Antibody-drug conjugate comprising an Anti-etb-r antibody and uses thereof

Abstract

The present invention relates generally to the field of medicine. More particularly, it relates to novel antibody-drug conjugates and uses thereof.

Description

[0001] DESCRIPTION TITLE: ANTIBODY-DRUG CONJUGATE AND ITS USESFIELD OF THE INVENTION The present invention relates generally to the field of medicine. More particularly, it relates to new antibody-drug conjugates and their uses. PRIOR ART The receptors for the different endothelins (designated ET1, ET2 and ET3 in humans) belong to the family of receptors with 7 transmembrane domains also designated GPCR 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. The endothelin axis and its receptors are involved in several physiopathological functions and dysfunctions. Non-limiting examples include high blood pressure, atherosclerosis,coronary heart disease, renal dysfunction, cerebrovascular disease, Crohn's disease, pulmonary fibrosis, asthma, etc. In addition, endothelin receptors have also been found to be associated with the development of many cancers, promoting the proliferation, survival and dissemination of cancer cells as well as angiogenesis. Regarding the endothelin receptor subtype B (ETB-R), the latter shows 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 paraganglioma, Kaposi's sarcoma, glioblastomas (brain tumors),and cases of bladder cancer. It has also been established that the B subtype of endothelin receptors 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, malignant pituitary or pineal germ cell tumors, and plexus tumors such as choroid plexus carcinomas can be cited. Finally, retinoblastomas, Ewing's sarcoma, osteosarcoma, neuroblastomas can also be mentioned.rhabdomyosarcomas and nephroblastomas. ETB-R is also overexpressed in certain patient populations with monoclonal gammopathies associated with hematological malignancies, such as multiple myeloma, Waldenström'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. 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. Only, in the arsenal of passive immunotherapy of cancers using monoclonal antibodies,no ADC to date has proven itself. Moreover, while ADCs appear to be a promising therapeutic tool, some are highly 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. To fill this therapeutic gap and meet the needs of patients, the inventors have therefore set themselves the goal of obtaining an optimized antibody-drug conjugate (ADC) capable of targeting conformers of the endothelin receptor subtype B expressed on the surface of cancer cells and causing their cell death. BRIEF OVERVIEW OF THE INVENTION Faced with this major challenge of having safe and effective tools to fight cancer,The inventors have developed new optimized antibody-drug conjugates (ADCs). 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 In its most general aspect, the invention relates to an antibody-drug conjugate (ADC) comprising the 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,the benzyl group, amines, ketones and thioester linkers stabilized upon hydrolysis with haloacetamides, keto-sulfones, 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 selected from: polysarcosine (PSAR) and polyethylene glycol (PEG), and wherein the drug-antibody ratio (DAR) is from 2 to 16 and said anti-ETB-R is capable of targeting a discontinuous epitope comprising or consisting of the sequences 28ERGFPPDRATP38 (SEQ ID NO: 1) and 70EVPKGDRT77 (SEQ ID NO: 2). Unexpectedly,the inventors have 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 of the latter. 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 have also demonstrated that the concentration of the antibody-drug conjugate of the invention in tumors was well beyond that which was predictable. The inventors, by developing the antibody-drug conjugate as described above, have therefore made available to the medical profession a new, innovative therapeutic tool for fighting cancer that is safe and effective. According to another embodiment,The subject of the invention is the antibody-drug conjugate (ADC) as described above comprising the formula (II): Ac-[TC-(LM)-AS] (II), in which:^ Ac is an anti-ETB-R antibody, a fragment thereof or a derivative thereof;^ 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 to hydrolysis with haloacetamides, keto-sulfones, methylsulfonylphenyloxadiazole, carbonylacrylic acid;^ 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 selected from: polysarcosine (PSAR) and polyethylene glycol (PEG), and wherein the drug-antibody ratio (DAR) is from 2 to 16 and said anti-ETB-R is capable of targeting a discontinuous epitope comprising or consisting of the sequences 28ERGFPPDRATP38 (SEQ ID NO: 1) and 70EVPKGDRT77 (SEQ ID NO: 2). By "medicine (M)", reference is made to any substance or composition presented as having curative or preventive properties with respect to human or animal diseases. In the invention, it is selected from: topoisomerase inhibitors, alkylating agents, antimicrotubule agents and their prodrug forms. In the family of topoisomerase I inhibitors, we can cite irinotecan, topotecan, camptothecin, SN38, exatecan, silatecan, cositecan, lurtotecan, gimatecan,bleotecan and rubitecan. In the family of alkylating agents, we can cite dacarbazine. In the family of antimicrotubule agents, we can cite the family of taxanes including in particular paclitaxel. As mentioned above, this drug can be in a prodrug form, that is to say an inactive form which, after its 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 can 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. 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 subject of the invention is the antibody-drug conjugate as described above in which M is exatecan. 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 region (or domain) (VH) and a constant region comprising 3 domains, usually designated CH1, CH2 and CH3. Each light chain comprises a variable region (or domain) (VL) 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: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The three-dimensional folding of these variable regions is such that the 6 CDRs are exposed on the same side of the protein and allow the formation of a specific structure recognizing a determined 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,Examples include Fab, F(ab')2, Fv, and other fragments that 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 solely 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 solely 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 that is too short to allow the formation of an scFv. The fragments according to the invention also cover 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 means, it is also possible to generate single or fused fragments of the antibody according to the present invention,exhibiting 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-type molecules that can be produced using phage display techniques or other random selection techniques and humanized mice such as Harbor Mice® technology. Thus, "antibody fragments" and "antibody derivatives" cover all molecules that contain a structure, advantageously peptide,which is part of the recognition site (i.e. the part of the antibody that binds to or combines with the epitope or 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". As mentioned above, in the invention is implemented an antibody, a fragment thereof or a derivative thereof, capable of recognizing the endothelin receptor of the B subtype (ETB-R; SEQ ID NO: 59). In the invention, it is capable of targeting a discontinuous epitope comprising or consisting of the sequences 28ERGFPPDRATP38 (SEQ ID NO: 1) and 70EVPKGDRT77 (SEQ ID NO: 2) and in particular has an affinity for said discontinuous epitope whose Kd value is less than or equal to 0.15 ± 0.03 nM. In addition,It is interesting to note that the antibody of the invention is capable of inhibiting the phospholipase C pathway and endothelin-induced migration. On the other hand, it fails to decrease endothelin-induced ERK1 / 2 phosphorylation. All these properties being in particular those of the antibody named Rendomab B4 [abbreviated RB4], advantageously the antibody of the invention is therefore Rendomab B4 [abbreviated RB4]. By “Rendomab B4”, reference is made to the antibody described in Aurélie Borrull et al. (2016, Rendomab B4, a monoclonal antibody that discriminates the human endothelin B receptor of melanoma cells and inhibits their migration, mAbs, 8:7, 1371-1385) or to an optimized version thereof (better affinity for example). As mentioned,this is known to recognize a discontinuous epitope on the endothelin receptor of subtype B (ETB-R; SEQ ID NO: 59) comprising or consisting of the sequences 28ERGFPPDRATP38 (SEQ ID NO: 1) and 70EVPKGDRT77 (SEQ ID NO: 2) present at the level of the N-terminal domain (Figure 27; Davenport AP et al. New drugs and emerging therapeutic targets in the endothelin signaling pathway and prospects for personalized precision medicine. Physiol Res.2018 Jun27;67(Suppl 1):S37-S54) with an affinity whose Kd value is equal to 0.15 ± 0.03 nM. As indicated in Aurélie Borrull et al. (2016), this was obtained by DNA immunization