WO2014112898A1 - КОНЪЮГАТЫ И МАЛЫЕ МОЛЕКУЛЫ, ВЗАИМОДЕЙСТВУЮЩИЕ С РЕЦЕПТОРОМ CD16a - Google Patents
КОНЪЮГАТЫ И МАЛЫЕ МОЛЕКУЛЫ, ВЗАИМОДЕЙСТВУЮЩИЕ С РЕЦЕПТОРОМ CD16a Download PDFInfo
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- WO2014112898A1 WO2014112898A1 PCT/RU2014/000015 RU2014000015W WO2014112898A1 WO 2014112898 A1 WO2014112898 A1 WO 2014112898A1 RU 2014000015 W RU2014000015 W RU 2014000015W WO 2014112898 A1 WO2014112898 A1 WO 2014112898A1
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- compound
- dihydro
- trioxo
- modified protein
- thiazepine
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- VKUFAIZUNWXRHO-UHFFFAOYSA-N CN(C(C=C1)=C)C1=O Chemical compound CN(C(C=C1)=C)C1=O VKUFAIZUNWXRHO-UHFFFAOYSA-N 0.000 description 1
- 0 CNC(CCC(C(ON)=O)NC(NC(CCC(OC)=O)C(O*)=O)=O)=O Chemical compound CNC(CCC(C(ON)=O)NC(NC(CCC(OC)=O)C(O*)=O)=O)=O 0.000 description 1
- FKEGWIJQFKFYLY-UHFFFAOYSA-N CON(C(CC1)=N)C1=O Chemical compound CON(C(CC1)=N)C1=O FKEGWIJQFKFYLY-UHFFFAOYSA-N 0.000 description 1
- WPHLEAPZUZLAOL-UHFFFAOYSA-M COc(c(OC)c1)ccc1NC(CC(N1OC(c(cc2)ccc2[NH-])=O)=O)C1=O Chemical compound COc(c(OC)c1)ccc1NC(CC(N1OC(c(cc2)ccc2[NH-])=O)=O)C1=O WPHLEAPZUZLAOL-UHFFFAOYSA-M 0.000 description 1
- KFAXVDZNMASJOM-UHFFFAOYSA-N Nc(cc1)ccc1OCC(ON(C(CC1)=O)C1=O)=O Chemical compound Nc(cc1)ccc1OCC(ON(C(CC1)=O)C1=O)=O KFAXVDZNMASJOM-UHFFFAOYSA-N 0.000 description 1
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D495/14—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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- A61K39/44—Antibodies bound to carriers
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D281/16—[b, f]-condensed
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- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/555—Interferons [IFN]
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/70503—Immunoglobulin superfamily
- C07K14/70535—Fc-receptors, e.g. CD16, CD32, CD64 (CD2314/705F)
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- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2887—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD20
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- C07K16/32—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against translation products of oncogenes
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- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Definitions
- the invention relates to medicine, in particular to oncology and immunology, to new compounds that bind to the CD16a receptor and their modified proteins (conjugates) used to induce gel-dependent cellular cytotoxicity and thus remove from the body a specific target i pyrnibi cells, for example, cancer cells or ayuimmune lymphocytes.
- the invention also relates to a method for producing conjugates, pharmaceutical compositions and drugs. containing modified proteins (conjugates) for the treatment of cancer and autoimmune diseases.
- the Fcyllla receptor belongs to the group of receptors responsible for the binding of Fc-fragmentite antibodies.
- CD16a is extirpated on the surface of ⁇ -cells (killers) and macrophages and is responsible for the induction of antibody-dependent cellular cytotoxicity (ADCC), interacting with 1 ; a c-fragment of a cell-bound antibody.
- ADCC antibody-dependent cellular cytotoxicity
- ADCC antibody-dependent cellular cytotoxicity
- CDC complement-dependent cytotoxicity
- anopuse is one of the main mechanisms for the destruction of cancer cells from the body.
- autoimmune diseases mediated by autoantibodies such as autoimmune polyendocrinopathy of the first type, autoimmune hemolytic anemia, idiopathic thrombocytopenia, hemolytic disease of the newborn, and so on. That is, antibody-dependent cellular cytotoxicity can play both a positive and negative role in the development of pathological processes in the human body.
- Autoimmune diseases are a group of diseases that develop as a result of the development of an immune response against healthy tissues of the body and lead to damage to these tissues.
- immunosuppressants are used to treat autoimmune diseases, suppressing the body's immune system as a whole. Selectively suppressing an autoimmune response would allow the existing I BCHHO to reduce the incidence of treatment side effects.
