Trastuzumab-drug conjugate

Abstract

The present invention relates to an antibody-drug conjugate of formula (I) or pharmaceutically acceptable salt, solvate or stereoisomer thereof, as well as to intermediates, to pharmaceutical compositions, to methods for treating diseases or disorders and the use of said compounds as pharmaceutical products for treating diseases or disorders.

Description

[0001] TRASTUZUMAB-DRUG CONJUGATE

[0002] Field of the invention

[0003] The present invention relates to a trastuzumab -drug conjugate, to a linker and a linker-toxin intermediate, as well as to salts, solvates and stereoisomers thereof, pharmaceutical compositions comprising the trastuzumab -drug conjugate, methods for treating diseases or disorders and the use of these compounds as pharmaceutical products for treating diseases or disorders.

[0004] Background of the invention

[0005] The antibody-drug conjugate consists of a potent cytotoxic agent covalently linked to the side chains of specific amino acid residues of the antibody. Such conjugates provide for improved delivery of drugs to target cells in the organism, where the drug exhibits its specific mechanism of action. Thus, the antibody conjugate acts as a prodrug that is activated only in tumor cells.

[0006] Cytotoxic drugs damage cells, causing their necrosis. Exatecan, a structural analogue of camptothecin, which has a stronger antitumor effect and overcomes resistance to SN38, and which is also of interest as a conjugation toxin, can act as a cytostatic agent (Shaun D. Fontaine et al, A Very Long-acting Exatecan and Its Synergism with DNA Damage Response Inhibitors. Cancer Res Commun. 2023 May; 3(5): 908-916).

[0007] The antibody may be trastuzumab, which is a monoclonal antibody that selectively binds to the antigen (target protein), human epidermal growth factor receptor 2 (HER2). HER2 is found in high amounts on the surface of some cancer cells, where it stimulates them to grow. Upon binding to HER2, trastuzumab can stop cancer cell growth and induce cell death by specifically binding to the extracellular domain IV of HER2 and causing antibody -dep endent cellular cytotoxicity or by exerting anti-cancer effects through inhibition of HER2 signal transduction. Trastuzumab is highly effective for tumors overexpressing HER2.

[0008] Despite trastuzumab is widely used in cancer therapy, there is a problem of primary or acquired resistance to trastuzumab treatment in patients, and there are also reports of resistance to the trastuzumab emtansine conjugate (Sneha Vivekanandhan et al. Resistance to Trastuzumab. Cancers (Basel). 2022 Oct; 14(20): 5115). Thus, there is a need to create novel drugs that do not show such resistance.

[0009] Description of the invention

[0010] The terms used in the description of this invention appear below.

[0011] "ADC", or "antibody -drug conjugate", or "trastuzumab-drug conjugate", or "trastuzumab- BCD-267 drug conjugate", or "antibody-BCD-267 drug conjugate", or "BCD-267 conjugate"

[0012] The term "stereoisomers" refers to compounds that have identical chemical composition and the same structure, but differ in the spatial arrangement of atoms or groups. Stereoisomers may include geometric isomers, enantiomers, diastereomers.

[0013] "Medicinal product (drug product, medicament)" is a compound (or a mixture of compounds as a pharmaceutical composition) in the form of tablets, granules, capsules, injections, infusions, ointments and other ready forms intended for restoration, improvement or modification of physiological functions in humans and animals, as well as for treatment and prophylaxis of diseases, for diagnostics, anesthesia, contraception, cosmetology and others.

[0014] "Treat", "treatment" and "therapy" refer to a method for alleviating or abrogating a biological disorder and / or at least one of attendant symptoms thereof. The term "to alleviate" a disease, disorder or condition means reducing the severity and / or occurrence frequency of the symptoms of the disease, disorder, or condition. Further, references herein to "treatment" include references to curative, palliative treatment. "Prophylaxis", "prophylactic therapy" refers to a set of measures aimed at preventing the onset, eliminating risk factors, or early detecting a disease or disorder, its exacerbation, relapse, complications or other consequences.

[0015] In one aspect, the patient, or subject of treatment, or prophylaxis, is a mammal. Examples of the patients include, but are not limited to, a human subject. Said subject may be either male or female, of any age.

[0016] The term "disorder" and / or "disease" means any condition that would benefit from treatment according to the present invention. The definition of this term includes chronic and acute disorders or pathological conditions that predispose the mammal to the onset of diseases in question. Non-limiting examples of diseases to be treated include cancer, including treatment of glioblastoma, recurrent glioblastoma, colorectal cancer, locally advanced, unresectable or metastatic colorectal cancer, with HER2 overexpression, gastric and gastroesophageal junction cancer, HER2-positive gastric and gastroesophageal junction cancer, adenocarcinoma, unresectable and / or locally advanced or metastatic HER2 -positive gastric and gastroesophageal junction cancer, non-squamous non-small cell lung cancer (NSCLC), advanced or metastatic non-squa- mous non-small cell lung cancer and HER2 receptor overexpression, HER2-mutated unresectable locally advanced / metastatic non-small cell lung cancer, breast cancer, early HER2 -positive breast cancer, HER2-positive breast cancer with metastatic lesions in the brain, unresectable and / or metastatic HER2-positive breast cancer, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0 combined with both a negative hormone receptor [HR] status and positive HR status; oligometastatic HER2 -positive breast cancer, biliary tract cancer, locally advanced or metastatic biliary tract cancer expressing HER2, osteosarcoma, recurrent Her2-positive osteosarcoma, endometrial cancer, locally advanced unresectable or metastatic Her2-positive endometrial cancer, pancreatic cancer, locally advanced unresectable or metastatic Her2 -positive pancreatic cancer, extramammary Her2 -positive Paget's disease, ovarian cancer, locally advanced unresectable or metastatic Her2-positive ovarian cancer, urothelial cancer, locally advanced unresectable or metastatic Her2 -positive urothelial cancer,

[0017] Her-2-positive neuroendocrine tumor

[0018] "Therapeutically effective amount" refers to that amount of the therapeutic agent being administered in the course of treatment which will relieve the severity or eliminate the symptoms of the disease being treated.

[0019] As used in the present description and claims that follow, unless otherwise dictated by the context, the words "have", "include," and "comprise" or variations thereof such as "has", "having," "includes", "including", "comprises," or "comprising," will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

[0020] Sequence 1 includes the trastuzumab heavy chain set forth in SEQ ID NO: 1. Sequence 2 includes the trastuzumab light chain set forth in SEQ ID NO: 2.

[0021] Detailed description of the invention

[0022] The present invention relates to an antibody-drug conjugate of formula I or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof, where f is a number in the range of 2.0 - 10.0, Ab is trastuzumab.

[0023] The present invention relates to an antibody-drug conjugate of formula I or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof, where f is a number in the range of 2.0 - 10.0,

[0024] Ab is an antibody with the heavy chain sequence set forth in SEQ ID NO: 1 and the light chain sequence set forth in SEQ ID NO: 2.

