, vegetable oils or other suitable organic solvents may be used. These compositions may also contain adjuvants, such as wetting agents, isotonizing agents, emulsifiers, etc. Compositions for topical administration may be, for example, creams, lotions, mouthwashes, nasal or eye drops or aerosols.

[0193] Advantageously, the subject of the invention is the pharmaceutical composition as described above for its use as described above, said pharmaceutical composition being administered by one of the following routes: parenteral, injectable, intratumoral, topical, by inhalation, subcutaneous, nasal, intratumoral or pulmonary.

[0194] According to this same aspect, the invention alternatively relates to a method for preventing and / or treating a solid tumor comprising administering to a patient in need thereof an effective amount of the antibody-drug conjugate as described above, or of the pharmaceutical composition as described above.

[0195] According to another aspect of the invention, the subject of the invention is a product comprising the formula (XV):

[0196] TC-B-(LM)-AS (XV),

[0197] in which: • TC is a conjugation head chosen from: maleimide coupled to a glutamic acid (Mal-Glu), polyether, amino acids, benzyl group, amines, ketones and thioester linkers stabilized upon hydrolysis with haloacetamides, keto-sulfones, methylsulfonylphenyl-loxadiazole, carbonylacrylic; • B represents “PEG2-Glu-(Glu-Met)” and is absent or present; • L is a linker cleavable by lysosomal cathepsins, said cleavable linker being optionally coupled to p-aminobenzyl alcohol (PAB) or one of its derivatives; • M is a drug selected from: topoisomerase inhibitors, alkylating agents, antimicrotubule agents and their prodrug forms; and • AS is a solubilizing agent chosen from: polysarcosine (PSAR) and polyethylene glycol (PEG).

[0198] According to another embodiment, this relates to a product comprising the formula (XVI):

[0199] TC-(LM)-AS (XVI),

[0200] in which: • TC is a conjugation head chosen from: maleimide coupled to a glutamic acid (Mal-Glu), polyether, amino acids, benzyl group, amines, ketones and thioester linkers stabilized upon hydrolysis with haloacetamides, keto-sulfones, methylsulfonylphenyl-loxadiazole, carbonylacrylic; • L is a linker cleavable by lysosomal cathepsins, said cleavable linker being optionally coupled to p-aminobenzyl alcohol (PAB) or one of its derivatives; • M is a drug selected from: topoisomerase inhibitors, alkylating agents, antimicrotubule agents and their prodrug forms; and • AS is a solubilizing agent chosen from: polysarcosine (PSAR) and polyethylene glycol (PEG).

[0201] According to another embodiment, the invention therefore relates to the product as described above, in which TC is a conjugation head chosen from: maleimide coupled to a glutamic acid (Mal-Glu), polyether, amino acids, the benzyl group, amines and ketones. In particular, the invention relates to the product as described above, in which TC is a maleimide conjugation head coupled to a glutamic acid (Mal-Glu).

[0202] According to another embodiment, the subject of the invention is the product as described above, in which L is a linker chosen from: the dipeptide Val-Cit, the dipeptide Phe-Lys, the dipeptide Val-Ala, the tripeptide Ala-Ala-Asn and the quadripeptide Gly-Gly-Phe-Gly, each of these linkers being optionally coupled to p-aminobenzyl alcohol (PAB) or a derivative thereof. In particular, the subject of the invention is the antibody-drug conjugate as described above, in which L is a linker, in particular coupled to p-aminobenzyl alcohol (PAB), chosen from: the dipeptide Phe-Lys and the dipeptide Val-Ala. In particular, the subject of the invention is also the product as described above, in which L is a linker coupled to p-aminobenzyl alcohol (PAB) chosen from: Phe-Lys-PAB and Val-Ala-PAB.

[0203] According to another embodiment, the subject of the invention is the product as described above, in which AS is polysarcosine (PSAR) either in the form of a monomer or in the form of a polymer whose PSAR number varies from 2 to 40. In particular, the subject of the invention is the product as described above, in which AS is polysarcosine (PSAR) in the form of a polymer whose PSAR number is 10.

[0204] According to another embodiment, the subject of the invention is the product as described above, in which AS is polyethylene glycol (PEG) either in the form of a monomer, or in the form of a bi-branched, tri-branched, cyclic or linear polymer whose number of PEGs varies from 2 to 40. In particular, the subject of the invention is the product as described above, in which AS is polyethylene glycol (PEG) in the form of a bi-branched polymer whose number of PEGs is 16.