as previously described (Bertrand Allard et al. (2013) Generation and characterization of rendomab-B1, a monoclonal antibody displaying potent and specificantagonism of the human endothelin B receptor, mAbs, 5:1,56-69; Bertrand Allard et al. Electroporation-Aided DNA Immunization Generates Polyclonal Antibodies Against the Native Conformation of Human Endothelin B Receptor, DNA and Cell Biology 201130:9, 727-737): Splenocytes collected from the 2 best-responding mice were fused with NS1 mouse myeloma cells. Hybridoma supernatants were examined for the production of specific anti-ETB-R antibodies by a live-cell ELISA assay, using untransfected CHO cells and CHO-ETB-R cells as targets, before confirmation of antibody specificity and reactivity by flow cytometry. After subcloning by limiting dilutions, the antibodies were isotyped using a mouse immunoglobulin isotyping kit according to the manufacturer's instructions (Pierce) and purified by affinity chromatography on Protein A Sepharose (Millipore). In another embodiment,The subject of the invention is therefore the antibody-drug conjugate as described above, in which said anti-ETB-R is capable of targeting a discontinuous epitope comprising or consisting of the sequences 28ERGFPPDRATP38 (SEQ ID NO: 1) and 70EVPKGDRT77 (SEQ ID NO: 2) and in particular has an affinity for said discontinuous epitope whose Kd value is less than or equal to 0.15 ± 0.03 nM. According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R has an affinity for said discontinuous epitope (comprising or consisting of the sequences 28ERGFPPDRATP38 (SEQ ID NO: 1) and 70EVPKGDRT77 (SEQ ID NO: 2)) whose Kd value is less than or equal to 0.15 ± 0.03 nM. Advantageously, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is Rendomab B4 (Aurélie Borrull et al. 2016, Rendomab B4,a monoclonal antibody that discriminates the human endothelin B receptor of melanoma cells and inhibits their migration, mAbs, 8:7, 1371-1385). Note that Rendomab B4 may, depending on the needs of the invention, be substituted (replaced) by one of the following antibodies: SKM101, SKM103, SKM104, SKM106 and SKM107 (or optimized versions thereof); the sequences of which are summarized in Table 1 below., Table 1. Anti-ETB-R & corresponding sequences.aa: amino acid; nt: nucleotide.Antibody drug conjugate (ADC) refers to 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 particularly 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. 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. These molecules include: the bioconjugation head (also called spacer or connectors), a linker (which can be coupled to the p-aminobenzyl alcohol (PAB) leaving group or one of its derivatives) and a solubilizing agent. By "bioconjugation head", we mean maleimide coupled to glutamic acid (Mal-Glu), polyether, amino acids, benzyl group, amines, ketones and thioester linkers stabilized by hydrolysis with haloacetamides, keto-sulfones, methylsulfonylphenyloxadiazole, carbonylacrylic. In particular, reference is made to maleimide coupled to glutamic acid (Mal-Glu), polyether, amino acids, benzyl group, amines and ketones. Advantageously, it is maleimide coupled to glutamic acid (Mal-Glu). According to another embodiment,The subject of the invention is therefore 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 subject of the invention is the antibody-drug conjugate as described above, in which TC is a maleimide conjugation head coupled to a glutamic acid. By "linker (L)" is meant in the invention a short assembly of amino acids cleavable by lysosomal cathepsins chosen from: the dipeptide Val-C1t, 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 the PAB to form the linkers Phe-Lys-PAB and Val-Ala-PAB. 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), 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. Note that between the bioconjugation head and the linker, an element B representing “PEG2-Glu-(Glu-Met)” can be added. Element B may therefore be absent or present in the ADC of the invention. By "solubilizing agent (SA)" is meant in the invention either polysarcosine (PSAR) or polyethylene glycol (PEG). Concerning the PSAR, this may be a monomer or a polymer whose PSAR number varies from 2 to 40,in particular from 8 to 24 and advantageously be 10 or 16. The polymer may 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 number of PSARs 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 number of PSARs is 10. 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 PEG. 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. "The drug-antibody ratio (DAR)" refers to the average number of drugs conjugated to the 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. In view of the above, it is therefore understood that according to another embodiment, the invention therefore has as its subject the antibody-drug conjugate as described above, said antibody-drug conjugate comprising the formula (III): Ac-[Mal-Glu-B-(LM)-AS] (III), in which:^ Ac is an anti-ETB-R antibody, a fragment thereof or a derivative thereof;^ 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-C1t, 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 chosen from: irinotecan, topotecan, camptothecin, SN38, exatecan, silatecan, cositycan, lurtotecan, gimatecan, bleotecan, rubitecan, dacarbazine, paclitaxel and their prodrug forms; and^ AS is a solubilizing agent selected from: polysarcosine (PSAR) and polyethylene glycol (PEG), and wherein the drug-antibody ratio (DAR) is from 2 to 16 and said anti-ETB-R is capable of targeting a discontinuous epitope comprising or consisting of the sequences 28ERGFPPDRATP38 (SEQ ID NO: 1) and 70EVPKGDRT77 (SEQ ID NO: 2). It is also understood that according to another embodiment, the invention therefore relates to the antibody-drug conjugate as described above, said antibody-drug conjugate comprising the formula (IV): Ac-[Mal-Glu-(LM)-AS] (IV),in which:^ Ac is an anti-ETB-R antibody, a fragment thereof or a derivative thereof;^ 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-C1t, 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;^ M is a drug chosen from: irinotecan, topotecan, camptothecin, SN38, exatecan, silatecan, cositycan, lurtotecan, gimatecan, bleotecan, rubitecan, dacarbazine, paclitaxel and their prodrug forms; and^ AS is a solubilizing agent selected from: polysarcosine (PSAR) and polyethylene glycol (PEG),and wherein the drug-antibody ratio (DAR) is from 2 to 16 and said anti-ETB-R is capable of targeting a discontinuous epitope comprising or consisting of the sequences 28ERGFPPDRATP38 (SEQ ID NO: 1) and 70EVPKGDRT77 (SEQ ID, NO :2).According to another embodiment, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R has an affinity for said discontinuous epitope (comprising or consisting of the sequences 28ERGFPPDRATP38 (SEQ ID NO: 1) and 70EVPKGDRT77 (SEQ ID NO: 2)) whose Kd value is less than or equal to 0.15 ± 0.03 nM. Advantageously, the subject of the invention is the antibody-drug conjugate as described above, in which said anti-ETB-R is Rendomab B4 (Aurélie Borrull et al. 2016, Rendomab B4, a monoclonal antibody that discriminates the human endothelin B receptor of melanoma cells and inhibits their migration, mAbs, 8:7, 1371-1385). According to another embodiment, the invention therefore relates to 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, in which L is a linker coupled to p-aminobenzyl alcohol (PAB) chosen from: Phe-Lys-PAB and Val-Ala-PAB. According to another embodiment, the subject of the invention is therefore 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 subject of the invention is the antibody-drug conjugate as described above, in which M is exatecan and its prodrug forms. 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 in which the number of PEGs varies from 2 to 40 (advantageously is 10 or 16). 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)-PEG10 of formula (V):. or Mal-Glu-(Val-Ala-PAB-M)-PEG10 of formula (VI): 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)-PEG16 of formula (VII): or Mal-Glu-(Val-Ala-PAB-M)-PEG16 of formula (VIII): (VIII). 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)-PSAR10 of formula (IX): According to another embodiment, the invention relates to the antibody-drug conjugate as described above, in which the anti-ETB-R, a fragment thereof or a derivative thereof, is linked to Mal-Glu-(Phe-Lys-PAB-M)-PSAR n or Mal-Glu-(Val-Ala-PAB-M)-PSAR nwhere n varies from 1 to 40. 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, a fragment thereof or a derivative thereof, is linked to:^ Mal-Glu-(Phe-Lys-PAB-M)-PEG10 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. 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. 