UA101632C2 - Normal;heading 1;heading 2;heading 3;COMBINATION THERAPY WITH ANTIBODY-DRUG CONJUGATES - Google Patents

Abstract

Methods for the treatment of Hudgkin's lymphoma comprising administering both a chemotherapeutic regimen and an antibody-drug conjugate compound to a subject in need thereof are provided.

Description

This application claims priority to prior US patent application 60/979594, filed Dec. 2007, prior US patent application 60/027668, filed Nov. 2, 2008, and prior US patent application 61/040641, filed Mar. 28, 2008 p., the content of which is fully included in this description by reference.

The field of technology

The present invention, among other things, relates to methods of treating Hodgkin's lymphoma, which include prescribing to a subject in need of it both a chemotherapy treatment regimen and an antibody-drug conjugate compound.

Prerequisites for creating an invention

Hodgkin's lymphoma (NO) is a tumor of lymphoid tissue, which is histopathologically defined by the presence of malignant Hodgkin-Reed-Sternberg (NK5) cells. A characteristic surface antigen expressed on NK5 cells is SOZ30O. An estimated 8,000 new cases of NI are diagnosed annually in the United States and Canada. Successes in the use of combined therapy and radiation therapy in NI. over the past half century have resulted in sustained remission rates of approximately 70 95. However, these multi-agent regimens cause significant clinical complications in patients, including secondary malignancies, heart disease, and infertility. In addition, approximately 30 95 patients with NI become insensitive to primary therapy or relapse. Salvage chemotherapy regimens and autologous stem cell transplantation (ASCT) represent additional options for these patients, but both these regimens and transplantation are associated with a significant number of clinical manifestations and limited long-term disease control. Patients who relapse after AZST or are unsuitable for salvage therapy have a very poor prognosis. At this time, there are no well-tolerated, effective treatment options for these patients.

Gemcitabine, alone or in combination with other chemotherapy, has been studied before and after

AB5ST. In the case of non-transplant, relapsed or treatment-refractory NI patients treated with gemcitabine, response rates are as high as 39.95 (Zapiogo et al., U. Sip. Ops. 2000 18(13): 2615 -2619). In relapsed/refractory patients, where most patients have received prior autologous or allogeneic transplantation, response rates to gemcitabine are low (22 95), and does the hematologic toxicity of the regimen necessitate a dose reduction to 1000 mg/m? (MepKaieznyi, Siip. utrpota 2004 5(2): 110-115). A combination regimen using gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (PED) has shown promising efficacy in refractory recurrent NI/NGI. In a joint analysis of patients before and after AZST, the proportions of all response reactions were observed, amounting to 70 95, however, in the population before AZST, limiting doses of toxicity consisting of mucositis were observed, and in the population after AZST, gaping neutropenia was observed (Vagiei ei aI., SA SV 59804 App. Opsoo, 2007 18(6): 1071-1079).

Only 32 95 and 26 95 patients who did not undergo transplantation and after A5ST, respectively, were able to receive all doses according to the scheme in a full dose. For patients unresponsive to standard chemotherapy or those who have relapsed, the only potentially curative therapy is high-dose chemotherapy in combination with stem cell transplantation. This treatment is also associated with significant morbidity and mortality, with a 5-year survival rate of 95. Thus, there remains an unmet therapeutic need for patients with NI.

This invention is directed to this and other needs.

Brief description of the drawings

Fig. 1A. Antitumor activity of CAC10-mMsMMAEE alone or in combination with AVMO against subcutaneous NI tumors. G540su in 5SIOYUO mice. NO cells were implanted into ZSIO mice. And 540su to the right. Groups of mice (9-10/group) were untreated or received CAC10-MsMMAE (1 mg/kg, d4ax3 (once every 4 days x 3), intraperitoneally) and/or AVMO: Adriamycin (1 mg/kg, a4ax3, i.v. ), bleomycin (7.5 μg/kg, ayah3, i.p.), vinblastine (0.015 mg/kg, ayahz, i.p.), and dacarbazine (20 mg/kg, d3ah4, i.p.) when tumor sizes ranged around the average size, which is approximately 100 mm3.

Fig. 18. Antitumor activity of CAC10-mMsMMAEE alone or in combination with AVMO against subcutaneous tumors NO. G540su in 5SIOYUO mice. NO cells were implanted into ZSIO mice. And 540su to the right. Groups of mice (9-10/group) were untreated or received CAC10-msMMAE (1 mg/kg, d4ax, intraperitoneally) and/or AVMO: adriamycin (0.75 mg/kg, a4ax3, intravenous), bleomycin (6 µ /kg, diax3, i.p.), vinblastine (0.01 mg/kg, d4ax3, i.p.), and dacarbazine (15 mg/kg, dax4, i.p.) when tumor sizes hovered around the median size of approximately 300 mm3.

Fig. 2A. Antitumor activity of CAC10-mMsMMAEE alone or in combination with gemcitabine against subcutaneous tumors NO. And 540su in 5SIU mice. NI cells were implanted into Z5SIO mice. And 540su to the right. Groups of mice (5-10/group) were untreated or received CAC10-msMMAE (1 mg/kg, diax3, i.p.) alone, gemcitabine (120 mg/kg, a4ax3, i.p.) alone, or combined treatment using cAC10-msMMAE and gemcitabine when tumor sizes hovered around the median size of approximately 100 mm3.

Fig. 28. Antitumor activity of CAC10-mMsMMAEE alone or in combination with gemcitabine against subcutaneous tumors NO. And 540su in 5SIU mice. 5CIO mice were implanted with NO cells. And 540su to the right. Groups of mice (5-10/group) were untreated or received CAC10-msMMAE (1 mg/kg, d4ax3, i.p.) alone, gemcitabine (120 μg/kg, a4ax3, i.p.) alone, or combined treatment using cAC10-msMMAE and gemcitabine when tumor sizes hovered around the median size of approximately 300 mm3.

Fig. BY. Antitumor activity of CAC10-mMsMMAEE alone or in combination with ZMO against subcutaneous NI tumors. G540su in 5SIOYUO mice. NO cells were implanted into ZSIO mice. And 540su to the right. Groups of mice (8-10/group) were untreated or received CAC10-mMsMMAE (1 mg/kg, d4hz, intraperitoneally) alone, WMO alone, or combined treatment using cAC10-

MEMMAE and MO, when the size of the tumors fluctuated around the average size, which is approximately 100 mm3. The treatment regimen for SMO included gemcitabine at a dose of 60 mg/kg, da4ax3, intraperitoneally, vinorelbine at a dose of 2 mg/kg, dbach3, intraperitoneally, and doxorubicin at a dose of 1.5 mg/kg, diax3, intravenously.

Fig. ZV. Antitumor activity of CAC10-mMsMMAEE alone or in combination with ZMO against subcutaneous NI tumors. G540su in 5SIOYUO mice. NO cells were implanted into ZSIO mice. And 540su to the right. Groups of mice (8-10/group) were untreated or received CAC10-mMsMMAE (1 mg/kg, d4hz, intraperitoneally) alone, WMO alone, or combined treatment using cCAC10-

MEMMAE and MO, when the size of the tumors fluctuated around the average size, which is approximately 100 mm3. The treatment regimen for SMO included gemcitabine at a dose of 60 mg/kg, da4ax3, intraperitoneally, vinorelbine at a dose of 2 mg/kg, d5ax3, intraperitoneally, and doxorubicin at a dose of 1.5 mg/kg, d4ax3, intravenously.

Fig. 4A. Antitumor activity of CAC10-cMMAE alone or in combination with vinorelbine against subcutaneous tumors NO. G540su in 5SIOYUO mice. NO cells were implanted into ZSIO mice. And 540su to the right. Groups of mice (5-10/group) were untreated or received CsCAC10-msMMAE (1 mg/kg, d4x3z, intraperitoneally) alone, vinorelbine (4 mg/kg, d54x3) alone, or combined treatment using CAC10-msMMAE and vinorelbine, when tumor sizes hovered around the average size of approximately 100 mm3.

Fig. 48. Antitumor activity of CAC10-"cMMAE alone or in combination with vinorelbine against subcutaneous tumors NO. G540su in 5SIOYUO mice. NO cells were implanted into ZSIO mice. And 540su to the right. Groups of mice (5-10/group) were untreated or received CAC10-msMMAE (1 mg/kg, d4hz, intraperitoneally) alone, vinorelbine (4 mg/kg, d54x3) alone, or combined treatment using CAC10-msMMAE and vinorelbine, when the sizes of the tumors hovered around the average size, which is about 100 mm.

Fig. 5A. Antitumor activity of CAC10-msMMAEE alone or in combination with doxorubicin against subcutaneous NI tumors. And 540su in 5SIUO mice. 5CIO mice were implanted with NO cells. And 540su to the right. Groups of mice (5-10/group) were untreated or received CAC10-mMsMMAE (1 mg/kg, adhz, intraperitoneally) alone, doxorubicin (3 mg/kg, a4ax3) alone, or combined treatment using CAC10-cMMAE and doxorubicin , when the sizes of the tumors fluctuated around the average size, which is approximately 100 mm3.

Fig. 58. Antitumor activity of CAC10-msMMAEE alone or in combination with doxorubicin against subcutaneous tumors NO. And 540su in 5SIUO mice. 5CIO mice were implanted with NO cells. And 540su to the right. Groups of mice (5-10/group) were untreated or received CAC10-mMsMMAE (1 mg/kg, adach3, intraperitoneally) alone, doxorubicin (1.5 mg/kg, diach3) alone, or combined treatment using CAC10-"cMMAE and doxorubicin when the tumors were around the average size of about 100 mm.

Fig. 6. Antitumor activity of CAC10-msMMAE alone or in combination with vinblastine against subcutaneous NI tumors. G540su in 5SIOYUO mice. NO cells were implanted into ZSIO mice. And 540su to the right. Groups of mice (7-10/group) were untreated or received CsCAC10-msMMAE (1 mg/kg, da4ax, intraperitoneally) alone, vinblastine (0.1 mg/kg, a4ax3) alone, or combined treatment using CAC10-mMsMMAE and vinblastine when tumor sizes hovered around the average size of approximately 300 mm3.

Fig. 7. Antitumor activity of CAC10-msMMAE alone or in combination with gemcitabine against subcutaneous NI tumors. G540su in 5SIOYUO mice. NO cells were implanted into ZSIO mice. And 540su to the right. Groups of mice (6-8c/group) were untreated or received CAC10-UsMMAE (1 mg/kg, d4ax, i.p.) alone, gemcitabine (120 mg/kg, d4ax3, i.p.) alone, or combined treatment using cAC10-msMMAE and gemcitabine when tumor sizes hovered around the median size of approximately 100 mm3.

Fig. 8. Antitumor activity of CAC10-tsMMAE alone or in combination with gemcitabine against subcutaneous NI tumors. G540su in 5SIOYUO mice. NO cells were implanted into ZSIO mice. And 540su to the right. Groups of mice (10/group) were untreated or received CAC10-tsMMAE (1 mg/kg, d4achz, i.p.) alone, gemcitabine (120 mg/kg, d4ach3, i.p.) alone, or combined treatment using cCAC10-ptsMIMARE and gemcitabine, when tumor sizes hovered around the average size of approximately 100 mm3.

Fig. 9. Changed scheme of prescribing doses of cСАС10-mMsMMAE. The total amount of CAC10-UsSMMAE was kept constant at the level of 3 mg/kg, and the dose was split in different schemes.

Detailed description of illustrative embodiments of the invention

A. General introduction

The present invention provides, among other things, methods of treating Hodgkin's lymphoma. The authors of this invention have found that combination therapy using two different classes of anticancer compounds, antibody-drug conjugates and chemotherapeutic agents, can increase the therapeutic benefit for subjects suffering from NI. In particular, the authors of this invention found that combined therapy using either gemcitabine or the scheme of introducing AVMO and antibodies against

CO30 conjugated with the compound auristatin provides synergistic therapeutic effects in the treatment of NI. Before the creation of this invention, it could not be expected that a chemotherapeutic agent and an antibody against SOZO, conjugated with the compound auristatin, could have a synergistic effect in the treatment of NI.

For purposes of clarity of description, but not as a limitation, the detailed description of the present invention is divided into the following subsections.

B. A brief summary

The present invention is based, among other things, on the discovery that combined therapy using either gemcitabine or the scheme of administration of AVMO and an antibody against SOZO conjugated with the compound auristatin provides synergistic therapeutic effects in the treatment of NG.

In one embodiment, methods of treating Hodgkin lymphoma are provided. The methods include administering gemcitabine and an antibody-drug conjugate compound to a subject in need thereof. Administration of the antibody-drug conjugate compound and gemcitabine provides a synergistic effect in the treatment of Hodgkin's lymphoma in a patient. The compound of the antibody-drug conjugate is an antibody against SOZ0O conjugated to the auristatin compound.

In another embodiment, methods of treating Hodgkin's lymphoma in a subject essentially consist of administering gemcitabine and an antibody-drug conjugate compound to a subject in need thereof.

Administration of the antibody-drug conjugate compound and gemcitabine provides a synergistic effect in the treatment of Hodgkin's lymphoma in a patient. The antibody-drug conjugate compound is an anti-SOZO antibody conjugated to the auristatin compound.

The delivery of the antibody-drug conjugate compound is usually carried out during the treatment cycle. The treatment cycle can be of any suitable length in time. In one aspect, it is three or four weeks.

The present invention also provides the use of an antibody-drug conjugate compound for the manufacture of a drug administered in combination therapy with gemcitabine for the treatment of Hodgkin's lymphoma in a subject. Administration of the antibody-drug conjugate compound and gemcitabine provides a synergistic effect in the treatment of Hodgkin's lymphoma in a patient. The compound of the antibody-drug conjugate is an antibody against SOZ0O conjugated to the compound auristatin.

In one embodiment, the methods of the present invention include administering to a subject in need thereof a chemotherapy regimen comprising doxorubicin, bleomycin, vinblastine, and dacarbazine (ABMO) and an antibody-drug conjugate compound. Administration of an antibody-drug conjugate compound and a chemotherapy regimen including doxorubicin, bleomycin, vinblastine, and dacarbazine provides a synergistic effect in the treatment of Hodgkin's lymphoma in a patient. The antibody-drug conjugate compound is an anti-SOZO antibody conjugated to the auristatin compound.

In another embodiment, methods of treating Hodgkin's lymphoma in a subject essentially consist of administering to the subject in need thereof a chemotherapy regimen comprising doxorubicin, bleomycin, vinblastine, and dacarbazine, and an antibody-drug conjugate compound.

Administration of an antibody-drug conjugate compound and a chemotherapy regimen including doxorubicin, bleomycin, vinblastine, and dacarbazine provides a synergistic effect in the treatment of Hodgkin's lymphoma in a patient. The antibody-drug conjugate compound is an antibody against

COZ30 conjugated with auristatin compound.

The delivery of the antibody-drug conjugate compound is usually carried out during the treatment cycle. The treatment cycle can be of any suitable length in time. In one aspect, it is three or four weeks.

The present invention also provides the use of an antibody-drug conjugate compound for the manufacture of a medicament administered in a combination therapy using a chemotherapy regimen comprising doxorubicin, bleomycin, vinblastine and dacarbazine for the treatment of Hodgkin's lymphoma in a subject. The appointment of an antibody-drug conjugate compound and a chemotherapy regimen provides a synergistic effect in the treatment of lymphoma

Hodgkin in the patient. The antibody-drug conjugate compound is an anti-SOZO antibody conjugated to the auristatin compound.

S. Definition and abbreviation

Except as specifically discussed, all technical and scientific terms used herein have the same meaning as they are commonly understood by one of ordinary skill in the art relevant to the methods and compositions described herein. The following terms and expressions used in this document have the meanings ascribed to them, except where specifically discussed.

As used herein, the term "inhibits" or "inhibits" means to reduce by a measurable amount or to prevent completely.

As used herein, the intermediate expression "consisting essentially of" limits the scope of the claim to precisely defined active agents or stages and those additional active agents and stages that do not affect the properties of precisely defined active agents.

As used herein, the term "agent" means an element, compound, or molecular entity, including, for example, a pharmaceutical, therapeutic, or pharmacological compound. The agents may be natural or synthetic or a combination thereof. A "therapeutic anticancer agent" is an agent that exhibits a therapeutic (eg, positive) effect on cancer cells either alone or in combination with another agent. Typically, therapeutic anticancer agents used in the methods and compositions described herein are agents that exhibit cytotoxic and/or cytostatic effects on target cells.

When applied to the effect of an agent on a cell, "cytotoxic effect" means killing the cell. "Cytotoxic effect" means inhibition of cell proliferation. "Cytotoxic agent" means an agent that exhibits a cytotoxic or cytostatic effect on a cell, thereby reducing or inhibiting the growth, respectively, of cells in a population of cells.

In the context of the effect of an anti-SOZO-drug conjugate, the term "depletes" refers to the reduction or elimination of SOZO-expressing cells.

The terms "specific binding" or "specifically binds" mean that the antibody against

CO30 will interact highly selectively with its corresponding target, SOZO, but not with many other antigens. Typically, an anti-SOZO antibody binds with an affinity of at least about 1x10-M and preferably from 1028 M to 1029 M, 10-99 M, 10-77 M, or 1072 M.

As used in this document, the term "antibody" refers to (a) immunoglobulin polypeptides or immunologically active parts of immunoglobulin polypeptides, i.e. polypeptides of the immunoglobulin family or fragments thereof, which contain an antigen-binding site that immunospecifically binds to a specific antibody (for example, SOZ30O) , or (b) a conservatively substituted derivative of such immunoglobulin polypeptides or fragments that immunospecifically bind to an antibody (for example, COZ0). Antibodies are generally described, for example, by Nagy/ 5 Gape c

Apiirodie5: And Aroghaiogu Mapia! (So Zrgipd Nagrog I aroghaiogu Rge55, 1988). As used herein, the term "antibody" includes antibodies that have been modified by covalent attachment of a heterologous molecule, such as, for example, attachment of a heterologous polypeptide, or by glycosylation, acetylation, or phosphorylation not normally associated with an antibody, and the like.

The term "monoclonal antibody" refers to an antibody that is derived from a clone of a single cell, including a clone of any eukaryotic or prokaryotic cell, or a phage clone, and not to the method by which it is produced. Therefore, the term "monoclonal antibody" as used herein is not limited to antibodies obtained by hybridoma technology.

The terms "identical" or "percent identity", in the context of two or more nucleic acid sequences or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a precisely defined percentage of nucleotides or amino acid residues that are the same, when comparisons and alignments for maximum compliance. To determine the percent identity, the sequences are aligned for optimal comparison (for example, breaks (gifts) can be introduced into the first amino acid or nucleotide sequence for optimal alignment with the second amino acid or nucleotide sequence. Then the amino acid residues or nucleotides in the corresponding amino acid or nucleotide positions are compared. When a position in the first sequence and the corresponding position in the second sequence share the same amino acid residue or nucleotide, the molecules are identical at that position. The percent identity between the two sequences depends on the number of identical positions common to the sequences (ie, 95 - 10 identical positions /total of 2 positions (eg, overlapping positions) x 100.) In some embodiments, the lengths of the two sequences are the same.

The term "substantially identical", in the context of two nucleic acids or polypeptides, refers to two or more sequences or subsequences that are identical by at least 70 95 or at least 75 95 , more usually by at least 80 95 or at least 85 95 , and even more usually by at least 90 95, at least 95 95 or at least 98 95 (as determined using one of the stated methods). "Similarity" or "percent similarity", in the context of two or more polypeptide sequences, refers to two or more sequences or subsequences having a precisely defined percentage of amino acid residues that are the same or conservatively substituted after comparison and alignment for maximum correspondence, determined , using one of the methods outlined below. As an example, a first amino acid sequence is considered similar to a second amino acid sequence when the first amino acid sequence is identical to, or conservatively substituted for, at least 50 95, 60 Z0, 70 9, 75 95, 80 U", 90 95, or even 95 95 of the second amino acid sequence after comparison with the number of amino acids equal to the number of amino acids contained in the first sequence, or after comparison with the alignment of the polypeptides, which was carried out using a computer program technique known in the field to determine similarity.

The term "significant similarity", in the context of polypeptide sequences, means that the region of the polypeptide has a sequence with at least 7095, usually at least 8095, more usually at least 8595 or even more usually at least 9095 or at least 9595 similarity to the control sequence. For example, a polypeptide is substantially similar to a second polypeptide, for example, when the two peptides differ by one or more conservative substitutions.

Determining the identity or percentage similarity between two sequences can be successfully performed using a mathematical algorithm. A preferred, non-limiting example of a mathematical algorithm used to compare two sequences is the Kagtiip algorithm and

AiYivsNii, 1990, Rhos. Mai). Asad bsi OBA 87: 2264-2268, modified as described by Caillip and Ai5epVii, 1993, in Rgos. May Asai. si. BOTH 90: 5873-5877. Such an algorithm is included in the programs of MVGAZ5T and

KhVI A5T, created by AIY5spPiY and others, 1990, 9. My. Axes 215: 403-410. The search for nucleotide sequences homologous to VHA5T can be performed using the MVIAZT program, with a score of 100 and a word size of 12, to obtain nucleotide sequences homologous to the nucleic acid encoding the protein of interest. The search for VIGA5BT homologous proteins can be performed using the Khvat program, with a score of 50, word size - 3, to obtain amino acid sequences homologous to the protein of interest. For the purpose of comparing alignments with the use of gaps, you can use VGA5T with the introduction of gaps, described by AiyYibePyY et al., 1997, Mysiveis Asia5 Ke5. 25: 3389-3402. Alternatively, Rbi-Base can be used to perform an iterative search that reveals distant relationships between molecules (I4.). When using programs VGA5T, VI A5T with the introduction of passes and RZI-VGA5T, you can use the default parameters of the corresponding programs (for example, KhVIABT and MVIABZT) (see, for example, at the address of the Internet Server: mumumu.pebri.pit.piy.dom) . Another preferred, non-limiting example of a mathematical algorithm used to compare sequences is the Mueg5 and MiPeg algorithm, SAVIOZ (1989). Such an algorithm is included in the AGISM program (version 2.0), which is part of the program package for sequence alignment (CO. When using the ACOM program to compare amino acid sequences, you can use the table of residues according to the mass of РАМ120, the penalty for the size of the omission is 12 and the penalty for the omission in sequences - 4. Additional algorithms for sequence analysis are known in the art and include AOMAMSE and ABAM, described by Togeii5 and Kobocki, 1994, in Sotria. in Rhos. Mai!. Asai. zobi. 85: 2444-2448. In BABTA, Kir is a control option that sets the discreteness and speed of the search. If Kiir-2, similar regions in the two compared sequences are detected by inspection of pairs of aligned residues; if Kishr -1, single amino acid alignments are checked Can be set Kiir-2 or 1 for protein sequences or 1 to b for DNA sequences Kisr default, if no caveat , equal to 2 for protein sequences or from 1 to b for DNA sequences. For additional description of BAZTA parameters, see, for example, riouger. rakhiieimgPp/dosz/tap/taplavia.1.pitiyvesi2, the content of which is included here by reference.

Alternatively, protein sequence alignment can be performed using the SHO5TAG MU algorithm described by Niddipz et al., 1996, in Meipoav5 Epgutoi. 266: 383-402.

As used in this document, the terms "treat" or "undergo treatment" refer to slowing, stopping, or reversing the development of NI. in the subject, which is confirmed by the reduction or elimination of the clinical or diagnostic symptom of the disease. Treatment may include, for example, reducing the severity of a symptom, the number of symptoms, or the frequency of recurrence, such as inhibiting tumor growth, stopping tumor growth, or regression of pre-existing tumors.

As used herein, the term "anticancer agent" refers to any agent that slows, stops, or reverses the development of cancer in a subject. For example, an anticancer agent is an agent that inhibits tumor growth, stops tumor growth, and/or causes regression of pre-existing tumors. Anti-inflammatory agents or other agents prescribed to a subject suffering from cancer to treat cancer-related symptoms, including, for example, inflammation, weight loss, and general malaise, are not considered anti-cancer agents.

As used herein, the term "Pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the limits of careful medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications that correspond to an acceptable benefit/risk ratio. The term "pharmaceutically compatible ingredient" refers to a pharmaceutically acceptable diluent, adjuvant, filler, or carrier with which the antibody-drug conjugate compound is administered.

As used herein when referring to combination therapy, the term "therapeutically effective amount" means such an amount of the combination of agents taken together that their combined action causes the desired biological or therapeutic response, that is, inhibits the occurrence or reduces the intensity of one or more clinical or diagnostic symptoms of Hodgkin's lymphoma. For example, as used herein when referring to combination therapy, the term "therapeutically effective amount" could be an amount of an antibody-drug conjugate compound or an amount of chemotherapeutic agent(s) that, when administered together, either sequentially or simultaneously, into the same or different days during the treatment cycle, have a cumulative effect that is therapeutically effective and synergistic. Additionally, one skilled in the art will appreciate that in the case of combination therapy using a therapeutically effective amount, as in the above example, the amount of antibody-drug conjugate compound and/or the amount of chemotherapeutic agent(s) individually may be or may not be therapeutically effective.

The abbreviation "MAE" refers to monomethylauristatin E.

The abbreviation "MMAE" stands for dovaline-valine-dolaisoleucine-dolaproin-phenylalanine.

The abbreviation "IR" and "rpe-Iuz" belongs to the dipeptide phenylalanine lysine.

The abbreviations "ms" and "maI-si" belong to the dipeptide valincitrulline.

The term "compound" refers to and includes the chemical compound itself and, whether expressly stated or not, and unless the context makes it clear that the following should be excluded: amorphous and crystalline forms of the compound, including polymorphic forms, and these forms can be part of a mixture or in a separate form; the free acid and free base forms of the compounds, which are typically the forms shown in the structures provided herein; isomers of a compound belonging to optical isomers and tautomeric isomers, optical isomers including enantiomers and diastereomers, chiral isomers and non-chiral isomers, and optical isomers including selected optical isomers, as well as mixtures of optical isomers including racemic and non-racemic mixtures; and the isomer can be in isolated form or in a mixture with one or more other isomers; compound isotopes, including compounds containing deuterium and tritium, which also include compounds containing radioisotopes, including therapeutically and diagnostically effective radioisotopes; multimeric forms of the compound, including dimeric, trimeric, etc. forms; salts of the compound, preferably pharmaceutically acceptable salts, including acid addition salts and base addition salts, including salts having organic counterions and inorganic counterions, and including zwitterionic forms, and if the compound is accompanied by two or more counterions, two or more than one counterion may be the same or different; and solvate compounds, including semi-solvates, monosolvates, disolvates, etc., including organic solvates and inorganic solvates, wherein said inorganic solvates include hydrates; moreover, if the compound is accompanied by two or more solvent molecules, the two or more solvent molecules may be the same or different. In some cases, reference herein to a compound of this invention will include direct reference to one or more of the above forms, for example salts and/or solvates; however, this reference is for emphasis only and should not be construed to exclude the other forms identified above.

In this document, "Pharmaceutically acceptable salts" refer to the derivatives of the compounds described in this document, and the original compound is modified by obtaining its acid or base addition salt. Examples of pharmaceutically acceptable salts include, but are not limited to, salts obtained by the interaction of basic residues, such as amines, with mineral or organic acids; salts obtained by the interaction of acidic residues, such as carboxylic acids, with bases or organic bases; etc. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. For example, such commonly accepted non-toxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, etc.; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, --2-

acetoxybenzoic, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic, isethionic acid, etc. These physiologically acceptable salts are prepared by methods known in the art, for example, by dissolving the bases as free amines with an excess of acid in aqueous alcohol or by neutralizing the free carboxylic acid with a base in the form of an alkali metal, such as a hydroxide, or an amine.