[0205] According to another embodiment, the subject of the invention is the product as described above, said product comprising the formula (XVII):

[0206] Mal-Glu-B-(LM)-AS (XVII),

[0207] in which: • Mal-Glu is a maleimide conjugation head coupled to a glutamic acid; • B represents “PEG2-Glu-(Glu-Met)” and is absent or present; • L is a linker cleavable by lysosomal cathepsins, said cleavable linker being chosen from: the dipeptide Val-Cit, the dipeptide Phe-Lys, the dipeptide Val-Ala, the tripeptide Ala-Ala-Asn and the quadripeptide Gly-Gly-Phe-Gly, each of these linkers being optionally coupled to p-aminobenzyl alcohol (PAB) or one of its derivatives; • M is a drug selected from: irinotecan, topotecan, camptothecin, SN38, exatecan, silatecan, cositycan, lurtotecan, gimatecan, bleotecan, rubitecan, dacarbazine, paclitaxel and their prodrug forms; and • AS is a solubilizing agent chosen from: polysarcosine (PSAR) and polyethylene glycol (PEG).

[0208] According to another embodiment, the subject of the invention is the product as described above, said product comprising the formula (XVIII):

[0209] Mal-Glu-(LM)-AS (XVIII),

[0210] in which: • Mal-Glu is a maleimide conjugation head coupled to a glutamic acid; • L is a linker cleavable by lysosomal cathepsins, said cleavable linker being chosen from: the dipeptide Val-Cit, the dipeptide Phe-Lys, the dipeptide Val-Ala, the tripeptide Ala-Ala-Asn and the quadripeptide Gly-Gly-Phe-Gly, each of these linkers being optionally coupled to p-aminobenzyl alcohol (PAB) or one of its derivatives; • M is a drug selected from: irinotecan, topotecan, camptothecin, SN38, exatecan, silatecan, cositycan, lurtotecan, gimatecan, bleotecan, rubitecan, dacarbazine, paclitaxel and their prodrug forms; and • AS is a solubilizing agent chosen from: polysarcosine (PSAR) and polyethylene glycol (PEG).

[0211] According to another embodiment, the subject of the invention is the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-M)-PEGio of formula (XIX):

[0212] [Chem. 13] (XIX)

[0213] or Mal-Glu-(Val-Ala-PAB-M)-PEG10 of formula (XX):

[0214] [Chem. 14] .0. . o' GH

[0215]

[0216] (XX). According to another embodiment, the subject of the invention is the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-M)-PEGi6 of formula (XXI): [Chem. 15]

[0217]

[0218] (XXI) or Mal-Glu-(Val-Ala-PAB-M)-PEG16 of formula (XXII): [Chem. 16]

[0219] (XXII). According to another embodiment, the invention relates to the product as described above, said product being Mal-Glu-PEG2 - Glu-(Glu-Met-PAB-(Val-Ala)-M)-PSAR10 of formula (XXIII):

[0220] [Chem. 17] (XXIII).

[0221] According to another embodiment, the invention relates to the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-M)-PSAR or Mal-Glu-(Val-Ala-PAB-M)-PSARn where n varies from 1 to 40.

[0222] In view of the above, it is understood that according to another embodiment, the invention relates to the product as described above, said product being: • Mal-Glu-(Phe-Lys-PAB-M)-PEG10 of formula (XIX); • Mal-Glu-(Val-Ala-PAB-M)-PEG10 of formula (XX); • Mal-Glu-(Phe-Lys-PAB-M)-PEG16 of formula (XXI); • Mal-Glu-(Val-Ala-PAB-M)-PEG16 of formula (XXII); • Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-M)-PSAR10 of formula (XXIII); • Mal-Glu-(Phe-Lys-PAB-M)-PSARn where n varies from 1 to 40; or • Mal-Glu-(Val-Ala-PAB-M)-PSARn where n varies from 1 to 40.

[0223] According to another embodiment, the subject of the invention is the product as described above, in which M is a drug chosen from: exatecan and its prodrug forms (eg salts, esters, ethers, glucuronides, galactamines, cyclodextrins and amides of exatecan). In particular, the subject of the invention is the antibody-drug conjugate as described above, in which M is a drug chosen from: exatecan and Dxd (Exatecan derivative). Advantageously, the subject of the invention is the antibody-drug conjugate as described above, in which M is exatecan.

[0224] According to another embodiment, the invention relates to the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGio of formula (XXV):

[0225] [Chem. 18] Û'" XÔH

[0226]

[0227] (XXV) or Mal-Glu-(Val-Ala-PAB-exatecan)-PEGio of formula (XXVI): [Chem. 19] ^o. ,-XO --- --- OH ^0-4^ 'O

[0228]

[0229] (XXVI), exatecan may be in a prodrug form. According to another embodiment, the subject of the invention is the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula

[0230] (XXVII): [Chem. 20]

[0231] (XXVII) or Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XXVIII):

[0232] [Chem.21] F (XXVIII),

[0233] exatecan may be in a prodrug form.

[0234] According to another embodiment, the invention relates to the product as described above, said product being Mal-Glu-PEG2 - Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSARio of formula (XXIX):

[0235] [Chem.22] (XXIX),

[0236] exatecan may be in a prodrug form.