- Antibodies have long been used for targeted destruction of cancer cells. Examples include rituximab, trastuzumab. tseguximab and many other antibodies that have targets on the surface of cancer cells and act through compliment-dependent cytotoxicity and antibody-dependent cellular pitotoxicity.
- ADC conjugate antibody-drug
- Such conjugates provide targeted drug delivery to tumors and their accumulation inside cells, adding to the cytotoxic effect of antibodies the antitumor activity of cytotoxic or cytostatic drugs.
- Examples of such conjugates are trastuzumab-DMl, an enhanced version of trastuzumab (Herceptin) (WO 201 169074) and a series of conjugates with auris gathia P (US 20120003248).
- An alternative direction was the strengthening of the intrinsic cytotoxicity of antibodies by enhancing the interaction with receptors that cause cytotoxicity.
- Roche has developed an obiputuzumab antibody with enhanced binding to the CD16a receptor. This effect is achieved by engineering glycosylation of antibodies.
- Obinutuzumab has dozens of times stronger antibody-dependent cell cytotoxicity (WO 2005044859, HA 01 009).
- Antibody-dependent cellular cytotoxicity is one of the main mechanisms of the cytotoxic effect of antibodies that bind to the antigen on the surface of the target cell via variable domains, while the constant part binds to the CD16a receptor on the surface of killer cells.
- This intercellular contact leads to the secretion by killers of hierforins and granzymes.
- the former form pores in the cell membrane of the target cell, while the latter activate caspases and other apoptosis molecules.
- the CD 16a receptor is a member of a large family of Fc receptors that bind to the constant domain of an antibody and differ in localization, function, and affinity for the constant domain.
- Alkyl means an aliphatic hydrocarbon linear or branched group with 1-12 carbon atoms in the chain. Branched means that the alkyl chain has one or more lower alkyl substituents.
- Alkyl may have one or more identical or different substituents (“alkyl substituents”) including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, terocyclyl, aroyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbnyl, alkylthio, hsteroaryl , aralkylthio, arylsulfonyl, alkylsulfoyl heteroaralkyloxy, anelated heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, anelated heteroaryl heterocyclyl, anelated heteroaryl heterocyclyl,
- annelated arylcycloalkyl annelated arylheroheoykenyl, annelated arylheterocyclyl, alkoxycarbonyl, aralkoxycarbopil, heteroaralkyloxycarbonyl or R k a R k fi a N-, R k a R k + i a NC ( ⁇ 0) -. R k a R k + t ⁇ NC (-S) -.
- R k a R k + i a NS0 2 - where R k a and R + i d independently represent a “kneading amino groups ”, the meaning of which is defined in this section, for example, hydrogen aum, alkyl, aryl, aralkyl, hetroaral, il, heterocyclyl or heteroaryl, or R k + i a together with the N atom to which they are bonded form through R ⁇ ' 1 and R k + i J 4 - 7 membered heterocyclyl or heterocyclenyl.
- Preferred alkyl groups are methyl, trifluoromethyl, cyclopropylmethyl, cyclopentylmethyl, egyl, n-nropyl, iso-iropyl, n-butyl, tert-butyl, n-pentyl, 3-pent pentyl, methoxyethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethylmethyl yuxycarbonylmethyl and pyridylmethyloxycarbonylmethyl.
- Alkyl means C n H 2 n + iNH - or (C n H 2n + i) (C n Il 2n + i) N - group in which alkyl is defined in this section.
- Preferred alkylamino groups are methylamino, ethylamino, n-propylamino, iso-propylamino and n-butylamino.
- “Ash Itelo” is a protein (immunoglobulin) synthesized by B-lymphocytes in the body in response to the ingestion of a foreign substance into it and having a specific affinity for this substance. They are an important factor in specific humoral immunity. Antibodies perform two functions: antigen-binding and effectorpuyu (cause one or another immune response).
- “Autoantigens” - free molecules of substances or molecules in the composition of cells, organs and tissues, which are recognized under certain conditions by the immune system as foreign and, in connection with it, cause a cellular or humoral immune response from their body. These are, as a rule, normal proteins or protein complexes (as well as protein complexes with DNA or RNA), which are recognized by the immune system in patients with autoimmune diseases. Such antigens should not normally be recognized by the immune system, but due to genetic factors or environmental conditions, immunological tolerance to such antigens may be lost.
- the so-called natural autoantigens can possess the properties of autoan gigens.
- proteins the synthesis of which begins after the maturation of the immune system (sperm, milk); macromolecules of organs separated from the immune systems with a histohsmatic barrier; macromolecules in the nucleus and cytoplasm of cells; macromolecules with the presence of new foreign determinia and pynn due to the action of endogenous (immune complexes, necrosis, inflammation) or exogenous (temperature, chemicals, including drugs, microbes and their toxins, viruses, etc.) factors; embryonic proteins with renewable synthesis under certain conditions (for example, with tumors).