Except as specifically discussed, the term "alkyl" refers to a saturated straight or branched hydrocarbon having from about 1 to about 20 carbon atoms (and all combinations and subcombinations of the ranges and specific number of carbon atoms therein), with the preferred range being from about 1 to about 8 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, n- hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-petyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl- 2-butyl and 3,3-dimethyl-2-butyl.

Alkyl groups, alone or as part of another group, may be optionally substituted with one or more groups, preferably 1-3 groups (and any additional substituents selected from halogen), including but not limited to -halogen , -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -F(O)8", -OC(O)B", -"С(О)ОВ8" -С(О)МН", -"С(О)МНА" -"С(О)М(А)", -

MNess)uVv", -58", -5038", -5(0)28", -5(0)8", -OH, -0, -Mz, -MNeg, -"MH(B"), - M(B")2 and -"CM", where each K" is independently selected from -H, -C1-C8 alkyl, -C8-C8 alkenyl, -C2-C8 alkynyl or -aryl, and where the specified groups -0-( C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -Ci-Cv alkyl, -C»-Cv alkenyl and -C2-Cv alkynyl can be optionally additionally substituted by one or more groups including, but not limited to, -C1-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl, -halogen, -O-(C1-Cv alkyl), -O- (C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -F(O)8", -OC(O)B", -F(O)OB8", -"C(O) МН", -Ф(О)МНА", -С(ОМ(А З", -МНе(О)А8", -587, -503187,. -5(0)28", -5(0)8" , -OH, -Mz, -MHg, -MH(B"), -M(A")2 and -CM, where each B" is independently selected from -H, -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl or -aryl.

Except as specifically discussed, the terms "alkenyl" and "alkynyl" refer to straight and branched hydrocarbon chains having from about 2 to about 20 carbon atoms (and all combinations and subcombinations of the ranges and specific numbers of carbon atoms therein), with a preferred ranges from about 2 to about 8 carbon atoms. An alkenyl chain has at least one double bond in the chain, and an alkynyl chain has at least one triple bond in the chain. Examples of alkenyl groups include, but are not limited to, ethylene or vinyl, allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, -3-methyl-1-butenyl, -2- methyl-2-butenyl and - 2,3-dimethyl-2-butenyl. Examples of alkynyl groups include, but are not limited to, an acetylene group, propargyl, acetylenyl, propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-petynyl, and -3-methyl-1-butynyl.

Alkenyl or alkynyl groups, alone or as part of another group, may be optionally substituted with one or more groups, preferably 1-3 groups (and any additional substituents selected from halogen), including, but not limited to, -halogen, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -C(O)8", -OC(O)B ", -С(О)ОНВ", -С(О)МН", -С(О)МНА", -Ф(О)М(А")2, -"МНО(О) В", -587, -50318", -5(0)28", -5(0) 8", -OH, -О, -Мз, -МН»е, -МН(Б"), -М(Б")» ии - CM, where each K" is independently selected from -H, -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl or -aryl, and where the indicated groups are -0O-(C1-Cv alkyl), -O- (C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -C1-Cv alkyl, -C2-Cv alkenyl and -C2-Cv alkynyl may be optionally additionally substituted with one or more substituents that include, but are not limited to, -C1-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl, -halogen, -O-(C:1-Cv alkyl), -

O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -F(O)8", -OC(O)B", -C(O0)0O8" -C(O) МН», -С(О)МНА», -

С(ООМ(А)2, -"МНО(О)А", -58"7, -5О03И8", -5(0)28", -5(0)8", -OH, -Mz, -МН », -MH(B"), -Щ(А")»2 and -CM, where each B" is independently selected from -H, -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl or - aril

Except as specifically discussed, the term "alkylene" refers to a straight- or branched-chain saturated hydrocarbon radical having from about 1 to about 20 carbon atoms (and all combinations and subcombinations of the ranges and specific numbers of carbon atoms therein), with the preferred range from about 1 to about 8 carbon atoms, which has two monovalent radical centers resulting from the removal of two hydrogen atoms from the same or two different carbon atoms of the parent alkane. Typical alkylenes include, but are not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, oxyethylene, nonylene, decalene, 1,4-cyclohexylene, and the like. Alkylene groups, alone or as part of another group, may be optionally substituted with one or more groups, preferably 1-3 groups (and any additional substituents selected from halogen), including but not limited to -halogen , -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -C(O)8", -OC(O)B", -С(О)ОНВ", -С(О)МН", -С(О)МНА", -Ф(О)М(А")2, -"МНО(О) В", -587, -50318 ", -5(0)28", -5(0) 8", -OH, -O, -Mz, -MH»e, -MH(B"), -M(B")» and -SM, where each B" is independently selected from -H, -C1-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl or -aryl, and where the indicated groups are -O-(C1-Cv alkyl), -O-(C2 -C 1 alkenyl), -O-(C 2 -C 1 alkynyl), -aryl, -C 1 -C 1 alkyl, -C 2 -C 1 alkenyl and -C 2 -C 2 alkynyl may optionally be further substituted with one or more substituents which include, but without limitation, -C1-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl, -halogen, -O-(C:1-Cv alkyl), -

O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -F(O)8", -OC(O)B", -C(O0)0O8" -C(O) МН», -С(О)МНА», -

С(ООМ(А)2, -"МНО(О)А", -58"7, -5О03И8", -5(0)28", -5(0)8", -OH, -Mz, -МН », -MH(B"), -Щ(А")»2 and -CM, where each B" is independently selected from -H, -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl or - aril

Except as specifically discussed, the term "alkenylene" refers to an optionally substituted alkylene group containing at least one carbon-carbon double bond. Exemplary alkenylene groups include, for example, ethenylene (-CHNeCH-) and propenylene (--CH:CHNHe-).

Except where specifically discussed, the term "alkynylene" refers to an optionally substituted alkylene group containing at least one carbon-carbon triple bond. Exemplary alkynylene groups include, for example, acetylene (-C-C-), propargyl ( -CH»С-С-) and 4-pentynyl -СНаСНСНоСЕСН-).

Except as specifically discussed, the term "aryl" refers to a monovalent aromatic hydrocarbon radical having 6 to 20 carbon atoms (and all combinations and subcombinations of the ranges and specific numbers of carbon atoms therein) resulting from the removal of one hydrogen atom from one carbon atom of the original aromatic ring system. Some aryl groups are represented in the exemplary structures as "Ag". Typical aryl groups include, but are not limited to, radicals arising from benzene, substituted benzene, phenyl, naphthalene, anthracene, biphenyl, and the like.

The aryl group, alone or as part of another group, may be optionally substituted by one or more, preferably 1-5 or even 1-2 groups, including, but not limited to, halogen, -C1-C8 alkyl, -C2 -Cv alkenyl, -C2-Cv alkynyl, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -C(O)8" . )VA", -58", -

Oz", -5(0)28", -5(0)8", -OH, -MO", -Mz, -MNeg, -MH(B"), -M(A")2 and -SM, where each EC" is independently selected from -H, -Ci-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl or -aryl, and where the specified groups are -C1-Cv alkyl, -C2o-Cv alkenyl, -C2- C 1 -C 1 alkynyl, -O-(C 1 -C 1 alkyl), -O-(C 2 -C 1 alkenyl), -O-(C 2 -C 2 alkynyl) and -aryl may optionally be further substituted with one or more substituents that include, but without limitation, -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl, -halogen, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -

О-(С2-Св alkynyl), -aryl, -С(О)Б8", -ОС(О)Б", -ССО)0ОВ8", -С(О)МН»е, -С(О)МНА" , -"С(О)М(А Й)", -МНОС(О)В", -

ZA", -50Oz38", -5(0)28", -5(O)8", -OH, -Mz, -MNeg, -MH(B"), -M(A)" and -SM, where each K" is independently selected from -H, -C1-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl or -aryl.

Except as specifically discussed, the term "arylene" refers to an optionally substituted aryl group that is divalent (i.e., one that results from the removal of two hydrogen atoms from the same or two different carbon atoms of the parent aromatic ring system) and whose substituents may be in the ortho-, meta-, or para-positions, as demonstrated in the following structures, with phenyl being the aryl group, exemplified by:- In

Exemplary groups "-(C 1 -C 1 alkylene)aryl", "-(C 1 -C 1 alkenylene)aryl" and "-(C 1 -C 2 alkynylene)aryl" include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, etc.

Except as specifically discussed, the term "heterocycle" refers to a monocyclic, bicyclic, or polycyclic system having from 3 to 14 ring atoms (also referred to as ring member(s)), wherein at least one ring atom in at least one ring is a heteroatom selected from with M, 0, P, or 5 (and all combinations and subcombinations of the ranges and specific amounts of carbon atoms and heteroatoms therein). The heterocycle may have from 1 to 4 heteroatoms independently selected from M, O, P, or 5. One or more M, C, or 5 atoms in the heterocycle may be oxidized. A monocyclic heterocycle preferably has 3-7 ring members (e.g., 2-6 carbon atoms and 1-3 heteroatoms independently selected from M, 0, P, or 5), and a bicyclic heterocycle preferably has 5-10 ring members (e.g., 4 -9 carbon atoms and 1-3 heteroatoms independently selected from M, O, P or 5). A ring that includes a heteroatom can be aromatic or non-aromatic. Except as specifically discussed, the heterocycle is attached to a side group at any heteroatom or carbon atom that provides a stable structure.

Heterocycles are described in Radiets, "Rgipsiriee5 oi Modegt Negiegosusiis Spetivigu" (MA Vepiatip, Mezh/

UogKk, 1968), especially chapters 1, 3, 4, 6, 7 and 9; "Spetivigu oi Neiegosusiis Sotroypav5, A 5egie5 oi

Mopodgary5" (opp UMieu 5 5op5, Mem HogK, 1950 to the present), especially volumes 13, 14, 16, 19128; and. At.

Spent boss. 82: 5566 (1960).

Except as specifically discussed, the term "heterocycle" refers to an optionally substituted heterocyclic group, as defined above, that is divalent (i.e., one that occurs when two hydrogen atoms are removed from the same or two different carbon atoms of the parent heterocyclic ring system).

Examples of "heterocyclic" groups include, but are not limited to, pyridyl, dihydropyridyl, tetrahydropyridyl (piperidyl), thiazolyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thiananaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl. , piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, bis- tetrahydrofuranyl, tetrahydropyranyl, bistetrahydropyranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2, 5H-thiazine, 2N-thiazine -1,5,2- dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxatinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, pyrinyl, 4H -quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinolinyl, pteridinyl, 4H-carbazolyl, carbazolyl, p-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl . Preferred "heterocyclic" groups include, but are not limited to, benzofuranyl, benzothiophenyl, indolyl, benzopyrazolyl, coumarinyl, isoquinolinyl, pyrrolyl, thiophenyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridinyl, pyridonyl, pyrazinyl, pyridazinyl, isothiazolyl , isoxazolyl and tetrazolyl.

The heterocyclic group, alone or as part of another group, may be optionally substituted by one or more groups, preferably 1-2 groups, including, but not limited to, -C1-

C2-C8 alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -halogen, -0O-(C1-C8 alkyl), -O-(C2-C8 alkenyl), -O-(C2-C8 alkynyl), -aryl . -"MNO(O)V", -587,. -50387, -

C(0)28", -5(O)8", -OH, -Mz, -MH", -MH(B"), -M(B")2 and -CM, where each K" is independently selected from -H, -C1-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl or -aryl, and where the indicated groups are -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O -(C2-Cv alkynyl), -Ci-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl and -aryl may be optionally further substituted with one or more substituents including, but not limited to, -Ci- Cl alkyl, -C»-Cv alkenyl, -C2-Cv alkynyl, -halogen, -O-(Ci-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), - aryl, -"F(O)B8", -OC(O)B", -C(O)0O8", -C(O)MH", -"CO(O)MNA", -C(OM(A 2, -"MNO(O)V", -58", -

Oz", -5(0)287, -(O)8", -OH, -Mz, -MH"e, -MH(B"), -M(A")" and -SM, where each B" independently choose from -

H, -C:-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl or aryl.

As a non-limiting example, heterocycles with a bond at the carbon atom can be linked in the following positions: in the 2, 3, 4, 5 or 6 position of pyridine; in position 3, 4, 5 or 6 of pyridazine; in position 2, 4, 5 or 6 of pyrimidine; in position 2, 3, 5 or 6 of pyrazine; in position 2, 3, 4 or 5 of furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole; in position 2, 4 or 5 of oxazole, imidazole or thiazole; position 3, 4 or 5 of isoxazole, pyrazole or isothiazole; in position 2 or C of aziridine; in position 2, C or 4 of azetidine; at position 2, 3, 4, 5, 6, 7 or 8 of quinoline or at position 1, 3, 4, 5, 6, 7 or 8 of isoquinoline. However, more common carbon-bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, b-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2- pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, b-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, b-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.

By way of example and not limitation, nitrogen-bonded heterocycles can be linked at the 1-position of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline , pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline or 1H-indazole; in position 2 of isoindole or isoindolin; in position 4 of morpholine and in position U of carbazole or p-carboline. However, more common nitrogen-bonded heterocycles include 1-aziridyl, 1-azetidyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

Except as specifically discussed, the term "carbocycle" refers to a saturated or unsaturated non-aromatic monocyclic, bicyclic or polycyclic system having from 3 to 14 ring atoms (and all combinations and subcombinations of the ranges and specific numbers of carbon atoms therein), wherein all ring atoms are carbon atoms. Monocyclic carbocycles preferably have 3-6 ring atoms, however, more preferably 5 or 6 ring atoms. Bicyclic carbocycles preferably have 7-12 ring atoms, for example, with an arrangement in the form of a bicyclo (4,51, (5,51, (5,61| or Ib,6) system, or 9 or 10 ring atoms with an arrangement in the form of ( |5,6| or I|b,6| systems. The term "carbocycle" includes, for example, a monocyclic carbocyclic ring fused to an aryl ring (eg, a monocyclic carbocyclic ring fused to a benzene ring). Preferably, the carbocycles have 3-8 ring carbon atoms.

Carbocyclic groups, alone or as part of another group, may be optionally substituted with, for example, one or more groups, preferably 1 or 2 groups (and any additional substituents selected from halogen), which include, but are not limited to , -halogen, -

C1-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -б(0)8", -ОС(О)В", -Б(О)ОВ8", -С(О)МН", -«С(О)МНА", -С(ОМ(А")» , -"МНО(О)В", -587, -50з38"7, -550)28", -

З(0)В8", -ОН, -О0, -Мз, -МН", -"МН(В"), -М(А")2 and -"СМ, where each EC" is independently chosen from -Н, -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl or -aryl, and where the indicated groups are -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl, -O-(Ci-Cv alkyl), -O-(C2-C8 alkenyl), -O-(C2-C8 alkynyl)y and -aryl may optionally be further substituted with one or more substituents including, but not limited to, -C1-C8 alkyl , -

C2-Cv alkenyl, -C2-Cv alkynyl, -halogen, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -

С(О)В", -ОС(О)В", -С(О)ОВ8", -"С(О)МН", -"С(О)МНА", -"СС(ОМ(А 2, -"МНО(О)В", -587, -50з3187, -5(0)28", -

З(О)8", -OH, -Mz, -MH", -MH(B"), -M(А7)» and -CM, where each B" is independently selected from -H, -C1-Cv alkyl , -

C2-Cv alkenyl, -C2-Cv alkynyl or -aryl.

Examples of monocyclic carbocyclic substituents include -cyclopropyl, -cyclobutyl, -cyclopentyl, -1-cyclopent-1-enyl, -1-cyclopent-2-enyl, -1-cyclopent-3-enyl, cyclohexyl, -1-cyclohex-1- enyl, -1-cyclohex-2-enyl, -1-cyclohexo-3-enyl, cycloheptyl, -cyclooctyl, -1,3-cyclohexadienyl, -1,4-cyclohexadienyl, -1,3-cycloheptadienyl, -1,3 ,5-cycloheptatrienyl and -cyclooctadienyl. "Carbocyclo", alone or as part of another group, refers to an optionally substituted carbocyclic group, as defined above, which is divalent (i.e., formed by the removal of two hydrogen atoms from the same or two different carbon atoms of the parent carbocyclic ring system ).

When any variable occurs more than once in any term or in any formula, its definition in each case is independent of its definition in every other case.

Combinations of substituents and/or variables are permitted only if such combinations result in stable compounds.

Unless otherwise stated in the context, a dash (-) indicates the site of attachment of a side molecule.

Accordingly, the term "-(C1-Cv alkylene)aryl" or "-C1i-Cv alkylene(aryl)y" belongs to the C1-Cv alkylene radical defined in this document, and the alkylene radical is attached to the side molecule at any of the atoms carbon of the alkylene radical, and one of the hydrogen atoms bound to the carbon atom of the alkylene radical is replaced by an aryl radical defined herein.

When a particular group is "substituted", that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents . However, the group may typically have any number of substituents selected from halogen. Groups that are substituted are thus indicated.

It is assumed that the definition of any substituent or variable at a particular position in a molecule is independent of its definition elsewhere in that molecule. It is understood that the substituents or sets of substituents in the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by methods known in the art, as well as those the methods described in this document.

Protecting groups herein refer to groups that selectively block, either temporarily or permanently, one reactive site in a multifunctional compound. Suitable hydroxy protecting groups for use in the present invention are pharmaceutically acceptable and may or may not require cleavage from the parent compound after administration to a subject in order for the compound to be active. Weaning occurs due to the normal metabolic process in the body. Protecting groups for hydroxy groups are well known in the art, see document

Rgoiesiime Stgoyrz ip Ogdapis bupipeviv ru T. MU. Steepe apa R.S.M. MUsv (Chopp UMieu b bBopv, Z Eayop), which is incorporated herein by reference in its entirety, and include, for example, protecting groups that form a simple ether (e.g., alkyl ethers and silyl ethers, including, for example, dialkylsilyl ether, trialkylsilyl ether, dialkylalkoxysilyl ether), ester, carbonate, carbamates, sulfonate and phosphate. Examples of hydroxy protecting groups include, but are not limited to, methyl ether, methoxymethyl ether, methylthiomethyl ether, (phenyldimethylsilyl)umethoxymethyl ether, benzyloxymethyl ether, para-methoxybenzyloxymethyl ether, para-nitrobenzyloxymethyl ether, ortho-nitrobenzyloxymethyl ether, (4 -methoxyphenoxy)methyl ether, guaiacol methyl ether, tert-butoxymethyl ether, 4-pentenyloxymethyl ether, siloxymethyl ether, 2-methoxyethoxymethyl ether, 2,2,2-trichloroethoxymethyl ether, bis(2-chloroethoxy)methyl ether, 2-(trimethylsilyl) uethoxymethyl ether, menthoxymethyl ether, tetrahydropyranyl ether, 1-methoxycyclohexyl ether, 4-methoxytetrahydrothiopyranyl ether, 4-methoxytetrahydrothiopyranyl ether 5, 5-dioxide, 1-(2-chloro-4-methyl)phenyl|-4-methoxypiperidin-4-yl ether, 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl ether, 1,4-dioxan-2-yl ether, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether; substituted ethyl ethers such as 1-ethoxyethyl ether, 1-(2-chloroethoxy)ethyl ether, 1-(2-(trimethylsilyl)ethoxyethyl ether, 1-methyl-1-methoxyethyl ether, 1-methyl-1-benzyloxyethyl ether, 1-methyl-1-benzyloxy-2-fluoroethyl ether, 1-methyl-1-phenoxyethyl ether, 2-trimethylsilyl ether, tert-butyl ether, allyl ether, propargyl ethers, para-chlorophenyl ether, para-methoxyphenyl ether, benzyl ether, para-methoxybenzyl ether, 3,4-dimethoxybenzyl ether, trimethylsilyl ether, triethylsilyl ether, tripropylsilyl ether, dimethylisopropylsilyl ether, diethylisopropylsilyl ether, dimethylhexylsilyl ether, tertbutyldimethylsilyl ether, diphenylmethylsilyl ether, benzoylformic acid ester, acetic acid ester, chloroacetic acid ester , dichloroacetic acid ester, trichloroacetic acid ester, trifluoroacetic acid ester, methoxyacetic acid ester, triphenylmethoxyacetic acid ester, phenylacetic acid ester, benzoic acid ester, alkyl methyl rbonate, alkyl-3-fluorenylmethylcarbonate, alkylethylcarbonate, alkyl-2,2,2-trichloroethylcarbonate, 1,1-dimethyl-2,2,2-trichloroethylcarbonate, alkylsulfonate, methanesulfonate, benzylsulfonate, tosylate, methylene acetal, ethylidene acetal, and tert-butylmethylidene ketal. Preferred protective groups are represented by the formulas -Nae, -51(82)(Ng) (VZ), -

С(О)вВа, -(О)ОНа, -С(О)МН(Наг), -5х0)282, -(Ф)2ОН, -П(ФОХОН)» and -А(ОХОНИНОНАВаa), where Vag is - WITH.-

C2 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C1-C6 alkylene (carbocycle), -C2-C6 alkenylene (carbocycle), -

C2-C0 alkynylene (carbocycle), -C1-C0 aryl, -C1-C0 alkylene (aryl), -C2-C0 alkenylene (aryl), -C2-C0 alkynylene (aryl), -C1-C0 alkylene (heterocycle), -C2-Сго alkenylene(heterocycle)y or /-С2-Сг2о alkynylene(heterocycle), where the indicated alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene radicals, individually or as part of another molecule, are optionally substituted by one or more by groups independently selected from At, the indicated carbocyclic radicals, alone or as part of another molecule, optionally substituted by one or more groups independently selected from A2, indicated aryl radicals, alone or as part of another molecule, optionally substituted by one or more groups independently selected from AZ, and the indicated heterocyclic radicals, alone or as part of another molecule, optionally substituted by one or more groups independently selected from A4. AT, A2, AZ and A4 have the meanings defined in this document. p. Antibody-drug conjugate

The methods described herein include the use of an antibody-drug conjugate compound in combination therapy for the treatment of NI. The antibody-drug conjugate compound for use in the present invention includes an anti-SOR antibody, that is, an antibody that specifically binds to the SOR associated with a component in the form of a medicinal product. The drug component is an auristatin-type drug that has been shown to interfere with microtubule dynamics and nuclear and cell division and has anticancer activity. The auristatins of this invention bind to tubulin and exhibit a cytotoxic or cytostatic effect on the NI cell line, for example, the Y540su cell line. In some embodiments of the present invention, the drug auristatin is conjugated to an antibody against SHUOZO using a linker that is cleavable under intracellular conditions such that cleavage of the linker results in the release of the auristatin compound from the antibody in the intracellular environment. In other embodiments, the linker unit is non-cleavable, and the drug is released by degradation of the antibody.

There are a number of different assays that can be used to determine whether auristatin or the resulting antibody-drug conjugate exerts a cytostatic or cytotoxic effect on an NO cell line. In one example, a thymidine incorporation assay is used to determine whether auristatin or the resulting antibody-drug conjugate exerts a cytotoxic or cytostatic effect on a NI cell line. For example, Ni cells at a density of 5,000 cells/well of a 96-well plate are cultured for a 72-hour time period and exposed to 0.5 µCi of H-thymidine for the final 8 hours of the 72-hour time period, and the incorporation of H-thymidine into culture cells is measured in the presence or absence of auristatin or antibody-drug conjugate. Auristatin or the resulting antibody-drug conjugate have a cytostatic or cytotoxic effect on the NO cell line, if the culture cells are characterized by reduced incorporation of "H-thymidine" compared to cells of the same cell line cultured under the same conditions, but which are not brought into contact with auristatin or antibody-drug conjugate.

To determine cytotoxicity, necrosis or apoptosis (programmed cell death) can be determined. Necrosis is usually accompanied by increased permeability of the plasma membrane, swelling of the cell, and rupture of the plasma membrane. Apoptosis is usually characterized by the formation of membrane vesicles, cytoplasmic condensation, and activation of endogenous endonucleases.

Determination of any of these effects on cells is NOT. indicates that auristatin or antibody-drug conjugate is applicable for the treatment or prevention of NI.

In another example, to determine whether auristatin or the resulting antibody-drug conjugate exerts a cytostatic or cytotoxic effect on a Ni cell line, cell viability is determined by determining the uptake of a dye such as neutral red, trypan blue, or AG AMAVE "M" into the cell blue (see, e.g., Rade et al., 1993, Ipi. U. o. Opsiod. 3: 473-476).In this assay, cells are incubated in media containing the dye, the cells are washed, and the dye that remains is determined spectrophotometrically , which is a reflection of the introduction of the dye into the cell. To determine the cytotoxicity, you can also use the protein-binding dye sulforhodamine B (ZEV) (5Kepap eyi ai!., 1990, U. Mai!. Sapseg Ipvi. 82: 1107-1112). Preferred con Antibody-drug conjugates include conjugates with an IC value (defined as the mAb concentration that causes 50 95 cell death) of less than 1000 ng/ml, preferably less than 500 ng/ml, more preferably less 100 ng/ml, most preferably even less than ng/ml or even less than 10 ng/ml in a Hodgkin's lymphoma cell line, for example, the I 540su cell line.

Methods for determining whether a compound binds to tubulin are known in the art. See, for example, Miiieg ei ai., ApaI. Spent 2006, 78, 4390-4397; Natei! sei ai!., Moiesshag Rpagtaso!iodu, 1995, 47: 965-976; and Natei ei aiI., Tpe doshgpai oi Vioiodisa! Spitivig, 1990, 265: 17141-17149. For the purposes of this invention, the relative affinity of a compound to tubulin can be determined. Preferred auristatins of the present invention bind to tubulin with an affinity ranging from 10-fold lower (weaker) binding affinity of MMAE to tubulin to 10-fold, 20-fold, or even 100-fold greater (stronger) binding affinity. binding of MMAE to tubulin.

E. Gemcitabine

Some methods of this invention include the administration of an antibody-drug conjugate compound and gemcitabine for the treatment of Hodgkin's lymphoma.

Gemcitabine, 4-amino-1-(2B, 48, 5H8)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl|pyrimidin-2-one, is currently sold under the brand ZEM7LAN "M EiYii Shu apa Sotrapu. Gemcitabine, a cytarabine analog, is a pyrimidine antimetabolite that has been shown to exhibit a broad spectrum of activity in NI.

The present invention encompasses combination therapy using an antibody-drug conjugate compound, gemcitabine, and optionally one or more additional agents, for example, anticancer agents including chemotherapeutic agents. For example, one or more of vinorelbine, dexamethasone, cisplatin, and doxorubicin, including pegylated liposomal doxorubicin, can be administered as part of a combination therapy (eg, a regimen of ZMO). In some embodiments, however, gemcitabine will be the only chemotherapeutic agent administered as part of a combination therapy using an antibody-drug conjugate compound.

For example, in some embodiments, during one or more cycles of therapy, gemcitabine will be the only chemotherapy agent administered as part of a combination therapy using an antibody-drug conjugate compound. In some embodiments, gemcitabine will be the only anticancer agent administered as part of a combination therapy using an antibody-drug conjugate. In some embodiments, doxorubicin, or more specifically pegylated liposomal doxorubicin, will be specifically excluded from the combination therapy. In some embodiments, vinorelbine and doxorubicin, or vinorelbine and pegylated liposomal doxorubicin, will be excluded from the combination therapy.