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)-PEG10 of formula (X):. or Mal-Glu-(Val-Ala-PAB-exatecan)-PEG10 of formula (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)-PEG16 of formula (XII): or Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16 of formula (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, a fragment thereof or a derivative thereof, is linked to Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSAR10 of formula (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, a fragment thereof or a derivative thereof, 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 may be in a prodrug form.In view of the above, it is understood that according to another embodiment, the invention relates to the antibody-drug conjugate as described above, in which the anti-ETB-R, a fragment thereof or a derivative thereof, is linked to:^ Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG10 of formula (X);^ Mal-Glu-(Val-Ala-PAB-exatecan)-PEG10 of formula (XI);^ Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG16 of formula (XII);^ Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16 of formula (XIII);^ Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSAR10 of 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, where 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)-PEG10 of formula (X);^ Mal-Glu-(Val-Ala-PAB-exatecan)-PEG10 of formula (XI);^ Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG16 of formula (XII);^ Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16 of formula (XIII);^ Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSAR10 of 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.According to another embodiment, the invention relates to the antibody-drug conjugate as described above, in which said anti-ETB-R, a fragment thereof or a derivative thereof, is linked to Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG16 of formula (XII):. 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)-PEG16 of formula (XIII): According to another embodiment, the subject of the invention is 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 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.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. According to another embodiment, the invention advantageously relates to the antibody-drug conjugate as described above, wherein 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 receptor Fcs FcγRI, FcγRII and FcγRIII as well as to complement C1q. This mutation is used to prevent activation of the receptor Fcs.Moreover, many therapeutic antibodies using LALA mutations have been the subject of clinical trials (for example bimagrumab NCT01925209, cemiplimab NCT02383212, galcanezumab NCT03559257, progolimab NCT03912389, risankizumab NCT02684370, spesolimab NCT03482635, teplizumab NCT00385697). 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, those of Synnafix, Mablink, Araris, Catalant, ThioBridge® and BTG (β-transglutaminase) may be mentioned. 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.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. 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-of-parts for the simultaneous, separate or sequential combined administration of said ADC and said other product. 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). 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 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 use in the prevention and / or treatment of a primary and metastatic solid tumor. In particular, the subject of the invention is also the antibody-drug conjugate as described above for use in the prevention and / or treatment of a relapse (e.g. reappearance of the primary tumor after a period of remission). Cancerous solid tumors, identifiable by a localized cluster of cells, are distinguished from cancers of the blood cells, such as leukemias, in which the 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 they alone represent 90% of human cancers. There are two types of tumors:^ carcinomas originating from epithelial cells (skin, mucous membranes, glands). Examples: breast, lung, prostate, intestinal cancers, etc.^ sarcomas, less common, originating from connective tissue cells (known as "support" tissues). Examples: bone, cartilage cancers, etc.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;^ kidney tumors and adrenal tumors such as pheochromocytoma and paragangliomas;^ Kaposi's sarcoma;^ glioblastomas (brain tumors);^ childhood brain tumors including embryonal tumors (egmedulloblastomas, rhabdoid and teratoid tumors) and glial tumors such as gliomas or ependydomas;^ pituitary or pineal malignant germ cell tumors;^ plexus tumors such as choroid plexus carcinomas;^ retinoblastomas;^ Ewing's sarcoma;^ osteosarcoma;^ neuroblastomas;^ rhabdomyosarcomas;^ nephroblastomas;^ monoclonal gammopathies associated with hematological malignancies, such as multiple myeloma, Waldenström's disease and B-cell lymphomas;^ lymphoma such as salivary gland lymphomas and lymphatic gland lymphomas;^ myelodysplasias;^ adenocarcinomas; and^ malignant hematological diseases (primary or metastatic).According to another aspect of the invention, the invention relates to a pharmaceutical composition comprising the antibody-drug conjugate as described above (as active ingredient or as active substance) and a pharmaceutically acceptable vehicle. 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. 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 1000 mg or at a (unit) dose of 0.015 to 15 mg / kg (based on a man weighing 66.6 kg).“From 1 to 1000 mg” also means that the (unit) dose can be from 1 to 100 mg, from 1 to 200 mg, from 1 to 300 mg, from 1 to 400 mg, from 1 to 500 mg, from 1 to 600 mg, from 1 to 700 mg, from 1 to 800 mg, from 1 to 900 mg, from 100 to 1000 mg, from 200 to 1000 mg, from 300 to 1000 mg, from 400 to 1000 mg, from 500 to 1000 mg, from 600 to 1000 mg, from 700 to 1000 mg, from 800 to 1000 mg, from 900 to 1000 mg, from 100 to 900 mg, from 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.“From 0.015 to 15 mg / kg” also means that the (unit) dose may be 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, 12 to 15 mg / kg, 13.5 to 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 may 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. According to another aspect of the invention, the invention relates to the pharmaceutical composition as described above for 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 invention relates to 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 (e.g. 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.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 in an adult (adult) or in a child (minor; pediatrics). 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 primary and / or metastatic solid tumor and / or a relapse. In particular, 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 primary solid tumor.In particular, 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 metastatic solid tumor. In particular, the subject of the invention is also 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 subject of the invention is also the pharmaceutical composition as described above for its use as described above in the prevention and / or treatment of a relapse (e.g. reappearance of the primary tumor after a period of remission).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 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;^ kidney tumors and adrenal tumors such as pheochromocytoma and paragangliomas;^ Kaposi's sarcoma;^ glioblastomas (brain tumors);^ childhood brain tumors including embryonal tumors (egmedulloblastomas, rhabdoid and teratoid tumors) and glial tumors such as gliomas or ependydomas;^ pituitary or pineal malignant germ cell tumors;^ plexus tumors such as choroid plexus carcinomas;^ retinoblastomas;^ Ewing's sarcoma;^ osteosarcoma;^ neuroblastomas;^ rhabdomyosarcomas;^ nephroblastomas;^ monoclonal gammopathies associated with hematological malignancies, such as multiple myeloma, Waldenström's disease and B-cell lymphomas;^ lymphoma such as salivary gland lymphomas and lymphatic gland lymphomas;^ myelodysplasias;^ adenocarcinomas; and^ malignant hematological diseases (primary or metastatic).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. As sterile compositions for parenteral administration, mention may be made of 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.The compositions for topical administration may be, for example, creams, lotions, mouthwashes, nasal or eye drops or aerosols. Advantageously, the subject of the invention is the pharmaceutical composition as described above for its use as described above, 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. 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. According to another aspect of the invention, the subject of the invention is a product comprising the 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 upon hydrolysis with haloacetamides, keto-sulfones, 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: polysarcosine (PSAR) and polyethylene glycol (PEG). According to another embodiment, this relates to a product comprising the formula (XVI) :TC-(LM)-AS (XVI), 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 upon hydrolysis with haloacetamides, keto-sulfones, methylsulfonylphenyloxadiazole, 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). According to another embodiment, the invention therefore relates to the product as described above,in which TC is a conjugation head selected from: maleimide coupled to a glutamic acid (Mal-Glu), polyether, amino acids, benzyl group, amines and ketones. In particular, the subject of the invention is the product as described above, in which TC is a maleimide conjugation head coupled to a glutamic acid (Mal-Glu). According to another embodiment, the subject of the invention is the product as described above, in which L is a linker selected from: the dipeptide Val-C1t, 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, 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: Phe-Lys dipeptide and Val-Ala dipeptide. 