- autoimmune diseases include, in particular, autoimmune polyendocrinopathy of the first type, autoimmune hemolytic anemia, idiopathic thrombocytopenia, hemolytic disease of newborns, multiple sclerosis, autoimmune thyroiditis, etc.
- Autoimmunity is a process and related diseases caused by the acquisition by the immune system of the ability to recognize the body's own antigens (autoantigens) and to respond to them by the formation of autoantibodies or autoimmune T lymphocytes.
- An autoimmune process is a process and related diseases, the basis of which is tissue damage due to the effects of the interaction of autoantibodies or autoimmune T lymphocytes with autoantigens.
- “Onyugag” is a protein modified with chemical compounds, an al igen, or an antibody. Conjugate formation is one of the important stages of enzyme-linked immunosorbent assay (ELISA). During the formation of the conjugate, such an optimal method of introducing the chemical compound is selected so that the conjugate component, antigen or antibody, retains its biological activity — atheininity and antigen binding activity, respectively. The ability of foreign compounds and metabolites to enter conjugation reactions depends on the presence of certain functional groups in their molecules.
- “Medicinal product (preparation)” a substance (or a mixture of substances in the form of a pharmaceutical composition), in the form of tablets, capsules of injections, ointments and other goyuv forms intended for the restoration, correction or change of physiological functions in humans and animals, as well as for the treatment and prevention of diseases, diagnostics, anesthesia, contraception, cosmetology and other things.
- “Receptors” (from the Latin recipere - to receive, to recognize) are biological macromolecules located on the cytoplasmic membrane of the cell or intracellular, capable of specifically interacting with a limited set of physiologically active substances (ligands) and transforming the basis of this interaction into a specific cellular answer.
- Solna 1 s products of the addition of a solvent to dissolved substances; a special case of solvates is hydrates (solvent is water). Usually, solvags are formed in solution, but often (upon cooling the solution, evaporating a solution of 1 spruce, etc.) they can be obtained in the form of crystalline phases - crystalline solvates.
- “Pharmaceutical composition” means a composition comprising an active component (modified protein) and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, excipients, distributing and perceiving means of delivery, such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, ⁇ spruce sweeteners, perfumes, flavor ators, antibacterial agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on the nature and method of administration and dosage.
- pharmaceutically acceptable and pharmacologically compatible excipients such as preservatives, stabilizers, fillers, grinders, moisturizers, emulsifiers, suspending agents, thickeners, ⁇ spruce sweeteners, perfumes, flavor ators, antibacterial agents, fungicides, lubricants, prolonged delivery regulator
- suspending agents examples include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, for example, parabens, chlorobutanol, sorbic acid and the like.
- the composition may also include isocyanic agents, for example, sugars, sodium chloride and the like.
- the prolonged action of the composition can be achieved using agents that slow down the absorption of the active principle, for example, aluminum monostatsarate and gelatin.
- suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohols, and also mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as tyloleate).
- excipients are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate and the like.
- choppers and dispensers are 1 starch. alginic acid and its salts, silicates.
- lubricants are magnesium ci eapaT, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.
- a pharmaceutical composition for oral, sublingual, trandermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, in the form of a mixture with traditional pharmaceutical carriers .
- Suitable unit dosage forms include oral forms such as tablets, gelatine capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and traysbuccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous intranasal or intraocular administration forms and rectal administration forms.
- Pharmaceutical compositions are generally prepared using standard procedures involving the mixing of the active compound with a liquid or finely divided solid carrier.
- “Pharmaceutically acceptable salt” means the relatively non-toxic organic and inorganic salts of the acids and bases of the present invention. These salts can be obtained in situ during the synthesis process. Isolation or purification of compounds or specially prepared. In particular, base salts can be prepared on the basis of the purified free base of the claimed compound and a suitable organic or inorganic acid. Examples of salts thus obtained are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valsriates, oleates, and almitates.
- Salts of the claimed acids can also be specially prepared by reaction of the purified acid with a suitable base, and metal and amine salts can be synthesized.
- the metal salts include nafia, potassium, calcium, barium, zinc, magnesium, lithium, and aluminum, the most desirable of which are sodium and potassium salts.
- Suitable inorganic bases from which metal salts can be obtained are hydroxide, carbonate, bicarbonate and nafium hydride, hydroxide and potassium bicarbonate, potash, lithium hydroxide, calcium hydroxide, maple hydroxide, zinc hydroxide.
- organic bases from which salts of the claimed acids can be obtained amines and amino acids having an additional atomic basicity to form a stable salt, and suitable for medical use (in particular, they must have low toxicity) are selected.