E. Therapy with doxorubicin, bleomycin, vinblastine and dacarbazine

The methods of this invention include the administration of an antibody-drug conjugate compound and a chemotherapy regimen comprising doxorubicin, bleomycin, vinblastine and dacarbazine as a combination therapy for the treatment of Hodgkin's lymphoma. Currently, doxorubicin, bleomycin, vinblastine, and dacarbazine are administered together in a chemotherapy regimen called ABMO.

At present, the scheme of chemotherapeutic treatment of AVMO is considered the standard treatment in NI therapy. first row A chemotherapy regimen for AVMO is usually given to patients every two weeks for a four-week treatment cycle. Typically, on days 1 and 15 of a four-week period, patients are treated with 25 mg/m doxorubicin, 10 U/m2 bleomycin, 6 mg/m2 vinblastine, and 375 mg/m dacarbazine.

The present invention encompasses combination therapy using an antibody-drug conjugate compound, doxorubicin, bleomycin, vinblastine, and dacarbazine (eg, the ABMO regimen) and optionally one or more additional agents, for example, anticancer agents including chemotherapeutic agents. In some embodiments, however, doxorubicin, bleomycin, vinblastine, and dacarbazine will be the only chemotherapeutic agents administered as part of a combination therapy using an antibody-drug conjugate compound. For example, in some embodiments, during one or more cycles of therapy, the AVMO regimen will be the only chemotherapy regimen administered as part of a combination therapy using an antibody-drug conjugate compound. In some embodiments, the AVMO scheme will be the only scheme of anticancer treatment prescribed as part of a combination therapy using an antibody-drug conjugate compound. In some embodiments, doxorubicin will be specifically excluded from the combination therapy, and the chemotherapeutic agents will include bleomycin, vinblastine, and dacarbazine. b. Synergism

In preferred embodiments of the present invention, therapy using a combination of an antibody-drug conjugate and a chemotherapeutic agent(s) provides a synergistic effect in the treatment of Hodgkin's lymphoma in a patient. As used herein, the term "synergism" or "synergistic effect" when used in connection with describing the effectiveness of a combination of agents means any conditioned effect of the combination that exceeds the effect that is predicted based on the sum of the effects of the individual agents. Accordingly, the present invention includes embodiments in which subjects treated with both the antibody-drug conjugate compounds and the chemotherapeutic agent(s) have significantly better treatment outcomes than subjects treated with only the compound con yugata antibody drug or only chemotherapeutic agent(s), with the appointment of the same administration and dosage schemes. The present invention includes embodiments in which subjects have better treatment outcomes than those that would be expected based on the sum of the effects of treatment with the antibody-drug conjugate compound alone and chemotherapy regimens alone, with the same administration regimens and dosage.

Methods of determining such synergism are known in the art. In one example, syngeneic (same gene lineage) tumors are obtained from donor animals, subjected to disaggregation, quantified, and injected back into syngeneic (same gene lineage) host mice. The anticancer combinations are usually then injected at some later point(s) in time, by either the intraperitoneal, intravenous, or oral route, and tumor growth rates and/or survival rates compared to untreated controls and controls are determined. exposed to only one of the therapies. Growth rates are usually determined for tumors growing in the front side of the animal, and the diameters perpendicular to the horizontal size of the tumor translate into an estimate of the total mass and volume of the tumor. The time required to reach a given mass (for example, the time required for a tumor to grow threefold, or the time required for a tumor to grow fourfold) is then compared to the time required for the tumor to grow equally in control animals. If the time required to reach a target weight for an animal treated with combination therapy exceeds the value obtained by summing the time required to reach a target weight for an animal treated with therapy "A" and for an animal treated with therapy "B" , (that is, by each therapy separately), it can be said that the combined therapy provides a synergistic effect. In another example, the time required to reach a target weight for an animal treated with the combination therapy may not exceed the value obtained by summing the time required to reach a target weight for an animal treated with therapy "A" and for an animal subjected to treatment therapy "B"; however, another conditional effect of the combination that exceeds the effect predicted based on the sum of the effects of the individual agents is adequate to identify/determine the combination therapy as synergistic. For example, if the number of long-term relevant responses for animals treated with combination therapy exceeds the sum of the number of long-term relevant responses in each treatment group alone, the combination therapy provides a synergistic effect.

A long-term response (OK) is defined as the absence of a palpable tumor in the animal.

N. Introduction (purpose)

Antibody-drug conjugate and gemcitabine or antibody-drug conjugate and regimen

AVMOs are administered in such a way that they provide a synergistic effect in the treatment of NI. in the patient. The introduction can be carried out in any suitable way, provided that the appointment provides the necessary therapeutic effect, that is, synergism. In preferred embodiments, the antibody-drug conjugate compound and gemcitabine or the antibody-drug conjugate compound and the AVMO regimen are administered during the same cycle of therapy, e.g., during one cycle of therapy, e.g., a time period of three or four weeks, both the antibody-drug conjugate compounds and the given chemotherapeutic agent(s) are administered to the subject. In some embodiments of the present invention, administration of the antibody-drug conjugate compound will be performed at a time such that it will sensitize the cancer cells to treatment with gemcitabine or the ABMO regimen, i.e. sequentially, e.g., immediately before chemotherapy treatment, e.g., in less than 2 hours before chemotherapy treatment.

The dose of the antibody-drug conjugate compound administered to a patient with NI will also depend on the frequency of administration. The present invention provides for the delivery of the antibody-drug conjugate compound only during the treatment cycle or by means of fractional delivery.

The present invention includes embodiments in which the antibody-drug conjugate compound will be administered in a dose range of 0.1 mg/kg to 2.7 mg/kg body weight of the subject in each dose, from 0, 2 mg/kg to 1.8 mg/kg of the subject's body weight in each dose, from 0.2 mg/kg to 1.2 mg/kg of the subject's body weight in each dose, from 0.4 mg/kg up to 1 mg/kg of the subject's body weight in each dose, from 1 mg/kg to 1.5 mg/kg of the subject's body weight in each dose, and from 0.5 mg/kg to 1 mg/kg of the subject's body weight object in each dose. Other ranges are encompassed by the present invention as long as they produce the desired result.

The present invention includes treatment regimens in which the total dose of the antibody-drug conjugate compound administered to a patient with NI will be, for example, from 0.1 mg/kg to 5 mg/kg, from 0.1 mg/kg up to 4 mg/kg, 0.1 mg/kg to 3.2 mg/kg, or 0.1 mg/kg to 2.7 mg/kg of the subject's body weight during a treatment cycle, e.g., a period of time that is 3 or 4 weeks. In some embodiments, the total dose of the antibody-drug conjugate compound administered to a patient with NI will be, for example, from about 0.6 mg/kg to about 5 mg/kg, from about 0.6 mg/kg to about 4 mg/kg, from about 0.6 mg/kg to about 3.2 mg/kg, from about 0.6 mg/kg to about 2.7 mg/kg, or even from about 1.5 mg/kg to about With mg/kg during a treatment cycle, for example, a time period of 3 or 4 weeks. In some embodiments, the dose will be about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1, 1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg /kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about C mg /kg, about 3.1 mg/kg, about 3.2 mg/kg, about 3.3 mg/kg, about 3.4 mg/kg, about 3.5 mg/kg, about 3.6 mg/kg , about 3.7 mg/kg or about 3.8 mg/kg of the subject's body weight during a treatment cycle, for example, a time period of 3 or 4 weeks. The present invention provides for the administration of a medicinal product during one or more cycles of treatment, for example, 1, 2, 3, 4, 5, 6 or more cycles of treatment. In some embodiments, there will be rest periods between one or more treatment cycles. For example, in some embodiments, the rest period will be between the second and third cycle of treatment, but not between the first and second cycle of treatment. In another embodiment, the rest period could be between the first and second cycle of treatment, but not between the second and third cycle of treatment. Dosing schedules include, for example, administering the antibody-drug conjugate compound once during the treatment regimen, e.g., on day 1 of a 21-day cycle, twice during the treatment cycle, e.g., on days 1 and 15 of a 28-day cycle and three times during the treatment cycle, for example on days 1, 8 and 15 of a 28-day cycle. Other dosage regimens are encompassed by the present invention.

The present invention includes treatment regimens in which the antibody-drug conjugate compound is administered once during a treatment cycle, for example, over a period of 3 or 4 weeks.

For example, in some embodiments, the antibody-drug conjugate will be administered on the third week of a three- or four-week treatment cycle, such as on day 21 of a three- or four-week cycle. In some embodiments, the antibody-drug conjugate will be administered on day 1 of a three- or four-week treatment cycle, or any other day of a three- or four-week treatment cycle. In some such embodiments, the dose of the antibody-drug conjugate compound administered to a patient with NI will typically be, for example, 0.1 mg/kg to 5 mg/kg of the subject's body weight per cycle treatment, for example, for a period of time of 3 or 4 weeks. More specifically, the dose will be from 0.1 mg/kg to 4 mg/kg, from 0.1 mg/kg to 3.2 mg/kg, from 0.1 mg/kg to 2.7 mg/kg, from 1 mg/kg to 2.7 mg/kg, 1.5 mg/kg to 2.7 mg/kg, or 1.5 mg/kg to 2 mg/kg of the subject's body weight during a treatment cycle, e.g., a period time, which is 3 or 4 weeks. In some embodiments, the total dose of the antibody-drug conjugate compound administered to a patient with NI will be, for example, from about 0.6 mg/kg to about 5 mg/kg, from about 0.6 mg/kg to about 4 mg/kg, from about 0.6 mg/kg to about 3.2 mg/kg, from about 0.6 mg/kg to about 2.7 mg/kg, or even from about 1.5 mg/kg to about With mg/kg during a treatment cycle, for example, a time period of 3 or 4 weeks. In some embodiments, the dose will be about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1, 1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg /kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about C mg /kg, about 3.1 mg/kg, about 3.2 mg/kg, about 3.3 mg/kg, about 3.4 mg/kg, about 3.5 mg/kg, about 3.6 mg/kg , about 3.7 mg/kg or about 3.8 mg/kg body weight of the subject during the treatment cycle.

In other embodiments, the antibody-drug conjugate compound will be administered more than once during a treatment cycle. For example, in some embodiments, the antibody-drug conjugate compound will be administered once a week for three consecutive weeks in a 3-week or 4-week treatment cycle. For example, in some embodiments, the antibody-drug conjugate will be administered on days 1, 8, and 15 of each 28-day treatment cycle. In some such embodiments, the dose of the antibody-drug conjugate compound administered to a patient with NI may, for example, be from 0.1 mg/kg to 5 mg/kg, from 0.1 mg/kg to 4 mg/ kg, from 0.1 mg/kg to 3.2 mg/kg or from 0.1 mg/kg to 2.7 mg/kg body weight of the subject during the treatment cycle. In some embodiments, the total dose of the antibody-drug conjugate compound administered to a patient with NI will be, for example, from about 0.6 mg/kg to about 5 mg/kg, from about 0.6 mg/kg to about 4 mg/kg, from about 0.6 mg/kg to about 3.2 mg/kg, from about 0.6 mg/kg to about 2.7 mg/kg, or even from about 1.5 mg/kg to about With mg/kg during the treatment cycle. In some embodiments, the dose will be about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1, 1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg /kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about C mg /kg, about 3.1 mg/kg, about 3.2 mg/kg, about 3.3 mg/kg, about 3.4 mg/kg, about 3.5 mg/kg, about 3.6 mg/kg , about 3.7 mg/kg, about 3.8 mg/kg, about 3.9 mg/kg, or about 4.0 mg/kg of the subject's body weight during the treatment cycle. In some embodiments, the dose will typically be from 0.1 mg/kg to 5 mg/kg body weight of the subject, from 0.1 mg/kg to 3.2 mg/kg body weight of the subject, even more commonly from 0 ,1 mg/kg to 2.7 mg/kg, from 0.2 mg/kg to 1.8 mg/kg, from 0.2 mg/kg to 1.2 mg/kg, from 0.2 mg/kg up to 1 mg/kg, from 0.4 mg/kg to 1 mg/kg or from 0.4 mg/kg to 0.8 mg/kg of the subject's body weight on days 1, 8 and 15 of each 28-day cycle . In some embodiments, the dose will be about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0, 7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg /kg, about 1.4 mg/kg or about 1.5 mg/kg body weight of the subject on days 1, 8 and 15 of each 28-day cycle.

In other embodiments, the antibody-drug conjugate compound will be administered every two weeks for a four-week treatment cycle. For example, in some embodiments, the antibody-drug conjugate will be administered on days 1 and 15 of each 28-day treatment cycle. In some such embodiments, the dose of the antibody-drug conjugate compound administered to a patient with NI may, for example, be from 0.1 mg/kg to 5 mg/kg, from 0.1 mg/kg to 4 mg/ kg, from 0.1 mg/kg to 3.2 mg/kg or from 0.1 mg/kg to 2.7 mg/kg body weight of the subject during the treatment cycle. In some embodiments, the total dose of the antibody-drug conjugate compound administered to a patient with NI will be, for example, from about 0.6 mg/kg to about 5 mg/kg, from about 0.6 mg/kg to about 4 mg/kg, from about 0.6 mg/kg to about 3.2 mg/kg, from about 0.6 mg/kg to about 2.7 mg/kg, or even from about 1.5 mg/kg to about With mg/kg during the treatment cycle. In some embodiments, the dose will be about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1, 1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg /kg, about 1.8 mg/kg, about 1.9 mg/kg, about 2 mg/kg, about 2.1 mg/kg, about 2.2 mg/kg, about 2.3 mg/kg, about 2.4 mg/kg, about 2.5 mg/kg, about 2.6 mg/kg, about 2.7 mg/kg, about 2.8 mg/kg, about 2.9 mg/kg, about C mg /kg, about 3.1 mg/kg, about 3.2 mg/kg, about 3.3 mg/kg, about 3.4 mg/kg, about 3.5 mg/kg, about 3.6 mg/kg , about 3.7 mg/kg or about 3.8 mg/kg body weight of the subject during the treatment cycle. In some embodiments, the dose of the antibody-drug conjugate compound will typically be from 0.1 mg/kg to 5 mg/kg body weight of the subject, from 0.1 mg/kg to 3.2 mg/kg body weight subject, more commonly 0.1 mg/kg to 2.7 mg/kg, even more commonly 0.2 mg/kg to 1.8 mg/kg, 0.2 mg/kg to 1.2 mg/ kg, from 0.2 mg/kg to 1.5 mg/kg, from 1 mg/kg to 1.5 mg/kg or from 0.5 mg/kg to 1.2 mg/kg body weight of the subject in days 1 and 15 of each 28-day cycle. In some embodiments, the dose will be about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1, 0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg /kg, about 1.7 mg/kg or about 1.8 mg/kg of the subject's body weight on days 1 and 15 of each 28-day cycle.

It will be obvious to those skilled in the art that other doses or frequencies of administration of the antibody-drug conjugate compound that provide the desired therapeutic effect are suitable for use in the present invention.

Administration of the antibody-drug conjugate compound and gemcitabine can be carried out on the same or different days, provided that the administration provides the necessary therapeutic effect. The present invention includes, for example, embodiments in which gemcitabine is administered once a week for three consecutive weeks in a treatment cycle of four weeks, for example, on day 1, at 15 of a 28-day cycle. The present invention includes, for example, embodiments in which gemcitabine is administered twice in a four-week treatment cycle, for example, on days 1 and 15 of a 28-day cycle. The present invention includes, for example, embodiments in which gemcitabine is administered twice in a three-week treatment cycle, for example, on days 1 and 8 or days 1 and 15 of a 21-day cycle. In some embodiments of the present invention, the administration of the antibody-drug conjugate compound and gemcitabine will be on the same days, for example, on days 1, 8, and 15 of a four-week cycle, or on days 1 and 15 of a four-week cycle weeks In some embodiments of the present invention, administration of the antibody-drug conjugate compound and gemcitabine will be on the same and/or different days, for example, the antibody-drug conjugate will be administered on day 1 of a 21-day cycle and gemcitabine will be to be administered on days 1 and 8 or days 1 and 15 of a 21-day cycle. In some embodiments, the antibody-drug conjugate compound and gemcitabine will be administered on the same days, and gemcitabine will be administered after administration of the antibody-drug conjugate is completed, e.g., gemcitabine will be administered less than 2 hours after administration of the con' antibody-drug conjugate, for example, 30 minutes after administration of the antibody-drug conjugate. The present invention covers alternative treatment regimens, if they lead to the desired result.

In some embodiments, gemcitabine will be administered at levels currently recommended in the art for the treatment of NI, or at levels lower or higher than levels currently recommended in the art for the treatment of NI, provided that such dose provides a therapeutic effect. Embodiments of the present invention include, for example, embodiments in which the gemcitabine regimen is administered approximately at the MTO, the maximum tolerated dose. Embodiments of the present invention include those in which gemcitabine is administered in a dose range of from about 100 mg/m to about 2000 mg/m, from about 500 mg/m? to about 1500 mg/m-, from about 500 mg/me to about 1250 mg/m2 or from about 750 mg/m to about 1250 mg/me per administration. In particularly preferred embodiments, gemcitabine is administered in a dose range of about 750 mg/m? up to about 1250 mg/m2 per administration or from about 1000 mg/m2 to about 1250 mg/m2 per administration. For example, in some embodiments, gemcitabine will be administered in a dose range of from about 750 mg/m2 to about 1250 mg/m2 or from about 1000 mg/m? to approximately 1,250 mg/m, on days 1, 8, and 15 of a 28-day treatment cycle.

In some embodiments, gemcitabine will be administered in a dose range of from about 750 mg/m? to about 1250 mg/m? or from about 1000 mg/m? to approximately 1250 mg/m, on days 1 and 15 of a 28-day treatment cycle. In some embodiments, gemcitabine will be administered in a dose range of from about 750 mg/m? to about 1250 mg/m? or from about 1000 mg/m? to about 1250 mg/m", on days 1 and 8 or days 1 and 15 of a 21-day treatment cycle. The present invention provides for the administration of gemcitabine during one or more treatment cycles, e.g., 1, 2, 3, 4, 5, 6 or more treatment cycles. Embodiments of the present invention include embodiments in which gemcitabine is administered by intravenous infusion over 30 minutes. In some embodiments, delivery of approximately 1,000 mg/m is delivered by intravenous infusion over 30 minutes on days 1, 8, or 15 of every 28 -daily treatment cycle It will be appreciated that each of the dose ranges specified herein for treatment with gemcitabine can be combined with each of the dose ranges specified herein for treatment with the antibody-drug conjugate compound provided that the administration provides the desired therapeutic effect , that is, synergism.

In some particularly preferred embodiments of the present invention, administering a synergistic amount of therapeutic agents comprises administering an antibody-drug conjugate compound in a total dose range of from about 0.5 mg/kg to about 5 mg/kg, from about 0.6 mg /kg to about 5 mg/kg, from about 0.6 mg/kg to about 2.7 mg/kg, from about 0.8 mg/kg to about 2.7 mg/kg, from about 1 mg/kg to about 5 mg/kg, about 1 mg/kg to about 4 mg/kg, about 1 mg/kg to about 3.5 mg/kg, about 1.5 mg/kg to about 3.5 mg/kg or even from about 1.8 mg/kg to about 2.5 mg/kg over a 21- or 28-day cycle, regardless of dosing regimen, in combination with gemcitabine administration in standard dosing regimens known in the art, eg from about 800 mg/m2 to about 1500 mg/m? per administration of gemcitabine during the treatment cycle, preferably from about 1000 mg/m? up to approximately 1,250 mg/m2 per administration of gemcitabine during a treatment cycle (eg, 1-3 times during a 21- or 28-day treatment cycle).

In some particularly preferred embodiments of the present invention, administering a synergistic amount of therapeutic agents comprises administering the antibody-drug conjugate compound once during a treatment cycle (eg, a 21- or 28-day treatment cycle) in a range of from about 0.5 mg/kg to about 2.7 mg/kg, from about 0.6 mg/kg to about 2.7 mg/kg, from about 0.6 mg/kg to about 2 mg/kg, from about 0.6 mg /kg to about 1 mg/kg, from about 0.8 mg/kg to about 2.7 mg/kg, from about 0.8 mg/kg to about 2 mg/kg, from about 1 mg/kg to about 2 .7 mg/kg, from about 1.5 mg/kg to about 2.7 mg/kg or even more preferably from about 1.0 mg/kg to about 2 mg/kg or from about 1.5 mg/kg to about 2 mg/kg body weight of the subject, in combination with the administration of gemcitabine in standard dosage regimens known in the art, for example, from about 800 mg/m? to about 1500 mg/m? per administration of gemcitabine during the treatment cycle, preferably from about 1000 mg/m? up to approximately 1250 mg/m2 for each gemcitabine administration during a treatment cycle (eg, 1-3 times during a treatment cycle).

For example, in one embodiment, administering a synergistic amount of therapeutic agents comprises administering the antibody-drug conjugate compound once during a 3-week treatment cycle (eg, on day 1 of a 21-day treatment cycle) in a range of from about 0 .5 mg/kg to about 2.7 mg/kg, from about 0.6 mg/kg to about 2.7 mg/kg, from about 0.8 mg/kg to about 2 mg/kg, from about 1, 5 mg/kg to about 2.7 mg/kg or from about 1.5 mg/kg to about 2 mg/kg body weight of the subject, in combination with the administration of gemcitabine on days 1 and 8 or days 1 and 15 21- daily treatment cycle in the range of approximately 800 mg/m? to about 1500 mg/m, preferably from about 1000 mg/m? to about 1250 mg/m.

In some particularly preferred embodiments of the present invention, administering a synergistic amount of therapeutic agents comprises administering the antibody-drug conjugate compound three times during a treatment cycle (eg, a 21- or 28-day treatment cycle) ranging from about 0.4 mg/kg to about 2.0 mg/kg, from about 0.4 mg/kg to about 1.8 mg/kg, from about 0.4 mg/kg to about 1 mg/kg, from about 0.4 mg /kg to about 1.5 mg/kg per administration, in combination with the administration of gemcitabine in standard dosage regimens known in the art, for example, from about 800 mg/m? to about 1500 mg/m? per administration of gemcitabine during the treatment cycle, preferably from about 1000 mg/m? up to approximately 1,250 mg/m2 per administration of gemcitabine during a treatment cycle (eg, 1-3 times during a treatment cycle).

For example, in one embodiment, administering a synergistic amount of therapeutic agents comprises administering the antibody-drug conjugate compound on days 1, 8, and 15 of a 28-day cycle in a range of from about 0.4 mg/kg to about 2 mg/ kg, from about 0.4 mg/kg to about 1.8 mg/kg, from about 0.4 mg/kg to about 1 mg/kg body weight of the subject, from about 0.4 mg/kg to about 1 .5 mg/kg body weight of the subject per administration, in combination with administration of gemcitabine on days 1, 8, and 15 of a 28-day cycle in a range of from about 800 mg/m to about 1250 mg/m, preferably from about 1000 mg/mg to about 1250 mg/m per administration.

In some particularly preferred embodiments of the present invention, administering a synergistic amount of therapeutic agents comprises administering the antibody-drug conjugate compound twice during a treatment cycle (eg, a 21- or 28-day treatment cycle) in a range of from about 0.4 mg/kg to about 2.0 mg/kg, from about 0.4 mg/kg to about 1.8 mg/kg, from about 0.4 mg/kg to about 1 mg/kg, from about 0.4 mg /kg to about 1.5 mg/kg per administration, in combination with the administration of gemcitabine at standard dosage regimens known in the art, e.g., from about 800 mg/m to about 1500 mg/m per administration of gemcitabine under time of the treatment cycle, preferably from about 1000 mg/m to about 1250 mg/m2 per administration of gemcitabine during the treatment cycle (eg, 1-3 times during the treatment cycle).

For example, administering a synergistic amount of therapeutic agents comprises administering the antibody-drug conjugate compound on days 1 and 15 of a 28-day cycle in a range of from about 0.4 mg/kg to about 2 mg/kg, from about 0, 4 mg/kg to about 1.8 mg/kg, from about 0.4 mg/kg to about 1 mg/kg body weight of the subject, from about 0.4 mg/kg to about 1.5 mg/kg body weight of the subject's body per administration, in combination with administration of gemcitabine on days 1, 8, and 15 of a 28-day cycle ranging from about 800 mg/m? to about 1250 mg/m-, preferably from about 1000 mg/m? to about 1250 mg/m? for each input.

In embodiments of the present invention, in which the treatment includes the administration of an antibody-drug conjugate compound and a chemotherapy regimen comprising bleomycin, vinblastine, and dacarbazine or doxorubicin, bleomycin, vinblastine, and dacarbazine, (ABMO), the administration of an antibody-drug conjugate compound - the drug can be administered on the same or different days relative to the appointment of the chemotherapeutic treatment regimen, provided that the appointment provides the necessary therapeutic effect. The present invention includes, for example, embodiments in which the chemotherapeutic treatment regimen is administered on days 1 and 15 of a four-week cycle. In some embodiments, both the chemotherapy regimen and the antibody-drug conjugate are administered on days 1 through 15 of the four-week cycle. In other embodiments, the chemotherapy regimen will be administered on days 1 and 15 of the four-week cycle, and the antibody-drug conjugate compounds will be administered on days 1, 8, and 15 of the four-week cycle, or day 1 of the cycle , which is three or four weeks. Methods of the present invention include other administration schemes.

Methods of administration of drugs bleomycin, vinblastine and dacarbazine or doxorubicin, bleomycin, vinblastine and dacarbazine in the scheme of chemotherapeutic treatment of Hodgkin's lymphoma are known. As a rule, administration is carried out on days 1 and 15 of a 28-day cycle, and doxorubicin is administered at a dose of mg/m2, bleomycin is administered at a dose of 10 U/me, vinblastine is administered at a dose of 6 mg/m, and dacarbazine is administered at a dose of 375 mg /m7. Embodiments of the present invention include those in which the drugs are administered at levels currently proposed in the art for the treatment of NI. Embodiments of the present invention include those in which the drugs are administered at lower or higher levels than those currently proposed in the art for the treatment of NI, provided that the administration provides the desired therapeutic effect. In some cases, dose levels may be reduced after combining with additional therapeutic agents. Embodiments of the present invention include, for example, embodiments in which the AVMO regimen is administered at approximately the MTO, the maximum tolerated dose. In some embodiments, doxorubicin is administered in a range of 0-35 mg/m, 10-30 mg/m2, or 10-25 mg/m per administration, for example, on days 1 and 15 of a 28-day treatment cycle; bleomycin is administered in a range of 2-15 U/m2, 5-15 U/me or 5-15

E/me for each administration, for example, on days 1 and 15 of a 28-day treatment cycle; vinblastine is administered in the range of 1-8 mg/m, 2-6 mg/m? or 3-6 mg/m2 for each administration, for example, on days 1 and 15 of a 28-day treatment cycle; and dacarbazine is administered in a range of 100-450 mg/m-, 150-370 mg/m, 200-375 mg/m2g, or 300-375 mg/m- per administration, for example on days 1 and 15 28 -day cycle of treatment, provided that the introduction provides the necessary therapeutic effect. The present invention provides for the appointment of an AVMO regimen during one or more cycles of treatment, for example, 1, 2, 3, 4, 5, 6 or more cycles of treatment. It will be appreciated that each of the dose ranges provided herein for treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine can be combined with each of the dose ranges provided herein for treatment with the antibody-drug conjugate compound provided that the purpose provides the desired therapeutic effect. effect.