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. 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. 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 polymer, tri-branched, cyclic or linear with the number of PEGs varying 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 PEG number is 16. According to another embodiment, the subject of the invention is the product as described above, said product comprising the formula (XVII): Mal-Glu-B-(LM)-AS (XVII), 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-C1t, 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 chosen from: irinotecan, topotecan, camptothecin, SN38, exatecan, silatecan, cositycan, lurtotecan, gimatecan,bleotecan, rubitecan, dacarbazine, paclitaxel and their prodrug forms; and^ AS is a solubilizing agent selected from: polysarcosine (PSAR) and polyethylene glycol (PEG). According to another embodiment, the subject of the invention is the product as described above, said product comprising the formula (XVIII): Mal-Glu-(LM)-AS (XVIII), 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-C1t, 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 chosen from: irinotecan, topotecan, camptothecin, SN38, exatecan, silatecan, cositecan, lurtotecan, gimatecan, bleotecan, rubitecan, dacarbazine,paclitaxel and their prodrug forms; and^ AS is a solubilizing agent chosen from: polysarcosine (PSAR) and polyethylene glycol (PEG). According to another embodiment, the subject of the invention is the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-M)-PEG10 of formula (XIX):, or Mal-Glu-(Val-Ala-PAB-M)-PEG10 of formula (XX): (XX). According to another embodiment, the invention relates to the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-M)-PEG16 of formula (XXI): or Mal-Glu-(Val-Ala-PAB-M)-PEG16 of formula (XXII): (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) : (XXIII). According to another embodiment, the subject of the invention is the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-M)-PSARn or Mal-Glu-(Val-Ala-PAB-M)-PSARn where n varies from 1 to 40. In view of the above, it is understood that according to another embodiment, the subject of the invention is 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.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 (egsalts, 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. According to another embodiment, the subject of the invention is the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG10 of formula (XXV):. or Mal-Glu-(Val-Ala-PAB-exatecan)-PEG10 of formula (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)-PEG16 of formula (XXVII): or Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16 of formula (XXVIII): 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-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSAR10 of formula exatecan may be in a prodrug form. According to another embodiment, the invention relates to the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-exatecan)-PSAR n or Mal-Glu-(Val-Ala-PAB- exatecan)-PSAR nwhere n varies from 1 to 40, exatecan can be in a prodrug form. 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)-PEG10 of formula (XXV);^ Mal-Glu-(Val-Ala-PAB-exatecan)-PEG10 of formula (XXVI);^ Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG16 of formula (XXVII);^ Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16 of formula (XXVIII);^ Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSAR10 of formula (XXIX);^ Mal-Glu-(Phe-Lys-PAB-exatecan)-PSARn where n ranges from 1 to 40; or^ Mal-Glu-(Val-Ala-PAB-exatecan)-PSARn where n ranges from 1 to 40, where 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)-PEG10 of formula (XXV);^ Mal-Glu-(Val-Ala-PAB-exatecan)-PEG10 of formula (XXVI);^ Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG16 of formula (XXVII);^ Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16 of formula (XXVIII);^ Mal-Glu-PEG2-Glu-(Glu-Met-PAB-(Val-Ala)-exatecan)-PSAR10 of 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.According to another embodiment, the invention relates to the product as described above, said product being Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG16 of formula (XXVII):. According to another embodiment, the subject of the invention is the product as described above, said product being Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16 of formula (XXVIII): In any respect, it should be noted that the various aspects of the invention, as well as the various 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. Furthermore, the present invention is illustrated, without however being limited thereto, by the following figures and examples. LIST OF FIGURES Figure 1. Analysis of DAR by HIC (hydrophobic interaction chromatography). Figure 2. Analysis of ADCs by size exclusion chromatography (SEC). Figure 3. Analysis of the stability of ADCs after a freeze-thaw cycle by size exclusion chromatography (SEC). Figure 4. Stability of ADCs in sera.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 serumFigure 5. In vitro cytotoxicity studies.Figure 6. Efficacy of ADCs tested in vivo in the uveal melanoma model 92.1. (A) Tumor growth measurement. (B) Survival curve. Statistics: No star: 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.Figure 7. Efficacy of ADCs tested in vivo in the Mel-202 uveal melanoma model.(A) Tumor growth measurement. (B) Survival curve.Statistics: No star: 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.Figure 8. Efficacy of ADCs tested in vivo in the MC38-hETBR colon model.(A) Tumor growth measurement. (B) Mouse weight measurement. Figure 9. ETB-R expression in a U266B1 multiple myeloma cell line measured by flow cytometry (FACS). Figure 10. Chemical structure of Deruxtecan (Maleimide-GGFG-DxD). Figure 11. Chemical structure of CL2A-SN38 (Payload linker structure used in TRODELVY®). Figure 12. Chemical structures. (A) Chemical structure of Maleimide-Glu-(Val-Ala-PAB-Exatecan)-PSAR. 10 (Mablink PSAR-linker-Exatécan). (B) Mal-PEG 10 -Phe-Lys-PAB-Exatecan (L3) Figure 13. Characterization by Hydrophobic Interaction Chromatography (HIC). (A) LALA mutated SKM104 naked antibody (SKM104 MA). (B) LALA mutated SKM104 DAR 8 conjugate with CL2A-SN38. (C) LALA mutated SKM104 DAR 8 conjugate with L2 (Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG 10 ). (D) DAR 8 SKM104 mutated LALA conjugate with L1 (Mal-Glu-(Val-Ala-PAB-exatecan)-PEG 10). (E) LALA-mutated DAR 8 SKM104 conjugate with Deruxtecan. (F) LALA-mutated DAR 8 SKM104 conjugate with Mablink PSAR-linker (Mal-Glu-(Val-Ala-PAB-exatecan)- PSAR 10). (G) LALA mutated DAR 4 SKM104 conjugate with vc-MMAE. (H) LALA mutated DAR 8 SKM104 conjugate with L3 (Mal-PEG10-Phe-Lys-PAB-Exatecan). Figure 14. In vitro cytotoxicity results. (A) SKM104 MA L2 at DAR 8 and DAR 4 compared to other topoisomerase inhibitor ADC platforms in tumor cells and (B) the corresponding IC50 (nM).Figure 15. SKM104 MA L1 versus SKM104 MA L2. In vitro cytotoxicity assay in solid tumor cell lines (melanoma, glioblastoma, lung cancer, breast cancer, kidney cancer) and hematological tumor cell lines (multiple myeloma) and the corresponding IC50 (nM).Figure 16. SKM104 MA L1 versus SKM104 MA L2. In vitro cytotoxicity assay in normal human endothelial cells, HHSEC (Human Hepatic Sinusoidal Endothelial Cells) and HUVEC (Human Umbilical Vein Endothelial Cells).Figure 17. Bystander effect » in vitro of SKM104 MA L1 vs SKM104 MA L2.Representative histograms of SKM104 MA L1 vs SKM104 MA L2 and negative controls, isotype control (IC) and culture medium condition (CTRL without antibody) at concentrations of 50 nM (A) and 100 nM (B) showing the % in vitro viability on a mixture of cells: CHO-K1 (ETBR-negative cells) at 67% and HS746T gastric tumor cells (ETBR-positive cells) at 33%. (C) ETBR expression measured by flow cytometry on HS746T (ETBR-positive tumor cells) and CHO-WT (ETBR-negative cells). Figure 18. In vitro efficacy of SKM104 MA L2 versus ENHERTU® and Datopotamabderuxtecan (Dato-DxD) in breast cancer tumor cells. (A) Summary table of 50% inhibitory concentration (IC) values. 50) obtained with ADCs and (B) representative in vitro cytotoxicity curves in triple negative breast cancer cells (MDAMB231 and BT549).Figure 19. In vitro efficacy of SKM104 MA L2 versus ENHERTU® in glioma tumor cells. (A) Table of IC50 values ​​and (B) representative in vitro cytotoxicity curves in patient-derived glioma cells. Figure 20. In vitro efficacy of SKM104 MA L2 versus ENHERTU® in gastric tumor cells (A) Table of IC50 values ​​obtained with ADCs in gastric and colon tumor cells and (B) representative in vitro cytotoxicity curves in gastric (Hs746T) and colon (Caco2) cells. Figure 21. In vitro efficacy of SKM104 MA L2 in pancreatic tumor cells and the table of Corresponding IC50.Figure 22. In vitro efficacy of SKM104 MA L2 versus ENHERTU® and Datopotamabderuxtecan (Dato-DxD) in lung tumor cells.