[0025] The present invention relates to an antibody-drug conjugate of formula I or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof, where f is a number in the range of 5.0 - 9.9,

[0026] Ab is an antibody with the heavy chain sequence set forth in SEQ ID NO: 1 and the light chain sequence set forth in SEQ ID NO: 2.

[0027] In another embodiment, the invention relates to a compound of formula I, where D is deuterium.

[0028] In another embodiment, the compound I is lb, or where f is a number in the range of 5.0 - 9.9,

[0029] Ab is an antibody with the heavy chain sequence set forth in SEQ ID NO: 1 and the light chain sequence set forth in SEQ ID NO: 2.

[0030] In another embodiment, the invention relates to compounds of formula la, lb or Ic, where D is deuterium.

[0031] In one embodiment, f is a number in the range of 2.0-10.0, or 2.0-9.0, or 3.0-9.0, or 4.0- 9.0, or 5.0-9.9, or 5.5-9.9, or 5.5-9.0, or 6.0-8.5, or 6.5-8.5, or 7.0-8.5, or 7.0-8.0, or 7.4-8.0, or 7.4-7.9, or 7.4-7.8, or 7.5-7.6.

[0032] In one embodiment, f is a number in the range of 5.0 - 9.9, or 5.5 - 9.9, or 5.5-9.0, or 6.0 -

[0033] 8.5, or 6.5 - 8.5, or 7.0 - 8.5, or 7.0-8.0, or 7.5-8.0, or 7.6-7.9, or 7.7-7.8.

[0034] In one embodiment, f is a number in the range of 5.5-5.6, or 5.6-5.7, or 5.7-5.8, or 5.8-5.9, or 5.9-6.0, or 6.0-6.1, or 6.1-6.2, or 6.2-6.3, or 6.3-6.4, or 6.4-6.5, or 6.5-6.6, or 6.6-6.7, or 6.7- 6.8, or 6.8-6.9, or 6.9-7.0, or 7.0-7.1, or 7.1-7.2, or 7.2-7.3, or 7.3-7.4, or 7.4-7.5, or 7.5-7.6, or 7.6-7.7, or 7.7-7.8, or 7.8-7.9 or 7.9-8.0 or 8.0-8.1 or 8.1-8.2 or 8.2-8.3 or 8.3-8.4 or 8.4-8.5 or 8.5- 8.6 or 8.6-8.7 or 8.7-8.8 or 8.8-8.9 or 8.9-9.0, or 9.0-9.1, or 9.1-9.2, or 9.2-9.3, or 9.3-9.4, or 9.4-

[0035] 9.5, or 9.5-9.6, or 9.6-9.7, or 9.7-9.8, or 9.8-9.9.

[0036] In one embodiment, f is 2.0, or 3.0, or 4.0, or 5.0, or 5.1, or 5.2, or 5.3, or 5.4, or 5.5, or

[0037] 5.6, or 5.7, or 5.8, or 5.9, or 6.0, or 6.1, or 6.2, or 6.3, or 6.4, or 6.5, or 6.6, or 6.7, or 6.8, or 6.9, or 7.0, or 7.1, or 7.2, or 7.3, or 7.4, or 7.5, or 7.55, or 7.6, or 7.7, or 7.75, or 7.8, or 7.9, or 8.0, or 8.1, or 8.2, or 8.3, or 8.4, or 8.5, or 8.6, or 8.7, or 8.8, or 8.9, or 9.0, or 9.1, or 9.2, or 9.3, or 9.4, or 9.5, or 9.6, or 9.7, or 9.8, or 9.9, or 10.0.

[0038] In one embodiment, the invention relates to a compound of formula II: or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0039] In one embodiment, the compound II is In another embodiment, the invention relates to a compound of formula II, or Ila, or lib, or lie, where D is deuterium.

[0040] In one embodiment, the invention relates to a compound of formula II.1 :

[0041]

[0042] In another embodiment, the invention relates to a compound of formula II.1, or ILla, or IL lb, or II.1c, where D is deuterium.

[0043] In one embodiment, the invention relates to a compound of formula III:

[0044] III or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0045] In one embodiment, the compound III is

[0046] Illb.

[0047] In another embodiment, the invention relates to a compound of formula III, or Illa, or Illb, where D is deuterium.

[0048] In one embodiment, the invention relates to a compound of formula III.1 : or to a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0049] In one embodiment, the compound of formula III.1 is

[0050] In another embodiment, the invention relates to a compound of formula III.l, or III. la, or III. lb, where D is deuterium.

[0051] In one embodiment, the compounds of the present invention, as well as salts, solvates and stereoisomers, are intended for the manufacture of a medicament. In another embodiment, the compounds of the present invention, as well as salts, solvates and stereoisomers, are intended for the manufacture of a medicament for the treatment of an oncological disease.

[0052] In another embodiment, the compounds of the present invention, as well as salts, solvates and stereoisomers, are intended for the manufacture of a medicament for the treatment of an oncological disease selected from glioblastoma, recurrent glioblastoma, colorectal cancer, locally advanced, unresectable or metastatic colorectal cancer, with HER2 overexpression, gastric and gastroesophageal junction cancer, HER2-positive gastric and gastroesophageal junction cancer, adenocarcinoma, unresectable and / or locally advanced or metastatic HER2 -positive gastric and gastroesophageal junction cancer, non-squamous non-small cell lung cancer (NSCLC), advanced or metastatic non-squa- mous non-small cell lung cancer and HER2 receptor overexpression, HER2-mutated unresectable locally advanced / metastatic non-small cell lung cancer, breast cancer, early HER2 -positive breast cancer, HER2-positive breast cancer with metastatic lesions in the brain, unresectable and / or metastatic HER2-positive breast cancer, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0 combined with both a negative hormone receptor [HR] status and positive HR status; oligometastatic HER2 -positive breast cancer, biliary tract cancer, locally advanced or metastatic biliary tract cancer expressing HER2, osteosarcoma, recurrent Her2-positive osteosarcoma, endometrial cancer, locally advanced unresectable or metastatic Her2-positive endometrial cancer, pancreatic cancer, locally advanced unresectable or metastatic Her2 -positive pancreatic cancer, extramammary Her2 -positive Paget's disease, ovarian cancer, locally advanced unresectable or metastatic Her2-positive ovarian cancer, urothelial cancer, locally advanced unresectable or metastatic Her2 -positive urothelial cancer,

[0053] Her-2-positive neuroendocrine tumor,

[0054] Her-2-positive head and neck tumor,

[0055] Her-2-positive salivary gland tumor.

[0056] Compounds, described in the present invention, may be obtained as, and / or used as, pharmaceutically acceptable salts. The type of pharmaceutical acceptable salts, include, but are not limited to: acid addition salts, formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; or with an organic acid such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanedisulfonic acid, benzenesulfonic acid, toluenesulfonic acid, 2-naphthalenesul- fonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4’-meth- ylenebis-3-hydroxy-2-ene-l-carboxylic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertbutylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like.