- Such amines include ammonia, methylamine, dimethylamine, three methylamine, n) guides n, diethylamines, triethylamine, bepsilamine, dibepsilamip, dicycloxylamino, iierazia, ethylpiperidine, tris (hydroxymethyl) aminomegan and the like.
- tetraalkylammonium hydroxides for example, such as choline, trimethylammonium, tetraethylammonium and the like, can be used for salt formation.
- amino acids the main amino acids can be used - lysine, ornithium and arginine.
- An object of the present invention is to provide novel compounds and their modified proteins (conjugates) capable of interacting with the CD16a receptor used to induce antibody-dependent cellular cytotoxicity and thus remove a specific target group of cells, e.g., cancer cells or autoimmune lymphocytes, from the body.
- conjugates capable of interacting with the CD16a receptor used to induce antibody-dependent cellular cytotoxicity and thus remove a specific target group of cells, e.g., cancer cells or autoimmune lymphocytes, from the body.
- R1 represents (CH 3 ) 2 N-
- R3 as a terminal substituent is unsubstituted aminoalkyl
- a R4 represents H or CgC 3 alkyl.
- R1 represents (SIc) 2 M or
- More preferred compounds are:
- the subject of this invention is a modified protein that is active against the CD16a receptor, co-encoded with a modifying compound having an affinity for the CD16a receptor selected from a compound of general formula 1 or 2.
- a modified protein (konogat) active against the CD16a receptor obtained by reacting the protein with a modifying compound of general formula 1 or 2.
- a modified protein derived from an antibody and a compound of general formula 1 or 2, wherein the antibody is rituximab, trastuzumab, or cetuximab.
- a modified protein Kerat, which is rituximab modified with a compound of the general formula 1 or 2.
- a modified protein Koin.iora i
- trastuzumao modified with a compound of general formula 1 or 2.
- a more preferred is also a modified protein (konyogat), which is cetuximab modified with a compound of the general formula 1 or 2.
- a modified protein which is interferon alpha, modified by a compound of the general formula 1 or 2.
- a modified protein (konyogat), which is the main myelin protein modified with a compound of the general formula 1 or 2.
- a more preferred is also a modified protein (konyogat), which is a Clq compliment protein modified with a compound of general formula 1 or 2.
- the subject of this invention is also a method for producing a modified protein (conjugate) according to which the protein is reacted with a compound of the general formula 1 or 2 dissolved in an organic solvent, for example, dimethyl sulfoxide, in the range of molar ratio from 1: 3 to 1: 100 in phosphate medium saline buffer solution (pH 7.4) at room temperature with constant stirring.
- an organic solvent for example, dimethyl sulfoxide
- a subject of the present invention is also a pharmaceutical composition active against the CD16a receptor, containing a therapeutically effective amount of a modified protein (konogat) and a pharmaceutically acceptable diluent, carrier or excipient.
- Pharmaceutical compositions may include pharmaceutically acceptable ⁇ zhstsipisnty.
- pharmaceutically acceptable excipients is meant pharmaceutical diluents, excipients and / or carriers.
- the pharmaceutical composition, along with a modified protein (conjugate) obtained by reacting a protein with a modifying compound of the general formula 1 or 2, or a pharmaceutically acceptable salt or solvate thereof, of the present invention may include other active substances, including those having anti-influenza activity, provided that they do not cause unwanted effects.
- the carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to produce common forms, including oral, injection, and local forms.
- the subject of this invention is also a medicament active in relation to the CD 16a receptor, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package intended for the treatment of diseases caused by pathological cells, including a new modified protein (conjugate), or a new pharmaceutical composition in a therapeutically effective amount.
- a pharmaceutically acceptable package intended for the treatment of diseases caused by pathological cells, including a new modified protein (conjugate), or a new pharmaceutical composition in a therapeutically effective amount.
- the conjugates of the present invention can be used to treat the same diseases for which iconjugated mopoclonal antibodies are used as drugs of such like, low-grade or follicular non-Hodgkin's lymphoma, breast cancer. It is also known that the activity of antibodies against the CD 16a receptor is used to treat autoimmune or oncological diseases (RL Ferris, et al. J. Clinical Oncology, 2010, Oct 1, Vol. 28, No. 28: 4390-4399), including such as lymphoma (K.-N. Heider, et al.
- the subject of the invention is a method of treating diseases caused by pathological cells that can be treated by indirect effects on CD 16a receptor, according to which a subject is administered therapist nical ⁇ an effective amount of the modified protein (conjugate) or pharmaceutical composition or medicament active towards CD 16a receptor.
- a preferred method is the treatment of autoimmune or oncological diseases defined above in this section, including such as lymphoma. lymphatic leukemia or breast cancer.