In some particularly preferred embodiments of the present invention, administering a synergistic amount of therapeutic agents comprises administering an antibody-drug conjugate compound in a total dose range of from about 0.5 mg/kg to about 5 mg/kg, from about 0.6 mg /kg to about 5 mg/kg, from about 0.6 mg/kg to about 2.7 mg/kg, from about 0.8 mg/kg to about 2.7 mg/kg, from about 1 mg/kg to about 5 mg/kg, about 1 mg/kg to about 4 mg/kg, about 1 mg/kg to about 3.5 mg/kg, about 1.5 mg/kg to about 3.5 mg/kg or even from about 1.8 mg/kg to about 2.5 mg/kg over a 21- or 28-day cycle, regardless of dosing regimen, in combination with the administration of AVMO in standard dosing regimens known in the art.

In some particularly preferred embodiments of the present invention, administering a synergistic amount of therapeutic agents comprises administering the antibody-drug conjugate compound once during a treatment cycle (eg, a 21- or 28-day treatment cycle) in a range of from about 0.5 mg/kg to about 2.7 mg/kg, from about 0.6 mg/kg to about 2.7 mg/kg, from about 0.6 mg/kg to about 2 mg/kg, from about 0.6 mg /kg to about 1 mg/kg, from about 0.8 mg/kg to about 2.7 mg/kg, from about 0.8 mg/kg to about 2 mg/kg, from about 1 mg/kg to about 2 .7 mg/kg, from about 1.5 mg/kg to about 2.7 mg/kg or even more preferably from about 1.0 mg/kg to about 2 mg/kg or from about 1.5 mg/kg to about 2 mg/kg of the subject's body weight, in combination with the appointment of AVMO in standard dosing regimens known in the art.

In some particularly preferred embodiments of the present invention, administering a synergistic amount of the therapeutic agent comprises administering the antibody-drug conjugate compound three times during a treatment cycle (e.g., a 21- or 28-day treatment cycle) ranging from about 0.4 mg/kg to about 2.0 mg/kg, from about 0.4 mg/kg to about 1.8 mg/kg, from about 0.4 mg/kg to about 1 mg/kg, from about 0.4 mg /kg to about 1.5 mg/kg per administration, in combination with AVMO administration in standard dosing regimens known in the art.

In some particularly preferred embodiments of the present invention, administering a synergistic amount of therapeutic agents comprises administering the antibody-drug conjugate compound twice during a treatment cycle (eg, a 21- or 28-day treatment cycle) in a range of from about 0.4 mg/kg to about 2.0 mg/kg, from about 0.4 mg/kg to about 1.8 mg/kg, from about 0.4 mg/kg to about 1 mg/kg, from about 0.4 mg /kg to about 1.5 mg/kg per administration, in combination with AVMO administration in standard dosing regimens known in the art.

I. Pharmaceutical compositions

Various delivery systems are known and can be used to administer antibody-drug conjugate compounds and chemotherapeutic agents. Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, and subcutaneous routes of administration. Administration can be carried out, for example, by infusion or bolus injection. In some preferred embodiments, both the chemotherapeutic agent and the antibody-drug conjugate are administered by infusion.

Antibody-drug conjugate compounds and chemotherapeutic agents can be administered in the form of pharmaceutical compositions containing one or more pharmaceutically compatible ingredients.

For example, a pharmaceutical composition typically includes one or more pharmaceutical carriers (e.g., sterile liquids such as water and oils including oils of mineral, animal, vegetable, or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like ). Water is a more typical carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous solutions of dextrose and glycerol can also be used as liquid carriers, in particular, for injectable solutions. Suitable pharmaceutical excipients are known in the art. The composition, if desired, may also contain minor amounts of wetting agents or emulsifiers, or pH-buffering agents. Examples of suitable pharmaceutical carriers are given in "Ketipidopye Rpaptaseshisa! Zsiepseb5" bu E.MU. Magpie Compositions correspond to the method of introduction.

In typical embodiments, the pharmaceutical composition is formulated according to conventional procedures as a pharmaceutical composition adapted for intravenous administration to humans.

As a rule, compositions for intravenous administration are solutions in a sterile isotonic aqueous buffer. If necessary, the drug may also include a solubilizing agent and a local anesthetic, such as lignocaine, to relieve pain at the injection site. Generally, the ingredients are supplied either individually or mixed together in a standard dosage form, for example, as a dry lyophilized powder or concentrate without water in a sealed container such as an ampoule or sachet, which indicates the amount of active agent. If the drug is to be administered by infusion, it can be dispersed using, for example, an infusion solution containing sterile water or pharmaceutical grade saline. If the drug is administered by injection, an ampoule containing sterile water for injection or saline may be provided, for example, provided that the ingredients can be mixed prior to administration.

U. Subjects

The methods of this invention include administering to a subject a combination therapy for the treatment of Hodgkin's lymphoma.

Subjects undergoing treatment with the methods of this invention are subjects diagnosed with Hodgkin's lymphoma or subjects suspected of having Hodgkin's lymphoma. Diagnosis can be made by methods known in the art, including, for example, lymph node biopsy. After the diagnosis of Hodgkin's lymphoma, if desired, the subject's disease can be classified according to its stage using one of the known classification schemes. One such classification scheme is the classification scheme according to the stage of Soyvmzhoiy'5. Briefly, stage | may be characterized by the involvement of one lymph node site or lymphoid structure, stage II may be characterized by the involvement of two or more lymph node sites or lymph node structures on the same side of the diaphragm, stage I may be characterized by the involvement of lymph node sites or lymph node structures on both sides of the diaphragm, and stage MI may characterized by a diffuse or disseminated lesion of one or more extranodal organs or tissues, except for those marked E, with or without lymph node involvement. Designation E refers to the spread to adjacent extranodal organs or tissues, which can be included in the radiation field, which is suitable for lymph node disease of the same anatomical grade.

Subjects in stages I or II may have a favorable or unfavorable prognosis depending on the presence or absence of certain clinical features. For the purposes of this invention, early-stage disease in subjects is classified as stage | or II, while late-stage disease in subjects is classified as stage Ш or IM. The methods of this invention can be used to treat subjects whose disease is classified into one of the four disease stages, including subjects with late stage disease.

The methods of the present invention include treating a subject who is newly diagnosed with NI and who has not previously undergone treatment related to NI.

The methods of this invention can also be used to treat subjects with lymphoma

Untreated and/or recurrent Hodgkin's disease.

A subject with refractory Hodgkin's lymphoma is a subject who does not respond to therapy for NI, that is, the subject continues to exhibit disease progression despite therapy.

A subject with relapsed Hodgkin lymphoma is a subject who has had an adequate response to therapy for NI. at one point in time, but had a relapse or further disease progression after an appropriate response.

Methods of the present invention also include treating a subject previously treated with a first-line chemotherapy regimen for Hodgkin's lymphoma, or a subject treated with a first-line chemotherapy regimen, or a salvage chemotherapy regimen. First-line chemotherapy regimens for Hodgkin lymphoma include, for example, the AVMO regimen (Vopadoppa apa Zapioogo, Sapseg Tgeai Chem. 1982; 9: 21-35), the

VEASORRR (Oiyeni ei a!., M. Epodi. U. May. 2003; 348: 2386-2395), scheme of VEASORRR with increasing doses (Oiyeyi ei a!., M. Epd)i. U. May. 2003; 348. 972-980). Salvage chemotherapy regimens include, for example, the EBNAR regimen (Aragisio et al., App. Opsoi. 1999; 10: 593-595), a modified 5iaptog M regimen (Amiiz et al., Med. Opsoi. 2001; 18: 261-267) , the SOR scheme (Vaievi? ei ai.,

App. Opsoi 2003; 14.

Eeitapadeg2g-itepe eyi ai., NajetaiyoiIodisa 1999; 84: 1007-1011), MIME scheme (Epriai ei ai., Yeig 5.

Hire!yo!. 1998; 60. (Chozinpu ei a!., App. Opsoi. 2002; 13: 1628-1645), ISE scheme (Mozkomiiyi ei aiI., Zetip. Opsoi. 2004; 31(5!rri): 54-59), IPMR scheme (Ouap hey ay.,

Vioi Vioo4 Maitomzh/ Tgapezriapi 2005; 11. 969-974), ABNAR scheme (Bodgidchne? ei ai., Viosa 1999; 93: 3632-3636), Oekha-beat scheme (Zsptii" evi ai., I apsei 2002; 359: 2065- 2071), SER scheme (57apio evyi aI., Opsoiodu 1991; 48: 456-458), the scheme of the Medical Center (Umaiemuzki ei a!., Med. Opso). 2000; 17: 195-202) and the MMC scheme (UmMetik ei a!., Sapseg u. 5si. At. 1998; 4: 254-260).

The methods of this invention also include treating a subject who has previously undergone a stem cell transplant.

K. Antibodies against SYUOZO

Antibodies against POPs suitable for use in accordance with the compositions and methods of the present invention include any antibody that specifically binds to the POPs antigen. Antibodies against

COZO0 are preferably monoclonal and may include, for example, chimeric (eg, having a human constant region and a mouse variable region), humanized antibodies, or human antibodies; single-chain antibodies or similar. Immunoglobulin molecules can be of any type (for example, I9E, IM, dO, IdA, and Idu), class (for example, Ids1, Ids2, IdaZ, yes, IDA1, and IdAg) or subclass of an immunoglobulin molecule.

In some embodiments, the antibody is an antigen-binding fragment of an antibody, such as, for example, Rab, E(ar"), E(ar")", Eda-chain, single-chain Em (5cEm), single-chain antibody, disulfide-linked Em ( zam), a fragment that includes either Mi- or Mn-domain, or fragments obtained using the expressing Rar library, or the SOZO-binding fragment of each of the above antibodies. Antigen-binding fragments of antibodies, including single-chain antibodies, can include the variable region () alone or together with all or part of the following domains: the hinge region, CNI1-, CH2-, CNH- and SI -domains. Also, antigen-binding fragments can include any combination of variable region(s) with a hinge region, CNI1-, CH2-, CNZ- and SI domains. Typically, the antibodies are human, rodent (eg, mouse and rat), donkey, sheep, rabbit, goat, guinea pig, camel, horse, or chicken antibodies. As used herein, "human" antibodies include antibodies having the amino acid sequence of a human immunoglobulin and include antibodies isolated from a human immunoglobulin library, from human B cells, or from animals transgenic for one or more human immunoglobulins (see, for example, in US patents

Mo 5939598 and 6111166).

Antibodies can be monospecific, bispecific, trispecific or with a greater degree of polyspecificity (see, for example, publications of PCT applications UMO 93/17715, UMO 92/08802, UMO 91/00360 and UMO 92/05793; Tyy ei ai., 1991, 9. Ittipoi. 147: 60-69; US patents Mo. 4474893, 4714681, 4925648, 5573920 and 5601819; KovzivIpu ei ai., 1992, 9. Ittipoi. 148: 1547-1553).

Exemplary anti-COZ30O antibodies include, but are not limited to, humanized or chimeric AC10 or Neri-1 antibodies. Accordingly, an exemplary anti-HIVZO antibody comprises one or more murine Neri-1 SOC (ZEO IO MO: 20.5EO IUO MO: 22.5EO IO MO: 24.5EO I

MO: 28, ZEO IU MO: 30 or ZEO IU MO: 32) or AC10 mouse (5EO IUO MO: 4, ZEO IO MO: 6, 5EO IO MO: 8,

ZEO IU MO: 12, 5EO IYUO MO: 14 or 5EO IU MO: 16). In some embodiments, the antibody against

CO30 includes one or more variable regions of mouse Nergi-1 (ZEO IU MO: 18 or 5EO IU MO: 26) or mouse ACI1O (ZEO IUO MO: 2 or 5EO IU MO: 10). Below is a table that indicates the AC10 or Neri-1 area to which each ZEO of the IU MO corresponds:

Table 1 MO sequence:

Heavy chain SO(H2 АСТО | 0 Amino acid./777/7/7/://|/ 6

СОвheavy chain (НЗЗАСТО 0 | 0 Amino acid.///:///|/-/ 8 (Variable in the light chain region ASTO | Nucleotide./:// | 9

Exemplary anti-COZ3O antibodies include functional derivatives or analogs

AC10 or Neri-1. As used herein, the term "functional" in this context means that a functional derivative or analogue of AC10 or Neri-1 is capable of binding to the SHUOZO.

In some embodiments, the anti-SOZO antibodies not only immunospecifically bind to the SOZO, but also exhibit a cytostatic and/or cytotoxic effect on cancer cells in NI, and the cytostatic or cytotoxic effect is complement-dependent and can be achieved in the absence of (and) con' yugation with a cytostatic or cytotoxic agent or (ii) effector cells.

The determination or specification of antibodies against SOZO can be carried out according to the specific SOCs that they include. In some embodiments, the antibodies include SOC AC10 and/or Neri-1. In some embodiments, the antibodies are chimeric or humanized forms of AC10 or Neri-1. The present invention encompasses an antibody that comprises a heavy or light chain variable domain, wherein said variable domain comprises (a) a set of three SOCs derived from murine monoclonal antibody AC10O or Neri-1, and (B) a set of four framework regions, which differs from the set of framework regions in the murine monoclonal antibody AC10O or

Neri-1, and which immunospecifically binds to SOZO.

In a specific embodiment, the present invention encompasses an antibody that includes a heavy chain variable domain, wherein said variable domain includes (a) a set of three SOCs that includes 5EO IU MO: 4, 6, or 8, or includes amino acid sequences that are substantially substantially identical to the amino acid sequences presented in 5EO IU MO: 4, 6, or 8, and (B) a set of four framework regions that differs from the set of framework regions in murine monoclonal antibody AC10, and which immunospecifically binds to SOZO.

In a specific embodiment, the present invention encompasses an antibody that includes a heavy chain variable domain, wherein said variable domain includes (a) a set of three SOCs that includes ZEO IU MO: 20, 22, or 24 or includes amino acid sequences that substantially identical to the amino acid sequences presented in 5EO IU MO: 20, 22 or 28, and (p) a set of four framework regions, which differs from the set of framework regions in the murine monoclonal antibody Neri-1, and which immunospecifically binds to SHUOZO.

In a specific embodiment, the present invention encompasses an antibody that includes a light chain variable domain, wherein said variable domain includes (a) a set of three SOCs that includes ZEO IU MO: 12, 14, or 16 or includes amino acid sequences that substantially identical to the amino acid sequences presented in 5EO IU MO: 12, 14 or 16, and (p) a set of four framework regions, which differs from the set of framework regions in mouse monoclonal antibody AC10, and which immunospecifically binds to SOZO.

In a specific embodiment, the present invention encompasses an antibody that includes a light chain variable domain, wherein said variable domain includes (a) a set of three SOCs that includes ZEO IU MO: 28, 30, or 32 or includes amino acid sequences that substantially identical to the amino acid sequences presented in the 5EO IUO MO: 28, 30 or 32, and (p) a set of four framework regions that differs from the set of framework regions in the murine monoclonal antibody Neri-1, and which immunospecifically binds to SHUOZO.

The present invention includes embodiments in which the AC10 chimeric antibody includes the heavy chain variable region represented in ZEO IU MO: 2, the light chain variable region represented in ZEO IUO MO: 10, the human gamma I constant region represented in ZEO IU MO: 33 or amino acids 1-329 5EO IO MO: 33, and the human kappa constant region represented in 5EO IU

MO: 34.

In addition, the identification or specification of antibodies can also be carried out by their primary structures. Antibodies against COZ0O that are at least 80 956, at least 85 95, at least 90 95, at least 95 95, and most preferably at least 98 95 identical (as calculated using methods known in the art and described herein) to the variable regions AC10 or Nergi mice are also included in the present invention. The determination or specification of the antibodies of this invention can also be carried out by their binding affinity to SOZO. Preferred binding affinities include those characterized by a dissociation constant or Ka of less than 5x105 M, 105 M, 5x10-M, 107 M, 5x109 M, 109 M, 5x1079 M, 109 M, 5x1079 M, 1079 M, 5x1077 M, 10-77 M, 5x10-2 M, 1072 M, 5x1073 M, 1073 M, 5x1072 M, 1072 M, 5x1075 M or 1075 M.

Antibodies can be purified, for example, by affinity chromatography using the antigen СОЗ3З0О. In some embodiments, the purity of the antibody is at least 50 95, at least 60 95, at least 70 95, or at least 80 95. In other embodiments, the purity of the antibody is greater than 85 95, greater than 90 95, greater than 95 95, or greater than 99 95.

Antibodies also include antibodies that are modified, for example, by attaching to the antibody any type of molecule so that the attachment does not interfere with the binding of the antibody to the SHUOZO.

For example, but not by way of limitation, the term "antibody" includes antibodies that have been modified, for example, by glycosylation, deglycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization using known protecting/blocking groups, binding to a cellular ligand or another protein, etc. Each of the numerous chemical modifications can be performed by known methods, including, but not limited to, specific chemical cleavage, acetylation, introduction of the CHO radical, metabolic synthesis of tunicamycin, and the like.

Antibodies of the present invention can be generated by any suitable method known in the art. Polyclonal antibodies against SOZO can be produced using various methods well known in the art. For example, SOZO can be administered to various animal hosts, including, but not limited to, rabbits, mice, rats, etc., to induce the production of sera containing polyclonal antibodies specific for this protein. Various adjuvants can be used to enhance the immunological response, depending on the host species.

Monoclonal antibodies can be prepared using a wide variety of methods known in the art, including the use of hybridoma, recombinant and phage display technologies, or a combination thereof. For example, monoclonal antibodies can be produced using hybridoma technologies, including those known in the art and available, for example, in Nagyom ei a!., Apiirodiev: A I arogaga Mapiai (Soyd rgipd Nagbog I arogagugu Rgez5, 279 ed. , 1998); Nattepipa ei ai., ip: Moposiopa! Apiirodiez apa T-Sei! Nubgidotav 563-681 (Eibzemivg, M.U., 1981) (these references are incorporated by reference in their entirety).

Methods of obtaining and screening specific antibodies using hybridoma technology are conventional and widely known in the art. In a non-limiting example, mice can be immunized with COZ3O or a cell expressing COZO, or a fragment or derivative thereof. After the detection of an immune response, for example, the detection of antibodies specific for SOZO in the mouse serum, the spleen of the mouse is obtained, and splenocytes are isolated. The splenocytes are then fused using well-known methods with any suitable myeloma cells, for example, cells of the 5P20 cell line available from the American Type Culture Collection, Kosciuszko, MO (ATSC).

Hybridomas are selected and cloned by the method of serial dilutions. Then, the hybridoma clones are examined using techniques known in the field for the presence of cells that secrete antibodies capable of binding to SOZ0O. Ascitic fluid, which usually contains high levels of antibodies, can be obtained by injecting mice with positive hybridoma clones.

Accordingly, the present invention provides methods of creating monoclonal antibodies, as well as antibodies produced by a method that includes the cultivation of an antibody-secreting hybridoma cell, and preferably the hybridoma is created by fusing splenocytes isolated from a mouse immunized with the antigen of the present invention with myeloma cells and then hybrid screening, which is the result of fusion, to obtain hybridoma clones that secrete an antibody capable of binding to SOZO.

Antibody fragments that recognize specific epitopes can be generated using known methods. For example, Rar- and E(ar"'i" fragments can be obtained by proteolytic cleavage of immunoglobulin molecules using enzymes such as papain (to obtain Rab-fragments) or pepsin (to obtain E(ar")2-fragments) E(ar")"-fragments contain a variable region, a constant region of the light chain, and the SNI1 domain of the heavy chain.

Antibodies can also be generated using various phage display methods known in the art. In phage display methods, the functional domains of antibodies are presented on the surface of phage particles that carry their coding sequences of nucleic acids. In a specific embodiment, such a phage can be used to display antigen-binding domains expressed from a repertoire or combinatorial library of antibodies (eg, human or mouse). In particular, DNA sequences encoding Mn- and Mi-domains are amplified from animal cDNA libraries (for example, cDNA libraries from human or mouse lymphoid tissues). DNA encoding Mn- and Mi-domains are joined together again using a 5cm linker by PCR and cloned into a phagemid vector (for example, PCAMTAV 6 or pSotr C H55). The vector is subjected to electroporation into E. soya, and E. soya is infected with a helper phage. The phages used in these methods are usually filamentous phages a and M13, which include binding domains expressed from the phage in the composition of Par-, Em-domains or Eu-domain with stabilization of disulfide bonds (y5Em) of antibodies recombinantly fused with phage protein or gene

AI, or MI gene. A phage expressing an antigen-binding domain that binds to POP30 or a variable region of AC10 or Neri-1 can be selected or identified using an antigen, for example, using a labeled antigen or an antigen bound or immobilized to a solid surface or balls Examples of phage display methods that can be used to generate antibodies of the present invention include the methods disclosed in Vhipktap et al., 1995, U). And so on. Meiyoa5 182: 41-50; Atez ei ai., 1995, u). And so on. Meipoise 184: 177-186; Kesherogotson ei ai!., 1994, Yeik. in. And so on. 24: 952-958; Regvis eyi a!., 1997, Sepe 187: 9-18; Vypop eyi ai., 1994, Adumapsez ip Ittypoiodu, 191-280;

PCT-application Mo PCT/ZVO1/01 134; publication of PCT applications M/O 90/02809; MO 91/10737; UMO 92/01047;

In 92/18619; MO 9311236; UMO 95/15982; MO 95/20401; and US Patent Nos. 5698426, 5223409, 5403484, 5580717, 5427908, 5750753, 5821047, 5571698, 5427908, 5516637, 5780225, 5658727, 57337431, and 59698, all of which are incorporated by reference in their entirety.

As described in the above references, after phage selection, the antibody-encoding regions can be isolated from the phage and used to generate whole antibodies, including human antibodies, or any other desired antigen-binding fragment and expressed in any desired host. , including mammalian cells, insect cells, plant cells, yeast and bacteria, for example, as detailed below. For example, methods of recombinant production Rar-, Rar" and

Cabr")2-fragments can also be applied using methods known in the art, such as the methods disclosed in PCT application publication UMO 92/22324; Myipakh ei ai., Viosiesppidne5 1992, 12(6): 864-869 ; Zaummai ei a!., 1995, AUVI 34: 26-34; and Vetseg ei ai!., 1988, Zsiepse 240: 1041-1043 (references indicated are incorporated in their entirety by reference).

Examples of methods that can be used to produce single-chain Ems and antibodies include the methods described in US Pat. Nos. 4,946,778 and 5,258,498; Nyeyuop ei ai., 1991, Method ip

Epigutoiodu 203: 46-88; Zpy ei ai., 1993, RMAB 90: 7995-7999; and ZKeita et al., 1988, 5siepse 240: 1038-1040. For some applications, including the use of antibodies for humans and the study of proliferation and cytotoxicity responses, it is preferred to use chimeric, humanized or human antibodies. A chimeric antibody is a molecule in which different parts of the antibody are derived from different animal species, such as antibodies having a variable region derived from a murine monoclonal antibody and a constant region from a human immunoglobulin. Methods of producing chimeric antibodies are known in the art. See, for example, Mogitizop, Zsiepse, 1985, 229: 1202; ОЙ ей ай!., 1986, Vioiyesnpidnev 4: 214; SsShievz sei a!., 1989, 9. Ittipoi. Meipoadz 125: 191-202; US Patent Nos. 5,807,715, 4,816,567 and 4,816,397, which are incorporated herein by reference in their entirety. Humanized antibodies are antibody molecules derived from an antibody of a non-human species that binds to the desired antigen, having one or more CRPs derived from a non-human species, and framework and constant regions from the molecule human immunoglobulin. Often residues in the framework regions of the human will be replaced by corresponding residues from the donor antibody SOC to change, preferably increase, binding to the antigen. These framework substitutions are determined by methods well known in the art, for example, by modeling the interactions of SOC residues and framework regions to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues. areas in specific provisions (see, e.g., Ocep et al., US Pat. No. 5,585,089; Kiesptapp et al., 1988, Maishge 332:323, which are incorporated herein by reference in their entirety). Antibodies can be humanized using a number of techniques known in the art, including, for example, SOV transplantation (EP 239400; UMO PCT Application Publication 91/09967; US Patents Mo 5225539, 5530101 and 5585089), venation or surface modification (EP 592106, ER 519596; Raadiap, MoiIesshag Ittypoiodu, 1991, 28(4/5): 489-498; 5iapisKa ei ai!., 1994, Rgoivip Epdipeegipu 7(6): 805-814; VodizkKa ei a!., 1994, RMAB 91: 969-973) and rearrangement of chains (US patent Mo 5565332).

Fully human antibodies are particularly desirable for therapeutic treatment of human patients.

Human antibodies can be created by a number of methods known in the art, including the phage display methods described above, using antibody libraries derived from human immunoglobulin sequences. See also US Patents Mo. 4,444,887 and 4,716,111 and publications

PCT applications UUO 98/46645, MO 98/50433, UMO 98/24893, UMO 98/16654, UMO 96/34096, UMO 96/33735 and UMO 91/10741, all of which are incorporated herein by reference in their entirety .

Human antibodies can also be produced using transgenic mice that express human immunoglobulin genes. For an overview of this human antibody production technology, see And oprega apa Nyzglag, 1995, Ipi. Vem. Ittypics. 13: 65-93. For a detailed discussion of this technology for the production of human antibodies and human monoclonal antibodies and protocols for the production of such antibodies, see publications of PCT applications M/O 98/24893, UMO 92/01047, UMO 96/34096, UMO 96/33735;

European patent MO 0598877; US Patent Nos. 5,413,923, 5,625,126, 5,633,425, 5,569,825, 5,661,016, 5,545,896, 5,814,318, 5,885,793, 5,916,771 and 5,939,598 are all incorporated by reference in their entirety. In addition, companies such as Atdep (Tpoizapa Oak5, CA) and Medageh (Rhipseyop, MU) can be engaged to provide human antibodies directed against the selected antibody using technology similar to that described above.

Fully human antibodies that recognize a selected epitope can be generated using a technology called "guided selection." In this approach, a selected non-human monoclonal antibody, such as a murine antibody, is used to control the selection of a fully human antibody that recognizes the same epitope (Ezregz et al., 1994, Biochemistry 12: 899-903).

Antibodies for use in the present invention include chimeric and humanized AC10, as well as chimeric and humanized Neri-1. Antibodies for use in the present invention include antibodies that competitively inhibit the binding of mouse AC10 or Nergi to SOZO, as determined by any method known in the art to determine competitive binding. For example, the antibody can inhibit AC10 or Neri-1 binding to SOZO by at least 50 95, by at least 60 95, by at least 70 95, by at least 80 95, by at least 85 95, by at least 90 95, or even by at least 95 95 One example of a competitive binding assay is a radioimmunoassay, which involves incubating a labeled (e.g., Zn or "2"I) CSO with an antibody of interest in the presence of increasing amounts of unlabeled CSO and detecting the bound antibody. with labeled COS0O. The affinity of the antibody for CSO and the rate of dissociation upon binding can then be determined from the Scatchard plot data. Competition with a second antibody (such as AC10 or Nergi-I) can also be determined using radioimmunoassays. In this case, the CSO is incubated with the antibody of interest conjugated to a labeled compound (e.g., ZH or 125!) in the presence of increasing amounts of an unlabeled second antibody.Antibodies for use in the present invention and also include antibodies that differ from chimeric or humanized AC10 or Neri-1 that specifically bind to SOZO.

One method by which protein and mimo interactions are detected, the two-hybrid system, is described in detail for illustrative purposes only and not by way of limitation. One variant of this system was described (SpPiep eyi ai., 1991, Rgos. Mai). Asai. 5 OBA, 88: 9578-9582), and it can be purchased at

Siopivesn (Rayo Ayo, SA).