[0057] The corresponding counterions of the pharmaceutically acceptable salts may be analyzed and identified using various methods including, but not limited to, ion exchange chromatography, ion chromatography, capillary electrophoresis, inductively coupled plasma, atomic absorption spectroscopy, mass spectrometry, or any combination thereof.

[0058] The salts are recovered by using at least one of the following techniques: filtration, precipitation with a non-solvent followed by filtration, evaporation of the solvent, or, in the case of aqueous solutions, lyophilization. It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described in the present patent can be conveniently prepared or formed during the processes described in the present invention. In addition, the compounds provided in the present invention can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided in the present invention. The screening and characterization of the pharmaceutically acceptable salts, polymorphs and / or solvates may be accomplished using a variety of techniques including, but not limited to, thermal analysis, x-ray diffraction, spectroscopy, vapor sorption, and microscopy. Thermal analysis methods address to analysis of thermo chemical degradation or thermo physical processes including, but not limited to, polymorphic transitions, and such methods are used to analyze the relationships between polymorphic forms, to determine weight loss, to find the glass transition temperature, or for excipient compatibility studies. Such methods include, but are not limited to, differential scanning calorimetry (DSC), modulated differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA), thermogravi-metric and infrared analysis (TG / IR). Crystallographic methods include, but are not limited to, single crystal and powder diffractometers and synchrotron sources. The various spectroscopic techniques used include, but are not limited to, Raman (combinational scattering), FTIR, UVIS, and NMR (liquid and solid state). The various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive x-ray analysis (EDX), environmental scanning electron microscopy with EDX (in gas or water vapor atmosphere), IR microscopy, and Raman microscopy.

[0059] In one embodiment, the present invention relates to a pharmaceutical composition that comprises at least one of the compounds described herein, or pharmaceutically acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients. In one embodiment, the present invention relates to a pharmaceutical composition that comprises a therapeutically effective amount of at least one of the compounds described herein, or pharmaceutically acceptable salt, solvate, stereoisomer thereof, and one or more pharmaceutically acceptable excipients. In yet another invention, the pharmaceutical composition comprising the compounds of the present invention is intended for the manufacture of a medicament for the treatment of an oncological disease. In yet another embodiment of the present invention, the pharmaceutical composition comprising the compounds of the present invention is intended for the treatment of an oncological disease. In yet another invention, the oncological disease is selected from glioblastoma, recurrent glioblastoma, colorectal cancer, locally advanced, unresectable or metastatic colorectal cancer, with HER2 overexpression, gastric and gastroesophageal junction cancer, HER2-positive gastric and gastroesophageal junction cancer, adenocarcinoma, unresectable and / or locally advanced or metastatic HER2 -positive gastric and gastroesophageal junction cancer, non-squamous non-small cell lung cancer (NSCLC), advanced or metastatic non-squa- mous non-small cell lung cancer and HER2 receptor overexpression, HER2-mutated unresectable locally advanced / metastatic non-small cell lung cancer, breast cancer, early HER2 -positive breast cancer, HER2-positive breast cancer with metastatic lesions in the brain, unresectable and / or metastatic HER2-positive breast cancer, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0 combined with both a negative hormone receptor [HR] status and positive HR status; oligometastatic HER2 -positive breast cancer, biliary tract cancer, locally advanced or metastatic biliary tract cancer expressing HER2, osteosarcoma, recurrent Her2-positive osteosarcoma, endometrial cancer, locally advanced unresectable or metastatic Her2-positive endometrial cancer, pancreatic cancer, locally advanced unresectable or metastatic Her2 -positive pancreatic cancer, extramammary Her2 -positive Paget's disease, ovarian cancer, locally advanced unresectable or metastatic Her2-positive ovarian cancer, urothelial cancer, locally advanced unresectable or metastatic Her2 -positive urothelial cancer,

[0060] Her-2-positive neuroendocrine tumor,

[0061] Her-2-positive head and neck tumor,

[0062] Her-2-positive salivary gland tumor.

[0063] The pharmaceutical composition of the present invention comprises, by way of example, from about 5 wt% to about 100 wt% of active ingredients, preferably from about 10 wt% to about 60 wt% of active ingredients. It is to be understood that each dosage unit may not comprise an effective amount of an active ingredient or ingredients, because the sufficient effective amount may be achieved by administering multiple dosage unit forms.

[0064] A typical composition is prepared by mixing the compound of the present invention with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe to be administered to a mammal. In general, safe solvents are aqueous solvents such as water and other solvents that are soluble or miscible in water. Suitable aqueous solvents include water, as the main ingredient, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The compositions may also include one or more buffers, stabilizing agents, surfactants, wefting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug product (i.e., compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e. medicinal product). The pharmaceutical compositions should preferably be manufactured in compliance with the GMP (Good Manufacturing Practice) requirements.

[0065] The pharmaceutical compositions of the invention may also be administered parenterally. As used herein, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue, thus generally resulting in the direct administration into the blood stream, into muscle, or into an internal organ. Parenteral administration thus includes, inter alia, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, inter alia, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, in- trasynovial injection or infusions; and kidney dialytic infusion techniques. Intratumoral delivery, e.g. intratumoral injection, may also be advantageous. Regional perfusion is also provided. Formulations of pharmaceutical compositions suitable for parenteral administration typically comprise the active ingredient combined with a pharmaceutically acceptable carrier, such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged, or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged, or sold in unit dosage form, such as in ampoules or in multi-dose containers containing a preservative. Formulations for parenteral administration include, inter alia, suspensions, solutions, emulsions in oily or aqueous vehicles, pastes, and the like.

[0066] In one embodiment, the present invention relates to a method for treating an oncological disease, which comprises administering the compound as described above or the pharmaceutical composition of the present invention. In yet another embodiment, the present invention relates to a method for treating an oncological disease, which comprises administering a therapeutically effective amount of any compound as described above or the pharmaceutical composition of the present invention.

[0067] In one embodiment, the present invention relates to a method for treating an oncological disease, which comprises administering a therapeutically effective amount of any compound as described above or the pharmaceutical composition of the present invention to a subject in need of such treatment.