(A) Table of IC50 values ​​obtained with ADCs tested on lung tumor cells and (B) representative in vitro cytotoxicity curves in two patient-derived lung tumor cell lines.Figure 23. In vivo efficacy of SKM104 MA L2. In vivo efficacy of SKM104 MA L2 versus (A) SKM104 MA DXD (Daiichi); (B) SKM104 MASN38 (Gilead (Immunomedics) and (C) SKM104 MA Mablink (Mablink-PSAR platforms) after two iv injections at doses of 5 and 10 mg / ml in mice xenografted with the RPMI8226 tumor model.Figure 24. In vivo efficacy of SKM104 MA L2. In vivo efficacy of SKM104 MA L2 versus ENHERTU® after an iv injection at the indicated doses in mice xenografted with the MKN1 gastric tumor model. Figure 25. Stability of ADCs in rat plasma. Monitoring of the % variation of the DAR (Drug to Antibody Ratio) compared to the DAR at t=0. Figure 26. Monitoring of concentrations.Monitoring of total antibody and ADC plasma concentrations in rat plasma after a single iv injection of 60 mg / kg for SKM104 MA L1, SKM104 MA L2, and ENHERTU®. Figure 27. Discontinuous epitope of Rendomab B4. EXAMPLES EXAMPLE No.1 - Production of ADCs MATERIALS & METHODS Linkers-drugsThe Linkers-drugs used are:^ Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG16 of formula (XXVII). ^Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16 of formula (XXVIII) These were produced by L EVENA. AntibodiesThe anti-ETB-R antibodies used are:^ SKM101; and^ SKM104 (with or without LALA mutation).An irrelevant antibody was also used: Motavizumab. Conjugation protocol This was carried out by ABZENA and includes 3 steps. During the first reduction step, the reducing agent TCEP (tris(2-carboxyethyl)phosphine) was tested at 8 molar equivalents and 10 molar equivalents respectively. During this first step, the duration of the reduction reaction was 1 hour, the temperature was 40°C and the concentration was 5.0 mg / mL. During the second conjugation step, 14.0 ± 4 molar equivalents of the reagent Mal-Glu-(Val-Ala-PAB-exatecan)-PEG 16 or Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG reagent 16were used with the different antibodies. In this second step, the conjugation reaction time was 1h, the temperature was 22°C and 10% DMSO was used as co-solvent. In the third purification step, preparative size exclusion chromatography (Superdex increase 20010 / 300 GL) as well as ultrafiltration and diafiltration were used. In addition, PBS + 10% isopropanol was used as eluent. Characterization of ADCs The reactions were analyzed by HIC (hydrophobic interaction chromatography), LC-MS (liquid chromatography mass spectrometry) and size exclusion chromatography (SEC). The ADCs SKM104 (with or without LALA mutation) and Motavizumab were produced in larger quantities according to the same protocol. Concentrations were determined by UV spectroscopy at 280 nm and using the following formula: où :^ A280: Absorption at 280 nm,^ MW: Molecular weight of the ADC,^ LP: linker-payloads, and^ mAb: monoclonal antibodies. Stability was monitored after a freeze-thaw cycle by analytical size exclusion chromatography (SEC). RESULTS At the end of the conjugation protocol, the ADCs obtained were all stable in PBS. The DAR (drug-antibody ratio) was analyzed by HIC (hydrophobic interaction chromatography) and it was 8 in the different conditions of TCEP (8 and 10 molar equivalents) and linker-payload reagents (14 molar equivalents for SKM104 and SKM101, and 18 molar equivalents for Motavizumab) (Figure 1). 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).Analysis by size exclusion chromatography (SEC) at 280 demonstrated that the ADCs produced had a high monomeric purity (greater than 95%) (Figure 2) including after a freeze-thaw cycle (greater than 99%) (Figure 3) where the data generated showed that the ADCs are very stable and that there is no aggregation phenomenon. Finally, the conjugation protocol implemented made it possible to produce the ADCs of the invention, which were characterized as follows: Table 2. Summary of characteristics of the produced ADCsEXAMPLE No. 2 - Stability of ADCs in serumMATERIALS & METHODS ADCs tested SKM104-[Mal-Glu-(Val-Ala-PAB-exatecan)-PEG 16]Clinically validated control: ENHERTU®MatricesADCs were incubated in human or mouse serum at 1 mg / mL. 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 Protein A magnetic beads (Cytiva) were used. Capture: 50 µL of serum was mixed with 150 µL of PBS and then incubated with the beads for 2 hours at room temperature, 1200 rpm. Washing: The beads were washed 3 times with 300 µL of PBS. Elution: This was carried out 3 times with 50 µL of 2 mM HCl solution (5 min incubation) and the aliquots were neutralized with 0.1 M Tris buffer. The extracted sample was treated with DTT. Analysis was performed by LC-MS (Waters Bioaccord). A column: UPLC protein BEH SEC was used. The mobile phase is 30% acetonitrile and 0.1% formic acid in water. Detection was done by: ESI, 400 to 7000 Da.The results were processed by mass spectrometry and represent an average of relative DAR based on the different species present in the sample. The percentage was calculated between the eluted sample and the initial product injected into the column. RESULTS A slight decrease in DAR was observed for ADC SKM104 and ENHERTU over time. 14% and 8% reduction in DAR was observed for ENHERTU and ADC SKM104 respectively in human serum (Figure 4A). 17% and 8% reduction in DAR was observed for ENHERTU and ADC SKM104 respectively in murine serum (Figure 4B). Conclusion ADC SKM104 showed better stability in serum than the clinical control ENHERTU used.The construction of the ADC according to the invention therefore offers an undeniable advantage in terms of improved stability and therefore reduced non-specific release of free toxin from the ADC of the invention into the circulation and therefore reduced toxicity.EXAMPLE No. 3 - In vitro cytotoxicity studiesMATERIALS & METHODS Cell linesThe following lines were used for the purpose of evaluating 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 (CVFSVF0001, 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 (CSTVAT000U, Eurobio Scientific) and 1% nonessential amino acids (X0557-100, Eurobio Scientific). 92.1v2 and UACC-257v2 were optimized in vivo to improve their growth rate in mouse xenografts. In vitro cytotoxicity assessment To determine the effect of ADC on cell viability, cells were seeded at 1500 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 the addition of 20 µL of CellTiter 96. ®AQueous One Solution Reagent (G3581, Promega). After 2 hours of incubation at 37°C, the absorbance was determined at 490nm (Multiskan, Thermo Fisher). The cell viability ratio (%) is calculated using the following formula: Viability 100 The 50% inhibitory concentration was calculated by GraphPad Prism software ® version 10. RESULTS 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)-PEG16] (abbreviated SKM104-Val-Ala-exatecan) induced a decrease in cell proliferation of 92.1 and Mel-202. The IC 50The calculated concentration of SKM104-[Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16] is 13 nM in 92.1 versus 37 nM in Mel-202 (Figure 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.Finally, these results demonstrated the efficacy of SKM104-[Mal-Glu-(Val-Ala-PAB-exatecan)-PEG16] on uveal melanoma lines.EXAMPLE No.4 - Efficacy of ADCs tested in vivo in two uveal melanoma models MATERIALS & METHODS Cell linesTwo 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.Tested compoundsADC: 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)-PEG16^ Vehicle: PBS^ On the day of treatment, the dilutions (see Table 3) were prepared from the stock solution in PBS. ^The different dilutions were kept at room temperature (to avoid thermal shock) for less than 1 hour. ^The required amount of ADC: SKM104 = 5 mg. Chicken Embryo Preparation Fertilized eggs (White Leghorn) 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 portion of the eggshell, 1 cm², was cut above the CAM. 15 eggs (minimum) were transplanted for each group. A significant number of deaths may have occurred a few hours after tumor transplantation (an invasive surgical procedure).Data could therefore be collected with less than 15 eggs per group (minimum of 10 eggs per group in the absence of treatment toxicity). Tumor cell amplification and transplantation Mel-202 and 92-1 tumor cells were cultured in RPMI-1640 medium + 10% FBS, 1% pyruvate and 1% penicillin / streptomycin. The cells were detached on day 9 with trypsin, washed with the culture medium and suspended in the graft medium. One million cells were inoculated onto the CAM of each egg on day 9. Then the eggs were randomized into groups. Treatments Tumors were detectable from day 10. The treatments of the different groups are detailed in the following table 3:.