After identification of a protein that binds to SOZO, if desired, it is possible to determine its ability (separately or after multimerization or fusion with the domain of dimerization or multimerization) to cause a cytostatic or cytotoxic effect on NI cells. by bringing a culture of an NI cell line, such as 1428, 1450, NI /M2 or KM-H2, into contact with white. The cultivation conditions are most preferably approximately 5,000 cells per cultivation area of approximately 0.33 cm and a contact period of approximately 72 hours. The culture is then exposed to 0.5 µCi of H-thymidine during the final 8 hours of the 72-hour time period, and the incorporation of H-thymidine into the culture cells is determined. The protein has a cytostatic or cytotoxic effect on the NI cell line if the culture cells are characterized by reduced H incorporation - thymidine compared to cells of the same cell line cultured under the same conditions but not exposed to the protein. A variety of other cytotoxicity responses are known to those skilled in the art. The methods of the present invention may employ any of them

Antibodies against COZ0O, applicable in the methods of this invention, can be produced using any method of protein synthesis known in the art, usually, for example, using recombinant expression methods. Recombinant expression of an antibody or its derivative, which binds to SOZO and reduces or inhibits the proliferation of expressing SOZOO cells, may include the construction of an expression vector containing a nucleic acid that encodes an antibody or its derivative. After obtaining the nucleic acid encoding such a protein, it is possible to obtain a vector for the production of a protein molecule using recombinant DNA technology, using methods widely known in the art. For recombinant nucleic acid methods, nucleic acid synthesis, cell culture, transgene insertion, and recombinant protein expression, standard methods can be used, such as, for example, methods described in ZzatrgookK apa KizzeiY,

Moiesshiag Siopipd: A And arogayugu Mapiai! (Soyd 5rgipd Nagbog I aroghaigu Rgezv5, Soyy brgipa Natotg, M.U.,

From the ed., 2001); Batogook ei ai!., Moiesshag Siopipd: And Igarogayugu Mapia! (So 5riipd Natog I arogayogu

Rgezv, Soid rgipa Nagrog, M.U., 279 ey., 1989); pop Rgoiosoiiv ip Moiesshag Vioiodu (A!yzibei! evy a!., dopp

Muyeu a Bop5, Mem Moi, 4 ey., 1999); Sik a Raviettak, Moiesshag Vioieyesppoiodu: Rgipsiriei apa

Arriisaiop5 oi Vesotripapi OMA (A5M Rgezz, UMaznpipdiop, O.S., 279 vd., 1989).

For example, for recombinant expression of an antibody against SOZO, the expression vector may encode its heavy or light chain or the variable domain of the heavy or light chain, functionally linked to the promoter. An expression vector may include, for example, a nucleotide sequence encoding a constant region of an antibody molecule (see, e.g., PCT application publication MO 86/05807; PCT application publication IMO 89/01036; and US patent MO 5122464), and in such vector can be cloned variable domain of the antibody to express the complete heavy or light chain.

The expression vector is transfected into a host cell using conventional methods, and the transfected cells are then cultured using conventional methods for the production of anti-COZ30O antibodies. In common embodiments for the expression of double-chain antibodies, vectors encoding both heavy and light chains can be coexpressed in a host cell to express a complete immunoglobulin molecule.

A number of expression systems using vectors in prokaryotic or eukaryotic hosts can be used to express an antibody against SOZ3Z0O or its derivative. As a rule, eukaryotic cells are used for expression of recombinant protein, especially whole molecules of recombinant antibody against POP30. For example, mammalian cells, such as Chinese Hamster Ovary (CHO) cells, in conjunction with a vector including, for example, the major immediate-early promoter element of a cytomegalovirus gene, are an efficient expression system for the production of anti-SOZO antibodies (see , for example, RoesKipud ei a!., 1986, Sepe 45: 101; SosKei ei ai., 1990,

Vio/Hespiodu 8:2). Antibodies against SOZO can also be expressed using the SNEE system (see, for example, US Pat. No. 5,888,809).

Other expression systems in hosts include, for example, expression systems using plasmid-based vectors in bacterial cells (see, e.g., KyiPeg et al., 1983, EMVO 1, 2: 1791; Ipotsug 5 Ipotsug, 1985, Mysivis Asiaz Vev. 13: 3101-3109; Map Neekke 5 Zspivieg 1989, u). Vio Spent 24: 5503-5509); expression systems in insect cells, such as, for example, the use of an expression vector based on the nuclear polyhedrosis virus Ashodharpa saiotis (Asprmy) in cells of 5rodoriega ygidiregaa; and expression systems using vectors based on viruses in mammalian cells, such as, for example, systems using vectors based on adenoviruses (see, for example, I odap 5 Zpepk, 1984, Rgos. Mai)!. Asad si. OBA 81: 355-359; Vitspeg ei a!., 1987, Meiyod ip Epgutoi. 153: 51-544).

In addition, a host cell strain can be selected that modulates the expression of embedded sequences or modifies and processes the gene product in a desired specific manner.

Appropriate cell lines or host systems can be selected to ensure proper modification and processing (eg, glycosylation, phosphorylation, and cleavage) of the expressed foreign protein. For this purpose, it is possible to use eukaryotic host cells that have a cellular apparatus for correct processing of the primary transcript and gene product. Such mammalian host cells include, for example, CHO (eg, ЮС44 and ХО-5), МЕНО, ВНК, Нея, СО5, МОСК, 293, 413 and M/138.

A stable expression system is usually used for long-term production of 3 high-yield recombinant antibodies against POP30. For example, cell lines that stably express an antibody against

CO30 or its derivative can be created by transforming host cells with DNA controlled by appropriate expression control elements (eg, promoter, enhancer sequences, transcription terminators, polyadenylation sites) and a selectable marker, followed by growing the transformed cells in selective media. A selectable marker confers resistance to selection and enables cells to stably integrate DNA into their chromosomes and grow to form foci that, in turn, can be cloned and expanded into cell lines.

A number of selection systems can be used, including, for example, herpes simplex virus thymidine kinase, hypoxanthineguanine-phosphoribosyltransferase, and adenine-phosphoribosyltransferase genes, which can be used in IK, parietal, or aria cells, respectively.

It is also possible to use resistance to antimetabolites as the basis of selection for the following genes: apit, which confers resistance to methotrexate; ori, which provides resistance to mycophenolic acid; peo, which confers resistance to aminoglycoside 5-418; and pudgo, which confers resistance to hygromycin. Methods generally known in the art of recombinant DNA technology may generally be used to select the desired recombinant clone, and such methods are described, for example, in System.

Vioiodu (A!yziei ei ai., ed5., doip U/ieu b Bop5, M.U., 1993); Kyediyeti, Sepe Tgapeieg apa Ehrgezviop, A

And aroghaiogu Mapiai! (SiosKiop Rgez5, M.U., 1990); Sitepi Rgoiosoiiv ip Nytap Sepeiysz (Ogasoroiyi eyi ai. edv., add. U/yeu in Bopv, M.U., 1994, Sparivyegz 12 apa 13); Soirette-Sagarip et al., 1981, 9). My. Vioi 150: 1.

After production of an anti-SOZO antibody (e.g., using an animal, chemical synthesis, or recombinant expression), it can be purified by any suitable protein purification method, including, for example, chromatography (e.g., ion exchange or affinity chromatography (such as, e.g. , chromatography using protein A to purify antibodies having an intact Es region), centrifugation, differential solubility, or by any other standard method of protein purification. The anti-SOZO antibody can, for example, be fused to a marker sequence, e.g. peptide, to facilitate purification by affinity chromatography. Suitable amino acid sequence markers include, for example, a hexahistidine peptide such as that provided in the rde vector (OIASEM, Ips., 9259 Eop Amepieee, Spaibmogy,

SA, 91311), and the "NA" label, which corresponds to an epitope derived from the hemagglutinin protein of the influenza virus (Hysop et al., 1984, SeI 37: 767), and the "Chad" label.

I. Antibody-drug conjugate units

The methods described herein include the use of antibodies that (a) specifically bind to SOZO and (b) are conjugated to the compound auristatin. Antibody-drug conjugate compounds include an anti-COZ30O antibody covalently linked to at least one drug unit, and the drug unit is an auristatin compound. Drug units can be covalently linked directly or through a linker unit (-I O-).

In some embodiments, the antibody-drug conjugate compound has the following formula:

I-(CO-)r (I) or is a pharmaceutically acceptable salt or solvate of a compound of the formula where

Y is an antibody unit, i.e. an antibody against SOZO (which includes fragments of an antibody against SOZO), and (HO-O) is a component in the form of a linker unit-a drug unit, where

M is a linker unit, and -O is an auristatin compound that has cytostatic or cytotoxic activity against a target cell; and p is an integer from 1 to about 20.

In some embodiments, p ranges from 1 to about 10, from 1 to about 9, from 1 to about 8, from 1 to about 7, from 1 to about 6, from 1 to about 5, from 1 to about 4, from 1 to about 3 or from 1 to 2. In some embodiments, p ranges from 2 to about 10, from 2 to about 9, from 2 to about 8, from 2 to about 7, from 2 to about b, from 2 to about 5, 2 to about 4, or 2 to 3. In other embodiments, p is 1, 2, 3, 4, 5, or 6. In some embodiments, p is 2 or 4.

In some embodiments, the antibody-drug conjugate compound has the following formula:

I -(Aa-UUk-XU-O)r (Ii) or is a pharmaceutically acceptable salt or solvate of a compound with the following formula, where

Y is an antibody unit, i.e. an antibody against SOZO (which includes anti-SOZO antibody fragments), and -Aa-MUk-Uy- is a linker unit (GO), where -A- is an extender unit, and is equal to 0 or 1, each -M/- independently represents an amino acid unit, m is an integer in the range from 0 to 12, -i- is a self-destructive spacer unit, y is 0, 1 or 2; -Ob is an auristatin compound that has cytostatic or cytotoxic activity against the target cell; and p is an integer from 1 to about 20.

In some embodiments, a is 0 or 1, m is 0 or 1, and y is 0, 1, or 2. In some embodiments, if m is in the range of 1 to 12, y is 1 or 2. In some embodiments, m/ is in the range of 2 to 12, and y is 1 or 2. In some embodiments, m/ is 0, y is 0, and a is 1. In some embodiments, a is 0 or 1, m is 0 or 1 , and y is 0 or 1. In some embodiments, p ranges from 1 to about 10, from 1 to about 9, from 1 to about 8, from 1 to about 7, from 1 to about 6, from 1 to about 5, from 1 to about 4, from 1 to about C, or from 1 to 2. In some embodiments, p is in the range from 2 to about 8, from 2 to about 7, from 2 to about 6, from 2 to about 5 , from 2 to about 4, or from 2 to 3. In other embodiments, p is 1, 2, 3, 4, 5, or 6. In some embodiments, p is 2 or 4.

Drug loading, the average number of drug molecules per antibody in the molecule, is represented by p. Drug loading can range from 1 to 20 drugs (0) per antibody. The average amount of drugs for each antibody in the preparation of conjugation reactions can be determined using a commonly accepted method, such as mass spectrometry, EGISA and NRIS analysis. It is also possible to determine the quantitative distribution of antibody-drug conjugates by the indicator p. In some cases, it is possible to successfully separate, purify, and determine the characteristics of homogeneous antibody-drug conjugates, in which p is a defined value, from antibody conjugates - a drug with other drug loads by such a method as NRI C with reverse phase or electrophoresis. In the variants given as examples, the implementation of p is in the range of 2 dov.

Each of these units is described in more detail in this document.

Linker units

As a rule, antibody-drug conjugate compounds include a linker region between the auristatin compound and the anti-POZ30 antibody. A "linker unit" (LO) is a bifunctional compound that can be used to join a drug unit and an antibody unit to form an antibody-drug conjugate compound. In some embodiments, the linker is intracellularly cleavable such that cleavage of the linker separates the auristatin compound from the antibody in the intracellular environment.

For example, in some embodiments, the linker is cleavable by a cleaving agent that is present in the intracellular environment (eg, within a lysosome or endosome or calveola). The linker may be, for example, a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. As a rule, the length of the peptidyl linker is at least two amino acids or at least three amino acids. Cleaving agents may include cathepsins B and O and plasmin, all of which are known to hydrolyze dipeptide derivatives of the drug, leading to the uncoupling of the active drug within the target cells (see, e.g., Oybom/spik apa UmaiKeg, 1999, RNagt.

Tpegareshiisv 83: 67-123). The most common are peptidyl linkers, which are cleaved by enzymes present in SOZO-expressing cells. For example, you can use a peptidyl linker that is cleavable by the thiol-dependent protease cathepsin-B, which is highly expressed in cancer tissue (for example, a linker Rpe-Iecy or Spiu-Rpe-I ey-Spu). Other such linkers are described, for example, in US Pat. No. 6,214,345. In specific embodiments, the intracellular protease-cleavable peptidyl linker is a MaI-SiI linker or a RPE-Guh linker (see, for example, US Pat. No. 6,214,345, in which describes the synthesis of doxorubicin with a MaI-SU linker.One advantage of using intracellular proteolytic cleavage of a therapeutic agent is that the agent is usually attenuated after conjugation, and the serum stability of the conjugates is usually high.

In other embodiments, the cleavable linker is pH sensitive, that is, sensitive to hydrolysis at certain pH values. As a rule, the pH-sensitive linker is hydrolyzed under acidic conditions. For example, an acid-labile linker that is hydrolyzed in the lysosome (e.g., hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic acid amide, orthoether, acetal, ketal, or the like) can be used (see, e.g., US Pat. Nos. 5,122,368, 5824805, 5622929; Vortex/spike apa

MuaiKeg, 1999, Rpagt. TPnegaretsshiisv 83: 67-123; MemyShe eyi ai., 1989, Vioi. Snet 264: 14653-14661). Such linkers are relatively stable under neutral pH conditions, such as those in blood, but are unstable at pH below 5.5 or 5.0, which approximates the pH in the lysosome. In some embodiments, the hydrolyzed linker is a thioether linker (such as, for example, a thioether attached to the therapeutic agent via an acylhydrazone bond (see, for example, US Pat. No. 5,622,929).

In still other embodiments, the linker is cleavable under reducing conditions (eg, a disulfide linker). A number of disulfide linkers are known in the art, including, for example, linkers that can be formed using ZATA (M-succinimidyl-5-acetylthioacetate), ЗПОР (M-succinimidyl-3-(2-pyridyldithio)propionate), 5ROV (M-succinimidyl-3-(2-pyridyldithio)butyrate) and ZMRT (M-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pyridyldithio)toluene), 5ROV and 5MRT (see, for example, Pogrei et al., 1987 , Sapseg Kev. 47: 5924-5931;

Mamggupsgak ei ai., Ip Ittiposopidaiev: Apiibodu Sopiidaiez ip Radioitadegu apa TNegaru oi Sapseg (S.M. Modei ed., Ohio |). Rgez5, 1987; see also US patent Mo 4880935).

In other specific embodiments, the linker is a malonate linker (Oppzop et al., 1995,

Apiisapseg Nev. 15: 1387-1393), maleimidobenzoyl linker (Iai ei ai., 1995, Vioga-Med-Spet.

C(10): 1299-1304) or 3-M-amide analogue (I ac eyi a!., 1995, Visoga-Med-Spet. 3(10): 1305-1312).

In still other embodiments, the linker unit is non-cleavable and the drug is released upon degradation of the antibody (see US Patent Application Publication No. 20050238649, which is incorporated by reference in its entirety).

As a rule, the linker is not significantly sensitive to the extracellular environment. As used herein, "not substantially sensitive to the extracellular environment," in the context of a linker, means that cleavable is no more than about 20 95 , typically no more than about 15 95 , more typically no more than about 10 95 , and even more typically no more than about 595, no more than about 3 95 , or no more than about 1 95 linkers in a sample antibody-drug conjugate compound when the antibody-drug conjugate compound is present in the extracellular environment (eg, in plasma). Whether the linker is not substantially sensitive to the extracellular environment can be determined, for example, by incubating the antibody-drug conjugate compound with plasma for a predetermined period of time (eg, 2, 4, 8, 16, or 24 hours) and then determining the amount of free drug present in the plasma.

In other, non-mutually exclusive embodiments, the linker accelerates internalization into the cell. In some embodiments, the linker accelerates internalization into the cell after conjugation with the therapeutic agent (ie, within the linker-therapeutic agent component of the antibody-drug conjugate described herein). In still other embodiments, the linker accelerates internalization into the cell after conjugation with both the auristatin compound and the anti-SOZO antibody.

A number of linkers that can be used with the compositions and methods of this invention are described, for example, in UMO 2004-010957, US Patent Application Publication Nos. 20060074008, 20050238649, and 20060024317 (all of which are incorporated herein by reference in their entirety and for all goals).

In some embodiments, the linker unit has the formula: -Aa-Muy-Hu- where -A- is an extender unit, and is equal to 0 or 1, each -M/- independently represents an amino acid unit, m is an integer located in ranges from 0 to 12, -th- is the self-destructing spacer unit, and y is 0, 1, or 2.

In some embodiments, a is 0 or 1, m/ is 0 or 1, and y is 0, 1, or 2. In some embodiments, if m is in the range of 1 to 12, y is 1 or 2. In some embodiments, implementation m/ is in the range of 2 to 12 and y is 1 or 2. In some embodiments, a is 0 or 1, m/ is 0 or 1, and y is 0 or 1. In some embodiments, p is in the range 1 to about 10, 1 to about 9, 1 to about 8, 1 to about 7, 1 to about 6, 1 to about 5, 1 to about 4, 1 to about 3, or 1 to 2. In some embodiments, p ranges from 2 to about 8, from 2 to about 7, from 2 to about 6, from 2 to about 5, from 2 to about 4, or from 2 to 3. In other embodiments, p is 1, 2, 3, 4, 5, or 6. In some embodiments, p is 2 or 4.

Extension unit

An extender unit (A), when present, is capable of binding an antibody unit to an amino acid unit (-Mu-), if present, to a spacer unit (-y-), if present, or to a drug unit (- 0). Suitable functional groups that may be present on an anti-SOZO antibody, either naturally or through chemical manipulation, include, but are not limited to, a sulfhydryl group, an amino group, a hydroxyl, an anomeric hydroxyl carbon group, or a carboxyl group.

Suitable functional groups are sulfhydryl groups and amino groups. Sulfhydryl groups can be formed during the restoration of intramolecular disulfide bonds of antibodies against

CO30. In an alternative case, sulfhydryl groups can be formed upon interaction of the amino group of the lysine component of the antibody against SOZO with 2-iminothiolane (Trot's reagent) or other sulfhydryl group-forming reagents. In some embodiments, the anti-SOZO antibody is a recombinant antibody and is engineered to carry one or more lysines. In some other embodiments, the recombinant antibody against SOZO is designed to carry additional sulfhydryl groups, for example, additional cysteines.

In some embodiments, the extender unit forms a bond with the sulfur atom of the antibody unit. The sulfur atom can come from the sulfhydryl group of the antibody. Representative units of the extender of this variant of implementation are presented in square brackets of the formulas Sha and ShB, where I -, -MU-, -M-, -O, m/ and y have the values defined above, K.:7 and are selected from the radicals: - C1-C:o alkylene-, -C1-C1o alkenylene-, -C1-Cio alkynylene-, -carbocyclo-, -O-(C1-Cv alkylene)-, -O-(Ci-Cv alkenylene)-, -O -(C1-Cv alkynylene)-, -arylene-, -C1-C:io alkylene-arylene-, -C2-Cio alkenylene-arylene-, -C2-Cio alkynylene-arylene-, - arylene-Ci-C0 alkylene- , -arylene-C2-Cio alkenylene-, -arylene-C2-Cio alkynylene-, -Ci-Cio alkylene- (carbocyclo)-, -C2-Cio alkenylene-(carbocyclo)-, -C2-Cio alkynylene-(carbocyclo) -, -(carbocyclo)-C1-C1o alkylene-, -(carbocyclo)-C2-Cio alkenylene-, -(carbocyclo)-C2-Cio alkynylene-, heterocyclo-, -C1-C10o alkylene-(heterocyclo)-, - C2-Cio alkenylene-(heterocyclo)-, -Co-Cio alkynylene-(heterocyclo)-, - (heterocyclo)-C1-Cio alkylene-, -(heterocyclo)-C2-Cio alkenylene-, -(heterocyclo)-C2- Cio alkynylene-, - (СНеСНГО); or -СНСН2гО),-СНе-, and r is an integer in the range from 1 to 10, where alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, aryl, carbocyclic, heterocyclic and arylene radicals are indicated, alone or in in the form of a part of another group, optionally substituted. Alkylene, alkenylene, alkynylene radicals, individually or as part of another group, may be optionally substituted, for example, by one or more groups independently selected from A1; carbocyclic radicals, alone or as part of another group, may be optionally substituted, for example, by one or more groups independently selected from A2; arylene radicals, alone or as part of another group, may be optionally substituted, for example, by one or more groups independently selected from AZ; heterocyclic radicals, alone or as part of another group, may be optionally substituted, for example, by one or more groups independently selected from A4. A1, A2, AZ and A4 have the meanings defined in this document. Based on all of the exemplary embodiments, it should be understood that, even if not explicitly noted, from 1 to 20 drug components (p-1-20) may be associated with the antibody.

at

IS

M-VO AJ U- - Hu-o 6;

Sha "Ieng-sokn--yay- oh mu sh

An illustrative unit of the extender is a unit of formula Ia, where K"7 represents -(СиН2г)в-: о тт (9) о .

Another illustrative unit of the extender is the unit of the formula Sha, where K'" represents - (СНеСНГО)-СНе-; and r is equal to 2: о о 0: о)

An illustrative unit of the extender is a unit of formula Ia, where K'" is -arylene- or -arylene-Ci-C:o alkylene-. In some embodiments, the aryl group is an unsubstituted phenyl group.

However, another illustrative unit of the extender is the unit of the PPB formula, where K'" represents - (СН2е)в-: 6;

AAU about

In some embodiments, the extender unit is linked to the antibody unit by a disulfide bond between the sulfur atom of the antibody unit and the sulfur atom of the extender unit.

A representative unit of the extender of this embodiment is represented in square brackets by the formula IM, where B 7 , I -, -M/-, -U-, -O, m/ and y have the values defined above. sv|v-yay-so| Well

IU

It should be noted that throughout this application, component 5 in the following formula refers to the sulfur atom of the antibody unit, unless otherwise specified in the context. ---

In other embodiments, the extender contains a reactive site that can form a bond with the primary or secondary amino group of the antibody. Examples of such reactive sites include, but are not limited to, activated esters such as succinimide esters, 4-nitrophenyl ethers, pentafluorophenyl ethers, tetrafluorophenyl ethers, anhydrides, chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates. Representative units of the extender of this embodiment are represented in square brackets by the formulas Ma and MB, where -B"7, I -, -MU-, -U-, -O, m and y have the values defined above.

- somn-yatsoyur myth r

Wow

HER

EEVASMNAV-s(0)-A-M- -Hu-0 t

In other embodiments, the extender contains a reactive site that reacts with the (-CHO) group of the modified carbohydrate present on the antibody. For example, a carbohydrate may be mildly oxidized using a reagent such as sodium periodate, and the resulting (-CHO) unit of the oxidized carbohydrate may be condensed with an extender having functionality such as a hydrazide, oxime, primary or secondary amine, hydrazine, thiosemicarbazone, hydrazine carboxylate and aryl hydrazide, which is described by Capeko et al., 1991, Viosopishdaiye

Spent 2: 133-141. Representative extender units of this embodiment are represented in square brackets by the formulas Mia, MIB and Mis, where -B7, I -, -Mu/-, -U-, -O, m/ and y have the values defined above.

And -natn-yatoyuu zhu-tuo

Wow

And fno-yaisor rye

UiB o)

I. machnA-Ya vyt.) We hu-o

Miss

Amino acid unit

The amino acid unit (-MU-), when present, links the extender unit to the spacer unit if the spacer unit is present, links the extender unit to the drug component if the spacer unit is absent, and links the antibody unit with the drug unit if the extender unit and the spacer unit are missing.

MUzh-, when present, is a monopeptide, dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit. Each -M/- unit independently has the formula shown below in square brackets, and m/ is an integer in the range 0 to 12:

СНа about | o nN your ee dya d'z "or de V"? is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, benzyl, para-hydroxybenzyl, -

СНН:оНн, -СН(ОН)СНз, -СНаСНагЗСНнН:з, -СНаСОМН:, -СНаЕСООН, -СНаСнН.СОМН»?, -СНаСНСНСООН, - (СнгзичНноЕ(и-МН)МН», -«(СНег)зМН »e, -«"СНг)ззМНоСОс Нв, -(СНг)ззМНеНО, -"(СнНг)зМНО(Я-МН)МН», -«(СНг)аМН», -«СНг2АМНоСОССНН», -(СНг)МНоСНО , -"(CHgzMNHSOMH", -""CHhaAMNHSOMHg, -CHNaCHNaH(OH)CHNaMH", 2- pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl,

- Joint Stock Company

OO x (I t ve ; or

In some embodiments, the amino acid unit can be enzymatically cleaved with one or more enzymes, including a cancer- or tumor-specific protease, to detach the drug unit (-0), which in one embodiment undergoes protonation ip mimo upon detachment from provision of medicinal product (0).

In some embodiments, the amino acid unit may include naturally occurring amino acids. In other embodiments, the amino acid unit may include non-natural amino acids.

Illustrative units of Umua are represented by the formulas (MI)-(IX): o vi n z, glue

M

H to (o; CM) where 220 and 7 have the following values:

СНо)МНе;

СНо)МНе;

СНо)МНе;

SNg) ZMNSOMN";

SNg) ZMNSOMN";

СН2)ЗЗМНСОМН";

СН2)ЗЗМНСОМН"; 5 UN / (SNgIZZMNSOMN";

M

N

СНг)зМНе(с-МНуМН»; o di o

M M

Where is K20, V? what is it? have the following meanings:

tv) ry Go) da a" і і

H N oh yes? in about; o ah) where Ko, ID2, ID22 and Kz have the following values:

Exemplary amino acid units include, but are not limited to, units of the formula MY, where 22? is benzyl, and K- is -(CHg)"MH"e; IN? is isopropyl, and

B is -(CHg)aMNh; or 229 represents isopropyl, and K"! represents -(CHg)izMNSOMN".

Another amino acid unit given as an example is the unit of the formula MI, where KO? represents benzyl, K"! represents benzyl; and 22? represents -(SiHg)aMH".

Suitable -MUm/- units can be designed and optimized with respect to their selectivity for enzymatic cleavage by a specific enzyme, for example, a tumor-specific protease.

In one embodiment, the unit -M/m/- is a unit whose cleavage is catalyzed by cathepsin

B, C and O or protease plasmin.

In one embodiment, the -M/m- unit is a dipeptide, tripeptide, tetrapeptide, or pentapeptide. When KU, B2o, ID2, ID22 or KZ is different from hydrogen, the carbon atom to which it is attached

B"", 20, B, Deg or Kg, is chiral.

Each carbon atom to which KU, B2o, Bg", Dg2 or K23 is attached is independently in (5) or (K)-configuration.

In one aspect of the amino acid unit, the amino acid unit is valinecitrulline (ie, ms or ma!-si). In another aspect, the amino acid unit is phenylalanine lysine (ie, lysine). In yet another aspect of the amino acid unit, the amino acid unit is M-methylvaline-citrulline. In yet another aspect, the amino acid unit is 5-aminopentanoic acid, homophenylalanine lysine, tetraisoquinolinecarboxylate-lysine, cyclohexylalanine-lysine, isonipecotinic acid, beta-alanine-lysine, glycine-serine-valine-glutamine, and isonipecotinic acid.