[0068] In yet another embodiment, the invention relates to a method for treating as described above, wherein said oncological disease is selected from glioblastoma, recurrent glioblastoma, colorectal cancer, locally advanced, unresectable or metastatic colorectal cancer, with HER2 overexpression, gastric and gastroesophageal junction cancer, HER2-positive gastric and gastroesophageal junction cancer, adenocarcinoma, unresectable and / or locally advanced or metastatic HER2 -positive gastric and gastroesophageal junction cancer, non-squamous non-small cell lung cancer (NSCLC), advanced or metastatic non-squa- mous non-small cell lung cancer and HER2 receptor overexpression, HER2-mutated unresectable locally advanced / metastatic non-small cell lung cancer, breast cancer, early HER2 -positive breast cancer, HER2-positive breast cancer with metastatic lesions in the brain, unresectable and / or metastatic HER2-positive breast cancer, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0 combined with both a negative hormone receptor [HR] status and positive HR status; oligometastatic HER2 -positive breast cancer, biliary tract cancer, locally advanced or metastatic biliary tract cancer expressing HER2, osteosarcoma, recurrent Her2-positive osteosarcoma, endometrial cancer, locally advanced unresectable or metastatic Her2-positive endometrial cancer, pancreatic cancer, locally advanced unresectable or metastatic Her2 -positive pancreatic cancer, extramammary Her2 -positive Paget's disease, ovarian cancer, locally advanced unresectable or metastatic Her2-positive ovarian cancer, urothelial cancer, locally advanced unresectable or metastatic Her2 -positive urothelial can- cer,

[0069] Her-2-positive neuroendocrine tumor,

[0070] Her-2-positive head and neck tumor, Her-2-positive salivary gland tumor.

[0071] In one embodiment, the present invention relates to the use of the compound of the present invention, or the pharmaceutically acceptable salt, solvate or stereoisomer thereof, or the pharmaceutical composition as described above, for treating an oncological disease. In another embodiment, the present invention relates to the use of the compound of the present invention, or the pharmaceutically acceptable salt, solvate or stereoisomer thereof, or the pharmaceutical composition for the manufacture of a medicament. In another embodiment, the present invention relates to the use of the compound of the present invention, or the pharmaceutically acceptable salt, solvate or stereoisomer thereof, or the pharmaceutical composition for the manufacture of a medicament for treating an oncological disease. In another embodiment, the oncological disease is selected from glioblastoma, recurrent glioblastoma, colorectal cancer, locally advanced, unresectable or metastatic colorectal cancer, with HER2 overexpression, gastric and gastroesophageal junction cancer, HER2-positive gastric and gastroesophageal junction cancer, adenocarcinoma, unresectable and / or locally advanced or metastatic HER2 -positive gastric and gastroesophageal junction cancer, non-squamous non-small cell lung cancer (NSCLC), advanced or metastatic non-squa- mous non-small cell lung cancer and HER2 receptor overexpression, HER2-mutated unresectable locally advanced / metastatic non-small cell lung cancer, breast cancer, early HER2 -positive breast cancer, HER2-positive breast cancer with metastatic lesions in the brain, unresectable and / or metastatic HER2-positive breast cancer, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0 combined with both a negative hormone receptor [HR] status and positive HR status; oligometastatic HER2 -positive breast cancer, biliary tract cancer, locally advanced or metastatic biliary tract cancer expressing HER2, osteosarcoma, recurrent Her2-positive osteosarcoma, endometrial cancer, locally advanced unresectable or metastatic Her2-positive endometrial cancer, pancreatic cancer, locally advanced unresectable or metastatic Her2 -positive pancreatic cancer, extramammary Her2 -positive Paget's disease, ovarian cancer, locally advanced unresectable or metastatic Her2-positive ovarian cancer, urothelial cancer, locally advanced unresectable or metastatic Her2 -positive urothelial cancer,

[0072] Her-2-positive neuroendocrine tumor.

[0073] Dosage regimens may be adjusted to provide the optimum desired response. For example, a single dose may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is especially advantageous to formulate peroral compositions in a unit dosage form for ease of administration and uniformity of dosage. A unit dosage form as used herein refers to physically discrete units suited as unitary dosages for patients / subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the desired pharmaceutical carrier. Specification for the unit dosage forms of the invention is typically dictated by and directly dependent on (a) the unique characteristics of a therapeutic agent and particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in subjects.

[0074] Thus, a skilled artisan would appreciate, based upon the disclosure provided herein, that the doses and dosage regimen are adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic effect to a patient may also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic effect to a patient. Thus, while certain doses and administration regimens are exemplified herein, these examples in no way limit the doses and administration regimens that may be provided to a patient in practicing the embodiments of the invention.

[0075] It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. Furthermore, it is to be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the judgment of a medical professional administering or supervising the administration of the compositions, and that dosage ranges set forth in the present description are exemplary only and are not intended to limit the scope or practice of the claimed compositions. Furthermore, the dosage regimen with the compositions of the present invention may be based on a variety of factors, including the type of disease, age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the particular compound of the present invention employed. Thus, the dosage regimen may vary widely, but can be determined routinely using standard methods. For example, doses may be adjusted based on pharmacokinetic and pharmacodynamic parameters, which may include clinical effects such as toxic effects or laboratory values. Thus, the present invention encompasses intra-patient dose-escalation as determined by one skilled in the art. Methods for determining appropriate dosage and regimens are well-known in the art and would be understood by a skilled artisan once provided the ideas disclosed herein.

[0076] As a rule, standard daily dosage for an adult human is typically in the range from 0.01 mg to 5000 mg or from about 1 mg to about 1500 mg.

[0077] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered, if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients may be however required periodic treatment on a long-term basis upon any relapse of symptoms.

[0078] The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. These dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disorder or condition to be treated, the method of administration, the requirements of the individual subject, the severity of the disorder or condition being treated, and the judgment of the physician.

[0079] The following examples are provided for better understanding of the invention. These examples are for purposes of illustration only and are not to be construed as limiting the scope of the invention in any manner.

[0080] All publications, patents, and patent applications cited in this specification are incorporated herein by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended embodiments.

[0081] Examples

[0082] List of abbreviations

[0083] SE HPLC - size-exclusion high-performance liquid chromatography

[0084] RP-HPLC - reversed-phase high-performance liquid chromatography

[0085] Nr-CE - non-reduced capillary electrophoresis

[0086] RFU - relative fluorescence unit.

[0087] Example 1. Method for producing trastuzumab.

[0088] To generate trastuzumab, used was the CHO-S cell line whereto the gene sequences for the heavy and light chains of trastuzumab were introduced.

[0089] The cell bank vial was defrosted into a flask containing a chemically defined nutrient medium free of animal-derived components. The cells were sequentially passaged increasing the flask volume to 2000 ml. Next, the cells were passaged to a wave bioreactor; after growing the cells in the wave bioreactor, the cells were transferred to a radial flow bioreactor followed by a product bioreactor. The product bioreactor culturing was carried out using a chemically defined nutrient medium free of animal-derived components. During the culturing process, chemically defined feedings free of animal-derived components were added to the reactor at predetermined intervals.

[0090] After completion of culturing, the culture liquid was filtered off using deep-bed and membrane filters.

[0091] Trastuzumab was extracted from the culture fluid by Protein A affinity chromatography using buffer solutions based on tris-(hydroxymethyl)-aminomethane and glycine. pH of the protein solution after affinity chromatography was reduced using hydrochloric acid; thereafter, the solution was neutralized and filtered off. Trastuzumab was then further purified using ion exchange and multimodal sorbent using buffer solutions containing sodium phosphate and sodium chloride.