[0237] According to another embodiment, the invention relates to the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-exatecan)-PSAR or Mal-Glu-(Val-Ala-PAB-exatecan)-PSARn where n varies from 1 to 40, the exatecan possibly being in a prodrug form.

[0238] In view of the above, it is understood that according to another embodiment, the invention relates to the product as described above, said product being: • Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGio of formula (XXV); • Mal-Glu-(Val-Ala-PAB-exatecan)-PEGio of formula (XXVI); • Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XXVII); • Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XXVIII); • Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSARio formula (XXIX); • Mal-Glu-(Phe-Lys-PAB-exatecan)-PSARn where n varies from 1 to 40; or • Mal-Glu-(Val-Ala-PAB-exatecan)-PSARn where n varies from 1 to 40,

[0239] exatecan may be in a prodrug form. In particular, the subject of the invention is the product as described above, said product being: • Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGio of formula (XXV); • Mal-Glu-(Val-Ala-PAB-exatecan)-PEGio of formula (XXVI); • Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XXVII); • Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XXVIII); • Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSARio formula (XXIX); • Mal-Glu-(Phe-Lys-PAB-exatecan)-PSARn where n varies from 1 to 40; or • Mal-Glu-(Val-Ala-PAB-exatecan)-PSARn where n varies from 1 to 40.

[0240] According to another embodiment, the subject of the invention is the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XXVII):

[0241] [Chem.23] (XXVII).

[0242] According to another embodiment, the subject of the invention is the product as described above, said product being Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XXVIII):

[0243] [Chem.24] (XXVIII).

[0244] In any respect, it should be noted that the different aspects of the invention, just like the different embodiments thereof, are interdependent. The latter can therefore be combined with each other as much as necessary to obtain preferred aspects and / or embodiments of the invention not explicitly described. This is also valid for all the definitions provided in the present description, which applies to all aspects of the invention and its embodiments.

[0245] Further, the present invention is illustrated, but not limited to, the following figures and examples. LIST OF FIGURES [Fig 1]

[0246] [Fig. 1]. Analysis of DAR by HIC (hydrophobic interaction chromatography). [Fig 2]

[0247] [Fig.2]. Analysis of ADCs by size exclusion chromatography (SEC). [Fig 3]

[0248] [Fig.3]. Analysis of the stability of ADCs after a freeze-thaw cycle by size exclusion chromatography (SEC). [Fig 4] Figure 4. Stability of ADCs in sera.

[0249] Monitoring of the stability of the DAR of the ADC SKM104 versus the control ADC ENHERTU as a function of time (A) in human serum (B) in mouse serum [Fig 5] Figure 5. In vitro cytotoxicity studies. [Fig 6]

[0250] [Fig.6]. Efficacy of ADCs tested in vivo in the uveal melanoma model 92.1.

[0251] (A) Measurement of tumor growth. (B) Survival curve.

[0252] Statistics: No stars: no statistical difference (p-value > 0.05); (*): 0.05 > p-value > 0.01; (**): 0.01 > p-value > 0.001; (***): 0.001 > p-value > 0.0001 and (****): 0.0001 > p-value. [Fig 7]

[0253] [Fig.7]. Efficacy of ADCs tested in vivo in the Mel-202 uveal melanoma model.

[0254] (A) Measurement of tumor growth. (B) Survival curve.

[0255] Statistic: No stars: no statistical difference (p-value > 0.05); (*): 0.05 > p-value > 0.01; (**): 0.01 > p-value > 0.001; (***): 0.001 > p-value > 0.0001 and (****); 0.0001 > p-value. [Fig 8]

[0256] [Fig.8]. Efficacy of ADCs tested in vivo in the colon model MC38-hETBR.

[0257] (A) Measurement of tumor growth. (B) Measurement of mouse weight. [Fig 9]

[0258] [Fig.9]. Expression of ETB-R in a multiple myeloma cell line U266B1 measured by flow cytometry (FACS). EXAMPLES EXAMPLE No. 1 - Production of ADCs MATERIALS & METHODS Linkers-drugs

[0259] The Linker-drugs used are: • Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 of formula (XXVII)

[0260] [Chem.25] (XXVII); and • Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 of formula (XXVIII)

[0261] [Chem.26] F (XXVIII).

[0262] These were produced by LEVENA. Antibody

[0263] The anti-ETB-R antibodies used are: • the SKM101; and • SKM104 (with or without LALA mutation).

[0264] An irrelevant antibody has also been used. This is Motavizumab. Conjugation protocol

[0265] This was carried out by ABZENA and includes 3 stages.

[0266] In the first step of the reduction, the reducing agent TCEP (tris(2-carboxyethyl)phosphine) was tested at 8 molar equivalents and 10 molar equivalents respectively. In this first step, the duration of the reduction reaction was 1 h, the temperature was 40°C and the concentration was 5.0 mg / mL.