- Medicines may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally or topically).
- the clinical dosage of the modified protein (conjugate) or pharmaceutical composition or drug that is active against the CD 16a receptor in patients can be adjusted depending on the therapeutic effective in and bioavailability of the active ingredients in the body, their metabolic rate and excretion, and also depending on the age, sex and stage of the patient’s disease, while the daily dose in adults is usually 300 ⁇ 1200 mg, preferably 500 ⁇ 1000 mg in the case when the protein in the conjugates is It is ashtelo, and 0.01 ⁇ 100 mg, preferably 0.1 ⁇ 10 mg, when the protein in the conjugate is an autoantigen.
- FIG. 1 Proton Math Resonance Spectrum (PMR Spectrum) 2.5-dioxopyrrolidin-1-yl ether (3-chlorobspzil) -5.5, 1 1 -trioxo-10, 1 1 -dihydro-5 // - dibenzo [0, /
- FIG. 2 NMR spectrum of 2,5-dioxopyrrolidin-1-yl ether (4- ⁇
- FIG. 3 PMR spectrum of 2,5-dioxopyrrolidin-1-yl ether 4 - ⁇ [10- (3-chlorobenzyl) -5.5, 1 1-trioxo-10.1 1-dihydro-5H-dibenzo [/>, / ] [1, 4] thiazepip-7-carbonyl] - amino ⁇ phenylcarboxylic acid 1 (3).
- FIG. 4 LCMS spectrum of 2,5-dioxo-pyrrolidip-1-yl ether 3- [8- (3,4-dimethoxyphenylcarbamoyl) -5,5,1 1 -trioxo-5,1 1-dihydro-5J-dibenzo [6 ,
- FIG. 6 NMR spectrum of 10- (3-chlorobenzyl) -5.5, 1 1 -trioxo-10, 1 1-dihydro-5 // - dibenzo [b, ⁇ [1, 4] thiazepine-8-carboxylic acid (2 -aminoethyl) -amide 1 (6).
- FIG. 7 PMR spectrum of 10- ⁇ 4 - [(2-amipo-egylcarbamoyl) methyl] benzyl ⁇ -5.5, 1 1-trioxo-10.1 1-dihydro-5 // - dibenzo [b, 1] [1,4] thiazepi11-8-carboxylic acid of [3- (4-bsnzil-11 and pery din-1-yl) -propyl] -amide 1 (7).
- FIG. 8 PMR spectrum of 2- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -tyl ether 10- (3-chlorobenzyl) -5.5.1 1 -trioxo-10.1 1- dihydro-5 // - dibenzo [b, 1] [1, 4] thiazspin-8-carboxylic acid 1 (8).
- FIG. 9. PMR spectrum 10- (4 - ⁇ [2- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -ethylcarbamoyl] methyl ⁇ bsnzil) - 5.5.1 1 -trioxo - 10.1 1-dihydro-5H-dibenzo [b, 1] [1,4] thiazepine-8-carboxylic acid [3- (4-benzyl-piperidium-1-yl) propyl
- FIG. 10 NMR spectrum of the compound L g - [2 - ( ⁇ L- (Me1 hydroxycarbonyl) -L ⁇ - [(1, 5-dimesoxy-1, 5-dioxopentan-2-yl) carbamoyl] -P-alanyl ⁇ amino) ethyl] - 10- (3-chlorobenzyl) -5.5, 1 1 - I dioxo-10.1 1-dihydrodibenzo [6
- FIG. 11 NMR spectrum of the compound L g - [2 - ( ⁇ L- (Me1 hydroxycarbonyl) -L ⁇ - [(1, 5-dimesoxy-1, 5-dioxopentan-2-yl) carbamoyl] -P-alanyl ⁇ amino) ethyl] - 10- (3-chlorobenzyl) -5.5, 1 1 - I dioxo-10.1
- FIG. 13 NMR spectrum of 4- [4- (dimethylamino) phenyl] -L g - (4- ⁇ 2 - [(2,5-dioxopyrrolidin-1-yl) oxy] -2-oxoethoxy ⁇ phenyl) -7.8, 9, 10-tetrahydro-4 // - [1] be11othieno [3,2-] pyrrolo [1, 2-a] [1, 4] diazepin-5 (6 //) - carboxamide 2 (2).
- FIG. 14 LCMS spectrum of 2,5-dioxopyrrolidin-1-yl N- [4- (5- ⁇ [(3,4-dimethoxyphenyl) amino] carbonyl ⁇ -5,6,7,8,9,10-hexahydro 4 // - [1] benzothieno [3.2- /] 11irrolo [1,2-a] [1,4] diazepin-4-yl) phenyl] -L g- methylglycinate 2 (3).