[0092] The resulting protein solution was filtered off using filters with a pore diameter of about 10-20 nm. Next, the protein solution was ultrafiltered using 30 kDa cutoff membranes.

[0093] Example 2. Synthesis of compound 3.

[0094] 1 3

[0095] To a mixture of L-phenyl-d5-alanine (Combi-Block, order no. QH-1796) (5.00 g, 29.37 mmol), 30 ml of acetonitrile, 30 ml of water, triethylamine (3.57 g, 35.28 mmol) added was 2,5-diox- opyrrolidine-l-yl-2-(2-(((benzyloxy)carbonyl)amino)acetamido)acetate (BLDPharm, order no. BD157066) (12.82 g, 35.29 mmol); the reaction mixture was stirred for 8 h at room temperature. After evaporating the solvent on a rotary evaporator, the product was isolated using silica gel column chromatography. 9.08 g [74%] of compound 3 were yielded.

[0096] Example 3. Synthesis of compound 5.

[0097] To a mixture of compound 3 (8.40 g, 20.10 mmol), 1-H-hydroxybenzotriazole (4.07 g, 30.13 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (5.78 g, 30.15 mmol) and benzyl 2-((2-aminoacetamido)methoxy)acetate (AstaTech, order no. F81361) (5.07 g, 20.10 mmol) in 100 ml of dimethylformamide added was diisopropylethylamine (7.74 g, 59.88 mmol). The reaction mass was stirred for 12 h at room temperature. After evaporating the solvent on a rotary evaporator, the product was isolated using silica gel column chromatography. 9.3 g [71%] of compound 5 were yielded.

[0098] Example 4. Synthesis of compound 6.

[0099] 5 6

[0100] To a mixture of compound 5 (8 g, 12.27 mmol) in 130 ml of tetrahydrofuran and 70 ml of water added was 1.72 g of 5% palladium on carbon. The reaction mixture was stirred for 4 hours at room temperature under hydrogen atmosphere. After the reaction was completed, the reaction mass was filtered off from palladium on carbon, and the filtrate was evaporated on a rotary evaporator. The product was isolated by silica gel column chromatography. 4.4 g [84%] of compound 6 were yielded.

[0101] Example 5. Synthesis of compound 8.

[0102] To a solution ofN-succinimidyl 6-maleimidohexanoate (Combi-Blocks, order no. QA-0763) (4.31 g, 14.01 mmol) in 70 ml of acetonitrile added were compound 6 (3 g, 7.01 mmol), diisopropylethylamine (0.90 g, 7.01 mmol), and 20 ml of water. The reaction mass was stirred for 12 h at room temperature. After evaporating the solvent on a rotary evaporator, the product was isolated using silica gel column chromatography. 3.6 g [84%] of compound 8 were yielded.

[0103] Example 6. Synthesis of compound 10.

[0104] To a solution of compound 9 (Sigma-Aldrich, order no. SML3461) (0.87 g, 1.64 mmol) in 40 ml of dimethylformamide added were compound 8 (1.00 g, 1.61 mmol), diisopropylethylamine (0.41 g, 3.17 mmol), and l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide (0.73 g, 1.92 mmol). The reaction mass was incubated at 10-20 °C for 1 hour. After the reaction was completed, 40 ml of water and 45 ml of dichloromethane were added and the lower organic phase was separated. The organic phase was washed with 3x50 ml of a saturated sodium chloride solution. The organic phase was separated and the solvent was evaporated on a rotary evaporator, and the product was purified using silica gel column chromatography. 0.97 g [58%] of compound 10 was yielded.

[0105] Example 7. Synthesis of antibody-BCD-267 drug conjugate.

[0106] 1.1 ml of trastuzumab in 25 mM histidine buffer pH 6.0 (trastuzumab at 18 mg / ml) was placed in a 2 ml polypropylene tube, the pH was brought to 7.0 with 500 mM ISfeHPC , and 141 pl of 5 mM tris(2-carboxyethyl)phosphine hydrochloride (5 equivalents per antibody molecule) were added. The antibody disulfide bonds were reduced by incubating the resulting reaction mixture for 2 hours at 22°C. After antibody disulfide bond reduction, 128 pl of a 10 mM solution of compound 10 in dimethyl sulfoxide (9 equivalents per antibody molecule) were added, and the mixture was incubated at 18 °C for 1.5 hours. After 1.5 hours, 30 pl of 100 mM N-acetylcysteine aqueous solution (20 equivalents per antibody molecule) was added, and the mixture was incubated at 18°C for 15 minutes to stop the reaction.

[0107] The sample is then purified from excess deuterated deruxtecan (compound 10) and other small molecule impurities by 10-fold buffer replacement with 25 mM histidine buffer pH 5.5 using a 2 ml ultrafiltration tube (Amikon, 30 KDa).

[0108] Example 8. Analytical data and equipment.

[0109] Equipment data:

[0110] Table 1. Chromatography / mass spectrometry

[0111] Table 2, NMR spectrometer Table 3. UV spectrophotometer

[0112] Table 6. Analytical data for exemplary compounds

[0113] Table 7. Analytical data for exemplary compounds

[0114] Table 8, Physico-chemical characteristics of BCD-267 conjugate

[0115] Example 9. Selectivity of BCD-267 conjugate.

[0116] The selectivity of the BCD-267 conjugate was assessed by its ability to exert a cytotoxic effect on the target breast cancer cell line, SK-BR-3, and the normal primary human umbilical vein endothelial cell line, HUVEC.

[0117] The selectivity of the BCD-267 conjugate was assessed by using a cytotoxicity assay.

[0118] For the assay using the HUVEC cell line, prepared were serial dilutions of the BCD-267 conjugate from 30 pg / ml to 0.3 ng / ml in the assay medium (medium composition: 450 ml DMEM / F12, 146 mg L-glutamine, 50 ml fetal bovine serum, 250 pl gentamicin).

[0119] A working suspension of HUVEC cells at 0.6* 105cells / ml was prepared.

[0120] A working suspension of HUVEC cells was added to a 96-well transparent culture plate (NEST, order no. T-701001) in a volume of 50 pl / well and 50 pl / well of working dilutions of the BCD-267 conjugate.

[0121] The contents were stirred and incubated in a CO2 incubator for 96 hours.

[0122] At the end of the incubation time, the culture plates were removed from the CO2 incubator and 10 pl / well of the Alamar Blue vital dye (Invitrogen™, order no. DALI 100) were added to the wells, the contents of the plates were mixed on an orbital shaker (Biosan, Latvia) for 1 minute at 400 RPM and kept at 37 °C in an incubator under 5% CO2 (Binder, Germany) until the characteristic color developed. Fluorescence intensity was detected using an Infinite M200Pro microplate spectrophotometer (Tecan Group Ltd, Switzerland) by measuring fluorescence signal in RFU using an absorption wavelength (ZEx) of 490 nm and an emission wavelength (ZEm) of 540 nm. ED50 value was calculated using the Magellan software (Tecan Group Ltd, Switzerland) by approximating experimental points by four-parameter model with the optimization by Levenberg- Marquardt:

[0123] Table 9. Equipment.