[0002] [ C] Negative ControlPBS (Vehicle) 100 - -Skymab ADC [1]SKM104 100 0.06 0.1Skymab ADC [2]SKM104 100 0.30 0.5Skymab ADC SKM104 100 1.20 2.0 Table 3. Description of treatments by group Tumor growth assessment AJ-18, the upper part of the CAM (with tumor) was removed, washed with PBS, and then transferred to PFA (para-formaldehyde) (fixation for 48 hours). Then, the tumors were carefully cut from the CAM and weighed. A statistical analysis of tumor masses, one-way ANOVA, was performed for all groups. Embryo toxicity assessment In order to assess treatment-induced embryo toxicity:^ Embryo viability was checked every day.^ The number of dead embryos was counted for 18 days.^ The observation of any visible abnormalities 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 For all analyses, the statistical difference between groups was marked on the graphs by stars:^ No star: no statistical difference (p-value > 0.05);5 ^ 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 tumors0 The following Table 4 summarizes the list of samples collected during this study. Samples L. ecture Send to Samples Group Tumor Storage Conditions by Skymab Inovotion ☒ ☐ Tumeurs All Fixation (PFA 4%) and ☒ 4°C eggs storage in PBS ☒ ☐ gDNA 10Extraction and freezing from -20°C CAM lower Table 4. Description of treatments by group RESULTS Line 92-1 5 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 the ADC SKM104-[Mal-Glu-(Val-Ala-PAB-exatecan)-PEG 16] (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 cell line 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 is 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) against 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). Finally, these data showed the efficacy of the ADCs of the invention.EXAMPLE No.5 - Efficacy of ADCs tested in vivo in a colon model resistant to microtubule inhibitors MATERIALS & METHODS Cell linesA syngeneic MC38 colon line transfected with the human ETB-R target was used in a subcutaneous xenograft mouse model. Test CompoundsThe 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)-PEG16^ Vehicle: PBSThe 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 a negative control. SKM104 vedotin DAR4 was also used as a control.Cell Amplification and Engraftment MC38-hETBR cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS), 1% Glutamax, 1X sodium pyruvate, NEAA (non-essential amino acids) and supplemented with 5µg of puromycin, at 37°C in a humid atmosphere. Cells were detached with trypsin, washed and counted in the presence of Trypan blue to assess cell viability before being suspended in the engraftment medium. One million cells were injected subcutaneously into the right flank of 32 8-week-old female C57BL / 6 mice (Janvier Labs). Mice were randomized into 4 groups of 8 mice when the tumor volume reached 100 mm3. TreatmentsMice 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 µL.Animal Monitoring Animal viability and behavior were assessed daily. Animal weight and tumor volume were measured twice a week. Tumor volume was calculated using the formula: ^^^^^^ ^^^^^^^ = width^ × ^^^^^^^^2 Statistical Analysis Statistical analysis of tumor masses was performed for all groups using the Mann-Whitney test for comparing two independent samples. For all analyses, the statistical difference between groups was marked on the graphs with. étoiles :^ 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 Tumor growth of MC38-hETBR was significantly slowed when tumors were treated with SKM104-Val-Ala-exatecan DAR8, compared to IC-Val-Ala-Exatecan and SKM104 vedotin DAR4. Indeed, after 18 days of treatment, the inhibition of tumor growth was 85.2% for SKM104-Val-Ala-exatecan DAR8 compared to 65% for IC-Val-Ala-Exatecan and 27% for SKM104 vedotin DAR4 (Figure 8A). Finally, these data showed the efficacy of the ADCs of the invention. EXAMPLE No. 6 - Expression of ETB-R in hematological tumors MATERIALS & METHODS Cell lines U266B1 multiple myeloma tumor cells were used. Protocol U266B1 cells were incubated with SKM-104 at 15 µg / mL for 3 hours at 4°C.After 2 washes with PBS, the cells were incubated for 1 hour with an APC-labeled anti-IgG1 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 It was measured that more than 40% of multiple myeloma cells express the ETB-R target (Figure 9). EXAMPLE No.7 - Characterization by Hydrophobic Interaction Chromatography (HIC) MATERIALS & METHODS Antibody SKM104 huIgG1 mutated antibody (MA) with the LALA mutation. Drug-linkersDeruxtecan (Maleimide-GGFG-DxD; Figure 10), CL2A-SN38 (Figure 11), Mablink PASR-Linker Exatécan (Mal-Glu-(Val-Ala-PAB-exatecan)-PSAR10; Figure 12A), L3 (Mal-PEG10-Phe-Lys-PAB-exatecan; Figure 12B), L2 (Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG10; FormulaX) and L1 (Mal-Glu-(Val-Ala-PAB-exatecan)-PEG. 10; Formula XI) and vc-MMAE. Conjugation protocol This consists of 3 steps. In the first reduction step, the reducing agent TCEP (tris(2-carboxyethyl)phosphine) was tested at 8 to 12 molar equivalents. In this first step, the reduction reaction time was 16h and the temperature was 22°C. In the second conjugation step, 8 to 16.0 molar equivalents of the reagent (linker-drug) were used with the antibody. In this second step, the conjugation reaction time was approximately 1h, the temperature was 22°C and 10% DMSO was used as a co-solvent. In the third purification step, ultrafiltration centrifugation (Amicon 30K) was used. ADCs were collected in the final buffer PBS 20 mM Histidine, 8% sucrose (w / v), pH (5.5) for all ADCs except SKM104 MA SN38 which was recovered by the buffer 20 mM MES, pH 6.5.Characterization of ADCs The reactions were analyzed by LC-MS (liquid chromatography mass spectrometry) and the DAR (antibody drug ratio) of the ADC was determined by LC-MS (liquid chromatography mass spectrometry (LC-MS) and HIC-HPLC at 280 nm wavelength. The monomeric purities by SEC and retention times were analyzed by HIC (hydrophobic interaction chromatography). RESULTS The results of HIC analysis at 280 nm showed that all ADCs were produced with high monomeric purity, above 99%, except for SKM104 MA DxD (93%), SKM104 MA L1 (97.45%) and SKM104 MA SN38 (98%) (Figure 13A-H and Table 5).All ADCs exhibit a homogeneous DAR of 8, except for:^ SKM104 MA vc-MMAE which was produced by stochastic conjugation, generating heterogeneous species with an average DAR of 3.95; and^ SKM104 MA L2 with an average DAR of 3.96 (species ranging from DAR0 to DAR8 were obtained, with a majority at DAR 4). In terms of yield, the three ADCs with the best yields > 95% are: SKM104 MA SN38 (98%) > SKM104 MA L2 (99%) > SKM104-MA Mablink (100%), and the ADCs with the lowest yields are: SKM104 MA L1 (73%) <SKM104 MA DxD (82%) < SKM104 MA L3 (85%). En termes de temps de rétention pour les ADC à DAR 8, les trois ADC qui ont eu des tempsde rétention les plus proches de l’AC nu (6,72 min) sont : SKM104 MA Mablink (8,058 min),suivi par SKM104 MA SN38 (8,086 min) puis SKM104 MA L2 (8,217 min).The ADCs with the highest retention times were: SKM104 MA L3 (9.772 min) followed by SKM104MA L1 (8.942 min) and then SKM104 MA DxD (8.838 min). Unexpectedly, while the linkers are very close between SKM104 MA L2 and SKM104 MA L3 (a difference that is limited to the position of bibranched vs. linear PEG), SKM104 MA L2 had a better retention time (8.217 min vs. 9.772 min respectively) and therefore had less hydrophobic interaction. This is also true between SKM104 MA L1 and SKM104 MA L3 where SKM104 MA L1 had a better retention time (8.942 min vs. 9.772 min respectively). Surprisingly, it was also observed that SKM104 MA L2, while differing only by two amino acids Phe-Lys vs Val-Ala from SKM104MA L1, had a better retention time (8.217 min vs 8.942 min) and yield (98.92% vs. 73.46%). Table 5. Characterization by Hydrophobic Interaction Chromatography (HIC)EXAMPLE No. 8 - In vitro study of the efficacy and selectivity of SKM104 MA L2 vs. other SKM104 MA conjugates MATERIALS & METHODS Cell lines RPMI-8226, Plasmacytoma (ECACC 87012702, RPMI-1640 + 10% FBS + Glutamax). SK-MEL-5 (ATCC-HTB-70, EMEM + 10% FBS). SK-MEL-23 (J. Stagg Lab., RPMI-1640 + 10% FBS + Glutamax). MEL202 (Merck 13012457, RPMI-1640 + 10% FBS + Glutamax). U-266-B1 (ATCC, TiB-196, RPMI-1640 + 15% FBS + Glutamax).MOLP-8 (DSMZ, ACC 569 RPMI-1640 + 10% FBS + Glutamax). U-251 MG (Merck 9063001, EMEM + 10% FBS + Glutamax + NEAA + NaP). HN-13-0059 (PDX, PDC Glioblastoma, Wuxi Apptec, Wuxi in-house culture medium). MCF7 (ECACC, 86012803, EMEM +10% FBS + 2mM L-Glutamax +1% NEAA). LU-01-0604 (PDX, PDC, NSCLC, Wuxi Apptec, Wuxi in-house culture medium). 