[0267] In the second step of the conjugation, 14.0 ± 4 molar equivalents of the Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 reagent or the Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6 reagent were used with the different antibodies. In this second step, the duration of the conjugation reaction was 1 h, the temperature was 22°C and 10% DMSO was used as co-solvent.

[0268] In the third step of purification, preparative size exclusion chromatography (Superdex increase 200 10 / 300 GL) as well as ultrafiltration and diafiltration were used. In addition, PBS + 10% isopropanol was used as eluent. Characterization of ADCs

[0269] The reactions were analyzed by HIC (hydrophobic interaction chromatography), LC-MS (liquid chromatography mass spectrometry) and size exclusion chromatography (SEC).

[0270] SKM104 ADCs (with or without LALA mutation) and Motavizumab were produced in larger quantities according to the same protocol.

[0271] Concentrations were determined by UV spectroscopy at 280 nm and using the following formula:

[0272] [Math.l] s®

[0273] where: • A28o: Absorption at 280 nm, • MW: Molecular weight of the ADC, • LP: linkers-payloads, and • mAb: monoclonal antibodies.

[0274] Stability was monitored after one freeze-thaw cycle by analytical size exclusion chromatography (SEC). RESULTS

[0275] At the end of the conjugation protocol, the ADCs obtained were all stable in PBS.

[0276] The DAR (drug-antibody ratio) was analyzed by HIC (hydrophobic interaction chromatography) and was 8 in the different conditions of TCEP (8 and 10 molar equivalents) and linker-payloads reagents (14 molar equivalents for SKM104 and SKM101, and 18 molar equivalents for Mo-tavizumab) ([Fig.l]). Similar data were obtained with LC-MS (liquid chromatography mass spectrometry) analysis with the precision that DAR 8 was obtained after 1 hour (data not shown). Size exclusion chromatography (SEC) analysis at 280 demonstrated that the produced ADCs had a high monomeric purity (greater than 95%) ([Fig.2]) including after a freeze-thaw cycle (greater than 99%) ([Fig.3]) where the data generated showed that the ADCs are very stable and that there is no aggregation phenomenon.

[0277] Finally, the conjugation protocol implemented made it possible to produce the ADCs of the invention, which were characterized as follows:

[0278] [Tables2] ADC DAR LC- MS and (HIC-UV) Monomer (SEC) Quantity (mg) Yield SKM104_LALA-Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6] 8 98.6 37.3 70 SKM104-[Mal-Glu-(Phe-Lys-P AB-exatecan)-PEGi6] 8 97 38 75 Motavizum-[Mal-Glu-(Phe-Lys-PAB-exatecan)-PEGi6] 8 98.6 37.1 74 SKM 104_LALA- [Mal-Glu-(Val -Ala-PAB-exatecan)-PEGi6] 8 98.8 28 56 SKM104-[Mal-Glu-(Val-Ala-P AB-exatecan)-PEGi6] 8(8) 99% 36.5 70% Motavizum- [Mal-Glu-(V al-Ala-PAB-exatecan)-PEGi6] 8(8) 99% 37 77%

[0279] Table 2. Summary of characteristics of the ADCs produced

[0280] EXAMPLE No. 2 - Stability of ADCs in serum MATERIALS & METHODS ADCs tested

[0281] SKM104-[Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6]

[0282] Clinically validated control: ENHERTU Matrices

[0283] ADCs were incubated in human or mouse serum at 1 mg / mL.

[0284] Samples were incubated at 37°C at 0°C, 24h, 48h, 72h and 96h and frozen at - 80°C thereafter until the day of extraction. Affinity capture

[0285] Protein A magnetic beads (Cytiva) were used.

[0286] Capture: 50 pL of serum was mixed with 150 pL of PBS then incubated with the beads for 2 hours at room temperature, 1200 rpm.

[0287] Washing: The beads were washed 3 times with 300 μL of PBS.

[0288] Elution: it was carried out 3 times with 50 pL of a 2 mM HCl solution (5 min incubation) and the aliquots were neutralized with 0.1 M Tris buffer.

[0289] The extracted sample was treated with DTT.

[0290] The analysis was carried out by LC-MS (Waters Bioaccord).

[0291] A column: UPLC protein BEH SEC was used.

[0292] The mobile phase is 30% acetonitrile and 0.1% formic acid in water.

[0293] Detection was made by: ESI, 400 to 7000 Da.

[0294] The results were processed by mass spectrometry and represent an average of relative DAR as a function of the different species present in the sample.