Spacer unit

A spacer unit (-u-), when present, connects the amino acid unit to the drug unit when the amino acid unit is present. Alternatively, the spacer unit connects the extender unit to the drug unit when the amino acid unit is missing. A spacer unit also connects a drug unit to an antibody unit when both the amino acid unit and the extender unit are missing.

Spacer units are spacers of two basic types: non-self-destructing or self-destructing.

A non-self-destructive spacer unit is a spacer unit in which some or all of the spacer unit remains bound to the drug component after cleavage of, in particular, an enzymatic, amino acid unit from the antibody-drug conjugate. Examples of a non-self-destructive spacer unit include, but are not limited to, a (glycine-glycine) spacer unit and a glycine spacer unit (both of which are shown in Scheme 1) (below). When a conjugate containing a spacer unit (glycine-glycine) or a glycine spacer unit is enzymatically cleaved by an enzyme (eg, a tumor cell-specific protease, a cancer cell-specific protease, or a lymphocyte-specific protease), the glycine component -glycinth medicinal product or ingredient glycinth medicinal product is separated from I -

Aa-ЖМ/m-. In one embodiment, an independent hydrolytic reaction occurs inside the target cell, cleaving the bond in the glycine component of the drug and dissociating the drug.

Scheme 1

I raIZhy-ov-oI BBASM,-su-buTo enzymatic enzymatic cleavage cleavage su-r Stu-su-O hydrolysis | hydrolysis drug drug

In some embodiments, the non-self-destructive spacer unit (-MU-) is -SPu-. In some embodiments, the unit of the non-self-destructive spacer (-U-) is -СПу-Спу-.

In one embodiment, a drug-linker conjugate is provided in which the spacer unit is absent (y-:0), or a pharmaceutically acceptable salt or solvate thereof.

Alternatively, -O can be dissociated from the conjugate containing the self-destructive spacer.

As used herein, the term "self-reducing spacer" refers to a bifunctional chemical component that is capable of covalently binding together two separate chemical components into a stable, three-part molecule. It will spontaneously separate from the second chemical component when its bond with the first component is split.

In some embodiments, -Zhu- is a unit in the form of a para-aminobenzyl alcohol (RAV) group (see Schemes 2 and 3), the phenylene part of which is replaced by Ot, where O is -C1-Cv alkyl, -C1-Cv alkenyl, -C1-Cv alkynyl, -O-(C1-Cv alkyl), -O-(C1-Cv alkenyl), -O-(C1-Cv alkynyl), -halogen, -nitro or -cyano; and t is an integer in the range 0 to 4.

In some embodiments, -U- is a RAV group that is connected to -MU/- through the nitrogen atom of the amino group in the RAV group and is connected directly to -Y via a carbonate, carbamate or ether group. Without being bound by any particular theory or mechanism, Scheme 2 shows a possible mechanism for the detachment from the drug of a RAV group that is directly attached to -O through a carbamate or carbonate group, as described by Toki et al., 2002, in y). Ogd. Spent 67: 1866-1872.

Scheme 2

Ot -- and o Zhym 0 o-5-o (c) p enzymatic cleavage

They heard me (o); 1,6-elimination drug

In scheme 2, O represents -C1-Cv alkyl, -C1i-Cv alkenyl, -C1-Cv alkynyl, -O-(C1-Cv alkyl), -O-(C1-Cv alkenyl), -O-(C1- St. alkynyl), -halogen, -nitro or -cyano; t is an integer in the range from 0 to 4; and p ranges from 1 to about 20.

Without being bound by any particular theory or mechanism, Scheme C shows a possible mechanism for the detachment from the drug of a RAV group that is directly attached to -ХО via an ether or amine bond, wherein О includes an oxygen or nitrogen group that is part of a unit of medicinal product.

Scheme Z

So ANA Y r

P enzymatic cleavage

Here I 2 What in 1,6-elimination

I am a medicine

In Scheme 3, O represents -C1-Cv alkyl, -C1i-Cv alkenyl, -C1-Cv alkynyl, -O-(C1-Cv alkyl), -O-(C1-Cv alkenyl), -O-(C1- St. alkynyl), -halogen, -nitro or -cyano; t is an integer in the range from 0 to 4; and p ranges from 1 to about 20.

Other examples of self-destructive spacers include, but are not limited to, aromatic compounds that are electronically similar to the RAV group, such as 2-aminoimidazole-5-methanol derivatives (Nau et al., 1999,

Visogd. Honey. Spent And hey. 9: 2237) or ortho- or para-aminobenzyl acetals. Spacers that undergo cyclization upon hydrolysis of the amide bond can be used, such as amides of substituted or unsubstituted 4-aminobutyric acid (Koagidtsev5 ei ai., 1995, Spetivzigu Vioiodu 2: 223), appropriately substituted bicyclic (2.2.11 and (2.2 .2 ring systems (50ogt ei ai., 1972, 9. Ateg. Spet. Bob. 94: 5815) and amides of 2-aminophenylpropionic acid (Atb5beigtu ei ai.,, 1990, 9. Og9u, Spet. 55: 5867).

An example of self-destructive spacers is also the elimination of amine-containing drugs, which are substituted in the c-positions of glycine (Kipdrygu ei, 1984, u). Honey. Spent 27: 1447).

In one embodiment, the spacer unit is a branched bis(hydroxymethyl)styrene (BHM5) unit, shown in Scheme 4, which can be used to incorporate and detach multiple drugs.

Scheme 4 her sno) o tia H -0 and: each t СНе(О(Ф(О in p r enzymatic cleavage of 2 medicinal products

In Scheme 4, O represents -C1-Cv alkyl, -C1i-Cv alkenyl, -C1-Cv alkynyl, -O-(C1-Cv alkyl), -O-(C1-Cv alkenyl), -O-(C1- St. alkynyl), -halogen, -nitro or -cyano; t is an integer in the range from 0 to 4; n is equal to 0 or 1; and p ranges from 1 to about 20.

In some embodiments, the components of -0O are the same. In yet another embodiment, the -O components are different.

In one aspect, the spacer units (-U/-) are represented by formulas (X)-(XII):

N o --IM t i s r shk

IF x where O represents -C:1-Cv alkyl, -C1-Cv alkenyl, -C1-Cv alkynyl, -O-(C1-Cv alkyl), -O-(C1-Cv alkenyl), -

O-(C1-Cv alkynyl), -halogen, -nitro or -cyano; and t is an integer in the range from 0 to 4; 1-NM-сНеСо-Я сх and i--ннснснсюучнонс(о-

HP.

Variants of the formula I and I, which include compounds of the antibody-drug conjugate, may include: o) sha t -ch-o --СХ "zhi o r where each of m/ and y is equal to 0, 1 or 2, and o ) ema

I-5 o o r de mi at level 0, no shi

And, A i

N. R

NM vach o o o 9) - saws of the M -th sheep (c) N o ) H R

MN o-

MN" and Fr

Her. o o u o ru aa r 0 N shchi ) N R chn o-

to me

A unit of medicinal product

Or is a compound of the drug auristatin having an atom that can form a bond with a spacer unit, with an amino acid unit, with an extender unit, or with an antibody unit.

In some embodiments, the drug unit Y has an M-terminal nitrogen atom that can form a bond with the spacer unit. As used herein, the terms "drug unit" and "drug component" are synonymous and used interchangeably, and refer to auristatin drug unit or auristatin drug component.

In some preferred embodiments, the auristatin drug unit is auristatin

E or its derivative. Accordingly, the term "auristatin" as used herein is understood to include auristatin derivatives. The synthesis and structure of examples cited as auristatin derivatives are given in US Patent Application Publication Nos. 2003-0083263, 2005-0238649 and 2005-0009751; Publications of the International Application for Patent MO UMO 04/010957, Publications of the International Patent for Patent MO UMO 02/088172 and patents of the USA MO 6323315, 6239104, 6034065, 5780588, 5665860, 566 , 5138036, 5076973, 4986988, 4978744, 4879278, 4816444 and 4486414, all of which are incorporated by reference in their entirety.

In some embodiments, -O is an auristatin of the formula Oe or Oc: vo ts o v Veoveo ut cho

Y Y vV'z do VA A Ve do o vo (o) g Yuk v iv) d'

N in o

I M to VA A de to o in o 10

V Yuk or is a pharmaceutically acceptable salt or solvate of a compound of the formula where, independently at each position: a wavy line means a bond;

Bg represents -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl;

BZ is -H, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl, -carbocycle, -C1-C0 alkylene (carbocycle), -C2-C0 alkenylene (icarbocycle), -C2-C0 alkynylene (carbocycle), -aryl, -C1-C0 alkylene (aryl), -C2-C20 alkenylene (aryl), -C2-C20 alkynylene (aryl), -heterocycle, -C1-C20 alkylene (heterocycle), -C2-C0 alkenylene (heterocycle) or -C2-C0 alkynylene (heterocycle);

A" represents -H, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl, carbocycle, -C1-C0 alkylene (carbocycle), -C2-C0 alkenylene (carbocycle), -C2-C0 alkynylene (carbocycle), -aryl, -C1-C0 alkylene (aryl), -C2-C20 alkenylene (aryl), -C2-C20 alkynylene (aryl), -heterocycle, -C1-C20 alkylene (heterocycle), -C2-C0 alkenylene (heterocycle) or -C2-C0 alkynylene (heterocycle);

B: represents -H or -C1-C6 alkyl; or B? and 5 together form a carbocyclic ring and have the formula -(СКаВР)»5-, where Na and B are independently -H, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl or a carbocycle, and 5 is 2, 3, 4, 5 or 6,

VU represents -H, -C1-C0 alkyl, -C2-C0 alkenyl or -C2-C0 alkynyl;

B is -H, -C:1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl, -carbocycle, -C1-C0 alkylene (carbocycle), -C2-C0 alkenylene (carbocycle), -C2- C0 alkynylene (carbocycle), aryl, -C1-C0 alkylene (aryl), -C2-C20 alkenylene (aryl), -C2-C20 alkynylene (aryl), -heterocycle, -C1-C20 alkylene (heterocycle), -C2- SCO alkenylene (heterocycle) or -C2-CSO alkynylene (heterocycle); each KZ independently represents -H, -OH, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl, -O-(C1-C0 alkyl), -O-(C2-C0 alkenyl), - O-(C2-C0 alkynyl) or -carbocycle;

IN? is -H, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl;

B" represents -aryl, -heterocycle or -carbocycle;

B2o represents -H, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl, -carbocycle, -O-(C1-C0 alkyl), -O- (C2-C0 alkenyl), -O- (C2-C0 alkynyl) or OK", where K'Z represents -H, a protective group for hydroxyl groups, or a direct bond, where OK C represents 50;

B represents -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -aryl, -heterocycle or -carbocycle;

Bc is -aryl or -heterocycle; 7 represents -О-, -5-, -МН- or -МВА"2-, where В"? is -C1-C0 alkyl, -C2-C0 alkenyl or -Co-

Sgo alkynyl;

A" represents -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -aryl, -heterocycle, -(B'ZO)t- B or -(B'ZO)t-CH (B 5)"; t is an integer in the range 1-1000;

B'Z represents -C2-C0 alkylene, -C2-C0 alkenylene or -C2-C0 alkynylene;

B" represents -H, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl; each case of B": independently represents -H, -COOH, -(CHg)-M(B'9)2, -"CHg)p-5OzH, -(CHg)-5Oz-

C1-C0 alkyl, -«"CHn)n-503-C2-C0 alkenyl or -(CHn)n-503-C2-C0 alkynyl; each occurrence of K'5 independently represents -H, -C1-C0 alkyl, - C2-C0 alkenyl, -C2-C0 alkynyl, or - (CHg)-COOH and n is an integer in the range 0-6, wherein alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, aryl, carbocyclic, and heterocyclic are indicated radicals, individually or as part of another group, are optionally substituted.

Auristatins of the formula Oe or Oe include compounds in which

B2 is -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl, each of which is optionally substituted by one or more groups independently selected from A1;

BZ is -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, monocyclic C3-C6 carbocycle, -

C1-C8 alkylene (monocyclic C3-C8 carbocycle), -C8-C8 alkenylene (monocyclic C3-C8 carbocycle), -

C2-C0 alkynylene (monocyclic C3-C0-carbocycle), -C0-C0 aryl, -C1-C0 alkylene (C0-C0 aryl), -C2-C0 alkenylene (C0-C0 aryl), -C2-C0 alkynylene (C0 -Cio aryl), -heterocycle, -C1-C0 alkylene (heterocycle), -C2-

SCO alkenylene (heterocycle) or -C2-CSO alkynylene (heterocycle); and the indicated alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A; specified carbocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A2; said aryl radicals, alone or as part of another group, are optionally substituted with one or more groups independently selected from

AZ; and the indicated heterocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A4;

B" represents -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, monocyclic C3-C6 carbocycle, -

C1-C8 alkylene (monocyclic C3-C8 carbocycle), -C2-C8 alkenylene (monocyclic C3-C8 carbocycle), -

C2-C0 alkynylene (monocyclic C3-C0 carbocycle), -C0-C0 aryl, -C1-C0 alkylene (C0-C0 aryl), -C2-C0 alkenylene (C0-C0 aryl), -C2-C0 alkynylene (C0 -Cio aryl), -heterocycle, -C1-C0 alkylene (heterocycle), -C2-

SCO alkenylene (heterocycle) or -C2-CSO alkynylene (heterocycle); and the indicated alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A; specified carbocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A2; said aryl radicals, alone or as part of another group, are optionally substituted with one or more groups independently selected from

AZ; and the indicated heterocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A4;

B: represents -H or -C1-C6 alkyl; or B? and 5 together form a carbocyclic ring and have the formula -(СВаВР)»5-, where Na and B independently represent -H, -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl or -carbocycle, and 5 is equal to 2,3,4,B5abovb,

B is -H, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl; and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1;

B' represents -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, monocyclic C3-C6 carbocycle, -

C1-C8 alkylene (monocyclic C3-C8 carbocycle), -C8-C8 alkenylene (monocyclic C3-C8 carbocycle), -

C2-C0 alkynylene (monocyclic C3-C0-carbocycle), -C0-C0 aryl, -C1-C0 alkylene (C0-Stio aryl), -C2-C0 alkenylene (C0-Stio aryl), -C2-C0 alkynylene (C0-C0 aryl -C:0 aryl), -heterocycle, -C1-C0 alkylene (heterocycle), -C2-C0 alkenylene (heterocycle) or -C2-C0 alkynylene (heterocycle); and the specified alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A!; specified carbocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A2; said aryl radicals, alone or as part of another group, are optionally substituted with one or more groups independently selected from

AZ; and the indicated heterocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A4; each RU is independently -H, -OH, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl, -O-(C1-C20 alkyl), -O-(C2-C0 alkenyl), - O-(C2-C0 alkynyl or carbocycle; and the specified alkyl, alkenyl and alkynyl radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A1; and the specified carbocycle is optionally substituted by one or more groups independently selected from A2;

IN? is -H, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl; and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1;

B" is -aryl, -heterocycle or -carbocycle; and the specified carbocyclic radical is optionally substituted by one or more groups independently selected from A2; the specified aryl radical is optionally substituted by one or more groups independently selected from

AZ; and the specified heterocyclic radical is optionally substituted by one or more groups independently selected from A4;

B2o is chosen from the radicals -H, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl, -carbocycle, -OH, -O- (C1-C0 alkyl), -O-(C2-C0 alkenyl) , -O-(C2-C0 alkynyl or OB", and the specified alkyl, alkenyl and alkynyl radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A1; and the specified carbocycle is not necessarily necessarily replaced by one or more groups independently selected from A2;

BZ represents -H, a protective group for hydroxyl groups, or a direct bond, where OK represents 0;

B" is selected from the radicals -H, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0-alkynyl or -carbocycle; and the specified alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1 and said carbocyclic radical is optionally substituted by one or more groups independently selected from A2;

V'b is an aryl optionally substituted by one or more groups independently selected from AZ, or a heterocycle optionally substituted by one or more groups independently selected from A4; 7 represents -O-, -5-, -MH- or -MA!-, where HB represents -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl, each of which is optionally substituted by one or more groups independently selected from A1;

BA" represents -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -aryl, -heterocycle, -(B'ZO)t-B"" or -(BZO)t-CH (B"»)", and the specified alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1; the indicated aryl radical is optionally substituted by one or more groups independently selected from AZ; and said heterocycle is optionally substituted with one or more groups independently selected from A4; t is an integer in the range 1-1000;

BZ is -C2-C0 alkylene, -C2-C0 alkenylene or -C2-C0 alkynylene, each of which is optionally substituted by one or more groups independently selected from A1;

B'" represents -H, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl, and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1; each case B'5 independently represents -H, -COOH, -(CHg)p-M(B'9)2, -"CHg)p-5OzH, -(CHg)-5Oz-

C-C0 alkyl, -(CHg)-5Oz3-C2-Cg2o alkenyl or -(CHg)-50Oz3-C2-Cg2o alkynyl, and the specified alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1;

each case of K'5 independently represents -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or - (CHg)-COOH, and the specified alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups that are independently selected from A1; n is an integer in the range 0-6;

A1 is a halogen, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -C(O)B", -

ОоС(О)В", -К(О)ОВ8", -СК(О)МН", -С(О)МНА", -С(О)М(А)2", -"МНО(О)В ", -587,. -5038", -5(0)28", -5(О)В", -

OH, -O, -Mz, -MH", -MH(B"), -"M(B")2 and -CM, where each B" is independently selected from -H, -C1-Cv alkyl, -C2- C1-C8 alkenyl, -C2-C8 alkynyl or aryl, and where the indicated groups are -O-(C1-C8 alkyl), -O-(C2-C8 alkenyl), -O-(C2-C8 alkynyl), -aryl, - Ci-Cv alkyl, -Co-Cv alkenyl and -C2-Cv alkynyl may optionally be additionally substituted by one or more groups independently selected from -C1-Cv alkyl, -C2-Cv alkenyl, -Co-

Alkynyl, -halogen, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -C(O)B", -

ОоС(О)В", -КО)ОВ", -С(О)МН", -"СК(О)МНА", -С(О)М(А 2), -"МНО(О)В", - 587, -50387, -5(0)28"7, -(О)В, -

OH, -Mz, -MH", -MH(B"), -M(A")" and "CM, where each B" is independently selected from -H, -C1-Cv alkyl, -C2-Cv alkenyl, - C2-Cv alkynyl or -aryl;

AND? is -halogen, -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -C(O)8", -OC(O)B", -C(O)OB" -C(O)MH", -C(O)MNA", -"C(O )M(A", -

MNess)uVv", -58", -5038", -5(0)28", -5(0)8", -OH, -0, -Mz, -MNeg, -"MH(B"), - M(B")2 and -"CM", where each K" is independently selected from -H, -C1-Cv alkyl, -Cg-Cv alkenyl, -C2-Cv alkynyl or -aryl, and where the indicated groups are -Ci-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl) and - aryl can be optional necessarily additionally substituted by one or more substituents independently selected from -C1-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl, -halogen, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -С(О)В8", -ОС(О)В", -Ф(О)ОВ8", -С(О)МН", -С (О)МНА", -С(ОМ(А У", -МНе(О)А8", -587, -503187,. -5(0)28", -5(0)8", -OH, - Mz, -MHg, -MH(B"), -M(A")2 and -CM, where each K" is independently selected from -H, -C1-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl or -aryl;

AZ is -halogen, -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2- Sv alkynyl), -aryl, -C(O)8", -OC(O)B", -C(O)OB" -C(O)MH", -C(O)MNA", -"C( O)M(A", -

MNess)uVv", -58", -50z318"7, -550)28", -5(0)8", -OH, -MO", -Mz, -MH", -MH(B"), - M(A")" and -CM, where each KE" is independently selected from -H, -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl or aryl, and where the indicated groups are -Ci-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl) and - aryl may optionally be additionally substituted by one or more substituents independently selected from -C1-Cv alkyl, -C2-Cv alkenyl, -C2-Cv alkynyl, -halogen, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl) , -O-(C2-Cv alkynyl), -aryl, -C(O)B8", -OC(O)B", -F(O)OB8", -C(O)MH", -C(O )МНА", -С(ОМ(А У", -МНе(О)А8", -587, -503187,. -5(0)28", -5(0)8", -OH, -Mz, -MHg, -MH(B"), -M(A")2 and -CM, where each K" is independently selected from -H, -C1-Cv alkyl, -C2-Cv alkenyl, -Co-Cv alkynyl or aryl and

A4 is -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl, -halogen, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2- Sv alkynyl), -aryl, -C(O)8", -OC(O)B", -C(O)OB" -C(O)MH", -C(O)MNA", -"C( O)M(A", -

MNO(O)VA" -5857,. -5058",. -5(0)28", -5(0О)8", -OH, -Mz, -MNeg, -MH(B"), -M(A")» and -SM, where each K" is independently selected from -H, -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl or aryl, and where the indicated groups are -0-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O- (C2-Cv alkynyl), -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl and aryl may optionally be additionally substituted with one or more substituents independently selected from -C1-Cv alkyl, -C2 -Cv alkenyl, -C2-Cv alkynyl, -halogen, -O-(C1-Cv alkyl), -O-(C2-Cv alkenyl), -O-(C2-Cv alkynyl), -aryl, -C(O )B8", -ОС(О)В", -Ф(О)ОВ8", -С(О)МН", -С(О)МНА", -С(ОМ(А У", -МНе(О) A8", -587, -503187,. -5(0)28", -5(0)8", -OH, -Mz, -MHg, -MH(B"), -M(A")2 and -CM, where each K" is independently selected from -H, -Ci-Cv alkyl, -C2-Cv alkenyl, -Cg-Cv alkynyl or aryl; or a pharmaceutically acceptable salt or solvate thereof.

Auristatins of the formula Oe include compounds in which the specified alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, aryl, carbocyclic and heterocyclic radicals are not substituted.

Auristatins of formula Oe include compounds in which the groups K?, BZ, B", B", Ne, B", Bi are unsubstituted, and the groups KU, B2oi B"! are optionally substituted, as described herein.

Auristatins of formula Oe include compounds in which

IN? represents -C1-C8 alkyl, optionally substituted by one or more groups independently selected from A1;

BZ and KE" are independently selected from the radicals -H, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl, monocyclic C3-C8 carbocycle, -C1-C0 alkylene (monocyclic C3-C8 carbocycle), /-C2-C0 alkenylene (monocyclic C3-C0-carbocycle), -C2-C0 alkynylene (monocyclic C3-C0-carbocycle), -C0-C0 aryl, -C1-C0 alkylene (C0-Stio aryl), -C2- C0 alkenylene (C1-C0 aryl), -C2-C0 alkynylene (C1-Stio aryl), - heterocycle, -C1-C20 alkylene (heterocycle), -C2-C20 alkenylene (heterocycle) or -C2-C0 alkynylene (heterocycle) ; and the indicated alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A; the indicated carbocyclic radicals, individually or as part of another group , optionally substituted by one or more groups independently selected from Ag; said aryl radicals, alone or as part of another group, optionally substituted by one or more groups independently but are selected from AZ; and the specified heterocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A4;

B" represents -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, monocyclic C3-C6 carbocycle, -

C1-C8 alkylene (monocyclic C3-C8 carbocycle), -C8-C8 alkenylene (monocyclic C3-C8 carbocycle), -

C2-C0 alkynylene (monocyclic C3-C0 carbocycle), -C0-C0 aryl, -C1-C0 alkylene (C0-C0 aryl), -C2-C0 alkenylene (C0-C0 aryl), -C2-C0 alkynylene (C0 -Cio aryl), -heterocycle, -C1-C0 alkylene (heterocycle), -C2-

SCO alkenylene (heterocycle) or -C2-CSO alkynylene (heterocycle); and the indicated alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A; specified carbocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A2; said aryl radicals, alone or as part of another group, are optionally substituted with one or more groups independently selected from

AZ; and the indicated heterocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A4;

B: represents -H or -C.-Cv alkyl; or KK" and 5 together form a carbocyclic ring and have the formula -(SVeRe)"5-, where Ka and ve are independently selected from -H, -C1-Cv alkyl, -Cge-Cv alkenyl, -C2-Cv alkynyl or carbocycle, and 5 equals 2, 3, 4, 5 or 6,

Bb is -C1-C8 alkyl, optionally substituted by one or more groups independently selected from A1; each KU is independently selected from the radicals -OH, -O-(C1-C0 alkyl), -O-(C2-C0 alkenyl) or -O-(Ce-

Sgo alkynyl); and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1;

B" represents hydrogen or -C1-C6 alkyl, optionally substituted by one or more groups independently selected from A1;

B" is an aryl, heterocycle, or carbocycle; and said carbocyclic radical is optionally substituted by one or more groups independently selected from A2; said aryl radical is optionally substituted by one or more groups independently selected from

AZ; and the specified heterocyclic radical is optionally substituted by one or more groups independently selected from A4;

B20 is OK'8, where KZ is -H, a protective group for hydroxyl groups, or a direct bond, where OK'Z is 50;

A" is selected from -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -carbocycle; and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1 ; and said carbocyclic radical is optionally substituted with one or more groups independently selected from A2; and

AT, A2, AZ, and A4 are as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

Auristatins of formula Oe include compounds in which

Bg is -C1-C8 alkyl;

BZ, Vy and K" are independently selected from the radicals -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, monocyclic C3-C6 carbocycle, -C1-C6 alkylene (monocyclic C3-C6 carbocycle ), /-C2-C0 alkenylene (monocyclic C3-C0-carbocycle), -C2-C0 alkynylene (monocyclic C3-C0-carbocycle), -C0-C0 aryl, -C1-C0 alkylene (C0-Sthio aryl), - C2-C0 alkenylene (C1-C0 aryl), -C2-C0 alkynylene (C1-C0 aryl), - heterocycle, -C1-C20 alkylene (heterocycle), -C2-C20 alkenylene (heterocycle) or -C2-C0 alkynylene ( heterocycle); and the indicated alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene radicals, individually or as a part of another group, are optionally substituted by one or more groups independently selected from A; the indicated carbocyclic radicals, individually or as a part of another group, optionally substituted by one or more groups independently selected from Ag; the specified aryl radicals, alone or as part of another group, optionally substituted by one or more groups that are not lying down are chosen from AZ; and the indicated heterocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A4;

B: represents -hydrogen;

VU is -C.1-Cv alkyl; each BZ is independently selected from -OH, -O-(C1-C6 alkyl), -O-(C2-C6 alkenyl) or -O-(C2-C6 alkynyl); and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1;

AV? represents hydrogen or -C.1-Cv alkyl;

IN'? is phenyl, optionally substituted by one or more groups independently selected from AZ;

BO represents OK 8, where KZ represents H, a protective group for hydroxyl groups, or a direct bond, where OK Z represents ZO;

A" is selected from -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or -carbocycle; and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1 ; and said carbocyclic radical is optionally substituted with one or more groups independently selected from A2; and

AT, A2, AZ, and A4 are as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

Auristatins of formula Oe include compounds in which

B: is methyl;

BZ represents -H, -C1-Cv alkyl, -C2-Cv alkenyl or -C2-Cv alkynyl, and the indicated alkyl, alkenyl or alkynyl radicals are optionally substituted by one or more groups independently selected from A1;

B" represents -H, -C1-Cv alkyl, -Co-Cv alkenyl, -C2-Cv alkynyl, monocyclic C3-Cv carbocycle, -Cv-

Co aryl, -C1-Cv alkylene (Cv-Co aryl), -Co-Cv alkenylene (Ce-C:io aryl), -C2-Cv alkynylene (Cv-Co aryl), -C1-

Sv alkylene (monocyclic Cz-Cv-carbocycle), -Cg-Cv alkenylene (monocyclic Cz-Cv-carbocycle), -C2-Cv alkynylene (monocyclic Cz-Cv-carbocycle), and indicated alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene radicals, individually or as part of another group, optionally substituted by one or more groups independently selected from A!1; the indicated carbocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from Ag; and the indicated aryl radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from AZ;

B: represents -H; B is methyl;

It is -C1-Cv alkyl, -C2-Cv alkenyl or -C2-Cv alkynyl; each EZ is methoxy;

IN? represents -hydrogen or -C4-Cv alkyl;

B"" is phenyl;

B20 is OK", where KZ is -H, a protecting group for hydroxyl groups, or a direct bond, where OK'Z is 50;

B is methyl; and JSC, A? and AZ have the meanings defined in this document, or their pharmaceutically acceptable salt or solvate.