786-O (ATCC, CRL-1932, RPMI + 10% FBS + Glutamax). HUV-EC (ATCC, CRL-1730, RPMI + 10% FBS + Glutamax).HHSEC (Merck, HLP601, RPMI + 10% FBS + Glutamax). ADC SKM104 MA L1 (L1 = Mal-Glu-(Val-Ala-PAB-exatécan)-PEG. 10 ; Formula XI). SKM104 MA L2 (L2 = Mal-Glu-(Phe-Lys-PAB-exatécan)-PEG 10 ; Formula X). SKM104 MA L3 (L3 = Mal-PEG 10-Phe-Lys-PAB-exatecan). SKM104 MA SN38 (SN38 = CL2A-SN38). SKM104 MA DxD (DxD = Maleimide-GGFG-DxD). SKM 104 Ma Mablink (Mablink = Mal-Glu-(Val-Ala-PAB-exatecan)-PSAR10). SKM104 MA vc MMAE. In vitro cytotoxicity assessment To determine the effect of ADC on cell viability, cells were seeded at 1500 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: Viability 100 The 50% inhibitory concentration was calculated by GraphPad Prism software® version 10. Statistics Statistical comparisons of IC values 50 between different treatment groups were performed using non-parametric methods due to the non-normal distribution of the data and the relatively small sample sizes in each group. Specifically, the Wilcoxon signed-rank test was chosen for comparisons between independent groups, as it does not assume normality and is well suited for small data sets. A significance level of p < 0.05 was used to determine statistically significant differences between groups. RESULTS A dose-dependent decrease in cell viability of RPMI-8226 was observed. At the doses evaluated, the ADC SKM104-[Mal-Glu-(Phe-Lys-PAB-Exatecan)-PEG 10] (abbreviated SKM104 MA L2) with DAR 8 or DAR4 induced a decrease in cell proliferation better than all other ADCs Exatecan SKM104 MA L1 (65 nM), SKM104 MA Mablink (86 nM) and all other ADCs Topoisomerase inhibitors SKM104 MA DxD (23 nM). The IC 50The calculated binding of SKM104 MA L2 is of the order of 1.5 nM for DAR8 and of the order of 5.4 nM for DAR4 (Figure 14). Finally, these results demonstrated an impressive and totally unexpected efficacy of SKM104 MA L2 to DAR8 and DAR4 on this aggressive multiple myeloma line, while it weakly expresses the ETBR target, compared to other ADC- Topoisomerase Inhibitors and even more surprisingly compared to ADCs using the same drug exatecan with minor variations on the peptide sequence and / or the water-soluble polymer PEG / PSAR. These data therefore showed a better efficacy of the ADC SKM104 MA L2 according to the invention.This result was also confirmed in a significant number of tumor lines (Figure 15), namely:^ different indications of cutaneous melanoma (SKML-5, SKMEL-23 or uveal melanoma (MEL202), ^multiple myeloma lines in addition to RPMI-8226: U266B1 and MOLP-8,^ glioma and glioblastoma (U-251, HN-13-0059),^ breast tumors (MCF-7),^ lung tumors (LU-01-604), and^ kidney (786-O). Impressively and totally unexpectedly, despite the very similar structures of L1 and L2, SKM104 MA L2 showed a statistically significant difference according to the Wilcoxon test on tumor growth inhibition compared to SKM104 MA L1. Indeed, at an equal DAR of 8, the SKM104 MA L2 exhibits consistently lower IC50 values ​​(close to 1 nM), indicating greater potency, while SKM104 MA L1 displays a broader range of higher IC50 values.Contrary to what might be expected, this increased efficacy of SKM104 MA L2 on tumor cells does not impact normal cells (Figure 16). Indeed, tested on normal human HUVEC and HHSEC cells, SKM104 MA L2 demonstrated little or no effect on cell viability on these healthy lines, in a manner comparable to SKM104 MA L1. Also, and unexpectedly, the therapeutic efficacy of the ADCs of the invention does not lead to toxicity. EXAMPLE No. 9 - Efficacy of SKM104 MA L2 in a mixture of two tumor cell populations with positive and negative ETBR expressions MATERIALS & METHODS CHO-K1 cell lines (J. Stagg Laboratory, DMEM + 10% FBS). HS746T (Hs746T, Gastric cancer ATCC, HTB-135, DMEM + 10% FBS). ADC SKM104 MA L1 (L1 = Mal-Glu-(Val-Ala-PAB-exatecan)-PEG10; Formula XI). SKM104 MA L2 (L2 = Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG10; Formula X).In vitro bystander effect assessmentTo determine the bystander effect on cell viability of tumor populations not expressing the target, a mixture of two cell populations was seeded at the optimal density of 100,000 for ETBR-positive cells (HS746T) and 200,000 cells for ETBR-negative cells (CHO-K1) in complete culture medium. After overnight incubation at 37°C, ADCs SKM104 MA L1, SKM104 MA L2 or IC were added at a concentration of 50 or 100 nM and / or culture medium containing no antibody (CTRL negative). After 6 days of incubation, cell survival was determined by counting the total number of live cells. Labeling was performed according to the following protocol: Adherent cells were detached using 2.5 mM EDTA and suspended. They were then collected in 100 μL of PBS per tube (300,000 cells) on ice.For each cell type, the cells were prepared in two identical samples, one for labeling with the anti-ETBR antibody (SKM104 MA) and the other for labeling with the control isotype. 1- In the first tube, the cells were incubated respectively with a cell viability marker (L / D BV421) in addition to the anti-human ETBR antibody (SKM104 MA) and secondly with a secondary antibody anti-human IgG Fc PE. 2- In the second tube, the cells were incubated with a cell viability marker (L / D BV421), in addition to the control isotype human IgG1 kappa and secondly the secondary antibody Anti-human IgG Fc PE. For this, 5 µL of the blocking human Fc solution and 0.15 µL of the dilution of the Live / Dead marker were added. After homogenization, the cell suspension was incubated at 4°C in the dark for 10 min.The anti-ETBR antibody (SKM104 MA) was added to tube 1 and the human IgG1 kappa isotype control was added to tube 2 to obtain a final concentration of 15 µg / ml. After homogenization, the cell suspensions were incubated at 4°C in the dark for 1 h. After two washes with 500 µL of DPBS, the cells were diluted in 100 µL of DPBS. Then, 5 µL of the secondary antibody anti-human IgG Fc-PE was added to each tube and incubated at 4°C for 45 min in the dark. After two washes with DPBS (500 µL), the cells were resuspended in 300 µL of DPBS and stored at 4°C for FACS reading. RESULTS It was observed that the number of live cells decreased over time to a greater extent for SKM104 MA L1 and SKM104 MA L2 than the negative control groups (IC and CTRL) in both HS746T and CHO-K1 lines, at both concentrations 50 and 100 nM (Figure 17).Unexpectedly, this decrease in the number of living cells was greater with SKM104 MA L2 than with SKM104 MA L1 in both tumor lines (ETBR positive (HS746T) and negative (CHO-K1)) and at both concentrations 50 and 100 nM. In conclusion, the bystander effect was demonstrated for these 2 ADCs and this tends to be more marked with SKM104 MA L2. In tumors that express ETBR heterogeneously, the use of SKM104 MA L2 is therefore to be favored. Furthermore, protein expression by FACS confirmed ETBR expression in the HS746T line with a higher mean fluorescence intensity (MFI) for SKM104 MA than IC and the absence of expression in CHO-K1 with the MFIs of SKM104 MA and IC overlapping (Figure 17 - bottom panel). EXAMPLE No.10 - In vitro efficacy studies of SKM104 MA L2 in different indications in comparison with approved anti-Topoisomerase ADCs or in advanced clinical stages MATERIALS & METHODS MCF7 cell lines (ECACC, 86012803, EMEM +10% FBS + 2mM L-Glutamax +1% NEAA). ZR-75-1 (ATCC, CRL-1500, RPMI-1640+10% FBS). BT-549 (ATCC, HTB-122, RPMI-1640+ 10% FBS, insulin). MDA-MB-231 (ATCC, HTB-26, RPMI-1640+10% FBS). HN-13-0063 (PDX, PDC, Glioma, Wuxi Apptec, Wuxi in-house culture medium). HN-13-0059 (PDX, PDC, Glioma, Wuxi Apptec, Wuxi in-house culture medium).HT-29 (ATCC, HTB-38, McCoy's 5A +10% FBS).Caco-2 and its CaCo2x derivatives (ATCC, HTB-37, DMEM+10% FBS +1% non-essential amino acids (NEAA)).Hs746T (ATCC, HTB-135, RPMI-1640 +10% FBS+ 1% glutamine).MKN7 (DSMZ, ACC-709, RPMI-1640 + 10% FBS). MKN1 (DSMZ, ACC-709, RPMI-1640 + 10% FBS). PC-07-0059 (PDX, PDC, pancreatic cancer, Wuxi Apptec, Wuxi in-house culture medium).LU-01-1672 (PDX, PDC, NSCLC, Wuxi Apptec, Wuxi in-house culture medium). LU-01-0604 ((PDX, PDC, NSCLC, Wuxi Apptec, Wuxi in-house culture medium). ADC SKM104 MA L2 (L2 = Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG10; Formula X). ENHERTU®. Datopotamab deruxtecan (abbreviated as Dato DxD). In vitro cytotoxicity assessment To determine the effect of ADC on cell viability, cells were seeded at 1500 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, the absorbance was determined at 490nm (Multiskan, Thermo Fisher). The cell viability ratio (%) is calculated using the following formula: Viability 100 The 50% inhibitory concentration was calculated by GraphPad Prism software ®version 10. RESULTS A dose-dependent decrease in cell viability was observed. At the doses evaluated, the anti-ETBR ADC SKM104-[Mal-Glu-(Phe-Lys-PAB-Exatecan)-PEG10] (abbreviated SKM104 MA L2) at DAR 8 induced a decrease in cell proliferation better than other anti-HER-2 (ENHERTU®) and anti-TROP2 (Dato-DxD) ADCs. Indeed, it has been demonstrated that with low IC50 (in the order of 1.6 to 9.4 nM) SKM104 MA L2 is able to effectively inhibit tumor growth in several models of breast cancer lines of subtypes, luminal and triple negative at different ETBR expression levels (high, medium and low): MCF7, ZR-75-1, BT-549, MDA-MB-231 versus ENHERTU® (where the IC50 was 60 to 100 nM) and Dato-DxD (where the IC50 was 150 to 250 nM) (Figure 18).This result was confirmed in:^ patient-derived cell (PDC) models of Glioma (HN-13-0063, HN-13-0059) (Figure 19), ^in gastric (Hs746T, MKN7, MKN1) and colon (HT-29, Caco-2, Caco2x (Caco-2 derived)) tumor lines with an IC50 ranging from 2.4 to 19 nM for SKM104 MA L2 versus ENHERTU® with an IC50 ranging from 39 nM to over 750 nM) (Figure 20), ^a pancreas PDC model (PC-O7-0059) with a very low IC50 of 3.97 nM (Figure 21), and ^non-small cell lung cancer PDC models where ENHERTU® and Dato-DxD have shown reduced efficacy with ICs. 50 from 47 nM to undetermined, while SKM104 MA L2 showed good antitumor activity with IC 50of 15 and 1 nM in LU-01-1672, LU-01-0604 respectively (Figure 22). These results all demonstrated an impressive and totally unexpected efficacy of SKM104 MA-L2 in several indications with different ETBR expression levels compared