[0295] The percentage was calculated between the eluted sample and the initial product injected into the column. RESULTS

[0296] A slight decrease in DAR was observed for ADC SKM104 and ENHERTU over time. 14% and 8% reduction in DAR was observed for ADC SKM104 and ENHERTU, respectively, in human serum (Figure 4A). 17% and 8% reduction in DAR was observed for ADC SKM104 and ENHERTU, respectively, in murine serum (Figure 4B). Conclusion

[0297] ADC SKM104 showed better stability in serum than the ENHERTU clinical control used.

[0298] The construction of the ADC according to the invention therefore offers an undeniable advantage in terms of improving stability and therefore reducing non-release specific toxin release from the ADC of the invention into the circulation and therefore reduction of toxicity. EXAMPLE No. 3 - In vitro cytotoxicity studies MATERIALS & METHODS Cell lines

[0299] The following lines were used to evaluate the efficacy of the ADC: 92.1v2 (uveal melanoma), Mel-202 (uveal melanoma), SK-MEL-23 (cutaneous melanoma), UACC-257v2, U251-MG (Glioma). 92.1 (13012458-1VL, Merck), Mel-202 (13012457-1VL, Merck) and SK-MEL-23 were cultured in RPMI (CM1RPM00K BP, Eurobio Scientific) containing 10% FCS (CVFSVF00 01, Eurobio Scientific). UACC-257 were cultured in DMEM / F12 medium (CM1DME60K BP and L0136-500, Eurobio Scientific) containing 10% FCS. U-251-MG (09063001-1VL, Merck) were cultured in EMEM medium (CM1MEM10K, Eurobio Scientific) containing 10% FCS, 2mM L-Glutamine (X0551-100, Eurobio Scientific), 1mM Sodium Pyruvate (CSTVAT00 OU, Eurobio Scientific) and 1% non-essential amino acids (X0557-100, Eurobio Scientific). 92.1v2 and UACC-257v2 were optimized in vivo to improve their growth rate in mouse xenografts. Evaluation of in vitro cytotoxicity

[0300] To determine the effect of ADC on cell viability, cells were seeded at 1,500 cells in 100 μL of complete culture medium in a 96-well flat-bottom plate. After overnight incubation at 37°C, 100 μL of medium containing a serial dilution of each compound was added in duplicate. After 5 days of incubation, cell survival was determined by adding 20 μL of CellTiter 96® AQueous One Solution Reagent (G3581, Promega). After 2 hours of incubation at 37°C, absorbance was determined at 490nm (Multiskan, Thermo Fisher). The cell viability ratio (%) is calculated using the following formula:

[0301] [Math.2] Viability (%) = 100 ohm pole 2 '■blcmc

[0302] The 50% inhibitory concentration was calculated by GraphPad Prism® version 10 software. RESULTS

[0303] A dose-dependent decrease in cell viability of 92.1 and Mel-202 was observed. 92.1v2 was used because it expresses high levels of ETB-R on its surface, unlike Mel-202, which expresses it more weakly. At the doses evaluated, the ADC SKM104-[Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6] (abbreviated SKM104-Val-Ala-exatecan) induced a decrease in proliferation cellular proliferation of 92.1 and Mel-202. The calculated IC50 of SKM104-[Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6] is 13 nM in 92.1 versus 37 nM in Mel-202 ([Fig.5]). The control ADC (abbreviated IC-Val-Ala-exatecan) induced cytotoxicity only at the highest concentrations, while the naked antibody did not induce a decrease in cell proliferation. The effect obtained was well correlated with the release of exatecan.

[0304] Finally, these results therefore demonstrated the efficacy of SKM104-[Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6] on uveal melanoma lines.

[0305] EXAMPLE No. 4 - Efficacy of ADCs tested in vivo in two models of uveal melanoma MATERIALS & METHODS Cell lines

[0306] Two human uveal melanoma cell lines (Mel-202 and 92-1) were tested, according to the Inovotion Assay, on Chicken Chorioallantoic Membrane (CAM). The formulation buffer (PBS) was used as a negative control. Compounds tested

[0307] ADC: SKM104 in PBS supplied by Skymab and stored at -80°C. • Stock solution: 5.37 mg / mL • Linker-Payload: Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 • Vehicle: PBS • On the day of treatment, dilutions (see Table 3) were prepared from of the stock solution in PBS. • The different dilutions were stored at room temperature (to avoid thermal shock) for less than 1 hour. • The required amount of ADC: SKM104 = 5 mg. Preparation of chicken embryos

[0308] Fertilized eggs (White Leghom) were incubated at 37.5°C with 50% humidity for 9 days. The CAM (Chicken Chorioallantoic Membrane) was lowered by drilling a small hole through the eggshell into the air sac. A 1 cm2 portion of the eggshell was cut above the CAM. 15 eggs (minimum) were grafted for each group. A significant number of deaths could have occurred a few hours after tumor grafting (an invasive surgical procedure). Data could therefore be collected with fewer than 15 eggs per group (minimum of 10 eggs per group in the absence of treatment toxicity). Tumor cell amplification and transplantation