Auristatins of formula Oe include compounds in which K? is methyl; ECZ is -H or -C1-C3 alkyl; KE" represents -C1-C5 alkyl; KE? represents H; 5 represents methyl; KE" represents isopropyl or sec-butyl; KZ is methoxy; IS? represents hydrogen or -C:1-Cv alkyl; BC? is phenyl; K2O is OK'8, where B'Z is -H, a protecting group for hydroxyl groups, or a direct bond, where OB" is 0; and B? is methyl; or a pharmaceutically acceptable salt or solvate thereof.

Auristatins of formula Oe include compounds in which B? is methyl or -C:i-C3 alkyl; KZ is H or -C:1-C3 alkyl; KE" represents -C1-Cx alkyl; E? represents H; K5 represents -C1-C3 alkyl; E/ represents -C1-C alkyl; EZ represents -C1-C3 alkoxy; EP represents hydrogen or - C1-Cv alkyl; K" is phenyl; K2O is OK'8Z, where K'Z is H, a protecting group for hydroxyl groups, or a direct bond, where OK'Z is 0; and K"! represents -C:1-C3 alkyl; or a pharmaceutically acceptable salt or solvate thereof.

Auristatins of the formula Oeg include compounds in which

B2 is -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl, each of which is optionally substituted by one or more groups independently selected from A1;

VAZ, BA and ВЕ" are independently selected from the radicals -H, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl, monocyclic C3-C0 carbocycle, -Ci-C0 alkylene (monocyclic C3-C0 carbocycle ), /-C2-C0 alkenylene (monocyclic C3-C0-carbocycle), -C2-C0 alkynylene (monocyclic C3-C0-carbocycle), -C0-C0 aryl, -C1-C0 alkylene (C0-Sthio aryl), - C2-C0 alkenylene (C1-C0 aryl), -C2-C0 alkynylene (C1-C0 aryl), - heterocycle, -C1-C20 alkylene (heterocycle), -C2-C20 alkenylene (heterocycle) or -C2-C0 alkynylene ( heterocycle); and the indicated alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene radicals, individually or as a part of another group, are optionally substituted by one or more groups independently selected from AT; the indicated carbocyclic radicals, individually or as a part of another group, optionally substituted by one or more groups independently selected from Ag; the specified aryl radicals, alone or as part of another group, optionally substituted by one or more groups that are independently selected from AZ; and the specified heterocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A4;

B: represents -H;

AB is -H, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl; and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1; each RU is independently selected from the radicals -H, -OH, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl, -0-(C1-C0 alkyl), -O-(C2-C0 alkenyl), -O-(C2-C0 alkynyl or carbocycle; and the specified alkyl, alkenyl and alkynyl radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from At; and the specified carbocycle is optionally substituted by one or more groups independently selected from A2;

IN? is -H, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl; and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1;

IN? is phenyl, optionally substituted by one or more groups independently selected from AZ; 7 represents -O-, -5-, -МН- or -МВ"2, where B"? is -C1-C6 alkyl, -C2-C6 alkenyl or -C2-

C 50 alkynyl, each of which is optionally substituted with one or more groups independently selected from A1;

A" represents -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -aryl, -heterocycle, -(B'ZO)t- B or -(830O)t-CH(B "")", and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1; the indicated aryl radical is optionally substituted by one or more groups independently selected from AZ; and said heterocycle is optionally substituted with one or more groups independently selected from A4; t is an integer in the range 1-1000;

B is -C2-C0 alkylene, -C2-C0 alkenylene or -C2-C0 alkynylene, each 3 of which is optionally substituted by one or more groups independently selected from A1;

B" represents -H, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl, and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1; each case B'5 independently represents -H, -COOH, -(CHg)p-M(B'9)2, -"CHg)p-5OzH, -(CHg)-5Oz-

C1-C6 alkyl, -(CHg)-5Oz3-C2-C6 alkynyl, and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1; each case of K'!E independently represents -H, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl or - (CHg)-COOH, and the specified alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1; n is an integer in the range 0-6; and AT, A2, AZ, and A4 are as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

Auristatins of the formula Oeg include compounds in which

Bg is methyl;

VAZ, BA and ВЕ" are independently selected from the radicals -H, -C1-C0 alkyl, -C2-C0 alkenyl, -C2-C0 alkynyl, monocyclic C3-C0 carbocycle, -Ci-C0 alkylene (monocyclic C3-C0 carbocycle ), /-C2-C0 alkenylene (monocyclic C3-C0-carbocycle), -C2-C0 alkynylene (monocyclic C3-C0-carbocycle), -C0-C0 aryl, -C1-C0 alkylene (C0-Sthio aryl), - C2-C0 alkenylene (C1-C0 aryl), -C2-C0 alkynylene (C1-C0 aryl), - heterocycle, -C1-C20 alkylene (heterocycle), -C2-C20 alkenylene (heterocycle) or -C2-C0 alkynylene ( heterocycle); and the indicated alkyl, alkenyl, alkynyl, alkylene, alkenylene and alkynylene radicals, individually or as a part of another group, are optionally substituted by one or more groups independently selected from AT; the indicated carbocyclic radicals, individually or as a part of another group, optionally substituted by one or more groups independently selected from Ag; said aryl radicals, alone or as part of another group, optionally substituted by one or more groups that are independently selected from AZ; and the specified heterocyclic radicals, individually or as part of another group, are optionally substituted by one or more groups independently selected from A4;

B: represents -H;

Ve is methyl; each EZ is methoxy;

IN? is -H, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl; and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1;

V'b is an aryl optionally substituted by one or more groups independently selected from AZ, or a heterocycle optionally substituted by one or more groups independently selected from A4; 7 represents -О-, -5-, -МН- or -МА!2-, where КК? is -C1-C0 alkyl, -C2-C0 alkenyl or -Co-

C 50 alkynyl, each of which is optionally substituted with one or more groups independently selected from A1;

BA" represents -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -aryl, -heterocycle, -(B'ZO)t-B"" or -(B'ZO)t -CH(B"»)", and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1; the indicated aryl radical is optionally substituted by one or more groups independently selected from AZ; and said heterocycle is optionally substituted with one or more groups independently selected from A4; t is an integer in the range 1-1000;

BZ is -C2-C0 alkylene, -C2-C0 alkenylene or -C2-C0 alkynylene, each of which is optionally substituted by one or more groups independently selected from A1;

B'" represents -H, -C1-C6 alkyl, -C2-C6 alkenyl or -C2-C6 alkynyl, and the indicated alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups independently selected from A1; each case B": independently represents -H, -COOH, -(CHg)-M(B'9)2, -"CHg)p-5OzH, -(CHg)-5Oz-

C1-C2 alkyl, -(CHg)y-503-C2-C0 alkenyl or -(CHg)-503-C2-C0 alkynyl, and the specified alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more independently selected groups from A1; each case of K'5 independently represents -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl or - (CHg)-COOH, and the specified alkyl, alkenyl and alkynyl radicals are optionally substituted by one or more groups that are independently selected from A1; n is an integer in the range 0-6; and AT, A2, AZ, and A4 are as defined herein, or a pharmaceutically acceptable salt or solvate thereof.

In some of these variants, the implementation of K'? is phenyl optionally substituted with one or more groups independently selected from AZ.

Auristatins of the Auger formula include compounds in which the groups K2, VU, B", B", Ne, B", BB and Ko are unsubstituted, and the groups Ki and KE" have the values defined in this document.

Auristatins of the formula Ov include compounds in which the specified alkyl, alkenyl, alkynyl, alkylene, alkenylene, alkynylene, aryl, carbocyclic and heterocyclic radicals are not substituted.

Auristatins of the formula Oeg include compounds in which

B2 is C.1-C3 alkyl; C is H or C:1-C3 alkyl; KE" represents C-C5 alkyl; Ko represents H; KE: represents C1-C3 alkyl; EE" represents C1-Cx alkyl; EZ is C:-C3 alkoxy;

IN? is hydrogen or C1-C8 alkyl; KZ is phenyl optionally substituted with one or more groups independently selected from AZ; 7 is O, 5 or MH; and K" and AZ have the meanings defined in this document; or a pharmaceutically acceptable salt or solvate thereof.

Auristatins of the formula Oeg include compounds in which

B: is methyl; KZ is H or C.1-C3 alkyl; KE" represents C:-C5 alkyl; E? represents H; ECZ represents methyl; KE" represents isopropyl or sec-butyl; RZ is methoxy; IN? represents hydrogen or C.1-Cv alkyl; B'E is phenyl optionally substituted with one or more groups independently selected from AZ; 7 is O, 5 or MH; and B" and AZ have the meanings defined in this document; or a pharmaceutically acceptable salt or solvate thereof.

Auristatins of the formula Oeg include compounds in which

B2 is methyl; KZ is H or C:1-C3 alkyl; KE" represents C-C5 alkyl; KE? represents H; Ke represents methyl; K" represents isopropyl or sec-butyl; KZ is methoxy; KU is hydrogen or Ci-Cv alkyl; QE is phenyl; 7 is O or MH; and CC" has the meaning defined in this document, preferably is hydrogen; or a pharmaceutically acceptable salt or solvate thereof.

Auristatins of the formula Oeg include compounds in which

B2 is C.1-C3 alkyl; EZ is H or C:1-C3 alkyl; B" represents C1-C5 alkyl; B? represents H; KU represents C1-C3 alkyl; B" represents C1-C5 alkyl; KZ is -C1-C3 alkoxy; eh? represents hydrogen or -C1-Cv alkyl; B'E is phenyl; 7 is O or MH; and

A" has a certain meaning in this document, preferably is hydrogen; or a pharmaceutically acceptable salt or solvate thereof.

Auristatins of the formula Oej or Oe include compounds in which KU, B" and E/ are independently isopropyl or t-butyl, and K? is -H. In an exemplary embodiment, each of KZ and K7 is isopropyl, K? is H, and K" is t-butyl. Other substitutes have the meanings defined in this document.

Auristatins of the formula Oej or Oe include compounds in which each of KZ and K9 is methyl, and

B" represents N. Other substituents have the meanings defined in this document.

Auristatins of the Yue or Yue formula include compounds in which each case of KU is -

OSN Other substitutes have the meanings defined in this document.

Auristatins of formula Oe or Og are compounds of compounds in which each of Ez and Ke" is isopropyl, each of K2 and Be is methyl, K? is H, K" is t-butyl, each occurrence of K8 is OSN", and E? represents H. Other substituents have the meanings defined in this document.

Auristatins of formula XX include compounds in which 2 is -O- or -MH-. Other substitutes have the meanings defined in this document.

Auristatins of the formula Og include compounds in which K'? is aryl. Other substitutes have the meanings defined in this document.

Auristatins of the formula Oe include compounds in which K"" is -phenyl. Other substituents have the meanings defined in this document.

Auristatins of formula Yue include compounds in which 7 represents -O-, and K'" represents H, methyl or tert-butyl. Other substituents have the meanings defined in this document.

Auristatins of the formula XX include compounds in which 7 is -MH, B" is -

CH(A)", where 5 is -(CHg)y-M(A' 6)", and "6 is -C1-Cv alkyl or -(CHeg)-COOH. Other substituents have the meanings defined in this document .

Auristatins of the Auger formula include compounds in which 7 represents -MH, A" represents -

SN(B)", where KK!" is -(CHg)-5OzH. Other substitutes have the meanings defined in this document.

In preferred embodiments, when Y is an auristatin of formula IV, m/ is an integer in the range from 1 to 12, preferably from 2 to 12, y is 1 or 2, and ia is preferably 1.

In other embodiments, when Y is an auristatin of the formula OK, and is equal to 1, am and y are equal to 0.

Illustrative units of the medicinal product (-0) include units of the medicinal product having the following structures: и Но у Нон

And a | b. o 0. o o

N

- We are M M

І о о о о о (9) - О ОН и вдач От и кыти и и и Осно и о о! autumn Z o i M.

Ye reny o (c) iv) chievav and Ж as n. AND

M. O. O. Cheeva and Z. O

J n

M,

M 7 M M M ma o | ost o N osnu o o

AL Z o oo chna t o S ra ,

AL MA

See Chapter 255; oh oh chenevav - oh and noos. M.; USOON

AL MA gu 255; oh because - Ha; There are 5 ozN

AH MA o oo was in charge - o Mn s son.

AND

KI MA re Y ni c) oo y. at. oh and tet tn

MN. or pharmaceutically acceptable salts or solvates thereof.

In one aspect, hydrophilic groups, such as, but not limited to, triethylene glycol esters (TES), can be attached to the KE" in the drug unit. Without being limited by any theory, the hydrophilic groups promote internalization and non-agglomeration of the drug unit.

In some embodiments, the drug unit is not T2T-1027. In some embodiments, the drug unit is not auristatin E, dolastatin 10, or auristatin PE.

Compounds of antibody-drug conjugates, which are given as examples, have the following structures, where ""par-5-" represents an antibody against SOZO: zo tA o (c) Н В сн; H 8 A M, M M

PBX o ra a o Osno osno

Ts mansi-oon r

I -MS-uso-RAV-MMAE tA o o N that CHz N on 8 A M,, MM kA IY TT pyt ust --K o osno osn o H r 1-MS-us-RAV-MMAE or tA y at

Co.; where AM M her Her" M

M y, M M M o Y o Y osno Osn o on

R

1-MS-MMAE where May means valine and Si means citrulline.

A unit of antibody

The antibody unit (I) has at least one functional group that can form a bond with the functional group of the linker unit or the drug unit. Suitable functional groups that may be present on an antibody unit, either naturally, by chemical manipulation, or by design, include, but are not limited to, a sulfhydryl group (-5H), an amino group, a hydroxyl group, a carboxyl group, an anomeric hydroxyl group of a carbohydrate, and a carboxyl group. . In some embodiments, the functional group of the antibody unit is a sulfhydryl group.

Typically, the sulfhydryl group is a solvent-exposed sulfhydryl group, such as a solvent-exposed sulfhydryl group on a cysteine residue. Sulfhydryl groups can be created by restoring an intramolecular or intermolecular disulfide bond of an antibody. Sulfhydryl groups can also be created by reacting the amino group of the lysine component of the antibody with 2-iminothiolane (Trot's reagent) or another reagent that creates a sulfhydryl group.

In some embodiments, one or more sulfhydryl groups can be engineered into an antibody unit, for example, by amino acid substitution. For example, a sulfhydryl group can be introduced into an antibody unit. In some embodiments, the sulfhydryl group is introduced by amino acid substitution of serine or threonine for a cysteine residue and/or by adding a cysteine residue to the antibody unit (engineered cysteine residue). In some embodiments, the cysteine residue is an internal cysteine residue, that is, one that is not located at the M-terminus or C-terminus of the antibody component.

To control the number of drug units or components in the form of linker unit - drug unit, one or more cysteine residues can be eliminated by amino acid substitution. For example, the number of solvent-exposed cysteine residues in the immunoglobulin hinge region can be reduced by amino acid replacement of cysteines with serine residues.

In some embodiments, an antibody unit contains 1, 2, 3, 4, 5, 6, 7, or 8 solvent-exposed cysteine residues. In some embodiments, the antibody unit contains 2 or 4 solvent-exposed cysteine residues.

The present invention also provides kits for the treatment of NI. The kit may include (a) a container containing an antibody-drug conjugate, and (B) one or more additional containers containing chemotherapeutic agents. Such kits may further include, if desired, one or more of various conventional components of a pharmaceutical kit, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, and the like, which will be clearly qualified in specialists in this field of technology. The kit may also include instructions in printed form, or in the form of inserts, or in the form of labels indicating the amounts of compounds to be administered, principles of administration and/or principles of compound mixing.

The scope of this invention is not limited to the specific embodiments described herein. Various modifications of the present invention, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description and accompanying figures. It is assumed that such modifications are within the scope of the appended claims.

All of the publications and patent documents cited above are hereby incorporated by reference in their entirety to the same extent as if each were so indicated.

The present invention is further described in the following examples, which are not intended to limit the scope of the invention.

Examples

Example 1: Antibody-drug conjugate combination САС10-у«СММАЕ (сас10-МО-мо-РАВ-

MMAE) with chemotherapy regimens for the treatment of NI.

The effects of combining CAC10-msSMMAE treatment with gemcitabine or AVMO or other chemotherapeutic treatment regimens were studied on the I 540su tumor model (Egapsizso ei ai., Viosa 2003, 102: 1458-146). To determine the maximum tolerated dose (MTO) of AVMO and gemcitabine, daily body weights of ZSIO mice treated with increasing amounts of drugs were determined.

The criteria defining MTO were 220 95 reduction in body weight or other signs of clinical manifestation during full treatment followed by a 2-week recovery period. The time required for a fourfold or threefold increase in tumor size was chosen as the time to reach the end position (TTE), which was determined using non-linear regression analysis of the exponential growth data of each individual tumor determined on a per experimental animal basis. The time required for the tumor to grow fourfold was calculated based on the tumor volume at the start of treatment. For animals that did not reach the final position, the TTE value equal to the last day of the study was set. The delay in reaching TTE relative to tumors subjected to control treatment is a reflection of 96 TO (tumor growth delay), which was determined using the formula: 95 Tar-CT-DRY100, where T and C represent the median time in days to reach TTE for treated and control groups, using the start of treatment as day 1. Statistical analysis and graphical representations were performed using Rgizt software (SsSgarprach) for M/pdomu5 3.03 software. Curves of average tumor growth demonstrate the time dependence of average tumor volumes for a group. A t-test was used to analyze the significance of differences between TTE groups with treated and control tumors, with differences considered significant (7) at 0.01:P-0.05 and highly significant (7) at

P«e0.01. For CsAC10-msMMAE, a treatment regimen using 1 mg/kg, a4achz (once every 4 days x 3) was selected based on previous reports demonstrating maximal therapeutic effects using the dach regimen.

Administration of AVMO or cAC10-msMMAE alone to tumor-bearing I540 mice caused tumor regression and significant delays in tumor growth compared to control treatment (Fig. 1A).

However, in the end, tumors developed. In animals treated with CAC1000-msMMAE monotherapy, 4/9 resistant tumors were observed, and in animals treated with AVMO monotherapy, -0/9 resistant tumors were observed. In contrast, the combination of cSAC10-UsMMAE with AVMO resulted in sustained tumor regressions (9/9 sustained appropriate responses) (Fig. 1A) and a statistically significant increase in tumor growth delay relative to each treatment group using monotherapy in all experimental animals. Similarly, when treatment was initiated at a tumor volume of 300 mm", animals treated with combination therapy showed a significant increase in TO and 50 95 long-lasting relevant responses (5/10 animals) (Fig. 18), while while in animals treated with CAC10- monotherapy

MOMMAE, 2/10 sustained relevant responses were observed, and no sustained relevant responses were observed in animals treated with AVMO monotherapy. It should be noted that the doses in the AVMO regimen were reduced by 25 95 in the large tumor model compared to the small tumor model. The delay in tumor growth caused by the combination treatment was highly significant relative to each individual treatment group using monotherapy (Table 1). There were no significant differences in body weight loss or clinical presentation in the combination treatment group, suggesting comparable tolerability (data not shown).

Table 1 . . . . Combination vs

Median TO (fig. 1A) Median TO (fig. 18) by a single agent (P-

Treatment (days to four times | (days to three times the value of tumor increase) | tumor increase) AB

AVMO with cАС10- « press 1 x The experiment was stopped. At this time point, sustained tumor regressions were observed in all animals.

Then the effect of combining CAC10-msMMAEE with gemcitabine was studied. For this purpose, mice were implanted with I 540su tumors and treated with CAC10-MsMMAE and gemcitabine, either alone or in combination. While single-drug treatment resulted in significant delays in tumor growth and one long-lasting relevant response, the combination of CAC10O0-msMMAE with gemcitabine enhanced the antitumor relevant response, and long-lasting relevant responses were found in all animals (5/5, Fig. 2A). Increased efficacy in the combined treatment group was also noted when the drugs were administered, when the tumors reached a significantly larger size (300 mm, Fig. 28). Immunohistochemical analysis of the tumors revealed no significant changes in the expression levels of SOZO in the tumors treated treatment with either ABMO or gemcitabine, which excludes drug interference with target gene expression (data not shown). Similar to the ABMO experiment, the combination treatment with gemcitabine resulted in a significant delay in tumor growth, which was more additive ( Table 2) and resulted in long-lasting appropriate responses.There were no significant differences in body weight loss or clinical presentation in the combination treatment group, suggesting comparable tolerability (data not shown).

Table 2 . . . . Combination vs

Median TO (fig. 2A) Median TO (fig. 28) by a single agent (P-

Treatment (days to quadruple | (days to triple value) tumor enlargement) | tumor growth)

cAS10-USMMAE o-0.0088 p-0.0375 o-0.0024 | p-0.0154

Gemcitabine

In a second study, illustrated in FIG. 7 and in Table 3, 7/8 long-lasting appropriate responses were observed with combined treatment using CAC10-xsMMAE and gemcitabine, while when treated with CAC10-msMMAE alone, 1/7 long-lasting appropriate responses were observed, and when treated with gemcitabine alone, 1/ 6 a long corresponding reaction.

Table C

Median TO (fig. 7) (dnido |Combination compared to single

Treatment of a fourfold increase with the agent (P-value) of the tumor) (A) cСАС10-усСММАЕ 78.01 p--0.0037

P-0.0021

Gemcitabine and CAC10-y x The experiment was stopped. At this point in time, 7/8 animals showed persistent tumor regressions.

The effect of combining CAC10-msMMAE with MO was studied. For this purpose, mice were implanted with tumors

And 540su were treated with CAC10-MsMMAE and MO, either alone or in combination. Treatment was started at a tumor volume of 100 mmU for two separate experiments that were performed (ZA and

ZV). In the first experiment, 6/9 long-term appropriate responses were observed with combination therapy, while 4/9 long-term appropriate responses were observed with CAC10-jezhsMMAE alone, and 0/9 long-term appropriate responses were observed with ZMO alone. In the second experiment, 7/7 long-lasting appropriate responses were observed with combination therapy, while 0/7 long-lasting appropriate responses were observed with cCAC10-UsMMAE alone, and 0/7 long-lasting appropriate responses were observed with ZMO alone.

Table 4. . . . Combination vs

Median TO (fig. ZA) Median TO (fig. ЗВ) by a single agent (P-

Treatment (days to fourfold | (days to threefold - : value of tumor increase) tumor increase) (АВС сАС10-UsMMAE 0-0.5089 р-0.0004 0-0.0001 р-0.0005

MO cAS1TO-

The effect of combining CAC10-msSMMAE with vinorelbine was studied. For this purpose, mice were implanted with I 540su tumors and treated with CAC10-msMMAE and vinorelbine, either alone or in combination.

Treatment was started at a tumor volume of 100 mm for two separate experiments that were performed (4A and 48). In the first experiment, a 1/6 long-term response was observed with combination therapy, while a 1/6 long-term response was observed with CAC10-msMMAEE alone, and a 0/6 long-term response was observed with vinorelbine alone.

In the second experiment, 6/10 long-lasting appropriate responses were observed with combination therapy, while 4/10 long-lasting appropriate responses were observed with CAC10-msMMAEE alone, and 0/9 long-lasting appropriate responses were observed with vinorelbine alone.

Table 5. . . . Combination vs

Median TO (fig. 4A) Median TO (fig. 48) by a single agent (P-

Treatment (days to quadruple | (days to triple value) tumor enlargement) | tumor increase) cАС10-USMMAE p-0.4500 o-0.3769 0-0.0004 | p-0.0001

Vinorelbin is at home

The effect of combining cSAC10-mMsMMAEE with doxorubicin was studied. For this purpose, mice were implanted with I 540su tumors and treated with CAC10-UsMMAE and doxorubicin, either alone or in combination. Treatment was started at a tumor volume of 100 mm for two separate experiments that were performed (XA and 58). In the first experiment, 0/4 sustained appropriate responses were observed with combination therapy, while 1/6 sustained appropriate responses were observed with CAC10-USMMAEE alone, and 0/3 sustained appropriate responses were observed with doxorubicin alone. In the second experiment, 7/10 long-lasting appropriate responses were observed with combination therapy, while 4/10 long-lasting appropriate responses were observed with CAC10-UsSMMAEE alone, and 0/9 long-lasting appropriate responses were observed with doxorubicin alone.

Table 6. . . . Combination vs

Median TO (fig. 5A) Median TO (fig. 58)

Treatment (days to quadruple | (days to threefold - : value of tumor increase) tumor increase) (ABS

Doxorubicin food vAoteMMAe 000201

The effect of combining СсСАС10-у«сMMAE with vinblastine was studied. For this purpose, mice were implanted with I 540su tumors and treated with CAC10-msMMAE and vinblastine, either alone or in combination.

Treatment was started when the volume of tumors was 300 mm (6). 0/10 sustained relevant responses were observed with combination therapy, while 1/8 sustained relevant responses were observed with CAC10-USMMAE alone, and 0/10 sustained relevant responses were observed with vinblastine alone.

Table 7

Median TO (Fig. 6) (days to Combination in comparison with

Treatment of a three-fold increase with a single agent (P- tumor) value) (VinblastinghsACi0USMMAye | 77770551

Example 2: Combination of an antibody-drug conjugate CAC10-ptsMMAE with gemcitabine for the treatment of NI.