to other ADC-Topoisomerase Inhibitors. Finally, these data demonstrated a pan-tumor efficacy of the anti-ETBR ADC SKM104 MA L2 according to the invention in aggressive and resistant models (poor responders) to Topoisomerase inhibitor ADCs used in clinical practice. EXAMPLE No. 11 - Studies of the in vivo efficacy of SKM104 MA L2 in comparison with other conjugates to SKM104 MA and other approved anti-Topoisomerase ADCs or in advanced clinical stages MATERIALS & METHODS Animals Female CB17 SCID or NSG mice, aged 6 to 8 weeks. RPMI8226 cell lines (Multiple myeloma model, ECACC 87012702, RPMI-1640 + 10% FBS + Glutamax). MKN1 (Gastric tumor model, DSMZ, ACC-709, RPMI-1640 + 10% FBS).ADC SKM104 MA L2 (L2 = Mal-Glu-(Phe-Lys-PAB-exatécan)-PEG. 10; Formula X). SKM104 MA SN38 (SN38 = CL2A-SN38). SKM104 MA DxD (DxD = Maleimide-GGFG-DxD). SKM 104 Ma Mablink (Mablink = Mal-Glu-(Val-Ala-PAB-exatecan)-PSAR10). ENHERTU®. Evaluation of in vivo antitumor efficacy Cell amplification and transplantation RMPI8226 and MKN1 cells were cultured in appropriate culture medium RPMI-1640 containing 10% fetal bovine serum (FBS), + / - 1% Glutamax, at 37°C in a humid atmosphere. Cells were detached with trypsin, washed before being counted in the presence of Trypan blue to assess cell viability before being suspended in the grafting medium. One million cells were injected subcutaneously into the right flank of mice in 200 µL of 50 / 50 PBS / Matrigel solution. Female CB17 SCID or NSG mice, aged 6 to 8 weeks, were used for in vivo efficacy studies.Randomization and Treatment When tumor volumes reached 150-200 mm³, mice were randomly divided into treatment groups with similar average tumor volumes. Each group, consisting of 4-5 mice depending on the experiment, received an intravenous injection of the assigned treatments: vehicle (PBS), SKM104 MA L2, SKM104-MA DxD (ggfg-deruxtecan), SKM104-MA Mablink (conjugated to PSAR linker), SKM104-MA CL2A-SN38 (linker-drug of TRODELVY®) for the RPMI8226 model; and vehicle (PBS), SKM104 MA L2, ENHERTU® for the MKN1 model. The regimen and dose of ADCs were specified in the figure legends of each experiment. Treatments For the RPMI8226 model, mice received 2 intravenous injections, one on D-0 and one on D-14, containing 5 and 10 mg / kg respectively or vehicle in a final volume of 100 µL.For the MKN1 model, mice received a single injection at doses of 1, 3 or 5 mg / kg for the three groups of mice treated with SKM104 MA L2 and a single injection of 5 mg / kg for the group treated with ENHERTU® or vehicle at a volume of 100 µL. Animal monitoring The viability and behavior of the animals were assessed daily. The weight and tumor volume of the animals were measured twice a week. The tumor volume was calculated using the formula: Tumor volume = (width² x length) / 2. Statistical analysis A statistical analysis of tumor masses was performed for all groups using the Mann-Whitney test allowing comparison of two independent samples. For all analyses, the statistical difference between groups was marked on the graphs by. étoiles :No star: 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 For the RPMI8226 model, it was observed that tumor growth of RPMI8226 cells was significantly slowed when tumors were treated with SKM104 MA L2, compared to other SKM104 MA conjugates (Figure 23). In particular, SKM104 MA L2 demonstrated remarkable efficacy in controlling tumor volumes, with a statistically significant difference compared to SKM104 MA SN38 (Figure 23A) and SKM104 MA DxD (Figure 23B), with p < 0.001. Thus, the anti-ETBR antibody SKM104, conjugated to Exatecan according to the invention, showed superior efficacy to other topoisomerase inhibitors such as DxD and SN38.Furthermore, SKM104 MA L2 demonstrated statistically significant efficacy (p < 0.05) with the same drug (Exatecan) and similar linkers (PSAR substitution by PEG and Val-Ala substitution by Phe-Lys), when compared to SKM104 MA Mablink (Figure 23C). Unexpectedly, these results demonstrated that SKM104 MA L2 exerts exceptional antitumor activity. Regarding the aggressive MKN1 gastric cancer model, tumor growth was significantly slowed under treatment with the anti-ETBR ADC SKM104 MA L2 at doses of 5 mg / kg and 3 mg / kg, compared to the anti-HER2 ENHERTU® (Figure 24). It should be noted that a single dose of SKM104 MA L2 effectively reduced tumor volumes, with a statistically significant difference compared to ENHERTU® at an equivalent dose of 5 mg / kg (p < 0.05, Figure 24). These data therefore confirmed the superiority of the anti-ETBR SKM104 conjugated to Exatecan according to the invention over DxD-based ADCs.In conclusion, these results highlighted the exceptional in vivo efficacy of the ADC developed in the invention. EXAMPLE No. 12 - DAR and PK stability studies in rat SKM104 MA L2 in comparison with SKM104 MA L1 and ENHERTU® MATERIALS & METHODS AnimalsRat: Sprague Dawley Rat (Non cross-reactive species).ADC SKM104 MA L1 (L1 = Mal-Glu-(Val-Ala-PAB-exatecan)-PEG10; Formula XI). SKM104 MA L2 (L2 = Mal-Glu-(Phe-Lys-PAB-exatecan)-PEG10; Formula X). ENHERTU®. ExperimentationSampling time:^ Two days before administration.^ After the first administration: 15 min, 2 h ± 10 min, 6 h ± 10 min, 10 h ± 10 min, 24 h ± 30 min, as well as days 5, 12, 19, 26, and 28. Collection method Approximately 0.5 mL of blood per animal and per sampling point was collected from the orbital venous plexus. Reference: OP TEC-02-03 V2.1, Blood sample collection in rodents.Sample Handling Blood samples (collected in EDTA-K2 anticoagulant tubes) were centrifuged (4°C, 2000g, 10 min). Four aliquots (approximately 50 µL per tube) of plasma were transferred to EP tubes (RNase / DNase free). Plasmas were then placed on dry ice and transferred to an ultra-low temperature freezer within two hours of collection for further analysis. All samples were transported on dry ice. Analytical Method The sample analysis method was performed by LC / MS after affinity capture extraction using an anti-human Fc antibody to separate antibodies from the rat matrix. Analyzed parameters ^Total antibody,^ ADC (conjugated toxin),^ Free toxin. DAR value The DAR value was calculated according to the formula DAR = M (conjugated drug) / M (total antibody).RESULTS DAR Value It was observed that the DAR value gradually decreased over time, with a slower decreasing trend from 0 to 24 hours and a more pronounced decrease after 24 hours. The mean DAR values, 15 minutes after injection, were 7.06, 8.32 and 7.78 for the SKM104 MA L1, SKM104 MA L2 and ENHERTU® groups respectively. These values ​​gradually decreased over time to reach 5.22, 6.54 and 4.08 at day 19 (456 hours). The stability of the ADCs of the invention (SKM104 MA L1 and SKM104 MA L2) was therefore better than that of the clinically approved control ADC. Surprisingly, a better stability of SKM104 MA L2 was measured compared to SKM104 MA L1 which nevertheless includes the Val-Ala linker known for its high stability in the clinic (Figure 25).SKM104 MA L1, SKM104 MA L2 and ENHERTU® (clinically approved control ADC) were administered to Sprague Dawley rats (non-cross-reactive species) with an initial dose of 60 mg / kg. The ADC half-lives (T1 / 2) after administration of 60 mg / kg were: 9.7 days for SKM104 MA L2, 8.7 days for SKM104 MA L1 and 8.5 days for ENHERTU®. The PK profile of the ADCs of the invention (SKM104 MA L1 and SKM104 MA L2) was therefore, again, better than that of the clinically approved control ADC. Surprisingly, both total antibody and ADC curves aligned for SKM104 MA L2 indicating an optimized PK profile for SKM104 MA L2 (Figure 26). Ultimately, the ADCs of the invention showed better stability in serum than the ENHERTU® clinical control. This is a considerable advantage in terms of reducing the non-specific release of free toxin from the SKM104 ADC into the circulation and thus reducing toxicity.In view of the above data, this is even more true for SKM104 MA L2.

Claims

R EVENDICATIONS1. Antibody-drug conjugate (ADC) of formula (I): Ac-[TC-B-(LM)-AS] (I), in which:^ Ac is an anti-ETB-R antibody, a fragment thereof or a derivative thereof;^ 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 upon hydrolysis with haloacetamides, keto-sulfones, methylsulfonylphenyloxadiazole, carbonylacrylic acid;^ 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 selected from: polysarcosine (PSAR) and polyethylene glycol (PEG), and wherein the drug-antibody ratio (DAR) is from 2 to 16 and said anti-ETB-R is capable of targeting a discontinuous epitope comprising or consisting of the sequences 28ERGFPPDRATP38 (SEQ ID NO: 1) and 70EVPKGDRT77 (SEQ ID NO: 2).

2. Antibody-drug conjugate according to claim 1, wherein said anti-ETB-R has an affinity for said discontinuous epitope whose Kd value is less than or equal to 0.15 ± 0.03 nM.

3. Antibody-drug conjugate according to claim 2,wherein said anti-ETB-R is Rendomab B4.

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

7. 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 use in the prevention and / or treatment of a tumor.

9. 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, inhalation, subcutaneous, nasal, intratumoral or pulmonary.,

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