[0309] Mel-202 and 92-1 tumor cells were cultured in RPML1640 medium + 10% FBS, 1% pyruvate, and 1% penicillin / streptomycin. Cells were detached on day 9 with trypsin, washed with culture medium, and suspended in grafting medium. One million cells were inoculated onto the CAM of each egg on day 9. Eggs were then randomized into groups. Treatments

[0310] Tumors were detectable from D10. The treatments of the different groups are detailed in the following Table 3:

[0311] [Tables3] Group Description ADC / Vehicle Injection Vol. (pL) Conc. (mg / mL) Conc. final [C] (mg / kg) Part I: The Mel-202 model 1 Negative Control PBS (Vehicle) 100 - - 2 Skymab ADC [1] SKM104 100 0.06 0.1 3 Skymab ADC [2] SKM104 100 0.30 0.5 4 Skymab ADC [3] SKM104 100 1.20 2.0 Part II: The 92-1 model 1 Negative Control PBS (Vehicle) 100 - - 2 Skymab ADC [1] SKM104 100 0.06 0.1 3 Skymab ADC [2] SKM104 100 0.30 0.5 4 Skymab ADC [3] SKM104 100 1.20 2.0 Table 3. Description of treatments by group Evaluation of tumor growth

[0312] At D-18, the upper part of the CAM (with tumor) was removed, washed with PBS, then transferred into PFA (para-formaldehyde) (fixation for 48 hours). Then, the tumors were carefully cut from the CAM and weighed.

[0313] A statistical analysis of tumor masses, one-way ANOVA, was performed for all groups. Assessment of embryo toxicity

[0314] In order to evaluate the embryonic toxicity induced by the treatment: • Embryonic viability was checked daily. • The number of dead embryos was counted over 18 days. • The observation of any visible anomalies was noted every day. • The final mortality rate and a Kaplan-Meyer were provided for all groups. Any abnormalities observed during the study were also reported. Statistical analysis

[0315] For all analyses, the statistical difference between groups was marked on the graphs by stars: • No stars: no statistical difference (p-value > 0.05); • One star (*): 0.05 > p-value > 0.01; • Two stars (**): 0.01 > p-value > 0.001; • Three stars (***); 0.001 > p-value > 0.0001; • Four stars (****); 0.0001 > p-value. Collection of samples from tumors

[0316] The following Table 4 summarizes the list of samples collected during this study.

[0317] [Tables4] Samples Samples Group Tumor Storage Conditions Read by Inovotion Send to Skymab S □ Tumors All eggs S Fixation (PFA 4%) and storage in PBS 4°CS □ gDNA 10 Extraction and freezing from lower CAM -20°C Table 4. Description of treatments by group RESULTS Lineage 92-1

[0318] A dose-dependent decrease in tumor growth was observed in embryos bearing tumors derived from 92.1 cell xenografts. Indeed, a 37% inhibition of tumor growth was observed at a dose of 0.5 mg / kg of ADC SKM104-[Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6] (abbreviated SKM104-Val-Ala-exatecan) versus 55% at the 2.0 mg / kg dose compared to the negative control (Figure 6A). A slight increase in mortality is observed for the 2.0 mg / kg dose, however this is not statistically significant at this stage (Figure 6B). Mel-202 Lineage

[0319] A dose-dependent decrease in tumor growth was observed in embryos bearing tumors derived from Mel-202 cell xenografts. Indeed, a 40% inhibition of tumor growth was observed at the dose of 0.5 mg / kg of the ADC SKM104-[Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16] (abbreviated SKM104-Val-Ala-exatecan) versus 53% at the dose of 2.0 mg / kg compared to the negative control (Figure 7A). A slight increase in mortality was observed for the dose of 2.0 mg / kg, however this is not statistically significant at this stage (Figure 7B).

[0320] Finally, these data showed the effectiveness of the ADCs of the invention.

[0321] EXAMPLE No. 5 - Efficacy of ADCs tested in vivo in a colon model resistant to microtubule inhibitors MATERIALS & METHODS Cell lines

[0322] A syngeneic MC38 colon line transfected with the human ETB-R target was used in a subcutaneous xenograft mouse model. Compounds tested

[0323] The ADC tested was SKM104-Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16 DAR8 (abbreviated SKM104-Val-Ala-exatecan DAR8) stored in PBS at -80°C until use. • Stock solution: 5.37 mg / mL • Linker-Payload: Mal-Glu-(Val-Ala-PAB-exatecan)-PEGi6 • Vehicle: PBS

[0324] Vehicle and an irrelevant antibody (IC) identically conjugated to SKM104-Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16 DAR8 (abbreviated SKM104-Val-Ala-exatecan DAR8) were used as negative control. SKM104 vedotin DAR4 was also used as control. Amplification and transplantation of cells