- FIG. 15 Chromatogram of conjugate P1 (1), on a TSK GEL SUPER SW3000 column.
- Fig 16. Immuno-enzyme assay (ELISA) of the binding of rituximab conjugates to the CD 16a receptor. Dependence of optical density at a wavelength of 450 nm on the concentration of the conjugate introduced into ELISA.
- Fig 17. Immuno-enzyme assay (ELISA) of binding of interferon (I) and KI1 conjugate (1) to the CD 16a receptor. Dependence of optical density at a wavelength of 450 nm on the concentration of the conjugate introduced into ELISA.
- FIG. 18 Comparison of the efficacy of rituximab (P) and conjugate KP1 (1) in honor of antibody-dependent cytotoxicity.
- FIG. 19 Comparison of the efficacy of rituximab (P) and conjugate P1 (2) in iccic antibody-dependent cytotoxicity.
- Fig 20 Immuno-enzyme assay (ELISA) of the binding of rituximab (P). trastuzumab (T) and their conjugates KP1 (7), KT1 (7) by fire retardation to the CD 16a receptor.
- ELISA Immuno-enzyme assay
- Compound 5 was obtained in a yield of 70%. 50 g of compound 5 are dissolved in 500 ml of aqueous ammonia, dissolved and 80 g of dithionite are added in portions, after which the reaction mixture is refluxed for 1 hour. Then the reaction mixture is cooled, ammonia is evaporated on a steam evaporator and the aqueous solution is acidified with conc. hydrochloric acid to pi I – 1, stirred for 1 h, filtered the precipitate, washed with water, dried. Compound 6 was obtained in 60% yield. 45 g of compound 6 are added portionwise to 200 ml of polyphosphoric acid at 50 ° C, after which it is stirred for 10 hours at 90 ° C.
- Extract 3x150 ml of aegilacetag the combined extracts are washed with concentrated Nal IC0 3 solution, dried, the solvent is evaporated on a rotary evaporator. Get the product 14 with a yield of 75%.
- 1.9 g of compound 11 and 0.87 g of compound 14 are mixed in 50 ml of dioxane. They are stirred for 1 h, after which 1.2 ml of triethylamine and 0.89 g of phosphorus oxychloride are added. Stirred for 3 hours at 50 ° C, add 150 ml of water, the precipitated precipitate was filtered, washed with water, and dried. Get product 15 with a yield of 60%.
- a mixture of 10.0 g of p-tolyluacetic acid, 13.0 g of N-bromosuccinimide and 0.1 g of 2,2'-azabisisobutyronitrile in 60 ml of carbon tetrachloride is refluxed for 4 hours.
- the mixture is cooled to room temperature, poured into 100 ml of water, the precipitate is filtered off, sushag. It is dissolved in 50 ml of ethanol, 3.7 ml of thionyl chloride are added at 0 ° C, stirred overnight at room temperature, the solvent is evaporated.
- the product is purified by column chromatography in the system choroform-methanol-triethylamine 10-1 - 1.
- Receive compound 33 with a yield of 15%. 180 mg of compound 33 is dissolved in 20 ml of THF, 47 mg of ⁇ -hydroxysukiinimide and 84 mg of dipylohexylcarbodiimide are added with stirring under argon atmosphere. The mixture is stirred overnight at room temperature. the temperature is night, after which the precipitate is filtered off, the solution is evaporated, and flash chromatography is carried out on silica gel (eluate ethyl acetate). Compound 1 (5) was obtained in a yield of 50%. The PMR spectrum of compound 1 (5) is shown in FIG. 5.
- Example 7 10- ⁇ 4 - [(2-amino-ethylcarbamoyl) methyl] benzyl ⁇ -5.5, 1 1 -trioxo-10, 1 1 - dihydro-5H- dibenzo [b, 1] [1, 4] thiazepine-8-carbopa sour ⁇ s [3- (4-bsnzil-pipsridi n-1 - yl) -propyl] -amide 1 (7) is prepared according to the following Scheme 7.
- Example 9 10- (4 - ⁇ [2- (2,5-dioxo-2,5-dihydro-pyrrol-1-yl) -gilcarbamoyl] methyl ⁇ benzyl) -5.5, 1 1 -trioxo 10, 1 1-dihydro-5 // - dibenzo [b, 1] [1, 41 hyazepine-8-carboxylic acid [3- (4-benzyl-piperidin-1-yl) -propyl] -amide 1 (9) receive according to the following Scheme 9.