[0124] Figure 1 and Table 10 show RFU signal intensity vs BCD-267 conjugate concentration on the HUVEC cell line, where

[0125] A - the value of the upper asymptote of the four-parameter curve,

[0126] B - the value of the slope of the four-parameter curve,

[0127] C - the value of median effective dose, ED50,

[0128] D - the value of the lower asymptote of the four-parameter curve

[0129] Table 10. Values of curve variables for BCD-267 conjugate on HUVEC cell line.

[0130] For the assay using the SK-BR-3 cell line (ATCC® H TB-30™), serial dilutions of the BCD-267 conjugate at 2.6 pg / ml to 1.7 ng / ml were prepared in assay medium (medium composition: 450 ml DMEM, 146 mg L-glutamine, 50 ml fetal bovine serum, 250 pl gentamicin).

[0131] Prepared was a working suspension of SK-BR-3 cells (ATCC® HTB-30™) at 2.5* 104cells / ml.

[0132] The working suspension of SK-BR-3 cells was added to a 96-well transparent culture plate (NEST, order no. T-701001) in a volume of 80 pl / well.

[0133] The plate was incubated in a CO2 incubator for 18 hours.

[0134] 20 pl / well of working dilutions of the BCD-267 conjugate were added to the wells of the plate.

[0135] The contents were stirred and incubated in a CO2 incubator for 96 hours.

[0136] At the end of the incubation time, the culture plates were removed from the CO2 incubator and 10 pl / well of the Alamar Blue vital dye (Invitrogen™, order no. DALI 100) were added to the wells, the contents of the plates were mixed on an orbital shaker (Biosan, Latvia) for 1 minute at 400 RPM and kept at 37 °C in an incubator under 5% CO2 (Binder, Germany) until the characteristic color developed. Fluorescence intensity was detected using an Infinite M200Pro microplate spectrophotometer (Tecan Group Ltd, Switzerland) by measuring fluorescence signal in RFU using an absorption wavelength (ZEx) of 490 nm and an emission wavelength (ZEm) of 540 nm. ED50 value was calculated using the Magellan software (Tecan Group Ltd, Switzerland) by approximating experimental points by four-parameter model with the optimization by Levenberg- Marquardt:

[0137] Figure 2 and Table 11 show RFU signal intensity vs BCD-267 conjugate concentration on the SK-BR-3 cell line (where A, B, C, D are as defined previously).

[0138] Table 11. Values of curve variables for BCD-267 conjugate on SK-BR-3 cell line.

[0139] The results of the experiment show that the BCD-267 conjugate exhibits a cytotoxic effect on the target SK-BR-3 cell line and does not exhibit cytotoxic activity on the HUVEC cell line.

[0140] Example 10. Ability of BCD-267 conjugate to induce caspase-dependent apoptosis in breast adenocarcinoma cell line, SK-BR-3.

[0141] The ability of the BCD-267 conjugate and the monoclonal antibody trastuzumab to induce caspase-dependent apoptosis was assessed by a biological assay on the SK-BR-3 breast adenocarcinoma cell line (ATCC® HTB-30™) expressing the human epidermal growth factor receptor Her2, using the Caspase 3 / 7 detection reagent kit (Promega, Apo-ONE® Homogeneous Caspase- 3 / 7 Assay, order no. G7791). The cells were grown in DMEM medium (PanEco, order no. C420n). The basal growth medium was enriched with L-glutamine at a concentration of 2 mM (PanEco, order no. <T>032) and 10% fetal bovine serum (Gibco, order no. 16140-071). The night before detection, SK-BR-3 adhesive cells were removed from plastic using a TrypLE™ Express Enzyme solution (Thermo Fisher Scientific Inc., order no. 12605010) which was then inactivated using a complete DMEM medium, spun at 1000 RPM in a centrifuge (Biosan, Latvia), and a cell suspension was prepared in a complete DMEM medium and added to 96-well culture plates (NEST, order no. T-701001) at 2* 104cells in 50 pl of the medium per well. The plates with the cells were kept at 37°C in an incubator under 5% CO2 (Binder, Germany) overnight. The next day, the test compounds were dissolved in water for injection (PFK OBNOVLENIE, AO, order no. 224761) and diluted with complete DMEM medium to a final concentration ranging from 1 pM to 3.9 nM. Serial dilutions of compounds in a volume of 50 pl were added to the wells of the plates with cells in triplicates, the contents of the plates were mixed on an orbital shaker (Biosan, Latvia) and kept at 37 °C in an incubator under 5% CO2 for 72 hours.

[0142] At the end of incubation of the culture plates and immediately before the start of detection, prepared was a mixture of Caspase 3 / 7 detection reagents. It was pre-thawed in a water bath at 25 °C and 7.920 ml of Apo-One buffer was mixed with 80 pL of Z-DEVD-Rno substrate in a reservoir (SPL Life Sciences Co., order no. 22050). The culture plates were removed from the CO2 incubator and 100 pl / well of the resulting mixture of detection reagents were added to the wells, the contents of the plates were mixed on a plate thermo-shaker (Biosan, Latvia) for 1 minute at 400 RPM and kept at room temperature for 3 hours in a dark place. The amount of free Ruo was detected on the Infinite M PLEX microplate spectrophotometer (Tecan Group Ltd, Switzerland) by measuring the RFU fluorescence signal using a reading time of 20 ms at an absorption wavelength (ZEx) of 494 nm and an emission wavelength (>Em) of 530 nm. ED50 value was calculated using the Magellan software (Tecan Group Ltd, Switzerland) by approximating experimental points by four-parameter model with the optimization by Levenberg-Marquardt:

[0143] Table 12 and Figure 3 show RFU signal intensity vs BCD-267-trastuzumab conjugate concentration after 3 day co-incubation with SK-BR-3 cells in caspase assay.

[0144] Table 12. Activity of caspase-dependent apoptosis in SK-BR-3 cell line induced by BCD- 267 conjugate in comparison with trastuzumab The results of the experiment demonstrate the ability of the BCD-267 conjugate to induce caspase-dependent apoptosis in SKBR3 cells expressing Her2 under three-day co-incubation, while the unconjugated monoclonal antibody trastuzumab does not exhibit similar activity.

[0145] Example 11. Ability of BCD-267 conjugate to exert antiproliferative effect on trastuzumab-resistant ductal breast carcinoma cell line, BT-474 clone 5.