[0325] MC38-hETBR cells were cultured in DMEM medium containing 10% fetal calf serum (FCS), 1% Glutamax, 1X sodium pyruvate, NEAA (non-essential amino acids) and supplemented with 5 μg of puromycin, at 37°C in a humid atmosphere. Cells were detached with trypsin, washed before to be counted in the presence of Trypan blue to assess cell viability before being suspended in the graft medium. One million cells were injected subcutaneously into the right flank of 32 8-week-old female C57BL / 6 mice (Janvier Labs). The mice were randomized into 4 groups of 8 mice when the tumor volume reached 100 mm3. Treatments

[0326] Mice received 3 intravenous injections, one per week, containing 10 mg / kg of IC-Val-Ala-Exatecan or SKM104-Val-Ala-exatecan DAR8, or 4 mg / kg of SKM104 vedotin DAR4 or vehicle in a final volume of 100 pL. Animal monitoring

[0327] The viability and behavior of the animals was assessed daily.

[0328] The weight and tumor volume of the animals were measured twice a week.

[0329] The tumor volume was calculated using the formula:

[0330] [Math.3] T, , , lareeur^oneueur Tumor volume = —-—5—i-- Statistical analysis

[0331] Statistical analysis of tumor masses was performed for all groups using the Mann-Whitney test to compare two independent samples. For all analyses, the statistical difference between groups was marked on the graphs by stars: • No stars: no statistical difference (p-value > 0.05); • One star (*): p-value < 0.05; • Two stars (**): p-value < 0.01; • Three stars (***); p-value < 0.001; and • Four stars (****); p-value < 0.0001. RESULTS

[0332] Tumor growth of MC38-hETBR was significantly slowed when tumors were treated with SKM104-Val-Ala-exatecan DAR8, compared to ITC-Val-Ala-Exatecan and SKM104 vedotin DAR4. Indeed, after 18 days of treatment, tumor growth inhibition was 85.2% for SKM104-Val-Ala-exatecan DAR8 versus 65% for IC-Val-Ala-Exatecan and 27% for SKM104 vedotin DAR4 (Figure 8A).

[0333] Finally, these data showed the effectiveness of the ADCs of the invention.

[0334] EXAMPLE No. 6 - Expression of ETB-R in hematological tumors MATERIALS & METHODS Cell lines

[0335] Multiple myeloma U266B1 tumor cells were used. Protocol

[0336] U266B1 cells were incubated with SKM-104 at 15 pg / mL for 3 h at 4°C. After 2 washes with PBS, the cells were incubated for 1 h with an APC-labeled anti-IgGl secondary antibody. After 2 washes with PBS (100 μl), the cells were labeled with the BV421-labeled viability / mortality kit. The cells were then read by FACS. The study was performed at Wuxi Biologics. RESULTS

[0337] It has been measured that more than 40% of multiple myeloma cells express the ETB-R target ([Fig.9]).

Claims

Claims

1. Antibody drug conjugate (ADC) of formula (I): Ac-[TC-B-(LM)-AS] (I), in which: • Ac is an anti-ETB-R antibody, one of its fragments or one of its derivatives; • TC is a conjugation head chosen from: maleimide coupled to a glutamic acid (Mal-Glu), polyether, amino acids, benzyl group, amines, ketones and thioester linkers stabilized upon hydrolysis with haloacetamides, ketosulfones, methylsulfonylphenyloxadiazole, carbonylacrylic; • B represents “PEG2-Glu-(Glu-Met)” and is absent or present; • L is a linker cleavable by lysosomal cathepsins, said cleavable linker being optionally coupled to p-aminobenzyl alcohol (PAB) or one of its derivatives; • M is a drug chosen from: topoisomerase inhibitors, alkylating agents, antimicrotubule agents and their prodrug forms; and • AS is a solubilizing agent chosen from: poly-sarcosine (PSAR) and polyethylene glycol (PEG), and wherein the drug-antibody ratio (DAR) is from 2 to 16 and said anti-ETB-R comprises: • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of QXiIVHSNGX2TY (SEQ ID NO: 1) where Xi represents S or N and X2 represents N or Y, • CDR2 whose amino acid sequence includes or consists of KVX3 where X3 represents S or F, and • the CDR3 whose amino acid sequence comprises or consists of FQGSHVPX4X5 (SEQ ID NO: 2) where X4 represents W or L, and X5 represents T or no amino acid, and a heavy chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of IDPNSGGTKYNEKFKS (SEQ ID NO: 4) or DPNSGGT (SEQ ID NO: 5), and • CDR3 whose amino acid sequence comprises or consists of AREGEFAWFAY (SEQ ID NO: 6) or VREGWDAWFVY (SEQ ID NO: 7); or • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of KSSQSLLDSDGKTYLN (SEQ ID NO: 8), • CDR2 whose amino acid sequence comprises or consists of LVSKLDS (SEQ ID NO: 9), and • CDR3 whose amino acid sequence comprises or consists of WQGTHFPYT (SEQ ID NO: 10), and a heavy chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYWMQ (SEQ ID NO: 11), • CDR2 whose amino acid sequence comprises or consists of TIYPGDGDTSYAQKFKG (SEQ ID NO: 12), and • CDR3 whose amino acid sequence comprises or consists of WGYAYDIDN (SEQ ID NO: 13).