- Example 10 ⁇ Y- [2 - ( ⁇ L ⁇ - (Methoxycarbooyl) -L g - [(1, 5-dimethoxy-1, 5-dioxopsntan-yl) carbamoyl] -P-alanyl ⁇ amino) ethyl] -10 - (3-chlorobenzyl) -5.5, 1 1 -trioxo-10, 1 1-dihydrodibenzo [0. ] [1,4] thiazepine-7-carboxamide 1 (10) is prepared according to the following Scheme 10.
- Hydrochloride 1 (10) * HC1 is obtained by adding to compound 1 (10) by dissolving in saturated ethyl acetate. The precipitated hydrochloride is filtered, dried, and purified by recrystallization. The hydrochlorides of the compounds obtained in examples 1-9 and 1 1 -14 are similarly prepared.
- carbonyl ⁇ glutamine 1 (11) is prepared according to the following Scheme 1 1.
- Example 15 The General method of obtaining modified proteins (conjugates).
- the protein is modified with a substance of general formula 1 or 2 in a molar ratio of ⁇ ⁇ 1: 1 to 1: 100.
- a portion of a substance of general formula 1 or 2 is dissolved in 50 ⁇ l of DMSO, then phosphate buffered saline (FSB, pH 7.4) is slowly added. and add a solution of protein in the FSB.
- the final concentration of protein in the reaction mixtures was 1 mg / ml.
- the reaction is carried out at room temperature for 20 hours with constant stirring.
- the reaction mass is centrifuged, the filtrate is applied to Superdex 75 gel (GE, USA); carrier column height - 23 cm; mobile phase - FSB; flow rate - 57.3 cm / hour; the injection volume is 2.2% of the volume of the carrier.
- Conyogate numbers are determined using HPLC on a Bio-Monolith Protein A affinity column (Agilent, USA).
- C1 (1) is the Clq (C) compliment protein with compound 1 (1), in a ratio of 1: 10.
- FIG. Figure 15 shows, for example, a chromatogram of Konogate P1 (1), indicating a basic substance content of more than 98%.
- Example 16 The determination of the activity of conjugates on ⁇ wearing to the CD 16A receptor.
- standard materials and equipment for enzyme immunoassay are used.
- CD16a is sorbed into the wells of the 96-well plate from a solution of 3.3 ⁇ g / ml in 75 ⁇ l / well phosphate-buffered saline. Sorption was carried out at 4 ° C for 16 hours.
- the CD 16a solution was removed from the plate, the loops were filled with a 2% BSA solution in PBS-P (150 ⁇ l / well).
- the plates were incubated at 37 ° C for 2 hours and washed three times with FSB-P buffer (300 ⁇ l / well each time).
- the 3ai CM tablet’s grooves were filled with 50 ⁇ l / well Konyogatmi solutions in FSB-P, in dilutions from 0.25 to 256 ⁇ g / ml. Each dilution of one konyogate in plate corresponds to three wells. To control nonspecific sorption of the samples, part of the wells were filled with a 2% BSA solution. The plate is incubated for one hour at 37 ° C in an ELISA shaker (rotation speed 180 rpm).
- the tablet was washed five times with 300 ⁇ l / well of FSB-P and filled with a solution of protein modified with horseradish peroxidase (75 ⁇ l / well in working dilution, which is indicated in the description to immunoconjugate).
- the plate is incubated for 30 minutes, washed n, once in 300 ⁇ l / vakov FSB-P and filled with a solution of ' GMB (100 ⁇ l / vaku).
- the depth of the enzyme1 and the reaction were visually assessed and the latter was stopped by the addition of 50 ⁇ l / well of a 500 mM sulfuric acid solution.
- the optical illosity in the wells of the plate is measured at room temperature at a wavelength of 450 nm. For oopaoo i Kn the results of the experiment use the program GraphPad Prism 5.0.
- FIG. Figure 16 shows the dependences of the binding of some conagions with respect to the CD 16a receptor, from which the dissociation constants of the complexes of conjugates with the CD 16a receptor were calculated (Konyogag activity with respect to the CD 16a receptor - Kj).
- the activity of rituximab conjugates is 10-100 times higher than the activity of unconjugated rituximab.
- FIG. 17 shows the dependences of the binding of interferon alpha and conjugate of interferon alpha to compound 1 (1) with the CD16a receptor.
- the activity of the conjugate of interferon is higher than the activity of unconjugated interferon alpha.
- Example 17 The effectiveness of the conjugates in the test for antibody-dependent (rituximab-dependent) cell cytotoxicity.
- the efficacy of rituximab equine horses compared with unconjugated rituximab was evaluated in TCC IC at antibody dependent cellular toxicity.
- target cells were used CO20-positive cells of the Daudi line (B-cell lymphoma of Berkit).
- effector cells pulirin peripheral mononuclear blood cells from 5 healthy donors isolated using the standard protocol are used.