The effects of combining CAC10-cMMAE treatment with gemcitabine were studied in the same way as in the CAC10-msMMAE experiments. For cAC10-tsMMARE, a treatment regimen using 1 mg/kg, 4d44x3 was selected. On day 51 of the experiment, 9/10 sustained relevant responses were observed with combination therapy, while 0/10 sustained relevant responses were observed with CAC10-toMMAEE alone, and 0/10 sustained relevant responses were observed with gemcitabine alone. The experiment is on day 51 and is not yet complete.

list of SEQUENCES "1105 Bbvgais1e belebisya, Ip5. zkutetyaE, Evgodeiykh

Ziechaeaktv, BTIs secrekh, Napverekek "1205 COMBINED THERAPY USING CONJUGATES

ANTIBODY-DRUG ASSAY "130" p038-005138С "1505 05 50/79, 554 "1515 2007-10-19 "ivo" P5 B1/027,658 "512 2008-02-11 "150" is 61T/040,641 "15i" 2003 -03-28 "160" 34 "1705 Raiepksiv watkviop 3.5 "-1p" 1 "lashes" ZBi1 "819 dyk "shii3" Mav shiazso)ice "sho" "82ih Coding protein sequence "Your (R... 8511 "Both sach wass sach so sve szu skh dua ss bat Zb obo avu sob bod All i8 pip Iie biv pe biz bij Bek slu Reka 514 az Uvi Buz rgo 51 Ta 1 V 12 15 sa b aza aa bos bus avu Yaes zhseE bab Sas o ass eats at Chas gas Coll

EvE Ua) Bud i1ie bak was MmUuv Ata Bey s51U Tukh Tih Ra TvVE AvBrotTuye 25 25 for bat absa ass o goy db vach sao aza ss ucha bu da sk: sha Za as 145

TuUuzk Iie TNt Tur wai There was a battle Ppuz RZHO Biu biu biu Pe biu Ttr 118 35 40 3 av sus as svo ss doda vososdai vve as aiv tae av zdav ava Ko 155

Tu Tkr Tiz Tuh Rhko piu Bek si» AvpozhzAh pu Tud oavp bib Puv vva 50 5 bo avo duye vah dso aba sb asi dta zas asa ss bos o ades vsa des Es 40 puv o ziu iuv Via TBzhI Bec TVk Uvi dar TVtg Beh Beh Bach TVvK Aia RNe to 75 Vo aba svu obo au vas su vsz isb dau sas vs us Ches bat se Ko 28

Met bip pek bek bah Te) Tpg Beh bib Art tah Aza Uvi Tuk Ra o suv 85 50 5 tSYA sas Kab dug «as bas bdud ES asE bas soud bus saa vod ase se 336

Atia deP Tuk 51 Avp tTuk Ter Re Aa Tukh Ttrr BIU ZM b1U tah viv 1589 and 110 s ws zo st dev 351

Uai TBg Mai Beh Aia "viz 2 "112 117 "18 RET "13z My5 tudepice "do00z 2

Sip T1ie bib vo bib bip bek bTiu Bho bib Ua1i Uai uz Rho Siu ATa i Z 19 15

Bek ayu uv i1i8 bek Suv uv Viv bat biu Tud Trg Re TBzh AvroTuk 39

Tuk Iie TK Ttr uzi Bu bip was Bo biu biu Siu Gay biv Toro oiiv 35 40 s siu Ter K1ie Tu Rko biu Bek bBiu Azp tt Buv Tuk Avp o bish Buv Rie: zo 55 o

Was p1u pu Atia TP o Bez Tk Ua! Avr o tTBrobek des Zee TgoAid Vr 70 75 850

Mab biz cem Back bBes Gray Tk back 51 dvrotTve Az Uvi Tuk Re Suv

Ve Zo 25 viv AvBp Tu ypiu Ap oTtUuYu Tur Re Aia Tuh Ter 51 biIip biu ToXh bil oo ho5 110

Uvi Tvt Uvi Beh div 115 "gid" Z "11" 15 ki12y DNA "13 Myv possyiiinav "apr Z kasietastaya szdeos 15 "g10ykh "115 5 "12" RE -2132 Myv shivschtiya "8005 v du tuyu Tuk YItie TiB i E ii in.

"IJ" 5 "from 51 kto" PE "riv Myv mizsiiiv "4005 5 iodasstato ssdozachseua bazsvsseachu Zabaaszade achkssaaschoed o 5 sip b "-1і5 17 "Ey VVt -213z Mov taksyvv "OP" b

Tkv tiv Tuk Robi Bei 51U Av oTVh MPue TUuK Av viz Tu BBe pui z 15 15 sh1U "In 7 kepi" ey ay". Dak "13 Myz tiysvii ov "uz 7 oh , shi : yah sakachsavnst asspakosas ssas ka "vii V "ETih 8 che RU "zha" Mi shivsyvtsa "OO I

TtUuk ZBU DE Tuk Tzhv Bie Aza Tut 1 5 "ERY OZ "Bim 333 "vii DNA "35. Moz spiadsaise ey kEai" Coding score sequence "ia SR; . 333) "kapa v spas as: sya sp aso shea sb ssv des Ks BIYA oso Java bo sv dat 18

VZ oYie Uvi ba TB Bit bek oRrgOo Aiv be Bey AT Uvu Bak Bevozhshiu i i 19 Iii sza apa se or vie be be sYas avu uuss avds sav van seb pub BE CHAYE 96 bipo Ah Aba TpE yiev be Suv U Aba Bek pip bek Chai Azov Be svo o EE zo des bas avose abs atga aas bab bas osav saYa aaz ssa was oz psa sov How

51 u vro beg Tuk Mebye Avp tiv Tudk ip bip Buv Rub lu bij rgo REb 35 40 45 zaa yabs ss bab chos Zzsa bos zab sta za bsi pub abssossa sob 192

Was in pes i1ie TU Via A18 Bek Ayep wai Zi beh siu Thie Ro AT ho 55 vo va ESE addr sce vog Fa ies pad yasa Chas to aso sts ays osatb sah A

Agu VBe Zeh Bi Zek 3Ziu bat siu Tnt o AvYu vve tru Sem Avip Ti16 NIV 65 7 75 po sob chu Chas sabo 439 dat Ches dev ase bah zo baye sad saz voi ad 255

RZHO wai bmy bij bij Avr Aza Aia Tv otuk Tukh Suv IV siy Zek Av vya zo 5 two tea osa bu all pos sei zaCha ss zss azu hundred two vo zve 335 sa Avr o rho Tzhr tah Ble 5iu biu bij tTrvzh Puv Be B was 135 her 110 "YO" 10 "VI 1 "tt? рRET hЧа13" We luvsyitse "00 o

Ava her Uvi (eats Ta biv Beh Rgo Aiba 5vu Pep Ala Uai Veza oAu i 5 15 15 ip o dka Ala Tezh tiv bek Suya Buv Aiiv Bek biy Zeb Uvi Ave o Bak dar 29 V Zobr dvo bej TUB Mei Bai TkKr tuye savzosev BUuya Rho bi bii bo Rgb for 40 45 tspuUuv Mai pes ii tuye vis Via bZeit Avp opets si Beh BI IK Ro Aga 50 5 BO

Aha rRBe Zeg biu dec Ziu Ves biu Tbu der Bbe TB cem AvBloiiv No ee yah 5 ay kozh ee I, p

Echo cha1i 51 bi sich der Ada Aza LBzhЖ tuyu TUYU Suv biv bib Bveu Up

Ka Z z5

Aa Bko Thr Tazh Ve shu biu pi TNK obuya vo zam tiv o Zuv o vav 119 "eV ti kvii" 45 "her" VYK kaM3" We sewed "aOoh 11 zvobosades vvachsotsevcha susetaseoot zahzusetasvz byva ah

"10" 17 "rii" 15 "212" VNI "13" My Shchyzvenita "801" 15

Was Via Beh bipobee Ovi dvr ble Avrosiu Dar bek Tuyuk Mei Dal 1 5 16 uz "210" 13 "b1ih 8 "2102 Dec "51і3" Had spikes "io" 1

Fseadsvssya vEbtalavstot 1 "vii" 14 "e112 7 "im RE "Vii My shtivsmMichv "400" 14 dia Afa Beh Vvpobem biv ek i 5 "viim 15 her 27 "vii2j DEC sa Mov shizhsyaTOie "oh 15 satesvasasa abtsvozchavst Cheochas 7 "ip 16 "kad o "P12" VV "neck" Myv shavsoitsie "ap 16 beep beep Yaet Ap b3iu vro Vo Tkr TE i 5 "210" 17 "112 Z "vis" DEC "13" Mov vyvstiche "ik. "1 o Komuyucha Vilek posldeovnistv "pra (r. 375) chas 17 chat che avs ska de baz ss Zav Zscha Chas sa sasv sach ke otsia 418 vich May was Ge); o Uaii bi beh si b3u po ZeOa Ua b Bkos stu Du

U Z 19 13 os ska apa sgo sob sa dsSa se OB uz all o vss o s5s az gives tae 6 sheh Teiy du ey Bek Suv Aza TE Bach Siu Re TB RBe bei AYU TUuK 25 30 tat or vas soch es sa svu boi ssa sov o vach dos sb Chad sob zha 145

Tukh Meyui dv" Tr UI Asya 56 Ro rho biu yuv Ada Bets bi Ttr lev "0 ka sya ss as z3av aas ava chos vas cho bas yasa asa zaz s az dev 1975

Ziu vve 11 Aha AvBooiiuv Aza Aa b1u tuye Tpg TtVveE biz rBe sec action -o BV kops osse osse vizu to bases vops ass ovo Sssoach dycha os osa atsoe all 240 century in Mee S1u Jo Rv TNE Her ZeKE ALgo Azr o Avr zach was ego TV and 75 in

EF sab sab sa sab sas aso sb voza sb ЗчвЯ sas vas aso ves ne How

May tuye her pain Me: AvposbiYe ieo Azh Aza biy Avr Beh Diya TP Tuk 85 za Z taye sii cho adv da sso es kaye za oaas se baYe bas be dos aso Zo

Tuk Suv DIa Aga AvvoOvBto Ro Tukhk 51uU AvO ho Viv Tuk Tukh Diyi MeE that 135 110 pas bas kosa sbshe sza sov ass soa ps oass ze pos sa B

Achyu TU Tr b1iu biv stu Tr ovvur o Uuki TVU Udi vu Zes 115 126 125 "10 18 "viim 125 cheia" RAH "ih We povzsmichlya "300" 18 biz aii uz tsem Uvi bish beh bEu 51U piu bey Ubi biy Ro bIu BI ; 1 of 15 of them

Pekotseo dk Theo bek Su with Tk o bvh biu Bae tTryu Bye Beh Azov otTuye 2O 25 for

Tu Mee Azy Tur Uvi Asu biv rea Bko vi Buv ia Tem biz Tkrobeo 35 40 s zi ElLe shchi ygu dz Buv dia Av» Siu TU TNE TvE si: rChe bek 818

YOU 5 BO pvi maei Meh: Z azhshsh RBe o otTvzh ii 5BeE Aku Avrodav bag osa dek oi 55 79 1 za

Kv» tuye Mem obi Mei Azp otyh ivy Aka Aiv o bib dvy be div o tve tuh 85 zo 35 tTuh su biv ygZ Ave Eko Rko Tukh 519 dai Rgo Niz TUue Tu oAIv Mach 100 105 ii

Avr o tuye Tthr bi siy siu TVh Beh Uai Tdh Uvi bek Bek 115 i20 125 "vi0x 189 "115 18 "1" DEC "ah We tovsigOoe "4005 189

ZaetastatE is і "air o eb "8115 5 "ій" SRET "ій" Mishzh shtivsy)e kaobz 20

Azr oTukh Tukh Meb Avp 1 in "10 1 "81i2 57 "10" DNA "21832" Myv shchyvsymyav kapo" ii

Ebvaskodav збавцацевая Едоссасаса возачьвсв Zbbevsskoye dzaevode 7 "their and "eyelashes" 15 "hiy BEtT "viz" We piasazhiv. "005

RE Ii18 Aku dvy buye dia Asia Slu Tud TB Ta ziv ve vek viv BV 1 Z Chho 15

Uvi Mek axis "RIizh 2 "211" 835 "riv dyk "rod" Language shiovomiche "aypym 23 zchaksiseset vEsodsaasss ssavtstassai zskasssas vo ta "VYam 2 s211zh 14 "viit VK "gIiZ3M Mav shshivsyuov

"OO" 25

Avr ortho Bu But si Akt Bto Niv TUYU Tu Aiv Mei Ave tuyu 1 5 10 "Ii05 25 kii" 833 kva PK "az Moz siesiiyv "aoh "giv Coding protein sequence "aha Jur. (333) "OO" 5 chas vi shcha sto asse svat sreb osss dob ss ba os po se osot ČU 8 dzv otia Uvi iey Tv bij bek REo Aia Hek Me dia u8v1i Zeh o yvy 1u ! 5 15 15 sza vu zssb ais voy sov spas ved dos vas vay vas is vat oasa bos za -5ip aAtYa Ata TANE TIE bek Sui AkKoa Div obav Buv beh Uaii bej Viv bek 2 25 B; shchue bass vaj pub vba sab bap bab saz svu wav osa Fa sadfossvo sis 144 siu Tuk Av Tuk Mek Mi Ter Tukh b5iy bit Muz Aza stu pil RKO Bk zh 4o 85 av ss v ab sas sob vsa sbo o azo sta chaa he zba uko ss dos Mach

Muv yny Gay her Niz Sei Aza Zak ZVO without 815 be biu Mag Bko Aiv

ZY 55 bo zup Ks gave zZs az zchaa oi chChcha vovz two ss aos ss vas ake se KV

Aka pe beh Siu Zv shiu ek Bi Tv Av o ra TNh be da Tie NIV 05 7 75 Vo. sec tsiZ zad dChah swo pat dob sv aso Bas bas Bus bat sab sad och eV ko Uai biz biz bi: Avr A1i1a beh TVk Tu Rukh Su bij Ni Sheh si1Uu

Ka o 35 pay st sov her s asYa4 Kos sas ss chdab asa az ss dav vaba ava 33 uv Oetsd go Bpe tp ve zu bezh biu TV duv mem Bim ble uv 100 105 t10 "210" 76 "shi" TB "hiy" RET "iZm Mia5 schizoeclia "Oh v

Av oi1ive Mai Pev Ts biyuya Beh RTo Ava Zach rey Aza Uai Be Bemosbi" y 5 15 15 bip vha 815 TVUu Gie eh Sub Ako Aa bes gu bek Uvi Beh dia bek 2 25 Zo si Tuk Avp o Tuk Mas Ni Tur Tuk Sip osbiy pu ' Aza p1u bij vka gko 0 45 yPuv o yivy Bei oi1te Niv Without Atia bee Av this siy obav o su Ua) BEZ Aia zv 59

Aka Va bak o ptu bak bi Vet bi TE o Avr Be Teh em Dva i1v NIiZ

TO 5 va

Bzhho Chai bish called Bii Ar o Aza zes TAK Tut Tuh Su ZEi Ya bek otu 85 ZO 5 ("VIL bem vho re Te Bbe biu des piu TVh Puv em b1I div was that vo5 p "105 97 "Mu" a "tiy ChK "2135 Ma pivom "00" 57 vchochlosvzoasa zachyaschssau Sosaitsvode sAabaavbasa boasaye 45 "shii eV "her" 5 "vyh VE h«v1iZ" Mav shshivsoio "005 o

Aku iz Beh Mu bek Uaiii Beh Viv bek o biU Tus AvpoTuk Met Nav 1 5 12 I5 "210" 79 -21ih 81 "kiy" DNE chte139 Mya shvshiazstvia "8005 23 subosvesSse vesevavaes Ye yai srid" 30 "TE 7 "i2h tu " them We shoasilo5 "OPO" 30 eat Viz Bek Ayap GPvo siyu vet 1 no kii 31 "y g "vig" DdNE "213 Mav shiv ia "4505 81 y svyasasvued opavastoss vossvoa Z

"v1ykh Z "vi a "v122 RVT "23" We vovsrivya ka" 32

Sip Niv back biu BIB Petz Bko Rde Tek 1 5 "2105 35 "lashes" With "at2x RT "rah Pposcho zariyee "300" with

Aiin Beh TBg Buv b1u Bo bek tuai rve Ro ate ABa Buo bek bak puv

U ii Z 10 15 bek o tTVBk bek bi bi Tv div dia bez bi Suz bey uv Buv BErotuye roar! х5 50 vve ro bij ro Ma tTnu Uzi Zvu Tzhvr Ai bat Z1U ATa her Tygobeh 35 45 a zi» Uvi nish TB Be Re Aa Uvi rei vii Zeh bek su Sem TuUuk BV 5O ZV 50 ishi bak obet Uvi Uvi Taj Mai Ryuko bej Bach Zeu Gay bi LZH Z) TE to 75 I tuyu y1iae Suye Av Uzi Avp o Kiv GPuvg Ryb bah VE TV Bush Uai Dash cm 5 vo za yuuv Uvi Si Rko Buv Beh Suv Dvr Buv TVu Niz TV Su Bo Bho Suv 195 ї05 110 rho Aiva o rho Si Bei pei obi STO Rgo Bezh Ma Be Gay Re bgo RKO ee to 125

Buv Echo su Avroijh Bey Moi ii ves Aa Tnh Rhz biz hi TvI su

I130 35 140 chai Udli Mai AvB oUai beh Viya Sb A5rorho bij Hai bu Re Av) Tr kVO 55 tep tuh Uai Avr shiu Uai bio Uai Niv Ei Aia Buv Tv buu Echo ha sty 58 Her 175 sich bip tuh Dwop obah Tl TuUuK Akta Uai Maii BZh Maii Bay TNK oMai izh) 80 1855 IVO

Niv Ii Avo tTko iets Aa oBiu Muv Si Tukh Guz Suye ruv Uvi et Av 135 239 205

Buz Viv yzy Ro from RBso y1i6e bib Guv TNJ TJiv bek was Aia Puv BZhu 215 15 g2y piv rho AkYa biv BEoO bik chzai Tukh TBZhZh pev ro rko 5 AKU ABOU IM 223 235 235 28

Without them pukh ap 50 Uaiii bek Bey Izh Suv Pec uv» Buv BUYE Rpe tuye i yi V. ; in ta5 25,225

Tgo vah Avroiie ATa Uvi pip Ter obi Bek Aelp bi siy Bkgo siv Ava 265 ato

Avp otut Bu TV TpPE rho RBEo Uai svi AvrobbE AvrovBiu VVE Bie reve a75 av -E5

Tez tTuk BVS Buk ce TK Uvi Ar osuz Best Aka Tzhrobziv biv b1iUu Ap 230 295 3650

Chai ree bat Suv Bezh Uvi Meh niv bis But sei piz V Ni Tuh Te 305 310 ZI5 zvi biz Bud begobem bak opea beu Ro b1u Bud 325 Zo "2105 34 "11" 106 "sVRЯ2 BET "213" Noto varivyv "poh 34 tTvs hi div Aza ro Bek Uzi rRpe Iiye Re rtb kb Zeh Avr Biy Siv yi V 16 15 yez ope Beh Bu tTve viv Beh Uvi Uvi Sub Bei Hey oAvp o dva Re tuye 2 Kaya Zo gro Aga osiv Aza Puv Mai bip Ter obu HMai Ar o Aa oAtTa Sei o bip Bek 38 40 45 su Avd Bach iya siyu Beh Uai TE sti bil AvroBek uv dar o Yavk Tu

Tuzh bek el bet bej Te ces TBu el obZakobuv harp Avo Tudsh biy Buv

With TO T5 in

Niv Muz Uai Tukh ABa Sua biv Mai TV Vb biv BI bo; bek shei rEb

VV Zo 5

Uvi TVE Buz bet Ra Azp ATO Sru 010 was 100 105

AND

" - -25 FIGHT WITHOUT PICKING WITH "I. Without pike

E 4500 - "On SAS O-SMMAE and this Z ee AVUO g BOV te -4- AVMO with 8 500 1 | ; SASTO-USMMAE in 200- and in OI 100 5 Sha". SHY usya 0 rn IY ' 1» h still t aa pr and about this ha 50 75 So

Two

V. is U

ТЕ 1200 ж: ее 00 Deglycation х 1000 4 g ИЙ "En сАС10-УсММАЕ is | Y. "At AVUO 800. I | ; y y -F-AVUYU I 8 in 4 ; JSC SASTO-USMMAE

I ; Э-Ф - 400 / че 5 А shchi

Not ode 1, but smear t cha 0 10 20 30 40 50 60 70 80

Fig. 1

And, 5,500 | I ey 0 Without treatment t That "their tot sASIO MMA

E 600 M. nn Hempitabine 500 is I o -frn Hemcytashi

X 400 4 / Ir. SASTOMEMMAE sh 300 7 -l ran, t 200 4 S MI

IN se 0 10 20 30 40 50 60 70 80 90 109

What?

IN.

TE 190 Z T tho Without treatment in 1000 4th t DU in-sASTOMoMMAE

KE Z This is the sur Hemnytabii 5. 800: in" as "ve Hemyitayein i 5 voi and 5 Ka sASTOKHSMMAE z shchyla i- 200 i ) khan y

And what else 0 10 20 30 40 50 60 70 80 80

Fig.

A. g 1200 5 ! that Without treatment and 1000 7 r - SASTOAEMMAE

Yes! not -- SU same - 94 i: SASTOUSMMAE re - Ky

B lov | Khai ku with Z 0 20 in 50 vo

Di

V. and 1200 and dk Without treatment: z z cha BAS1O-SMMAE

E Eat Y an SU i

There are 500 I a. I SASiIiAeMMAEE Fr. pi t v Rody - yo her v Ya y 7 ot ev-v-o-eva-yaavvie 6 50 40 bo vo 0 120

Days

Fig. WITH

A. is 1200 | what -ve Without treatment 1. and "ek SASTOMMMAE

E And there is also "-e PnnOoreloin

Z 00 1 y shen Vinoreyabin x zh voi i / SASTO-USMMAE che: i chek - yu- i i Z shk, I r o 20 40 bo 80

WHERE

V. - 700 with - Without treatment there is Sha "and САС10-UsMMAE and 500 MORE. St. Vinoreyadbin x 400 | ! And tave Kivorehbin m - for hi ee ih; and. What?

With ze / / SASTOUYEMMAE that 100 "and you

At 20 yes BO 80 on

Days

Fig, 4

D.- 1200 0 women Without treatment 1000. ,. ote сАС1ОЕММАЕ х вой ШИ! and D «me Doksorubitsnya i K i sce DOKSoruvshchyna i ia ia ia ia ia ia ia ia ia 6004

E 200 4 Rai m

Hook | as well as "0 ai bo vo

Days at 1200" for Without treatment

With her in SASTOMSMMAE! "year 0 Doxorubicin 5 500 i -e ZHUyuKxorubischin i voi /i SASTOLEMMAE 8 ayu chi TI a shchi i 5 o fest Euro) o 20 40 50 va 100

DV

Fig, 5

Without treatment t- 1200 5 Binblastin 8 , "She 0 violet vo01000 4 chi

Bo m E

In and in the sheet

Yari 8; "Mne s 6004 And /y sSASITO-USMMAye 400 with , How. and : how

About festins:

Not 40 days either.

FIG. 6 more

Dozhksoruzvitsiv

Without swearing I Hemcitabvi with ;

Yes! in : -ko Hemtsyhabin - 000 5 yak "in sASIO-UOMMAE S my ah)

E woo 4 | t te p2o mg "Fakhz) I SU i; Hamtsitabyk: и вой Я MO я есАМТОУЮМАЕ о че и в шчи

RAN oh those about inst b 20 and and what

Fig, 7

Without treatment x Hemcntans

The same THemcytvbinoe

Zh t 1200 5 c

In 1000. , -8- SASIO-TeMMAK)

With ! and 500; tre

Because I am. SASTO-toMMAK) sho 00 yes; se 200 - shchi / in o) then 0 for a shsh 50

Fig. 8 : | rez treatment xx

SAME 1 4 - I 00 tt that 58! 1-2 we САС1ОМСММАЕ С as ЧИ

EE rt ton sASIOUSMMAE eat Fi

ZE 604 OT et oASIOCHSMMAE 06 ne 0 dedho sv VO and vysh --SASIOSMMAE OZ km 0 othio ki and z Larin sha i sht i 1 st Sha kt schi

What days MV! i - o 70 20 30 ab 50 60 70 Vo 96 300

Fig, 9

Claims (21)

1. A method of treating Hodgkin's lymphoma in a subject, comprising administering to a subject in need thereof, a chemotherapy regimen comprising doxorubicin, bleomycin, vinblastine, and dacarbazine, and an antibody-drug conjugate compound, wherein said compound con The conjugated antibody drug is an antibody against SHUOZ30O conjugated to the compound auristatin. 2. The method according to item I, in which the delivery of the specified antibody-drug conjugate compound is carried out during the treatment cycle, and the total dose during the treatment cycle is from about 0.1 mg/kg to about 3.8 mg/kg of body weight subject 3. The method according to item I, in which the delivery of the indicated antibody-drug conjugate compound is carried out during the treatment cycle, and the total dose during the treatment cycle is from 0.1 mg/kg to 2.7 mg/kg of the subject's body weight object 4. The method according to claim 2 or 3, in which the delivery of the antibody-drug conjugate compound is carried out in the form of a fractional dose during the treatment cycle. 5. The method according to claim 2 or 3, in which the delivery of the antibody-drug conjugate compound is carried out in the form of a single dose during the treatment cycle. 6. The method according to any one of claims 2-5, in which the treatment cycle is three or four weeks. 7. The method according to item b, in which the indicated scheme of chemotherapeutic treatment and the indicated compound of the antibody-drug conjugate are prescribed on days 1 1 15 of the treatment cycle, which is four weeks. 8. The method according to item I, in which the indicated compound of the antibody-drug conjugate is administered in a dose range of 0.2 to 1.2 mg/kg body weight of the subject in each dose. 9. The method according to item I, in which the specified compound of the antibody-drug conjugate is administered in a range of doses, which is from I1 to 1.5 mg/kg of the subject's body weight in each dose. 10. The method of any one of claims 1-9, wherein said subject is treated with approximately mg/m? doxorubicin, about 10 U/m" bleomycin, about b mg/m" vinblastine and about 375 mg/m" dacarbazine on days 1 and 15 of a four-week treatment cycle. 11. The method according to any one of claims 1-10, in which the antibody-drug conjugate compound 1 chemotherapy regimen including doxorubicin, bleomycin, vinblastine 1 dacarbazine is administered during a treatment cycle of three or four weeks , and no additional anticancer agents are administered during the treatment cycle. 12. The method of any one of claims 1-11, wherein said subject has relapsed or refractory Hodgkin's lymphoma and has not previously undergone treatment using said chemotherapy regimen. 13. The method according to any one of claims 1-12, in which the antibody-drug conjugate compound is administered during two or more cycles of treatment. 14. The method according to any one of claims 1-13, in which the auristatin compound is conjugated to an antibody against SYUZ3O by means of a linker that is cleavable under intracellular conditions so that cleavage of the linker releases the auristatin compound from the antibody in the intracellular environment. 15. The method according to claim 14, in which the compound of the antibody-drug conjugate has the following structure: ne o o sn, on tA i) N N M, M M o o m "i M KASA | (c) | basic o osn, o mansi-k H (9) p 5 where tAbB-5 is an antibody against SOZO, and p has a value from 1 to approximately 10. 16. The method according to any one of claims 1-13, in which the auristatin compound is conjugated to an antibody against ХО3О using a linker that is not cleavable under intracellular conditions, and the auristatin compound is released by degradation of the antibody. 17. The method according to claim 16, in which the antibody-drug conjugate compound has the following structure: IV) tAb not 5 (c) (c) sn, n N och M,, M M Y and 9 (c) base. o osn o on p 5 where tAbB-5 is an antibody against SOZO, and p has a value from 1 to about 10. 18. The method according to claim 15 or 17, in which an average of 4 auristatin drugs are conjugated to each antibody. 19. The method according to any one of claims 1-18, in which the specified antibody against SYU3O is a chimeric antibody AC10 or competes for binding with a chimeric antibody AC10. 20. The method according to claim 19, in which the antibody against SHUOZ3O is a chimeric antibody AC10. 21. Use of an antibody-drug conjugate compound, which includes an anti-SIZO antibody conjugated with an auristatin compound, for the production of a drug prescribed in combination therapy using a chemotherapy treatment regimen that includes doxorubicin, bleomycin, vinblastine, and dacarbazine for treatment of Hodgkin's lymphoma in a subject.