2. The antibody-drug conjugate of claim 1, wherein said anti-ETB-R comprises: • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of QSIVHSNGNTY (SEQ ID NO: 14), • CDR2 whose amino acid sequence comprises or consists of KVS (corresponding to amino acids 55 to 57 of the sequence SEQ ID NO: 19), and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPWT (SEQ ID NO: 15), and a heavy chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of IDPNSGGTKYNEKFKS (SEQ ID NO: 4), and • CDR3 whose amino acid sequence comprises or consists of AREGEFAWFAY (SEQ ID NO: 6); or • a light chain comprising from the N-terminus to the C-terminus • CDR1 whose amino acid sequence comprises or consists of QSIVHSNGNTY (SEQ ID NO: 14), • CDR2 whose amino acid sequence comprises or consists of KVF (corresponding to amino acids 54 to 56 of the sequence SEQ ID NO: 43), and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPLT (SEQ ID NO: 16), and a heavy chain comprising from the N-terminus to the

3. C-terminal: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of DPDSGGT (SEQ ID NO: 5), and • CDR3 whose amino acid sequence comprises or consists of VREGWDAWFVY (SEQ ID NO: 7); or • a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of QNIVHSNGYTY (SEQ ID NO: 17), • CDR2 whose amino acid sequence comprises or consists of KVS (corresponding to amino acids 55 to 57 of the sequence SEQ ID NO: 51), and • CDR3 whose amino acid sequence comprises or consists of FQGSHVPL (SEQ ID NO: 18), and a heavy chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYW (SEQ ID NO: 3), • CDR2 whose amino acid sequence comprises or consists of DPDSGGT (SEQ ID NO: 5), and • CDR3 whose amino acid sequence comprises or consists of AREGEFAWFAY (SEQ ID NO: 6). The antibody-drug conjugate of claim 1, wherein said anti-ETB-R comprises a light chain comprising from the N-terminus to the C-terminus: • CDR1 whose amino acid sequence comprises or consists of KSSQSLLDSDGKTYLN (SEQ ID NO: 8), • CDR2 whose amino acid sequence comprises or consists of LVSKLDS (SEQ ID NO: 9), and • CDR3 whose amino acid sequence comprises or consists of WQGTHFPYT (SEQ ID NO: 10), and a heavy chain comprising from the N-terminal end to the C-terminal end: • CDR1 whose amino acid sequence comprises or consists of GYTFTSYWMQ (SEQ ID NO: 11), • CDR2 whose amino acid sequence comprises or consists of TIYPGDGDTSYAQKFKG (SEQ ID NO: 12), and • CDR3 whose amino acid sequence comprises or consists of WGYAYDIDN (SEQ ID NO: 13).

4. An antibody-drug conjugate according to any one of claims 1 to 3 for use as a medicament.

5. Antibody-drug conjugate according to any one of claims 1 to 3 for use in the prevention and / or treatment of a tumor.

6. A pharmaceutical composition comprising the antibody-drug conjugate according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition according to claim 6 wherein said antibody-drug conjugate is at a dose of 1 to 1000 mg.

8. Pharmaceutical composition according to claim 6 or 7 for its use in the prevention and / or treatment of a tumor.

9. A pharmaceutical composition for use according to claim 8, said pharmaceutical composition being in a form suitable for administration by one of the following routes: parenteral, injectable, intratumoral, topical, by inhalation, subcutaneous, nasal, intratumoral or pulmonary.

10. Product of formula (XV): TC-B-(LM)-AS (XV), in which: TC is a conjugation head selected from: maleimide coupled to glutamic acid (Mal-Glu), polyether, amino acids, benzyl group, amines, ketones and thioester linkers stabilized by hydrolysis with haloacetamides, ketosulfones, methylsulfonylphenyloxadiazole, carbonylacrylic; B represents “PEG2-Glu-(Glu-Met)” and is absent or present; L is a linker cleavable by lysosomal cathepsins, said cleavable linker being optionally coupled to p-aminobenzyl alcohol (PAB) or one of its derivatives; M is a drug selected from: topoisomerase inhibitors, alkylating agents, antimicrotubule agents and their prodrug forms; and AS is a solubilizing agent chosen from: poly-sarcosine (PSAR) and polyethylene glycol (PEG).

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