[0146] The ability of the BCD-267 conjugate and the monoclonal antibody trastuzumab to inhibit proliferation was assessed using an antiproliferative assay on the trastuzumab -resistant BT-474 clone 5 ductal breast carcinoma cell line (ATCC® CRL-3247™) expressing the human epidermal growth factor receptor Her2. The cells were grown in DMEM / F12 medium (PanEco, order no. C470n). The basal growth medium was enriched with L-glutamine at a concentration of 2 mM (PanEco, order no. <T>032) and 10% fetal bovine serum (Gibco, order no. 16140-071). The night before detection, BT-474 clone 5 adhesive cells were removed from plastic using a TrypLE™ Express Enzyme solution (Thermo Fisher Scientific Inc., order no. 12605010) which was then inactivated using a complete DMEM / F12 medium, spun at 1000 RPM in a centrifuge (Biosan, Latvia), and a cell suspension was prepared in a complete DMEM / F12 medium and added to 96- well culture plates (NEST, order no. T-701001) at 0.5* 104cells in 100 pl of the medium per well. The plates with the cells were kept at 37°C in an incubator under 5% CO2 (Binder, Germany) overnight.

[0147] The next day, the test compounds were dissolved in water for injection (PFK OB- NOVLENIE, AO, order no. 224761) and diluted with complete DMEM / F12 medium to a final concentration ranging from 10 pg / ml to 0.0256 ng / ml. Serial dilutions of compounds in a volume of 100 pl were added to the wells of the plates with cells in triplicates, the contents of the plates were mixed on an orbital shaker (Biosan, Latvia) and kept at 37 °C in an incubator under 5% CO2 for 3 and 5 days.

[0148] At the end of the incubation time, the culture plates were removed from the CO2 incubator and 20 pl / well of the Alamar Blue vital dye (Invitrogen™, order no. DALI 100) were added to the wells, the contents of the plates were mixed on an orbital shaker (Biosan, Latvia) for 1 minute at 400 RPM and kept at 37 °C in an incubator under 5% CO2 (Binder, Germany) until the characteristic color developed. Fluorescence intensity was detected using an Infinite M PLEX microplate spectrophotometer (Tecan Group Ltd, Switzerland) by measuring fluorescence signal in RFU using an absorption wavelength (ZEx) of 490 nm and an emission wavelength (ZEm) of 540 nm. ED50 value was calculated using the Magellan software (Tecan Group Ltd, Switzerland) by approximating experimental points by four-parameter model with the optimization by Levenberg- Marquardt:

[0149] Table 13 and Figure 4 show RFU signal intensity vs BCD-267-trastuzumab conjugate concentration after 3 day co-incubation with BT-474 clone 53 cells (where A, B, C, D are as defined earlier).

[0150] Table 13. Values of curve variables for BCD-267-trastuzumab conjugate after 3 day co- incubation with BT-474 clone 5 cells The results of the experiment demonstrate the ability of the BCD-267 conjugate to dose- dependently inhibit proliferation in BT-474 clone 5 cells expressing Her2 under three-day co-in- cubation, while the unconjugated monoclonal antibody trastuzumab does not exhibit similar activity.

[0151] Table 14 and Figure 5 show RFU signal intensity vs BCD-267-trastuzumab conjugate concentration after 5 day co-incubation with BT-474 clone 5 cells.

[0152] Table 14. Values of curve variables for BCD-267-trastuzumab conjugate after 5 day coincubation with BT-474 clone 5 cells

[0153] The results of the experiment demonstrate the ability of the BCD-267 conjugate to dose- dependently inhibit proliferation in BT-474 clone 5 cells expressing Her2 under five-day co-incu- bation, while the unconjugated monoclonal antibody trastuzumab does not exhibit any activity.

Claims

Claims1. An antibody-drug conjugate of formula Ior a pharmaceutically acceptable salt, solvate or stereoisomer thereof, where f is a number in the range of 5.0 - 9.9,Ab is an antibody with the heavy chain sequence set forth in SEQ ID NO: 1 and the light chain sequence set forth in SEQ ID NO: 2.

2. The conjugate according to claim 1, which isAb is an antibody with the heavy chain sequence set forth in SEQ ID NO: 1 and the light chain sequence set forth in SEQ ID NO: 2.

3. The compound according to claims 5-6, where f is a number in the range of 5.0 - 9.9, or5.5 - 9.9, or 5.5-9.0, or 6.0 - 8.5, or 6.5 - 8.5, or 7.0 - 8.5, or 7.0-8.0, or 7.4-8.0, or 7.4-7.9, or 7.4-7.8, or 7.5-7.6.

4. The compound according to claims 5-6, where f is a number in the range of 5.5-5.6, or 5.6- 5.7, or 5.7-5.8, or 5.8-5.9, or 5.9-6.0, or 6.0-6.1, or 6.1-6.2, or 6.2-6.3, or 6.3-6.4, or 6.4-6.5, or 6.5-6.6, or 6.6-6.7, or 6.7-6.8, or 6.8-6.9, or 6.9-7.0, or 7.0-7.1, or 7.1-7.2, or 7.2-7.3, or 7.3-7.4, or 7.4-7.5, or 7.5-7.6, or 7.6-7.7, or 7.7-7.8, or 7.8-7.9 or 7.9-8.0 or 8.0-8.1 or 8.1-8.2 or 8.2-8.3 or 8.3-8.4 or 8.4-8.5 or 8.5-8.6 or 8.6-8.7 or 8.7-8.8 or 8.8-8.9 or 8.9-9.0, or 9.0-9.1, or 9.1-9.2, or 9.2-9.3, or 9.3-9.4, or 9.4-9.5, or 9.5-9.6, or 9.6-9.7, or 9.7-9.8, or 9.8-9.9.

5. The compound according to claims 5-6, where f is 5.0, or 5.1, or 5.2, or 5.3, or 5.4, or 5.5, or 5.6, or 5.7, or 5.8, or 5.9, or 6.0, or 6.1, or 6.2, or 6.3, or 6.4, or 6.5, or 6.6, or 6.7, or 6.8, or 6.9, or 7.0, or 7.1, or 7.2, or 7.3, or 7.4, or 7.5, or 7.55, or 7.6, or 7.7, or 7.75, or 7.8, or 7.9, or 8.0, or 8.1, or 8.2, or 8.3, or 8.4, or 8.5, or 8.6, or 8.7, or 8.8, or 8.9, or 9.0, or 9.1, or 9.2, or 9.3, or 9.4, or 9.5, or 9.6, or 9.7, or 9.8, or 9.9.

6. The compound of formula II:or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

7. The compound according to claim 6, which is8. The compound of formula II.1:pharmaceutically acceptable salt, solvate or stereoisomer thereof.

9. The compound according to claim 8, which isor a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

11. The compound according to claim 10, which isIllb.

12. The compound of formula III.1:or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

13. The compound according to claim 12, which is14. The compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1-13, intended for the manufacture of a medicament for treating an oncological disease.