- Dilutions of the studied conjugates and rituximab were prepared in RPMI 1640 medium. 50 ⁇ l of the solutions of the studied conjugates and rituximab were placed in the wells of a 96-well round-bottom plate. Cells of the Daudi line resuscitate g in RPMI 1640 medium to a concentration of 8x10 5 cells / ml. 75 ⁇ l of the resulting cell suspension is added to the prepared rituximab solutions in a plate. The plate is incubated in a thermostat at a temperature of 37 ° C for 50 minutes.
- the obtained samples were precipitated by centrifugation at 1200 rpm for 10 minutes. 50 ⁇ l of the supernatant were transferred to a new plate, where they were mixed with 50 ⁇ l of the reaction mixture (lactate dehydrogenase detection kit, Promega (USA), catalog number G1780). The resulting mixture was incubated at room temperature for 25 minutes, after which the reaction was stopped. Measure the absorption on a spot spectrophotometer at a wavelength of 490 im.
- cytotoxicity,% 100 * (A - (S E -S T )) / (Hr-S T ),
- A is the signal level in the mixture of effector cells and target cells
- SE is the signal level of effector cells
- ST is the signal level of target cells
- Example 18 Obtaining konyogat rituximab KP1 (7) and tra.utumaba KT1 (7).
- To 1.5 g of the sugar part of the antibody in a solution of 100 mm sodium acetate, 200 mm sodium chloride, pH 5.5 add 2.0 g of sodium periodate, incubated for 30 min at room temperature in the dark with stirring.
- Example 19 Comparative activity of rituximab (P) and trastuzumab (T) and their conjugates P1 (7), CT1 (7) with respect to the CD 16a receptor.
- the study of the binding of the obtained conjugates of trastuzumab and rituximab to the CD 16a receptor was carried out identically to example 17.
- the activity of the konogates KP1 (7), T1 (7) with respect to the CD16a receptor is 1–2 orders of magnitude higher than the activity of modified rituximab (P), trastuzumab (T) (Table 3).
- Table 3 The activity of (Ka) rituximab (P), trastuzumab (T) and their conogates KP1 (7), KT1 (7) with respect to the CD 16a receptor.
- the invention can be used in medicine, veterinary medicine, biochemistry.
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AU2014207918A AU2014207918B2 (en) | 2013-01-16 | 2014-01-15 | Conjugates and small molecules which interact with the CD16a receptor |
EP14740983.3A EP2947074A4 (en) | 2013-01-16 | 2014-01-15 | CONJUGATES AND MOLECULES OF LOW DIMENSIONS REACTING WITH THE CD16A RECEIVER |
KR1020157020861A KR20150109383A (ko) | 2013-01-16 | 2014-01-15 | CD16a 수용체와 상호작용하는 결합체 및 소분자 |
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EP3596070A1 (en) | 2017-03-13 | 2020-01-22 | Assembly Biosciences, Inc. | Process for making hepatitis b core protein modulators |
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- 2013-01-16 RU RU2013101884/04A patent/RU2519546C1/ru active IP Right Revival
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2014
- 2014-01-15 EA EA201500506A patent/EA028617B1/ru active IP Right Revival
- 2014-01-15 CN CN201480003529.7A patent/CN104870428A/zh active Pending
- 2014-01-15 JP JP2015553677A patent/JP2016505629A/ja not_active Ceased
- 2014-01-15 KR KR1020157020861A patent/KR20150109383A/ko not_active Application Discontinuation
- 2014-01-15 CA CA2897629A patent/CA2897629A1/en not_active Abandoned
- 2014-01-15 AU AU2014207918A patent/AU2014207918B2/en not_active Expired - Fee Related
- 2014-01-15 US US14/652,521 patent/US20150368261A1/en not_active Abandoned
- 2014-01-15 EP EP14740983.3A patent/EP2947074A4/en not_active Withdrawn
- 2014-01-15 WO PCT/RU2014/000015 patent/WO2014112898A1/ru active Application Filing
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Also Published As
Publication number | Publication date |
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AU2014207918B2 (en) | 2017-06-08 |
CA2897629A1 (en) | 2014-07-24 |
AU2014207918A1 (en) | 2015-06-11 |
EP2947074A1 (en) | 2015-11-25 |
EP2947074A4 (en) | 2016-06-29 |
EA201500506A1 (ru) | 2015-08-31 |
US20150368261A1 (en) | 2015-12-24 |
EA028617B1 (ru) | 2017-12-29 |
KR20150109383A (ko) | 2015-10-01 |
CN104870428A (zh) | 2015-08-26 |
JP2016505629A (ja) | 2016-02-25 |
RU2519546C1 (ru) | 2014-06-10 |
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