15. The compound according to claim 14, wherein the oncological disease is selected from glioblastoma, recurrent glioblastoma, colorectal cancer, locally advanced, unresectable or metastatic colorectal cancer, with HER2 overexpression, gastric and gastroesophageal junction cancer, HER2-positive gastric and gastroesophageal junction cancer, adenocarcinoma, unresectable and / or locally advanced or metastatic HER2- positive gastric and gastroesophageal junction cancer, non-squamous non-small cell lung cancer (NSCLC), advanced or metastatic non-squamous nonsmall cell lung cancer and HER2 receptor overexpression, HER2 -mutated unresectable locally advanced / metastatic non-small cell lung cancer, breast cancer, early HER2 -positive breast cancer, HER2-positive breast cancer with metastatic lesions in the brain, unresectable and / or metastatic HER2-positive breast cancer, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (H4C) score of 0, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (H4C) score of 0 combined with both a negative hormone receptor [HR] status and positive HR status; oligometastatic HER2-positive breast cancer, biliary tract cancer, locally advanced or metastatic biliary tract cancer expressing HER2,osteosarcoma, recurrent Her2 -positive osteosarcoma, endometrial cancer, locally advanced unresectable or metastatic Her2-positive endometrial cancer, pancreatic cancer, locally advanced unresectable or metastatic Her2-positive pancreatic cancer, extramammary Her2-positive Paget's disease, ovarian cancer, locally advanced unresectable or metastatic Her2 -positive ovarian cancer, urothelial cancer, locally advanced unresectable or metastatic Her2 -positive urothelial cancer, Her-2 -positive neuroendocrine tumor,Her-2 -positive head and neck tumor,Her-2 -positive salivary gland tumor.

16. A pharmaceutical composition comprising the compound according to any one of claims 1-13 or pharmaceutically acceptable salt, solvate or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

17. The pharmaceutical composition according to claim 16, intended for treating an oncological disease.

18. The pharmaceutical composition according to claim 17, wherein the oncological disease is selected from glioblastoma, recurrent glioblastoma, colorectal cancer, locally advanced, unresectable or metastatic colorectal cancer, with HER2 overexpression, gastric and gastroesophageal junction cancer, HER2-positive gastric and gastroesophageal junction cancer, adenocarcinoma, unresectable and / or locally advanced or metastatic HER2- positive gastric and gastroesophageal junction cancer, non-squamous non-small cell lung cancer (NSCLC), advanced or metastatic non-squamous nonsmall cell lung cancer and HER2 receptor overexpression, HER2 -mutated unresectable locally advanced / metastatic non-small cell lung cancer, breast cancer, early HER2 -positive breast cancer, HER2-positive breast cancer with metastatic lesions in the brain, unresectable and / or metastatic HER2-positive breast cancer, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0 combined with both a negative hormone receptor [HR] status and positive HR status; oligometastatic HER2-positive breast cancer, biliary tract cancer, locally advanced or metastatic biliary tract cancer expressing HER2, osteosarcoma, recurrent Her2 -positive osteosarcoma, endometrial cancer, locally advanced unresectable or metastatic Her2-positive endometrial cancer, pancreatic cancer, locally advanced unresectable or metastatic Her2-positive pancreatic cancer, extramammary Her2-positive Paget's disease, ovarian cancer, locally advanced unresectable or metastatic Her2 -positive ovarian cancer, urothelial cancer, locally advanced unresectable or metastatic Her2 -positive urothelial cancer, Her-2 -positive neuroendocrine tumor,Her-2 -positive head and neck tumor,Her-2 -positive salivary gland tumor.

19. A method for treating an oncological disease by the compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1-13, or by the pharmaceutical composition according to claim 16.

20. The method for treating according to claim 19, wherein the oncological disease is selected fromglioblastoma, recurrent glioblastoma, colorectal cancer, locally advanced, unresectable or metastatic colorectal cancer, with HER2 overexpression, gastric and gastroesophageal junction cancer, HER2-positive gastric and gastroesophageal junction cancer, adenocarcinoma, unresectable and / or locally advanced or metastatic HER2- positive gastric and gastroesophageal junction cancer, non-squamous non-small cell lung cancer (NSCLC), advanced or metastatic non-squamous nonsmall cell lung cancer and HER2 receptor overexpression, HER2 -mutated unresectable locally advanced / metastatic non-small cell lung cancer, breast cancer, early HER2 -positive breast cancer, HER2-positive breast cancer with metastatic lesions in the brain, unresectable and / or metastatic HER2-positive breast cancer, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0 combined with both a negative hormone receptor [HR] status and positive HR status; oligometastatic HER2-positive breast cancer, biliary tract cancer, locally advanced or metastatic biliary tract cancer expressing HER2, osteosarcoma, recurrent Her2 -positive osteosarcoma, endometrial cancer, locally advanced unresectable or metastatic Her2-positive endometrial cancer, pancreatic cancer, locally advanced unresectable or metastatic Her2-positive pancreatic cancer, extramammary Her2-positive Paget's disease, ovarian cancer, locally advanced unresectable or metastatic Her2 -positive ovarian cancer, urothelial cancer, locally advanced unresectable or metastatic Her2 -positive urothelial cancer, Her-2 -positive neuroendocrine tumor,Her-2 -positive head and neck tumor,Her-2 -positive salivary gland tumor.

21. Use of the compound or pharmaceutically acceptable salt, solvate or stereoisomer thereof according to any one of claims 1-13, or the pharmaceutical composition according to claim 16 for treating an oncological disease.

22. The use according to claim 21, wherein the oncological disease is selected from glioblastoma, recurrent glioblastoma, colorectal cancer, locally advanced, unresectable or metastatic colorectal cancer, with HER2 overexpression, gastric and gastroesophageal junction cancer, HER2-positive gastric and gastroesophageal junction cancer, adenocarcinoma, unresectable and / or locally advanced or metastatic HER2- positive gastric and gastroesophageal junction cancer, non-squamous non-small cell lung cancer (NSCLC), advanced or metastatic non-squamous non- small cell lung cancer and HER2 receptor overexpression, HER2 -mutated unresectable locally advanced / metastatic non-small cell lung cancer, breast cancer, early HER2 -positive breast cancer, HER2-positive breast cancer with metastatic lesions in the brain, unresectable and / or metastatic HER2-positive breast cancer, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0, unresectable and / or metastatic breast cancer with a low level of the HER2 receptor or HER2 immunohistochemistry (IHC) score of 0 combined with both a negative hormone receptor [HR] status and positive HR status; oligometastatic HER2-positive breast cancer,biliary tract cancer, locally advanced or metastatic biliary tract cancer expressing HER2, osteosarcoma, recurrent Her2 -positive osteosarcoma, endometrial cancer, locally advanced unresectable or metastatic Her2-positive endometrial cancer, pancreatic cancer, locally advanced unresectable or metastatic Her2-positive pancreatic cancer, extramammary Her2-positive Paget's disease, ovarian cancer, locally advanced unresectable or metastatic Her2 -positive ovarian cancer, urothelial cancer, locally advanced unresectable or metastatic Her2 -positive urothelial cancer, Her-2 -positive neuroendocrine tumor, Her-2 -positive head and neck tumor, Her-2 -positive salivary gland tumor.

Images